ORCID Profile
0000-0003-3059-5730
Current Organisations
Macquarie University
,
University of Melbourne
,
Peter MacCallum Cancer Centre
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Publisher: Springer Science and Business Media LLC
Date: 24-07-2017
Publisher: Oxford University Press (OUP)
Date: 06-06-2007
DOI: 10.1093/JNCI/DJK195
Abstract: Some but not all patients with non-small-cell lung cancer (NSCLC) respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We developed and tested the ability of a predictive algorithm based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) analysis of pretreatment serum to identify patients who are likely to benefit from treatment with EGFR TKIs. Serum collected from NSCLC patients before treatment with gefitinib or erlotinib were analyzed by MALDI MS. Spectra were acquired independently at two institutions. An algorithm to predict outcomes after treatment with EGFR TKIs was developed from a training set of 139 patients from three cohorts. The algorithm was then tested in two independent validation cohorts of 67 and 96 patients who were treated with gefitinib and erlotinib, respectively, and in three control cohorts of patients who were not treated with EGFR TKIs. The clinical outcomes of survival and time to progression were analyzed. An algorithm based on eight distinct m/z features was developed based on outcomes after EGFR TKI therapy in training set patients. Classifications based on spectra acquired at the two institutions had a concordance of 97.1%. For both validation cohorts, the classifier identified patients who showed improved outcomes after EGFR TKI treatment. In one cohort, median survival of patients in the predicted "good" and "poor" groups was 207 and 92 days, respectively (hazard ratio [HR] of death in the good versus poor groups = 0.50, 95% confidence interval [CI] = 0.24 to 0.78). In the other cohort, median survivals were 306 versus 107 days (HR = 0.41, 95% CI = 0.17 to 0.63). The classifier did not predict outcomes in patients who did not receive EGFR TKI treatment. This MALDI MS algorithm was not merely prognostic but could classify NSCLC patients for good or poor outcomes after treatment with EGFR TKIs. This algorithm may thus assist in the pretreatment selection of appropriate subgroups of NSCLC patients for treatment with EGFR TKIs.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2020
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2010
Abstract: To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial. Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction. Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74% hazard ratio [HR], 0.36 95% CI, 0.17 to 0.74 P = .004) and failure-free survival (87% v 72% HR, 0.39 95% CI, 0.20 to 0.74 P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45 95% CI, 0.21 to 0.96 P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33 95% CI, 0.09 to 1.24 P = .13). HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2011
DOI: 10.1158/1541-7786.MCR-11-0312
Abstract: DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive β-galactosidase staining, G2–M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. Mol Cancer Res 9(12) 1696–707. ©2011 AACR.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Wiley
Date: 20-04-2007
DOI: 10.1111/J.1365-2222.2007.02701.X
Abstract: Ara h 2 is a potent peanut allergen but its contribution to the ability of a crude peanut extract (CPE) to cross-link IgE and activate mast cells has not been rigorously evaluated. To measure the contribution that Ara h 2 makes to the effector function of a CPE. Ara h 2 was specifically removed from a CPE as demonstrated by immunoblots, 2D gels, and an inhibitory ELISA. Functional assays of sham-treated and Ara h 2-depleted CPEs were performed with RBL SX-38 cells sensitized with IgE from highly peanut-allergic subjects and with naturally sensitized basophils. Depletion of approximately 99% of the Ara h 2 from the CPE led to an increase in the concentration of the CPE necessary to give 50% of maximal degranulation (EC50) of the SX-38 cells following sensitization with sera that contain anti-Ara h 2 IgE. Assays with a pool of 10 sera showed a small but significant increase in the EC50 following depletion of Ara h 2 (1.65+/-0.15-fold P<0.05) and assays of seven in idual sera showed a similar increase in the average EC50 (1.7+/-0.2-fold P<0.02). The percent of the anti-peanut IgE that binds Ara h 2 correlated with an increase in the EC50 of the CPE following depletion of Ara h 2 (r=0.83 P<0.02). On the other hand, data from three of these patients studied with a basophil histamine release assay did not show a significant effect of depletion of Ara h 2. Based on its ability to cross-link IgE effectively, Ara h 2 is clearly an important peanut allergen. Its ability to cross-link IgE effectively from a specific serum is related to the proportion of anti-Ara h 2 in that serum but Ara h 2 does not account for a majority of the effector activity of the CPE for any of the sera studied.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Elsevier BV
Date: 05-2011
Publisher: Elsevier BV
Date: 09-2018
Abstract: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small s le sizes. Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054 PFS, P = 0.17). Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2015
Publisher: Future Medicine Ltd
Date: 12-2021
Abstract: This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608 .
Publisher: Wiley
Date: 26-02-2018
DOI: 10.1002/LARY.27131
Abstract: The outcomes of unilateral radiotherapy treatment for patients with p16/HPV-positive squamous cell carcinomas of unknown primary (SCCUP) affecting cervical lymph nodes are under-reported. Compared to radiating large volumes of the pharyngeal axis (the more common approach), this is potentially a much less toxic treatment for a good prognosis group. Retrospective cohort study. We identified patients with SCCUP who were treated radically at our center and did not have parotid or isolated level IV or V nodal involvement. Failure-free and overall survivals were calculated using Kaplan-Meier methods. From 2004 to 2012, there were 49 radically treated patients with SCCUP. Fourteen patients had bilateral neck treatment (they had bilateral nodal disease or suspected lesions in the base of tongue, though not proven with biopsy), two had surgery alone, whereas 33 had unilateral radiotherapy (after neck dissection, excisional biopsy, or definitively with concurrent chemotherapy). Of the 33 patients, 21 tested positive to p16/HPV and had median follow-up of 57 months. In this group, no isolated contralateral neck failures or putative primaries emerged. There was 1/21 (4.3%) ipsilateral neck failure, 1/21 (4.3%) concurrent contralateral neck and distant failure, and 1/21 (4.3%) patient with distant failure. The 5-year freedom from failure was 78% (95% confidence interval [CI]: 56%-100%) and overall survival was 90% (95% CI: 79%-100%). With no emergence of putative primaries and no isolated contralateral neck failures, this single-institution experience in p16/HPV-positive SCCUP patients suggests that unilateral radiotherapy may be an underutilized management strategy. 4 Laryngoscope, 128:2076-2083, 2018.
Publisher: Elsevier BV
Date: 2012
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 21-07-2021
Abstract: The purpose of this study was to describe the nature and impact of dysphagia and dysphonia in patients with limited‐stage small‐cell lung cancer (SCLC) before and after chemoradiation. A prospective cohort study was conducted on patients receiving chemoradiotherapy for limited‐stage SCLC. Patients received either 40, 45 or 50 Gy, commencing the second cycle of chemotherapy. Outcomes included: videofluoroscopy (VFSS) to investigate aspiration, swallowing function and oesophageal motility oral intake limitations patient‐reported dysphagia and patient‐reported dysphonia. Data were collected before treatment and one, three and six months post‐treatment. Twelve patients were enrolled. Oropharyngeal swallowing was safe and functional at all times. Three patients exhibited oesophageal motility disorders before treatment, and a further three post‐treatment. Oral intake was most compromised one month post‐treatment with five patients either tube dependent or eating very limited diets. At all other times patients were eating normal or near‐normal diets. Despite normal oropharyngeal swallowing on VFSS, three patients reported moderate or severe dysphagia one month post‐treatment. Three additional patients reported moderate or severe difficulties three and six months post‐treatment. Patients who reported dysphagia one month post‐treatment all received a mean and maximum oesophageal dose of ≥15.7 Gy and ≥42 Gy, respectively. Dose–response relationships were not apparent three and six months post‐treatment. Voice problems varied, with worst scores reported one month post‐treatment. This study identified discordance between observed swallowing function and patient‐reported problems, which has clinical implications for patient management, and highlights future research needs. Ongoing efforts to reduce mucosal toxicity in patients with lung cancer are essential.
Publisher: Wiley
Date: 23-12-2019
DOI: 10.1002/QRE.2597
Publisher: Frontiers Media SA
Date: 20-12-2016
Publisher: Massachusetts Medical Society
Date: 27-08-2020
Publisher: Elsevier BV
Date: 04-2023
Publisher: Massachusetts Medical Society
Date: 30-04-2015
Publisher: Massachusetts Medical Society
Date: 27-08-2020
Publisher: Springer Science and Business Media LLC
Date: 17-07-2018
Publisher: Elsevier BV
Date: 07-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2009
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-04-2023
DOI: 10.1126/SCITRANSLMED.ABK1900
Abstract: Patients who receive chimeric antigen receptor (CAR)–T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 + memory T cell progenitors that can become either functional stem-like T (T STEM ) cells or dysfunctional T progenitor exhausted (T PEX ) cells. To that end, we demonstrated that T STEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T STEM -like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T STEM -like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4 + T cells during T STEM -like CAR-T cell production. Adoptive transfer of T STEM -like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T STEM -like CAR-T cells and an increased memory T cell pool. Last, T STEM -like CAR-T cells and anti–programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8 + CAR + T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T STEM -like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0169-5002(03)00235-6
Abstract: The optimal chemoradiation regimen for stage III non-small cell lung cancer (NSCLC) has not been determined. In this phase I/II study, the use of twice-weekly paclitaxel concomitant with weekly cisplatin and thoracic radiotherapy (RT) was evaluated. Patients with stage III NSCLC (without pleural effusion or cervical lymphadenopathy) were treated with thoracic RT (60 Gy in 30 fractions over 6 weeks) with concurrent weekly cisplatin 20 mg/m(2) and escalating doses of twice-weekly paclitaxel (starting dose of paclitaxel of 20 mg/m(2) increased in increments of 5 mg/m(2)) in successive cohorts of three to six patients until two or more patients experienced dose limiting toxicities (DLTs) at a particular dose level. All patients were planned to be given a further two cycles of consolidation chemotherapy consisting of paclitaxel 175 mg/m(2) and carboplatin AUC 5 after completion of RT. Twenty-five patients were enrolled in this study from two institutions. At a dose of paclitaxel 35 mg/m(2), two of four treated patients had DLTs (1 grade 3 oesophagitis and pulmonary toxicity 1 grade 3 oesophagitis and infection). The recommended dose was therefore determined to be 30 mg/m(2) and a total of 15 patients were enrolled in an expanded cohort at this level. The overall response rate for all patients was 64% (95% CI: 43-82%). The estimated median survival was 23.6 months with an estimated 1-year and 2-year survival of 72 and 49%, respectively. Paclitaxel can be safely given twice-weekly at a dose of 30 mg/m(2) in combination with weekly cisplatin (20 mg/m(2)) and thoracic RT (60 Gy), and this regimen has significant activity in stage III NSCLC.
Publisher: Elsevier BV
Date: 12-2009
Publisher: Elsevier BV
Date: 2013
Publisher: Springer International Publishing
Date: 29-12-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-08-2020
DOI: 10.1200/JCO.20.01437
Publisher: Wiley
Date: 14-09-2017
DOI: 10.1111/ANS.13728
Abstract: Lung cancer has markedly poorer survival in men. Recognized important prognostic factors are ided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors. Two cohorts of patients treated surgically with curative intent between 2000 and 2009 were utilized. The primary cohort was from Melbourne, Australia, with an independent validation set from the American Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate analyses of validated host-related prognostic factors were performed in both cohorts to investigate the differences in survival between men and women. The Melbourne cohort had 605 patients (61% men) and SEER cohort comprised 55 681 patients (51% men). Disease-specific 5-year survival showed men had statistically significant poorer survival in both cohorts (P < 0.001) Melbourne men at 53.2% compared with women at 68.3%, and SEER 53.3% men and 62.0% women were alive at 5 years. Being male was independently prognostic for disease-specific mortality in the Melbourne cohort after adjustment for ethnicity, smoking history, performance status, age, pathological stage and histology (hazard ratio = 1.54, 95% confidence interval: 1.10-2.16, P = 0.012). Sex differences in non-small cell lung cancer are important irrespective of age, ethnicity, smoking, performance status and tumour, node and metastasis stage. Epidemiological findings such as these should be translated into research and clinical paradigms to determine the factors that influence the survival disadvantage experienced by men.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2021
Publisher: Future Medicine Ltd
Date: 05-2023
Abstract: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase, or ALK. This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years. After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib. The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.LUNGCAN.2014.02.009
Abstract: Thromboembolism is common in lung cancer. Current thromboprophylaxis guidelines lack specific recommendations for appropriate strategies in this high thrombotic risk patient cohort. We profiled lung cancer patients receiving anti-cancer therapy. Thromboembolism incidence and thromboembolism-related mortality rates are reported and we explored patient, disease, and treatment-related risk factors associated with higher thrombotic rates. Retrospective review of lung cancer patients referred to a Comprehensive Cancer Centre between 01/07/2011 and 30/06/2012 for anti-cancer therapy. Data were collected from medical, pharmacy, pathology and diagnostic imaging electronic records. After a median follow up of 10 months (range: 0.03-32 months), 24/222 patients (10.8%) had developed radiologically confirmed thromboembolism 131 events per 1000 person-years (95%CI 87-195). Thromboembolism occurred equally in patients with non-small cell and small cell lung cancer (10.8% and 10.5% respectively), and more frequently among patients with adenocarcinoma compared to squamous cell carcinoma (14.7% and 5.3% respectively). Chemotherapy-treated patients experienced thromboembolism more often than patients who did not receive chemotherapy (HR 5.7 95%CI 2.2-14.8). Radiotherapy was also associated with more frequent thromboembolism (HR 5.2 95%CI 2.0-13.2). New lung cancer diagnosis, presence of metastatic disease, second primary malignancy and Charlson Index ≥ 5 were also associated with higher rates of thromboembolism. Importantly, pharmacological thromboprophylaxis (P-TP) was not routinely or systematically prescribed for ambulant lung cancer patients during any treatment phase, at this institution. The majority (83%) of thromboembolic events occurred in the ambulatory care setting. Morbidity and mortality from thromboembolism occurs frequently in lung cancer. Thromboprophylaxis guidelines should be developed for the ambulatory care setting.
Publisher: AME Publishing Company
Date: 07-2021
DOI: 10.21037/TLCR-20-994
Publisher: Wiley
Date: 10-03-2015
DOI: 10.1002/CAM4.437
Publisher: Springer Science and Business Media LLC
Date: 2013
Abstract: The identification of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in ~3-5% of non-small cell lung cancer (NSCLC) tissues and the demonstration that the first-in-class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. Single-arm studies demonstrating rapid and durable responses in the majority of ALK-positive NSCLC patients treated with crizotinib have been followed by a randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK-positive NSCLC patients. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK-positive NSCLC are currently under evaluation in clinical trials, including second-generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802802), and AP26113, and heat shock protein 90 inhibitors.
Publisher: Future Medicine Ltd
Date: 28-09-2023
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.JOCN.2015.06.005
Abstract: There are limited treatment options for patients with recurrent glioblastoma (GBM). The EnGeneIC delivery vehicle (EDV) is a novel nanocellular (minicell) compound which packages theoretically effective concentrations of chemotherapeutic drugs that are designed to target tumors via minicell-surface attached bispecific proteins (EnGeneIC, Lane Cove West, NSW, Australia). Epidermal growth factor receptor (EGFR) is overexpressed in 40-50% of patients with GBM and is a promising target for new therapeutics. (V)EDVDox contains doxorubicin (Dox) within the minicells and targets EGFR through Vectibix (V Amgen Biologicals, Thousand Oaks, CA, USA). We conducted a first in human Phase I study of (V)EDVDox in adults with recurrent GBM expressing EGFR on immunohistochemistry, following standard therapy including radiation and temozolomide, to establish a safe maximum tolerated dose and determine a recommended Phase II dose (RPTD). (V)EDVDox was administered weekly in an 8week cycle, with dose escalation in successive cohorts of patients using a standard 3+3 design. In total, 14 patients were treated at three dose levels, and the RPTD was identified as 5×10(9)(V)EDVDox. Overall (V)EDVDox was well tolerated, with no dose limiting toxicity and no withdrawals from the study due to adverse events. The most common adverse events were nausea, fever, and chills or rigors, experienced in seven, five and five patients, respectively. Transient uncomplicated hypophosphatemia was seen in seven patients and was not dose-related. Our results demonstrate that (V)EDVDox, up to a dose of 5×10(9)(V)EDVDox weekly, is well tolerated in patients with recurrent GBM.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
Publisher: Springer Science and Business Media LLC
Date: 22-10-2019
Publisher: Elsevier BV
Date: 11-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
Publisher: Springer International Publishing
Date: 24-08-2021
Publisher: Elsevier BV
Date: 03-2019
Publisher: Massachusetts Medical Society
Date: 19-02-2015
DOI: 10.1056/NEJMC1415973
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1038/S41467-021-23331-5
Abstract: Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A 2A receptor (A 2A R). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting A 2A R with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of A 2A R are superior to shRNA mediated knockdown or pharmacological blockade of A 2A R. Mechanistically, human A 2A R-edited CAR T cells are significantly resistant to adenosine-mediated transcriptional changes, resulting in enhanced production of cytokines including IFNγ and TNF, and increased expression of JAK-STAT signaling pathway associated genes. A 2A R deficient CAR T cells are well tolerated and do not induce overt pathologies in mice, supporting the use of CRISPR/Cas9 to target A 2A R for the improvement of CAR T cell function in the clinic.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2020
DOI: 10.1200/JCO.19.02654
Abstract: Lifirafenib is an investigational, reversible inhibitor of B-RAF V600E , wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. The maximum tolerated dose was established as 40 mg/d dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23 17.6%) and fatigue (n = 13 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAF V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF V600E thyroid cancer apillary thyroid cancer (PTC n = 2), and B-RAF V600E low-grade serous ovarian cancer (LGSOC n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 –mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2015
DOI: 10.1007/S40265-015-0415-9
Abstract: Rearrangements of the anaplastic lymphoma kinase (ALK) gene originally discovered nearly 20 years ago in the context of anaplastic large cell lymphoma were identified as oncogenic drivers in a subset of non-small cell lung cancers (NSCLCs) in 2007. These ALK gene rearrangements are present in 3-5 % of NSCLC patients, typically younger, never or light smokers with adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor with significant activity in ALK-positive NSCLC that received accelerated US Food and Drug Administration approval for treatment of ALK-positive NSCLC in 2011, just 4 years after identification of ALK rearrangements in this setting. Subsequently, two phase III trials have shown crizotinib to have a tolerable toxicity profile and to be superior to standard chemotherapy for the first- or second-line treatment of advanced ALK-positive lung cancer and numerous countries have approved its use. Despite initial responses, acquired resistance to crizotinib invariably leads to disease progression. Mechanisms of resistance have been described to include ALK tyrosine kinase mutations, activation of bypass signalling pathways and pharmacokinetic failure of crizotinib. Several next-generation ALK inhibitors, including ceritinib and alectinib, are in clinical development and show efficacy in both the crizotinib naïve and crizotinib refractory settings. Ongoing clinical trials will identify the optimal strategy to incorporate these novel agents in the treatment of patients with ALK-positive NSCLC.
Publisher: MDPI AG
Date: 12-09-2023
DOI: 10.3390/PR11092730
Publisher: Future Medicine Ltd
Date: 12-2005
Abstract: Pemetrexed is a new generation antifolate anticancer agent that inhibits several folate-dependent enzymes required for production of DNA and RNA intermediates. Early studies showed significant hematologic and nonhematologic toxicities with this agent. However it was found that many of these toxicities related to functional folate status and could be markedly reduced through routine supplementation with folic acid and vitamin B 12 , without adversely affecting efficacy. Phase III studies with pemetrexed have established a clinical role for this drug as a single agent in the second-line treatment of non-small cell lung cancer and in combination with cisplatin for the frontline treatment of unresectable malignant pleural mesothelioma. Clinical trials of pemetrexed alone or in combination with other chemotherapeutic agents have shown considerable activity in many tumor types including colorectal, pancreatic and breast cancer, and urothelial tumors.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 06-2022
Publisher: Elsevier BV
Date: 07-2019
Publisher: MDPI AG
Date: 30-12-2020
DOI: 10.3390/RS13010101
Abstract: The presence of noise in remote sensing satellite images may cause limitations in analysis and object recognition. Noise suppression based on thresholding neural network (TNN) and optimization algorithms perform well in de-noising. However, there are some problems that need to be addressed. Furthermore, finding the optimal threshold value is a challenging task for learning algorithms. Moreover, in an optimization-based noise removal technique, we must utilize the optimization algorithm to overcome the problem. These methods are effective at reducing noise but may blur some parts of an image, and they are time-consuming. This flaw motivated the authors to develop an efficient de-noising method to discard un-wanted noises from these images. This study presents a new enhanced adaptive generalized Gaussian distribution (AGGD) threshold for satellite and hyperspectral image (HSI) de-noising. This function is data-driven, non-linear, and it can be fitted to any image. Applying this function provides us with an optimum threshold value without using any least mean square (LMS) learning or optimization algorithms. Thus, it is possible to save the processing time as well. The proposed function contains two main parts. There is an AGGD threshold in the interval [−σn, σn], and a new non-linear function behind the interval. These combined functions can tune the wavelet coefficients properly. We applied the proposed technique to various satellite remote sensing images. We also used hyperspectral remote sensing images from AVIRIS, HYDICE, and ROSIS sensors for our experimental analysis and validation process. We applied peak signal-to-noise ratio (PSNR) and Mean Structural Similarity Index (MSSIM) to measure and evaluate the performance analysis of different de-noising techniques. Finally, this study shows the superiority of the developed method as compared with the previous TNN and optimization-based noise suppression methods. Moreover, as the results indicate, the proposed method improves PSNR values and visual inspection significantly when compared with various image de-noising methods.
Publisher: Wiley
Date: 11-12-2007
DOI: 10.1111/J.1471-4159.2007.05183.X
Abstract: This study was designed to assess the influence of high-energy head-focused microwave irradiation and the post-mortem interval on measurements of the mouse brain proteome. Difference gel electrophoresis was used to compare mouse brain protein levels in animals killed by decapitation, where the tissue was held at 25 degrees C for selected time intervals post-mortem, and by high-energy head-focused microwave irradiation followed by immediate resection. Microwave-mediated killing was used because it comprehensively snap-inactivates enzymes while largely retaining brain cytoarchitecture. Of the 912 protein spots common to at least eight of 10 gels analyzed, 35 (3.8%) showed significant differences in levels (t-test p < 0.05) depending on whether animals were killed by microwave irradiation or decapitation. When animals were killed by decapitation, 43 protein spots (4.7%) showed changes in levels over the post-mortem interval (anova p < 0.05). The vast majority of the near 1000 proteins evident on a 2D gel were stable for up to 4 h. These data have important implications for studies of proteins in the brain, whether based on analysis of tissue derived from animal models or from humans.
Publisher: Society of Nuclear Medicine
Date: 27-05-2014
DOI: 10.2967/JNUMED.113.136127
Abstract: Historically, it has been difficult to monitor the acute impact of anticancer therapies on hematopoietic organs on a whole-body scale. Deeper understanding of the effect of treatments on bone marrow would be of great potential value in the rational design of intensive treatment regimens. 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a functional radiotracer used to study cellular proliferation. It is trapped in cells in proportion to thymidine-kinase 1 enzyme expression, which is upregulated during DNA synthesis. This study investigates the potential of (18)F-FLT to monitor acute effects of chemotherapy on cellular proliferation and its recovery in bone marrow, spleen, and liver during treatment with 2 different chemotherapy regimens. Sixty patients with non-small cell lung cancer underwent concurrent radical chemoradiotherapy to 60 Gy in 6 wk with either cisplatin/etoposide (C/E, n = 28) weeks 1 and 5 or weekly carboplatin aclitaxel (C/P, n = 32) regimens. (18)F-FLT and (18)F-FDG PET with CT were performed at baseline, week 2 (day 9 for (18)F-FLT and day 10 for (18)F-FDG PET), and week 4 (day 23 for (18)F-FLT and day 24 for (18)F-FDG PET). Visual and semiquantitative standardized uptake value (SUV) measurements were performed in bone marrow outside the radiotherapy field, liver, spleen, and small bowel. These were correlated to blood counts and smears in a subset of patients. The C/E group exhibited a drop in bone marrow (18)F-FLT uptake at week 2 (median SUVmax [maximum SUV] decrease to 31%, 8.7-6.0, P 0.05). Spleen uptake in both cohorts decreased at week 2, with intense rebound activity at week 4 (SUVmax week 4 at 58% above baseline: 2.4-3.8, for C/E, respectively, 30% for C/P: 2.7-3.5, P < 0.001). Liver uptake changed little. (18)F-FLT changes preceded neutrophil count reductions. (18)F-FDG uptake in marrow liver and spleen changed much less than (18)F-FLT. (18)F-FLT imaging may be used to quantify impairment and recovery of bone marrow by specific chemotherapy regimens and may also enable imaging of organ-specific processes such as spleen activation. (18)F-FLT is superior to (18)F-FDG for this purpose. This technology may support novel treatment planning and monitoring approaches in oncology patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 20-07-2017
DOI: 10.1038/BJC.2017.232
Publisher: Elsevier BV
Date: 12-2017
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: 12-05-2016
DOI: 10.1158/1078-0432.CCR-15-1260
Abstract: Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. Experimental Design: S les were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing. Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P & 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 – 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 – 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response. Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res 22(10) 2386–95. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2014
DOI: 10.1007/S00520-014-2170-Y
Abstract: The purpose of this study was to report the opinions and self-reported practices of clinicians, as well as the availability of decision support tools, regarding appropriate thromboprophylaxis for patients with lung cancer to identify variation in practice and/or ergence from evidence-based clinical practice guidelines (CPG). A computer-generated survey (SurveyMonkey software) was distributed to surgical, radiation and medical oncologists with lung cancer specialisation, via membership of the Australian Lung Cancer Trials Group (ALTG) from May to September 2013. Seventy-two clinicians, from public, private, specialist and general hospitals, completed the survey (46% response rate). Hospital-endorsed CPG were widely available (91%) however, these routinely lacked robust recommendations for the ambulatory care setting (98%) and risk stratification tools (65%). Clinicians consistently identified ambulatory care treatment modalities (chemotherapy, alone or in combination with radiotherapy) as having similar (high) thrombotic risk as surgery. Timing and duration of pharmacological thromboprophylaxis prescribing among surgical oncologists varied and were ergent from guideline recommendations. Fifty-eight percent of surveyed clinicians cited a lack of high-quality data to guide preventative strategies in lung cancer patients. Clinicians consistently identified patients with lung cancer as having a high thromboembolic risk in both ambulatory and surgical settings, but with differences in recommendations and variation in practice. CPG lacked robust recommendations for the ambulatory care setting, the main arena for the multimodality lung cancer treatment paradigm.
Publisher: Korean Cancer Association
Date: 15-07-2018
DOI: 10.4143/CRT.2017.280
Publisher: Wiley
Date: 30-01-2014
DOI: 10.1002/IJC.28727
Abstract: CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2017
Publisher: Elsevier BV
Date: 10-2019
Publisher: MDPI AG
Date: 11-06-2020
Abstract: Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-γ), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-β) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.
Publisher: AME Publishing Company
Date: 06-2021
DOI: 10.21037/TLCR-20-772
Publisher: Wiley
Date: 06-2014
DOI: 10.1111/IMJ.12449
Abstract: Molecular characterisation of non-squamous non-small-cell lung cancer (NSCLC) is required to direct optimal treatment. Treatment of NSCLC with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase (EGFR-TKI) should be guided by the presence of activating mutations of the EGFR gene. To gain insight into the rate of testing, the range of tissues s les, test utility and outcome when cost of testing as a barrier to access is removed in the Australian setting. In October 2010, a sponsored programme was commenced to gather data on EGFR gene mutation testing in Australia. Partnering laboratories were funded for provision of de-identified results. For participating patients, the programme supported the test charge. Mutation testing was performed using Sanger sequencing of exons 18-21 of the EGFR. S les 2013 were submitted from 2012 patients. Full sequencing was achieved in 1717 (85%). Failure of full sequencing was more likely in s les derived from fine needle aspiration(FNA) biopsy than tissue biopsy or pleural ericardial fluid cell blocks OR 3.1 (95% CI 1.9-5.2). There were 359 mutations seen in 337 patients. 14.5% of cases had a classical mutation conferring sensitivity to EGFR-TKI. In addition there was a range of less common mutations - some predicting responses and others of uncertain significance. 1.4% of cases had mutations associated with non-responsiveness to EGFR-TKI. EGFR gene mutation testing is feasible on local and interstate lung cancer s les. The rate of valid test outcomes is high, but FNA s les are associated with more frequent test failure.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 02-2019
Publisher: Springer Science and Business Media LLC
Date: 09-2005
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.PATHOL.2017.07.002
Abstract: We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.IJROBP.2017.02.088
Abstract: To report on the outcomes of a novel treatment regimen for patients with locally advanced head and neck squamous cell carcinoma who were fit for curative treatment but not fit for cisplatin. Single-arm phase 1/2 study of previously untreated patients with biopsy-proven SCC of the oropharynx, larynx, or hypopharynx. The primary endpoint was feasibility of the regimen, defined as the proportion of patients successfully completing treatment. Secondary endpoints were locoregional control (LRC), failure-free survival (FFS), overall survival (OS), and treatment toxicities. Sixty patients were included in the study. Their mean age was 66 years (range, 42-87 years) 28% of patients were >70 years. The median follow-up time was 4 years. Compliance with treatment was very high: feasibility was 55/60 (91.7%, 90% CI: 83.3%-96.7%), which satisfied the predefined criteria. The 4-year LRC was 82% (95% CI: 71-94), the FFS was 72% (95% CI: 60-85), and the OS was 77% (95% CI: 66-90). The cumulative incidences of first failure of any type at 4 years were 5.2% local, 1.8% local and distant, 8.5% regional, 1.7% regional and distant, 3.5% distant, and 7.7% death (any cause). The 4-year FFS in the patients aged ≤70 years and >70 years were 71% (95% CI: 58-88) and 73% (95% CI: 54-100), respectively (log-rank P=.801). Their 4-year OS was 79% (95% CI: 66-93) and 73% (95% CI: 53-100), respectively (log-rank P=.708). Significant late treatment toxicities were very few. This treatment regimen was feasible and safe in this patient cohort unfit for cisplatin, 28% of whom were older than 70 years. Carboplatin-based and cetuximab-based chemoradiation regimens warrant further investigation in patients with a contraindication to cisplatin.
Publisher: Oxford University Press (OUP)
Date: 20-07-2023
DOI: 10.1093/BJD/LJAD250
Abstract: Cutaneous squamous cell carcinomas (cSCCs) are the second most diagnosed skin cancer worldwide however, little is known about the pathobiological factors that contribute to the erse clinical outcomes seen. To profile cSCCs comprehensively and identify the pathological processes that contribute to the disparities seen in their clinical behaviour. We characterized the genomic, transcriptomic and immunohistochemical profiles of 211 cSCC tumours, including 37 cSCCs from immunocompromised patients. cSCCs from immunocompromised patients were characterized by a lack of B cells in the peritumoral stroma compared with immunocompetent patients. Further, an abundance of a memory B-cell-like population in the peritumoral stroma was associated with a better prognosis in all patients (immunocompetent and immunocompromised), as well as only immunocompetent patients. No differences in genetic variants, tumour mutational burden or mutational signatures were observed between cSCCs from immunocompetent and immunocompromised patients. Thus, differences in survival between cSCCs from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but may be associated with differential host immune response. cSCC not from a primary head and neck site had lower tumour mutational burden and exhibited upregulation of the epithelial–mesenchymal transition programme compared with head and neck cSCC. Both factors were implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. We identified tumour and host immune factors that contribute to the disparate clinical behaviour of cSCC, with broad translational application, including prognostication, treatment prediction to current therapies and the identification of novel anticancer therapy approaches in cSCC.
Publisher: Wiley
Date: 03-09-2019
DOI: 10.1002/QRE.2566
Publisher: Elsevier BV
Date: 02-2022
Publisher: IEEE
Date: 18-12-2020
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JMOLDX.2017.11.004
Abstract: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. To systematically review and update the 2013 guideline to affirm its validity to assess the evidence of new genetic discoveries, technologies, and therapies and to issue an evidence-based update. The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology s les, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2009
Publisher: Future Medicine Ltd
Date: 03-2020
Abstract: Selpercatinib, a novel, highly selective and potent, inhibitor of RET, demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov)
Publisher: Elsevier BV
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 03-09-2018
DOI: 10.1007/S00280-018-3679-4
Abstract: 5-Fluorouracil (5FU) drug exposure correlates with treatment response and toxicity in cancer patients. Dosing is based upon body surface area which does not correlate with 5FU pharmacokinetics (PK) harmacodynamics. Therapeutic drug monitoring has enabled real-time 5FU dose adjustments: reducing toxicity with increased efficacy. The aim of this study was to assess feasibility of a 5FU monitoring service utilising a commercial kit in a quaternary cancer centre and to compare PK parameters to previously published studies. Cancer patients receiving continuous infusional (CI) 5FU with ECOG PS 0-2, and adequate organ function, were eligible. Patients had blood s les taken at t = 0, mid infusion (if feasible) then 2 h pre infusion end. 5FU levels were measured using a commercial kit (My-5FU PCM™). A feasibility questionnaire was completed by trial nurses and toxicity data were recorded at baseline and at the commencement of the next cycle. 5FU pharmacokinetic exposure parameters were calculated. Twenty patients (12 male 8 female), median age 62, (range 37-71) had s les taken. Twenty (100%) feasibility forms were available for assessment. Blood s les were taken at 51/69 (74%) specified time points. Ease of s le processing was recorded as easy in all 20 patients. Patient compliance with scheduled visits was 18/20 (90%). One form noted other difficulties with predicting end of infusion time. 19/20 patients had blood s les analysed. Mean measured 5FU AUC (0-Tlast) for 5FU 1 g/m Therapeutic 5FU drug monitoring was feasible using commercial kits and analysers and hence warrants development as a routine standard of care in cancer patients. The variability in the 5FU exposure parameters is consistent with other studies using the My 5FU PCM kit.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-06-2019
DOI: 10.1126/SCITRANSLMED.AAW2293
Abstract: Immune checkpoints can be targeted using exogenous reagents or via genetic modification to enhance the efficacy of adoptive T cell therapy.
Publisher: Society of Nuclear Medicine
Date: 28-12-2019
Publisher: MDPI AG
Date: 11-11-2021
Abstract: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer diagnosed worldwide. CSCC is generally localized and managed with local therapies such as excision and/or radiotherapy. For patients with unresectable or metastatic disease, recent improvements in our understanding of the underlying biology have led to significant advancements in treatment approaches—including the use of immune checkpoint inhibition (ICI)—which have resulted in substantial gains in response and survival compared to traditional cytotoxic approaches. However, there is a lack of understanding of the biology underpinning CSCC in immunocompromised patients, in whom the risk of developing CSCC is hundreds of times higher compared to immunocompetent patients. Furthermore, current ICI approaches are associated with significant risk of graft rejection in organ transplant recipients who make up a significant proportion of immunocompromised patients. Ongoing scientific and clinical research efforts are needed in order to maintain momentum to increase our understanding and refine our therapeutic approaches for patients with CSCC.
Publisher: American Association for Cancer Research (AACR)
Date: 28-02-2018
DOI: 10.1158/2326-6066.CIR-17-0299
Abstract: Human papilloma virus–positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a distinct subgroup of head and neck cancers associated with clinical outcomes that are not accurately categorized by existing tumor–node–metastasis-based staging methods. Given the significant impact of immune parameters, such as tumor-infiltrating lymphocytes (TIL) in many cancers, we sought to determine if immunophenotyping tumors can improve categorization of HPV+ OPSCCs for prognostic purposes. In a cohort of 190 patients with HPV+ OPSCC, we quantified and determined the localization of CD8+ TILs, as well as PD-L1–expressing tumor cells (TC) and immune cells (IC). The prognostic significance of these parameters on overall survival (OS) was evaluated, and their contribution to existing prognostic models was determined. High CD8+ TIL abundance (≥30% on stromal or intratumoral ICs) was seen in 61.3% patients and was associated with improved OS [HR, 0.4 95% confidence interval (CI), 0.2–0.9 P = 0.017]. Although the expression of PD-L1 on TC was not prognostic, high expression of PD-L1 on ≥5% of intratumoral ICs was found in 38.5% patients and was significantly associated with improved OS (HR, 0.37 95% CI, 0.15–0.93 P = 0. 023). Both high intratumoral IC PD-L1 expression and abundant CD8+ TILs in HPV+ OPSCCs identify subgroups of patients with excellent outcomes and provide additional prognostic information beyond existing staging systems. Cancer Immunol Res 6(3) 295–304. ©2018 AACR.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1038/MODPATHOL.2013.87
Abstract: Rearrangements of anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) define a molecular subgroup of tumors characterized clinically by sensitivity to ALK tyrosine kinase inhibitors such as crizotinib. Although ALK rearrangements may be detected by reverse transcriptase-PCR, immunohistochemistry or fluorescence in situ hybridization (FISH), the optimal clinical strategy for identifying ALK rearrangements in clinical s les remains to be determined. We evaluated immunohistochemistry using three different antibodies (ALK1, 5A4 and D5F3 clones) to detect ALK rearrangements and compared those with FISH. We report the frequency and clinicopathologic features of lung cancers harboring ALK translocations in 594 resected NSCLCs (470 adenocarcinomas 83 squamous carcinomas, 26 large cell carcinomas and 15 other histological subtypes) using a tissue microarray approach. We identified an ALK gene rearrangement in 7/594 cases (1%) by FISH and all anti-ALK antibodies correctly identified the seven ALK-positive cases (100% sensitivity), although the intensity of staining was weak in some cases. These data indicate that the use of antibodies with high sensitivity and avidity to ALK may provide an effective pre-screening technique to complement the more expensive and labor-intensive approach of ALK FISH testing.
Publisher: Springer International Publishing
Date: 2022
Publisher: Elsevier BV
Date: 10-2021
Publisher: Springer Science and Business Media LLC
Date: 18-07-2016
Publisher: Springer Science and Business Media LLC
Date: 22-06-2018
Publisher: Springer International Publishing
Date: 2022
Publisher: Elsevier BV
Date: 09-2022
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.CLLC.2018.08.004
Abstract: Non-small-cell lung cancer (NSCLC) has disproportionately negative outcomes in men compared with women. The importance of the relationship between sex and tumor, node, metastases (TNM) staging system remains unknown. The objective of this study was to investigate the effect of sex on NSCLC survival for each stage in the eighth edition of the TNM staging system in NSCLC. Two cohorts treated surgically with curative intent between 2000 and 2010 were analyzed. The primary cohort was from Australia with a second population set from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses of putative and validated prognostic factors were undertaken to investigate sex-dependent prognostication with detailed analyses of sex differences in each TNM stage. The primary outcome was disease-specific survival (DSS) at 5 years. Inclusion criteria were met by 555 patients in the Australian cohort, 335 men (60.4%) and 220 (39.6%) women and 47,706 patients from the SEER cohort, 24,671 men (51.7%) and 23,035 women (48.3%). Five-year DSS was significantly worse for men in multivariate analyses for the Australian (hazard ratio [HR], 1.44 95% confidence interval [CI], 1.04-1.98 P = .026) and SEER (HR, 1.24 95% CI, 1.20-1.28 P < .001) cohorts. Detailed analysis of TNM stage sex differences revealed a consistent pattern of men having worse survival than women across stages in both cohorts. The poorer survival in men with NSCLC presents research and clinical communities with an important challenge. This study's findings suggest that for men and women diagnosed with NSCLC, and managed surgically, stage-specific outcomes should be quoted separately and consideration to a rapid prognostic score with sex combined with staging as a key element.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.ORALONCOLOGY.2019.104516
Abstract: We previously showed in human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV+OPSCC) that the presence of intratumoral (IT) PD-L1
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: Wiley
Date: 09-12-2022
DOI: 10.1002/QRE.3247
Abstract: This research aims to study the applicability of game theory to system safety and reliability decision‐making problems and corresponding objective conflicts using non‐cooperative games. The non‐cooperative games would solve the games considering non‐cooperative cognitive decision‐makers behaviors, which are commonly ignored by other system safety and reliability analysis (SSRA) techniques, assuming that there would be perfect cooperation between the players (decision‐makers). Game theory can also recognize and understand the decision‐makers' behaviors and provide a “win‐win” situation for all players and the best broader system outcomes. The paper also shows the use of dynamic game theory in system safety and reliability decision‐making problems over time. The results indicate the effectiveness and efficiency of game theory and show how this can better reflect decision‐makers’ opinions in system safety and reliability decision‐making problems.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2015
DOI: 10.1038/NATURE14664
Publisher: Elsevier BV
Date: 09-2016
Publisher: Springer International Publishing
Date: 2022
Publisher: American Association for Cancer Research (AACR)
Date: 08-2017
DOI: 10.1158/1535-7163.MCT-17-0174
Abstract: Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including lification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 lification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridization is a better predictor of response to FGFR inhibition than FGFR1 gene lification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histologic subtypes of non–small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single-agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors. Mol Cancer Ther 16(8) 1610–22. ©2017 AACR.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-06-2015
Abstract: Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non–small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652 P .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.EJCA.2013.11.032
Abstract: This randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1-3, to standard carboplatin aclitaxel chemotherapy in advanced non-small cell lung cancer. Eligible patients received paclitaxel (200mg/m(2)) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib lacebo 20mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4-6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽ 0.70. The trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66-1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71-1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69-1.30, p=0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia. The addition of cediranib 20mg daily to carboplatin aclitaxel chemotherapy increased RR and toxicity, but not survival.
Publisher: Springer Science and Business Media LLC
Date: 2020
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.JTHO.2017.05.019
Abstract: Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.
Publisher: Wiley
Date: 12-12-2018
DOI: 10.5694/MJA2.12046
Abstract: Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers. Immunotherapy has revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre-existing active immune microenvironment that can be reactivated by ICIs. It is now recognised that radiotherapy does not only directly kill tumour cells but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system and, therefore, acting as an in situ vaccine. Radiotherapy increases expression of tumour-associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and, most importantly, stimulates the proliferation and priming of cytotoxic CD8+ T cells in the tumour microenvironment. This immunological cascade specifically generates activated T cells able to induce immunogenic cell death directed against cancer cells bearing those antigens. By its ability to overcome some tumour immune escape mechanisms, radiation provides a non-pharmacological and cost-effective approach to potentially improve the systemic response to immune checkpoints inhibitors.
Publisher: Wiley
Date: 27-02-2015
DOI: 10.1111/AJCO.12178
Abstract: The potential beneficial interaction between erlotinib and chemotherapy may require sequencing or pharmacodynamic separation. The aim of this study was to evaluate the efficacy and tolerance of sequential erlotinib and gemcitabine versus gemcitabine monotherapy as first-line therapy in elderly or ECOG PS-2 patients with advanced non-small cell lung carcinoma. The primary objective of this multicenter randomized Phase II study was progression-free survival (PFS). Secondary objectives were overall response rate (ORR), disease control rate, response duration, overall survival and safety. Patients were randomized to either gemcitabine (1250 mg/m2 Day 1, 8 q28 days) followed by erlotinib (150 mg/day on day 15 through day 28), (EG-arm), or gemcitabine monotherapy (1000 mg/m2 Days 1, 8, 15 q28 days), (G-arm) for up to six cycles. Fifty-four patients were recruited, 28 G-arm and 26 EG-arm. Overall, efficacy results were not significantly different between study arms. Median PFS and ORR for the G- versus EG-arms were 8.0 versus 10.3 weeks (hazard ratio 1.3 95% confidence interval [0.63 .68] P=0.48) and 7.1 versus 3.8 percent respectively (difference -3.30 95% confidence interval [-17.5 .9]). The majority of adverse events (AEs) in both arms were Grade 1-2. The commonest AEs recorded in the EG- and G-arms were rash-like events (65 percent) and nausea (42 percent) respectively. Four patients (17 percent) in EG-arm and five (16 percent) in G-arm experienced at least one treatment-related serious AE. In this study, patients with non-small cell lung carcinoma at ECOG PS-2 or aged ≥70 years derived no efficacy advantage from sequential erlotinib in combination with gemcitabine relative to gemcitabine alone. No unexpected safety findings were noted.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2012
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.CLLC.2021.04.009
Abstract: Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non-small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established we sought to clarify them using a multinational patient database. Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics. Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51% P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62). Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.
Publisher: Elsevier BV
Date: 03-2014
Publisher: Massachusetts Medical Society
Date: 04-12-2014
Publisher: Springer Science and Business Media LLC
Date: 02-09-2012
DOI: 10.1038/NG.2396
Publisher: Elsevier BV
Date: 2017
Publisher: Massachusetts Medical Society
Date: 28-10-2010
Publisher: Elsevier BV
Date: 10-2011
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2011
DOI: 10.1158/1078-0432.CCR-10-2763
Abstract: Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib. Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions atient) of 15% or more maximum standardized uptake value. PFS was investigator-determined. Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders. Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res 17(10) 3304–15. ©2011 AACR.
Publisher: Elsevier BV
Date: 11-2005
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 10-2019
Abstract: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.
Publisher: Springer Science and Business Media LLC
Date: 05-01-2015
Publisher: AMPCo
Date: 24-11-2020
DOI: 10.5694/MJA2.50426
Publisher: Springer International Publishing
Date: 2022
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1038/MODPATHOL.2014.71
Abstract: The aim of this study was to investigate the prevalence of fibroblast growth factor receptor 1 (FGFR1) lification by fluorescence in situ hybridization (FISH) in a lung cancer patient cohort and to correlate results with morphology, silver in situ hybridization (SISH), and patient outcome. FGFR1 FISH and SISH were performed in 406 and 385 lung cancer cases, respectively, and the results were compared. High-level FGFR1 lification was defined as the ratio of FGFR1/centromere 8 ≥2, or tumor cell percentage with ≥15 signals ≥10%, or average number of signals/tumor cell nucleus ≥6. Low-level lification was defined as tumor cell percentage with ≥5 signals ≥50%. Of 406 tumors tested, there were 191 squamous cell carcinomas, 28 carcinomas with focal squamous morphology, 24 large cell carcinomas with squamous immunoprofile, 115 adenocarcinomas, 17 neuroendocrine tumors, and 31 carcinomas without squamous morphology or immunoprofile. FGFR1 FISH was assessable in 368 tumors, with FGFR1 lification identified in 50, including 48 tumors with either squamous morphology or immunoprofile (48 of 225, 21.3%), and two 'marker-null' tumors without squamous or glandular morphology or immunoprofile (2 of 143, 1.4% P<0.0001). FGFR1 SISH was assessable in 347 tumors. All 46 FGFR1 FISH- lified tumors with tumor available for testing showed lification with SISH, while all other tumors were negative. There was no relationship between FGFR1 lification status and disease-free (P=0.88, HR=1.04, 95% confidence interval (CI)=0.67-1.60) or overall survival (P=0.97, HR=1.01, 95% CI=0.65-1.58) in surgically radically treated patients with tumors with any squamous morphology or immunoprofile. FGFR1 lification is a common abnormality in tumors with any squamous morphology or immunoprofile, but it is also present in 'marker-null' tumors. The results of FGFR1 SISH showed 1:1 correlation with the results of FGFR1 FISH, indicating that SISH may be an alternative method to detect FGFR1 lification. No relationship was detected between patient outcome and FGFR1 lification.
Publisher: Society of Nuclear Medicine
Date: 15-07-2011
DOI: 10.2967/JNUMED.110.086967
Abstract: The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling. Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting. Treatment of c-MET- lified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 μM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively. While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JTHO.2017.12.001
Abstract: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. To systematically review and update the 2013 guideline to affirm its validity to assess the evidence of new genetic discoveries, technologies, and therapies and to issue an evidence-based update. The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology s les, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
Publisher: Wiley
Date: 13-10-2015
DOI: 10.1002/HED.24169
Abstract: There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus-positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009. Data from patients with low-risk HPV(+) oropharyngeal SCC treated with weekly cisplatin (40 mg/m(2) ) and 70 Gy radiotherapy were collected. Low risk was defined as stage III to IV oropharyngeal SCC excluding T1-2N1, T4 or N3 disease, or N2b to N2c disease in patients with >10 pack-year smoking history. Of 31 patients, the median age was 56 years (range, 41-69 years). All patients completed 70 Gy radiotherapy within 51 days and 84% completed at least 5 cycles of cisplatin. Grade 3 mucositis occurred in 22 patients (71%) and grade 3 febrile neutropenia in 6 patients (19%). No patients required enteral feeding at 12 months. The median follow-up was 30 months (range, 21-57 months) with no recurrences or deaths. Concurrent weekly cisplatin is relatively well-tolerated and associated with excellent disease control in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1117-E1121, 2016.
Publisher: Public Library of Science (PLoS)
Date: 11-12-2015
Publisher: Springer Science and Business Media LLC
Date: 09-2014
DOI: 10.1038/NATURE13673
Publisher: Hindawi Limited
Date: 08-03-2022
DOI: 10.1155/2022/6162829
Abstract: The hazardous nature of the chemical materials is of significant concern in the economic viability of rail transportation globally. The potential risks of these materials to cause severe health impairments and catastrophic accidents have been widely studied and reported. Moreover, several models have been employed for assessing the risks associated with transporting hazardous materials by rail. However, a more holistic, quantitative, and robust model should incorporate more potential risk-triggered criteria, especially those causing severe health loss and devastating consequences like vapor cloud explosion. This study develops a risk assessment model by incorporating potential health risk factors and the obstacle circumstances. The potential risk factors are population density, route distance from residential areas, and the availability of sensitive third parties for health consequences. The proposed model utilizes Bayesian networks for causality modeling of the material release scenarios and fuzzy set theory for estimating the health effects and severity impact coefficient. Finally, in idual risk curves and safe distances from the railway are developed. A real rail system for gasoline transportation in Tehran is investigated to evaluate the model’s effectiveness. The study provides panoramic leverages for risk-managed decision-making for safely transporting hazardous material by rail.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2014
DOI: 10.1038/NCOMMS4518
Publisher: Springer Science and Business Media LLC
Date: 09-01-2019
Publisher: Springer International Publishing
Date: 2022
Publisher: Elsevier BV
Date: 10-2017
Publisher: Informa UK Limited
Date: 09-05-2020
DOI: 10.1080/10803548.2018.1454636
Abstract: This study aimed at establishing fault tree analysis (FTA) using expert opinion to compute the probability of an event. To find the probability of the top event (TE), all probabilities of the basic events (BEs) should be available when the FTA is drawn. In this case, employing expert judgment can be used as an alternative to failure data in an awkward situation. The fuzzy analytical hierarchy process as a standard technique is used to give a specific weight to each expert, and fuzzy set theory is engaged for aggregating expert opinion. In this regard, the probability of BEs will be computed and, consequently, the probability of the TE obtained using Boolean algebra. Additionally, to reduce the probability of the TE in terms of three parameters (safety consequences, cost and benefit), the importance measurement technique and modified TOPSIS was employed. The effectiveness of the proposed approach is demonstrated with a real-life case study.
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: American Association for Cancer Research (AACR)
Date: 08-10-2021
DOI: 10.1158/1535-7163.MCT-21-0632
Abstract: NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK+ patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKAG595R SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA–NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK+ cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
Publisher: Springer International Publishing
Date: 2022
Publisher: Wiley
Date: 17-01-2022
Abstract: Internal temperature estimation is critical to the safe operation of lithium‐ion batteries (LIBs), and electrochemical impedance spectroscopy (EIS)‐based methods have been demonstrated to be promising. However, accurate internal temperature estimation under variant state‐of‐charge (SoC) is still challenging due to the combined impact of temperature and SoC on the EIS. Accordingly, this work proposes a novel EIS‐based internal temperature estimation approach, for which SoC‐insensitive EIS features are quantitatively selected and utilized for temperature estimation using support vector regression (SVR) with unknown SoC. First, the EIS feature selection is performed to select SoC‐insensitive features from the imaginary of impedance spectrum. Subsequently, an SVR‐based framework and a well‐trained SVR model are created to estimate the internal temperature of LIBs. The performance of the proposed model is validated by its lowest estimation error (0.57 °C) under known and unknown SoCs compared to that of the existing methodologies. The results confirmed that the proposed method holds the advantage in estimating the internal battery temperature with different SOCs.
Publisher: Springer International Publishing
Date: 2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2023
DOI: 10.1200/JCO.23.01768
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/AJCO.12754
Abstract: Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-09-2009
Abstract: The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non–small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK–positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.LUNGCAN.2021.11.007
Abstract: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study. ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg. NGS data were generated for 85 pts (ALKi-pretreated [n = 54] ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF lification. This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients. ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, t2/show/NCT01283516.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Wiley
Date: 16-02-2016
DOI: 10.1002/CNCR.29901
Abstract: The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08 95% confidence interval [CI], 0.85-1.36 P = .528), cancer-specific (hazard ratio, 1.12 95% CI, 0.77-1.64 P = .542), or progression-free survival (hazard ratio, 1.03 95% CI, 0.83-1.29 P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.
Publisher: Wiley
Date: 09-2010
DOI: 10.1111/J.1445-5994.2009.02141.X
Abstract: Lung cancer accounts for more cancer‐related deaths than any other malignancy in Australia and worldwide. Non‐small cell lung cancer (NSCLC) accounts for about 85% of lung cancers and is associated with a 5‐year survival of only 15%. Treatment with platinum‐based doublets in the first‐line setting and single agent chemotherapy in the second‐line setting has improved survival and quality of life in patients with NSCLC. However, the benefits associated with chemotherapy are modest and serve to stress the need for novel therapeutic approaches. In the last decade a range of targeted therapies has been evaluated in NSCLC. Dramatic and often durable responses were seen in patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib particularly in females, non‐smokers, patients of East Asian ethnicity and those with adenocarcinomas – a group subsequently found to be enriched for tumours with activating EGFR mutations. Large randomized phase III trials have since established a role for EGFR TKI in the second‐ and third‐line setting as well as a potential role for the monoclonal antibodies bevacizumab and cetuximab, directed at vascular endothelial growth factor and EGFR, respectively, in the combination with chemotherapy in the first‐line setting. Recently it has been shown that patients with EGFR mutations may benefit from gefitinib in the first‐line setting. Other promising agents under evaluation are inhibitors of the insulin‐like growth factor‐1 receptor and inhibitors of recently described ALK gene rearrangements.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 14-02-2018
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.ORALONCOLOGY.2013.01.006
Abstract: Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 (FGFR1) lification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 lification in OTSCC. The frequency of FGFR1 lification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 lification with clinical characteristics and outcome were determined. FGFR1 gene lification was present in 9.3% (10/107) of cases and was significantly associated with smoking status (P = 0.03). FGFR1 lification was seen more commonly in males (9/10 lified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P>0.05). Outcome was not significantly different between FGFR1 lified and non- lified patients. Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing lification of the gene. FGFR1 lification may represent a therapeutic target in OTSCC.
Publisher: American Society of Hematology
Date: 03-09-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-2014
DOI: 10.1158/2159-8290.CD-13-0633
Abstract: We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P & 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov 4(4) 415–22. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 377
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490194.V1
Abstract: Supplementary material
Publisher: Elsevier BV
Date: 12-2019
Publisher: Society of Nuclear Medicine
Date: 14-09-2012
DOI: 10.2967/JNUMED.112.105197
Abstract: The identification of robust prognostic factors for patients with early-stage non-small cell lung cancer (NSCLC) is clinically important. The International Association for the Study of Lung Cancer has identified both sex and the maximum standardized uptake value (SUVmax) of (18)F-FDG in the primary tumor as measured by PET as potential prognostic variables. We examined the prognostic value of SUVmax in a surgical cohort of patients with NSCLC and disaggregated the findings by sex. Patients who had undergone a preoperative PET/CT scan and surgical resection with curative intent from 2001 to 2009 were identified from a prospective database. An SUVmax cutoff was calculated using receiver-operating-characteristic curves. Overall survival was correlated with SUVmax for the whole cohort and disaggregated by sex. Inclusion criteria were met by 189 patients: 127 (67%) men and 62 (33%) women. Five-year survival was 54.6% for the whole cohort, 47.7% for men, and 68.2% for women. SUVmax correlated negatively with survival in a univariate analysis for the whole cohort (hazard ratio [HR], 2.51 95% confidence interval [CI], 1.54-4.09 P < 0.001) and men (HR, 3.42 95% CI, 1.94-6.05 P < 0.001) but not for women (HR, 1.61 95% CI, 0.43-3.12 P = 0.77), using 8 as a cutoff. In multivariate analysis, SUVmax correlated with overall survival for the whole cohort (HR, 1.70 95% CI, 1.05-2.99 P = 0.05) and men (HR, 2.40 95% CI, 1.32-4.37 P = 0.004) but not for women (HR, 0.80 95% CI, 0.15-4.47 P = 0.80). SUVmax independently predicted overall survival for men but not for women in this surgical cohort. Our results suggest that SUVmax is an independent prognostic variable in men with surgically treated early NSCLC.
Publisher: AME Publishing Company
Date: 04-2019
Publisher: Wiley
Date: 28-07-2014
DOI: 10.1111/EJH.12404
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2023
DOI: 10.1200/EDBK_389968
Abstract: Antibody Drug Conjugates (ADCs) are a novel class of therapeutic that structurally comprise an antibody directed at a tumor epitope connected via a linker to a cytotoxic payload that have shown significant antitumor activity across a range of malignancies including lung cancer. In this article we review the pharmacology of ADCs, describe results of trials with ADCs directed at targets in lung cancer including Trophoblast cell-surface antigen 2(TROP2), HER3, MET, Carcinoembryonic antigen-related cell adhesion molecular 5(CECAM-5) and HER2. Trastuzumab Deruxtecan (also known as DS-8201a or T-DXd) an ADC directed at HER2 recently became the first ADC to receive FDA approval in lung cancer, on the basis of its activity in tumors with HER2 mutations, demonstrated in the Destiny-Lung01 and Lung02 trials.
Publisher: Mary Ann Liebert Inc
Date: 11-2019
Publisher: Wiley
Date: 07-01-2022
Publisher: Elsevier BV
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 24-03-2023
DOI: 10.1007/S40747-023-01002-W
Abstract: Healthcare tends to be one of the most complicated sectors, and hospitals exist at the core of healthcare activities. One of the most significant elements in hospitals is service quality level. Moreover, the dependency between factors, dynamic features, as well as objective and subjective uncertainties involved endure challenges to modern decision-making problems. Thus, in this paper, a decision-making approach is developed for hospital service quality assessment, using a Bayesian copula network based on a fuzzy rough set within neighborhood operators as a basis of that to deal with dynamic features as well as objective uncertainties. In the copula Bayesian network model, the Bayesian Network is utilized to illustrate the interrelationships between different factors graphically, while Copula is engaged in obtaining the joint probability distribution. Fuzzy rough set theory within neighborhood operators is employed for the subjective treatment of evidence from decision makers. The efficiency and practicality of the designed method are validated by an analysis of real hospital service quality in Iran. A novel framework for ranking a group of alternatives with consideration of different criteria is proposed by the combination of the Copula Bayesian Network and the extended fuzzy rough set technique. The subjective uncertainty of decision makers’ opinions is dealt with in a novel extension of fuzzy Rough set theory. The results highlighted that the proposed method has merits in reducing uncertainty and assessing the dependency between factors of complicated decision-making problems.
Publisher: Springer International Publishing
Date: 2022
Publisher: AME Publishing Company
Date: 02-2023
DOI: 10.21037/TLCR-22-656
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 05-2021
Publisher: Wiley
Date: 2011
DOI: 10.1111/J.1445-5994.2010.02342.X
Abstract: An abundance of new evidence regarding treatment strategies for neutropenic fever is likely to contribute to variability in practice across institutions and clinicians alike. To describe current clinical practices in Australia, by surveying haematologists, oncologists and infectious diseases physicians involved in cancer care. Clinician members from Australian professional associations, accounting for the vast majority of Australian cancer specialists, were invited to participate in an electronic survey, comprising of a clinical case-based questionnaire. Clinical practice areas explored were: use of risk-assessment and empiric antibiotic strategies across various treatment settings use of anti-bacterial prophylaxis and use of granulocyte-colony stimulating factors for established neutropenic fever and for secondary prophylaxis. A total of 252 clinicians returned responses (approximately 30% response rate). The majority (>70%) were representative of practices in public, major city, tertiary referral hospitals. Less than half of clinicians were aware of risk-assessment tools and less than quarter currently used ambulatory care strategies. If adequate resources were made available, more than 80% were willing to use risk-assessment tools and 60% more clinicians were likely to use ambulatory care strategies. Most clinicians prescribed dual therapy parenteral antibiotics, even for clinically stable patients (53% haematologists, 56% oncologists). Granulocyte-colony stimulating factor was used frequently as secondary prophylaxis in the breast cancer case (91%), follicular lymphoma case (59%) and non-small cell lung cancer case (31%). Fluoroquinolone prophylaxis was infrequently prescribed (19% oncologists, 30% haematologists). Evidence-practice gaps were identified around the use of risk-assessment-based empiric therapy, and help to inform better clinical guidance.
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 07-2021
DOI: 10.1111/IMJ.15414
Publisher: Oxford University Press (OUP)
Date: 19-03-2019
DOI: 10.1634/THEONCOLOGIST.2018-0380
Abstract: Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI.
Publisher: BMJ
Date: 06-2021
Abstract: Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.
Publisher: Elsevier BV
Date: 2019
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/07357900701206281
Abstract: Nearly half of all patients who undergo surgical resection of localized non-small cell lung cancer (NSCLC) will develop and ultimately die of recurrent disease. The postoperative radiotherapy (PORT) meta-analysis showed adjuvant thoracic radiotherapy to have a detrimental effect on survival in this patient population. A meta-analysis of early trials of adjuvant chemotherapy by the Non-Small Cell Lung Cancer Collaborative Group showed that while chemotherapy with alkylating agents was also detrimental, chemotherapy with cisplatin-based adjuvant chemotherapy was associated with an improved hazard ratio for death (HR = 0.87), equating to a 5 percent survival benefit at 5 years. However, the result was not statistically significant (p = 0.08). Recently, results have been reported for several large Phase III trials of adjuvant chemotherapy which differed with respect to the stage of resected disease included, the type of chemotherapy used and the use of post-operative radiotherapy. Three trials (IALT, JBR 10, and ANITA) that utilized cisplatin-based doublets showed a significantly positive survival benefit of adjuvant chemotherapy in patients with Stage II-IIIA NSCLC. The magnitude of this benefit, which was suggested to be 4-5 percent at 5 years in the meta-analysis and by the IALT study, may be as large as 8-15 percent as indicated by more recent studies with modern platinum-based doublet chemotherapy. These data indicate that medically fit patients with resected Stage II-IIIA NSCLC should be offered adjuvant chemotherapy with a modern cisplatin-based doublet.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2018
DOI: 10.1200/JOP.18.00485
Publisher: Springer International Publishing
Date: 2022
Publisher: American Association for Cancer Research (AACR)
Date: 13-01-2023
DOI: 10.1158/1078-0432.CCR-22-3094
Abstract: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET lification. The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.
Publisher: Wiley
Date: 28-08-2011
DOI: 10.1111/J.1743-7563.2011.01420.X
Abstract: Over the past three decades there has been a move toward organ preservation protocols in the management of locally advanced mucosal head and neck squamous cell carcinomas (LAHNSCC) with combinations of radiotherapy (RT), chemotherapy and, more recently, biological agents. Current standard chemoradiation strategies have reached the upper limits of toxicity. In addition, the traditional one size fits all approach of grouping patients according to traditional clinicopathological features fails to take into account the vast underlying biological heterogeneity of tumors and their host. A number of recent advances such as highly conformal RT, molecular profiling and targeted agents, and improvements in treatment response assessment have set the scene for a fundamental paradigm shift toward greater tailoring of therapy with the aim of improving outcomes and reducing the burden of survivorship. This review focuses on the recognition of the prognostic value of tumor human papillomavirus (HPV) status, the incorporation of biologically targeted therapies and the evolving role of molecular imaging in predicting tumor response and prognosis in the curative management of LAHNSCC.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Massachusetts Medical Society
Date: 27-03-2014
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.21.00127
Publisher: Wiley
Date: 10-02-2021
DOI: 10.1111/AJCO.13505
Abstract: Decreased cancer incidence and reported changes to clinical management indicate that the COVID‐19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. A model was developed and made publicly available to estimate population‐level health economic outcomes by extrapolating and weighing stage‐specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3‐ and 6‐month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma). Using a conservative once‐off 3‐month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6‐month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years. The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate in idual patient data on shifts in stage of disease during and after the COVID‐19 pandemic are critical for further analyses.
Publisher: Wiley
Date: 19-01-2023
DOI: 10.1002/QRE.3271
Abstract: Fault tree analysis (FTA) is one of the most popular failure analysis techniques that reveal the potential pathways leading to systems or components failure. It has been widely employed in numerous sectors to understand how a system fails and is improved. However, the conventional FTA has been criticized due to a series of inherent shortcomings in the FTA state of the arts. Accordingly, scholars, engineers, and practitioners made their attempts to improve the FTA by dealing with its critical deficiencies over the last decade. However, a few works have been performed to review and synthesize the relevant studies on FTA improvement topics. Thus, the present study is aimed to carry out a systematic literature review of the state‐of‐the‐art theoretical and empirical findings concerning FTA improvement from 2011 to 2021 using the Scopus database collection. In this sense, an in‐depth investigation is conducted using statistical metadata analysis. This subject discusses frontier directions and development trends to reveal the research status. In addition, a bibliometric study is undertaken to ascertain the most productive and influential researchers, research centers, and hotspot fields. It also sheds light on the FTA shortcomings in the existing literature, the evolution in FTA improvement topics, and research opportunities. The outcomes of the present work highlighted that the annual publications on FTA improvement topics are significantly growing, especially after 2019. Besides, Jianxiu Wang, Yan‐Feng Li, and Yihuan Wang are the most productive, prolific, and highly cited authors worldwide and Asia, particularly China, is the leading contributor in the FTA area. According to Bradford's law, one‐third of all publications (7995) in the field of FTA improvement have been published by 40 sources. Finally, “Decision‐making,” “Risk analysis,” “Uncertainty Analysis,” and “Bayesian Networks” are the four major hot topics integrated into improving the conventional FTA.
Publisher: Elsevier BV
Date: 07-2014
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2023
DOI: 10.1200/JCO.22.00393
Abstract: Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion–positive non–small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion–positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92) 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated) 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67) 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated) 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96) 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion–positive NSCLC.
Publisher: Elsevier BV
Date: 04-2022
Publisher: Massachusetts Medical Society
Date: 12-02-2015
DOI: 10.1056/NEJMC1415359
Publisher: Wiley
Date: 08-05-2020
DOI: 10.1002/CAM4.3106
Publisher: Springer International Publishing
Date: 2022
Publisher: Informa UK Limited
Date: 25-10-2018
Publisher: Elsevier BV
Date: 11-2018
Publisher: Informa UK Limited
Date: 09-2006
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: Springer International Publishing
Date: 2022
Publisher: Elsevier BV
Date: 2021
Publisher: Springer International Publishing
Date: 2022
Publisher: Bioscientifica
Date: 2022
DOI: 10.1530/EDM-21-0081
Abstract: Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed. Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.
Publisher: Public Library of Science (PLoS)
Date: 24-11-2015
Publisher: BMJ
Date: 10-2021
Abstract: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib–trametinib and ipilimumab–nivolumab have similar intracranial response rates (50%–55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab–nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. Patients who received first-line ipilimumab–nivolumab for MBMs or second/third line ipilimumab–nivolumab for intracranial metastases with BRAF V600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded s les of BRAF V600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. Twenty-five and 30 patients who received first and second/third line ipilimumab–nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab–nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab–nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab–nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value .05, false discovery rate (FDR) .1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). Second-line ipilimumab–nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab–nivolumab showed enrichment of the IPRES gene signature.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0959-8049(01)00320-3
Abstract: Hickman catheters (HC) are associated with complications, in particular infection, occlusion and thrombosis. We tested the hypothesis that regular flushing of catheters with urokinase would reduce the frequency of these complications. Patients who required a double-lumen HC for (1) bone marrow or peripheral blood progenitor cell transplantation or (2) intensive combination chemotherapy for haematological malignancies were randomised to receive twice-weekly flushes of either urokinase (5000 units) or heparin (50 units). HC-survival analysis was determined by Cox regression. 100 patients were enrolled (urokinase=52 heparin=48) and treated for a mean of 8.5 weeks. No significant difference was observed in the incidence of HC-associated septicaemic events, which occurred in 8/52 in the urokinase group and 9/48 in the heparin group (actuarial incidence 20% versus 25%, P=0.50). Similarly, there was no differences in the incidence of exit site infections (urokinase=27/52 and heparin=28/48, P=0.122) HC-septic thromboses (urokinase=2/52 and heparin=4/48, P=0.34) lumen occlusion (urokinase=30/52 and heparin=30/48, P=0.681) or venous thrombosis (urokinase=8/52 and heparin=6/48, P=0.726). Overall, a high incidence of HC-related complications was seen in both groups 40/52 in the urokinase group and 40/48 in the heparin group (actuarial incidence 80% versus 90%, P=0.367). Despite this only 18% of HC required early removal due to complications (urokinase=8, heparin=10). There was no difference in the incidence of complications in patients undergoing transplantation (n=68) compared with chemotherapy alone (n=32). Patients with haematological malignancies were more likely to have HC-related infective complications (P=0.006), and patients with solid tumours more likely to have venous thrombosis (P=0.027). The cumulative incidence of HC-related complications in this prospective study was higher than in previously reported series. Urokinase did not appear effective in reducing the frequency of these complications.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490194
Abstract: Supplementary material
Publisher: Springer Science and Business Media LLC
Date: 02-2023
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PATHOL.2019.08.006
Abstract: Lung cancer is the most commonly diagnosed malignancy and the leading cause of death from cancer globally. Diagnosis of advanced non-small cell lung cancer (NSCLC) is associated with 5-year relative survival of 3.2%. ROS proto-oncogene 1 (ROS1) is an oncogenic driver of NSCLC occurring in up to 2% of cases and commonly associated with younger age and a history of never or light smoking. Results of an early trial with the tyrosine kinase inhibitor (TKI) crizotinib that inhibits tumours that harbour ROS1 rearrangements have shown an objective response rate (ORR) of 72% (95% CI 58-83%), median progression free survival (PFS) of 19.3 months (95% CI 15.2-39.1 months) and median overall survival (OS) of 51.4 months (95% CI 29.3 months to not reached). Therefore, with the availability of highly effective ROS1-targeted TKI therapy, upfront molecular testing for ROS1 status alongside EGFR and ALK testing is recommended for all patients with NSCLC. We review the tissue requirements for ROS1 testing by immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) and we present a testing algorithm for advanced NSCLC and consider how the future of pathology testing for ROS1 may evolve.
Publisher: Elsevier BV
Date: 12-2011
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2011
DOI: 10.1158/1078-0432.CCR-10-1591
Abstract: Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation. Deregulation of tyrosine kinase–mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non–small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The aberrant activation of ALK signaling leads to “oncogene addiction” and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance. Clin Cancer Res 17(8) 2081–6. ©2011 AACR.
Publisher: Springer International Publishing
Date: 20-11-2019
Publisher: MDPI AG
Date: 10-04-2012
DOI: 10.3390/JPM2020035
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
DOI: 10.1038/SREP04186
Publisher: MDPI AG
Date: 08-01-2019
Abstract: Prevention of cancer-associated thromboembolism (TE) remains a significant clinical challenge and priority world-wide safety initiative. In this prospective non-small cell lung cancer (NSCLC) cohort, longitudinal TE risk profiling (clinical and biomarker) was undertaken to develop risk stratification models for targeted TE prevention. These were compared with published models from Khorana, CATS, PROTECHT, CONKO, and CATS/MICA. The NSCLC cohort of 129 patients, median follow-up 22.0 months (range 5.6—31.3), demonstrated a hypercoagulable profile in % patients and TE incidence of 19%. High TE risk patients were those receiving chemotherapy with baseline fibrinogen ≥ 4 g/L and d-dimer ≥ 0.5 mg/L or baseline d-dimer ≥ 1.5 mg/L or month 1 d-dimer ≥ 1.5 mg/L. The model predicted TE with 100% sensitivity and 34% specificity (c-index 0.67), with TE incidence 27% vs. 0% for high vs. low-risk. A comparison using the Khorana, PROTECHT, and CONKO methods were not discriminatory TE incidence 17–25% vs. 14–19% for high vs. low-risk (c-index 0.51–0.59). Continuous d-dimer (CATS/MICA model) was also not predictive of TE. Independent of tumour stage, high TE risk was associated with cancer progression (HR 1.9, p = 0.01) and mortality (HR 2.2, p = 0.02). The model was tested for scalability in a prospective gastrointestinal cancer cohort with equipotency demonstrated 80% sensitivity and 39% specificity. This proposed TE risk prediction model is simple, practical, potent and can be used in the clinic for real-time, decision-making for targeted thromboprophylaxis. Validation in a multicentre randomised interventional study is underway (ACTRN12618000811202).
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533113.V1
Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /
Publisher: British Institute of Radiology
Date: 02-2000
DOI: 10.1259/BJR.73.866.10884736
Abstract: Intravenous extension of lung carcinoma is rare. A right upper lobe bronchogenic carcinoma with unusually elongated intravenous extension to the left atrium was first visualized with positron emission tomography (PET) and then confirmed with dynamic CT. The PET appearance of intravascular tumour spread is striking, and presents only a short differential diagnosis.
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: American Association for Cancer Research (AACR)
Date: 14-06-2015
DOI: 10.1158/1078-0432.CCR-14-3009
Abstract: Purpose: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non–small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents. Experimental Design: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib. Results: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4–10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1–694). The mPFS on ceritinib was 7.8 months (6.5–9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4–9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5–19.4). Among 23 patients who underwent post-crizotinib re-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively P = 0.510). In the overall study population, median OS was 49.4 months (35.5–63.1). Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC—even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. Clin Cancer Res 21(12) 2745–52. ©2015 AACR.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.SCITOTENV.2017.03.001
Abstract: Wastewater indicator is a useful tool for evaluating the wastewater impact on natural water, but there is little information about the suitability of wastewater indicators for different regions. This study aimed to select suitable wastewater indicators in the Pearl River Delta region, south China by screening a range of wastewater related organic compounds. The screening c aign was carried out by investigating the occurrence and removal efficiencies of 93 pharmaceuticals and personal care products (PPCPs) and 5 artificial sweeteners (ASs) in nine wastewater treatment plants (WWTPs) located in the region, and the occurrence of these target compounds in the contaminated and clean surface water of the Pearl River. An ideal wastewater indicator should be hydrophilic, source-specific for domestic wastewater, ubiquitous in contaminated surface water with detection frequency (DF) >80% and absent in background water s les. For liable indicators, high removal rates (>90%) should be observed in WWTPs and they should be detected in all the influent s les at concentrations fifty times higher than their limits of quantification. For conservative indicators, low removal rates (<50%) should be observed in WWTPs and they should be detected in all the effluent s les at concentrations fifty times higher than their limits of quantification. Based on the above criteria, sucralose and fluconazole were selected as conservative indicators in the region, while cyclamate, saccharin, methyl paraben, ethyl paraben, propyl paraben, paracetamol, salicylic acid and caffeine were selected as liable indicators.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2019
DOI: 10.1007/S40265-019-01164-3
Abstract: ROS1 gene rearrangements exist in 1-2% of non-small cell lung cancers, typically occurring in younger, never or light smokers with adenocarcinoma. ROS1 gene fusions are potent oncogenic drivers, the presence of which results in the susceptibility of tumours to ROS1-targeted therapy. Crizotinib was the first tyrosine kinase inhibitor to demonstrate activity in ROS1-rearranged lung cancer, and remains the recommended first-line therapy for patients with advanced ROS1-rearranged non-small cell lung cancer. Despite excellent initial responses to crizotinib, the majority of patients develop disease progression, which may be intracranial or extracranial. Identification of resistance mechanisms to crizotinib, and newer generation tyrosine kinase inhibitors with increased potency against ROS1 and ROS1-resistance mutations, and improved intracranial activity are under evaluation in clinical trials. In this review, we discuss ROS1 rearrangements in non-small cell lung cancer, and provide an update on targeting ROS1-rearranged non-small cell lung cancer with crizotinib and newer generation tyrosine kinase inhibitors.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.SEMCANCER.2018.01.008
Abstract: Head and neck squamous cell carcinoma (HNSCC) comprises a heterogeneous group of tumors that arise from the squamous epithelium of the oral cavity, oropharynx, larynx and hypopharynx. While many HNSCCs are related to classical etiologic factors of smoking and alcohol, a clinically, genomically, and immunologically distinct subgroup of tumors arise from the epithelium of the tonsil and the base of tongue as a result of infection with Human Papilloma Virus (HPV). In this review we describe the genomic and immunologic landscape of HNSCC, highlighting differences between HPV-positive and HPV-negative HNSCC. While HPV-negative tumors are characterized by tobacco-associated mutations in genes including TP53 and CDKN2A, in HPV-positive HNSCC integration of viral genome from HPV into the host cellular genome results in expression of the E6 and E7 viral oncoproteins, with consequent degradation of p53 and functional inactivation of Rb. The immune microenvironment of HNSCC is characterized by changes in immune cell populations, immune checkpoints, as well as tumor or microenvironmental factors that alter the balance of the immune milieu in favor of immunosuppression, allowing tumor evasion and escape from immune surveillance. Immune therapies, in particular those targeting the PD1 receptor or its ligand PD-L1, including nivolumab, pembrolizumab, durvalumab, and atezolizumab have shown significant efficacy in subsets of patients with HNSCC. Current trials are evaluating the efficacy of these agents in combination with chemotherapy, radiotherapy and other immune therapies including CTLA-4 and IDO-1 inhibitors. While biomarkers including PD-L1 expression, PD-L2 expression and the interferon-gamma gene signature show potential to predict benefit from checkpoint inhibitor therapy - it is hoped that improved understanding of the genomic and immune landscape will lead to ways to improved strategies to stratify patients and to select which HNSCC are most likely to benefit from these therapies.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Massachusetts Medical Society
Date: 19-11-2020
Publisher: Springer Science and Business Media LLC
Date: 23-11-2015
DOI: 10.1038/CDDISCOVERY.2015.49
Abstract: Although the incidence of lung cancer has decreased due to the reduction of tobacco use, lung cancer remains the leading cause of cancer-related death. Lung squamous cell carcinoma represents 30% of lung cancers and only recently have possible drug-targetable mutations been identified in this disease, including fibroblast growth factor receptor 1 (FGFR1) gene lification and genetic alterations in the phosphoinositide-3 kinase pathway. These discoveries have generated a great interest in the clinic and the initiation of clinical trials using FGFR tyrosine kinase inhibitors to treat FGFR-altered lung cancers. However, preliminary results from these studies have shown that not all patients respond to therapy. Here we review current unresolved questions on the selection of patients for their recruitment in FGFR tyrosine kinase inhibitor trials, how FGFR inhibitors could be combined with other targeted therapies or immunotherapies to improve patient outcome, and how the current preclinical models can help address these questions.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2015
DOI: 10.1038/BJC.2015.59
Publisher: Informa UK Limited
Date: 06-02-2018
DOI: 10.1080/10803548.2017.1419654
Abstract: The risk graph (RG) is widely used to evaluate the safety integrity level (SIL) of safety instrument systems (SIS). However, subjective opinion-based conventional RGs cannot provide successful results for the problems of risk parameters, such as shortages or lack of data hence, the output of a conventional approach lacks sufficient reliability. We introduced the fuzzy improved risk graph (FIRG), an extension of fuzzy set theory, to deal with possible ambiguities during SIL study and increase the reliability of conventional RGs. In the present study, the levels of consequences defined as linguistic terms were converted into qualitative intervals therefore, by correlating the proposed approach with experts' opinions and attributing weight factors, a desired SIL value was obtained. The output of this new approach can be compared directly with quantitative risk assessment techniques to improve the safety performance of industrial systems.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2018
Publisher: Oxford University Press (OUP)
Date: 05-2020
DOI: 10.1093/JAMIAOPEN/OOAA002
Abstract: The objective of this technical study was to evaluate the performance of an artificial intelligence (AI)-based system for clinical trials matching for a cohort of lung cancer patients in an Australian cancer hospital. A lung cancer cohort was derived from clinical data from patients attending an Australian cancer hospital. Ten phases I–III clinical trials registered on clinicaltrials.gov and open to lung cancer patients at this institution were utilized for assessments. The trial matching system performance was compared to a gold standard established by clinician consensus for trial eligibility. The study included 102 lung cancer patients. The trial matching system evaluated 7252 patient attributes (per patient median 74, range 53–100) against 11 467 in idual trial eligibility criteria (per trial median 597, range 243–4132). Median time for the system to run a query and return results was 15.5 s (range 7.2–37.8). In establishing the gold standard, clinician interrater agreement was high (Cohen’s kappa 0.70–1.00). On a per-patient basis, the performance of the trial matching system for eligibility was as follows: accuracy, 91.6% recall (sensitivity), 83.3% precision (positive predictive value), 76.5% negative predictive value, 95.7% and specificity, 93.8%. The AI-based clinical trial matching system allows efficient and reliable screening of cancer patients for clinical trials with 95.7% accuracy for exclusion and 91.6% accuracy for overall eligibility assessment however, clinician input and oversight are still required. The automated system demonstrates promise as a clinical decision support tool to prescreen a large patient cohort to identify subjects suitable for further assessment.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Elsevier BV
Date: 2021
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2020
Publisher: Wiley
Date: 08-01-2020
DOI: 10.1002/QRE.2607
Publisher: MDPI AG
Date: 23-11-2022
DOI: 10.3390/ELECTRONICS11233863
Abstract: In this paper, the aging characteristics and state-of-health (SOH) estimation of retired batteries were studied by leveraging the electrochemical impedance spectroscopy (EIS) technique. A battery aging experiment was designed and implemented to monitor the aging process of batteries, after which a comprehensive analysis of the collected EIS data was conducted to characterize the corresponding aging properties of retired batteries. Based on the aging data analysis results, an equivalent circuit model (ECM) was constructed, and the correlation between ECM parameters and the battery age was identified. An EIS-based and ECM-based SOH estimation method for retired batteries was developed and demonstrated. Furthermore, to further leveraging the EIS data from battery aging tests, a Bayesian neural network-based SOH estimation method with automatic feature extraction was developed. Comparisons among the proposed model-based method, data-driven method, and state-of-the-art SOH estimation method for retired batteries were implemented. Overall, insights into the aging characteristics and SOH estimation of retired batteries were achieved by leveraging the EIS technique.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 2018
DOI: 10.1111/IMJ.13491
Abstract: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease comprising not only different histological subtypes but also different molecular subtypes. To describe the frequency of oncogenic drivers in patients with metastatic NSCLC, the proportion of patients tested and survival difference according to mutation status in a single-institution study. Metastatic NSCLC patients enrolled in a prospective Thoracic Malignancies Cohort Study between July 2012 and August 2016 were selected. Patients underwent molecular testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangements, Kirsten rat sarcoma (KRAS), B-Raf proto-oncogene (BRAF) mutations and ROS1 gene rearrangements. Survival was calculated using the Kaplan-Meier method for groups of interest, and comparisons were made using the log-rank test. A total of 392 patients were included, 43% of whom were female with median age of 64 years (28-92). Of 296 patients tested, 172 patients (58%) were positive for an oncogenic driver: 81 patients (27%) were EGFR positive, 25 patients (9%) were ALK positive, 57 patients (19%) had KRAS mutation and 9 patients (3%) were ROS1 or BRAF positive. Patients with an actionable mutation (EGFR/ALK) had a survival advantage when compared with patients who were mutation negative (hazard ratio (HR) 0.49 95% confidence interval (CI) 0.33-0.71 P < 0.01). Survival difference between mutation negative and mutation status unknown was not statistically significant when adjusted for confounding factors in a multivariate analysis (HR 1.29 95% CI 0.97-1.78, P = 0.08). In this prospective cohort, the presence of an actionable mutation was the strongest predictor of overall survival. These results confirm the importance of molecular testing and suggest likely survival benefit of identification and treatment of actionable oncogenes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-12-2010
DOI: 10.1126/SCITRANSLMED.3001451
Abstract: FGFR1 lification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted lung cancer drugs.
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 16-02-2017
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JTHO.2016.01.022
Abstract: This phase I study investigated the activity of the irreversible pan-human epidermal growth factor receptor inhibitor dacomitinib in combination with the mesenchymal-epithelial transition factor/anaplastic lymphoma kinase/ROS proto-oncogene 1, receptor tyrosine kinase inhibitor crizotinib in advanced non-small cell lung cancer. Patients with progression after at least one line of chemotherapy or targeted therapy received dacomitinib once daily and crizotinib once daily or twice daily, with doses escalated until intolerable toxicity the expansion cohorts received the maximum tolerated dose of the combination. The primary objective was to define the recommended phase II dose secondary objectives included assessment of safety and activity of the combination in epidermal growth factor receptor inhibitor-resistant patients and correlation with tumor biomarkers. Seventy patients were treated in the dose-escalation (n = 33) and expansion phases (n = 37), with the maximum tolerated dose defined as dacomitinib, 30 mg once daily, plus crizotinib, 200 mg twice daily. Grade 3 or 4 treatment-related adverse events were reported in 43% of patients: the most common were diarrhea (16%), rash (7%), and fatigue (6%). There were 16 deaths none were considered treatment related. One patient (1%) had a partial response 46% had stable disease. Most of the tumor s les analyzed had activating epidermal growth factor receptor gene (EGFR) mutations (18 of 20 [90%]) 50% (10 of 20) had a concurrent resistance mutation. Only one s le showed MMNG HOS Transforming gene (MET) lification (the patient had progressive disease), whereas 59% (13 of 22) and 47% (14 of 30) had high levels of expression of epidermal growth factor receptor and mesenchymal-epithelial transition factor on the basis of H-scores, respectively. There was no apparent association between biomarker expression and antitumor activity. The combination of dacomitinib and crizotinib showed limited antitumor activity in patients with advanced non-small cell lung cancer and was associated with substantial toxicity.
Publisher: Elsevier BV
Date: 2024
Publisher: Elsevier BV
Date: 10-2012
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
DOI: 10.1038/S41467-018-03099-X
Abstract: Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic ( n = 60) and transcriptomic ( n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11 / KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1 high / DLL3 high / NOTCH low , type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low / DLL3 low / NOTCH high , and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.
Publisher: Elsevier BV
Date: 12-2010
Publisher: Wiley
Date: 30-03-2018
DOI: 10.1002/PBC.27055
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.ORALONCOLOGY.2012.02.014
Abstract: Ataxia-Telangiectasia-Mutated (ATM) gene loss has been associated with poor prognosis and treatment resistance in head and neck squamous cell carcinomas (HNSCC). We investigated the relationship between ATM loss detected by fluorescence in-situ hybridisation (FISH) with patient outcome, and its relationship with Human Papillomavirus (HPV) 16(INK4A) status. Copy number of the ATM gene and chromosome 11 were determined by FISH and HPV status was determined using p16(INK4A) immunohistochemistry in 87 paraffin embedded tumour s les from patients with HNSCC treated with chemoradiation at a single institution. ATM loss was correlated with patient outcome as both a continuous and dichotomous variable. Of 73 evaluable patients, 44 (60.3%) demonstrated loss of the ATM gene. There was no correlation between ATM loss (defined as a mean ratio of ATM: chromosome 11 2.5 copies of chromosome 11) which was significantly associated with p16(INK4A) negative status (p=0.0004), but did not influence outcome. ATM loss is a frequent event in HNSCC, however it does not impact outcome after treatment with chemoradiation. Polysomy of chromosome 11 was significantly associated with p16(INK4A) negative status but also lacks prognostic significance.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NBT.3674
Publisher: Wiley
Date: 02-2014
Abstract: We investigated the relationship between hypoxia, human papillomavirus (HPV) status and outcome in head and neck squamous cell carcinoma. Patients with stage III and IV head and neck squamous cell carcinoma treated on phase I and II chemoradiation trials with 70-Gy radiation combined with tirapazamine/cisplatin or cisplatin/fluorouracil (5FU), hypoxic imaging using [18F]-misonidazole positron emission tomography and known HPV status (by p16 immunohistochemistry) were included in this sub-study. Separate analyses were conducted to consider the impact of tirapazamine on HPV-negative tumours in the phase II trial. Both p16-positive oropharyngeal tumours and p16-negative head and neck squamous cell carcinoma tumours had a high prevalence of tumour hypoxia 14/19 (74%) and 35/44 (80%), respectively. The distribution of hypoxia (primary, nodal) was similar. On phase II, trial patients with p16-negative hypoxic tumours had worse loco-regional control with cisplatin and 5FU compared with tirapazamine and cisplatin (P < 0.001) and worse failure-free survival (hazard ratio = 5.18 95% confidence interval, 1.98-13.55 P = 0.001). Only 1 out of 14 p16-positive patients on the phase II trial experienced loco-regional failure. Hypoxia, as assessed by [18F]-misonidazole positron emission tomography, is frequently present in both p16-positive and negative head and neck cancer. Further research is required to determine whether hypoxic imaging can be used to predict benefit from hypoxia-targeting therapies in patients with p16-negative tumours.
Publisher: World Scientific Pub Co Pte Lt
Date: 04-2021
DOI: 10.1142/S0218488521500098
Abstract: The fault tree analysis (FTA) is one of the important probabilistic risk assessment tools that is extensively used in different industrial applications. However, the classical FTA has been widely criticized due to its ambiguity and vagueness in finding the probability of basic events (BEs), and accordingly, in computing the probability of top events (TEs). In this paper, we propose a new approach considering the integration of fuzzy set theory and evidence theory for handling both types of uncertainties, i.e., epistemic and aleatory. In addition, to estimate the probability of TEs alternatively, the normal distribution is applied. By performing a numerical ex le of risk assessment in a collapse case study for a common offshore facility platform, the effectiveness of the approach is demonstrated. Finally, in this study, the sensitivity analysis is also performed to represent the vulnerability of the causes and the interaction of different inputs, meaning that the proposed model is highly reliable and effective for real applications.
Publisher: Elsevier BV
Date: 03-2003
DOI: 10.1016/S0360-3016(02)04357-2
Abstract: Signaling pathways initiated by the epidermal growth factor receptor (EGFR) play important roles in the response to ionizing radiation. In this study the consequences of inhibiting the EGFR on the response of A431 cells (human vulvar squamous cell carcinoma cells that overexpress EGFR) to radiation, were investigated in vitro and in vivo, using the selective EGFR-tyrosine kinase inhibitor, ZD1839 ("Iressa"). The effect of ZD1839 on proliferation, apoptosis, and clonogenic survival after radiation was determined in vitro. For in vivo studies, athymic nude mice with established subcutaneous A431 xenografts (approximately 100 mm(3)) were treated with either a single 10 Gy fraction or 4 daily 2.5 Gy fractions of radiation with or without ZD1839 (75 mg/kg/day intraperitoneally for 10 days) to determine effects on tumor growth delay. Treatment of A431 cells with ZD1839 in vitro reduced proliferation, increased apoptosis, and reduced clonogenic survival after radiation. Strikingly greater than additive effects of ZD1839 in combination with radiation on tumor growth delay were observed in vivo after either a single 10 Gy fraction (enhancement ratio: 1.5) or multiple 4 x 2.5 Gy fractions (enhancement ratio: 4). ZD1839 reduced tumor vascularity, as well as levels of vascular endothelial growth factor (VEGF) protein and mRNA induced by stimulation with epidermal growth factor (EGF), suggesting a possible role of inhibition of angiogenesis in the effect. Inhibiting EGFR-mediated signal transduction cascades with ZD1839 potentiates the antitumor effect of single and multiple fractions of radiation. These data provide preclinical rationale for clinical trials of EGFR inhibitors including ZD1839 in combination with radiation.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2021
Publisher: Springer Science and Business Media LLC
Date: 06-09-2017
DOI: 10.1007/S12032-017-1031-1
Abstract: Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1 hosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2021
Publisher: Springer Science and Business Media LLC
Date: 31-03-2021
Publisher: Massachusetts Medical Society
Date: 20-11-2014
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JTHO.2019.03.022
Abstract: In 2018 research in the field of advanced NSCLCs led to an expanded reach and impact of immune checkpoint inhibitors (ICIs) as part of a frontline treatment strategy, regardless of histologic subtype, with ICI use extended to include stage III disease, shifting the prognosis of all these patients. This new standard first-line approach opens a gap in standard second-line treatment, and older combinations may again become standard of care after progression during treatment with an ICI. The characterization of predictive biomarkers, patient selection, the definition of strategies with ICI combinations upon progression during treatment with ICIs, as well as prospective evaluation of the efficacy of ICIs in subpopulations (such as patients with poor performance status or brain metastases) represent upcoming challenges in advanced thoracic malignancies. In oncogene-addicted NSCLC three major steps were taken during 2018: next-generation tyrosine kinase inhibitors have overtaken more established agents as the new standard of care in EGFR and ALK receptor tyrosine kinase gene (ALK)-positive tumors. Mechanisms of acquired resistance have been reported among patients treated with next-generation EGFR tyrosine kinase inhibitors, reflecting the ersity of the landscape. One major step forward was the approval of personalized treatment in very uncommon genomic alterations, mainly fusions. This raises a new question about the challenge of implementation of next-generation sequencing in daily clinical practice to detect new and uncommon genomic alterations and to capture the heterogeneity of the mechanisms of acquired resistance during treatment, as well as the need to extend research into new therapeutic strategies to overcome them.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Springer Science and Business Media LLC
Date: 22-06-2021
Publisher: Elsevier BV
Date: 09-2001
Abstract: We have analyzed 25 patients with primary testicular large-cell non-Hodgkin's lymphoma managed at our institution from 1972-1998. The median age was 69 years, with bilateral testicular involvement in 16%. The disease stage was I in 56%, II in 32%, and IV in 12%. Twenty-four patients received further therapy after orchiectomy, including chemotherapy in 18 and radiation therapy in 11 (encompassing regional nodes in 8 and the contralateral testis in 6), with 5 patients receiving both modalities. The complete remission rate was 88%, but a continuous pattern of recurrence is evident up to 10 years, when only 23% of patients are predicted to be in ongoing remission. The dominant sites of first failure were extranodal (91%), with prominent involvement of the contralateral testis and cerebral parenchyma. The 10-year overall survival rate is 32%, and the median overall survival is 4.4 years. Within the entire cohort, adverse prognostic factors for treatment failure were serum albumin < or = to 3.5 g/dL (P = 0.02), advanced age, advanced stage, and lack of anthracycline-containing chemotherapy (each P < or = to 0.3). Among patients with locoregional disease, albumin < or = to 3.5 g/dL (P = 0.08), no anthracycline-containing chemotherapy (P = 0.15), and fewer than 6 cycles of chemotherapy (P = 0.03) remained predictive. Based on this analysis, we are prospectively evaluating a treatment program for patients with testicular non-Hodgkin's large-cell lymphoma comprising (1) 6 cycles of anthracycline-based chemotherapy, (2) prophylactic radiation therapy to the contralateral testis, and (3) central nervous system prophylaxis with both intrathecal chemotherapy and systemic high-dose methotrexate.
Publisher: AMPCo
Date: 13-05-2020
DOI: 10.5694/MJA2.50607
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.JTHO.2016.01.016
Abstract: We addressed the uncertainty of comorbidity as a prognosticator by evaluating comorbidity and the Simplified Comorbidity Score (SCS) as predictors of overall survival in non-small cell lung cancer (NSCLC). A prospective study included patients in whom NSCLC was diagnosed at an Australian cancer hospital between 2012 and 2014. Patients were assessed for SCS at recruitment and followed up every 3 months until death. The cohort included 633 patients their median age was 67 years (range 28-93), 63% were male, and 86% were ever-smokers. The median SCS at enrolment was 8 (range 0-19) 20% had an SCS higher than 9, and 11% had an SCS of 0. An SCS higher than 9 was associated with male sex, age older than 75 years, an Eastern Cooperative Oncology Group performance status of 2 or higher, and fewer cancer treatments. The 1-year overall survival rate was 62% (95% confidence interval: 58-66). In multivariate analysis, the strongest associations with mortality were metastatic disease (hazard ratio [HR] = 2.8, p < 0.01), Eastern Cooperative Oncology Group performance status of 2 or higher (HR = 2.0, p < 0.01), male sex (HR = 1.6, p < 0.01), more than 10% weight loss at diagnosis (HR = 1.5, p < 0.01), and age older than 75 years (HR = 1.5, p = 0.01). An SCS higher than 9 was not associated with overall survival (HR = 1.0, p = 0.8), and the effect of continuous SCS (HR = 1.1, p < 0.01) was explained by smoking status. In this cohort of patients with NSCLC the SCS was not a clinically significant predictor of overall survival over and above basic patient and disease factors.
Publisher: Harborside Press, LLC
Date: 12-2011
Abstract: Crizotinib was recently approved by the US FDA for the treatment of advanced non–small cell lung cancer (NSCLC) harboring the ALK (anaplastic lymphoma kinase) gene rearrangement. To ensure identification of patients most likely to benefit, the FDA approved crizotinib concurrently with a companion diagnostic test—the Vysis ALK Break Apart FISH Probe Kit. This kit was used in 1 of the 2 pivotal trials leading to the FDA approval of crizotinib and has become the gold standard for detecting ALK rearrangement in NSCLC. Although ALK FISH is clinically validated, the assay can be technically challenging and costly. Therefore, other diagnostic modalities are being explored, including immunohistochemistry (IHC) and reverse transcriptase–polymerase chain reaction. This article provides an overview of the diagnostic assays available for detecting ALK rearrangement. Each assay, including ALK FISH, has its strengths and weaknesses. Recent work with commercially available ALK antibodies suggests that IHC-based tests may represent a reliable and cost-effective screening strategy however, large multicenter studies comparing IHC with FISH are needed to validate ALK IHC. While ALK FISH remains the current standard for diagnosing ALK positivity, large-scale screening of patients with newly diagnosed advanced NSCLC, as recommended by NCCN, may require development and validation of alternative screening strategies, such as combination IHC and FISH.
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2020
DOI: 10.1101/2020.05.30.20117630
Abstract: Decreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic will result in diagnostic and treatment delays for cancer patients. We aimed to develop a flexible model to estimate the impact of delayed diagnosis and treatment initiation on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. The stage-shift model estimates population-level health economic outcomes by weighting disease stage-specific outcomes by the distribution of stages at treatment initiation, assuming delays lead to stage-progression. It allows for extrapolation of population-level survival data using parametric distributions to calculate the expected survival in life years. The model was demonstrated based on an analysis of the impact of 3 and 6-month delays for stage I breast cancer, colorectal cancer and lung cancer patients, and for T1 melanoma, based on Australian data. In the absence of patient-level data about time to stage progression, two approaches were explored to estimate the proportion of patients that would experience a stage shift following the delay: 1) based on the relation between time to treatment initiation and overall survival (breast, colorectal and lung cancer), and 2) based on the tumour growth rate (melanoma). The model is available on stage-shift.personex.nl/ . A shift from stage I to stage II due to a 6-month delay is least likely for colorectal cancer patients, with an estimated proportion of 3% of the stage I patients diagnosed in 2020 progressing to stage II, resulting in 11 excess deaths after 5 years and a total of 96 life years lost over a 10-year time horizon. For breast and lung cancer, progression from stage I to stage II due to a 6-month delay were slightly higher at 5% (breast cancer) and 8% (lung cancer), resulting in 25 and 43 excess deaths after 5 years, and 239 and 373 life years lost over a 10-year time horizon, respectively. For melanoma, with 32% of T1 patients progressing to T2 disease following a 6-month delay, the model estimated 270 excess death after 5 years and 2584 life years lost over a 10-year time horizon. Using a conservative 3-month delay in diagnosis and treatment initiation due to the COVID-19 pandemic, this study predicts nearly 90 excess deaths and $12 million excess healthcare costs in Australia over 5 years for the in 2020 diagnosed patients for 4 cancers. If the delays increase to 6 months, excess mortality and cost approach nearly 350 deaths and $46 million in Australia. More accurate data on stage of disease during and after the COVID-19 pandemic are critical to obtain more reliable estimates.
Publisher: Society of Nuclear Medicine
Date: 31-03-2016
Publisher: Wiley
Date: 30-01-2013
Abstract: To compare nodal response rates following chemoradiotherapy in patients with p16+ and p16- oropharyngeal squamous cell carcinoma (OPSCC). Patients with node-positive OPSCC treated at Peter MacCallum Cancer Centre on the published phase I-III tirapazamine trials were identified. All patients had conventional assessment (clinical examination (CA), CT and/or MRI) and positron emission tomography (PET) at both baseline and 2-4 months post-treatment. There were 30 p16+ and 18 p16- patients, the former group having significantly higher stage nodal disease (P = 0.016). The mean overall reduction in nodal size at post-treatment assessment was similar in p16+ and p16- patients (78% vs. 75%), and no statistically significant difference in nodal complete response (CR) rates was detected by either CA (50% vs. 39%, P = 0.35) or PET/PET-CT (93% vs. 83%, P = 0.19). PET was significantly more accurate in determining the true nodal CR rate in both groups, with a negative predictive value of 96%. Nodal response rates following chemoradiotherapy appear to be similar in p16+ and p16- patients when assessed by either CA or PET/PET-CT. However, higher nodal CR was seen in PET/PET-CT compared with CA in both groups. Metabolic imaging is more accurate than CA in assessing nodal response post-treatment.
Publisher: Elsevier BV
Date: 2020
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2019
DOI: 10.1200/JCO.18.02236
Abstract: Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non–small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. Baseline plasma and tumor tissue s les were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma] 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months hazard ratio, 0.47). In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2022
DOI: 10.1200/JCO.21.02278
Abstract: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non–small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN. Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day) no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted. PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention 17% with lorlatinib dose modification), and 38% were unresolved most required no intervention. Lorlatinib dose modification did not notably influence PFS. First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non–small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2020
DOI: 10.1200/EDBK_281101
Abstract: A common pathway for an effective immune anticancer response involves recognition of tumor neoantigens and subsequent targeting of cancer cells by T cells. In this article, we provide an overview of the current status of two approaches to directly enhance this interaction using either adoptive cell therapy or personalized cancer vaccines with focus on recent advances in solid tumors, including lung cancer.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.IJROBP.2013.10.043
Abstract: To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells. The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation. Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive β-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent β-galactosidase activity. Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.
Publisher: Elsevier
Date: 2022
Publisher: Wiley
Date: 08-2021
DOI: 10.1111/IMJ.15450
Publisher: Massachusetts Medical Society
Date: 20-06-2013
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-12-2011
Abstract: Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET- lified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study. From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39% III, 25% IV, 36% n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 lification status was assessed by using fluorescence in situ hybridization. Ten (2%) of 489 patients screened harbored MET lification 23 (4.7%) harbored EGFR lification 45 (8.9%) harbored HER2 lification and 411 (84%) were wild type for all three genes (ie, negative). MET- lified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5% n = 4 of 80). EGFR- lified tumors showed the highest fraction of squamous cell carcinoma (17% n = 4 of 23). HER2, MET, and EGFR lification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR- lified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months P .001) less than EGFR (11.2 months P = .16) less than HER2 (16.9 months P = .89) when compared with the negative group (16.2 months). Two of four patients with MET- lified tumors treated with crizotinib experienced tumor shrinkage (−30% and −16%) and experienced progression after 3.7 and 3.5 months. MET lification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 02-2023
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-10-2013
DOI: 10.1126/SCITRANSLMED.3006802
Abstract: The pattern of mutations in human lung cancer differs by tumor subtype and is a useful addition to histology for selecting targeted therapy and improving patient survival.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 04-2019
Publisher: Wiley
Date: 12-2000
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.JTHO.2021.12.011
Abstract: Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC. Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28) those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included. There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR) group B's median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD. Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2008
Abstract: A recurrent somatic mutation, E17K, in the pleckstrin homology domain of the AKT1 gene, has been recently described in breast, colorectal, and ovarian cancers. AKT1 is a pivotal mediator of signalling pathways involved in cell survival, proliferation and growth. The E17K mutation stimulates downstream signalling and exhibits transforming activity in vitro and in vivo . We developed a sensitive high resolution melting (HRM) assay to detect the E17K mutation from formalin-fixed paraffin-embedded tumours. We screened 219 non-small cell lung cancer biopsies for the mutation using HRM analysis. Four s les were identified as HRM positive. Subsequent sequencing of those s les confirmed the E17K mutation in one of the cases. A rare single nucleotide polymorphism was detected in each of the remaining three s les. The E17K was found in one of the 14 squamous cell carcinomas. No mutations were found in 141 adenocarcinomas and 39 large cell carcinomas. The AKT1 E17K mutation is very rare in lung cancer and might be associated with tumorigenesis in squamous cell carcinoma. HRM represents a rapid cost-effective and robust screening of low frequency mutations such as AKT1 mutations in clinical s les.
Publisher: Harborside Press, LLC
Date: 03-2016
Abstract: The efficacy of targeted monotherapy for BRAF(V600E)-positive anaplastic thyroid carcinomas (ATC) is not established. We report 2 cases of BRAF(V600E)-positive ATC treated with a BRAF inhibitor. A 49-year-old woman with a T4bN1bM0 ATC manifested symptomatic metastatic disease 8 weeks after radical chemoradiotherapy. Within 1 month of BRAF inhibitor monotherapy, a complete symptomatic response was observed, with FDG-PET scan confirming metabolic and radiologic response. Treatment was terminated after 3 months because of disease progression. The patient died 11 months after primary diagnosis. A 67-year-old man received first-line BRAF inhibitor for a T4aN1bM0 ATC. Within 10 days of treatment his pain had stabilized and his tumor had clinically halved in size. Stable disease was achieved for 11 weeks but the patient died 11 months after diagnosis because of disease progression. BRAF inhibitor monotherapy in ATC may obtain clinical benefit of short duration. Upfront combination therapy should be investigated in this patient subgroup.
Publisher: Wiley
Date: 29-07-2019
DOI: 10.1002/QRE.2545
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.ORALONCOLOGY.2012.12.012
Abstract: To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m(2) day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m(2)/day for 5 days of weeks 1, 4 and 7. 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5-98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6-96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.
Publisher: MDPI AG
Date: 11-10-2023
DOI: 10.3390/FIRE6100391
Publisher: Elsevier BV
Date: 07-2022
Publisher: Elsevier BV
Date: 09-2023
Publisher: Harborside Press, LLC
Date: 03-2015
Abstract: Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy with limited evidence guiding standard treatment. SDC is known to overexpress the androgen receptor, with only a handful of cases reporting responses to androgen blockade. This report presents a case of SDC responding to multiple lines of androgen blockade, including a rapid response to abiraterone, a CYP17 inhibitor effective in prostate cancer. This case represents the first published report of SDC responding to abiraterone and illustrates that androgen receptor expressing SDC may be treated with multiple lines of androgen blockade, including newer agents such as abiraterone. This case suggests that SDC may continue to be androgen-dependent after progression on androgen deprivation, which is analogous to prostate cancer.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.20.00464
Abstract: Leptomeningeal disease (LMD) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma is associated with a poor prognosis and limited treatment options. Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor with confirmed CNS penetration. This study reports on outcomes of patients with EGFR-mutated non–small-cell lung cancer who developed LMD and were subsequently treated with osimertinib. We identified patients treated with osimertinib 80 mg PO daily under a compassionate access scheme across nine tertiary Australian institutes between July 2017 and July 2020. Patient demographics, tumor characteristics, and treatment history were collected. Median overall survival, median progression-free survival, disease control rates (DCR), and overall response rates (ORR) were assessed. Kaplan-Meier analysis was performed and descriptive statistics were used. Thirty-nine patients were analyzed of which 74% were female. Exon 19 deletions (49%) and L858R point mutations (41%) were the most common EGFR mutations. Forty-nine percentage of patients were Eastern Cooperative Oncology Group 1. The median duration of osimertinib therapy was 6 months. The extracranial DCR and ORR were 60% and 54%, and the intracranial DCR and ORR were 68% and 53%, respectively. Median overall survival was 10.5 months (95% CI, 8.17 to 15.05 months). There are limited treatment options for LMD in EGFR-positive lung cancer, and osimertinib at a dose of 80 mg daily is an active therapeutic option for these patients.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Springer Science and Business Media LLC
Date: 08-06-2022
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 04-2015
Publisher: Begell House
Date: 2012
DOI: 10.1615/CRITREVONCOG.V17.I1.60
Abstract: The phosphatidylinositol 3 kinase (PI3K) pathway is one of the major pathways modulating cell growth, proliferation, metabolism, survival, and angiogenesis. Hyperactivation of this pathway is one of the most frequent occurrences in human cancer and is thus an obvious target for treatment of this disease. Currently there are 26 novel compounds targeting the PI3K pathway being assessed in more than 150 cancer-related clinical trials. Although this pathway is involved in many vital biologic functions, data emanating from these clinical trials indicate that these drugs are well tolerated. This review outlines the interaction of the PI3K pathway with other signaling cascades, highlights mechanisms involved in hyperactivation, discusses current therapeutics in cancer-related clinical trials that target this pathway, and, based on preclinical data, discusses possible leads on patient selection and combinational therapy, including targeting multiple components of the associated signaling network.
Publisher: Elsevier BV
Date: 07-2009
Publisher: Informa UK Limited
Date: 07-03-2017
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.CLLC.2013.03.007
Abstract: The standard of care for locoregionally advanced non-small-cell lung cancer is concurrent platinum-based chemoradiation. Many patients relapse, and subsequent systemic treatment may involve platinum-doublet chemotherapy. It is not known if prior platinum-based chemoradiation influences the response to platinum-based chemotherapy given subsequently for relapse. Therefore, we compared outcomes in these patients with those in patients without prior treatment. A retrospective study of patients who had been treated with carboplatin and gemcitabine chemotherapy for de novo metastatic disease or recurrent non--small-cell lung cancer after receiving platinum-based chemoradiation. The primary outcome was progression-free survival (PFS). A total of 104 patients were analyzed. The median age was 63 years (range, 35-81 years), with 63 (61%) patients with newly diagnosed disease and with 41 (39%) who were previously treated. The response rate was significantly lower for those previously exposed to chemoradiation (10% vs. 29%: P = .001), as was the median PFS (3.6 months vs. 5.7 months P = .002), and median overall survival (OS) (8.6 months vs. 12.1 months P = .007). Only the treatment group was a significant predictor (P = .032) of PFS by univariate analysis. In univariate analysis sex (men P = .04), histology (squamous cell P = .04), Eastern Cooperative Oncology Group Performance Status Scale (P = .002), and treatment group (P = .023) predicted significantly inferior OS. Multivariate analysis showed that performance status was the only significant predictor of inferior OS. Outcomes were inferior in patients previously exposed to platinum-based chemoradiation. An approach of stratifying such patients in future trials of chemotherapy should be adopted. Alternative options such as non--platinum-based agents or targeted therapies should be considered in this group.
Publisher: Wiley
Date: 11-10-2018
DOI: 10.1002/QRE.2408
Publisher: Elsevier BV
Date: 10-2013
Abstract: Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients with lung cancer. We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database. From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, 50% of suicides occurred in those with locoregional and potentially curable disease. Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2011
DOI: 10.1158/1055-9965.EPI-10-1262
Abstract: Background: Human papilloma virus (HPV) infection is a powerful prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). Increased epidermal growth factor receptor (EGFR) gene copy number and protein expression have been reported to be negative predictors of outcome. This study examined the relationship between HPV status, EGFR gene copy number, EGFR protein expression, and clinical outcome in HNSCC patients treated with chemoradiation. Methods: HPV status was determined using p16INK4A immunohistochemistry (IHC), EGFR gene copy number was evaluated with FISH, and EGFR protein expression by IHC in 212 subjects. Results: EGFR FISH was positive in 41 of 204 (20%) patients and was negatively correlated with failure-free survival (FFS HR = 1.84, P = 0.027) and overall survival (OS HR = 1.78, P = 0.082). For p16INK4A, 85 of 200 (42.5%) patients were found to be p16 positive, including 75 of 131 (57%) with oropharyngeal cancer. Patients with p16-positive oropharyngeal cancer had significantly improved FFS (HR = 0.28, P & 0.001) and OS (HR = 0.31, P = 0.002). Only 2 of 126 (1.6%) oropharyngeal cancer patients were found to be p16+/EGFR FISH+. EGFR IHC was positive in 81 of 93 (87%) of patients and was associated with poorer FFS (HR = 1.98, P = 0.35) and OS (HR = 2.52, P = 0.22). Conclusions: Increased EGFR gene copy number is largely restricted to p16INK4A-negative oropharyngeal cancer. Although p16INK4A and EGFR FISH are both predictive of outcome in univariate analyses, only p16INK4A remains independently predictive. Impact: Knowledge of HPV and EGFR status can have implications for treatment options and prognosis in HNSCC. Cancer Epidemiol Biomarkers Prev 20(6) 1230–7. ©2011 AACR.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 02-01-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2018
Abstract: The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) –positive advanced nonsquamous non–small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin (area under the concentration–time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053 two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non–small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Elsevier BV
Date: 12-2018
Publisher: American Association for Cancer Research (AACR)
Date: 09-2005
DOI: 10.1158/1535-7163.MCT-05-0066
Abstract: Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [18F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 ± 1.0 (pretreatment) versus 2.3 ± 0.6 (posttreatment) P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 ± 3.0 versus 2.7 ± 0.8 P = 0.007 or tumor to muscle ratio controls versus gefitinib, 8.6 ± 2.8 versus 2.6 ± 1.0 P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.CPET.2017.08.004
Abstract: Significant advances in understanding the genomic landscape of non-small cell lung cancer (NSCLC) together with the coupling discovery of key oncogenic drivers and the development of effective targeted and immunotherapeutic agents have revolutionized the management of this malignancy. Although these therapies have resulted in improved outcomes for a subgroup of patients, their benefit may not necessarily be reflected by conventional response assessment criteria, because these therapeutic agents differ in their mechanism of action and response time compared with cytotoxic chemotherapy. Here the authors review available therapies in NSCLC and the utility of PET in therapeutic response assessment.
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533113
Abstract: AbstractPurpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Results: Thirty-two patients with i BRAF /i V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal i KRAS /i , i NRAS /i , and i MAP2K1 /i mutations, and i MET /i lification. Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance. /
Publisher: Elsevier BV
Date: 04-2020
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-08-2016
Abstract: Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non–small-cell lung cancer. Patients were randomly assigned to receive crizotinib (250 mg twice daily n = 172) or chemotherapy (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively intracranial time to tumor progression (IC-TTP per protocol) and intracranial disease control rate (IC-DCR post hoc) were measured. The intent-to-treat population was also assessed. Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60 P = .069), patients with tBM (HR, 0.45 P = .063), and patients without BM (HR, 0.69 P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively P .001) and 24 weeks (56% v 25%, respectively P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40 P .001 median, 9.0 v 4.0 months, respectively BM absent: HR, 0.51 P .001 median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45 P .001 median, 10.9 v 7.0 months, respectively). Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-02-2012
DOI: 10.1126/SCITRANSLMED.3003316
Abstract: Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation of receptor tyrosine kinases.
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 30-08-2015
DOI: 10.1007/S11864-015-0367-Z
Abstract: ALK rearrangements are present in 3-5% of patients with non-small cell lung cancer (NSCLC) and after epidermal growth factor receptor (EGFR) mutations represent the second molecular target in NSCLC to be validated through phase III clinical trials. The PROFILE 1014 international multicentre phase III trial demonstrated the superiority of crizotinib over standard chemotherapy, establishing crizotinib as standard first-line therapy for patients with advanced ALK-positive NSCLC and indicating the requirement for ALK testing to guide selection of optimal first-line therapy for non-squamous NSCLC. Despite impressive and durable responses, progression on treatment reflecting the development of acquired resistance is inevitable. There are several mechanisms of resistance including ALK kinase mutation or copy number gain, activation of bypass pathways and potentially pharmacokinetic failure of therapy (most commonly in CNS). A broad array of newer generation ALK inhibitors are in development that appear effective in the crizotinib-resistant setting including in patients with intracranial progression. These agents, including ceritinib and alectinib, have a higher potency against ALK kinase than crizotinib, activity against mutations that confer resistance to crizotinib and potentially improved CNS penetration. While in selected patients, continued therapy with crizotinib after local ablative treatments of oligo-progressive systemic or CNS disease may be an option, for many patients use of a newer generation compound will be effective. First-line treatment with newer generation ALK inhibitors may have potential advantages over sequential treatment after crizotinib however, the optimal sequence of therapy with ALK inhibitors has not been determined and is being explored in ongoing phase III studies.
Publisher: Elsevier BV
Date: 03-2017
Publisher: Springer Science and Business Media LLC
Date: 21-09-2022
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2020
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Elsevier BV
Date: 2020
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Elsevier BV
Date: 11-2019
Publisher: Archives of Pathology and Laboratory Medicine
Date: 22-01-2014
DOI: 10.5858/ARPA.2017-0388-CP
Abstract: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. To systematically review and update the 2013 guideline to affirm its validity to assess the evidence of new genetic discoveries, technologies, and therapies and to issue an evidence-based update. The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology s les, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors and the use of cell-free DNA to “rule in” targetable mutations when tissue is limited or hard to obtain.
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: AME Publishing Company
Date: 10-2020
DOI: 10.21037/TLCR-20-579
Publisher: Springer Nature Switzerland
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00063030-200317050-00004
Abstract: For molecular targeted cancer therapies to fulfill their promise in cancer treatment, innovative approaches are required to overcome significant obstacles that exist in the clinical development of these agents. Positron emission tomography (PET) is a functional imaging technology that allows rapid, repeated, noninvasive, in vivo assessment and quantification of many biological processes and in some cases molecular pathways targeted by these therapies. It is highly sensitive, with the capacity to detect subnanomolar concentrations of radiotracer and provides superior image resolution to conventional nuclear medicine imaging with gamma cameras. Novel PET radiotracers have been developed that allow visualisation of a variety of processes including tumour metabolism, cell proliferation, apoptosis, hypoxia and blood flow. Furthermore, specific molecular targets including cellular receptors can be identified using radiolabelled receptor ligands or specific monoclonal antibodies. Improvements in imaging technology leading to the development of small-animal PET scanners, with resolution capable of imaging commonly used mouse models of cancer, will enable PET to play an important role in preclinical proof-of-principle drug studies. Such improvements will also facilitate the validation of imaging protocols that can be readily translated to studies in humans. The greatest utility of PET in the development of molecular targeted therapeutics, however, lies in clinical studies, where PET may play a valuable role in a number of situations. These include selection of patients for therapy through noninvasive identification of the presence of specific molecular targets, pharmacokinetic studies with labelled drugs and pharmacodynamic evaluations of biological parameters to select the optimal biological dose, and assessment of response to therapies.
No related grants have been discovered for Benjamin Solomon.