Explore the vast range of titles available.

IDH1 -mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1 m and IDH1 wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1 m and IDH1 wt patients. Overall, 125 patients were IDH1 m and 122 IDH1 wt. IDH1 m patients showed higher mutation rates compared to IDH1 wt in CDKN2B and lower mutation rates in several genes including TP53 , FGFR2 , BRCA2 , ATM , MAP3K1 , NOTCH2 , ZNF703 , CCND1 , NBN , NF1 , MAP3 KI3 , and RAD21 . At the survival analysis, IDH1 m and IDH1 wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1 m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B , and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1 m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1 m and IDH1 wt patients.

Gastric cancer (GC) is a complex and heterogeneous disease with poor prognosis and limited available treatment options. During recent years, several molecular stratifications have been proposed to optimize the overall treatment strategy for GC patients. Breakthroughs in cancer biology and in molecular profiling through DNA and RNA sequencing are now opening novel landscapes, leading to the personalization of molecular matched therapy. In particular, therapies against HER2, Claudine 18.2, Fibroblast Growth Factor Receptors (FGFR), and other molecular alterations could significantly improve survival outcomes in the advance phase of the disease. Furthermore, immunotherapy with checkpoint inhibitors also represents a promising option in a selected population. Hoping that precision oncology will enter soon in clinical practice, our review describes the state of the art of many novel pathways and the current evidence supporting the use of monoclonal antibodies implicated in GC treatment.

Novel targeted therapies for metastatic colorectal cancer are needed to personalize treatments by guiding specific biomarkers selected on the genetic profile of patients. RAS and BRAF inhibitors have been developed for patients who become unresponsive to standard therapies. Sotorasib and adagrasib showed promising results in phase I/II basket trial and a phase III trial was planned with a combination of these RAS inhibitors and anti-EGFR monoclonal antibodies. Encorafenib and binimetinib were administered in phase II clinical trials for BRAF mutated patients. Pembrolizumab is now recommended in patients exhibiting microsatellite instability. Larotrectinib and entrectinib showed a fast and durable response with few and reversible adverse events in cases with NTRK fusions. Trastuzumab and trastuzumab deruxtecan exhibited promising and durable activity in HER-2-positive patients. In this review, the reasons for an extension of the molecular profile of patients were assessed and placed in the context of the advancements in the understanding of genetics. We highlight the differential effect of new targeted therapies through an ever-deeper characterization of tumor tissue. An overview of ongoing clinical trials is also provided.

Background FLOT regimen is the standard perioperative treatment in Western countries for patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC). High microsatellite instability (MSI-H) and Mismatch Repair deficient (dMMR) demonstrated a favorable prognostic role and a concomitant negative predictive impact on the benefit of perioperative 5-fluorouracil-based doublets; however, its role in pts receiving FLOT chemotherapy is still unclear. Methods This is a retrospective, multicenter observational study of 265 pts with GC/GEJC treated with perioperative FLOT regimen in 11 Italian oncology centers between January 2017 to December 2021 and analyzed for microsatellite status. Results The MSI-H phenotype was found in 27 (10.2%) of 265 analyzed tumors. Compared to microsatellite stable (MSS) and Mismatch Repair proficient (pMMR) cases, MSI-H/dMMR were more frequently female (48.1% vs. 27.3%, p  = 0.0424), elderly pts (age > 70 years, 44.4% vs. 13.4%, p  = 0.0003), Laurens’s intestinal type (62.5% vs. 36.1%, p  = 0.02) and pts with a primary location tumor in the antrum (37 vs. 14.3%, p  = 0.0004). A statistically significant difference in the rate of pathologically negative lymph node emerged (63% vs 30.7%, p  = 0.0018). Compared to the MSS/pMMR tumor population, the MSI-H/dMMR subgroup had a better DFS (median not reached [NR] vs. 19.5 [15.59–23.59] mos, p  = 0.031) and OS (median NR vs. 34.84 [26.68–47.60] mos, p  = 0.0316). Conclusions These real-world data confirm that FLOT treatment is effective in daily clinical practice for locally advanced GC/GEJC, also in the MSI-H/dMMR subgroup. It also showed a higher rate of nodal status downstaging and a better outcome of MSI-H/dMMR pts in comparison to MSS/pMMR.

BackgroundIsocitrate dehydrogenase-1 (IDH1) mutations occur in a significant proportion of intrahepatic cholangiocarcinomas (iCCAs). No data are available regarding the prognostic impact of IDH1 mutations in advanced iCCA patients after progression on first-line therapies.ObjectiveWe investigated the role of IDH1 mutation in advanced iCCA after progression on first-line therapies.Patients and MethodsAfter progression on first-line therapies for advanced iCCA, consecutive patients were retrospectively collected. The IDH1 status was tested at baseline. This analysis aimed to examine the association between the presence of IDH1 missense mutations and survival outcomes in patients with advanced iCCA treated with a second-line therapy.ResultsThe analysis included 119 patients; 56/119 (47%) were IDH1 mutated (IDH1m) and 63/119 (53%) were IDH1 wild type (IDH1 WT). At univariate analysis for overall survival (OS), the presence of IDH1 mutation was associated with a worse median OS (mOS; 8.2 vs. 14.1 months; hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2–3.0, p = 0.0047). Patients harboring IDH1 mutations showed a worse objective response rate (ORR) compared with patients without IDH1 mutation, whereas no significant differences in disease control rate (DCR) were found. Multivariate analysis confirmed IDH1 mutations as an independent negative prognostic factor for OS (HR 1.7, 95% CI 1.1–2.7, p = 0.0256). By evaluating only patients receiving FOLFOX as second-line therapy, no statistically significant differences were found in terms of both OS and PFS between IDH1m and IDH1 WT patients. In this subset of patients, those harboring an IDH1 mutation showed a worse ORR and DCR compared with those without. Finally, at univariate analysis for OS from third-line treatment, the presence of an IDH1 mutation was associated with a trend toward a worse mOS (6.0 vs. 11.9 months; HR 1.6, 95% CI 0.8–3.2, p = 0.25).ConclusionThe present analysis constitutes the first evidence of a negative prognostic impact of IDH1 mutations in a cohort of patients treated after progression on first-line therapies in contrast to IDH1 inhibitors.

Hepatoid adenocarcinoma is a rare extra hepatic neoplasm that displays morphological and phenotypic features similar to those of hepatocellular carcinoma. We report a case of a 75-year-old woman, presenting with abdominal pain and complaints of weakness and lost of appetite, who was found to have a mass on her right colon. She underwent right hemicolectomy for a pT3N2M0, stage IIIC colon cancer. The tumor phenotype and immunophenotype, as documented by alpha-fetoprotein immunoreaction positivity, were consistent with adenocarcinoma of hepatoid origin. The patient received FOLFOX-4 regimen as adjuvant treatment, relapsed after six cycles, then was switched to FOLFIRI regimen plus Bevacizumab and progressed after only four cycles. She died 1 month later, eight months after the diagnosis. The lack of any clinical benefit despite an aggressive and multimodal therapeutic strategy, raises a question about what should be targeted when we face this rare disease associated with a very poor prognosis.

Background: This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events. Patients and methods: Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported. Results: Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3–2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5–3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated (p = 0.009, p < 0.0001, p < 0.0001). Overall COVID-19 prevalence was 1.2% for vaccinated (six of 482 cases, all confirmed) and 1.7% for unvaccinated (8 of 473, 3 confirmed COVID-19 and 5 COVID-like), p = 0.52. The difference remained non-significant, considering confirmed COVID-19 only (p = 0.33). Conclusion: COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

Increasing global demand for energy along with climate change claims for sustainable and renewable energy sources. In this study, we investigated transcriptomic changes in two cardoon ( Cynara cardunculus L. var. altilis ) calli cell culture lines engineered for production of valuable fatty acids, therefore suitable for large-scale production of biofuel precursors, as alternative to triacylglycerols (TAGs) engineered plants. Namely, to gain insight in the molecular effects of genetic transformation, we analyzed the transcriptome of SAD -OE line (overexpressing stearic acid desaturase), and FAD -KD line (a fatty acid desaturase RNA interference line, FAD2.2-RNAi) accumulating oleic and linoleic acids, respectively. Differentially expressed genes (DEGs) involved in fatty acid metabolism and streamed pathways such as glycolysis, pyruvate, glycerolipid, and glycerophospholipid metabolism, were enriched in the KEGG analysis in both lines. In addition to analyzing DEGs, we used qRT-PCR to monitor key regulatory and biosynthetic genes involved in TAGs formation and assembly, aiming to understand their transcriptional dynamics over ten days of cell growth in liquid culture. In transgenic scaled up lines, upon observing increased lipid accumulation, we investigated how genetic transformation influenced sugar metabolism. Fructan depletion analysis further supported their role as carbon sources for TAG biosynthesis. Confocal microscopy confirmed a significantly higher accumulation of oil bodies in transgenic lines compared to wild-type (WT) calli. Overall, this study presents a comprehensive characterization of a cardoon cell-based platform for large-scale vegetable oil production. Unlike whole plants, these engineered cell cultures do not suffer from severe oxidative stress or growth and metabolic impairments, making them a promising alternative for sustainable fatty acid biosynthesis.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.