BRCA mutated pancreatic cancer: A change is coming Rosen, Michael N; Goodwin, Rachel A; Vickers, Michael M
World journal of gastroenterology : WJG,
2021-May-07, 2021-5-7, 20210507, Letnik:
27, Številka:
17
Journal Article
Odprti dostop
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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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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Rural patients face known healthcare disparities and worse cardiovascular outcomes compared to urban residents due to inequitable access and delayed care. Few studies have assessed rural-urban ...differences in outcomes following Transcatheter Aortic Valve Implantation (TAVI). We compared short-term post-TAVI outcomes between rural and urban patients.
We performed a retrospective analysis of n = 413 patients who underwent TAVI at our large academic medical center, between 2011 and 2020 (rural/urban patients = 93/320. Rural/urban males = 53/173). Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes included stroke/transient ischemic attack, myocardial infarction, atrial fibrillation, acute kidney injury, bleeding, vascular complications, and length of stay.
The mean age in years was 77 IQR 70-82 for rural patients and 78 IQR 72-84 for urban patients. Baseline characteristics were similar between groups, except for a greater frequency of active smokers and diabetics as well as a greater body mass index in the rural group. There were no statistically significant differences in all-cause or cardiovascular mortality between the groups. There was also no statistically significant difference in secondary outcomes.
Rural and urban patients had no statistically significant difference in all-cause mortality or cardiovascular mortality following TAVI. Given its minimally invasive nature and quality-centric, multidisciplinary care provided by the TAVI Heart Teams, TAVI may be the preferred modality for the treatment of severe aortic stenosis in rural populations.
Abstract
CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 ...patients are treated across 10 dose levels (50–650 mg/m
2
) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m
2
days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.
Memory problems are reported in 40%-60% of people with multiple sclerosis (MS). These problems affect independence and may limit the ability to benefit from rehabilitation. Our aim was to evaluate ...the effectiveness of NeuroPage for people with MS living in the community. A multicentre, single-blind, randomised controlled crossover trial was conducted. The intervention comprised the NeuroPage service, which sends reminder messages to mobile phones at pre-arranged times. In the control condition participants received "non-memory texts", that is, messages not aimed at providing a reminder; for example, supplying news headlines or sport updates. Outcome measures were completed using postal questionnaires after each condition. There were 38 participants aged 28 to 72 (mean 48, SD 11) and 10 (26%) were men. There were no significant differences between NeuroPage and control conditions on the Everyday Memory Questionnaire (p = 0.41, d = 0.02). The number of daily diary items forgotten in the NeuroPage condition was significantly less than in the control (9% vs. 31%, p = 0.01, d = −0.64). Psychological distress was less in the NeuroPage condition than control (p = 0.001, d = −0.84). Further evaluation of the effect on everyday memory is required.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The COVID-19 pandemic resulted in an unprecedent shift towards virtual cancer care, including the care of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of this study was to ...evaluate the use of virtual care for GEP-NETs during the COVID-19 pandemic at a high-volume academic cancer center.
This retrospective, observational study performed at the Ottawa Hospital Cancer Center in Canada evaluated adult patients with GEP-NETs seen in consultation by medical oncology between 1 June 2019 and 31 December 2022. Demographic, clinicopathologic, cancer treatment and visit data were collected. Univariable and multivariable analyses assessed the relationship between patient characteristics and virtual care use.
A total of 103 patients with well-differentiated GEP-NETS were included. Overall, 18/103 (17.5%) consults and 594/781 (76.1%) follow-ups were performed virtually. All consultation visits returned to in-person assessment by 2022, while 67.0% and 41.4% follow-ups remained virtual in 2022 and 2023, respectively. The year of follow-up, sex, employment and Charlston comorbidity index were associated with virtual follow-up use in the multivariable analysis.
Virtual care remained a predominant method of GEP-NET patient assessment in the peri-pandemic period. These results highlight an opportunity to improve access to subspecialty neuroendocrine cancer care through the continued use of virtual care.
(1) Aim: The prevalence and incidence of small bowel NETs have increased significantly over the past two decades. This study aims to report the 10-year experience of SB-NET management at a regional ...cancer center in Canada. (2) Materials and methods: We conducted a retrospective study of the clinical and pathological data of patients diagnosed with biopsy-proven SB-NET at The Ottawa Hospital (TOH), Ottawa, Canada between 2011 and 2021. We report the clinicopathological characteristics of these patients, as well as their outcomes data, including survival rates. (3) Results: Between 2011 and 2021, a total of 177 SB-NET cases were identified with 51% (n = 91) of cases being males. The most common sites of the tumors were the ileum 53% (n = 94), followed by the duodenum 9% (n = 16) and jejunum 7% (n = 12). Approximately 24% (n = 42) of the patients had symptoms for over six months prior to diagnosis and 18% (n = 32) had functioning SB-NET during the course of the disease. The majority of patients had locally advanced or metastatic disease at the time of presentation with stage III, and stage IV representing 42% (n = 75), and 41% (n = 73) respectively. The majority of patients 84% (n = 148) had well-differentiated histology. One hundred twenty patients underwent surgical resection of the primary tumor including 28 patients (16%) with limited metastatic disease. A total of 21 patients (18%) had recurrence after curative surgery. A total of 62 patients (35%) received first-line somatostatin analog (SSA) therapy for unresectable disease and seven patients had PRRT after progression on SSA. Five years OS was 100%, 91%, 97%, and 73% for stages I, II, III, and IV respectively. In univariate analysis, carcinoid symptoms, T stage, and differentiation were significant predictors for worse overall survival, but not RFS. (4) Conclusions: Compared to published historical controls, our study suggests improvement in the 5-year survival rate of SB-NETs over the last 10 years.
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