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Background Small bowel adenocarcinoma is a rare disease. The genomic profiling tumours according to clinical characteristics and its impact on the prognosis remains unclear. Methods A pooled analysis of clinical data, genomic profiling and MisMatch Repair (MMR) status from three databases was performed. Results A total of 188 tumour samples were analysed. A predisposing disease was reported in 22.3%, mainly Lynch syndrome and Crohn’s disease. The tumours were localized in 80.2% and metastatic in 18.8%. The most frequent mutations were KRAS (42.0%) among them 7/79 are G12C , TP53 (40.4%), APC (19.1%), PIK3CA (18.6%), SMAD4 (12.8%) and ERBB2 (9.6%). Mutation distribution differed according to predisposing disease for TP53 , ERBB2, IDH1, FGFR3, FGFR1 and KDR. KRAS and SMAD4 mutations were more frequent in metastatic tumour, whereas ERBB2 mutations were absent in metastatic tumour. For localized tumour, APC mutation was independently associated with a poor overall survival (OS) ( p  = 0.0254). 31.8% of localized tumours and 11.3% of metastatic tumours were dMMR (29.8% of the entire cohort). A dMMR status was associated with a better OS (HR = 0.61 [0.39–0.96], p  = 0.0316). Conclusions There is a different genomic profile according to the stage and predisposing disease. dMMR and APC mutation in localized tumour predict a better prognosis.

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.

Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment options. Despite advances with durvalumab plus chemotherapy, prognosis remains poor. The tumor immune microenvironment (TIME) is increasingly recognized as a determinant of immunotherapy response, yet its spatial organization in BTC is poorly understood. We applied multiplex immunofluorescence to pre-treatment tumor samples from 11 patients with advanced BTC, staining for CD4, CD8, CD20, and CD163 to identify T cells, B cells, and macrophages. Across 198 regions of interest sampled at the invasive tumor margin, approximately 400,000 individual cells were segmented and phenotyped. Spatial organization was analyzed using hierarchical clustering, distance-based approaches, and cellular neighborhood classification. Unsupervised analysis identified two distinct immune phenotypes, one enriched in CD4 T cells and CD163 macrophages and the other in CD8 T cells and CD20 B cells. These phenotypes displayed distinct spatial architectures, with CD4 T cells and CD20 B cells acting as organizing hubs, respectively. Targeted sequencing, available for a subset of cases, showed a higher frequency of co-occurring TP53 and ARID1A alterations in the B-cell-enriched phenotype. No statistically significant differences in overall or progression-free survival were observed between immune phenotypes. However, among patients treated with adjuvant cisplatin/gemcitabine alone, lower CD20/CD8 fractions and higher CD163 abundance at baseline were associated with improved survival. Spatial immune profiling revealed distinct BTC immune architectures at the invasive margin, with different possible impact on survival, thus warranting further characterization and validation in larger cohorts.

Background: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations. We recently published the first data on the use of ivosidenib in a real-world setting. Objective: Here we report the updated survival results of 11 patients with locally advanced or metastatic IDH1-mutated CCA who received ivosidenib in clinical practice. Patients and methods: Patients treated with ivosidenib as second- and third-line treatments for advanced CCA have been collected with the aim to evaluate the survival outcomes. A molecular study has been performed by next generation sequencing essay. Results: Overall, 11 patients were included. After a median follow-up of 13.7 months, median progression-free survival from the start of treatment with ivosidenib was 4.4 months (95% CI: 2.0–5.8), whereas median overall survival was 15 months (95% CI: 6.6–15.0) regardless of treatment line. Disease control rate was 63%, with two patients achieving a partial response (18%). Eighteen percent of patients experienced at least one treatment-related adverse events (AEs), but no grade ⩾3 was reported. The most frequently observed grade 2 AEs were prolonged QT interval and hypomagnesemia. A molecular profiling was performed on 8 out of 11 patients, highlighting TP53, BAP1, CDKN2A, and CDKN2B as the most common co-altered genes in these patients. Conclusion: The present update confirms the results of our previous real-world experience on the use of ivosidenib in IDH1-mutated CCA. Real-world evidence on larger numbers of patients is needed to confirm our findings.

PurposeNeuroendocrine carcinomas (NECs) are a rare subgroup of neuroendocrine neoplasms that occasionally originate from gastro-entero-pancreatic (GEP) tract. Evidence of the effectiveness of chemotherapy is scarce. Platinum plus Etoposide regimens are currently the standard treatment in first-line, while little data are available on second-line treatments. The aim of this study is to evaluate the efficacy and safety of irinotecan (IRI)-based chemotherapy in a series of extrapulmonary NECs.MethodsPatients with NEC diagnosis treated at University Hospitals of Modena, Florence, Pisa, and European Institute of Oncology of Milan with an IRI-based regimen (FOLFIRI or XELIRI) after progression to a first-line platinum-based therapy were enrolled. Objective responses were assessed according to RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were calculated.ResultsThirty-four patients, 16 males, and 18 females, median age of 59 years (range 32–77), with metastatic NEC were included. Twenty-seven patients had Ki-67 ≥ 55% and four patients Ki-67 of <55% (for three patients data were not available). The median number of treatment cycles of the IRI-based regimen was 7.5 (range 1–16). Six partial responses (17.6%) and 9 stable diseases (26.5%) were observed, with a disease control rate of 44.1%. Median PFS and OS were 4.4 and 5.9 months, respectively. Neutropenia, anemia, and nausea were the only G3–G4 toxicities reported.ConclusionsDespite the relatively small sample size, IRI-based therapy demonstrated to be a valid option for patients with pretreated extrapulmonary NEC.

Abstract Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0–1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

BackgroundRegorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients.ObjectiveWe performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib–regorafenib compared with sorafenib and physician’s choice in a real-life setting.Patients and MethodsA propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S–R) and the arm treated with sorafenib and physician’s choice (S–P). Survival analysis was conducted on the matched population.ResultsAfter the application of propensity score matching, we analysed 99 patients in the arm treated with S–R and 99 patients in the arm treated with S–P. For the S–R group, the median overall survival was 22.2 months (95% CI 17.1–27.4), compared to 17.9 months (95% CI 15.1–50.0) for the S–P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S–R (p = 0.0382) compared to patients treated with S–P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread.ConclusionThis study provides additional proof of the superiority of the S–R treatment over the S–P treatment approach in advanced HCC patients from a real-life setting.

Lurbinectedin is responsible for DNA recognition and binding, producing double-strand DNA (dsDNA) breaks thus resulting in apoptosis. Sensitivity to lurbinectedin is linked to the nucleotide excision repair (NER) system. Furthermore, irinotecan, a topoisomerase I inhibitor, provokes dsDNA breaks that could be reinforced abrogating the NER system using lurbinectedin. BRCA-mutated patients, already treated with platinum-derived drugs, who suffered DNA damage, cannot repair the breaks due to lurbinectedin interaction, whereas irinotecan provokes a dsDNA break that promotes synthetic lethality. This article describes an exceptional response to lurbinectedin alone followed by the association with irinotecan in a BRCA-mutated platinum-resistant ovarian cancer patient. A 44-year-old BRCA1-mutated ovarian cancer patient was treated in sixth line with lurbinectedin and irinotecan with a time to further progression (TTFP) equal to 8 months. In our case, the association with irinotecan overcame the resistance to lurbinectedin alone. In conclusion, lurbinectedin and irinotecan demonstrated a promising response in platinum-resistant patients. However, further studies should be conducted to validate our findings and future trials will be important to further define the clinical utility of lurbinectedin.

Introduction: Two distinct molecular groups of HCC have been recently associated with a better response to atezolizumab-bevacizumab. One of these, “angiogenesis-driven,” is related to HCC vascularization. Vessels that encapsulate tumor clusters (VETCs) is a morphological form of angiogenesis associated with worse prognosis in resected and transplanted HCC. The aim of this study was to explore if VETC can be used, at morphological level, to potentially surrogate the angiogenesis-driven molecular subgroup to identify HCC patients who might benefit of antiangiogenic treatments. Methods: The significance of VETC was first explored in a retrospective, single institution series of 75 patients with unresectable HCC (study cohort) and later validated in an external, retrospective series of 82 patients (validation cohort). The VETC phenotype was identified in the liver biopsy obtained just before the onset of systemic treatment. Results: Patients with VETC+ HCC experienced a significant survival benefit from antiangiogenic drugs, as tyrosine kinase inhibitors and/or bevacizumab (TKI/BEVA), across the study, validation, and overall cohorts. In the whole series of 157 patients, those with VETC+ HCC (n = 70, 45%) treated with TKI/BEVA had a significantly longer overall survival (OS) as compared to those receiving immune checkpoint inhibitors (19.8 months vs. 8.8 months; HR: 0.34; 95% CI: 0.20–0.59; p = 0.0001). The significant treatment-by-biomarker interaction test (p = 0.002) demonstrated that treatment effect varies by VETC status. Case with higher extent of VETC+ or with VETC+ detected before the onset of 1st-line treatment showed even longer survival. Conclusion: VETC+ predicts a significantly longer OS in patients with unresectable HCC treated with TKI/BEVA and can be used as surrogate marker on liver biopsy of angiogenesis-driven molecular class.

A correction to this paper has been published: https://doi.org/10.1007/s11523-021-00808-3