Search

Background The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P  =   0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P -interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43–1.62), 0.50 (0.33–0.76), 0.31 (0.13–0.75) and 1.24 (0.68–2.25), respectively. Conclusions This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number This is a molecular sub-study of MAX clinical trial (NCT00294359). [ABSTRACT FROM AUTHOR]

Faba bean crops (Vicia faba L.) were exposed to elevated SO2 concentrations in three different years in an open-air field exposure system for the controlled release of air pollutants. The treated crops were exposed to an average SO2 concentration of 165 μg m&sup-3; in 1985, 62 μg m&sup-3; in 1986 and 74 μg m&sup-3; in 1988. The ambient SO2 concentration was about 10 μg m&sup-3;. Plant height, number of internodes and number of pods were not affected by SO2. The specific leaf area was reduced in the plants exposed to SO2 at the end of the growing season. Leaf area development was strongly affected during the pod-filling period in 1985 and 1988 as a result of leaf injury and defoliation in the fumigated plots. In 1986 a similar trend in leaf area reduction was observed in the early reproductive phase. N and Mg content of the different organs was unaffected by SO2. The S content was strongly elevated in the leaves and pods of the fumigated plants, and the Ca content of the leaves was reduced by SO2. Chlorophyll content of different leaf numbers was unaffected by SO2. [ABSTRACT FROM AUTHOR]

The highlands of South America are the probable geographic origin for the potato gangrene fungus Phoma exigua var. foveata (Foister) Boerema which was found parasitizing plants of Chenopodium quinoa in the Altiplano area of Peru. In vitro studies showed no dissimilarities between it and the antibiotic 'E' producing virulent European isolates of P. exigua var. foveata. It is as pathogenic to potatoes as the virulent European isolates but on C. quinoa and C. album it is more pathogenic than the European isolates. So far the fungus has not been found on potato tubers in South America and the reasons why gangrene problems have not arisen there are discussed. [ABSTRACT FROM AUTHOR]

Introduction: There are significant challenges and a lack of data related to culturally and linguistically diverse (CALD) cancer patients. We compared patient characteristics, treatment patterns, and outcomes of patients with advanced pancreatic cancer that required an interpreter., Methods: Registry data was extracted for advanced pancreatic cancer patients from a single health institution with a comprehensive Transcultural and Language Service (TALS). Demographic and clinicopathologic characteristics were compared. Kaplan-Meier survival estimates with log-rank testing, and univariate and multivariable regression analysis were performed to compare the group with limited English proficiency (LEP) to the English proficient (EP) group., Results: Of 155 patients, 32.9% (n = 51) required the TALS. The LEP group had a higher mean age (71.2 vs. 76.8 years; p = 0.005) and received less chemotherapy (42.3% vs. 31.4%, p = 0.220). Univariate analysis revealed a shorter median overall survival (OS) in the LEP group (3.6 vs. 5.0 months), with a hazard ratio [HR] of 1.51 (95% confidence interval [CI]: 1.03-2.21, p = 0.033). Upon multivariable analysis, adjusting for Eastern Cooperative Oncology Group (ECOG) performance scale, the number of sites of metastatic disease and chemotherapy use, the strength of association between LEP and OS reduced marginally (HR 1.42, 95% CI: 0.93-2.16), and was no longer statistically significant (p = 0.103)., Conclusions: In patients with advanced pancreatic cancer utilizing a comprehensive TALS, there was a trend to poorer survival with limited English proficiency, although this association was not statistically significant. An ongoing research commitment to the CALD experience is necessary to build a granular understanding of this population and ensure equitable outcomes., (© 2024 John Wiley & Sons Australia, Ltd.)

Adherens junctions (AJs) are a defining feature of all epithelial cells. They regulate epithelial tissue architecture and integrity, and their dysregulation is a key step in tumor metastasis. AJ remodeling is crucial for cancer progression, and it plays a key role in tumor cell survival, growth, and dissemination. Few studies have examined AJ remodeling in cancer cells consequently, it remains poorly understood and unleveraged in the treatment of metastatic carcinomas. Fascin1 is an actin-bundling protein that is absent from the normal epithelium but its expression in colon cancer is linked to metastasis and increased mortality. Here, we provide the molecular mechanism of AJ remodeling in colon cancer cells and identify for the first time, fascin1's function in AJ remodeling. We show that in colon cancer cells fascin1 remodels junctional actin and actomyosin contractility which makes AJs less stable but more dynamic. By remodeling AJs fascin1 drives mechanoactivation of WNT/β-catenin signaling and generates "collective plasticity" which influences the behavior of cells during cell migration. The impact of mechanical inputs on WNT/β-catenin activation in cancer cells remains poorly understood. Our findings highlight the role of AJ remodeling and mechanosensitive WNT/β-catenin signaling in the growth and dissemination of colorectal carcinomas., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Context: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment modality for primary and metastatic renal cell carcinoma (RCC)., Objective: To review and summarise the evidence on the use of SABR in RCC in a narrative review., Evidence Acquisition: We performed an online search of the PubMed database from January 2000 through December 2021. Studies of SABR/stereotactic radiosurgery (SRS) targeting primary, extracranial, or intracranial metastatic RCC were included., Evidence Synthesis: Two meta-analyses (including 54 studies), and 13 prospective and 20 retrospective studies were included in this review. In aggregate, SABR for 589 primary RCCs in 575 patients resulted in a local control rate of above 90% with grade 3-4 toxicity of 0-9%. Similarly, the local control rate ranged between 90% and 97% with SRS in 1225 patients with intracranial metastatic RCC. SABR was able to delay systemic therapy for at least 1 yr in 70-90% of oligometastatic RCC patients with grade 3-4 toxicity of <10%. As per the early data, the combination of SABR with systemic therapy for metastatic RCC, such as targeted therapy or immunotherapy, appears safe, feasible, and tolerable., Conclusions: We outlined data supporting SABR in the key clinical scenarios of primary and metastatic, including oligometastatic, RCC in lieu of systemic therapy, in combination with systemic therapy, and palliation of brain and spinal metastases., Patient Summary: Stereotactic ablative body radiotherapy (SABR) is a relatively new treatment option in kidney cancer. Here, we review the published literature on the experience of using SABR in kidney cancer. The accumulated evidence demonstrates that SABR can be used safely and effectively to treat selected cases of primary or secondary kidney cancer., (Copyright © 2022 European Association of Urology. All rights reserved.)

Background: Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic clear cell renal cell carcinoma (ccRCC) but is limited by a lack of prospective clinical trial data., Objective: The RAPPORT trial evaluated the safety and efficacy of total metastatic irradiation followed by short-course anti-programmed death receptor-1 immunotherapy in patients with oligometastatic ccRCC., Design Setting, and Participants: RAPPORT was a single-arm multi-institutional phase I/II trial (NCT02855203). Patients with two or fewer lines of prior systemic therapy and one to five oligometastases from ccRCC were eligible., Intervention: A single fraction of 20 Gy SABR (or if not feasible, ten fractions of 3 Gy) was given to all metastatic sites, followed by pembrolizumab 200 mg administered Q3W for eight cycles., Outcome Measurements and Statistical Analysis: The endpoints were adverse events (AEs), disease control rate (DCR) for at least 6 mo, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The Kaplan-Meier method was used for time-to-event endpoints. Freedom from local progression (FFLP) was assessed per lesion adding patient as a cluster effect., Results and Limitations: Thirty evaluable patients, with a median age of 62 yr, were enrolled. The median follow-up was 28 mo. There were 44% of patients with intermediate-risk and 56% with favorable-risk disease. Eighty-three oligometastases were irradiated (median three per patient): eight adrenal, 11 bone, 43 lung, 12 lymph node, and nine soft tissue. Four patients (13%) had grade 3 treatment-related AEs: pneumonitis (n = 2), dyspnea (n = 1), and elevated alkaline phosphatase/alanine transaminase (n = 1). There were no grade 4 or 5 AEs. FFLP at 2 yr was 92%. ORR was 63% and DCR was 83%. Estimated 1- and 2-yr OS was 90% and 74%, respectively, and PFS was 60% and 45%, respectively. Limitations include a single-arm design and selected patient population., Conclusions: SABR and short-course pembrolizumab in oligometastatic ccRCC is well tolerated, with excellent local control. Durable responses and encouraging PFS were observed, warranting further investigation., Patient Summary: The RAPPORT trial investigated the combination of high-dose precision radiotherapy and a short course of immunotherapy in patients with low-volume metastatic kidney cancer. We found that this treatment regimen was well tolerated, with excellent cancer control in sites of known disease. A proportion of patients were free from cancer relapse in the longer term, and these encouraging findings warrant further investigation., (Copyright © 2021 European Association of Urology. All rights reserved.)

Purpose: To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC)., Patients and Methods: This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis-related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined., Results: Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47-77]. ORR was 17% (95% CI, 7-32), comprising of seven PRs. Median duration of response was 20 months (range, 10-48 months). Median PFS was 8.4 months and median OS 31.4 months. Grade 1-2 peripheral edema and joint-related symptoms were common. Overall incidence of grade 3-4 adverse events (AE) of any type was 33% ( n = 15). Expected AEs of bevacizumab treatment did not appear to be increased by the addition of trebananib., Conclusions: In a first-line mCRC population, the dual antiangiogenic combination, bevacizumab plus trebananib, without chemotherapy, was efficacious with durable responses. The toxicity profile of the combination was manageable and did not exceed that expected with bevacizumab +/- chemotherapy. Exploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer., (©2021 American Association for Cancer Research.)

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

Background: The management of oligometastatic clear cell renal cell carcinoma (ccRCC) varies widely, ranging from observation to resection or systemic therapies. Prolonged survival has been observed following resection or stereotactic ablative body radiotherapy (SABR). Immunotherapy combinations have shown survival benefits, however, toxicity is higher than that for monotherapy and complete response rates remain less than 10%. The combination of effective local therapies in conjunction with immunotherapy may provide more durable control and pre-clinical models have suggested a synergistic immune-priming effect of SABR., Objectives: and Methods: RAPPORT is a prospective, single arm, phase I/II study assessing the safety, efficacy and biological effects of single fraction SABR followed by pembrolizumab for oligometastatic ccRCC. The study will include 30 patients with histological confirmed ccRCC and 1-5 oligometastases, one or more of which must be suitable for SABR. Patients can have received prior systemic therapy but not prior immunotherapy. A single 20Gy of SABR is followed 5 days later by 8 cycles of 200 mg pembrolizumab, every 3 weeks. Adverse events are recorded using CTCAE V4.03 and tumour response evaluated by Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). Tumour tissue and peripheral blood samples will be collected pre-, during and post-treatment to assess longitudinal changes in immune subsets., Outcomes and Significance: The RAPPORT study will provide important safety and early efficacy data on the combination of SABR and pembrolizumab in oligometastatic ccRCC and will provide an insight into the underlying biological effects of combination therapy., Trial Registration: clinicaltrials.gov ID NCT02855203., (© 2021 Published by Elsevier Inc.)

177 Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted β-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177 Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177 Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177 Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of -1.2 (95% CI, -0.5 to -1.9; P = 0.001) and -1.0 (95% CI, -0.2 to -0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177 Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177 Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177 Lu-PSMA radioligand therapy. On progression, rechallenge 177 Lu-PSMA demonstrated higher response rates than other systemic therapies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)