ORCID Profile
0000-0001-5092-5544
Current Organisations
University of Sydney
,
Melanoma Institute Australia
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Biostatistics | Clinical Sciences not elsewhere classified | Statistics |
Application Software Packages (excl. Computer Games) | Expanding Knowledge in the Mathematical Sciences | Expanding Knowledge in the Medical and Health Sciences
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541629
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: MDPI AG
Date: 22-01-2021
DOI: 10.3390/IJMS22031099
Abstract: Nanotargeted liposomes may be modified with targeting peptide on the surface of a prepared liposome to endow specificity and elevate targeting efficiency. The aim of this study was to develop a radioactive targeted nanoparticle, the 111In-cyclic RGDfK-liposome, and its advantage of recognizing the αVβ3 integrin was examined. The cyclic RGDfK modified liposomes were demonstrated the ability to bind the αVβ3 integrin expressed on the surface of human melanoma cell in vitro and in vivo. The effects of the cyclic RGDfK-liposome on the functioning of phagocytes was also examined, showing no considerable negative effects on the engulfment of bacteria and the generation of reactive oxygen species. Based upon these findings, the cyclic RGDfK- liposome is said to be a promising agent for tumor imaging.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2020
DOI: 10.1200/JCO.20.01680
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541626
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490746.V1
Abstract: Clinical and mIHC data generated within the study.
Publisher: Sissa Medialab
Date: 27-06-2019
DOI: 10.22323/1.352.0135
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2016
Abstract: Standard cancer staging and prognostic estimates are determined at the time of the patient’s initial disease presentation. Conditional survival is an alternative, dynamic assessment from follow-up time points after the initial disease diagnosis and is based on the condition of survivorship. Estimates of conditional survival can provide critical prognostic information for patients and clinicians, guide subsequent cancer follow-up schedules, and influence decisions regarding treatments. The current study presents conditional survival estimates developed from a cohort of 4,540 patients diagnosed with stage III melanoma treated at a single institution. Patients with stage III disease at first melanoma diagnosis (initial n = 2,042), or who developed locoregional metastasis as a first recurrence some time after primary diagnosis (recurrent n = 2,498), were assessed. Conditional melanoma-specific survival (MSS) estimates up to 5 years after diagnosis were adjusted for age, sex, and 8th edition American Joint Committee on Cancer (AJCC) stage. Older age at diagnosis of stage III disease conveyed a worse prognosis at each conditional survival time point. Males had significantly worse MSS outcomes for up to 2 years of conditional survival, after which males and females had similar MSS. For patients with AJCC stage IIIB and stage IIIC disease, MSS outcomes were similar to those of patients with stage IIIA disease after 3 and 5 years of survivorship, respectively. Adjuvant systemic treatments may have the greatest benefit when administered within the first 2 years of stage III melanoma diagnosis, during which period prognosis is significantly worse for male patients of increasing age and AJCC substage. Conditional survival estimates illustrate improved survival prospects for patients with cancer returning for follow-up and may define a finite period of increased risk after diagnosis.
Publisher: Elsevier BV
Date: 09-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541620
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490752.V1
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: Elsevier BV
Date: 10-2009
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541623
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Wiley
Date: 06-10-2020
DOI: 10.1002/IJC.33312
Publisher: Springer Science and Business Media LLC
Date: 26-06-2018
Publisher: BMJ
Date: 10-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2017
DOI: 10.1097/CCM.0000000000002568
Abstract: To determine whether blood flow rate influences circuit life in continuous renal replacement therapy. Prospective randomized controlled trial. Single center tertiary level ICU. Critically ill adults requiring continuous renal replacement therapy. Patients were randomized to receive one of two blood flow rates: 150 or 250 mL/min. The primary outcome was circuit life measured in hours. Circuit and patient data were collected until each circuit clotted or was ceased electively for nonclotting reasons. Data for clotted circuits are presented as median (interquartile range) and compared using the Mann-Whitney U test. Survival probability for clotted circuits was compared using log-rank test. Circuit clotting data were analyzed for repeated events using hazards ratio. One hundred patients were randomized with 96 completing the study (150 mL/min, n = 49 250 mL/min, n = 47) using 462 circuits (245 run at 150 mL/min and 217 run at 250 mL/min). Median circuit life for first circuit (clotted) was similar for both groups (150 mL/min: 9.1 hr [5.5–26 hr] vs 10 hr [4.2–17 hr] p = 0.37). Continuous renal replacement therapy using blood flow rate set at 250 mL/min was not more likely to cause clotting compared with 150 mL/min (hazards ratio, 1.00 [0.60–1.69] p = 0.68). Gender, body mass index, weight, vascular access type, length, site, and mode of continuous renal replacement therapy or international normalized ratio had no effect on clotting risk. Continuous renal replacement therapy without anticoagulation was more likely to cause clotting compared with use of heparin strategies (hazards ratio, 1.62 p = 0.003). Longer activated partial thromboplastin time (hazards ratio, 0.98 p = 0.002) and decreased platelet count (hazards ratio, 1.19 p = 0.03) were associated with a reduced likelihood of circuit clotting. There was no difference in circuit life whether using blood flow rates of 250 or 150 mL/min during continuous renal replacement therapy.
Publisher: AMPCo
Date: 12-2014
DOI: 10.5694/MJA14.00266
Abstract: To measure the costs of a polypill strategy and compare them with those of usual care in people with established cardiovascular disease (CVD) or at similarly high cardiovascular risk. A within-trial cost analysis of polypill-based care versus usual care with separate medications, using data from the Kanyini Guidelines Adherence with the Polypill (GAP) trial and linked health service and medication administrative claims data. Kanyini GAP participants who consented to Australian Medicare record access. Mean health service and pharmaceutical expenditure per patient per year, estimated with generalised linear models. Costs during the trial (randomisation January 2010 - May 2012, median follow-up 19 months, maximum follow-up 36 months) were inflated to 2012 costs. Our analysis showed a statistically significantly lower mean pharmaceutical expenditure of $989 (95% CI, $648-$1331) per patient per year in the polypill arm compared with usual care (P < 0.001 adjusted, excluding polypill cost). No significant difference was shown in health service expenditure. This study provides evidence of significant cost savings to the taxpayer and Australian Government through the introduction of a CVD polypill strategy. The savings will be less now than during the trial due to subsequent reductions in the costs of usual care. Nonetheless, given the prevalence of CVD in Australia, the introduction of this polypill could increase considerably the efficiency of health care expenditure in Australia. Australian New Zealand Clinical Trials Registry ACTRN126080005833347.
Publisher: Elsevier BV
Date: 2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-09-2022
DOI: 10.1158/2159-8290.CD-22-0603
Abstract: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711
Publisher: Oxford University Press (OUP)
Date: 09-05-2021
DOI: 10.1111/BJD.19895
Publisher: Wiley
Date: 07-10-2019
DOI: 10.1111/AJD.12942
Publisher: MDPI AG
Date: 14-02-2021
DOI: 10.3390/IJMS22041902
Abstract: Epidermal growth factor receptor (EGFR) specific therapeutics is of great importance in cancer treatment. Fcy-hEGF fusion protein, composed of yeast cytosine deaminase (Fcy) and human EGF (hEGF), is capable of binding to EGFR and enzymatically convert 5-fluorocytosine (5-FC) to 1000-fold toxic 5-fluorocuracil (5-FU), thereby inhibiting the growth of EGFR-expressing tumor cells. To develop EGFR-specific therapy, 188Re-liposome-Fcy-hEGF was constructed by insertion of Fcy-hEGF fusion protein onto the surface of liposomes encapsulating of 188Re. Western blotting, MALDI-TOF, column size exclusion and flow cytometry were used to confirm the conjugation and bio-activity of 188Re-liposome-Fcy-hEGF. Cell lines with EGFR expression were subjected to treat with 188Re-liposome-Fcy-hEGF/5-FC in the presence of 5-FC. The 188Re-liposome-Fcy-hEGF/5-FC revealed a better cytotoxic effect for cancer cells than the treatment of liposome-Fcy-hEGF/5-FC or 188Re-liposome-Fcy-hEGF alone. The therapeutics has radio- and chemo-toxicity simultaneously and specifically target to EGFR-expression tumor cells, thereby achieving synergistic anticancer activity.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2018
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541638
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JAAD.2019.10.065
Abstract: Mitotic rate is a strong predictor of outcome in adult patients with primary cutaneous melanoma, but for children and adolescent patients this is unknown. We sought to assess the prognostic value of primary tumor mitotic rate in children and adolescents with primary melanoma. This was a cohort study of 156 patients who were <20 years of age and who had clinically localized cutaneous melanoma. Patients <12 years of age were classified as children and those 12 to 19 years of age as adolescents. Clinicopathologic and outcome data were collected. Recurrence-free and melanoma-specific survival were calculated. Univariable and multivariable analyses were performed using Cox proportional hazard models. Thirteen of 156 patients (8%) were children. The mitotic rate was ≥1/mm This research was conducted at a single institution and the s le size was small. Mitotic rate is an independent predictor of recurrence-free survival in children and adolescents with clinically localized melanoma.
Publisher: Oxford University Press (OUP)
Date: 23-11-2018
DOI: 10.1093/NDT/GFX308
Abstract: There is no consensus whether higher intensity dose renal replacement therapy (RRT) compared with standard intensity RRT has survival benefit and achieves better renal recovery in acute kidney injury (AKI). In an in idual patient data meta-analysis, we merged in idual patient data from randomized controlled trials (RCTs) comparing high with standard intensity RRT in intensive care unit patients with severe AKI. The primary outcome was all-cause mortality. The secondary outcome was renal recovery assessed as the proportion of patients who were RRT dependent at key trial endpoints and by time to the end of RRT dependence. Of the eight prospective RCTs assessing different RRT intensities, seven contributed in idual patient data (n = 3682) to the analysis. Mortality was similar between the two groups at 28 days [769/1884 (40.8%) and 744/1798 (41.4%), respectively P = 0.40] after randomization. However, more participants assigned to higher intensity therapy remained RRT dependent at the most common key study point of 28 days [e.g. 292/983 (29.7%) versus 235/943 (24.9%) relative risk 1.15 (95% confidence interval 1.00-1.33) P = 0.05]. Time to cessation of RRT through 28 days was longer in patients receiving higher intensity RRT (log-rank test P = 0.02) and when continuous renal replacement therapy was used as the initial modality of RRT (log-rank test P = 0.03). In severe AKI patients, higher intensity RRT does not affect mortality but appears to delay renal recovery. Australian New Zealand Clinical Trials Registry (ANZCTR) identifier ACTRN12615000394549 (www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000394549).
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533212.V1
Abstract: AbstractPurpose: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental Design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. Results: Patients who responded to combination immune checkpoint inhibitor contained higher CD16 sup + /sup macrophage densities than those who did not respond (196 vs. 7 cells/mm sup /sup i P = /i 0.0041). There was no diffidence in CD16 sup + /sup macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm sup /sup i P /i = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16 sup + /sup macrophages compared with those with low densities (87% vs. 42%, i P /i = 0.0056, i n /i = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, i P /i = 0.4636, i n /i = 50). Melanoma biopsies with high densities of CD16 sup + /sup macrophages contained upregulated gene expression of critical T-cell recruiting chemokines ( i CXCL9 /i , i CXCL10 /i , and i CXCL11 /i ). Conclusions: Our data demonstrate that tumor microenvironments enriched with CD16 sup + /sup macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. /
Publisher: Wiley
Date: 14-11-2022
Abstract: The objective was to evaluate the impact of an ED clinical redesign project that involved team-based care and early senior assessment on hospital performance. This was an interrupted time series analysis performed using daily hospital performance data 6 months before and 8 months after the implementation of the clinical redesign intervention that involved Emergency Consultant-led team-based care, redistribution of ED beds and implementation of a senior nursing coordination roles in the ED. The primary outcome was the daily National Emergency Access Target (NEAT) performance (proportion of total daily ED presentations that were admitted to an inpatient ward or discharged from ED within 4 h of arrival). Secondary outcomes were daily ALOS in ED, inpatient Clinical Emergency Response System (CERS) calls and hospital mortality. Autoregressive Integrated Moving Average analysis was used to model NEAT performance. Hospital mortality was modelled using negative binomial regression. After adjusting for patient volume, inpatient admissions, ambulance, hospital occupancy, weekends ED Consultant numbers, weekends and underlying trends, there was a 17% improvement in NEAT associated with the post-intervention period (95% CI 12, 19% P < 0.001). There was no change in the number of CERS calls and the median daily hospital mortality rate reduced from 1.04% to 0.96% (P = 0.025). An ED-focused clinical redesign project was associated with a 17% improvement in NEAT performance with no evidence of an increase in clinical deterioration on inpatient wards and evidence for an improvement in hospital mortality.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
DOI: 10.1161/CIRCOUTCOMES.114.001235
Abstract: Despite effective treatments to reduce cardiovascular disease risk, their translation into practice is limited. Using a parallel arm cluster-randomized controlled trial in 60 Australian primary healthcare centers, we tested whether a multifaceted quality improvement intervention comprising computerized decision support, audit/feedback tools, and staff training improved (1) guideline-indicated risk factor measurements and (2) guideline-indicated medications for those at high cardiovascular disease risk. Centers had to use a compatible software system, and eligible patients were regular attendees (Aboriginal and Torres Strait Islander people aged ≥35 years and others aged ≥45 years). Patient-level analyses were conducted using generalized estimating equations to account for clustering. Median follow-up for 38 725 patients (mean age, 61.0 years 42% men) was 17.5 months. Mean monthly staff support was hour/site. For the coprimary outcomes, the intervention was associated with improved overall risk factor measurements (62.8% versus 53.4% risk ratio 1.25 95% confidence interval, 1.04–1.50 P =0.02), but there was no significant differences in recommended prescriptions for the high-risk cohort (n=10 308 56.8% versus 51.2% P =0.12). There were significant treatment escalations (new prescriptions or increased numbers of medicines) for antiplatelet (17.9% versus 2.7% P .001), lipid-lowering (19.2% versus 4.8% P .001), and blood pressure–lowering medications (23.3% versus 12.1% P =0.02). In Australian primary healthcare settings, a computer-guided quality improvement intervention, requiring minimal support, improved cardiovascular disease risk measurement but did not increase prescription rates in the high-risk group. Computerized quality improvement tools offer an important, albeit partial, solution to improving primary healthcare system capacity for cardiovascular disease risk management. URL: www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336630 . Australian New Zealand Clinical Trials Registry No. 12611000478910.
Publisher: BMJ
Date: 03-2022
DOI: 10.1136/BMJOPEN-2021-054337
Abstract: Fear of cancer recurrence (FCR) is commonly reported by patients diagnosed with early-stage (0–II) melanoma and can have a significant impact on daily functioning. This study will pilot the implementation of the Melanoma Care Program, an evidence-based, psychological intervention to reduce FCR, into routine practice, using a stepped-care model. Intervention effectiveness and level of implementation will be investigated using a hybrid type I design. Between 4 weeks before and 1 week after their next dermatological appointment, patients with melanoma will be invited to complete the Fear of Cancer Recurrence Inventory Short-Form, measuring self-reported FCR severity. Using a stepped-care model, clinical cut-off points will guide the level of support offered to patients. This includes: (1) usual care, (2) Melanoma: Questions and Answers psychoeducational booklet, and (3) three or five psychotherapeutic telehealth sessions. This longitudinal, mixed-methods pilot implementation study aims to recruit 108 patients previously diagnosed with stage 0–II melanoma. The primary effectiveness outcome is change in FCR severity over time. Secondary effectiveness outcomes include change in anxiety, depression, stress, health-related quality of life and melanoma-related knowledge over time. All outcomes are measured at baseline, within 1 week of the final telehealth session, and 6 and 12 months post-intervention. Implementation stakeholders at each study site and interested patients will provide feedback on intervention acceptability and appropriateness. Implementation stakeholders will also provide feedback on intervention cost, feasibility, fidelity and sustainability. These outcomes will be measured throughout implementation, using questionnaires and semistructured interviews/expert group discussions. Descriptive statistics, linear mixed-effects regression and thematic analysis will be used to analyse study data. Ethics approval was granted by the Sydney Local Health District–Royal Prince Alfred Zone (2020/ETH02518), protocol number: X20-0495. Results will be disseminated through peer-reviewed journals, conference presentations, social media and result summaries distributed to interested participants. (ACTRN12621000145808).
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-11-2019
DOI: 10.1200/JCO.19.01414
Abstract: The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma. In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status. Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71 95% CI, 0.41 to 1.23 P = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79 95% CI, 0.45 to 1.36 P = .39). Local failure rate was lower after WBRT (20.0% v 33.6% P = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died ( P = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation ( P = .32). WBRT was associated with more grade 1 to 2 acute toxicity. After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2022
DOI: 10.1101/2022.03.07.22272003
Abstract: Although there are well-known prognostic factors for survival from cutaneous melanoma (CM) such as primary tumour thickness and stage of the tumour at diagnosis, the role of germline genetic factors in determining survival is not well understood. To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia (MIA 5,762 patients with melanoma 800 deaths from melanoma) and UK Biobank (UKB: 5,220 patients with melanoma 241 deaths from melanoma). The GWAS were adjusted for age, sex and the first ten genetic principal components, and combined in a fixed-effects inverse-variance-weighted meta-analysis. Significant (P ×10 −8 ) results were investigated in the Leeds Melanoma Cohort (LMC 1,947 patients with melanoma 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts, with replication in the LMC. Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.61-2.71, P=2.08×10 −8 ) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR=2.38, 95% CI=1.77—3.21, P=1.07×10 −8 ) on chromosome 7. While neither SNP replicated (P .05) in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets and requires confirmation in additional cohorts. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR=0.88, 95% CI=0.83—0.94, P=6.93×10 −5 I 2 =88%). The association with the PRS was not replicated (P 0.05) in LMC, but remained significantly associated with MSS in the meta-analysis of the discovery and replication results. We found two loci potentially associated with MSS, and evidence that increased germline genetic susceptibility to develop CM may be associated with improved MSS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2012
Publisher: Wiley
Date: 07-11-2023
DOI: 10.1111/JDV.18665
Abstract: Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta‐analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB‐positivity. Meta‐analysis was performed on the SNB‐positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow‐up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta‐analysis was 32% (95% CI: 23–44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma‐related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541635
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490758.V1
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Oxford University Press (OUP)
Date: 22-06-2017
DOI: 10.1111/BJD.15187
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1038/S41467-021-21207-2
Abstract: Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10 −5 ) and overall survival (HR = 1.61, p = 1.67 × 10 −4 ), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates ( p AUROC = 7.03 × 10 −4 ), or published prognostic signatures ( p AUROC 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p 2.2 × 10 −16 ), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
Publisher: Informa UK Limited
Date: 11-2017
DOI: 10.1111/CXO.12517
Abstract: Older adults with visual loss have high rates of depression, restricted participation and reduced quality of life. We sought to measure the impact of lessons in the Alexander technique on vision-related emotional and social well-being, as secondary outcomes to a study on improving physical functioning in this population. This is a single-blind randomised controlled trial. One hundred and twenty community-dwelling adults aged 50 to 90 years with visual impairments were randomised to either 12 Alexander lessons over 12 weeks and usual care or usual care. The Perceived Visual Ability Scale, the Keele Assessment of Participation, the emotional subscale of the Impact of Vision Impairment Profile, the Positive and Negative Affect Scale and the five-item Geriatric Depression Scale were administered at baseline and three and 12 months. Participants were receiving services from Guide Dogs NSW/ACT. None of the validated questionnaires found statistically significant improvements after adjustment for baseline at three or 12 months, although the emotional subscale of the Impact of Vision Impairment approached significance in favour of the intervention group (4.54 points, 95 per cent CI: -0.14 to 9.21, p = 0.06). Depressive symptoms were prevalent and associated with greater impact of visual impairment on emotional well-being (odds ratio: 1.12, 95 per cent CI: 1.07 to 1.17, p < 0.0001). Faster gait, an indicator of general mobility, was associated with less depressive symptoms (odds ratio: 1.27, 95 per cent CI: 1.06 to 1.54, p = 0.01). On average, there was no significant impact of weekly lessons in the Alexander technique on social and emotional well-being, although the emotional impact of visual impairment showed a trend toward less distress in the intervention group. Our data found that emotional distress associated with visual impairment influences depressive symptoms but contrary to expectations, the level of social support received was not significant. Additionally, gait speed is a significant predictor of depressive symptoms, suggesting that general mobility is of importance to the well-being of older adults with visual impairments.
Publisher: Elsevier BV
Date: 09-2015
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.JAAD.2022.01.040
Abstract: Survival tends to decrease as the Breslow thickness of a primary melanoma increases. However, little is known about the prognostic value of Breslow thickness in patients with very thick melanomas. We sought to assess survival in patients with melanomas ≥4.0 mm in Breslow thickness. A pooled cohort of 5595 patients (4107 Dutch and 1488 Australian) with melanomas ≥4.0 mm in thickness diagnosed from 2000 to 2014 was analyzed. Standard and spline Cox regressions were generated for overall survival (OS) and recurrence-free survival (RFS). The median follow-up was 3.4 years. The continuous hazard ratios (HRs) for OS and RFS increased steadily as the Breslow thickness increased to 15 mm, stabilized up to 20 mm, and decreased thereafter. Using patients with melanomas 4 to <10 mm thick as a reference group, the categoric HR for OS increased up to the 15- to -<20-mm thickness category and then decreased (HR, 1.46 [95% CI, 1.29-1.66], P < .0001 for 10-<15 mm HR, 1.97 [95% CI, 1.55-2.51], P < .0001 for 15-<20 mm and HR, 1.36 [95% CI, 1.07-1.84], P = .045 for ≥20 mm). For the RFS, similar trends were observed. Retrospective study. Small cohorts of patients with melanomas 15-<20mm and ≥20mm. The progressive relationship between increasing Breslow thickness and decreasing survival is lost in patients with melanomas ≥15 mm in thickness.
Publisher: Oxford University Press (OUP)
Date: 16-07-2019
DOI: 10.1002/BJS.11262
Abstract: Identifying patients with sentinel node-negative melanoma at high risk of recurrence or death is important. The European Organisation for Research and Treatment of Cancer (EORTC) recently developed a prognostic model including Breslow thickness, ulceration and site of the primary tumour. The aims of the present study were to validate this prognostic model externally and to assess whether it could be improved by adding other prognostic factors. Patients with sentinel node-negative cutaneous melanoma were included in this retrospective single-institution study. The β values of the EORTC prognostic model were used to predict recurrence-free survival and melanoma-specific survival. The predictive performance was assessed by discrimination (c-index) and calibration. Seeking to improve the performance of the model, additional variables were added to a Cox proportional hazards model. Some 4235 patients with sentinel node-negative cutaneous melanoma were included. The median follow-up time was 50 (i.q.r. 18·5–81·5) months. Recurrences and deaths from melanoma numbered 793 (18·7 per cent) and 456 (10·8 per cent) respectively. Validation of the EORTC model showed good calibration for both outcomes, and a c-index of 0·69. The c-index was only marginally improved to 0·71 when other significant prognostic factors (sex, age, tumour type, mitotic rate) were added. This study validated the EORTC prognostic model for recurrence-free and melanoma-specific survival of patients with negative sentinel nodes. The addition of other prognostic factors only improved the model marginally. The validated EORTC model could be used for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Elsevier BV
Date: 07-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541641
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Springer Science and Business Media LLC
Date: 25-05-2022
Publisher: Elsevier BV
Date: 06-2018
Publisher: Wiley
Date: 25-03-2023
DOI: 10.1111/JDV.18998
Abstract: Lentigo maligna (LM), a form of melanoma in situ, has no risk of causing metastasis unless dermal invasive melanoma (LMM) supervenes. Furthermore, the detection of invasion impacts prognosis and management. To assess the accuracy of RCM for the detection of invasion component on LM/LMM lesions. In the initial case–control study, the performance of one expert in detecting LMM at the time of initial RCM assessment of LM/LMM lesions was recorded prospectively ( n = 229). The cases were assessed on RCM‐histopathology correlation sessions and a panel with nine RCM features was proposed to identify LMM, which was subsequently tested in a subset of initial cohort ( n = 93) in the matched case–control study by two blinded observers. Univariable and multivariable logistic regression models were performed to evaluate RCM features predictive of LMM. Reproducibility of assessment of the nine RCM features was also evaluated. A total of 229 LM/LMM cases evaluated by histopathology were assessed blindly and prospectively by an expert confocalist. On histopathology, 210 were LM and 19 were LMM cases. Correct identification of an invasive component was achieved for 17 of 19 LMM cases (89%) and the absence of a dermal component was correctly diagnosed in 190 of 210 LM cases (90%). In the matched case–control (LMM n = 35, LM n = 58), epidermal and junctional disarray, large size of melanocytes and nests of melanocytes were independent predictors of LMM on multivariate analysis. The interobserver analysis demonstrated that these three features had a fair reproducibility between the two investigators ( K = 0.4). The multivariable model including those three features showed a high predictive performance AUC = 74% (CI 95% 64–85%), with sensitivity of 63% (95% CI 52–78%) and specificity of 79% (CI 95% 74–88%), and likelihood ratio of 18 ( p ‐value 0.0026). Three RCM features were predictive for identifying invasive melanoma in the background of LM.
Publisher: Elsevier BV
Date: 11-2012
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627306
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: BMJ
Date: 12-2022
DOI: 10.1136/BMJOPEN-2022-066852
Abstract: The benefits of patient-reported feedback, using questionnaires that allow patients to report how they feel and function without any interpretation from healthcare professionals, are well established. However, patient-reported outcomes measures (PROMs) are not routinely collected in patients with melanoma in Australia. The aim of this study is to evaluate the feasibility and acceptability of implementing electronic PROMs (ePROMs) into routine care from the perspectives of patients with stage III melanoma and their treating clinical team. A minimum of 50 patients and 5 clinicians will be recruited to this prospective, longitudinal pilot study (ePROMs-MELanoma). The study uses a mixed-methods approach (quantitative PROMs questionnaires and end-of-study surveys with qualitative interviews) and commenced in May 2021 in surgical and medical melanoma clinics at two sites in metropolitan Sydney, Australia. The primary outcomes are measures of feasibility and acceptability, comprising descriptive questionnaire completion statistics, and proportion of patients who reported that these PROMs were easy to complete and measured items they considered important. Clinician and clinic staff views will be canvassed on the appropriateness of these PROMs for their patients, change in referral practice and uptake and incorporation into routine practice. Secondary aims include measurement of improvements in patients’ emotional and physical health and well-being, and utility of real-time data capture and clinician feedback. All participants will complete the Distress Thermometer and EQ-5D-5L questionnaires in the clinic using a tablet computer at baseline and two to three subsequent follow-up appointments. Participants who report a score of 4 or higher on the Distress Thermometer will be triaged to complete an additional three questionnaires: the QLQ-C30, Depression, Anxiety and Stress Scale and Melanoma Concerns Questionnaire-28. Results will be generated in real time patients with psychosocial distress or poor quality of life will discuss possible referral to appropriate allied health services with their clinician. Thematic analysis of interviews will be conducted. Ethics approval obtained from St Vincent’s Hospital Human Research Ethics Committee on 19 September 2019 (2019/ETH10558), with amendments approved on 8 June 2022. Patient consent is obtained electronically prior to questionnaire commencement. Dissemination strategies will include publication in peer-reviewed journals and presentation at international conferences, tailored presentations for clinical societies and government bodies, organisational reporting through multidisciplinary meetings and research symposia for local clinicians and clinic staff, and more informal, lay reports and presentations for consumer melanoma representative bodies and patient participants and their families. ACTRN12620001149954.
Publisher: Massachusetts Medical Society
Date: 22-10-2009
Publisher: Springer Science and Business Media LLC
Date: 11-2020
Abstract: In this paper, a new technique for reconstructing and identifying hadronically decaying τ + τ − pairs with a large Lorentz boost, referred to as the di- τ tagger, is developed and used for the first time in the ATLAS experiment at the Large Hadron Collider. A benchmark di- τ tagging selection is employed in the search for resonant Higgs boson pair production, where one Higgs boson decays into a boosted $$ b\\overline{b} $$ b b ¯ pair and the other into a boosted τ + τ − pair, with two hadronically decaying τ -leptons in the final state. Using 139 fb − 1 of proton-proton collision data recorded at a centre-of-mass energy of 13 TeV, the efficiency of the di- τ tagger is determined and the background with quark- or gluon-initiated jets misidentified as di- τ objects is estimated. The search for a heavy, narrow, scalar resonance produced via gluon-gluon fusion and decaying into two Higgs bosons is carried out in the mass range 1–3 TeV using the same dataset. No deviations from the Standard Model predictions are observed, and 95% confidence-level exclusion limits are set on this model.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627309
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2018
DOI: 10.1245/S10434-017-6325-1
Abstract: Counterintuitively, more deaths from melanoma occur among patients with thin (T1) primary melanomas (≤ 1 mm) than among those with thick primary melanoma because the great majority present with T1 tumors. Therefore, it is important to stratify their risk as accurately as possible to guide their management and follow-up. This study sought to explore the relationship between tumor thickness and prognosis for patients with thin primary melanomas. A retrospective, single-institution study investigated 6263 patients with cutaneous melanoma (including 2117 T1 cases) who had a minimum follow-up period of 10 years. For the entire patient cohort, the 10-year melanoma-specific survival (MSS) rate ranged between 92% for the patients with primary melanomas up to 0.3 mm thick and 32% for those with melanomas thicker than 8 mm. When ided into 25-quantile-thickness groups there was a significant difference in 10-year MSS between the two consecutive groups 0.8 and 0.9 mm the differences in survival were not significantly different for any other consecutive cut points within the less than or equal to 1 mm thickness range, indicating a biologically-relevant difference in outcome above and below 0.8 mm. For the patients treated initially at the authors' institution, the 10- and 20-year MSS rates for those with tumors up to 0.8 mm thick were respectively 93.4 and 85.7%, and for tumors 0.9 to 1.0 mm, the rates were respectively 81.1 and 71.4%. Only 29.3% of the T1 patients who died of melanoma were deceased within 5 years. A naturally occurring thickness cut point of 0.8 mm predicts higher or lower risk for patients with thin primary cutaneous melanomas. Long-term follow-up assessment of patients with T1 melanoma is important because late mortality due to melanoma is more common than early mortality.
Publisher: Oxford University Press (OUP)
Date: 05-2021
DOI: 10.1002/BJS.11946
Abstract: Identifying patients with sentinel node (SN)-negative melanoma who are at greatest risk of recurrence is important. The European Organization for Research and Treatment of Cancer (EORTC) Melanoma Group proposed a prognostic model that has not been validated in population-based data. The EORTC nomogram includes Breslow thickness, ulceration status and anatomical location as parameters. The aim of this study was to validate the EORTC model externally using a large national data set. Adults with histologically proven, invasive cutaneous melanoma with a negative SN biopsy in the Netherlands between 2000 and 2014 were identified from the Dutch Pathology Registry, and relevant data were extracted. The EORTC nomogram was used to predict recurrence-free survival. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. A total of 8795 patients met the eligibility criteria, of whom 14·7 per cent subsequently developed metastatic disease. Of these recurrences, 20·9 per cent occurred after the first 5 years of follow-up. Validation of the EORTC nomogram showed a C-statistic of 0·70 (95 per cent c.i. 0·68 to 0·71) for recurrence-free survival, with excellent calibration (R2 = 0·99 P = 0·999, Hosmer–Lemeshow test). This population-based validation confirmed the value of the EORTC nomogram in predicting recurrence-free survival in patients with SN-negative melanoma. The EORTC nomogram could be used in clinical practice for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 07-2021
Publisher: Springer Science and Business Media LLC
Date: 16-12-2022
Publisher: BMJ
Date: 07-2022
Abstract: Patients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy and safety of PD1 versus IPI +PD1 after BRAF/MEK inhibitors (BRAF/MEKi). Patients with V600BRAF mutant metastatic melanoma treated with BRAF/MEKi who had subsequent PD1 versus IPI+PD1 at eight centers were included. The endpoints were objective response rate (ORR), PFS, OS and safety in each group. Of 200 patients with V600E (75%) or non-V600E (25%) mutant metastatic melanoma treated with BRAF/MEKi (median time of treatment 7.6 months treatment cessation due to progressive disease in 77%), 115 (57.5%) had subsequent PD1 and 85 (42.5%) had IPI+PD1. Differences in patient characteristics between PD1 and IPI+PD1 groups included, age (med. 63 vs 54 years), time between BRAF/MEKi and PD1±IPI (16 vs 4 days), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 (62% vs 44%), AJCC M1C/M1D stage (72% vs 94%) and progressing brain metastases at the start of PD1±IPI (34% vs 57%). Median follow-up from PD1±IPI start was 37.8 months (95% CI, 33.9 to 52.9). ORR was 36% 34% with PD1 vs 39% with IPI+PD1 (p=0.5713). Median PFS was 3.4 months 3.4 with PD1 vs 3.6 months with IPI+PD1 (p=0.6951). Median OS was 15.4 months 14.4 for PD1 vs 20.5 months with IPI+PD1 (p=0.2603). The rate of grade 3 or 4 toxicities was higher with IPI+PD1 (31%) vs PD1 (7%). ORR, PFS and OS were numerically higher with IPI+PD1 vs PD1 across most subgroups except for females, those with days between BRAF/MEKi and PD1±IPI, and those with stage III/M1A/M1B melanoma. The combination of ECOG PS=0 and absence of liver metastases identified patients with years OS (area under the curve, AUC=0.74), while ECOG PS ≥1, progressing brain metastases and presence of bone metastases predicted primary progression (AUC=0.67). IPI+PD1 and PD1 after BRAF/MEKi have similar outcomes despite worse baseline prognostic features in the IPI+PD1 group, however, IPI+PD1 is more toxic. A combination of clinical factors can identify long-term survivors, but less accurately those with primary resistance to immunotherapy after targeted therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627303
Abstract: Clinical and mIHC data generated within the study.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2022
DOI: 10.1186/S12967-022-03613-2
Abstract: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA 5,762 patients with melanoma 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC 1,947 patients with melanoma 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5 I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90). We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.
Publisher: Elsevier BV
Date: 2009
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: AMPCo
Date: 11-2018
DOI: 10.5694/MJA18.00522
Publisher: Springer Science and Business Media LLC
Date: 18-12-2019
DOI: 10.1245/S10434-018-07094-W
Abstract: The diagnosis of subungual melanoma (SUM) can be challenging and SUMs generally have a worse prognosis than melanomas arising elsewhere. Due to their rarity, the evidence to guide management is limited. This study sought to identify clinicopathological features predictive of outcome and to provide guidelines for management. From a large, single-institution database, 103 patients with in situ (n = 9) or invasive (n = 94) SUMs of the hand treated between 1953 and 2014 were identified and their features analyzed. The most common site of hand SUMs was the thumb (53%). Median tumor thickness was 3.1 mm, and SUMs were commonly of the acral subtype (57%), ulcerated (58%), amelanotic (32%), and had mitoses (73%). Twenty-one patients reported prior trauma to the tumor site. Twenty-two patients were stage III at diagnosis 7 underwent therapeutic lymph node dissection and 22 underwent elective lymph node dissection (5 positive), while 36 had sentinel node biopsy (SNB), 28% of which were positive. Forty percent of SNB-positive patients had involved non-sentinel nodes (SNs) in their completion lymph node dissection. Five-year melanoma-specific survival (MSS) and disease-free survival (DFS) rates were 70% and 52%, respectively. On multivariate analysis, regional node metastasis and right-hand tumor location were significant predictors of shorter DFS and MSS, whereas mitoses negatively impacted DFS only and increasing Breslow thickness impacted MSS only. This study confirms that SUMs on the hand usually present at an advanced stage. Distal utation appears safe for invasive SUMs, and SNB should be considered as these patients have a high risk of both SN and non-SN metastasis.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.EJCA.2018.09.027
Abstract: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543306
Abstract: Supplementary Figures 1-8 and Supplementary Tables 1-4
Publisher: Wiley
Date: 11-08-2020
DOI: 10.1002/CNCR.33088
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.AAP.2015.10.015
Abstract: Motorcycle riding is increasing globally and confers a high risk of crash-related injury and death. There is community demand for investment in rider training programs but no high-quality evidence about its effectiveness in preventing crashes. This randomised trial of an on-road rider coaching program aimed to determine its effectiveness in reducing crashes in novice motorcycle riders. Between May 2010 and October 2012, 2399 newly-licensed provisional riders were recruited in Victoria, Australia and completed a telephone interview before randomisation to intervention or control groups. Riders in the intervention group were offered an on-road motorcycle rider coaching program which involved pre-program activities, 4h riding and facilitated discussion in small groups with a riding coach. Outcome measures were collected for all participants via telephone interviews at 3 and 12 months after program delivery (or equivalent for controls), and via linkage to police-recorded crash and offence data. The primary outcome was a composite measure of police-recorded and self-reported crashes secondary outcomes included traffic offences, near crashes, riding exposure, and riding behaviours and motivations. Follow-up was 89% at 3 months and 88% at 12 months 60% of the intervention group completed the program. Intention-to-treat analyses conducted in 2014 indicated no effect on crash risk at 3 months (adjusted OR 0.90, 95% CI: 0.65-1.27) or 12 months (adjusted OR 1.00, 95% CI: 0.78-1.29). Riders in the intervention group reported increased riding exposure, speeding behaviours and rider confidence. There was no evidence that this on-road motorcycle rider coaching program reduced the risk of crash, and we found an increase in crash-related risk factors.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 09-2023
Publisher: Wiley
Date: 07-12-2012
DOI: 10.1111/J.1742-6723.2011.01504.X
Abstract: To compare the proportion of patients exposed to a radiation dose in excess of 20 mSv, and to document missed injuries before and after the introduction of a panscan protocol for blunt trauma. Data were collected retrospectively from our trauma database for 6 months before and after implementation of the protocol. All radiological studies performed during the initial patient assessment were identified. Radiation doses for each patient were calculated. Subgroup analyses were age ≤30 and >30 years, injury severity score (ISS) 20 mSv increased by 8% (95% confidence interval [CI] 4-12), which equated to one extra person being exposed to >20 mSv for every 13 patients treated after the introduction of the protocol. The odds of receiving a radiation dose >20 mSv after the introduction of the protocol compared with the odds before were increased across all subgroups (≤30 years: odds ratio [OR] 2.7, 95% CI 1.3-5.8, P = 0.008 >30 years: OR 2.2, 95% CI 1.5-3.4, P < 0.001 ISS < 16: OR 2.4, 95% CI 1.5-3.9, P < 0.001 ISS ≥ 16: OR 2.0, 95% CI 1.0-3.7, P = 0.04 discharged home: OR 2.1, 95% CI 0.7-6.0, P = 0.17 admitted: OR 2.2, 95% CI 1.5-3.3, P 20 mSv. This increased risk occurred regardless of age or injury severity.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Wiley
Date: 26-04-2022
DOI: 10.1002/SIM.9415
Abstract: Time‐to‐event data in medical studies may involve some patients who are cured and will never experience the event of interest. In practice, those cured patients are right censored. However, when data contain a cured fraction, standard survival methods such as Cox proportional hazards models can produce biased results and therefore misleading interpretations. In addition, for some outcomes, the exact time of an event is not known instead an interval of time in which the event occurred is recorded. This article proposes a new computational approach that can deal with both the cured fraction issues and the interval censoring challenge. To do so, we extend the traditional mixture cure Cox model to accommodate data with partly interval censoring for the observed event times. The traditional method for estimation of the model parameters is based on the expectation‐maximization (EM) algorithm, where the log‐likelihood is maximized through an indirect complete data log‐likelihood function. We propose in this article an alternative algorithm that directly optimizes the log‐likelihood function. Extensive Monte Carlo simulations are conducted to demonstrate the performance of the new method over the EM algorithm. The main advantage of the new algorithm is the generation of asymptotic variance matrices for all the estimated parameters. The new method is applied to a thin melanoma dataset to predict melanoma recurrence. Various inferences, including survival and hazard function plots with point‐wise confidence intervals, are presented. An R package is now available at Github and will be uploaded to R CRAN.
Publisher: American Medical Association (AMA)
Date: 02-2019
Publisher: Wiley
Date: 28-04-2201
DOI: 10.1002/ART.38329
Abstract: Recent research suggests that sleep quality and pain intensity are intimately linked. Although sleep problems are common in patients with low back pain, the effect of sleep quality on the levels of pain intensity is currently unknown. The aim of this study was to investigate the effect of sleep quality on subsequent pain intensity in patients with recent-onset low back pain. Data on 1,246 patients with acute low back pain were included in the analysis. Sleep quality was assessed using the sleep quality item of the Pittsburgh Sleep Quality Index, scored on a 0-3-point scale, where 0 = very good sleep quality and 3 = very bad sleep quality. Pain intensity was assessed on a numerical rating scale (range 0-10). A generalized estimating equation (GEE) analysis modeled with an exchangeable correlation structure was used to examine the relationship between sleep quality and pain intensity. The model further controlled for symptoms of depression and prognostic factors for low back pain. The GEE analysis demonstrated a large effect of poor sleep on subsequent pain intensity, such that for every 1-point decrease in sleep quality (based on a 0-3-point scale), pain intensity (based on a 0-10-point scale) increased by 2.08 points (95% confidence interval 1.99-2.16). This effect was independent of depression and common prognostic factors for low back pain. Sleep quality is strongly related to subsequent pain intensity in patients with acute low back pain. Future research is needed to determine whether targeting sleep improvement contributes to pain reduction.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543309
Abstract: Legends for Supplementary Figures
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 02-11-2020
DOI: 10.1111/PCMR.12831
Abstract: The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2020
DOI: 10.1200/JCO.19.01508
Abstract: Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma. Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis. At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined. Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541626.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Wiley
Date: 06-2015
DOI: 10.1111/JGS.13440
Abstract: To explore and deepen understanding of factors influencing driving exposure for older drivers. Cross-sectional. Baseline data on function and driving exposure from 1 week of driving were evaluated. A convenience s le of 380 drivers aged 75 and older, residing in northwest Sydney, was recruited. Participants were required to be the primary drivers of their own vehicle. Driver function was evaluated using the DriveSafe and DriveAware clinic-based assessments to measure visual attention to the driving environment and awareness of driving ability. Demographic information was obtained through interview. An in-vehicle monitoring device with data logger and GPS receiver, was used to measure driving exposure in 362 of 380 participants' vehicles. Driving exposure outcomes were total distance driven, furthest distance traveled from home, and average trip length. Factors influencing these exposure outcomes were analyzed using generalized linear regression. Drivers typically drove 100 km in local and surrounding areas during the week. Function was predictive of all driving exposure outcomes. Drivers with lower levels of function drove fewer kilometers and took shorter trips closer to home. Age, health status, and personal circumstance (e.g., rural residence) also influenced exposure, but sex did not. Using objective measures, this study provides evidence that function, age, health status, and personal circumstance influence driving exposure of older drivers. Understanding how older people use driving to preserve their independence is important for exploring safe driving strategies for older people.
Publisher: SAGE Publications
Date: 17-01-2022
DOI: 10.1177/09622802211070254
Abstract: Competing risks models are attractive tools to analyze time-to-event data where several causes of an event are competing. However, a complexity may arise when, for instance, some subjects experience the event of interest but the causes are not known. Assuming that unknown causes of events are missing at random, we developed a novel constrained maximum penalized likelihood method for fitting semi-parametric cause-specific Cox regression models. Here, penalty functions were used to smooth the baseline hazards. An appealing feature of this approach is that all the relevant estimands in competing risks models are estimated including cause-specific hazard ratios, cause-specific baseline hazards, and cumulative incidence functions. Asymptotic results for these estimators were also developed, allowing for direct inferences. The proposed method was compared with some existing methods through a simulation study. A real data ex le was analyzed using the new method to evaluate the association of age at diagnosis with melanoma-death and non-melanoma-death in patients diagnosed with thin melanoma (tumour thickness [Formula: see text]1.0 mm). An R function for our proposed method is currently available on GitHub and will be included in the R package "survivalMPL" at CRAN.
Publisher: Chapman and Hall/CRC
Date: 30-06-2015
DOI: 10.1201/B18640
Publisher: BMJ
Date: 06-2019
DOI: 10.1136/BMJOPEN-2018-024650
Abstract: The aim of the present study is to investigate the effectiveness of pulsed low-frequency magnetic field (PLFMF) on the management of chronic low back pain (CLBP). A randomised double-blinded controlled clinical trial will be conducted, involving 200 patients with CLBP. Participants will be randomised in a 1:1 ratio to receive either active PLFMF (experimental arm) or sham treatment (control arm) using a permuted-block design which will be stratified according to three subtypes of musculoskeletal CLBP (nociceptive, peripheral neuropathic or central sanitisation). The intervention consists of three sessions/week for 6 weeks. The primary outcome is the percentage change in Numerical Rating Scale (NRS) pain at week 24 after treatment completion with respect to the baseline. Secondary outcomes include percentage NRS pain during treatment and early after treatment completion, short form 36 quality of life, Roland and Morris Disability Questionnaire Depression Anxiety Stress Scale 21, Patient Specific Functional Scale, Global perceived effect of condition change, Pittsburgh Sleep Quality Index and Modified Fatigue Impact Scale. Measures will be taken at baseline, 3 and 6 weeks during the intervention and 6, 12 and 24 weeks after completing the intervention. Adverse events between arms will be evaluated. Data will be analysed on an intention-to-treat basis. The study is funded by Imam Abdulrahman Bin Faisal University (IAU). It has been approved by the institutional review board of IAU (IRB‐ 2017‐03–129). The study will be conducted at King Fahd Hospital of the University and will be monitored by the Hospital monitoring office for research and research ethics. The trial is scheduled to begin in September 2018. Results obtained will be presented in international conferences and will be published in peer-reviewed journals. ACTRN12618000921280, prospectively.
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2020
DOI: 10.1101/2020.04.13.20064246
Abstract: The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviors, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention. To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis. This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data. This SAP is consistent with best practice and will enable transparent reporting. This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias. Prospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12617000691347 (date registered: 15/05/2017).
Publisher: Wiley
Date: 22-03-2011
DOI: 10.1002/SIM.4179
Abstract: This article has been motivated by an ongoing international adaptive confirmatory trial. At the interim analysis of this two-stage trial, none, one or two active treatment regimens are selected for further study in the second stage. A combination test approach is used in this practical setting with an extension of the theory to unbalanced randomization. We show that a combination test with suitable weights can still preserve the overall Type I error rate provided that the test statistic is chosen appropriately and the unpooled Z-test for proportions is not used. The accuracy of stagewise p-values is also discussed in a more general framework. Monte Carlo simulations confirm the validity of the approach retained and evaluate the necessary s le size. Additional issues addressed during the design of the trial are also examined such as multiplicity due to testing hypotheses on key secondary endpoints, a non-inferiority comparison to an active treatment and covariate adjusted analyses for various types of outcome.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2021
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 09-2022
Publisher: Wiley
Date: 03-05-2017
DOI: 10.1002/SIM.7324
Abstract: Adaptive designs encompass all trials allowing various types of design modifications over the course of the trial. A key requirement for confirmatory adaptive designs to be accepted by regulators is the strong control of the family-wise error rate. This can be achieved by combining the p-values for each arm and stage to account for adaptations (including but not limited to treatment selection), s le size adaptation and multiple stages. While the theory for this is novel and well-established, in practice, these methods can perform poorly, especially for unbalanced designs and for small to moderate s le sizes. The problem is that standard stagewise tests have inflated type I error rate, especially but not only when the baseline success rate is close to the boundary and this is carried over to the adaptive tests, seriously inflating the family-wise error rate. We propose to fix this problem by feeding the adaptive test with second-order accurate p-values, in particular bootstrap p-values. Secondly, an adjusted version of the Simes procedure for testing intersection hypotheses that reduces the built-in conservatism is suggested. Numerical work and simulations show that unlike their standard counterparts the new approach preserves the overall error rate, at or below the nominal level across the board, irrespective of the baseline rate, stagewise s le sizes or allocation ratio. Copyright © 2017 John Wiley & Sons, Ltd.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2022
DOI: 10.1245/S10434-022-11761-4
Abstract: Patients presenting with early-stage melanoma (AJCC pT1b-pT2a) reportedly have a relatively low risk of a positive SNB (~5–10%). Those patients are usually found to have low-volume metastatic disease after SNB, typically reclassified to AJCC stage IIIA, with an excellent prognosis of ~90% 5-year survival. Currently, adjuvant systemic therapy is not routinely recommended for most patients with AJCC stage IIIA melanoma. The purpose was to assess the SN-positivity rate in early-stage melanoma and to identify primary tumor characteristics associated with high-risk nodal disease eligible for adjuvant systemic therapy An international, multicenter retrospective cohort study from 7 large-volume cancer centers identified 3,610 patients with early primary cutaneous melanomas 0.8–2.0 mm in Breslow thickness (pT1b-pT2a AJCC 8th edition). Patient demographics, primary tumor characteristics, and SNB status/details were analyzed. The overall SNB-positivity rate was 11.4% (412/3610). Virtually all SNB-positive patients (409/412 99.3%) were reclassified to AJCC stage IIIA. Multivariate analysis identified age, T-stage, mitotic rate, primary site and subtype, and lymphovascular invasion as independent predictors of sentinel node status. A mitotic rate of /mm 2 was associated with a significantly increased SN-positivity rate and was the only significant independent predictor of high-risk SNB metastases ( mm maximum diameter). The new treatment paradigm brings into question the role of SNB for patients with early-stage melanoma. The results of this large international cohort study suggest that a reevaluation of the indications for SNB for some patients with early-stage melanoma is required.
Publisher: Springer Science and Business Media LLC
Date: 02-2021
Publisher: American Medical Association (AMA)
Date: 02-2021
Publisher: Springer Science and Business Media LLC
Date: 10-02-2022
DOI: 10.1245/S10434-021-11231-3
Abstract: It is not known whether there is a survival benefit associated with more frequent surveillance imaging in patients with resected American Joint Committee on Cancer stage III melanoma. The aim of this study was to investigate distant disease-free survival (DDFS), melanoma-specific survival (MSS), post distant recurrence MSS (dMSS), and overall survival for patients with resected stage III melanoma undergoing regular computed tomography (CT) or positron emission tomography (PET)/CT surveillance imaging at different intervals. A closely followed longitudinal cohort of patients with resected stage IIIA–D disease treated at a tertiary referral center underwent 3- to 4-monthly, 6-monthly, or 12-monthly surveillance imaging between 2000 and 2017. Survival outcomes were estimated using the Kaplan–Meier method, and log-rank tests assessed the significance of survival differences between imaging frequency groups. Of 473 patients (IIIA, 19% IIIB, 31% IIIC, 49% IIID, 1%) 30% underwent 3- to 4-monthly imaging, 10% underwent 6-monthly imaging, and 60% underwent 12-monthly imaging. After a median follow-up of 6.2 years, distant recurrence was recorded in 252 patients (53%), with 40% detected by surveillance CT or PET/CT, 43% detected clinically, and 17% with another imaging modality. Median DDFS was 5.1 years (95% confidence interval 3.9–6.6). Among 139 IIIC patients who developed distant disease, the median dMSS was 4.4 months shorter in those who underwent 3- to 4-monthly imaging than those who underwent 12-monthly imaging. Selecting patients at higher risk of distant recurrence for more frequent surveillance imaging yields a higher proportion of imaging-detected distant recurrences but is not associated with improved survival. A randomized comparison of low versus high frequency imaging is needed.
Publisher: Oxford University Press (OUP)
Date: 07-2018
DOI: 10.1111/BJD.16742
Publisher: Springer Science and Business Media LLC
Date: 07-2016
Publisher: BMJ
Date: 10-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/1078-0432.CCR-16-0698
Abstract: Purpose: Disruption of PD-L1/cytotoxic T-cell PD-1 signaling by immune checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response. Experimental Design: Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, n = 21), within 2 months of commencing treatment (EDT, n = 20) and on disease progression after previous response (PROG, n = 5). Thirteen patients responded (defined as CR, PR, or durable SD by RECIST/irRC criteria), and 10 did not respond. Results: PRE intratumoral and peritumoral PD-1+ T-cell densities were sevenfold (P = 0.006) and fivefold higher (P = 0.011), respectively, in responders compared with nonresponders and correlated with degree of radiologic tumor response (r = −0.729, P = 0.001 and r = −0.725, P = 0.001, respectively). PRE PD-L1 expression on tumor and macrophages was not significantly different between the patient groups, but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders versus nonresponders (P = 0.025 and P = 0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intratumoral CD8+ lymphocytes (P = 0.046) and intratumoral CD68+ macrophages (P = 0.046). Conclusions: Higher PRE PD-1+ T cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies and may allow better selection of patients most likely to benefit from anti-PD-1 therapies and warrants further evaluation. Clin Cancer Res 23(17) 5024–33. ©2017 AACR.
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000363175
Abstract: b i Background and Aims: /i /b We aimed to examine the association between daily b /b rotein intake (DPI) and outcomes in patients from the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. b i Methods: /i /b We analyzed the association between DPI and clinical outcomes using multivariable logistic regression, Cox proportional hazards models and time-adjusted analysis. b i Results: /i /b During ICU stay, mean DPI was 37.6 g/day among survivors and 37.7 g/day among nonsurvivors (p = 0.96 DPI of 0.5 g/kg/day). Only 159 (10.9%) of the patients received a mean DPI of g/kg. Patients with a DPI above the median had a 43.1% mortality compared with 46.1% for a DPI below the median (p = 0.25). On multivariate analysis, a lower DPI was not associated with increased odds ratios for 90-day mortality or any secondary outcomes. Cox proportional hazards models and time-adjusted analysis confirmed these findings. b i Conclusions: /i /b In the RENAL study, mean DPI was low. Within the confines of such low DPI, greater amounts of DPI were not independently associated with improved clinical outcomes. Video Journal Club “Cappuccino with Claudio Ronco” at www.karger.com/?doi=363175.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1038/S41379-021-00870-2
Abstract: Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p < 0.0001). Multivariable analysis showed that regression in combination with TILs independently predicted a negative SLN biopsy (OR 0.33 95% C.I. 0.20-0.52 p < 0.0001). Patients whose tumors showed both regression and TILs had the highest 10-year OS (65%, 95% C.I. 59-71%), MSS (85%, 95% C.I. 81-89%), and RFS (60%, 95% C.I. 54-66%). On multivariable analyses, the concurrent presence of regression and TILs independently predicted the lowest risk of death from melanoma (HR 0.69 95% C.I. 0.51-0.94 p = 0.0003) as well as the lowest rate of disease recurrence (HR 0.71 95% C.I. 0.58-0.85 p < 0.0001). However, in contrast, in the subgroup analysis of Stage III patients, the presence of regression predicted the lowest OS and RFS, with MSS showing a similar trend. Overall, these findings indicate a prognostically favorable role of regression in primary cutaneous melanoma. However, in Stage III melanoma patients, regression may be a marker of more aggressive disease.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627306.V1
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.ANNONC.2022.06.004
Abstract: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.
Publisher: Massachusetts Medical Society
Date: 16-06-2022
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.CLON.2022.06.012
Abstract: Adjuvant radiotherapy can be beneficial after regional lymph node dissection for high-risk stage III melanoma, as it has been shown to reduce the risk of recurrence in the node field. However, the optimal fractionation schedule is unknown and both hypofractionated and conventionally fractionated adjuvant radiotherapy are used. The present study examined the oncological outcomes of these two approaches in patients treated in an era before effective systemic immunotherapy became available. This retrospective cohort study involved 335 patients with stage III melanoma who received adjuvant radiotherapy after therapeutic regional lymph node dissection for metastatic melanoma between 1990 and 2011. Information on tumour characteristics, radiotherapy doses and fractionation schedules and patient outcomes was retrieved from the institution's database and patients' medical records. Hypofractionated radiotherapy (median dose 33 Gy in six fractions over 3 weeks) was given to 95 patients (28%) and conventionally fractionated radiotherapy (median dose 48 Gy in 20 fractions over 4 weeks) to 240 patients (72%). Five-year lymph node field control rates were 86.0% (95% confidence interval 78.4-94.4%) for the hypofractionated group and 85.5% (95% confidence interval 80.5-90.7%) for the conventional fractionation group (P = 0.87). There were no significant differences in recurrence-free survival (RFS) (41.7%, 95% confidence interval 32.5-53.5 versus 31.9%, 95% confidence interval 26.1-38.9 P = 0.18) or overall survival (41.2%, 95% confidence interval 32.1-52.8 versus 45.0%, 95% confidence interval 38.7-52.4 P = 0.77). On multivariate analysis, extranodal spread was associated with decreased RFS (P = 0.04) and the number of resected lymph nodes containing metastatic melanoma was associated with decreased RFS (P = 0.0006) and overall survival (P = 0.01). Lymph node field control rates, RFS and overall survival were similar after hypofractionated and conventionally fractionated adjuvant radiotherapy. The presence of extranodal spread and an increasing number of positive lymph nodes were predictive of an unfavourable outcome.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543306.V1
Abstract: Supplementary Figures 1-8 and Supplementary Tables 1-4
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-04-2021
DOI: 10.1200/JCO.20.02446
Abstract: Although the prognosis of patients with thin primary cutaneous melanomas (T1, ≤ 1.0 mm) is generally excellent, some develop recurrence. We sought to develop and validate a model predicting recurrences in patients with thin melanomas. A Dutch population-based cohort (n = 25,930, development set) and a cohort from an Australian melanoma treatment center (n = 2,968, validation set) were analyzed (median follow-up 6.7 and 12.0 years, respectively). Multivariable Cox models were generated for local, regional, and distant recurrence-free survival (RFS). Discrimination was assessed using Harrell's C-statistic for each outcome. Each nomogram performance was evaluated using calibration plots defining low-risk and high-risk groups as the lowest and top 5% of the nomogram risk score, respectively. The nomograms' C-statistics were compared with those of a model including the current American Joint Committee on Cancer staging parameters (T-stage and sentinel node status). Local, regional, and distant recurrences were found in 209 (0.8%), 503 (1.9%), and 203 (0.8%) Dutch patients, respectively, and 23 (0.8%), 61 (2.1%), and 75 (2.5%) Australian patients, respectively. C-statistics of 0.79 (95% CI, 0.75 to 0.82) for local RFS, 0.77 (95% CI, 0.75 to 0.78) for regional RFS, and 0.80 (95% CI, 0.77 to 0.83) for distant RFS were obtained for the development model. External validation showed C-statistics of 0.80 (95% CI, 0.69 to 0.90), 0.76 (95% CI, 0.70 to 0.82), and 0.74 (95% CI, 0.69 to 0.80), respectively. Calibration plots showed a good match between predicted and observed rates. Using the nomogram, the C-statistic was increased by 9%-12% for the development cohort and by 11%-15% for the validation cohort, compared with a model including only T-stage and sentinel node status. Most patients with thin melanomas have an excellent prognosis, but some develop recurrence. The presented nomograms can accurately identify a subgroup at high risk. An online calculator is available at www.melanomarisk.org.au .
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627312.V1
Abstract: Representativeness of study participants
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627318
Abstract: Cohort and dataset overview
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541638.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: BMJ
Date: 15-01-2014
DOI: 10.1136/INJURYPREV-2013-041124
Abstract: Falls result in >$1 billion in treatment, disability, lost output and mortality each year in Australia and people with cataract are at increased risk. Previous research is inconclusive one large Australian study using linked hospital data found no protective effect of cataract surgery. We aim to examine the impact of cataract-related vision impairment on falls risk and the additional effects of delays in access to surgery, refractive management (type of spectacles and changes to spectacle prescription) and the resulting level of function, particularly binocular function which can impact balance. A prospective, 24-month cohort study is planned involving over 700 patients aged 70 years or older with bilateral cataract presenting for surgery at five public hospital eye clinics in Sydney, Melbourne and Perth, Australia. The primary outcomes will be self-reported falls and falls requiring medical care, assessed objectively using administrative data sets. Secondary outcomes include community participation, quality of life, mood and depressive symptoms. McNemar's test will be used to evaluate differences in falls rate before, after first eye and after second eye cataract surgery. Generalised Estimating Equations linear regression analysis will be undertaken to examine factors associated with falls risk and the secondary outcomes. With limited resources to further shorten public waiting lists, there is a need to better understand an in iduals' risk of fall injury or other negative consequences while waiting for surgery. The findings of this project will inform the development of strategies to reduce falls risk in the many older people with cataract.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627315
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: Wiley
Date: 03-03-2021
DOI: 10.1111/JDV.17135
Abstract: Lentiginous melanoma or lentigo maligna is a slow‐growing type of melanoma frequently arising in sun‐damaged skin and often first diagnosed in the elderly. Few studies report long‐term follow‐up. To define characteristics of lentiginous melanoma in situ (LM) and invasive lentiginous melanoma (LMM) in Australian patients managed at a tertiary centre and describe local recurrence or treatment failure rates after long‐term follow‐up. Retrospective single‐centre study of LM/LMM patients evaluated between January 2005 and March 2007. Medical and photographic records were reviewed. One hundred two patients were included, with a total of 117 lesions (70 LM and 47 LMM). Seventy‐nine were new primary LM/LMM, and 38 were recurrences. Primary cases were mostly pigmented (71%), while 77% of recurrent cases were partially pigmented/light brown or amelanotic. The margins were clinically ill‐defined in the majority of cases (64% of primary cases and 94% of recurrent cases). Dermoscopy of the primary LM/LMM showed either classic ‘common’ melanoma features (33%) or classic LM/LMM features (41%), while 95% of recurrent cases had no features for melanoma or LM/LMM. Primary cases that were initially excised (113, 97%) had mean histopathological clear margins of 4.9 mm (range 0.1–22 mm). The median follow‐up time was 7.5 years (95% CI 5.2–10.0) with more than 10‐year follow‐up in 32% and 5–10 years in 24% of patients. There were 44 (38%) recurrences over the entire follow‐up period. Half of the patients who recurred did so within the first 3.8 years after the first treatment. LM/LMM often recur late and are clinically subtle therefore, careful monitoring and long‐term follow‐up are required.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Elsevier BV
Date: 09-2022
Publisher: Wiley
Date: 04-10-2020
DOI: 10.1002/CNCR.32522
Abstract: Patients with metastatic melanoma have variable responses to combination ipilimumab and nivolumab. The objectives of this study were to examine the patterns of response and survival in patients treated with combination ipilimumab and anti-PD-1 therapy (IPI + PD1) and to explore the nature of pseudoprogression and acquired resistance. Patients with metastatic melanoma who received treatment with first-line IPI + PD1 had all metastases ≥5 mm measured on computed tomography/magnetic resonance imaging studies. The lesional response rate (LRR) and the overall response rate (ORR) were determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 140 patients who had 833 metastases were studied. The ORR and the overall complete response (CR) rate decreased as tumor burden or the number of metastases increased. Metastases that had a CR (49%) were smaller than metastases without a CR (median, 13 vs 17 mm P < .0001). Soft-tissue and lung metastases had the highest LRR (79% and 77%, respectively), whereas liver metastases had the lowest (46%). In multivariate analysis, patients with lung metastases had superior ORR (odds ratio [OR], 2.75 P = .02) and progression-free survival (hazard ratio [HR], 0.46 P = .02), whereas those with liver metastases had inferior ORR (OR, 0.33 P = .02), progression-free survival (HR, 4.03 P < .01), and overall survival (HR, 3.17 P = .01). Pseudoprogression occurred in one-third of patients who had progressive disease as their best response, with an overall survival that was comparable to that of patients without disease progression. Acquired resistance occurred in 12% of responders after a median of 9.6 months, with an overall survival rate of 83% at 1 year from progression. Metastases in different anatomical locations display distinct response patterns and also are associated with overall response and survival with combination immunotherapy. Specific sites of disease may hold unique mechanisms of resistance and should allow for more personalized treatment.
Publisher: Public Library of Science (PLoS)
Date: 11-02-2014
Publisher: Springer Science and Business Media LLC
Date: 30-06-2020
DOI: 10.1186/S13063-020-04351-W
Abstract: The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviours, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention. To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis. This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data. This SAP is consistent with best practice and should enable transparent reporting. This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias. Prospectively registered with the Australian New Zealand Clinical Trials Registry, ID: ACTR N12617000691347 . Registered on 15 May 2017.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2013
DOI: 10.1007/S00134-013-2840-0
Abstract: To determine whether fluid resuscitation of acutely ill adults with 6 % hydroxyethyl starch (6 % HES 130) with a molecular weight of 130 kD and a molar substitution ratio of approximately 0.4 (6 % HES 130) compared with other resuscitation fluids results in a difference in the relative risk of death or treatment with renal replacement therapy (RRT). Systematic review and meta-analysis of randomized controlled trials comparing intravascular fluids for resuscitation of hospitalised adults that reported mortality or treatment with RRT. The risk of bias was assessed independently by two reviewers and meta-analysis was performed using random effects. Thirty-five trials enrolling 10,391 participants were included. The three largest trials had the lowest risk of bias, were published (or completed) in 2012, and together enrolled 77 % of all participants. Death occurred in 928 of 4,691 patients (19.8 %) in the 6 % HES 130 group versus 871 of 4,720 (18.5 %) in the control fluid groups relative risk (RR) in the 6 % HES 130 group 1.08, 95 % confidence interval (CI) 1.00 to 1.17, I (2) = 0 %). Treatment with RRT occurred in 378 of 4,236 patients (8.9 %) in the 6 % HES 130 group versus 306 of 4,260 (7.2 %) in the control fluid group (RR in the 6 % HES 130 group 1.25, 95 % CI 1.08 to 1.44, I (2) = 0 %). The quality and quantity of data evaluating 6 % hydroxyethyl starch (130/0.4 and 130/0.42) as a resuscitation fluid has increased in the last 12 months. Patients randomly assigned to resuscitation with 6 %HES 130 are at significantly increased risk of being treated with RRT.
Publisher: American Association for Cancer Research (AACR)
Date: 05-05-2027
DOI: 10.1158/1078-0432.23627312
Abstract: Representativeness of study participants
Publisher: Springer Science and Business Media LLC
Date: 13-04-2016
DOI: 10.1245/S10434-016-5196-1
Abstract: Breslow thickness is the most important prognostic factor in patients with clinically localized primary cutaneous melanomas, and its accuracy has important implications for staging and management. A review of the Melanoma Institute Australia database and population-based data for the state of New South Wales, Australia, found an unexpectedly large number of melanomas reported as being exactly 1.0 mm thick. We sought to determine possible causes for this biologically implausible finding. The tumor thickness of 125 invasive cutaneous melanomas with a recorded Breslow thickness of 0.9-1.1 mm was remeasured and recorded by two pathologists. Concordance of measurements between the two pathologists was high (intraclass correlation coefficient 0.816, 95 % CI 0.733-0.873). The original measurements showed clustering at 0.9, 1.0, and 1.1 mm, whereas the review measurements did not. The original measurements staged 84 cases (72 %) as T1 and 33 (28 %) as T2, while the reviewed measurements staged 58 cases (50 %) as T1 and 59 (50 %) as T2 (p < 0.001). Our study demonstrated imprecision in Breslow thickness measurements and its significant impact on staging. Two potential sources of imprecision are failure to follow standardized thickness measurement guidelines and the phenomenon of terminal digit bias, not previously identified as a problem in this field. Educating pathologists about this phenomenon and the importance of utilizing ocular micrometers may improve the precision of melanoma thickness measurements around critical staging cut-off points. Clinicians must also be educated to appreciate that there is an inevitable margin of error with Breslow thickness measurements that should be considered when making management decisions.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 16-11-2201
Publisher: Elsevier BV
Date: 10-2023
Publisher: Future Medicine Ltd
Date: 2023
Abstract: This is a summary of an article describing the development of risk calculators for use in people who develop a type of melanoma on their skin called “thin” melanoma to predict the likelihood that their cancer will return. The article was originally published in the Journal of Clinical Oncology in 2021. Calculations were performed to predict the chance of people with thin melanomas surviving without their melanoma recurring. Three graphical prediction calculators (called nomograms) were developed, along with easy-to-use online calculators using the same underlying calculation methods. The model was developed using data for 25,930 Dutch people diagnosed with thin melanomas (called the “development set”). To test its ability to predict melanoma recurrence, it was then compared with data for 2,968 Australian people with melanoma (the “validation set”). The calculators developed in the Dutch patients were found to accurately predict the risk of melanoma recurring for people with melanoma in the Australian “validation” group. The calculators provide estimates of the risk of the melanoma returning for people with thin melanomas. The easy-to-use online calculators are freely available on a smartphone, tablet or computer, and will assist in providing accurate estimates of recurrence risks for in iduals with thin melanomas, allowing more intensive follow-up of those whose predicted risk of their melanoma returning is high.
Publisher: Future Medicine Ltd
Date: 06-2023
Abstract: Aims: To describe the health-related quality of life (HRQoL) of melanoma brain metastasis (MBM) patients throughout the first 18 weeks of ipilimumab–nivolumab or nivolumab treatment. Materials & methods: HRQoL data (European Organisation for Research and Treatment of Cancer's Core Quality of Life Questionnaire, additional Brain Neoplasm Module, and EuroQol 5-Dimension 5-Level Questionnaire) were collected as a secondary outcome of the Anti-PD1 Brain Collaboration phase II trial. Mixed linear modeling assessed changes over time, whereas the Kaplan–Meier method was used to determine median time to first deterioration. Results: Asymptomatic MBM patients treated with ipilimumab–nivolumab (n = 33) or nivolumab (n = 24) maintained baseline HRQoL. MBM patients with symptoms or leptomeningeal rogressive disease treated with nivolumab (n = 14) reported a statistically significant trend toward improvement. Conclusion: MBM patients treated with either ipilimumab–nivolumab or nivolumab did not report a significant deterioration in HRQoL within 18 weeks of treatment initiation. Clinical trial registration: NCT02374242 ( ClinicalTrials.gov )
Publisher: Wiley
Date: 05-08-2021
DOI: 10.1111/IJD.15815
Abstract: Atypical intraepidermal melanocytic proliferations (AIMP) is a descriptive term sometimes applied to biopsies that do not fulfill diagnostic criteria of melanoma. They are common on sun‐damaged skin, but their definition and management are controversial. To describe dermoscopic (DS), reflectance confocal microscopic (RCM) and histopathological features of AIMP and identify features associated with subsequent melanoma in situ (MIS). A retrospective analysis of AIMP lesions correlated with patient outcome at two melanoma tertiary centers between 2005 and 2015. Thirty‐four patients were included. Nine (26%) patients had MIS in subsequent biopsies. Predictors of later MIS were target‐like pattern (OR:12.0 [CI: 1.23, 117.41] P = 0.032) and high‐density vascular network (OR:12 [CI: 1.23–117.41], P: 0.032) on DS, and presence of dendritic cells touching each other (OR:9.1 [CI: 1.54, 54.59], P = 0.014) on RCM. Clinical predictors of worse outcome included a previous history of MIS at the same site. Radiotherapy for AIMP had a high failure rate (all patients presented with recurrent disease, three as AIMP and two as MIS). Considering that most cases in this series received non‐surgical treatment at baseline, we recommend close monitoring for lesions with target‐like pattern and density vascular network on DS and treatment for lesions with progression of atypia and/or with “confluent” dendritic cells on RCM. Although the number of patients in this series is very low, early surgery is recommended for MIS cases that recur as AIMP.
Publisher: Wiley
Date: 14-10-2023
DOI: 10.1111/JDV.19524
Publisher: Cold Spring Harbor Laboratory
Date: 06-09-2021
DOI: 10.1101/2021.09.02.21262816
Abstract: Detection of circulating tumour DNA (ctDNA) after curative intent treatment reflects the presence of minimal residual disease and predicts for recurrence. DYNAMIC trial is a randomised phase II investigating the clinical utility of ctDNA-guided adjuvant treatment strategy compared with the standard of care (non-ctDNA based) approach in patients with stage II colon cancer. The primary trial endpoint is recurrence-free survival estimated from Kaplan Meier Method at 2 years. Secondary endpoints include proportion of patients treated with adjuvant chemotherapy, time-to-recurrence, overall survival, ctDNA clearance rate (investigational arm) and quality-adjusted life-years. To outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis. The SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data. ANZ Clinical Trials Registry, ACTRN12615000381583. Registered on 27 th April 2015.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.AHJ.2014.12.005
Abstract: Acute coronary syndromes (ACSs) are a major cause of morbidity and mortality, yet effective ACS treatments are frequently underused in clinical practice. Randomized trials including the CPACS-2 study suggest that quality improvement initiatives can increase the use of effective treatments, but whether such programs can impact hard clinical outcomes has never been demonstrated in a well-powered randomized controlled trial. The CPACS-3 study is a stepped-wedge cluster-randomized trial conducted in 104 remote level 2 hospitals without PCI facilities in China. All hospitalized ACS patients will be recruited consecutively over a 30-month period to an anticipated total study population of more than 25,000 patients. After a 6-month baseline period, hospitals will be randomized to 1 of 4 groups, and a 6-component quality improvement intervention will be implemented sequentially in each group every 6months. These components include the following: establishment of a quality improvement team, implementation of a clinical pathway, training of physicians and nurses, hospital performance audit and feedback, online technical support, and patient education. All patients will be followed up for 6months postdischarge. The primary outcome will be the incidence of in-hospital major adverse cardiovascular events comprising all-cause mortality, myocardial infarction or reinfarction, and nonfatal stroke. The CPACS-3 study will be the first large randomized trial with sufficient power to assess the effects of a multifaceted quality of care improvement initiative on hard clinical outcomes, in patients with ACS.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: Elsevier BV
Date: 11-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 09-11-2018
Publisher: Springer Science and Business Media LLC
Date: 02-01-2021
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.JID.2018.06.165
Abstract: S le size and power calculations help determine if a study is feasible based on a priori assumptions about the study results and available resources. Trade-offs must be made between the probability of observing the true effect and the probability of type I errors (α, false positive) and type II errors (β, false negative). Calculations require specification of the null hypothesis, the alternative hypothesis, type of outcome measure and statistical test, α level, β, effect size, and variability (if applicable). Because the choice of these parameters may be quite arbitrary in some cases, one approach is to calculate the s le size or power over a range of plausible parameters before selecting the final s le size or power. Considerations that should be taken into account could include correction for nonadherence of the participants, adjustment for multiple comparisons, or innovative study designs.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2019
Publisher: Wiley
Date: 17-06-2021
DOI: 10.1111/JDV.17349
Abstract: Lentigo maligna (LM) is a subtype of melanoma in situ with poorly defined margins and a high recurrence rate. The biological behaviour of LM appears to differ widely between cases, from biologically indolent to biologically active variants, with some patients experiencing multiple recurrences. It is not known whether this is secondary to inadequate margins, field cancerization or the innate biology of the lesion itself. (a) Describe the margins of LM in detail by analysing LM in three zones, that is centre, edge and surround using reflectance confocal microscopy (RCM) and histopathology (b) ascertain association of histological distance of LM and atypical melanocytic hyperplasia from the surgical margin with multi‐recurrent (MR) disease and (c) identify features (clinical, dermoscopy, RCM and histopathology) associated with MR LM. (1) Descriptive observational study comparing the centre, edge and surround of LM on histopathology and RCM (2) retrospective cohort study comparing parameters associated with MR and non‐recurrent (NR) LM. 30 patients (median follow‐up time 6.2 years) were included. On histopathology, confluent or near confluent lentiginous proliferation, melanocyte density per 0.5 mm and adnexal spread were best for distinguishing surround from edge of LM. On RCM, predominant melanocytes, lentiginous proliferation and pleomorphism distinguished surround from centre/edge. MR patients had a median histological distance of LM from the surgical margin of 2mm (versus NR patients with an average distance of 4mm). MR patients had a greater proportion of more florid features, compared with NR on histopathology at both the centre and the edge but were similar in the surround. These data may help pathologists and confocalists better define margins of LM. More florid features in MR patients, despite a similar background of sun‐damaged skin, suggest the innate biology of the lesion rather than the field of cancerization may explain MR LM.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2015
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 06-2021
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627318.V1
Abstract: Cohort and dataset overview
Publisher: Elsevier BV
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 11-2020
DOI: 10.1140/EPJC/S10052-020-08469-8
Abstract: This paper presents a search for direct top squark pair production in events with missing transverse momentum plus either a pair of jets consistent with Standard Model Higgs boson decay into b -quarks or a same-flavour opposite-sign dilepton pair with an invariant mass consistent with a Z boson. The analysis is performed using the proton–proton collision data at $$\\sqrt{s}=13$$ s = 13 TeV collected with the ATLAS detector during the LHC Run-2, corresponding to an integrated luminosity of 139 fb $$^{-1}$$ - 1 . No excess is observed in the data above the Standard Model predictions. The results are interpreted in simplified models featuring direct production of pairs of either the lighter top squark ( $$\\tilde{t}_1$$ t ~ 1 ) or the heavier top squark ( $$\\tilde{t}_2$$ t ~ 2 ), excluding at 95% confidence level $$\\tilde{t}_1$$ t ~ 1 and $$\\tilde{t}_2$$ t ~ 2 masses up to about 1220 and 875 GeV, respectively.
Publisher: Wiley
Date: 22-04-2026
DOI: 10.1002/CNCR.29586
Abstract: The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31 P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.EJCA.2017.01.007
Abstract: With new systemic therapies demonstrating activity in melanoma brain metastasis, most of the previously reported stereotactic radiosurgery (SRS) data are superseded. In this study, we report the outcomes (overall survival [OS] and brain control [BC]) and identify factors that associate with such outcomes in the era of modern systemic therapy. A total of 108 patients treated with SRS from 2010 to 2015 were included. Systemic treatment use within 6 weeks of SRS was noted. OS was defined as time from SRS to death or last follow-up, and BC was defined as absence of any active intracranial disease during follow-up. Univariate and multivariate Cox proportional hazard analyses were performed on clinico-pathological prognostic features associated with OS and BC. The median age was 64.3 years, and the median follow-up was 8.6 months. Seventy-nine (73.1%) patients received systemic treatment. The median OS were as follows: anti-CTLA4 - 7.5 months (95% CI: 4.4-15.6), anti-PD1 - 20.4 months (95% CI: 8.8 - N/A) and BRAF inhibitor (BRAFi) ± MEK inhibitor (MEKi) - 17.8 months (95% CI: 11.8 - N/A). Median BC was as follows: anti-CTLA4 - 7.5 months (95% CI: 4.0-15.6), anti-PD1 - 12.7 months (95% CI: 5.5 - N/A) and BRAFi ± MEKi - 12.7 months (95% CI: 8.3-18.5). In multivariate analysis, age and type of systemic therapy were strongly associated with OS. Age, Eastern Cooperative Oncology Group performance status, Graded Prognostic Assessment (GPA) score, and presence of symptoms were associated with BC. Favourable outcomes are seen in patients treated with SRS and with the best survival seen in patients treated with anti-PD1. Known independent prognostic factors for survival such as age and performance status and GPA score remain relevant in this setting.
Publisher: Oxford University Press (OUP)
Date: 11-2022
DOI: 10.1111/CED.15220
Abstract: The SunSafe Student Ambassador Program (SSSAP) in Australia uses the peer-to-peer learning environment to educate high-school students about sun-safety. To assess whether the SSSAP would improve knowledge, attitudes and behaviours towards sun safety in high-school students and whether this would be sustained at 3 months. An assessment survey was delivered before, immediately after and 3 months after participation in the SSSAP in 2019. In total, 503 participants completed the pre-presentation survey, 274 completed the post-presentation survey, and 218 completed both. Immediately following presentation, the total composite score for all 18 knowledge questions increased from a mean ± SD of 11.8 ± 3.5 to 13.8 ± 4.7 (P & 0.001). There was strong evidence for an improvement in one attitude-based question ‘Is it healthy to have a tan?’ (P & 0.01) and one behaviour question about wearing sunscreen daily (P = 0.02). After 3 months, 235 students were matched to their pre-presentation survey. The composite score of all knowledge questions had improved from 11.2 ± 3.5 to 12.1 ± 4.5 (out of a total of 18) (P & 0.01). There was also an improvement in two attitude questions ‘Do you feel better when you have a tan?’ (P = 0.03) and ‘Is it healthy to have a tan?’ (very strong evidence: P & 0.001), and evidence for a reduction in time spent outdoors on a weekday (P = 0.04). The SSSAP was associated with improvements in knowledge, attitude and behaviour towards sun safety immediately and at 3 months post-presentation. Further research is required to determine whether these positive effects are sustained and whether they ultimately reduce skin cancers.
Publisher: Wiley
Date: 27-09-2014
DOI: 10.1111/NEP.12284
Abstract: Acute kidney injury (AKI) is associated with increased mortality. While angiotensin-converting enzyme inhibitors (ACEI) are known to slow progression of chronic kidney disease, their role in AKI remains unclear. The Randomised Evaluation of Normal vs. Augmented Level Replacement Therapy (RENAL) study data were analysed according to ACEI use over time. The primary outcome was all-cause mortality at 90 days following randomisation. Analyses used a multivariate Cox model adjusted for either baseline or for time-dependent covariates, and a sensitivity analysis of patients surviving to at least the median time to ACEI initiation. Of the 1463 participants with available data on ACE inhibitors usage, 142 (9.7%) received ACEI at least once during study data collection. Participants treated with ACEI were older (P = 0.02) and had less sepsis at baseline (P < 0.001). ACEI use was significantly associated with lower mortality at 90 days (HR 0.46, 95% CI 0.30-0.71, P < 0.001), and an increase in renal replacement therapy-free days (P < 0.001), intensive care unit-free days (P < 0.001) and hospital free-days (P < 0.001) after adjusting for baseline covariates. Using the time-dependent analysis, however, the effect of ACEI administration was not significant (HR 0.78, 95% CI 0.51-1.21, P = 0.3). The sensitivity analysis in day 8 survivors produced similar results. In the RENAL study cohort, the use of ACEI during the study was not common and, after adjustment for time-dependent covariates, was not significantly associated with reductions in mortality. Further assessment of the effect of ACEI use in AKI patients is needed.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 09-2019
Publisher: Oxford University Press (OUP)
Date: 21-02-2012
DOI: 10.1093/NDT/GFS022
Abstract: Diabetes and chronic kidney disease (CKD) are both associated with an increased risk of cancer but it is unclear whether diabetes complicated by CKD further augments an in idual's cancer risk. The aim of our study was to determine the association of CKD [defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min] with the overall and site-specific risks of incident cancers among in iduals with Type 2 diabetes. Cox proportional hazard regression models and competing risk analyses were used to examine the univariate and multivariate adjusted associations between reduced kidney function and the overall and site-specific risks of cancer in participants enrolled in the Action in Diabetes and Vascular disease: Preterax and Diamicron MR controlled evaluation (ADVANCE) trial. Over a median follow-up of 5.0 years, 700 malignant neoplasms occurred in the 11 140 (6.4%) participants. There was no increase in overall cancer risk [adjusted hazard ratio: 1.07 (95% confidence interval: 0.89-1.29, P = 0.50)] or site-specific cancer risk for in iduals with CKD (defined as eGFR < 60 mL/min) compared to those without CKD at baseline. These results were robust to multiple methods and thresholds used to estimate CKD. Mild to moderate CKD does not increase the risk of cancer in people with Type 2 diabetes. ADVANCE is registered with ClincalTrial.gov (number NCT00145925).
Publisher: Springer Science and Business Media LLC
Date: 16-10-2019
DOI: 10.1245/S10434-018-6858-Y
Abstract: Wide surgical excision is the standard treatment for localized primary cutaneous melanomas, with a narrow histologic margin associated with an increased risk of local recurrence. The correlation between surgical and histologic margins is poorly documented in the literature. An audit was performed to (1) document the shrinkage of formalin-fixed specimens, and (2) use a precisely measured surgical margin in vivo to predict the histologic margin. For patients presenting for wide excision of melanomas and other malignant skin tumors, measured surgical margin, in vivo and ex vivo specimen width, and histologic margins after formalin fixation were recorded. The effects of clinicopathologic characteristics, including age, sex, body mass index (BMI), tumor type, anatomic site, and presence of visible tumor in predicting specimen shrinkage and histologic margin were assessed. In total, 252 specimens were evaluated. When compared with measured width in vivo, the formalin-fixed specimens showed a mean shrinkage of 14% (R A consistent 14% shrinkage rate of wide excision specimens was found across all patients and excision sites, and we propose a clinically useful 15% correction factor that will account for fixation and shrinkage of cutaneous excision specimens. Excision margins measured by the surgeon were a poor predictor of the histologic margins.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: Elsevier BV
Date: 03-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2017
Abstract: The relationship between increased hemodialysis hours and patient outcomes remains unclear. We randomized (1:1) 200 adult recipients of standard maintenance hemodialysis from in-center and home-based hemodialysis programs to extended weekly (≥24 hours) or standard (target 12–15 hours, maximum 18 hours) hemodialysis hours for 12 months. The primary outcome was change in quality of life from baseline assessed by the EuroQol 5 dimension instrument (3 level) (EQ-5D). Secondary outcomes included medication usage, clinical laboratory values, vascular access events, and change in left ventricular mass index. At 12 months, median weekly hemodialysis hours were 24.0 (interquartile range, 23.6–24.0) and 12.0 (interquartile range, 12.0–16.0) in the extended and standard groups, respectively. Change in EQ-5D score at study end did not differ between groups (mean difference, 0.04 [95% confidence interval, −0.03 to 0.11] P =0.29). Extended hours were associated with lower phosphate and potassium levels and higher hemoglobin levels. Blood pressure (BP) did not differ between groups at study end. Extended hours were associated with fewer BP-lowering agents and phosphate-binding medications, but were not associated with erythropoietin dosing. In a substudy with 95 patients, we detected no difference between groups in left ventricular mass index (mean difference, −6.0 [95% confidence interval, −14.8 to 2.7] g/m 2 P =0.18). Five deaths occurred in the extended group and two in the standard group ( P =0.44) two participants in each group withdrew consent. Similar numbers of patients experienced vascular access events in the two groups. Thus, extending weekly hemodialysis hours did not alter overall EQ-5D quality of life score, but was associated with improvement in some laboratory parameters and reductions in medication burden. (Clinicaltrials.gov identifier: NCT00649298).
Publisher: Oxford University Press (OUP)
Date: 24-09-2023
DOI: 10.1093/IJE/DYAC179
Publisher: Oxford University Press (OUP)
Date: 13-03-2019
DOI: 10.1093/JNCI/DJZ034
Abstract: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness. Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided. In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P & .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis). T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma.
Publisher: Elsevier BV
Date: 06-2014
Publisher: Springer Science and Business Media LLC
Date: 30-06-2022
DOI: 10.1245/S10434-022-11997-0
Abstract: In-transit metastases (ITMs) affect approximately 4% of patients with cutaneous melanoma. This study sought to identify clinical and pathological characteristics that predict further recurrence and survival following resection of ITMs. Patients ( n = 573) who underwent surgical resection of their first presentation of ITM following previous surgical treatment of an American Joint Committee on Cancer (AJCC) stage I–II melanoma between 1969 and 2017 were identified from an institutional database. Clinicopathological predictors of patterns of recurrence and survival following ITM resection were sought. The median time of ITM development was 2.4 years after primary melanoma resection. ITMs were most frequently located on the lower limb (51.0%). The most common melanoma subtype associated with ITM development was nodular melanoma (44.1%). After surgical resection of a first ITM, 65.4% of patients experienced recurrent disease. Most recurrences were locoregional (44.7%), with distant metastasis occurring in 23.9% of patients. Lower limb ITMs were more frequently associated with subsequent ITMs [odds ratio (OR) 2.41, p = 0.0002], and the lowest risk of distant metastasis ( p 0.0001) compared with other primary sites. Primary melanomas and ITM on head and neck, as well as the presence of ulceration, were associated with worse survival. Recurrence after surgical resection of a first ITM was common. Patterns of recurrence differed according to anatomical site further ITM recurrences were more likely for lower limb ITMs, which were also associated with longer distant recurrence-free survival. Distant metastasis was more common for ITM on the head and neck, with worse survival.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Elsevier BV
Date: 08-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-08-2020
DOI: 10.1200/JCO.19.02362
Abstract: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity. Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496). The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model ( P .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%). A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au .
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.EJCA.2021.04.045
Abstract: Combination ipilimumab and nivolumab is approved for several malignancies. Toxicity most often occurs 6-10 weeks into treatment. Whether very early toxicity is harder to manage or influences efficacy is unknown. Consecutive metastatic melanoma patients who developed hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 were retrospectively identified from nine centres. A total of 82 patients developed hyperacute toxicity (estimated incidence 9%), at a median 10 days (range 1-21). Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis). Fifty-nine percent required treatment beyond oral steroids, including IV steroids (28%), infliximab and other immunosuppression (30%). A total of 29% patients developed an additional hyperacute toxicity and 26% another toxicity >21 days after treatment commencement but before further immunotherapy. The objective response rate (ORR) was 54%, and after a median 11.6 mo follow-up, median PFS was 7.4 mo. Increasing levels of immunosuppression was associated with a reduced PFS (12-month PFS 62% no immunosuppression versus 49% oral steroids versus 33% IV steroids versus 20% further immunosuppressants, p = 0.006). There was no significant difference in ORR or PFS by duration of immunosuppression. Hyperacute toxicities from combination immunotherapy have a wide spectrum and can be severe. Many patients require significant immunosuppression for prolonged durations and remain at risk of further severe toxicity. Melanoma outcomes in such patients appear similar to those of trial populations, although greater immunosuppression requirements may be associated with inferior outcomes.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1038/LABINVEST.2016.143
Abstract: Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.9508
Abstract: 9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19% V600BRAF 54%, 56% and 81% prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490749.V1
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: Oxford University Press (OUP)
Date: 25-07-2020
DOI: 10.1111/BJD.17990
Abstract: People with melanoma want and need effective interventions for living with fear of cancer recurrence (FCR). This study reports the 12-month outcomes of a brief, psychological intervention designed to reduce FCR in people at high risk of developing another primary melanoma compared with usual care. In this two-arm randomized controlled trial, adults previously diagnosed with stage 0, I or II melanoma were randomly allocated to the intervention (n = 80) or control (usual care) arm (n = 84). The trial was registered with the Australian and New Zealand Clinical Trials Registry on 19 March 2013 (registration: ACTRN12613000304730). The intervention comprised a 76-page psychoeducational resource and three in idually tailored, telephone-based sessions with a psychologist, scheduled at specific time points around participants' dermatological appointments. The primary outcome was the level of self-reported fear of new or recurrent melanoma assessed at 12 months postintervention using the severity subscale of the Fear of Cancer Recurrence Inventory. Compared with the control arm, the intervention group reported significantly lower FCR at 12 months postintervention the between-group mean difference was -1·41 for FCR severity [95% confidence interval (CI) -2·6 to -0·2 P = 0·02] and -1·32 for FCR triggers (95% CI -2·6 to -0·02 P = 0·04). The odds ratio for FCR severity scores ≥13 (54% intervention, 63% control) was 0·59 (95% CI 0·30-1·14, P = 0·12). There were no differences between groups in secondary outcomes, such as anxiety, depression or health-related quality of life. The previously reported 6-month benefits of this brief, patient-centred psychological intervention in reducing FCR were found to continue 12 months postintervention, with no known adverse effects, supporting implementation as part of routine melanoma care.
Publisher: Elsevier BV
Date: 09-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2020
DOI: 10.1200/PO.20.00160
Publisher: Springer Science and Business Media LLC
Date: 22-08-2022
Publisher: Oxford University Press (OUP)
Date: 04-2021
DOI: 10.1111/BJD.19819
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2022
DOI: 10.1200/JCO.21.01701
Abstract: Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti–PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI] anti–PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation. One thousand six hundred forty-four patients with metastatic melanoma treated with anti–PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created. The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti–PD-1 ± IPI. Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making.
Publisher: BMJ
Date: 07-2022
Abstract: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR) secondary outcomes were progression-free survival (PFS) and overall survival (OS). In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.
Publisher: Springer Science and Business Media LLC
Date: 11-2020
DOI: 10.1140/EPJC/S10052-020-08509-3
Abstract: A search is presented for four-top-quark production using an integrated luminosity of 139 fb $$^{-1}$$ - 1 of proton–proton collision data at a centre-of-mass energy of $$13~\\text {TeV}$$ 13 TeV collected by the ATLAS detector at the LHC. Events are selected if they contain a same-sign lepton pair or at least three leptons (electrons or muons). Jet multiplicity, jet flavour and event kinematics are used to separate signal from the background through a multivariate discriminant, and dedicated control regions are used to constrain the dominant backgrounds. The four-top-quark production cross section is measured to be $$24^{+7}_{-6}$$ 24 - 6 + 7 fb. This corresponds to an observed (expected) significance with respect to the background-only hypothesis of 4.3 (2.4) standard deviations and provides evidence for this process.
Publisher: Elsevier BV
Date: 07-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550207.V1
Abstract: Abstract Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient s les using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8 sup + /sup lymphocytes, CD103 sup + /sup tumor-resident T cells (Trm), CD45RO sup + /sup cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma. /
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.C.6533212
Abstract: AbstractPurpose: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental Design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. Results: Patients who responded to combination immune checkpoint inhibitor contained higher CD16 sup + /sup macrophage densities than those who did not respond (196 vs. 7 cells/mm sup /sup i P = /i 0.0041). There was no diffidence in CD16 sup + /sup macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm sup /sup i P /i = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16 sup + /sup macrophages compared with those with low densities (87% vs. 42%, i P /i = 0.0056, i n /i = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, i P /i = 0.4636, i n /i = 50). Melanoma biopsies with high densities of CD16 sup + /sup macrophages contained upregulated gene expression of critical T-cell recruiting chemokines ( i CXCL9 /i , i CXCL10 /i , and i CXCL11 /i ). Conclusions: Our data demonstrate that tumor microenvironments enriched with CD16 sup + /sup macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-23-0490" target="_blank" See related commentary by Smithy and Luke, p. 2345 /a /i /
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.EJCA.2021.04.037
Abstract: Although previously the mainstay of treatment, the role of surgery in the management of patients with oligometastatic stage IV melanoma has changed with the advent of effective systemic therapies (most notably immunotherapy). Contemporary treatment options for patients with asymptomatic solitary or oligo-metastases include upfront surgery followed by adjuvant immunotherapy or upfront immunotherapy with salvage surgery as required. For suspected solitary or oligo-metastases, surgery serves both diagnostic and therapeutic purposes. Advances in radiological technology allow metastases to be detected earlier and surgery to be less morbid. Surgical morbidities are generally more tolerable than serious immune-related adverse effects, but surgery may be less effective. Upfront immunotherapy ensures that futile surgery is not offered for rapidly progressive disease. It also provides an opportunity to assess response to treatment, which predicts outcome, and may obviate the need for surgery. However, it is important not to miss a window of opportunity for surgical intervention, whereby if disease progresses on immunotherapy it becomes unresectable. In situations where local therapy is recommended but surgery is not desired, stereotactic radiosurgery may be an effective alternative. The decision-making process regarding upfront surgery versus immunotherapy needs to take place within a specialist melanoma multidisciplinary setting and be customised to in idual patient and tumour factors. Ultimately, high-level clinical trial evidence is required to resolve uncertainties in the management of patients with oligometastatic stage IV melanoma but the complexity of the varying presentations may make trial design challenging.
Publisher: Elsevier BV
Date: 2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-03-2021
Publisher: Elsevier BV
Date: 02-2021
DOI: 10.1016/J.PATHOL.2021.05.094
Abstract: Wide local excision (WLE) to achieve adequate clearance margins is the standard initial definitive treatment for patients with biopsy-proven primary cutaneous melanoma. Residual melanoma in WLE specimens after prior complete excision-biopsy (CEB) is reported in 0-6.3% of cases. However, studies evaluating the prevalence, clinicopathological features and relevance of persistent disease in WLE specimens are limited. This study sought to determine the frequency of and clinicopathological characteristics associated with residual melanoma in WLE specimens performed after a CEB of primary cutaneous or acral melanoma (in situ or invasive) with clinically and histologically tumour-free margins, and assess its relevance. A review of the research database and pathology archives of a large Australian tertiary referral melanoma treatment centre was performed. Eligible patients were those for whom a definitive WLE was performed after CEB of a primary melanoma (in situ or invasive) with negative clinical and histological margins, between May 2013 and May 2015. All partial biopsies were excluded. Of 640 eligible patients, 510 (79.7%) had invasive melanoma and 130 (20.3%) had melanoma in situ. Residual disease was identified in 20 cases (20/640, 3.1%), of which three (15%) were melanoma in situ on CEB and 17 (85%) were invasive melanoma. On univariate analysis, the presence of residual disease in WLE specimens was associated with lentigo maligna (LM)/LM melanoma (LMM) subtype [odds ratio (OR) 10.33 95% confidence interval (CI) 2.84-37.54 p=0.004], nodular melanoma (NM) subtype (OR 4.92 95% CI 1.53-15.85 p=0.0076) and, for invasive tumours, higher tumour mitotic rate (mean 7.7, SD 7.51 vs 3.4, SD 4.83 OR 1.11 95% CI 1.04-1.18 p=0.0014). Breslow thickness >4 mm was associated with a higher risk of residual disease (OR 7.30 95% CI 1.88, 28.26 p=0.004). Cases with residual disease had primary tumours with a significantly larger diameter (median 14 mm, range 4-25) than those without residual disease (median 9 mm, range 2-60), (OR 1.07 95% CI 1.03-1.11 p≤0.001) and were also more likely to be amelanotic (38% vs 14%), (OR 3.69 95% CI 1.17, 11.60 p=0.026). Residual disease was associated with assessment of >3 slides of tissue (OR 6.98 95% CI 1.54-31.62 p=0.0118) and complete blocking of the scar (OR 31.69 95% CI 3.98-252.21 p=0.0011). Residual melanoma in WLE specimens is an infrequent occurrence. Risk factors for residual disease are LM/LMM and NM melanoma subtypes, higher mitotic rate, larger lesion diameter and amelanosis. Tumours with these features warrant more extensive pathological s ling. WLE after CEB for melanoma remains an important procedure to reduce local recurrence however, limited pathological s ling of the WLE scar is probably appropriate for cases lacking high risk features.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490755.V1
Abstract: Representativeness of study participants
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490761.V1
Abstract: Cohort and dataset overview
Publisher: Oxford University Press (OUP)
Date: 22-03-2023
DOI: 10.1093/BJD/LJAD076
Abstract: This cross-sectional survey identified risk factors for developing a second primary melanoma. Patients with melanoma who had characteristics such as male sex, older age, high naevus count, or melanoma on the trunk or upper limbs had a substantially higher risk of subsequent melanoma and should therefore be more intensively monitored.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 06-05-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2018
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.EJPB.2016.01.015
Abstract: PurSil®AL20 (PUS), a copolymer of 4,4'-dicyclohexylmethane diisocyanate (HMDI), 1,4-butane diol (BD), poly-tetramethylene oxide (PTMO) and poly-dimethyl siloxane (PDMS) was investigated for stability as a vehicle for Docetaxel (DTX) delivery through oesophageal drug eluting stent (DES). On exposure to stability test conditions, it was found that DTX release rate declined at 4 and 40 °C. In order to ulge reasons underlying this, changes in DTX solid state as well as PUS microstructure were followed. It was found that re-crystallization of DTX in PDMS rich regions was reducing the drug release at both 4 °C and 40 °C s les. So far microstructural features have not been correlated with stability and drug release, and in this study we found that at 40 °C increase in microstructural domain sizes and the inter-domain distances (from ∼85 Å to 129 Å) were responsible for hindering the DTX release in addition to DTX re-crystallization.
Publisher: Wiley
Date: 03-03-2019
DOI: 10.1111/PCMR.12775
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.EJCA.2021.11.022
Abstract: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown. Patients with metastatic melanoma treated with chemotherapy after progression on immunotherapy with checkpoint inhibitors were identified retrospectively from 24 melanoma centres. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety were examined. In total, 463 patients were treated between 2007 and 2017. Fifty-six per cent had received PD-1-based therapy before chemotherapy. Chemotherapy regimens included carboplatin + paclitaxel (32%), dacarbazine (25%), temozolomide (15%), taxanes (9%, nab-paclitaxel 4%), fotemustine (6%) and others (13%). Median duration of therapy was 7.9 weeks (0-108). Responses included 0.4% complete response (CR), 12% partial response (PR), 21% stable disease (SD) and 67% progressive disease (PD). Median PFS was 2.6 months (2.2, 3.0), and median PFS in responders was 8.7 months (6.3, 16.3), respectively. Twelve-month PFS was 12% (95% CI 2-15%). In patients who had received anti-PD-1 before chemotherapy, the ORR was 11%, and median PFS was 2.5 months (2.1, 2.8). The highest activity was achieved with single-agent taxanes (N = 40), with ORR 25% and median PFS 3.9 months (2.1, 6.2). Median OS from chemotherapy start was 7.1 months (6.5, 8.0). Subsequent treatment with checkpoint inhibitors achieved a response rate of 16% with a median PFS of 19.1 months (2.0-43.1 months). No unexpected toxicities were observed. Chemotherapy has a low response rate and short PFS in patients with metastatic melanoma who have failed checkpoint inhibitor therapy, although activity varied between regimens. Chemotherapy has a limited role in the management of metastatic melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541620.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Springer Science and Business Media LLC
Date: 13-04-2022
DOI: 10.1245/S10434-022-11669-Z
Abstract: pT3/4 head and neck cutaneous squamous cell carcinomas (HNcSCCs) are associated with poor outcomes, including local recurrence, metastasis and death. Whilst surgery remains the standard treatment for advanced HNcSCC, novel systemic therapies, such as immunotherapy, are being used earlier in the treatment paradigm. It is imperative that the clinical outcomes of surgery are clearly described so that conventional and emerging treatment modalities can be better integrated and sequenced in the management of pT3/4 HNcSCC. Patients with confirmed pT3/4 HNcSCC undergoing curative surgical resection between 2014-2020 were identified retrospectively from a prospectively maintained research database. The primary outcomes of interest were locoregional control (LRC), disease-specific survival (DSS), and overall survival (OS). The secondary outcome was surgical complication rate. A total of 104 patients (median age 74, range 41–94 years) were included, 90% of which had pT3 tumors 36.5% received adjuvant radiotherapy. Median follow-up was 24.3 (range 1.0–84.3) months. LRC at 5 years was 62.0%, DSS at 5 years was 83.7%, and OS at 5 years was 71.9%. Median time to recurrence was 8.4 months. LRC was reduced in the presence of margin involvement and previous treatment (radiotherapy/surgery). The major surgical complication rate was 9.6%. More than 60% of patients treated surgically for pT3/4 head and neck cSCC were alive and free of disease at 5 years posttreatment. High-risk features such as margin involvement and having had previous treatment (radiotherapy/surgery) should be used to guide adjuvant therapy.
Publisher: Elsevier BV
Date: 11-2015
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: Elsevier BV
Date: 09-2018
Publisher: Radiological Society of North America (RSNA)
Date: 05-2023
Publisher: American Association for Cancer Research (AACR)
Date: 11-2020
DOI: 10.1158/2326-6066.CIR-19-0835
Abstract: Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient s les using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8+ lymphocytes, CD103+ tumor-resident T cells (Trm), CD45RO+ cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
Publisher: Elsevier BV
Date: 05-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490746
Abstract: Clinical and mIHC data generated within the study.
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.EJCA.2021.04.021
Abstract: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549709
Abstract: Abstract Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation uveal melanoma occurs in the eyes mucosal melanoma occurs in internal mucous membranes and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490749
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627303.V1
Abstract: Clinical and mIHC data generated within the study.
Publisher: AMPCo
Date: 26-04-2021
DOI: 10.5694/MJA2.51030
Publisher: BMJ
Date: 03-2023
Abstract: In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma who recur during or after adjuvant immunotherapy, including those that may or may not have undergone prior CLND. In this study, we aimed to answer this question. Patients with resected stage III melanoma who received adjuvant anti-programmed cell death protein-1 (PD-1) (±ipilimumab) immunotherapy with a subsequent locoregional (lymph node and/or in-transit metastases) recurrence were retrospectively identified. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was rate of subsequent locoregional recurrence secondary outcomes were locoregional recurrence-free survival (lr-RFS2) and overall RFS (RFS2) to second recurrence. In total, 71 patients were identified: 42 (59%) men, 30 (42%) BRAF V600E mutant, 43 (61%) stage IIIC at diagnosis. Median time to first recurrence was 7 months (1–44), 24 (34%) received adjuvant RT and 47 (66%) did not. Thirty-three patients (46%) developed a second recurrence at a median of 5 months (1–22). The rate of locoregional relapse at second recurrence was lower in those who received adjuvant RT (8%, 2/24) compared with those who did not (36%, 17/47, p=0.01). Adjuvant RT at first recurrence was associated with an improved lr-RFS2 (HR 0.16, p=0.015), with a trend towards an improved RFS2 (HR 0.54, p = 0.072) and no effect on risk of distant recurrence or overall survival. This is the first study to investigate the role of adjuvant RT in patients with melanoma with locoregional disease recurrence during or after adjuvant anti-PD-1-based immunotherapy. Adjuvant RT was associated with improved lr-RFS2, but not risk of distant recurrence, demonstrating a likely benefit in locoregional disease control in the modern era. Further prospective studies are required to validate these results.
Publisher: BMJ
Date: 2021
Abstract: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. COVID-19–related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.
Publisher: SAGE Publications
Date: 15-07-2015
Abstract: To investigate the impact of Alexander Technique lessons on balance and mobility in older adults with visual impairments. Randomized assessor blinded controlled trial with intervention and usual care control groups. Participants’ homes. A total of 120 community-dwellers aged 50+ with visual impairments. Twelve weeks of Alexander lessons and usual care. Short Physical Performance Battery items were primary outcomes at 3 months and secondary outcomes at 12 months. Additional secondary outcomes were postural sway, maximal balance range and falls over 12 months. Between-group differences in primary outcomes were not significant. The intervention group reduced postural sway on a firm surface with eyes open at 3 months after adjusting for baseline values (–29.59 mm, 95%CI −49.52 to −9.67, P 0.01). Planned sub-group analyses indicated a greater intervention effect among past multiple-fallers (2+) than non-multiple fallers for gait speed ( P = 0.02) and step length ( P 0.01) at 3 months and chair stand at 12 months ( P 0.01). There was a non-significant reduction in falls rate (IRR = 0.64, 95%CI 0.34 to 1.15, P = 0.13) and injurious falls (IRR = 0.61, 95% CI 0.28 to 1.30, P = 0.20) in the intervention group compared to the control group. The intervention did not have a significant impact on the primary outcomes but benefits for the intervention group in postural sway, trends towards fewer falls and injurious falls and improved mobility among past multiple-fallers suggest further investigation of the Alexander Technique is warranted.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2013
DOI: 10.1007/S00134-013-2864-5
Abstract: Choice of renal replacement therapy (RRT) modality may affect renal recovery after acute kidney injury (AKI). We sought to compare the rate of dialysis dependence among severe AKI survivors according to the choice of initial renal replacement therapy (RRT) modality applied [continuous (CRRT) or intermittent (IRRT)]. Systematic searches of peer-reviewed publications in MEDLINE and EMBASE were performed (last update July 2012). All studies published after 2000 reporting dialysis dependence among survivors from severe AKI requiring RRT were included. Data on follow-up duration, sex, age, chronic kidney disease, illness severity score, vasopressors, and mechanical ventilation were extracted when available. Results were pooled using a random-effects model. We identified 23 studies: seven randomized controlled trials (RCTs) and 16 observational studies involving 472 and 3,499 survivors, respectively. Pooled analyses of RCTs showed no difference in the rate of dialysis dependence among survivors (relative risk, RR 1.15 [95 % confidence interval (CI) 0.78-1.68], I(2) = 0 %). However, pooled analyses of observational studies suggested a higher rate of dialysis dependence among survivors who initially received IRRT as compared with CRRT (RR 1.99 [95 % CI 1.53-2.59], I (2) = 42 %). These findings were consistent with adjusted analyses (performed in 7/16 studies), which found a higher rate of dialysis dependence in IRRT-treated patients [odds ratio (OR) 2.2-25 (5 studies)] or no difference (2 studies). Among AKI survivors, initial treatment with IRRT might be associated with higher rates of dialysis dependence than CRRT. However, this finding largely relies on data from observational trials, potentially subject to allocation bias, hence further high-quality studies are necessary.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2013
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-05-2022
Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 08-2023
Publisher: Informa UK Limited
Date: 19-08-2016
Publisher: Wiley
Date: 27-03-2023
DOI: 10.1002/JSO.27245
Abstract: Adjuvant radiotherapy (RT) can be given to melanoma patients following salvage surgery for node field recurrence after a previous regional node dissection, but the value of this treatment strategy is poorly documented. This study evaluated long‐term node field control and survival of patients treated in this way in an era before effective adjuvant systemic therapy became available. Data for 76 patients treated between 1990 and 2011 were extracted from an institutional database. Baseline patient characteristics, treatment details and oncological outcomes were analysed. Adjuvant RT with conventional fractionation (median dose 48 Gy in 20 fractions) was given to 43 patients (57%) and hypofractionated RT (median dose 33 Gy in 6 fractions) to 33 patients (43%). The 5‐year node field control rate was 70%, 5‐year recurrence‐free survival 17%, 5‐year melanoma‐specific survival 26% and 5‐year overall survival 25%. Salvage surgery with adjuvant RT achieved node field control in 70% of melanoma patients with node field recurrence following a prior node dissection. However, disease progression at distant sites was common and survival outcomes were poor. Prospective data will be required to assess outcomes for contemporary combinations of surgery, adjuvant RT and systemic therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549709.V1
Abstract: Abstract Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation uveal melanoma occurs in the eyes mucosal melanoma occurs in internal mucous membranes and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes. Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Publisher: Elsevier BV
Date: 11-2020
Publisher: Springer Science and Business Media LLC
Date: 11-01-2013
DOI: 10.1007/S00134-012-2800-0
Abstract: In acute kidney injury patients, metabolic acidosis is common. Its severity, duration, and associated changes in mean arterial pressure (MAP) and vasopressor therapy may be affected by the intensity of continuous renal replacement therapy (CRRT). We aimed to compare key aspects of acidosis and MAP and vasopressor therapy in patients treated with two different CRRT intensities. We studied a nested cohort of 115 patients from two tertiary intensive care units (ICUs) within a large multicenter randomized controlled trial treated with lower intensity (LI) or higher intensity (HI) CRRT. Levels of metabolic acidosis at randomization were similar [base excess (BE) of -8 ± 8 vs. -8 ± 7 mEq/l p = 0.76]. Speed of BE correction did not differ between the two groups. However, the HI group had a greater increase in MAP from baseline to 24 h (7 ± 3 vs. 0 ± 3 mmHg p < 0.01) and a greater decrease in norepinephrine dose (from 12.5 to 3.5 vs. 5 to 2.5 μg/min p < 0.05). The correlation (r) coefficients between absolute change in MAP and norepinephrine (NE) dose versus change in BE were 0.05 and -0.37, respectively. Overall, LI and HI CRRT have similar acid-base effects in patients with acidosis. However, HI was associated with greater improvements in MAP and vasopressor requirements (clinical trial no. NCT00221013).
Publisher: Springer Science and Business Media LLC
Date: 04-08-2021
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 06-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6550207
Abstract: Abstract Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient s les using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8 sup + /sup lymphocytes, CD103 sup + /sup tumor-resident T cells (Trm), CD45RO sup + /sup cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma. /
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Medical Association (AMA)
Date: 02-08-2022
Publisher: Wiley
Date: 06-05-2022
DOI: 10.1111/AJD.13841
Abstract: Regular skin examinations for early detection of melanoma are recommended for high‐risk in iduals, but there is minimal consensus regarding what constitutes ‘high‐risk’. Melanoma risk prediction models may guide this. We compared two online melanoma risk prediction tools: Victorian Melanoma Service (VMS) and Melanoma Institute Australia (MIA) risk tools to assess classification differences of patients at high‐risk of a first primary melanoma. Risk factor data for 357 patients presenting with their first primary melanoma were entered into both risk tools. Predicted risks were recorded: 5‐year absolute risk (VMS tool and MIA tool) 10‐year, lifetime, and relative risk estimates (MIA tool). Sensitivities for each tool were calculated using the same high‐risk thresholds. The MIA risk tool showed greater sensitivity on comparison of 5‐year absolute risks (90% MIA vs 78% VMS). Patients had significantly higher odds of being classified as high or very‐high risk using the MIA risk tool overall, and for each patient subgroup. Using either tool, patients of male gender or with synchronous multiple first primary melanomas were more likely to be correctly classified as high‐ or very‐high risk using 5‐year absolute risk thresholds but tumour invasiveness was unrelated to risk. Classification differed when using the MIA risk categories based on relative risk. Both melanoma risk prediction tools had high sensitivity for identifying in iduals at high‐risk and could be used for optimising prevention c aigns. The choice of which risk tool, measure, and threshold for risk stratification depends on the intended purpose of risk prediction, and ideally requires information on specificity.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 12-2020
DOI: 10.1140/EPJC/S10052-020-08477-8
Abstract: The jet energy scale, jet energy resolution, and their systematic uncertainties are measured for jets reconstructed with the ATLAS detector in 2012 using proton–proton data produced at a centre-of-mass energy of 8 TeV with an integrated luminosity of $$20 \\, \\hbox {fb}^{-1}$$ 20 fb - 1 . Jets are reconstructed from clusters of energy depositions in the ATLAS calorimeters using the anti- $$k_t$$ k t algorithm. A jet calibration scheme is applied in multiple steps, each addressing specific effects including mitigation of contributions from additional proton–proton collisions, loss of energy in dead material, calorimeter non-compensation, angular biases and other global jet effects. The final calibration step uses several in situ techniques and corrects for residual effects not captured by the initial calibration. These analyses measure both the jet energy scale and resolution by exploiting the transverse momentum balance in $$\\gamma $$ γ + jet, Z + jet, dijet, and multijet events. A statistical combination of these measurements is performed. In the central detector region, the derived calibration has a precision better than 1% for jets with transverse momentum $$150 \\, \\hbox {GeV} p_{{\\mathrm {T}}} $$ 150 GeV p T 1500 GeV, and the relative energy resolution is $$(8.4\\pm 0.6)\\%$$ ( 8.4 ± 0.6 ) % for $$p_{{\\mathrm {T}}}= 100 \\, \\hbox {GeV}$$ p T = 100 GeV and $$(23\\pm 2)\\%$$ ( 23 ± 2 ) % for $$p_{{\\mathrm {T}}}= 20 \\, \\hbox {GeV}$$ p T = 20 GeV . The calibration scheme for jets with radius parameter $$R=1.0$$ R = 1.0 , for which jets receive a dedicated calibration of the jet mass, is also discussed.
Publisher: AMPCo
Date: 05-2021
DOI: 10.5694/MJA2.51020
Abstract: CHAPTER 1: HOW AUSTRALIA IMPROVED HEALTH EQUITY THROUGH ACTION ON THE SOCIAL DETERMINANTS OF HEALTH: Do not think that the social determinants of health equity are old hat. In reality, Australia is very far away from addressing the societal level drivers of health inequity. There is little progressive policy that touches on the conditions of daily life that matter for health, and action to redress inequities in power, money and resources is almost non-existent. In this chapter we ask you to pause this reality and come on a fantastic journey where we envisage how COVID-19 was a great disruptor and accelerator of positive progressive action. We offer glimmers of what life could be like if there was committed and real policy action on the social determinants of health equity. It is vital that the health sector assists in convening the multisectoral stakeholders necessary to turn this fantasy into reality. CHAPTER 2: ABORIGINAL AND TORRES STRAIT ISLANDER CONNECTION TO CULTURE: BUILDING STRONGER INDIVIDUAL AND COLLECTIVE WELLBEING: Aboriginal and Torres Strait Islander peoples have long maintained that culture (ie, practising, maintaining and reclaiming it) is vital to good health and wellbeing. However, this knowledge and understanding has been dismissed or described as anecdotal or intangible by Western research methods and science. As a result, Aboriginal and Torres Strait Islander culture is a poorly acknowledged determinant of health and wellbeing, despite its significant role in shaping in iduals, communities and societies. By extension, the cultural determinants of health have been poorly defined until recently. However, an increasing amount of scientific evidence supports what Aboriginal and Torres Strait Islander people have always said - that strong culture plays a significant and positive role in improved health and wellbeing. Owing to known gaps in knowledge, we aim to define the cultural determinants of health and describe their relationship with the social determinants of health, to provide a full understanding of Aboriginal and Torres Strait Islander wellbeing. We provide ex les of evidence on cultural determinants of health and links to improved Aboriginal and Torres Strait Islander health and wellbeing. We also discuss future research directions that will enable a deeper understanding of the cultural determinants of health for Aboriginal and Torres Strait Islander people. CHAPTER 3: PHYSICAL DETERMINANTS OF HEALTH: HEALTHY, LIVEABLE AND SUSTAINABLE COMMUNITIES: Good city planning is essential for protecting and improving human and planetary health. Until recently, however, collaboration between city planners and the public health sector has languished. We review the evidence on the health benefits of good city planning and propose an agenda for public health advocacy relating to health-promoting city planning for all by 2030. Over the next 10 years, there is an urgent need for public health leaders to collaborate with city planners - to advocate for evidence-informed policy, and to evaluate the health effects of city planning efforts. Importantly, we need integrated planning across and between all levels of government and sectors, to create healthy, liveable and sustainable cities for all. CHAPTER 4: HEALTH PROMOTION IN THE ANTHROPOCENE: THE ECOLOGICAL DETERMINANTS OF HEALTH: Human health is inextricably linked to the health of the natural environment. In this chapter, we focus on ecological determinants of health, including the urgent and critical threats to the natural environment, and opportunities for health promotion arising from the human health co-benefits of actions to protect the health of the planet. We characterise ecological determinants in the Anthropocene and provide a sobering snapshot of planetary health science, particularly the momentous climate change health impacts in Australia. We highlight Australia's position as a major fossil fuel producer and exporter, and a country lacking cohesive and timely emissions reduction policy. We offer a roadmap for action, with four priority directions, and point to a scaffold of guiding approaches - planetary health, Indigenous people's knowledge systems, ecological economics, health co-benefits and climate-resilient development. Our situation requires a paradigm shift, and this demands a recalibration of health promotion education, research and practice in Australia over the coming decade. CHAPTER 5: DISRUPTING THE COMMERCIAL DETERMINANTS OF HEALTH: Our vision for 2030 is an Australian economy that promotes optimal human and planetary health for current and future generations. To achieve this, current patterns of corporate practice and consumption of harmful commodities and services need to change. In this chapter, we suggest ways forward for Australia, focusing on pragmatic actions that can be taken now to redress the power imbalances between corporations and Australian governments and citizens. We begin by exploring how the terms of health policy making must change to protect it from conflicted commercial interests. We also examine how marketing unhealthy products and services can be more effectively regulated, and how healthier business practices can be incentivised. Finally, we make recommendations on how various public health stakeholders can hold corporations to account, to ensure that people come before profits in a healthy and prosperous future Australia. CHAPTER 6: DIGITAL DETERMINANTS OF HEALTH: THE DIGITAL TRANSFORMATION: We live in an age of rapid and exponential technological change. Extraordinary digital advancements and the fusion of technologies, such as artificial intelligence, robotics, the Internet of Things and quantum computing constitute what is often referred to as the digital revolution or the Fourth Industrial Revolution (Industry 4.0). Reflections on the future of public health and health promotion require thorough consideration of the role of digital technologies and the systems they influence. Just how the digital revolution will unfold is unknown, but it is clear that advancements and integrations of technologies will fundamentally influence our health and wellbeing in the future. The public health response must be proactive, involving many stakeholders, and thoughtfully considered to ensure equitable and ethical applications and use. CHAPTER 7: GOVERNANCE FOR HEALTH AND EQUITY: A VISION FOR OUR FUTURE: Coronavirus disease 2019 has caused many people and communities to take stock on Australia's direction in relation to health, community, jobs, environmental sustainability, income and wealth. A desire for change is in the air. This chapter imagines how changes in the way we govern our lives and what we value as a society could solve many of the issues Australia is facing - most pressingly, the climate crisis and growing economic and health inequities. We present an imagined future for 2030 where governance structures are designed to ensure transparent and fair behaviour from those in power and to increase the involvement of citizens in these decisions, including a constitutional voice for Indigenous peoples. We imagine that these changes were made by measuring social progress in new ways, ensuring taxation for public good, enshrining human rights (including to health) in legislation, and protecting and encouraging an independent media. Measures to overcome the climate crisis were adopted and democratic processes introduced in the provision of housing, education and community development.
Publisher: Wiley
Date: 07-12-2018
DOI: 10.1111/PCMR.12675
Abstract: This study evaluated patterns of response as discerned by comprehensive metastasis-specific analysis in metastatic melanoma patients receiving anti-PD-1 antibodies. Bi-dimensional measurements of every metastasis in patients enrolled in the KEYNOTE-001 trial at a single institution were obtained at baseline and throughout treatment. Twenty-seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627309.V1
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.2019.37.15_SUPPL.TPS9600
Abstract: TPS9600 Background: Nivolumab combined with ipilimumab is active in melanoma brain metastases, with intracranial response rates 55% and durable survival in treatment naïve patients (pts) (Long GV et al Lancet Onc 2018 Tawbi H et al NEJM 2018). We seek to determine if the addition of stereotactic radiotherapy (SRS) results in improved intracranial outcomes. Methods: This is a multisite, open-label, phase 2 trial in systemic treatment-naïve pts with melanoma brain metastases. Pts must have ≥1 asymptomatic brain metastases that are ≥5mm and ≤40mm as per modified RECIST 1.1, on gadolinium-enhanced MRI, and no history of previous treatment with SRS. Eligible pts are randomly assigned to either receive nivolumab plus ipilimumab with SRS or nivolumab plus ipilimumab alone. Nivolumab (1mg/kg) and ipilimumab (3mg/kg) are given every 3 weeks for 4 doses. Following induction, 480mg nivolumab is given every 4 weeks until progression, unacceptable toxicity, or a maximum of 2 years. SRS is administered as single fraction of 16-22Gy, or hypofractionated for larger lesions (24-27Gy in 3 fractions), within 7 days of immunotherapy commencement. Pts will be evaluated for intracranial and extracranial tumour response, and overall response, every 6 weeks to week 24 and 12 weekly thereafter until overall disease progression or death. The primary endpoint is neurologic specific survival (NSS) at 12 months. Secondary endpoints include intracranial response rate, intracranial PFS, overall PFS, overall progression free survival, overall survival, neurocognitive function and incidence of radiation necrosis. 109 patients in each cohort (218 total) will achieve 80% power at the significance level (alpha) of 0.10 to detect a minimum absolute increase of 9% in the NSS rate at 12 months. Clinical trial information: NCT03340129.
Publisher: BMJ
Date: 11-2020
Abstract: Colitis is one of the common immune-related adverse events that leads to morbidity and treatment discontinuation of immunotherapy. The clinical presentation, endoscopic and histopathological features and best management of this toxicity are not well defined. Patients with metastatic melanoma who received immunotherapy (programmed cell death protein 1 (PD1) antibodies, alone or in combination with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (PD1 +CTLA-4)) and who developed clinically significant colitis (requiring systemic corticosteroids) were identified retrospectively from two academic centers. Clinical data were collected for all patients endoscopic and histopathological data were examined in a subset. From May 2013 to May 2019, 118/1507 (7.8%) patients developed significant colitis 80/553 (14.5%) after PD1+CTLA-4, 35/1000 (3.5%) PD1 alone, and three patients after Ipilimumab (IPI) alone. Combination therapy-induced colitis was more frequent (14.5% vs 3.5% in PD1 alone, p= .0001), had an earlier onset (6.3 weeks vs 25.7 weeks, p= .001), was more severe (grade 3/4 69% vs 31%, p= .001), and are more likely to require higher doses of steroids (91% vs 74%, p=0.01) than PD1 colitis. Among all patients treated with steroids (N=114), 54 (47%) responded and required no further therapy (steroid sensitive), 47 patients (41%) responded to infliximab (infliximab sensitive), and 13 (11%) were infliximab refractory and needed further immunosuppressive drugs. Infliximab-refractory patients all had onset within 4 weeks of immunotherapy commencement and were more likely to have an underlying autoimmune disease, have higher grade colitis, and require longer immunosuppression, yet had similar response and survival than other patients with colitis. Of 43 (37%) patients re-resumed treatment with PD1 monotherapy after colitis resolution, 16 (37%) of whom developed recurrent colitis. Endoscopic and histopathologic data were available for 64 patients. Most had left-sided colitis, with an increase in chronic inflammatory cells and neutrophils within the lamina propria, an increase in neutrophils in the surface epithelium, without increased lymphocytes or increased eosinophils. Infliximab-refractory colitis had a trend towards more confluent pancolitis with edema, erythema, ulceration, and absent vascularity with neutrophilic infiltration and erosion. Clinically significant colitis varies in presentation, response to immunosuppression, and endoscopic/histologic features depending on the immunotherapy type. Infliximab-refractory colitis occurs early, is often high grade, and has adverse endoscopic and histopathologic features
Publisher: Oxford University Press (OUP)
Date: 24-09-2016
DOI: 10.1111/BJD.14714
Abstract: Superficial basal cell carcinoma (sBCC) can be safely treated topically. Potentially noninvasive imaging techniques, such as optical coherence tomography (OCT), may be useful to diagnose and manage patients with sBCC and obviate the need for biopsy. To evaluate in OCT (i) the sensitivity and specificity for sBCC diagnosis, (ii) the accuracy in determining BCC depth and (iii) the role in management of sBCC mimickers. A prospective, consecutive cohort of lesions for which sBCC was considered in the differential diagnosis. These lesions underwent clinical, dermoscopic and OCT assessment. Diagnosis and its confidence were recorded for each modality and were correlated with the histopathological diagnosis (punch biopsy). Interpretation of the OCT images and assessment of in idual features were performed blinded to the biopsy results. In total, 168 lesions were recruited: 52% were sBCC, 26% were other BCC variants and the remaining lesions were actinic keratosis, squamous cell carcinoma in situ, other benign inflammatory processes and two other malignant tumours. The sensitivity and specificity of OCT for diagnosis of sBCC were 0·87 and 0·80, respectively. There was excellent correlation between OCT and biopsy for tumour depth amongst tumours ≤ 0·4 mm (Pearson correlation r = 0·86, P < 0·001), but the correlation was less as depth increased (Pearson correlation r = 0·71, P < 0·001 for all tumours < 1·0 mm). OCT has good diagnostic accuracy for diagnosing sBCC and measuring depth in tumours ≤ 0·4 mm. Potentially OCT can reduce the need for biopsy in clinically suspected sBCCs. However, careful follow-up is required in such cases as there is a small risk (5%) of misdiagnosis.
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 09-06-2015
DOI: 10.1111/NEP.12488
Abstract: While patients with chronic kidney disease have reduced health-related quality of life (HRQOL), long-term HRQOL of survivors of severe acute kidney injury (AKI) remains unclear. We analysed HRQOL from the Prolonged Outcomes Study of the Randomized Evaluation of Normal versus Augmented Level Replacement Therapy (POST-RENAL) study and compared findings with those from a general Australian adult population enrolled in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. We used a multivariate analysis adjusted for baseline characteristics along with sensitivity analysis using age and sex-matched case controls. In the POST-RENAL study, 282 participants had HRQOL data collected using the SF-12 questionnaire. This was compared with 6330 participants from the AusDiab study. Unadjusted analyses showed that POST-RENAL participants had lower physical component scores (PCS, mean score 40.0 vs 49.8, P<0.0001) and lower mental component scores (MCS, mean score 49.8 vs 53.9, P<0.0001) than the AusDiab group. After age and sex matching, the difference in PCS and MCS remained statistically significant (P<0.0001). Advanced age, reduced renal function and albuminuria (all P ≤ 0.01) were all strongly associated with lower PCS values but not MCS values. After matching subsets of the cohorts on the basis of age, sex and renal function, PCS and MCS were lower in the POST-RENAL group (P<0.0001). Survivors of severe AKI in the POST-RENAL study had lower physical and mental components of HRQOL compared with general population, even after adjustment for their reduced renal function. Increasing age and reduced renal function were associated with poorer physical QOL.
Publisher: BMJ
Date: 09-2016
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627315.V1
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22543309.V1
Abstract: Legends for Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1538-7445.AM2019-975
Abstract: Melanoma patients (pts) with liver mets have a lower response rate (RR), and shorter progression-free (PFS) and overall survival (OS) compared to pts without liver mets when treated with anti-PD-1 (PD1) therapy. The liver microenvironment (ME) induces T-cell tolerance through the interaction of T cells with liver sinusoidal endothelial cells. To explore this further we compared clinicopathological features, circulating cytokines and tumor gene expression (GE) profiles of pts with and without liver mets treated with PD1 combined with ipilimumab (PD1+IPI), and treated with BRAF targeted therapy (TT). Demographics, disease characteristics and outcome data were collected from 140 pts treated with PD1+IPI and from 76 pts treated with BRAF+/-MEKi. Tumor-infiltrating lymphocytes (TILs) immunoreactivity score (TILs density x % of tumor with TILS), % of tumor content, necrosis and fibrosis were assessed by immunohistochemistry in liver and lung s les. Pre-treatment circulating cytokines and tumor GE data (RNA seq) were compared between pts with and without liver mets. In pts treated with IPI+PD1, liver mets had the lowest tumor regression (med -7%) compared to all other sites of disease (med -66%), while in TT-treated pts the response was similar across all sites of disease. Pts with liver mets (n=39) had lower RR (44% v 75%), and shorter median PFS and OS (p& .05) when treated with IPI+PD1 than those without liver mets (n=101). In contrast, in pts treated with TT, RR, PFS and OS were similar between pts with (n=19) vs without (n=57) liver mets. Pts with liver mets had less response in adrenal and LN mets when treated with IPI+PD1 compared to pts without liver mets, but not with TT. In a multivariate analysis performed on the PD1+IPI cohort and validated in the TT group, presence of bone (OR 4.6 p=0.004) and spleen mets (OR 13.5 p=0.01) were associated with the presence of liver mets. Compared to lung mets (n=22), liver mets ME (n=22) had a lower TILs immunoreactivity score (med 30 vs 80, p=0.05), while there was no difference in the % of tumor content, fibrosis or necrosis. The expression of 65 cytokines was measured in plasma of treatment-naive pts pts with liver mets (n=37) had higher levels of Eotaxin 2 (p=0.01), IP-10 (p=0.02) & IL-8 (p=0.03) compared to pts without liver mets (n=99). GE analysis of melanoma s les showed higher expression of MMP-8 and HIF1a in pts with (n=58) vs without (n=28) liver mets, validated in an independent cohort (n=58). Pts with liver mets display distinct clinicopathological features, distinct circulating cytokines and melanoma GE profiles, and are less responsive to PD1+IPI compared to pts without liver mets. The levels of Eotaxin-2, IP-10 and IL-8 are higher in melanoma pts with liver mets compared to pts without liver mets, similar to what is seen in pts with colon cancer liver mets. Liver mets’ ME may hold unique immunosuppressive mechanisms that are amenable to therapeutic targeting. Citation Format: Ines Silva, Annie Tasker, Camelia Quek, Robert Rawson, Su Yin Lim, Kevin Wang, Jordan Conway, Rebecca Velickovic, Tasnia Ahmed, Serigne Lo, Jean Yang, Helen Rizos, James S. Wilmott, Richard A. Scolyer, Alexander M. Menzies, Georgina V. Long. Liver metastases (mets) induce systemic immunosuppression and immunotherapy resistance in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019 2019 Mar 29-Apr 3 Atlanta, GA. Philadelphia (PA): AACR Cancer Res 2019 (13 Suppl):Abstract nr 975.
Publisher: The Endocrine Society
Date: 20-04-2021
Abstract: Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy P & .001), as was female sex (OR 2.02, 95% CI 1.37-2.95 P & .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95 P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33 P & .001) and female sex (OR 3.31, 95% CI 1.67-6.56 P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94 P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84 P = .005). There was no association between hypothyroidism and cancer outcomes. Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Informa UK Limited
Date: 28-01-2014
DOI: 10.1080/15389588.2013.828346
Abstract: Evidence that rider training reduces motorcycle-related injuries or crashes is currently lacking. However, significant community demand for training persists, which in turn can influence policy. The present study aims to contribute to the understanding of this demand via two objectives: to (1) offer a method, namely, contingent valuation, to measure the value motorcyclists place on training and (2) examine determinants of such value. Value was elicited through a willingness to question, using a bidding format, novice motorcyclists who were randomly assigned to groups either offered the training or not. The group that was offered and subsequently received training provided a lower mean perceived value of the training than the group that was not. Perceived value increased with rider age and decreased with training participation and near-crash experiences, controlling for bidding order, income, education, and experience of other training. This study demonstrates the utility of contingent valuation in quantifying the perceived value of training, as well as the modifiability of perceived value, with age, training participation, and near-crash experiences as key determinants. This indicates that research to determine ways to align the perceived value with evidence on training effectiveness is worthwhile in order to facilitate more appropriate and justified allocation of road safety resources. Potential options to explore and evaluate may include community education on evidence of training effectiveness as well as alternative measures with demonstrated effectiveness in reducing crash risks.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PATHOL.2018.09.060
Abstract: Primary melanoma involving the anorectal region is rare, accounting for <1% of all melanomas in most Western countries. It characteristically presents at an advanced clinical stage and is associated with poor clinical outcomes. Preliminary reports suggest that response rates to immunotherapies in patients with advanced stage mucosal melanoma are much lower than in cutaneous (or acral) melanoma patients but reasons for this are unclear. Comprehensive characterisation of the immune microenvironment in anorectal melanoma has not previously been performed. A single-institution cohort of 43 primary anorectal melanoma patients was examined to describe clinicopathological features and characterise the immune microenvironment to provide insights into the behaviour of this rare melanoma subtype. The tumours displayed multiple adverse prognostic attributes including deep thickness (median 11.5 mm), ulceration (81%) and high mitotic rate (median 12/mm
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
Publisher: American Association for Cancer Research (AACR)
Date: 04-0001
DOI: 10.1158/2159-8290.22541635.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2202
DOI: 10.1158/2159-8290.22541641.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2023
DOI: 10.1158/1078-0432.CCR-22-2657
Abstract: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. Patients who responded to combination immune checkpoint inhibitor contained higher CD16+ macrophage densities than those who did not respond (196 vs. 7 cells/mm2 P = 0.0041). There was no diffidence in CD16+ macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm2 P = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16+ macrophages compared with those with low densities (87% vs. 42%, P = 0.0056, n = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, P = 0.4636, n = 50). Melanoma biopsies with high densities of CD16+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11). Our data demonstrate that tumor microenvironments enriched with CD16+ macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. See related commentary by Smithy and Luke, p. 2345
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490761
Abstract: Cohort and dataset overview
Publisher: Oxford University Press (OUP)
Date: 27-11-2020
DOI: 10.1111/BJD.18524
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541623.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Elsevier BV
Date: 12-2021
Publisher: Wiley
Date: 10-01-2018
DOI: 10.1111/PCMR.12682
Abstract: Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4-6 months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan-Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0-8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9 months (95% CI 10.7-19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4 months (95% CI 5.4-7.5), systemic therapy 5.4 months (95% CI 3.1-7.7), systemic therapy and WBRT 5.2 months (95% CI 4.1-6.4), WBRT 4.4 months (95% CI 2.4-6.3), and best supportive care 1.8 months (95% CI 1.2-2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery.
Publisher: American Medical Association (AMA)
Date: 05-2018
Publisher: Oxford University Press (OUP)
Date: 12-2021
DOI: 10.1111/BJD.20600
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541617.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2017
DOI: 10.1200/JCO.2017.35.15_SUPPL.9508
Abstract: 9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19% V600BRAF 44%, 56% and 81% prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]
Publisher: AMPCo
Date: 31-07-2020
DOI: 10.5694/MJA2.50714
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490758
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: Elsevier BV
Date: 10-2018
Abstract: Immune checkpoint inhibitor therapy has resulted in impressive and durable clinical activity for many cancers including melanoma however, there remain few reliable predictors for long-term response. This study investigated whether [18F]2-fluoro-2-deoxy-D-glucose (FDG-PET) imaging may better predict long-term outcomes compared with standard computed tomography (CT) response criteria. Retrospective analysis of metastatic melanoma patients treated with anti-PD-1-based immunotherapy with baseline and 1-year FDG-PET and CT imaging at Melanoma Institute Australia. One-year response was determined using RECIST for CT and EORTC criteria for PET, coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD). Progression-free survival (PFS) was determined from the 1-year landmark. Patients (n = 104) were evaluated with median follow-up 30.1 months and 98% remain alive. Most received anti-PD-1 as monotherapy (67%) or combined with ipilimumab (31%). At 1 year, 28% had CR, 66% had PR and 6% had SD on CT, while 75% had CMR, 16% PMR and 9% SMD/PMD on PET. CMR was observed in 68% of patients with PR on CT. RECIST PFS post 1-year landmark was similar in patients with CR versus PR/SD, but improved in patients with CMR versus non-CMR {median not reached [NR] versus 12.8 month hazard ratio [HR] 0.06 [95% confidence interval (CI) 0.02-0.23] P < 0.01}. In patients with PR on CT, PFS was improved in patients with PR + CMR versus PR + non-CMR (median NR versus 12.8 months HR 0.07 [95% CI 0.02-0.27] P < 0.01). In the 78 CMR patients, 78% had discontinued treatment and 96% had ongoing response. Whilst only a small proportion of patients have a CR at 1 year, most patients with a PR have CMR on PET. Almost all patients with CMR at 1 year have ongoing response to therapy thereafter. PET may have utility in predicting long-term benefit and help guide discontinuation of therapy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
DOI: 10.1161/CIRCOUTCOMES.113.000526
Abstract: Substantial evidence-practice gaps exist in the management of acute coronary syndromes (ACS) in China. Clinical pathways are tools for improving ACS quality of care but have not been rigorously evaluated. Between October 2007 and August 2010, a quality improvement program was conducted in 75 hospitals throughout China with mixed methods evaluation in a cluster randomized, controlled trial. Eligible hospitals were level 2 or level 3 centers routinely admitting patients with ACS per year. Hospitals were assigned immediate implementation of the American Heart Association/American College of Cardiology guideline based clinical pathways or commencement of the intervention 12 months later. Outcomes were several key performance indicators reflecting the management of ACS. The key performance indicators were measured 12 months after commencement in intervention hospitals and compared with baseline data in control hospitals, using data collected from 50 consecutive patients in each hospital. Pathway implementation was associated with an increased proportion of patients discharged on appropriate medical therapy, with nonsignificant improvements or absence of effects on other key performance indicators. Among hospitals in China, the use of a clinical pathway for the treatment of ACS compared with usual care improved secondary prevention treatments, but effectiveness was otherwise limited. An accompanying process evaluation identified several health system barriers to more successful implementation. URL: www.anzctr.org.au/default.aspx . Unique identifier: ACTRN12609000491268.
Publisher: S. Karger AG
Date: 20-10-2016
DOI: 10.1159/000439581
Abstract: b i Aims: /i /b The study aims to describe the use of dialysis catheters in critically ill patients treated with continuous renal replacement therapy (CRRT) and to study the impact of femoral versus non-femoral access on CRRT dose. b i Methods: /i /b Statistical analysis and predictive modelling of data from the Randomized Evaluation of Normal vs. Augmented Level renal replacement therapy trial. b i Results: /i /b The femoral vein was the first access site in 937 (67%) of 1,399 patients. These patients had higher Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores (p = 0.009) and lower pH (p 0.001) but similar mortality to patients with non-femoral access (44 vs. 45% p = 0.63). Lower body weight was independently associated with femoral access placement (OR 0.97, 95% CI 0.96-0.98). Femoral access was associated with a 1.03% lower CRRT dose (p = 0.05), but a 4.20% higher dose was achieved with 13.5 Fr catheters (p = 0.03). b i Conclusions: /i /b Femoral access was preferred in lighter and sicker patients. Catheter gauge had greater impact than catheter site in CRRT dose delivery. Video Journal Club “Cappuccino with Claudio Ronco” at www.karger.com/?doi=439581.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2017
DOI: 10.1245/S10434-016-5723-0
Abstract: Inconsistent data suggests extranodal spread (ENS) is an adverse prognostic factor in Stage III melanoma patients but it remains contentious. By rigorously matching cohorts, this study sought to clarify associations with recurrence and survival. Melanoma patients with lymph node metastases (AJCC Stage III), with or without ENS, sub-classified on the basis of known (MKP) or unknown primary (MUP), were identified from a single institution prospective database. Of 725 ENS patients identified, 567 were able to be precisely matched 1:1 with a non-ENS cohort. Clinicopathologic factors were analyzed for associations with outcome. There were 481 MKP and 86 MUP patients in each cohort. ENS, compared to non-ENS, was an independent predictor of worse melanoma specific survival (MSS) (HR = 1.71, 95% CI = 1.39-2.11, P < 0.0001) with median MSS 56.4 versus 175.2 months, P < 0.001 worse disease free survival (DFS) (HR = 1.16, 95%CI = 1.00-1.34, P = 0.044) with median DFS 15.6 versus 21.5 months, P = 0.009 and worse post-recurrence survival (PRS) (HR = 1.66, 95%CI = 1.37-2.02, P < 0.0001) with median PRS 20.1 versus 51.1 months, P < 0.001. ENS was also associated with reduced time to distant recurrence (Distant Disease Free Survival [DDFS]) (HR = 2.00, 95% CI = 1.24-3.24, P = 0.0047), however median time to distant recurrence not reached within the study time period. ENS represents a significant independent predictor of worse MSS, DFS, PRS and DDFS in Stage III melanoma patients. ENS should be considered in the stratification of patients in adjuvant therapy trials.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.2019.37.15_SUPPL.9500
Abstract: 9500 Background: The role of adjuvant WBRT in MBMs is controversial. This trial compares WBRT with Obs after local treatment of 1-3 MBMs. Methods: The primary endpoint is distant intracranial failure (DIF) within 12 months of randomization. The a priori neurocognitive function (NCF) endpoint is Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months. Secondary endpoints include local failure (LF), overall survival (OS) and global quality of life (QoL). Analyses were conducted on intention-to-treat basis with nominal two-sided significance level 5%. Drug therapy was allowed. Effective drugs became available during trial and their impact was analysed. Results: Of 586 eligible patients (pts), 215 consented from 31 sites in 3 countries (Australia, UK and Norway) between 2009 and 2017. Eight (0.04%) who withdrew or had no data collected were excluded. 107 randomized to Obs and 100 to WBRT. Mean age 62 years, 67% males, 61% with single MBM of mean size 2cm, 67% had extracranial disease at randomization. The two arms were well matched. NCF was completed by English speakers 50 WBRT and 70 Obs at baseline, declining to 26 and 35 respectively at 4 months. Within 12 months, 54 (50.5%) Obs had DIF compared with 42 (42.0%) WBRT pts (OR 0.71 95%CI 0.41-1.23 p = 0.222). There was no difference in LF (p = 0.100) or OS (log-rank p = 0.861). 53% (Obs) and 59% (WBRT) pts were alive at 12 months. There was no significant between-group difference in mean intervention effect on global QoL (p = 0.083). Pts who received T-cell checkpoint inhibitors and/or mitogen-activated protein kinase (MAPK) pathway inhibitors and WBRT before or within 12 months of randomization had DIF rate 29% compared with Obs and no systemic therapy had 44%, but was not significant (p = 0.228). Obs had greater relative improvement from baseline in HVLT-R at every timepoint. At 4 months, Obs had 20.9% improvement from baseline in HVLT-R-delayed recall compared to 2.7% decline in WBRT overall adjusted average intervention effect 23.6% (95%CI 9.0, 38.2 p = 0.0018). There was no difference in time to cognitive failure or in proportions with global cognitive impairment. Conclusion: This level one evidence shows WBRT does not improve outcomes in MBMs. This practice-changing trial justifies the recent move away from WBRT that occurred during the course of the trial. Clinical trial information: NCT01503827.
Publisher: Oxford University Press (OUP)
Date: 10-08-2023
DOI: 10.1093/BJD/LJAD275
Abstract: People with a previous melanoma are at increased risk of developing another primary melanoma when compared with the general population. Understanding risk factors associated with multiple primary melanomas can inform patient education and tailored surveillance. We conducted a systematic review and meta-analysis to examine risk factors for subsequent primary melanoma. A systematic literature search was conducted on CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and MEDLINE. Studies reporting a risk estimate or raw frequencies and conducted between 1982 and August 2022 were included. Adjusted risk estimates were prioritised over univariable risk estimates. PRISMA reporting guidelines were followed. Random effects meta-analysis was conducted to derive pooled estimates. Quality assessment was conducted by two researchers using the Newcastle-Ottawa scale. GRADE was used to rate certainty and quality of evidence. Data from 27 studies involving 388,424 participants were pooled and analysed. Risk factors assessed included age and gender, environmental, lifestyle, phenotypic, genetic, and histopathological factors, and there was wide variation in how they were categorised and analysed. Independent risk factors identified from pooled analyses included male gender (HR 1.46, 95% confidence interval (CI) 1.40-1.53), increasing age per 10-years (HR 1.19, 95% CI 1.14-1.24), light skin colour (HR 1.44, 95% CI 1.23-1.70), family history (OR 1.79, 95% CI 1.25-2.56), CDKN2A mutation (OR 5.29, 95% CI 2.70-10.37), high or moderate nevus count (OR 2.63, 95% CI 1.61-4.30) and (OR 1.64, 95% CI 1.07-2.51) respectively, one or more atypical nevi (OR 3.01, 95% CI 1.52-5.97), first lesions occurring on the head/neck, lentigo maligna subtype (HR 1.16, 95% CI 1.15-1.17), other subtype (HR 1.14, 95% CI 1.03-1.27), and inadequate sun protection (HR 1.85, 95% CI 0.98-3.50). Based on GRADE criteria, there was high to very low confidence in the pooled effect estimates. This meta-analysis identified several consistent, independent risk factors for the development of subsequent primary melanoma. These findings can assist in stratifying risk of subsequent melanoma, tailoring skin check schedules and informing patient education. PROSPERO registration number - CRD42020191255.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490755
Abstract: Representativeness of study participants
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.2019.37.15_SUPPL.9503
Abstract: 9503 Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16) 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p 0.001), including in those with IT (100% vs 72%, p 0.001) and TT (88% vs 43%, p 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490752
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.2019.37.15_SUPPL.9502
Abstract: 9502 Background: Adjuvant anti-PD1 monoclonal antibodies (mAbs) prolong recurrence-free survival in high-risk resected melanoma, however patients (pts) recur during or after therapy. The patterns of recurrence and optimal management are unclear. Methods: Pts from 15 melanoma centres who recurred having received adjuvant anti-PD1 mAbs (adj-PD1) for resected stage III/IV cutaneous melanoma were included. Disease characteristics, adjuvant treatment, recurrence characteristics, subsequent management and outcomes were examined. Results: 137 pts had melanoma recurrence 97 (71%) during adj-PD1 and 40 (29%) following treatment cessation (25 had stopped early for toxicity after a median 3 months, 14 after completing 12 months, 1 who withdrew consent after 1 month). Median time to recurrence from start of anti-PD1 was 4.6 months (IQR 2.7-8.5), and median follow up from recurrence was 7.7 months (IQR 3.8-12.3). At 1st recurrence, 78 (57%) pts had distant disease (including 22 with both locoregional and distant), 59 (43%) had locoregional disease only. Of those who recurred locally, 22/59 (37%) later developed distant disease. 26 (19%) pts have died. 81 (59%) pts had systemic therapy for distant recurrence (either 1 st recurrence or subsequent). Of those who recurred during adj-PD1, no pts (0/20) subsequently responded to anti-PD1 alone (N = 8) or with any investigational agent (N = 12 anti-LAG3, IDOi, MEKi, TLR9 agonist) 9/27 evaluable pts (33%) responded to ipilimumab-based therapy (alone or in combination with anti-PD1), and 15/19 (79%) responded to BRAF/MEKi . Of those who recurred after ceasing adj-PD1, 2/5 (40%) responded to anti-PD1 monotherapy, 2/5 (40%) responded to ipilimumab-based therapy, 7/8 (88%) responded to BRAF/MEKi. Conclusions: These data suggest minimal activity of further anti-PD1 monotherapy in those who recur while on adj-PD1, but possible activity in those who recur off treatment. Anti-CTLA4 and BRAF/MEKi therapy appear active in those who recur on or following adj-PD1. Data on locoregional recurrence and its management will also be presented.
Publisher: Wiley
Date: 24-06-2023
DOI: 10.1111/AJD.14113
Publisher: Springer Science and Business Media LLC
Date: 18-05-2017
DOI: 10.1038/BJC.2017.142
Publisher: Oxford University Press (OUP)
Date: 27-12-2022
DOI: 10.1111/BJD.20939
Publisher: Oxford University Press (OUP)
Date: 09-2019
DOI: 10.1111/BJD.17889
Publisher: American Medical Association (AMA)
Date: 07-2013
DOI: 10.1001/JAMAPEDIATRICS.2013.1429
Abstract: Short sleep duration is common in adolescents and young adults, and short sleep duration is a risk factor for motor vehicle crash. To assess the association between hours of sleep and the risk for motor vehicle crash, including the time of day of crash and types of crash (single, multiple vehicle, run off road, and intersection). Prospective cohort study. New South Wales, Australia. Questionnaire responses were obtained from 20,822 newly licensed drivers aged 17 to 24 years. Participants held a first-stage provisional license between June 2003 and December 2004 prospectively linked to licensing and police-reported crash data, with an average of 2 years of follow-up. Analyses were conducted on a subs le of 19,327 participants for which there was full information. Sleeping 6 or fewer hours per night. The main outcome variable was police-reported crash. Multivariable Poisson regression models were used to investigate the role of sleep duration on the risk for crash. On average, those who reported sleeping 6 or fewer hours per night had an increased risk for crash compared with those who reported sleeping more than 6 hours (relative risk [RR], 1.21 95% CI, 1.04-1.41). Less weekend sleep was significantly associated with an increased risk for run-off-road crashes (RR, 1.55 95% CI, 1.21-2.00). Crashes for in iduals who had less sleep per night (on average and on weekends) were significantly more likely to occur between 8 pm and 6 am (RR, 1.86 95% CI, 1.11-3.13, for midnight to 5:59 am and RR, 1.66 95% CI, 1.15-2.39, for 8:00 pm to 11:59 pm). Less sleep per night significantly increased the risk for crash for young drivers. Less sleep on weekend nights increased the risk for run-off-road crashes and crashes occurring in the late-night hours. This provides rationale for governments and health care providers to address sleep-related crashes among young drivers.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2022
DOI: 10.1200/JCO.21.02488
Abstract: Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy. Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b T2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed. Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44] P .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk ( 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits 1 mm in maximum dimension. Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.
Publisher: Elsevier BV
Date: 10-2016
Publisher: BMJ
Date: 09-2016
Publisher: The Sax Institute
Date: 2017
Abstract: Objective and importance of study: To describe characteristics and temporal trends of fall-related ambulance service use and hospital admission in older adults in New South Wales (NSW), Australia. Such information will facilitate a more targeted approach to planning and delivery of health services to prevent falls and their adverse sequelae in different groups of older adults. Retrospective population-based descriptive study. Fall-related ambulance use and hospital admissions for all falls and injurious falls in NSW residents aged ≥65 years between 2006 and 2013 were obtained from two discrete sources of routinely collected data. Rates of use are presented descriptively. There were 314 041 occasions of fall-related ambulance use by older adults and 331 311 fall-related hospitalisations, of which 69% (n = 227 753) were for injurious falls. Fractures accounted for 57% of injurious hospitalisations. Slips and trips were the most common mechanism of falls requiring hospitalisation (52%). Residents of aged care facilities had a greater proportion of fall injury hospitalisations compared with people living in the community (85% and 65%, respectively). Rates of fall-related ambulance use and hospitalisation were similar and continued to increase over time. Increased effort is needed to prevent falls and associated injury among older people in NSW, particularly among people living in aged care facilities. Ongoing monitoring of rates and the characteristics of people who fall are needed to determine the long-term impact of fall prevention interventions.
Publisher: Public Library of Science (PLoS)
Date: 09-02-2016
Publisher: Elsevier BV
Date: 05-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: Oxford University Press (OUP)
Date: 11-10-2017
DOI: 10.1111/BJD.15595
Abstract: Electrical impedance spectroscopy (EIS) is a noninvasive diagnostic technique that measures tissue impedance. To evaluate the effect of adding an EIS measurement at baseline to suspicious melanocytic lesions undergoing routine short-term sequential digital dermoscopy imaging (SDDI). Patients presented with suspicious melanocytic lesions that were eligible for short-term SDDI (with no clear feature of melanoma on dermoscopy). EIS measurement was performed at the first visit following dermoscopic photography. Normally, an EIS score of ≥ 4 is considered positive however, this protocol investigated a higher cut-off in combination with SDDI. When the EIS score was ≥ 7 the lesion was excised immediately owing to the high risk of melanoma. Lesions with a score < 7 were monitored with standard SDDI over a 3-month period. From a total of 160 lesions analysed, 128 of 154 benign lesions received an EIS score of 0-6, giving a specificity of the EIS method for the diagnosis of melanoma of 83·1% [95% confidence interval (CI) 76·3-88·7]. Five of the six melanomas found in this study had an EIS score ≥ 7, with a sensitivity for melanoma diagnosis of 83·3% (95% CI 35·9-99·6). When EIS 0-6 lesions were subsequently followed up with SDDI, one additional melanoma was detected (EIS = 6) giving a sensitivity for the diagnosis of melanoma overall of 100% (95% CI 54·1-100 six of six malignant melanomas excised) and a specificity of 69·5% (95% CI 61·5-76·6 107 of 154 benign lesions not excised). If utilizing a protocol where an EIS score ≤ 3 requires no SDDI and ≥ 7 requires immediate excision, it reduced the need for SDDI by 46·9% (n = 75/160 95% CI 39·0-54·9).
Publisher: Elsevier BV
Date: 06-2021
Publisher: Elsevier BV
Date: 2019
Publisher: SAGE Publications
Date: 2015
DOI: 10.3141/2516-06
Abstract: Driving confidence is thought to influence driving exposure among older drivers and may affect driver safety. Studies to date have relied primarily on self-reported measures of driving exposure to explore this relationship. The objective of this study was to explore the relationship between confidence and actual driving exposure among drivers aged 75 years and older. A cross-sectional analysis of survey data (function, confidence, personal circumstances) and naturalistic measures of driving exposure was conducted with 380 older drivers in northwest Sydney, Australia. Driving exposure, including total distance traveled, radius of travel from home, average trip distance, and nighttime driving, was measured for 1 week. The mean age of participants was 80 years. More males (n = 230) than females (n = 150) were enrolled. Successful instrumentation was achieved for 362 of 380 vehicles. Driving confidence was found to be independently associated with the farthest distance traveled from home, average trip distance, and night driving. Older drivers with lower confidence took shorter trips, stayed closer to home, and were less likely to drive at night. This study provided evidence of a responsive process in which drivers with lower confidence and poorer function were found to have different patterns of driving—specifically, driving in familiar areas, during daylight hours, and closer to home. It is likely that drivers in later life change their driving patterns to preserve safety and mobility. This understanding will help policy makers and educators shape responsive programs that help older drivers drive safely for as long as possible.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: BMJ
Date: 06-2022
Abstract: Adjuvant immune checkpoint inhibitor (ICI) immunotherapies have significantly reduced the recurrence rate in high-risk patients with stage III melanoma compared with surgery alone. However, 48% of anti-PD-1-treated patients will develop recurrent disease within 4 years. There is a need to identify biomarkers of recurrence after adjuvant ICI to enable identification of patients in need of alternative treatment strategies. As cytotoxic T cells are critical for the antitumor response to anti-PD-1, we sought to determine whether specific subsets were predictive of recurrence in anti-PD-1-treated high-risk patients with stage III melanoma. Associations with recurrence in patients with stage III melanoma were sought by analyzing resection specimens (n=103) taken prior to adjuvant nivolumab embrolizumab±low-dose/low-interval ipilimumab. Multiplex immunohistochemistry was used to quantify intratumoral CD8+ T-cell populations using phenotypical markers CD39, CD103, and PD-1. With a median follow-up of 19.3 months, 37/103 (36%) of patients had a recurrence. Two CD8+ T-cell subpopulations were significantly associated with recurrence. First, CD39+ tumor-resident memory cells (CD39+CD103+PD-1+CD8+ (CD39+ Trm)) comprised a significantly higher proportion of CD8+ T cells in recurrence-free patients (p=0.0004). Conversely, bystander T cells (CD39−CD103−PD-1−CD8+) comprised a significantly greater proportion of T cells in patients who developed recurrence (p=0.0002). Spatial analysis identified that CD39+ Trms localized significantly closer to melanoma cells than bystander T cells. Multivariable analysis confirmed significantly improved recurrence-free survival (RFS) in patients with a high proportion of intratumoral CD39+ Trms (1-year RFS high 78.1% vs low 49.9%, HR 0.32, 95% CI 0.15 to 0.69), no complete lymph node dissection performed, and less advanced disease stage (HR 2.85, 95% CI 1.13 to 7.19, and HR 1.29, 95% CI 0.59 to 2.82). The final Cox regression model identified patients who developed recurrence with an area under the curve of 75.9% in the discovery cohort and 69.5% in a separate validation cohort (n=33) to predict recurrence status at 1 year. Adjuvant immunotherapy-treated patients with a high proportion of CD39+ Trms in their baseline melanoma resection have a significantly reduced risk of melanoma recurrence. This population of T cells may not only represent a biomarker of RFS following anti-PD-1 therapy, but may also be an avenue for therapeutic manipulation and enhancing outcomes for immunotherapy-treated patients with cancer.
Publisher: Oxford University Press (OUP)
Date: 22-11-2022
DOI: 10.1111/BJD.20828
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541617
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Elsevier BV
Date: 03-2017
Publisher: Oxford University Press (OUP)
Date: 03-07-2018
Abstract: The Driving Change programme was developed to facilitate access to licensing in Aboriginal communities in Australia. This process evaluation aimed to explore whether Driving Change was implemented as intended and was addressing the needs of the communities. A mixed methods approach was used, with triangulation of client data (n = 984), semi-structured interviews (n = 18) and client discussion groups (n = 21). Descriptive and regression analyses of quantitative and thematic analysis of qualitative data were drawn together to develop an integrated understanding of implementation barriers and facilitators. The programme reached 984 clients, with the majority from the target age group 16-24 years (56-89%). In multivariate analysis, clients who had supervised driving practice were 2.4 times more likely to attain a licence (95% CI: 1.9-3.1) and clients who received a high level of case management were 1.8 times more likely to progress to attain a licence than those who received low levels of case management (95% CI: 1.3-2.6). Implementation was facilitated by community partnerships and this was attributed to local delivery, Aboriginal leadership, connections with community networks and community ownership of solutions. Driving Change is engaging communities and reaching clients with a high level of need for licensing support. The programme is working with communities, benefiting from the input of cultural values and sharing ownership of local solutions. Community partnerships were critical to successfully supporting clients to overcome challenging barriers to participation. The learnings from this programme are relevant to complex community programme implementation and evaluation, particularly with erse or hard to reach populations.
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1186/CC13767
Publisher: Wiley
Date: 13-12-2014
DOI: 10.1002/SIM.6060
Abstract: Transform methods have proved effective for networks describing a progression of events. In semi-Markov networks, we calculated the transform of time to a terminating event from corresponding transforms of intermediate steps. Saddlepoint inversion then provided survival and hazard functions, which integrated, and fully utilised, the network data. However, the presence of censored data introduces significant difficulties for these methods. Many participants in controlled trials commonly remain event-free at study completion, a consequence of the limited period of follow-up specified in the trial design. Transforms are not estimable using nonparametric methods in states with survival truncated by end-of-study censoring. We propose the use of parametric models specifying residual survival to next event. As a simple approach to extrapolation with competing alternative states, we imposed a proportional incidence (constant relative hazard) assumption beyond the range of study data. No proportional hazards assumptions are necessary for inferences concerning time to endpoint indeed, estimation of survival and hazard functions can proceed in a single study arm. We demonstrate feasibility and efficiency of transform inversion in a large randomised controlled trial of cholesterol-lowering therapy, the Long-Term Intervention with Pravastatin in Ischaemic Disease study. Transform inversion integrates information available in components of multistate models: estimates of transition probabilities and empirical survival distributions. As a by-product, it provides some ability to forecast survival and hazard functions forward, beyond the time horizon of available follow-up. Functionals of survival and hazard functions provide inference, which proves sharper than that of log-rank and related methods for survival comparisons ignoring intermediate events.
Publisher: Wiley
Date: 2022
DOI: 10.1111/ANAE.15613
Abstract: Peri‐operative neurocognitive disorders are the most common complication experienced by older in iduals undergoing anaesthesia and surgery. Peri‐operative neurocognitive disorders, particularly postoperative delirium, result in long‐term poor outcomes including: death dementia loss of independence and poor cognitive and functional outcomes. Recent changes to the nomenclature of these disorders aims to align peri‐operative neurocognitive disorders with cognitive disorders in the community, with consistent definitions and clinical diagnosis. Possible mechanisms include: undiagnosed neurodegenerative disease inflammation and resulting neuroinflammation neuronal damage and comorbid systemic disease. Pre‐operative frailty represents a significant risk for poor postoperative outcomes it is associated with an increase in the incidence of cognitive decline at 3 and 12 months postoperatively. In addition to cognitive decline, frailty is associated with poor functional outcomes following elective non‐cardiac surgery. It was recently shown that 29% of frail patients died or experienced institutionalisation or new disability within 90 days of major elective surgery. Identification of vulnerable patients before undergoing surgery and anaesthesia is the key to preventing peri‐operative neurocognitive disorders. Current approaches include: pre‐operative delirium and cognitive screening blood biomarker analysis intra‐operative management that may reduce the incidence of postoperative delirium such as lighter anaesthesia using processed electroencephalography devices and introduction of guidelines which may reduce or prevent delirium and postoperative neurocognitive disorders. This review will address these issues and advocate for an approach to care for older peri‐operative patients which starts in the community and continues throughout the pre‐operative, intra‐operative, postoperative and post‐discharge phases of care management, involving multidisciplinary medical teams, as well as family and caregivers wherever possible.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
Publisher: Springer Science and Business Media LLC
Date: 18-07-2019
DOI: 10.1038/S41467-019-11107-X
Abstract: Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2 . Significantly mutated genes are NRAS , BRAF , NF1 , KIT , SF3B1 , TP53 , SPRED1 , ATRX , HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
Publisher: Wiley
Date: 21-02-2022
DOI: 10.1111/AJD.13807
Abstract: Immune checkpoint inhibitors have improved survival in advanced stage melanoma patients. Rates of new primary melanomas (NPM) in patients with prior melanoma have been reported to be as high as 12%. Little is currently known regarding the frequency or characteristics of NPMs occurring in melanoma patients treated with immune checkpoint inhibitors. To determine the frequency and describe clinicopathologic characteristics of NPMs diagnosed in patients during or after treatment with immune checkpoint inhibitors for metastatic melanoma. A retrospective analysis of prospectively collected data from the Melanoma Institute Australia and Westmead Hospital Dermatology databases. Clinicopathological data for the initial primary melanoma (IPM) and NPM were compared. Between 2013–2017, 14 NPMs in 13 patients (out of a total of 1047) treated with checkpoint inhibitors were identified. NPMs were significantly thinner than the IPM (median Breslow thickness 0.35 mm vs 2.0 mm, P = 0.0003), less likely to be ulcerated (0/14 vs 6/13, P = 0.004) and less likely to have nodal metastases (0/14 vs 6/13, P = 0.004). NPMs were significantly more likely to be detected in the in‐situ stage (6/14 vs 0/13, P = 0.0016). NPMs are infrequent in patients treated with checkpoint inhibitors. When they occur, they are usually detected at an early stage and have features associated with a favourable prognosis, most likely reflecting close surveillance. Further study is required to determine long‐term risk in patients achieving a durable response to immune checkpoint inhibitors, and to determine whether the immunotherapy itself influences both their development and biology.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.INJURY.2013.11.005
Abstract: Quality improvement programmes are an important part of care delivery in trauma centres. The objective was to describe the effect of a comprehensive quality improvement programme on long term patient outcome trends at a low volume major trauma centre in Australia. All patients aged 15 years and over with major trauma (Injury Severity Score>15) admitted to a single inner city major trauma centre between 1992 and 2012 were studied. The outcomes of interest were in-hospital mortality and transfer to rehabilitation. Time series analysis using integer valued autoregressive Poisson models was used to determine the reduction in adjusted monthly count data associated with the intervention period (2007-2012). Risk adjusted odds ratios for mortality over three yearly intervals was also obtained using multivariable logistic regression. Crude and risk adjusted mortality was compared before and after the implementation period. 3856 patients were analysed. Crude in-hospital mortality fell from 16% to 10% after implementation (p<0.001). The intervention period was associated with a 25% decrease in monthly mortality counts. Risk adjusted mortality remained stable from 1992 to 2006 and did not fall until the intervention period. Crude and risk adjusted transfer to in-patient rehabilitation after major trauma also declined during the intervention period. In this low volume major trauma centre, the implementation of a comprehensive quality improvement programme was associated with a reduction in crude and risk adjusted mortality and risk adjusted discharge to rehabilitation in severely injured patients.
Publisher: BMJ
Date: 09-2022
Abstract: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases. We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma. Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p .05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p .0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p .0001) and liver metastases (p=0.0392). Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes.
Publisher: Elsevier BV
Date: 05-2017
Abstract: Programmed death 1 (PD1) inhibitors are now a foundation of medical management of metastatic melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information. We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab. ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [hazard ratio (HR) 0.09 P < 0.001 for group A versus C, and 0.16 P < 0.001 for group B versus C]. The median OS was not reached for groups A and B and was 9.2 months for group C (HR 0.02 P < 0.001 for group A versus C and 0.14 P < 0.001 for group B versus C). The poor outcome measures associated with group C remained significant in multivariate analysis adjusted for LDH, performance status, tumour stage and disease volume. The predictive value for ctDNA for response was confirmed in a separate validation cohort (n = 29, P < 0.01). Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541629.V1
Abstract: Supplementary Data from Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.EJCA.2021.12.036
Abstract: This study sought to assess whether the interval between diagnostic excision-biopsy of a primary melanoma and definitive wide excision with sentinel node biopsy (SNB) influenced the size of SN metastatic deposits, which might have implications for management and prognosis. Data were collected for (i) a Dutch population-based cohort of patients treated between 2004 and 2014 who underwent SNB within 100 days of complete excision of their primary melanoma and who were SN-positive with known SN metastasis diameter (n = 1027) and (ii) a cohort from a large Australian melanoma treatment centre (n = 541) who presented in the same time period. The effects of SNB timing on the size of SN metastatic deposits were analysed. Dutch patients whose SNB was performed in the second or third months after diagnosis had significantly larger SN metastasis diameters than patients who had their SNB in the first month (median increases of 17% (95%CI -14, 60%, p = 0.211) and 71% (95%CI 15, 119%, p = 0.004), respectively). No significant difference in tumour diameter for early and late SNB was found in the Australian cohort. SN metastasis diameter became progressively greater with SN biopsy in the second and third months after primary melanoma diagnosis in the larger, population-based patient cohort. An increase in metastasis diameter was not observed in the smaller, institutional cohort, possibly due to detection of larger SN metastases by routine pre-operative ultrasound, with fine-needle biopsy confirmation. These patients did not proceed to SNB and were therefore not included in the study.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2018
DOI: 10.1245/S10434-018-6470-1
Abstract: There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma 1 mm in BT. This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma 1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients’ QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation. Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6% p 0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6% p = 0.036). After 12 months’ follow-up, no differences were noted in QoL between groups. This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.EJCA.2021.12.035
Abstract: The optimal time interval between diagnostic excision of a primary cutaneous melanoma and sentinel node (SN) biopsy is unknown. The current study sought to determine whether this interval influenced the SN-positivity rate, recurrence or survival. Data collected from 2004 to 2014 for a Dutch population-based cohort of patients with melanoma who underwent SN biopsy (SNB) within 100 days of initial diagnosis (n = 7660) and for a similarly specified cohort from a large Australian melanoma treatment centre (n = 3478) were analysed. Time to SNB was analysed continuously (in weeks) and categorically (per month). The effects of SNB timing on SN-positivity were assessed using multivariable logistic regression, and its effects on recurrence-free survival (RFS) and overall survival (OS) were assessed using Cox proportional hazard regression analyses. Advanced modelling using a multivariable Cox model with penalised splines for modelling the continuous effects of time to SNB on RFS and OS was also performed. In neither the Dutch nor the Australian cohort was there a significant association between time to SNB and SN-positivity in either cohort, nor was there an impact of time to SNB on RFS or OS in either cohort. The spline-based HR curves for RFS and OS confirmed these findings. The time interval between diagnostic excision of a primary melanoma and SNB did not influence the SN-positivity rate or survival outcomes. This provides reassurance that neither early nor delayed definitive wide excision and SNB will adversely affect prognosis.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2019
DOI: 10.1007/S11764-019-00770-0
Abstract: Immune checkpoint inhibitors (ICI) and BRAF and MEK inhibitors (BMi) have improved survival in metastatic melanoma (MM). However, the experience of long-term responders remains undescribed. This study characterised survivorship issues faced by long-term responders to ICI or BMi. Patients with MM, aged ≥ 18 years old, ≥ 6 months post-ICI or BMi initiation with an objective response or stable disease. A 72-question survey assessed physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports. One hundred and five of 120 (88%) patients completed the survey (ICI 69/BMI 36). For the ICI cohort, 39 (57%) were receiving ongoing treatment, 17 ceased due to toxicity and 13 due to a sustained response. For the BMi cohort, 31 (85%) were receiving ongoing treatment, 4 ceased due to toxicity and 1 due to a sustained complete response. At data cut-off on 18 December 2018, median PFS (range) was 2.5 years (1.3-8.5) for ICI and 3.1 years (0.6-7.3) for BMi. Long-term toxicities included dry/itchy skin (ICI 51, 74%/ BMi 25, 69%), arthralgias (ICI 30, 58%/ BMi 23, 64%) and fatigue (ICI 62, 90%/ BMi 33, 92%). Psychological morbidity was common, including anxiety awaiting results (ICI 50, 72%/ BMi 29, 81%), fear of melanoma recurring or progressing (ICI 56, 81%/ BMi 31, 86%) or death (ICI 44, 64%/ BMi 26, 72%). MM survivors experience chronic treatment toxicities and frequently report psychological concerns. Survivors may benefit from discussions regarding long-term toxicities and tailored psychological supports.
Publisher: American Medical Association (AMA)
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 29-09-2020
DOI: 10.1007/S10689-020-00209-X
Abstract: Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of in iduals diagnosed with melanoma under 40 years of age, number of in iduals diagnosed with more than one primary melanoma, and number of in iduals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of in iduals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .
Location: Senegal
Start Date: 06-2022
End Date: 05-2025
Amount: $405,000.00
Funder: Australian Research Council
View Funded Activity