The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.

BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.

Comparative evaluation of a language model and human specialists in the application of European guidelines for the management of inflammatory bowel diseases and malignancies.

BACKGROUND: Society guidelines on colorectal dysplasia screening, surveillance, and endoscopic management in inflammatory bowel disease (IBD) are complex, and physician adherence to them is suboptimal. We aimed to evaluate the use of ChatGPT, a large language model, in generating accurate guideline-based recommendations for colorectal dysplasia screening, surveillance, and endoscopic management in IBD in line with European Crohn's and Colitis Organization (ECCO) guidelines. METHODS: 30 clinical scenarios in the form of free text were prepared and presented to three separate sessions of ChatGPT and to eight gastroenterologists (four IBD specialists and four non-IBD gastroenterologists). Two additional IBD specialists subsequently assessed all responses provided by ChatGPT and the eight gastroenterologists, judging their accuracy according to ECCO guidelines. RESULTS: ChatGPT had a mean correct response rate of 87.8%. Among the eight gastroenterologists, the mean correct response rates were 85.8% for IBD experts and 89.2% for non-IBD experts. No statistically significant differences in accuracy were observed between ChatGPT and all gastroenterologists (P=0.95), or between ChatGPT and the IBD experts and non-IBD expert gastroenterologists, respectively (P=0.82). CONCLUSIONS: This study highlights the potential of language models in enhancing guideline adherence regarding colorectal dysplasia in IBD. Further investigation of additional resources and prospective evaluation in real-world settings are warranted.

[FRONTIERS IN CANCER PREDICTION AND EARLY DETECTION].

INTRODUCTION: Israel is below the global average of cancer mortality thanks to early diagnosis plans and advanced treatment, yet every year about 30,000 patients are diagnosed with cancer and 11,000 die from it. Many patients are diagnosed at an advanced stage of malignancy in which curative surgery cannot be offered. Early detection and intervention have been proven to be of greatest importance in reducing cancer morbidity and mortality. However, despite the clinical use of a limited number of technologies, the means for detecting malignancy as early as possible, to the extent of predicting malignancy within a significant period of time before its clinical detection, some current efforts still exist only within the framework of development and clinical research. The main challenge remains - the development of a test with high sensitivity on the one hand, but with sufficient specificity to prevent unnecessary follow-up tests at the other hand.

Gut microbial signatures are associated with Lynch syndrome (LS) and cancer history in Druze communities in Israel.

Lynch syndrome (LS) is a hereditary cancer syndrome caused by autosomal dominant mutations, with high probability of early onset for several cancers, mainly colorectal cancer (CRC). The gut microbiome was shown to be influenced by host genetics and to be altered during cancer development. Therefore, we aimed to determine alterations in gut microbiome compositions of LS patients with and without cancer. We performed fecal microbiome analyses on samples of LS and non-LS members from the Druze ethnoreligious community in Israel, based on both their LS mutation and their cancer history. Our analysis revealed specific bacterial operational taxonomic units (OTUs) overrepresented in LS individuals as well as bacterial OTUs differentiating between the LS individuals with a history of cancer. The identified OTUs align with previous studies either correlating them to pro-inflammatory functions, which can predispose to cancer, or to the cancer itself, and as such, these bacteria can be considered as future therapeutic targets.

Intratumoral HLA-DR-/CD33+/CD11b+ Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Capecitabine-based neoadjuvant chemoradiation therapy (nCRT) is currently the mainstay of treatment for locally advanced rectal cancer (LARC), prior to surgical tumor removal. While response to this treatment is partial, it carries significant risk of side effects. As of today, there is no accepted model to predict tumor response, and allow for patient stratification. The level of circulating Myeloid-derived suppressor cells (MDSCs), a subpopulation of early myeloid cells (EMCs), has been shown to correlate with prognosis and response to therapy in advanced colon cancer, but their role in LARC is not clear. We sought to study the effect of intratumoral and circulating levels of different EMCs subpopulations including MDSCs on response to nCRT. We analyzed tumor, normal mucosa, and peripheral blood samples from 25 LARC patients for their different EMCs subpopulation before and after nCRT, and correlated them with degree of pathologic response, as determined postoperatively. In addition, we compared LARC patient to 10 healthy donors and 6 metastatic patients. CD33+HLA-DR-CD16-CD11b+EMCs in the circulation of LARC patients were found to inhibit T-cell activation. Furthermore, elevated levels of CD33+HLA-DR- myeloid cells were found in the tumor relative to normal mucosa, but not in the circulation when compared to healthy subjects. Moreover, intratumoral, but not circulating levels of MDSCs correlated with clinical stage and response to therapy in patients treated with nCRT, with high levels of MDSCs significantly predicting poor response to nCRT. Importantly, therapy by itself, had significant differential effects on MDSC levels, leading to increased circulating MDSCs, concomitantly with decreasing intratumoral MDSCs. Our results suggest that high levels of intratumoral, but not circulating MDSCs may confer drug resistance due to immunomodulatory effects, and serve as a biomarker for patient stratification and decision-making prior to nCRT.

Translational reprogramming marks adaptation to asparagine restriction in cancer.

While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cells activates receptor tyrosine kinase-MAPK signalling as part of a feedforward mechanism involving mammalian target of rapamycin complex 1 (mTORC1)-dependent increase in MAPK-interacting kinase 1 (MNK1) and eukaryotic translation initiation factor 4E (eIF4E), resulting in enhanced translation of activating transcription factor 4 (ATF4) mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine synthetase (ASNS), sensitizing melanoma and pancreatic tumours to asparagine restriction, reflected in inhibition of their growth. Correspondingly, low ASNS expression is among the top predictors of response to inhibitors of MAPK signalling in patients with melanoma and is associated with favourable prognosis when combined with low MAPK signalling activity. These studies reveal an axis of adaptation to asparagine deprivation and present a rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches.

Synergistic effect of cigarette smoke and saliva on lymphocytes--the mediatory role of volatile aldehydes and redox active iron and the possible implications for oral cancer.

Oral squamous cell carcinoma (SCC) is most induced by exposure of the oral epithelial cells to tobacco products such as cigarette smoke. This exposure always occurs in the presence of saliva and presumably is induced by free radicals. To explore the effects of CS on cells in the presence of saliva, we used peripheral blood lymphocytes (PBL) and exposed them to CS, alone or in the presence of saliva. We discovered that after 80min, exposure of the lymphocytes to CS alone resulted in a time-dependent cellular loss with a survival rate of 56%, while following lymphocyte exposure to CS in the presence of saliva, less than 15% of the cells survived. This was accompanied by concomitant accumulation of cellular protein carbonyls which could be protected by the exogenous addition of uric acid or glutathione, but not by the addition of ascorbate (Asc), N-acetyl-l-cystein (NAC) or desferal (DES). Exposure of the lymphocytes to aldehydes present in CS, such as acrolein and croton-aldehyde, also resulted in the elevation of protein carbonyls, which was ameliorated primarily by the addition of glutathione. However, lymphocyte exposure to acroline in the presence of saliva did not show the same synergism in cell death observed as when the lymphocytes were exposed to CS and saliva. Thus, we postulated the existence of another mechanism and examined the role of redox active iron as an additional explanation for this synergism. In fact, it was found that in the presence of saliva and ascorbate there was a marked decrease in the lymphocyte survival rate; this was reversed by the addition of the iron chelator desferal. In light of these results, a comprehensive mechanism for the induction of oral cancer by cigarette smoke is suggested, stressing the role of a pivotal player in the process leading to oral cancer which has never been previously considered in this regard - the saliva.

Antioxidants and healthy aging.

Although the free radical theory of aging is widely accepted among scientists, the possibility of using antioxidants to delay the aging processes seems to encounter considerable skeptism among clinicians. This may be due, at least in part, to lack of knowledge about the basic chemistry and biological behavior of oxidative stress, antioxidants, and the complex interactions between them. However, one cannot ignore the explosive growth of information concerning the mechanisms underlying the processes of aging, their consequences, and the use of antioxidants in suppressing such effects. In order to provide patients with the most accurate information regarding the use of antioxidant supplementation in their diet, it is important to obtain basic data regarding oxidative stress and antioxidants. This article explores the role of oxidative stress in the aging phenomena, recent evidence supporting supplementation of antioxidants for aged people, the ability of antioxidants to prevent or retard cancer and atherosclerosis (the major causes of mortality in the aged population), and the ability of antioxidant supplementation to delay age-dependent deterioration of cognitive function. Based on the data presented, we conclude that current knowledge provides insufficient and inconclusive support for antioxidant supplementation as a means of delaying aging processes, despite the encouraging results obtained in many studies.

Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.

Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.

Low-dose metronomic chemotherapy: from past experience to new paradigms in the treatment of cancer.

Low-dose metronomic (LDM) chemotherapy represents an emerging concept in the treatment of cancer. Directed against tumor cells and other types of cells, such as endothelial and immune cells, this treatment regimen alters the tumor microenvironment and suppresses innate features which support tumor growth. Ongoing Phase III clinical studies explore various applications of LDM chemotherapy, mostly combined with other anticancer agents, to act as complementary treatments to conventional maximum tolerated dose (MTD) chemotherapy. In this article we summarize preclinical and clinical experience with LDM chemotherapy, emphasizing the potential contribution of this new treatment modality to future paradigms in the systemic treatment of patients with cancer.