ORCID Profile
0000-0003-4607-3937
Current Organisations
University of South Australia
,
University of Adelaide
,
Adelaide Oncology and Haematology
,
Lyell McEwin Hospital
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Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2012
DOI: 10.1200/JCO.2012.30.15_SUPPL.E19513
Abstract: e19513 Background: Available data suggest that the OX-induced neuropathy is usually reversible and a minority of pts will have persistent severe (grade 3) side effects (24.1% any grade and 0.7% grade 3 at 18 months follow up from MOSAIC trial). We have explored the frequency of persistent peripheral neuropathy in pts who received OX for colorectal cancer at 2 local centres in South Australia. Methods: Pts who completed treatment with OX for colorectal cancer at least 20 months prior to entering the study were eligible and were sent consent and questionnaire. Neuropathy questions were adapted from the FACT/GOG-Ntx (V.4) questionnaire. No pts received Calcium and Magnesium with OX. Statistical tests used to analyze the data were t-test and chi- square. Results: Of the 56 eligible pts, 27 consented to enrol in the study. Median age was 66 yrs. 19 were stage 3, 8 stage 4. Mean total OX dose was 712.1 mg/m2 (range: 170 - 1200 mg/m2) mean number of OX cycles was 8.2 (range 2 - 13), median time between last dose of OX and completing the questionnaire was 37 months (range 20 - 93). 7 pts (25.9%) had a history of diabetes mellitus and 7 had significant alcohol intake. No pts had neuropathic symptoms prior to treatment with OX. 25 pts (92.7%) experienced neuropathic symptoms during their treatment, 11 had grade 2, and 2 had grade 3 symptoms (limiting self care activities of daily living). At the time of completing the questionnaire, 17 pts (63%) were still symptomatic with 9 pts (33.3%) having grade 2 and 3 pts (11.1%) having grade 3 neuropathic symptoms. In the cohort of pts with persistent grade 2 symptoms, 3 pts had walking difficulty and 2 pts could not drive safely due to side effects. Persistent grade 2/3 symptoms were more common in pts who received total OX doses of 722 mg/m2 or more (p 0.05). Conclusions: Our observation indicates that a majority of pts will have persistent neuropathy more than 20 months after completing treatment with OX and a significant proportion will still have grade 2/3 symptoms. Higher total OX dose might be one of the risk factors in this group. These results should be further prospectively evaluated in a larger population as these long term side effects may affect pts’ daily activities and safety.
Publisher: Elsevier BV
Date: 10-2013
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2020
DOI: 10.1158/1538-7445.SABCS19-P3-09-04
Abstract: BACKGROUND: Anti-PD-1 checkpoint inhibitor (CPI) monotherapy has demonstrated modest activity in pre-treated mTNBC, with single digit objective response rates (ORR) observed. Our prior data suggests that local electroporation after intratumoral administration of tavokinogene telseplasmid (IT-tavo-EP), a plasmid encoding the proinflammatory cytokine IL-12, can render CPI non-responsive pre-treated mTNBC sensitive to CPI therapy. The phase II KEYNOTE-890/OMS-I141 study was therefore designed to evaluate IT-tavo-EP and IV pembrolizumab in patients with mTNBC previously treated with chemotherapy +/- CPI therapy. METHODS: Patients with histologically confirmed inoperable locally advanced or metastatic TNBC with at least 1 line of prior systemic therapy for advanced disease, including prior CPI therapy, were eligible. Patients were required to have RECIST v1.1 measurable disease with at least 1 anatomically distinct cutaneous or subcutaneous lesion accessible for intratumoral injection and electroporation. Scans were obtained every 12 weeks. Patients received pembrolizumab 200 mg IV on day 1 of each 3-week cycle and IT-tavo-EP at a concentration of 0.5 mg/mL and dose volume of ~1/4 of the calculated lesion volume to the accessible lesion(s) on days 1, 5, and 8 every 6 weeks. The primary endpoint of this open-label, non-randomized phase II trial is ORR by investigator review. Secondary endpoints include safety and tolerability of the combined therapy, duration of response, progression-free survival (PFS), immune PFS and overall survival. The correlation between changes in the immune cell subsets and response to treatment was also evaluated. RESULTS: At the time of abstract submission, 16 of the planned 25 patients have been enrolled and 11 patients completed a post-treatment RECIST v1.1 assessment at the initial 12-week evaluation or discontinued prior to assessment. Patients had a median of 3 prior lines of therapy for advanced disease. Partial responses have been observed in 3 patients (ORR 27.3%), including a deep confirmed response in a patient with multiple liver, bone, skin and nodal metastases and a short disease-free interval following neoadjuvant chemotherapy. Regression of IT-tavo-EP untreated lesions have been observed. Treatment was well tolerated and any grade treatment emergent adverse events (AEs) regardless of attribution were observed in 11 of 16 (68.8%) [grade ≥3 in 6 of 16 (37.5%)]. Only one grade ≥3 AE was attributed to pembrolizumab and none were attributed to IT-tavo or EP. Patients demonstrated immunological responses in blood consistent with an IL-12-associated mechanism of action, including on-treatment reduction of peripheral gMDSC suppressors. Additional biomarker analysis of patient tumor and blood s les are ongoing. CONCLUSIONS: When compared to the results of KEYNOTE-086, which demonstrated a 5.3% ORR in pretreated mTNBC patients with pembrolizumab monotherapy, our preliminary data from patients who have reached an assessment time-point suggests that IT-tavo-EP may enhance sensitivity to pembrolizumab in this patient population. Updated data will be presented. Citation Format: Melinda L. Telli, Irene Wapnir, Bianca Devitt, Katharine Cuff, Hatem Soliman, Shaveta Vinayak, David A. Canton, Christopher Twitty, Kellie Malloy Foerter, Rohit Joshi. Phase 2, open-label study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation in combination with intravenous pembrolizumab therapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (mTNBC) (KEYNOTE- 890/OMS-I141) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium 2019 Dec 10-14 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2020 (4 Suppl):Abstract nr P3-09-04.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-10-2022
DOI: 10.1200/JCO.2022.40.36_SUPPL.397600
Abstract: 397600 Background: While PD-1 inhibitors demonstrated survival benefit compared to chemotherapy in patients (pts) with PD-L1-high, NSCLC, less than half of pts respond to monotherapy. Novel therapeutics or combinations are necessary to improve outcomes. Domvanalimab (D) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domain (TIGIT), thereby reducing immunosuppression of T/NK cells and promoting antitumor activity. Etrumadenant (E) is a selective dual antagonist of both A 2a and A 2b receptors (R) expressed on immune cells thereby reducing immunosuppressive extracellular adenosine. ARC-7 evaluates whether inhibition of TIGIT and adenosine pathways augments activity of zimberelimab (Z) (anti-PD-1 mAb) in pts with PD-L1-high NSCLC. Methods: ARC-7 (NCT04262856) is a randomized, open-label phase 2 clinical trial which enrolled treatment-naïve pts with Stage IV, squamous or non-squamous NSCLC with locally assessed high PD-L1 expression (TPS ≥ 50%), no EGFR or ALK alterations, and ECOG PS ≤1. Pts were randomized (1:1:1) to: Arm 1 (Z): Z 360 mg intravenously (IV) every 3 weeks (Q3W) Arm 2 (DZ): D 15 mg/kg IV Q3W + Z Arm 3 (EDZ): E 150 mg orally once daily + DZ. Pts in Arm 1 with confirmed progression had the option to cross over to EDZ. Co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS) per RECIST v1.1. Results: As of 31 August 2022, 149 pts received at least one dose of study treatment. Efficacy for this interim analysis included 133 pts randomized at least 13 weeks prior to data cut-off (ITT-13), allowing for ≥ 2 post-baseline scans. With median follow-up of 11.8 months (mo), D-containing arms, demonstrated improved ORR and PFS compared to Z. In the safety population, grade ≥3 treatment-emergent adverse events occurred in 58% (Z), 47% (DZ), and 52% (EDZ). All cases of rash were grade 1-2, manageable with topical corticosteroids, and more common in EDZ (Table). Conclusions: In the first published, randomized dataset evaluating an Fc-silent TIGIT mAb, both D containing arms demonstrated clinically meaningful improvement in ORR and PFS compared to Z. Treatment with Z, DZ and EDZ was well tolerated, and the safety profiles of D-containing arms were similar to Z. Ongoing phase 3 trials are evaluating DZ compared to standard of care in metastatic NSCLC. Clinical trial information: NCT04262856. [Table: see text]
Publisher: American Association for Cancer Research (AACR)
Date: 03-2023
DOI: 10.1158/1538-7445.SABCS22-OT2-10-01
Abstract: Background: Improving outcomes for patients (pts) with triple-negative breast cancer (TNBC) remains a high unmet need. Immune checkpoint inhibitors (ICIs) + chemotherapy (chemo) and single-agent sacituzumab govitecan, a trophoblast cell-surface antigen 2–targeted antibody-drug conjugate coupled to SN38 via a proprietary, hydrolysable linker, are approved in newly diagnosed pts with programmed death-ligand 1 (PD-L1)–positive tumors and pts who received ≥2 prior systemic therapies (≥1 for metastatic disease), respectively. However, additional options are urgently needed, particularly for pts with tumors that do not express PD-L1 and for those with progression on chemo ± ICI. Magrolimab is an antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells, including TNBC, inducing tumor phagocytosis by macrophages. Magrolimab has shown preclinical activity and promising clinical efficacy in hematologic and solid tumors. Chemo agents, including taxanes, can enhance prophagocytic signals on tumor cells, leading to the potential for synergistic antitumor activity with magrolimab. This study is evaluating the safety/tolerability and efficacy of magrolimab in combination with nab-paclitaxel aclitaxel or with sacituzumab govitecan in unresectable locally advanced/metastatic TNBC. Trial Design: This open-label, 2-cohort (C) study consists of safety run-in and phase (ph)2 portions evaluating nab-paclitaxel aclitaxel (choice) + magrolimab (safety run-in) or ± magrolimab (ph2, randomized 1:1) in pts with untreated, advanced/metastatic TNBC ineligible for ICI (C1) and magrolimab + sacituzumab govitecan (safety run-in and ph2) in pts with advanced TNBC who received 1 prior systemic treatment in the metastatic setting (C2). Stratification factors for C1 are neoadjuvant and/or adjuvant taxane therapy, liver metastases, and nab-paclitaxel vs paclitaxel. In both cohorts, magrolimab will be administered intravenously (IV) in de-escalating doses to establish the recommended ph2 dose (RP2D). Nab-paclitaxel aclitaxel and sacituzumab govitecan will be administered IV per standard of care. Eligibility Criteria: Eligible pts are ≥18 y with PD-L1–negative, untreated, unresectable locally advanced/metastatic TNBC (C1) or unresectable locally advanced/metastatic TNBC who received 1 prior line of therapy in the advanced setting, including a taxane and an ICI if PD-L1 positive (C2), with measurable disease per RECIST v1.1. Exclusion criteria include active central nervous system disease, red blood cell transfusion dependence, or prior treatment with CD47/signal regulatory protein α–targeting agents for both cohorts. Additional exclusions are disease progression within 6 months of (neo)adjuvant therapy or rapid visceral progression and/or symptomatic disease, for which single-agent chemo would not be appropriate (C1) chronic inflammatory bowel disease and a history of bowel obstruction or gastrointestinal perforation within 6 months of enrollment, prior treatment with topoisomerase I inhibitors or antibody-drug conjugates containing a topoisomerase inhibitor, and receipt of high-dose systemic corticosteroids within 2 weeks of cycle 1 day 1 (C2). Specific Aims: The primary objectives are safety/tolerability and magrolimab RP2D (safety run-in) and efficacy (ph2: C1, progression-free survival [PFS] C2, objective response rate [ORR] both by investigator). Secondary objectives include ORR, PFS, and duration of response by investigator and independent central review, overall survival, and magrolimab concentration vs time and antidrug antibodies. Present and Target Accrual: The study is enrolling in the US, Australia, and Hong Kong. Target accrual is 144 pts. Contact Information: ClinicalTrials.gov: NCT04958785. Citation Format: Natalie Rainey, Rohit Joshi, Joanne Win Yang Chiu, Ann Chen, Hao Wang, Jared Odegard, Michael Howland, Sylvia Adams. A phase 2, randomized study of magrolimab combination therapy in adult patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium 2022 Dec 6-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2023 (5 Suppl):Abstract nr OT2-10-01.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2020
DOI: 10.1186/S12885-020-07549-Y
Abstract: This analysis aims to evaluate health-related quality of life (HrQoL) (primary outcome for this analysis), nausea and vomiting, and pain in patients with inoperable malignant bowel obstruction (IMBO) due to cancer or its treatments randomised to standardised therapies plus octreotide or placebo over a maximum of 72 h in a double-blind clinical trial. Adults with IMBO and vomiting recruited through 12 services spanning inpatient, consultative and community settings in Australia were randomised to subcutaneous octreotide infusion or saline. HrQoL was measured at baseline and treatment cessation (EORTC QLQ-C15-PAL). Mean within-group paired differences between baseline and post-treatment scores were analysed using Wilcoxon Signed Rank test and between group differences estimated using linear mixed models, adjusted for baseline score, sex, age, time, and study arm. One hundred six of the 112 randomised participants were included in the analysis ( n = 52 octreotide, n = 54 placebo) 6 participants were excluded due to major protocol violations. Mean baseline HrQoL scores were low (octreotide 22.1, 95% CI 14.3, 29.9 placebo 31.5, 95% CI 22.3, 40.7). There was no statistically significant within-group improvement in the mean HrQoL scores in the octreotide ( p = 0.21) or placebo groups ( p = 0.78), although both groups reported reductions in mean nausea and vomiting (octreotide p 0.01 placebo p = 0.02) and pain scores (octreotide p 0.01 placebo p = 0.03). Although no statistically significant difference in changes in HrQoL scores between octreotide and placebo were seen, an adequately powered study is required to fully assess any differences in HrQoL scores. The HrQoL of patients with IMBO and vomiting is poor. Further research to formally evaluate the effects of standard therapies for IMBO is therefore warranted. Australian New Zealand Clinical Trials Registry ACTRN12608000211369 (date registered 18/04/2008)
Publisher: Wiley
Date: 12-03-2012
DOI: 10.1111/J.1743-7563.2011.01493.X
Abstract: Guillain-Barré syndrome has been reported in the setting of different malignancies. To the best of our knowledge, the association of Guillain-Barré syndrome and colorectal cancer has been reported in only two cases. As Guillain-Barré syndrome is potentially life threatening, it should be considered in the differential diagnosis of patients with colorectal cancer with neurological findings. Here we report two cases of Guillain-Barré syndrome in the setting of metastatic colorectal cancer.
Publisher: Wiley
Date: 22-09-2017
DOI: 10.1111/JEP.12640
Abstract: Screening has been found to reduce breast cancer mortality at a population level in Australia, but these studies did not address local settings where numbers of deaths would generally have been too low for evaluation. Clinicians, administrators, and consumer groups are also interested in local service outcomes. We therefore use more common prognostic and treatment measures and survivals to gain evidence of screening effects among patients attending 4 local hospitals for treatment. To compare prognostic, treatment, and survival measures by screening history to determine whether expected screening effects are occurring. Employing routine clinical registry and linked screening data to investigate associations of screening history with these measures, using unadjusted and adjusted analyses. Screened women had a 10-year survival from breast cancer of 92%, compared with 78% for unscreened women and 79% of screened surgical cases had breast conserving surgery compared with 64% in unscreened women. Unadjusted analyses indicated that recently screened cases had earlier tumor node metastasis stages, smaller diameters, less nodal involvement, better tumor differentiation, more oestrogen and progesterone receptor positive lesions, more hormone therapy, and less chemotherapy. Radiotherapy tended to be more common in screening participants. More frequent use of adjunctive radiotherapy applied when breast conserving surgery was used. Results confirm the screening effects expected from the scientific literature and demonstrate the value of opportunistic use of available registry and linked screening data for indicating to local health administrations, practitioners, and consumers whether local screening services are having the effects expected.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.BIOPSYCH.2014.03.007
Abstract: Psychopathy is characterized by a distinctive interpersonal style that combines callous-unemotional traits with inflexible and antisocial behavior. Traditional emotion-based perspectives link emotional impairment mostly to alterations in amygdala-ventromedial frontal circuits. However, these models alone cannot explain why in iduals with psychopathy can regularly benefit from emotional information when placed on their focus of attention and why they are more resistant to interference from nonaffective contextual cues. The present study aimed to identify abnormal or distinctive functional links between and within emotional and cognitive brain systems in the psychopathic brain to characterize further the neural bases of psychopathy. High-resolution anatomic magnetic resonance imaging with a functional sequence acquired in the resting state was used to assess 22 subjects with psychopathy and 22 control subjects. Anatomic and functional connectivity alterations were investigated first using a whole-brain analysis. Brain regions showing overlapping anatomic and functional changes were examined further using seed-based functional connectivity mapping. Subjects with psychopathy showed gray matter reduction involving prefrontal cortex, paralimbic, and limbic structures. Anatomic changes overlapped with areas showing increased degree of functional connectivity at the medial-dorsal frontal cortex. Subsequent functional seed-based connectivity mapping revealed a pattern of reduced functional connectivity of prefrontal areas with limbic-paralimbic structures and enhanced connectivity within the dorsal frontal lobe in subjects with psychopathy. Our results suggest that a weakened link between emotional and cognitive domains in the psychopathic brain may combine with enhanced functional connections within frontal executive areas. The identified functional alterations are discussed in the context of potential contributors to the inflexible behavior displayed by in iduals with psychopathy.
Publisher: Wiley
Date: 12-12-2019
DOI: 10.1111/ANS.15608
Publisher: BMJ
Date: 09-2019
DOI: 10.1136/BMJOPEN-2019-031421
Abstract: Some early studies indicated lower survival with longer time from diagnosis to cancer treatment, but others showed the reverse. We investigated time to treatment of colorectal cancer and associations with survival. Clinical registry data for colorectal cancer cases diagnosed in 2000–2010 at four major public hospitals in South Australia and treated by surgery (n=1675), radiotherapy (n=616) and/or systemic therapy (n=1556). A historic cohort design, with rank-order tests for ordinal clinical and sociodemographic predictors and multiple logistic regression for comparing time from diagnosis to treatment. Unadjusted Kaplan-Meier estimates and adjusted Cox proportional hazards regression were used to investigate disease-specific survival by time to treatment. Time to treatment and survival from diagnosis to death from colorectal cancer. Treatment (any type) commenced for 87% of surgical cases 60 days of diagnosis, with 80% having surgery within this period. Of those receiving radiotherapy, 59% began this treatment 60 days, and of those receiving systemic therapy, the corresponding proportion was 56%. Adjusted analyses showed treatment delay days was more likely for rectal cancers, 2006–2010 diagnoses, residents of northern than other metropolitan regions and for surgery, younger ages years and unexpectedly, those residing closer to metropolitan services. Adjusting for clinical and sociodemographic factors, and diagnostic year, better survival occurred in 2 years from diagnosis for time to treatment days. Survival in the 3–10 years postdiagnosis generally did not differ by time to treatment, except for lower survival for any treatment days for surgical cases. The lower survival 2 years from diagnosis for treatment 30 days of diagnosis is consistent with other studies attributed to preferencing more complicated cases for earlier care. Lower 3–10 years survival for surgical cases first treated days from diagnosis is consistent with previously reported U-shaped relationships.
Publisher: Springer International Publishing
Date: 2018
Publisher: Wiley
Date: 23-04-2014
DOI: 10.1002/AJMG.B.32233
Abstract: While past twin studies indicate moderate levels of heritability of "obsessive-compulsive related" and anxiety disorder symptoms, no single study has reported such estimates in the same twin population nor examined potential genetic sex differences. We assessed symptoms of obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, hypochondriasis, panic disorder, social phobia and generalized anxiety disorder in 2,495 adult twins (1,468 female). Prevalence estimates for the corresponding symptom measures were determined using empirically derived cut-off scores. Twin resemblance was assessed by Pearson correlations and biometrical model-fitting analyses, incorporating sex-specific effects, using OpenMx. Prevalence estimates ranged from 1.6% in the symptoms of generalized anxiety to 16.9% for social phobia. Female twins demonstrated significantly higher prevalence rates across all domains with the exception of obsessive-compulsive symptoms. Additive genetic factors accounted for a moderate proportion of the total liability to each symptom domain. Evidence suggesting qualitative genetic sex differences (i.e., distinct genetic influences between genders) was observed for body dysmorphic concern and panic symptoms, while quantitative differences were observed for hoarding and social phobia symptoms, indicating stronger heritability in females. Novel findings in this study include the observation of probable genetic sex differences in liability towards hoarding symptoms and dysmorphic concern, as well as the lack of such differences in hypochondriasis. The trend towards qualitative sex differences in panic symptoms has some intuitive appeal with regard to biological-experimental models of panic.
Publisher: BMJ
Date: 06-2020
DOI: 10.1136/BMJOPEN-2020-037069
Abstract: Using linked cancer registry and administrative data to monitor, tumour, node and metastases (TNM) stage and survival from female breast cancer in Australia. Analysis of 2000–2014 diagnoses with linked population-based data to investigate: (1) sociodemographic predictors of advanced stage (stages III and IV), using unadjusted and adjusted logistic regression and (2) sociodemographic factors and stage as predictors of breast cancer survival using competing risk regression. Population-based registry cohort. 14 759 South Australian women diagnosed in 2000–2014. Stage and survival. At diagnosis, 46% of women were classified as stage I, 39% as stage II, 12% as stage III and 4% as stage IV. After adjusting for sociodemographic factors, advanced stage was more common: (1) for ages years and although not statistically significant, for ages 80+ years and (2) in women from socioeconomically disadvantaged areas. Compared with 2000–2004 diagnoses, stage and sociodemographic adjusted risks (sub-HRs (SHRs)) of breast cancer death were lower in 2005–2009 (SHR 0.75, 95% CI 0.67 to 0.83) and 2010–2015 (SHR 0.57, 95% CI 0.48 to 0.67). Compared with stage I, the SHR was 3.87 (95% CI 3.32 to 4.53) for stage II, 10.87 (95% CI 9.22 to 12.81) for stage III, and 41.97 (95% CI 34.78 to 50.65) for stage IV. Women aged 70+ years at diagnosis and those living in the most socioeconomically disadvantaged areas were at elevated risk of breast cancer death, independent of stage and sociodemographic factors. Stage varied by age, diagnostic period and socioeconomic status, and was a stronger predictor of survival than other statistically significant sociodemographic predictors. Achieving earlier diagnosis outside the original BreastScreen target of 50–69 years (as applying ) and in residents of socioeconomically disadvantaged areas likely would increase cancer survival at a population level.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2023
DOI: 10.1200/JCO.2023.41.16_SUPPL.TPS1130
Abstract: TPS1130 Background: Improving outcomes in patients (pts) with TNBC remains a high unmet need. Immune checkpoint inhibitors (ICIs) + chemotherapy (chemo) is approved for newly diagnosed pts with PD-L1+ tumors. Further, single-agent sacituzumab govitecan (SG), a Trop-2–directed antibody-drug conjugate, is approved for pts with mTNBC who received ≥2 prior systemic therapies (≥1 for metastatic disease). However, more options are needed for pts with PD-L1–negative mTNBC and for those with disease progression on chemo ± ICI. Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal often overexpressed on TNBC cells. Magrolimab blockade of CD47 induces macrophage-mediated phagocytosis of tumor cells and has shown preclinical activity and promising clinical efficacy in hematologic malignancies. Certain chemos, including taxanes, enhance prophagocytic signals on tumor cells, which may lead to synergistic antitumor activity with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab + nab-paclitaxel aclitaxel or + SG in mTNBC. Methods: This open-label study has 2 cohorts (C) with safety run-in and phase (ph) 2 portions. Eligible pts are ≥18 y with measurable disease per RECIST 1.1. C1 pts have PD-L1–negative untreated mTNBC. C2 pts have mTNBC and received 1 prior line of therapy in the advanced setting, a taxane in the neoadjuvant/adjuvant or metastatic setting, and, if PD-L1+, an ICI. Exclusion criteria include active central nervous system disease, RBC transfusion dependence, and prior treatment with CD47/SIRPα-targeting agents. C1 assesses nab-paclitaxel aclitaxel + magrolimab (safety run-in) or ± magrolimab (ph 2 randomized 1:1). C2 assesses magrolimab + SG (safety run-in and ph 2). In C1 safety run-in, magrolimab is given intravenously (IV) as a 1-mg/kg priming dose on day (D) 1 of cycle 1 to mitigate on-target anemia, followed by 30 mg/kg (cycle 1: D8, 15, 22 cycle 2: D1, 8, 15, 22 cycle 3+: D1, 15) (28-d cycles). In C2 safety run-in, pts receive a 1-mg/kg priming dose on D1, followed by 30 mg/kg (cycle 1: D8, 15 cycle 2: D1, 8, 15) and 60 mg/kg (cycle 3+: D1) (21-d cycles). The recommended ph 2 dose (RP2D) is determined in the safety run-in, with de-escalation if prespecified dose-limiting toxicity (DLT) criteria are met. Once RP2D is determined, the ph 2 cohorts will follow their respective dose schedules. Nab-paclitaxel aclitaxel and SG are given IV per standard of care. The primary endpoints are incidence of DLTs, adverse events, and abnormal lab results by CTCAE v5.0 (safety run-in) progression-free survival by RECIST 1.1 (ph 2 C1) and confirmed objective response rate by RECIST 1.1 (C2 pooled safety run-in and ph 2). Planned enrollment is ≈144 pts. Clinical trial information: NCT04958785 .
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2022
DOI: 10.1158/1538-7445.SABCS21-OT2-01-03
Abstract: BACKGROUND: Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells promoting anti-tumor immune responses. DNA plasmid-based IL-12 delivered to accessible tumors by intratumoral injection and electroporation (TAVO-EP) has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that has limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Early clinical data indicate similar potential for eliciting strengthened immunogenic responses in TNBC. KEYNOTE-890 (OMS-I141) is a Phase 2 study in patients with metastatic TNBC to evaluate the safety and efficacy of TAVO-EP + pembrolizumab in the second-line or later (2L+) treatment setting (Cohort 1) or TAVO-EP + pembrolizumab + chemotherapy in the first-line (1L) setting (Cohort 2). Cohort 1 data are presented in a separate abstract. Enrollment in Cohort 2 is ongoing. METHODS: Cohort 2 of this Phase 2, open-label, multicenter study will be assessing the safety and efficacy of TAVO-EP in combination with pembrolizumab and chemotherapy as a first-line treatment for metastatic TNBC. Eligible patients are adults with metastatic TNBC (ER and PR staining & %, HER2 0 to 1+ or [F]ISH-negative), no prior systemic therapy for advanced disease (neo/adjuvant therapy allowed if at least 6-month disease-free interval from last treatment), measurable disease by RECIST v1.1, at least one lesion accessible for TAVO-EP treatment, and biopsy tissue available for post-hoc central determination of PD-L1 expression. Patients will receive pembrolizumab (200 mg IV) every 3 weeks, TAVO-EP (0.5 mg/mL at dose volume of ~1/4 lesion volume) on Days 1, 5, and 8 every 6 weeks, and nab-paclitaxel (100 mg/m2 IV) on Days 1, 8, and 15 every 4 weeks. Additional chemotherapy options may be introduced in future protocol amendments. Tumor assessments will be performed every 12 weeks. On-study biopsies will be collected approximately 3 weeks after start of treatment and at disease progression. The primary endpoint will be ORR assessed by blinded independent review per RECIST v1.1. Additional endpoints will include safety and tolerability, duration of response, immune ORR, progression-free survival (PFS), immune PFS, disease control rate, and overall survival. Planned enrollment in Cohort 2 is 40 patients. Based on positive efficacy data in Cohort 1, additional cohorts are being planned and will be presented. ClinicalTrials.gov: NCT03567720 Citation Format: Melinda Telli, Bianca Devitt, Katharine Cuff, Shaveta Vinayak, Rita Nanda, Alberto J. Montero, Rina Hui, David A. Canton, Christopher Twitty, Sunny Xie, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium 2021 Dec 7-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2022 (4 Suppl):Abstract nr OT2-01-03.
Publisher: Wiley
Date: 14-03-2019
DOI: 10.1111/AJCO.13140
Abstract: Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.JAD.2015.06.047
Abstract: Familiality, stressful life events (SLE) and gender significantly affect the onset of obsessive-compulsive disorder (OCD). However, their combined impact on the probability of OCD chronicity is largely unknown. With the objective of clarifying their predictive value, we tested a model of interaction effects between these influences. A s le of 449 patients with OCD was systematically assessed for familial loading, exposure to stressful life events, gender and course of the disease at the OCD referral unit at Bellvitge University Hospital. Multiple ordinal logistic regression was used to test interaction models. Familiality presented a main negative association with chronicity (OR=0.83, CI97.5%=0.70-0.98). This association was additively moderated by both exposure to SLE before onset and gender, and showed a positive slope among female patients not exposed to SLE before onset (Familiality*SLEbo: OR=0.69, CI97.5%=0.47-1 Familiality*gender: OR=1.30, CI97.5%=0.91-1.84). The findings are based on cross-sectional data. Assessment of course is based on a retrospective measure, which may imply the possibility of overestimation of chronicity. The predictive value of familiality on the course of OCD is only partially informative as both SLEbo and gender modify the association. When other risk factors are included in the model, familiality may predict decreased chances of chronicity. The mediation effects identified could explain the discrepancies found in previous research on this topic. Increased chances of presenting a chronic course of OCD may be found in association with familial vulnerability among female patients not exposed to SLEbo.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2023
DOI: 10.1200/JCO.2023.41.16_SUPPL.9024
Abstract: 9024 Background: PD-1 or PD-L1 inhibitors have transformed clinical care of NSCLC patients. However, many patients may develop primary or secondary resistant to PD-(L)1 inhibitors. The marketed anti-CTLA-4 mAbs are ineffective as monotherapy for NSCLC. ONC-392 is a novel target-preserving anti-CTLA-4 antibodies that confers immunotherapeutic effect by selective depletion of regulatory T cells (Treg) in the tumor microenvironment. Preclinical studies show that ONC-392 is more effective and less toxic for immunotherapy than other clinically used anti-CTLA-4 antibodies. In first-in-human study in patients with advanced solid cancer, the recommended Phase 2 dose (RP2D) for ONC-392 monotherapy was established as 10 mg/kg. In this study, we tested safety and clinical activities of ONC-392 in NSCLC patients who progressed on PD(L)1-targeted therapy. Methods: Anti-PD-(L)1 resistant NSCLC patients were enrolled as parts of PRESERVE-001 studies (NCT04140526) expansion cohort Part C Arm I and treated with 2 cycles of 10 mg/kg, followed by 6 mg/kg, q3w, ONC-392 by IV infusion. Safety was evaluated based on treatment emergent and treatment-related adverse events, while efficacy was evaluated by investigators using RECIST1.1 criteria. Results: As of December 18, 2022, 33 NSCLC patients have received at least one dose of ONC-392 at 10 mg/kg. The median age is 66 yrs (range 43 - 89 yr), 61% male. 61% were non-squamous cell carcinoma and 39% were squamous cell carcinoma. 27% are ECOG score 0 and 73% were ECOG score 1. The median prior treatment was 2 cycles (range 1 to 4). The average ONC-392 treatment period was 3.5 cycles (range 1 to 13 cycles). Overall, the patients with TRAE in grade 3 or above is 33% (11/33), including diarrhea/colitis (3, 9%), AST/ALT increase or hepatitis (3, 9%), muscular weakness (2, 6%), nephritis (1, 3%), adrenal insufficiency (1, 3%). Due to pace of enrollment, efficacy data are available in 22 patients. 6 of 22 evaluable patients have partial response and 12 patients have stable disease per RECIST 1.1, resulting in a response rate of 27% and disease control rate of 82% among evaluable patients. The median follow-up period for all patients is 5.8 months and 8.6 months for 20 alive patients (range 2.9 to 14.1 months). The estimated 6- and 12-month overall survival (OS) rates were 65% and 55%. Median OS has not reached. Conclusions: Overall, ONC-392 monotherapy with 10 mg/kg is safe and tolerable. Onc-392 monotherapy has showed encouraging anti-tumor activity in IO-resistant NSCLC when compared with historical data. Based on these encouraging data, we have initiated a Phase 3 study testing ONC-392 monotherapy among NSCLC who progressed on PD(L)1-targeting immunotherapy (NCT05671510). Clinical trial information: NCT04140526 .
Publisher: Informa UK Limited
Date: 08-01-2021
Publisher: Springer Science and Business Media LLC
Date: 22-05-2007
DOI: 10.1007/S00520-007-0267-2
Abstract: A phase I study was performed to establish the minimum effective dose safety of the topical 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor lovastatin (FP252S) in preventing chemotherapy-induced alopecia in cohorts of three patients receiving their first doses of chemotherapy with doxorubicin (eight patients) or taxanes (four patients). One patient at the first dose level receiving doxorubicin and cyclophosphamide had only grade 1 hair loss at 3 weeks. At dose level 2, one patient on doxorubicin took more than 4 weeks to lose her hair and another on docetaxel retained some hair throughout her chemotherapy. At level 3, one patient had grade 2 hair loss at week 4 and another on docetaxel for 6 cycles showed evidence of hair growth between cycles. There were no grade 3 or 4 toxicities, but at the fourth dose level, no higher concentrations could be formulated. Lovastatin was well-tolerated at the maximum concentration achievable but showed little efficacy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2017
DOI: 10.1200/JCO.2017.35.4_SUPPL.643
Abstract: 643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms P 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 & p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.APPET.2015.03.024
Abstract: This study was aimed to examine if adolescent obesity is associated with alterations of insula function as indexed by differential correlations between insula activation and perception of interoceptive feedback versus external food cues. We hypothesized that, in healthy weight adolescents, insula activation will positively correlate with interoceptive sensitivity, whereas in excess weight adolescents, insula activation will positively correlate with sensitivity towards external cues. Fifty-four adolescents (age range 12-18), classified in two groups as a function of BMI, excess weight (n = 22) and healthy weight (n = 32), performed the Risky-Gains task (sensitive to insula function) inside an fMRI scanner, and completed the heartbeat perception task (measuring interoceptive sensitivity) and the Dutch Eating Behaviour Questionnaire (measuring external eating as well as emotional eating and restraint) outside the scanner. We found that insula activation during the Risky-Gains task positively correlated with interoceptive sensitivity and negatively correlated with external eating in healthy weight adolescents. Conversely, in excess weight adolescents, insula activation positively correlated with external eating and negatively correlated with interoceptive sensitivity, arguably reflecting obesity related neurocognitive adaptations. In excess weight adolescents, external eating was also positively associated with caudate nucleus activation, and restrained eating was negatively associated with insula activation. Our findings suggest that adolescent obesity is associated with disrupted tuning of the insula system towards interoceptive input.
Publisher: AME Publishing Company
Date: 10-2020
DOI: 10.21037/TBCR-20-55
Publisher: CMA Joule Inc.
Date: 11-2014
DOI: 10.1503/JPN.130135
Publisher: Wiley
Date: 29-08-2014
DOI: 10.1002/HBM.22625
Publisher: Wiley
Date: 31-03-2008
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Wiley
Date: 02-08-2013
DOI: 10.1111/AJCO.12092
Publisher: Royal College of Psychiatrists
Date: 08-2015
DOI: 10.1192/BJP.BP.114.152223
Abstract: In iduals with cocaine and gambling addictions exhibit cognitive flexibility deficits that may underlie persistence of harmful behaviours. We investigated the neural substrates of cognitive inflexibility in cocaine users v. pathological gamblers, aiming to disambiguate common mechanisms v. cocaine effects. Eighteen cocaine users, 18 pathological gamblers and 18 controls performed a probabilistic reversal learning task during functional magnetic resonance imaging, and were genotyped for the DRD2/ANKK Taq1A polymorphism. Cocaine users and pathological gamblers exhibited reduced ventrolateral prefrontal cortex (PFC) signal during reversal shifting. Cocaine users further showed increased dorsomedial PFC (dmPFC) activation relative to pathological gamblers during perseveration, and decreased dorsolateral PFC activation relative to pathological gamblers and controls during shifting. Preliminary genetic findings indicated that cocaine users carrying the DRD2/ANKK Taq1A1+ genotype may derive unique stimulatory effects on shifting-related ventrolateral PFC signal. Reduced ventrolateral PFC activation during shifting may constitute a common neural marker across gambling and cocaine addictions. Additional cocaine-related effects relate to a wider pattern of task-related dysregulation, reflected in signal abnormalities in dorsolateral and dmPFC.
Publisher: Elsevier BV
Date: 2012
Publisher: Hindawi Limited
Date: 28-03-2021
DOI: 10.1111/ECC.13451
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: Wiley
Date: 17-04-2014
DOI: 10.1111/ADB.12143
Abstract: Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent in iduals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3-Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.
Publisher: Public Library of Science (PLoS)
Date: 21-07-2015
Publisher: Wiley
Date: 14-01-2013
DOI: 10.1111/ADB.12027
Abstract: Neuroimaging studies have shown that chronic consumption of cannabis may result in alterations in brain morphology. Recent work focusing on the relationship between brain structure and the catechol-O-methyltransferase (COMT) gene polymorphism suggests that functional COMT variants may affect brain volume in healthy in iduals and in schizophrenia patients. We measured the influence of COMT genotype on the volume of four key regions: the prefrontal cortex, neostriatum (caudate-putamen), anterior cingulate cortex and hippoc us-amygdala complex, in chronic early-onset cannabis users and healthy control subjects. We selected 29 chronic cannabis users who began using cannabis before 16 years of age and matched them to 28 healthy volunteers in terms of age, educational level and IQ. Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition. COMT genotyping was performed and structural magnetic resonance imaging data was analyzed by voxel-based morphometry. The results showed that the COMT polymorphism influenced the volume of the bilateral ventral caudate nucleus in both groups, but in an opposite direction: more copies of val allele led to lesser volume in chronic cannabis users and more volume in controls. The opposite pattern was found in left amygdala. There were no effects of COMT genotype on volumes of the whole brain or the other selected regions. Our findings support recent reports of neuroanatomical changes associated with cannabis use and, for the first time, reveal that these changes may be influenced by the COMT genotype.
Publisher: Wiley
Date: 30-01-2022
DOI: 10.1111/AJCO.13656
Abstract: Nonadherence to oral chemotherapy (OC) can lead to health complications, including premature death. Mobile phones are increasingly used to deliver medication adherence interventions. However, there is limited evidence about mobile phone-based interventions to increase adherence to OC, specifically. This study explores the proof-of-concept of a smartphone program to support adherence to OC in people with cancer. This was a 10-week, nonrandomized, multisite trial. The outcomes assessed were acceptability, satisfaction with the intervention, adherence to OC, knowledge about OC, and side-effects presence and severity. The program consisted of short message service (SMS) reminders to take OC, as well as information about OC, including the management of side-effects. Twenty-two participants (17-74 y/o, median age 60 y/o) were recruited at six hospitals. The s le included 10 different cancer diagnoses (predominance of breast cancer) and 11 OC medications. Acceptability of the intervention was high, with 95% of the enrolled participants completing postintervention measures, and 81% reporting high satisfaction with the program. The intervention was found to have no effect on supporting adherence to OC (assessed by self-report and medication event monitoring system) in this s le. An increase in knowledge about OC was observed at postintervention (p = 0.010). This study demonstrated proof-of-concept of the smartphone program and highlighted the need for intervention and trial design-related refinements. Future work should evaluate the effect of the program on adherence to OC with nonadherent patients.
Publisher: Wiley
Date: 08-10-2017
DOI: 10.1111/JEP.12819
Abstract: Clinical registry data from major South Australian public hospitals were used to investigate trends in invasive breast‐cancer treatment and survival by age. Disease‐specific survival was calculated for the 1980 to 2013 diagnostic period using Kaplan‐Meier product‐limit estimates, with a censoring of live cases on December 31, 2014. Cox proportional hazards regression was used to examine differences in survival by age and tumour characteristic. First‐round treatments following diagnosis were analysed, using multiple logistic regression to adjust for confounding. Five‐year survival increased from 75% in the 1980s to 87% in 2000 to 2013, consistent with national trends, and with increases occurring irrespective of age. There was an increased use of breast conserving surgery, radiotherapy, chemotherapy, and hormone treatments. Five‐year survival was lower for women aged 80+ years, increasing from 65% in the 1980s to 74% in 2000 to 2013. Lower survival in these older women persisted after adjusting for TNM stage, other clinical variables, and diagnostic year, without evidence of a reduced disparity over time. Older women were less likely to have surgery, radiotherapy, and chemotherapy throughout 1980 to 2013. By comparison, their use of hormone therapy was elevated. The adjusted relative odds of mastectomy (as opposed to breast conserving surgery) were lower for the 80+ year age range. Breast‐cancer survival increases applied to all ages, including 80+ years, but poorer outcomes persisted in this older group and the gap did not reduce. A key question is whether the best trade‐off now exists between optimally therapeutic cancer treatment and accommodations for frailty and co‐morbidity in the aged, or whether opportunities exist for better trade‐offs and better survival. Local registry data are important for describing local service activity and outcomes by age for local service providers, health administrations and consumer groups monitoring disparities and indicating effects of local initiatives.
Publisher: Savvy Science Publisher
Date: 15-06-2022
DOI: 10.12974/2313-0946.2014.01.02.2
Abstract: Objectives: Given the expanding role of medical oncology practice, with increasing therapeutic options for those with advanced malignancy, we sought to document the population of patients receiving inpatient medical oncology consultation. The aim of the study was to document patterns of inpatient referral to medical oncology in order to better understand service needs. We looked to define the relative frequency of cancer types, stage and treatment recommendations. Design: A large prospective clinical audit was undertaken between January 2005 and January 2007. Settings: The audit was conducted at the Royal Adelaide Hospital, a major tertiary referral hospital. Participants: During the two year study period 1,173 consecutive inpatient referrals for medical oncology consultations were included in this analysis. Main Outcome Measures: Information was collected regarding patient demographics, referral unit, cancer diagnosis and stage, treatment recommendations and follow-up plans. Results: The most common referral units were General Medicine (19.8%) and Thoracic medicine (15%). The most common primary sites of cancer were lung (22.6%), colorectal (14.9%), primary brain tumours (9.6%) and head and neck (9.3%). The clear majority of patients had Stage 4 disease (80%) and were thus incurable in most cases. Chemotherapy was recommended in 43.7% of patients, chemo-radiation in 12.6% of patients, radiotherapy alone in 16.9% of patients and best supportive care in 24.1% of patients. Conclusions: This large prospective clinical audit defines the population of patients referred for inpatient medical oncology consultation at our tertiary hospital. Cancer patients are being cared for by a wide variety of non-cancer specialists. The majority of patients have advanced, non-curable disease but anticancer therapy is provided to most with the intention of prolonging survival and maintaining quality of life.
Publisher: Hindawi Limited
Date: 30-11-2022
DOI: 10.1111/ECC.13539
Abstract: To examine the screening-treatment-mortality pathway among women with invasive breast cancer in 2006-2014 using linked data. BreastScreen histories of South Australian women diagnosed with breast cancer (n = 8453) were investigated. Treatments recorded within 12 months from diagnosis were obtained from linked registry and administrative data. Associations of screening history with treatment were investigated using logistic regression and with cancer mortality outcomes using competing risk analyses, adjusting for socio-demographic, cancer and comorbidity characteristics. For screening ages of 50-69 years, 70% had participated in BreastScreen SA ≤ 5 years and 53% ≤ 2 years of diagnosis. Five-year disease-specific survival post-diagnosis was 90%. Compared with those not screened ≤5 years, women screened ≤2 years had higher odds, adjusted for socio-demographic, cancer and comorbidity characteristics, and diagnostic period, of breast-conserving surgery (aOR 2.5, 95% CI 1.9-3.2) and radiotherapy (aOR 1.2, 95% CI 1.1-1.3). These women had a lower unadjusted risk of post-diagnostic cancer mortality (SHR 0.33, 95% CI 0.27-0.41), partly mediated by stage (aSHR 0.65, 95% CI 0.51-0.81), and less breast surgery (aSHR 0.78, 95% CI 0.62-0.99). Screening ≤2 years and conserving surgery appeared to have a greater than additive association with lower post-diagnostic mortality (interaction term SHR 0.42, 95% CI 0.23-0.78). The screening-treatment-mortality pathway was investigated using linked data.
Publisher: American Physical Society (APS)
Date: 11-04-2017
Publisher: AME Publishing Company
Date: 10-2022
DOI: 10.21037/TBCR-22-46
Publisher: Hindawi Limited
Date: 07-03-2017
DOI: 10.1111/ECC.12673
Abstract: Monitoring screening mammography effects in small areas is often limited by small numbers of deaths and delayed effects. We developed a risk score for breast cancer death to circumvent these limitations. Screening, if effective, would increase post-diagnostic survivals through lead-time and related effects, as well as mortality reductions. Linked cancer and BreastScreen data at four hospitals (n = 2,039) were used to investigate whether screened cases had higher recorded survivals in 13 small areas, using breast cancer deaths as the outcome (M1), and a risk of death score derived from TNM stage, grade, histology type, hormone receptor status, and related variables (M2). M1 indicated lower risk of death in screened cases in 12 of the 13 areas, achieving statistical significance (p < .05) in 5. M2 indicated lower risk scores in screened cases in all 13 areas, achieving statistical significance in 12. For cases recently screened at diagnosis (<6 months), statistically significant reductions applied in 8 areas (M1) and all 13 areas (M2). Screening effects are more detectable in small areas using these risk scores than death itself as the outcome variable. An added advantage is the application of risk scores for providing a marker of screening effect soon after diagnosis.
Publisher: AME Publishing Company
Date: 10-2019
Publisher: BMJ
Date: 07-2019
Abstract: We report a case of a 74-year-old man who developed myocarditis complicated by atrioventricular (AV) block following two doses of nivolumab for the treatment of non-small cell lung cancer. A diagnosis of drug-induced acute myocarditis with complete AV block was considered on the basis of elevated troponin, new onset left ventricular (LV) systolic dysfunction, absence of acute myocardial infarction and some findings suggestive of myocarditis on cardiac magnetic resonance. The patient was commenced on glucocorticoids, perindopril and carvedilol. AV block and LV dysfunction persisted despite 2 weeks of treatment. He ultimately became hypotensive which prompted an implantation of a cardiac resynchronisation therapy pacemaker. Follow-up echocardiogram at 6 weeks showed resolution of LV systolic dysfunction. However, he continued to have AV block.
Publisher: BMJ Publishing Group Ltd
Date: 11-2022
Publisher: BMJ
Date: 07-2017
Publisher: Asian Pacific Organization for Cancer Prevention
Date: 02-09-2015
DOI: 10.7314/APJCP.2015.16.14.5923
Abstract: Registry data from four major public hospitals indicate trends over three decades from 1980 to 2010 in treatment and survival from colorectal cancer with distant metastases at diagnosis (TNM stage IV). Kaplan-Meier product-limit estimates and Cox proportional hazards models for investigating disease-specific survival and multiple logistic regression analyses for indicating first-round treatment trends. Two-year survivals increased from 10% for 1980-84 to 35% for 2005-10 diagnoses. Corresponding increases in five-year survivals were from 3% to 16%. Time-to-event risk of colorectal cancer death approximately halved (hazards ratio: 0.48 (0.40, 0.59) after adjusting for demographic factors, tumour differentiation, and primary sub-site. Survivals were not found to differ by place of residence, suggesting reasonable equity in service provision. About 74% of cases were treated surgically and this proportion increased over time. Proportions having systemic therapy and/or radiotherapy increased from 12% in 1980-84 to 61% for 2005-10. Radiotherapy was more common for rectal than colonic cases (39% vs 7% in 2005-10). Of the cases diagnosed in 2005-10 when less than 70 years of age, the percentage having radiotherapy and/or systemic therapy was 79% for colorectal, 74% for colon and 86% for rectum (and RS)) cancers. Corresponding proportions having: systemic therapies were 75%, 71% and 81% respectively radiotherapy were 24%, 10% and 46% respectively and surgery were 75%, 78% and 71% respectively. Based on survey data on uptake of offered therapies, it is likely that of these younger cases, 85% would have been offered systemic treatment and among rectum (and RS) cases, about 63% would have been offered radiotherapy. Pronounced increases in survivals from metastatic colorectal cancer have occurred, in keeping with improved systemic therapies and surgical interventions. Use of radiotherapy and/or systemic therapy has increased markedly and patterns of change accord with clinical guideline recommendations.
Publisher: Wiley
Date: 05-2013
DOI: 10.1111/IMJ.12123
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2023
DOI: 10.1158/1538-7445.AM2023-CT050
Abstract: Background: The modified nucleoside 6-thio-2'-deoxyguanosine (THIO) is a first-in-class direct telomere-targeting agent that is preferentially incorporated in telomeres of telomerase-positive cells, leading to telomere uncapping and cancer cell death. Preclinical evidence indicates that THIO pretreatment sensitizes non-small cell lung cancer (NSCLC) cells to cemiplimab, a PD-1 inhibitor approved as 1L treatment for patients with locally advanced/metastatic NSCLC with ≥50% PD-L1 expression. The THIO-101 trial is designed to evaluate safety and efficacy of THIO followed by cemiplimab in patients with advanced NSCLC who have developed resistance or relapsed after prior immune checkpoint inhibitor (ICI) therapy. Trial Design: THIO-101 enrolls adult patients with stage 3/4 NSCLC, who have progressed or relapsed after treatment with an ICI alone or in combination with platinum-based therapy. Using a 3+3 design, the safety lead-in (Part A) is enrolling up to 6 patients in the first cohort to receive a total dose of THIO 360 mg IV (120 mg QD, D1-3) followed by a fixed dose of cemiplimab 350 mg on D5 Q3W. If ≥2 patients experience dose-limiting toxicities, a second cohort will receive a total dose of THIO 180 mg IV (60 mg QD, D1-3) followed by cemiplimab. In the dose- finding portion of the study (Part B), patients will be randomized 1:1:1 in a Simon 2-stage design (n=41 per arm) to receive THIO 360 mg [if cleared in Part A], 180 mg, or 60 mg followed by cemiplimab. Sequential THIO and cemiplimab treatment may be continued Q3W for up to 1 year, or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints are safety, objective response rate, and disease control rate (CR, PR, and SD). Secondary endpoints include duration of response, progression-free survival, and overall survival exploratory endpoints include PK/PD parameters (type I IFN, IL-6, CRP) and assessment of tumor telomerase status by IHC. Investigators will assess disease progression per RECIST v1.1 and/or iRECIST, with radiographic scans performed on D1 of cycles 3 and 5 and every 9-12 weeks thereafter. Adverse events are evaluated according to NCI CTCAE v5.0. The trial is enrolling patients at sites in Europe and Australia. The trial has completed enrollment in Part A without DLTs and opened enrollment in Part B. NCT05208944 EUDRA CT Number, 2021-005136-34 Citation Format: Mihail Obrocea, Brenton Seidl, Rohit Joshi, Melissa Moore, Vlad Vitoc, Bin Yao, Sergei Gryaznov. A phase 2, multi-center, open-label, dose-finding study evaluating telomere targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023 Part 2 (Clinical Trials and Late-Breaking Research) 2023 Apr 14-19 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2023 (8_Suppl):Abstract nr CT050.
Publisher: Georg Thieme Verlag KG
Date: 2013
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2018
DOI: 10.1158/1078-0432.CCR-17-3590
Abstract: Purpose: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab, and everolimus. Patients and Methods: Patients with KRAS exon 2 wild-type (WT) mCRC following failure of fluoropyrimidine-based therapy received i.v. irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14-day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using the Kaplan–Meier method, and results were analyzed as intention to treat. A preplanned exploratory biomarker analysis was performed. Results: Forty-nine patients were enrolled. Dose level 1 (irinotecan 200 mg/m2, panitumumab 6 mg/kg, and everolimus 5 mg alternate day) was declared the MTD with no dose-limiting toxicities in six patients. Forty patients were treated at dose level 1: median age, 60 years (37–76) 65% male 45% and 52.5%, respectively, with Eastern Cooperative Oncology Group values of 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhea (23%), mucositis (18%), rash (13%), fatigue (8%), dehydration (5%), neutropenia (20%), febrile neutropenia (8%), hypomagnesemia (20%), and hypokalemia (8%). Grade 4 toxicities were hypomagnesemia (5%) and neutropenia (3%). RR was 48%, and stable disease was 43%. Median progression-free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.8 months. Twenty-five patients were RAS/RAF WT and had an RR of 60%, median PFS of 6.4 months, and OS of 11.8 months. Conclusions: The toxicity of the panitumumab, irinotecan, and everolimus regimen is as expected and manageable. The RR of 60% in all RAS/RAF WT supports further study of this combination. Clin Cancer Res 24(16) 3838–44. ©2018 AACR.
Publisher: Medknow
Date: 2008
Publisher: Asian Pacific Organization for Cancer Prevention
Date: 03-04-0011
DOI: 10.7314/APJCP.2015.16.6.2431
Abstract: Registry data from four major public hospitals indicate trends in clinical care and survival from colorectal cancer over three decades, from 1980 to 2010. Kaplan-Meier product- limit estimates and Cox proportional hazards models were used to investigate disease-specific survival and multiple logistic regression analyses to explore first-round treatment trends. Five-year survivals increased from 48% for 1980-1986 to 63% for 2005-2010 diagnoses. Survival increases applied to each ACPS stage (Australian Clinico-Pathological Stage), and particularly stage C (an increase from 38% to 68%). Risk of death from colorectal cancer halved (hazards ratio: 0.50 (0.45, 0.56)) over the study period after adjusting for age, sex, stage, differentiation, primary sub-site, health administrative region, and measures of socioeconomic status and geographic remoteness. Decreases in stage were not observed. Survivals did not vary by sex or place of residence, suggesting reasonable equity in service access and outcomes. Of staged cases, 91% were treated surgically with lower surgical rates for older ages and more advanced stage. Proportions of surgical cases having adjuvant therapy during primary courses of treatment increased for all stages and were highest for stage C (an increase from 5% in 1980-1986 to 63% for 2005-2010). Radiotherapy was more common for rectal than colonic cases. Proportions of rectal cases receiving radiotherapy increased, particularly for stage C where the increase was from 8% in 1980-1986 to 60% in 2005-2010. The percentage of stage C colorectal cases less than 70 years of age having systemic therapy as part of their first treatment round increased from 3% in 1980-1986 to 81% by 1995-2010. Based on survey data on uptake of adjuvant therapy among those offered this care, it is likely that all these younger patients were offered systemic treatment. We conclude that pronounced increases in survivals from colorectal cancer have occurred at major public hospitals in South Australia due to increases in stage-specific survivals. Use of adjuvant therapies has increased and the patterns of change accord with clinical guideline recommendations. Reasons for sub-optimal use of radiotherapy for rectal cases warrant further investigation, including the potential for limited rural access to impede uptake of treatments at metropolitan-based radiotherapy centres.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
Publisher: Wiley
Date: 04-05-2018
DOI: 10.1111/JEP.12757
Abstract: Adjuvant care for colorectal cancer (CRC) has increased over the past 3 decades in South Australia (SA) in accordance with national treatment guidelines. This study explores the (1) receipt of adjuvant therapy for CRC in SA as related to national guideline recommendations, with a focus on stage C colon and stage B and C rectal cancer (2) timing of these adjuvant therapies in relation to surgery and (3) comparative survival outcomes. Data from the SA Clinical Cancer Registry from 4 tertiary referral hospitals for 2000 to 2010 were examined. Patterns of care were compared with treatment guidelines using multivariable logistic regression. Disease-specific survivals were calculated by treatment pathway. Four hundred forty-three (60%) patients with stage C colon cancer and 363 (46%) with stage B and C rectal cancer received guideline-recommended care. While an overall increase in proportion receiving adjuvant care was not evident across the study period, the proportion having neoadjuvant care increased substantially. Older age was an independent predictor of not receiving adjuvant care. Patients with stage C colon cancer who received recommended adjuvant care had a higher 5-year survival than those not receiving this care, ie, 71.2% vs 53.2%. Similarly adjuvant therapy was associated with better outcomes for stage C rectal cancers. The median time for receiving adjuvant care was 8 weeks. Survival was better for stage C CRC treated according to guidelines. Adjuvant care should be provided except where clear contraindications present. Other possible contributors to guideline adherence warranting additional investigation include co-morbidity status, multidisciplinary team involvement, and choice.
Publisher: Wiley
Date: 06-07-2015
DOI: 10.1002/HBM.22889
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 13-10-2014
DOI: 10.1007/S00520-013-2004-3
Abstract: Prolonged neurotoxicity after systemic chemotherapy has the potential to impact on quality of life. We explored the frequency of persistent peripheral neuropathy in patients who received oxaliplatin for colorectal cancer at two local centres. Questionnaires were sent to patients who completed treatment with oxaliplatin for colorectal cancer at least 20 months prior to entering the study. Neuropathy questions were adapted from the FACT/GOG-Ntx (V.4) questionnaire. Of the 56 eligible patients, 27 returned the questionnaire. Twenty-five patients (93 %) experienced neuropathic symptoms during their treatment 11 had grade-2, and two had grade-3 symptoms. At the time of completing the questionnaire, 17 patients (63.0 % 95%CI 43.9-79.4 %) were still symptomatic with 12 patients (44.4 % 95%CI 26.8-63.3) having grade-2 or grade-3 symptoms and three patients (11.1 % 95%CI 2.9-27.3) having grade-3 neuropathic symptoms. Participants who received more than 900 mg/m2 oxaliplatin had a significantly higher risk of persistent grade-2 or grade-3 neuropathy (p = 0.031, RR = 8.3 95%CI = 1.2-57.4). There was a trend toward increased risk of persistent neuropathy of any grade among participants with a history of regular alcohol use (p = 0.051 RR = 1.7 95%CI 1.0-2.8). Persistent oxaliplatin-induced neuropathy is not as uncommon as previously suggested, and the rate of grade-2 and grade-3 symptoms could be considerably higher than previous reports.
Publisher: BMJ Publishing Group Ltd
Date: 11-2022
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2022
DOI: 10.1158/1538-7445.SABCS21-P2-14-06
Abstract: BACKGROUND: Electroporated plasmid interleukin-12 (tavokinogene telseplasmid TAVO-EP) delivered to accessible tumors by intratumoral injection induces sustained local expression of IL-12. IL-12 is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells, promoting anti-tumor immune responses. TAVO-EP has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Anti-PD1 monotherapy has just over 5% overall response rate (ORR) in the second-line or later (2L+) treatment setting for advanced TNBC. New antibody-directed conjugate (ADC) chemotherapy has increased rates of responses compared with prior standard chemotherapy in 2L+ advanced TNBC however, short duration of response (DOR), and toxicity are issues of concern. Therapies that can induce durable responses with limited toxicity are needed. METHODS: Cohort 1 of this Phase 2, open-label, multicenter study assessed the safety and efficacy of TAVO-EP in combination with pembrolizumab as 2L+ treatment for advanced TNBC. Eligible patients had at least 1 line of prior systemic therapy for advanced or metastatic disease, measurable disease by RECIST v1.1, and ≥1 lesion accessible for TAVO-EP treatment. Patients received pembrolizumab (200 mg IV) every 3 weeks and TAVO-EP (0.5 mg/mL at dose volume of ~1/4 lesion volume) on Days 1, 5, and 8 every 6 weeks. Tumor assessments were performed every 12 weeks. The primary endpoint was RECIST v.1.1 ORR by investigator review. Secondary endpoints included safety and tolerability, DOR, progression-free survival (PFS), immune-related RECIST (iRECIST) ORR and PFS, disease control rate, and overall survival (OS). ClinicalTrials.gov: NCT03567720. RESULTS: Between 01Nov2018 and 30Jan2020, 26 patients were enrolled and received at least one dose of study treatment (median follow up of 11.1 months). Patients had a median of 2 prior lines of systemic therapy for advanced disease (range 1-5). Among 23 patients evaluable for response, the ORR was 17.4% (4 with partial response [PR]). One responder with centrally confirmed PD-L1-negative disease and chest wall and bulky liver metastases had a sustained PR and an iRECIST complete response (CR). One responder had near complete regression of a large fungating chest wall skin lesion. The median DOR was 16.6 months. Median OS was 11.0 months (range 0.6-27.5+). The most common treatment-related adverse events (TRAEs) (all grades) were administration site pain and fatigue. Grade 3 TRAEs were reported in 6 patients (23%) including fatigue (11.5%) acute kidney injury, enterocolitis, and myocarditis (3.8% each). There were no Grade 4 or 5 TRAEs. CONCLUSIONS: The combination of TAVO-EP and pembrolizumab in pretreated patients with advanced TNBC resulted in durable RECIST v1.1 responses, including in PD-L1-negative disease, and was well tolerated. This novel immunotherapeutic regimen warrants further evaluation in 2L+ advanced TNBC. Cohort 2 exploring TAVO-EP + pembrolizumab + chemotherapy in frontline TNBC is currently enrolling. Citation Format: Melinda L. Telli, Irene Wapnir, Bianca Devitt, Katharine Cuff, Hatem Soliman, Shaveta Vinayak, David A. Canton, Christopher G. Twitty, Sunny Xie, Ying Lu, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Durable responses with intratumoral electroporation of plasmid interleukin-12 plus pembrolizumab in patients with advanced triple-negative breast cancer: Cohort 1 update from KEYNOTE-890 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium 2021 Dec 7-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2022 (4 Suppl):Abstract nr P2-14-06.
No related grants have been discovered for Rohit Joshi.