BRCA mutated pancreatic cancer: A change is coming Rosen, Michael N; Goodwin, Rachel A; Vickers, Michael M
World journal of gastroenterology,
2021-May-07, 2021-5-7, 20210507, Volume:
27, Issue:
17
Journal Article
Open access
Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline
mutations have received increased attention due ...to advances in the management of
mutated ovarian and breast tumors. Germline
mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline
mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of
-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.
A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline ...neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC.
We reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes.
Of 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23-88), 69% were male, and 80% had performance status (PS) 0-1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66-72%) and 79% (95% CI 77-82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR.
NLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.
An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the ...Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.
To describe the infrapubic approach to penile prosthesis insertion in transmen after phalloplasty.
After verifying phalloplasty vascular pedicle anatomy and reliable micturition, patients may be ...considered for implant surgery. Specific modifications of the infrapubic approach to penile prosthesis insertion as well as individualization of commercially available implants are performed intraoperatively to help reduce the risk of postoperative complications.
In our single surgeon series (MLC) using the infrapubic approach with these specific implants after phalloplasty, 17/107 (16%) patients from October 2017 to November 2020 required revision surgery after mean follow-up of 79.8 weeks.
Our infrapubic prosthesis insertion after phalloplasty technique with modifications to commercially available implants may help reduce the risk of postoperative complications.
•COVID-19 is typified by SARS-CoV-2 replication and an excessive inflammatory response.•PTC299 is a small orally bioavailable DHODH inhibitor that blocks pyrimidine synthesis.•PTC299 is a potent ...inhibitor of the replication of SARS-CoV-2 and other RNA viruses.•PTC299 also reduces the production of cytokines associated with COVID-19 inflammation.•PTC299 may be a promising therapeutic for COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS−COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti−COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS−COV-2 replication (EC50 range, 2.0–31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an ...immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling
. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8
T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.
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•STAT3 regulates genes for cell growth and differentiation, inflammation, neoplasia.•STAT3 is a potential therapeutic target in colorectal cancer.•Most liver metastases stain STAT3 ...positive.•Discordant pSTAT3 expression in paired primary tumors and liver metastases.•Test on archived or a fresh liver biopsy.
Signal Transducer and Activator of Transcription-3 (STAT3) mediates cellular functions. We assessed the IHC expression of phosphorylated STAT3 (pSTAT3) in paired primary tumors and liver metastases in patients with advanced stage colorectal cancer (CRC).
We included patients with tissue blocks available from both the primary CRC and a surgically resected liver metastasis. The IHC pSTAT3 expression agreement was measured using Cohen's kappa statistic.
The study included 103 patients, 55% male, median age was 64. 43% tumors originated in rectum, and 63% of the primary tumors were synchronous. Expression of pSTAT3 was 76% in liver metastases and 71% in primary tumors. A difference in pSTAT3 staining between the primary tumor and liver metastases was noted in 64%. There was lost expression of pSTAT3 in the liver metastases in 28% and gained expression in 36% of cases compared to the primary. The kappa statistic comparing agreement between staining patterns of the primary tumors and liver metastases was a “less-than-chance”, at -0.02. Median survival was 4.9 years, with no difference in survival outcomes by pSTAT3 expression in the primary tumor or liver metastases.
STAT3 is not a prognostic marker in the selective setting of metastatic CRC to liver, but it may remain a potential therapeutic target given most liver metastases expressed pSTAT3. Discordant pSTAT3 expression in between primary tumors and paired liver metastases suggests that use of this class of drug to treat liver predominant metastatic colorectal cancer in a biomarker-driven approach may require confirmatory liver tumor biopsy.
ABSTRACT
Colorectal cancer (CRC) is the third most common cancer and second leading cause of death from cancer in North America. The authors provide an overview of the indications for both ...chemotherapy and targeted therapy, as well as discuss the efficacy and toxicity of systemic therapy. They highlight the key studies that lead to the initial historical use of fluorouracil (5FU) based chemotherapy in the adjuvant and metastatic setting, the recent adoption of 5FU plus leucovorin (LV) and oxaliplatin (FOLFOX) chemotherapy over 5FU when treating adjuvant patients, and the use of FOLFOX or 5FU plus LV and irinotecan (FOLFIRI) in metastatic patients. They also review the role of chemotherapy in treating rectal cancer and resectable liver metastatic disease. Future areas of research focus for systemic therapy of colorectal cancer are highlighted.
Following acquired brain injury (ABI), deficits in executive functioning (EF) are common. As a result many brain-injured patients encounter problems in every-day functioning, and their families ...experience significant strain. Previous research has documented the benefits of cognitive rehabilitation for executive dysfunction, and rehabilitation programmes designed to ameliorate functional problems associated with ABI.
This study primarily aims to evaluate whether a neuropsychological rehabilitation programme reduces reported symptoms of everyday dysexecutive behaviour and carer strain.
In this study 66 ABI outpatients attended comprehensive holistic neuropsychological rehabilitation programme. A repeated-measures design was employed to determine the effect of rehabilitation on EF and carer strain, as part of a service evaluation. Outcome measures comprised the dysexecutive questionnaire (DEX/DEX-I) and carer strain index (CSI), applied pre- and post-rehabilitation.
Results indicate rehabilitation benefited clients and carers in 5 of 6 DEX/DEX-I subscales, and 2 of 3 CSI subscales, (p < 0.05). An effect of aetiology on rehabilitation was found on the metacognitive scale of the DEX-I.
Therefore, this study supports a comprehensive holistic neuropsychological rehabilitation programme as effective in reducing reported symptoms of dysexecutive behaviour and carer strain following ABI.
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