Survival benefit with adjuvant chemotherapy in stage III microsatellite-high/deficient mismatch repair colon cancer: a systematic review and meta-analysis

Clinical observations have demonstrated that microsatellite instability-high (MSI-H) and/or deficient MMR (dMMR) status are associated with favorable prognosis and no benefit from 5-Fluorouracil (5-FU)-based adjuvant chemotherapy in patients with resected stage II colorectal cancer (CRC). This study represents a systematic review and meta-analysis exploring the predictive role of MSI-H status in stage III CRC undergoing or not adjuvant chemotherapy. Published articles that evaluated the role of adjuvant chemotherapy in resected stage III CRC from inception to September 2020 were identified by searching the PubMed, EMBASE, and Cochrane Library databases. The random-effects model was conducted to estimate the pooled effect size of OS and DFS. The primary outcome of interest was OS. 21,590 patients with MSI-H/dMMR stage III CRC, from n = 17 retrospective studies, were analyzed. Overall, OS was improved with any adjuvant chemotherapy vs. any control arm (single-agent 5-FU or surgery alone): HR 0.42, 95% CI 0.26-0.66; P < 0.01. Conversely, DFS was not significantly improved (HR 0.7, 95% CI 0.45-1.09; P = 0.11). In patients with stage III MSI-H/dMMR CRC, adjuvant chemotherapy is associated with a significant OS improvement. Thus, MSI-H/dMMR status does represent a predictive factor for postoperative chemotherapy benefit in stage III CRC beyond its prognostic role

Surgery or Locoregional Approaches for Hepatic Oligometastatic Pancreatic Cancer: Myth, Hope, or Reality?

Despite extensive research, pancreatic ductal adenocarcinoma (PDAC) remains a difficult-to-treat cancer associated with poor survival. Due to the known aggressive disease biology, palliative chemotherapy is the only routinely recommended treatment in the metastatic setting in patients with adequate performance status. However, in a subset of patients with oligometastatic disease, multimodality treatment with surgery and/or locoregional approaches may provide long-term disease control and prolong survival. In fact, in highly selected cases, median overall survival has been reported to extend to 56 months in patients treated with surgery. In particular, liver and extraregional nodal resections may provide long-term tumor control with acceptable morbidity. Current guidelines do not recommend surgery for patients with metastatic PDAC and, in the case of PDAC with oligometastases, there are no published randomized controlled trials regarding locoregional or surgical approaches. Here we review the literature on surgical and locoregional approaches including radiofrequency ablation, irreversible electroporation, and stereotactic body radiation, and focus on patients with hepatic oligometastatic pancreatic cancer. We provide a summary regarding survival outcomes, morbidity and mortality and discuss selection criteria that may be useful to predict the best outcomes for such strategies

Adjuvant chemotherapy for resected biliary tract cancers: a systematic review and meta-analysis

Introduction: The use of adjuvant treatment (AT) in resected biliary tract cancers (BTC) is still controversial. No efficacy comparison has been performed between chemotherapy (CT) and chemoradiotherapy (CTRT). A systematic review of the available evidence regarding adjuvant chemotherapy (AC) in resected BTC was performed. Methods: PubMed, EMBASE, Web of Science, SCOPUS and The Cochrane Library databases were searched for relevant articles published. Only studies including at least 50 patients affected by tumors of gallbladder, intrahepatic, perihilar, and distal bile ducts were considered. Data were pooled using a random-effects model. The primary endpoint of the study was overall survival (OS). Results: Thirty studies were analyzed with a total of 22,499 patients, 3967 of whom received AC. Eleven cohorts included Western patients and 19 were Asiatic. Surgeries were classified as R0 with negative margins, R1 with positive microscopic and R2 with positive macroscopic margins. Weighted mean OS difference among experimental (AC) and control arm was 4.3 months (95% CI 0.88–7.79, P = 0.014). AC reduced the risk of death by 41% (Hazard ratio [HR] = 0.59, 95% CI 0.49–0.71; P < 0.001). Conclusions: AC administration gives an OS benefit in resected BTC. The results of prospective randomized studies are awaited in order to define the standard AT in BTC

Better survival of patients with oligo- compared with polymetastatic cancers: a systematic review and meta-analysis of 173 studies

Background: The modern concept of oligometastatic (OM) state has been initially developed to describe patients with a low burden of disease and with a potential for cure with local ablative treatments. We systematically assessed the risk of death and relapse of oligometastatic (OM) cancers compared to cancers with more diffuse metastatic spread, through a meta-analysis of published data. Methods: PubMed, the Cochrane Library, and EMBASE were searched for studies reporting prognosis of patients with OM solid tumors. Risk of death and relapse were extracted and pooled to provide an adjusted hazard ratio with a 95% confidence interval (HR 95%CI). The primary outcome of the study refers to overall mortality in OM vs. polymetastatic (PM) patients. Results. Mortality and relapse associated with OM state in patients with cancer were evaluated among 104,234 participants (n=173 studies). Progression-free survival was better in patients with OM disease (hazard ratio [HR] = 0.62, 95% CI 0.57–0.68; P <.001; n=69 studies). Also, OM cancers were associated with a better OS (HR = 0.65, 95% CI 0.62-0.68; P<.01; n=161 studies). In colorectal (CRC), breast, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) the reduction in the risk of death for OM patients were 35, 38, 30 and 42%, respectively. Conclusions. Patients with oligometastases have a significantly better prognosis than those with more widespread stage IV tumors. We suggest that a treatment strategy that involves bot the primary and the metastases should be identified at the time of diagnosis

Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer

A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.

Background Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

In Vitro Phenotypic, Genomic and Proteomic Characterization of a Cytokine-Resistant Murine β-TC3 Cell Line

Type 1 diabetes mellitus (T1DM) is caused by the selective destruction of insulin-producing β-cells. This process is mediated by cells of the immune system through release of nitric oxide, free radicals and pro-inflammatory cytokines, which induce a complex network of intracellular signalling cascades, eventually affecting the expression of genes involved in β-cell survival

Growth of Mytilus galloprovincialis (mollusca, bivalvia) close to fish farms: a case of integrated multi-trophic aquaculture within the Tyrrhenian Sea

A current practice of marine aquaculture is to integrate fish with low-trophic-level organisms (e.g. molluscs and/or algae) during farming to minimise effects of cultivation on the surrounding environment and to potentially increase economic income. This hypothesis has been tested in the present article experimentally, by co-cultivating fish and mussels (Mytilus galloprovincialis) in the field. Integrated multi-trophic aquaculture (IMTA) experiments were started in July 2004 by transplanting mussel seed at two depths (-3 and -9 m) within 1,000 m downstream to fish cages and at 1,000 m upstream from cages. Mussels were cultured in nylon net bags for 12 months and the growth recorded biometrically. The outcome of our field experiment corroborated the idea of IMTA effectiveness. In fact, in the study area, the organic matter from fish-farm biodeposition caused changes in the chemical environment (i.e. controls and impacted sites were significantly different for organic matter availability and chlorophyll-a) and this induced changes in growth performance of co-cultivated mussels. Mussels cultivated close to cages, under direct organic emission, reached a higher total length, weight and biomass than mussel cultivated far from farms