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Background: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection., Patients and Methods: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0., Results: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations., Conclusion: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...

Background: Up to 50% of patients with advanced small-intestinal neuroendocrine tumors (SI-NETs) and carcinoid syndrome (CS) develop carcinoid heart disease (CHD). However, the true frequency and prognostic markers for CHD in CS are lacking. We described the real-world management of patients in two NET referral centers in this clinical context and relationships between clinical features, including CHD and overall survival (OS)., Patients and Methods: This is a retrospective analysis of patients with stage IV SI-NET and CS, treated at the European Institute of Oncology in Milan and Uppsala University in Sweden between 2015 and 2021. CHD was defined as at least one moderate right-sided heart valve defect. Median OS and cumulative incidence of CHD were estimated from the diagnosis of metastatic disease, and the association between clinical parameters with both OS and occurrence of CHD was evaluated., Results: We included 165 patients, with 97% having low-intermediate-grade SI-NETs and 86% having synchronous liver metastases. Ninety-eight patients (59%) became refractory to full label dose of somatostatin analogues and 25% developed a CHD. At CHD diagnosis, baseline urine 5-hydroxyindoleacetic acid (24-h u5-HIAA) value and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) value were known in 76% of patients. Moderate-to-severe tricuspid insufficiency was the most common alteration of CHD. Prognosis was significantly impaired by CHD (multivariable hazard ratio for OS = 2.85, P < 0.001). The median OS from the CHD diagnosis was 4.5 years [95% confidence interval (CI) 2.1-7.2 years], and the 5-year survival rate was 34% (95% CI 13% to 57%)., Conclusions: In our study population of SI-NET patients with CS, more than half had a refractory carcinoid syndrome (RCS) and one-quarter developed a CHD, with a negative impact on OS. Therefore, it is recommended to screen and monitor patients with CS for CHD, ideally with a combination of u5-HIAA, NT-proBNP values, and echocardiography at CS baseline, preferably in NET referral centers., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Neuroendocrine neoplasms incidence has been increasing, arising the need for precise and early diagnostic tools. Liquid biopsy (LB) offers a less invasive alternative to tissue biopsy, providing real-time molecular information from circulating tumour components in body fluids. The aim of this review is to analyse the current evidence concerning LB in NENs and its role in clinical practice. We conducted a systematic review in July 2024 focusing on LB applications in NENs, including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), micro RNA (miRNA), messenger RNA (mRNA) and extracellular vesicles. Sixty-five relevant articles were analysed. The LB showed potential in diagnosing and monitoring NENs. While CTCs face limitations due to low shedding, ctDNA provides valuable information on high-grade neoplasms. MiRNA and mRNA (e.g., the NETest) offer high sensitivity and specificity for diagnosis and prognosis, outperforming traditional markers like chromogranin A. The LB has significant potential for NEN diagnosis and monitoring but lacks widespread clinical integration due to limited prospective studies and guidelines, requiring further validation. Advances in sequencing technologies may enhance the clinical utility of LB in NENs. Future research should focus on refining LB methods, standardising protocols and exploring applications in high-grade NENs. more...

Background: Based on the Khorana score, guidelines recommend anticoagulation for primary prophylaxis (PP) in outpatients with cancer with an intermediate-to-high risk of venous thromboembolism (VTE). ONKOTEV score has been prospectively externally validated as novel risk assessment model (RAM) with good discriminatory performances but no direct comparisons with Khorana Score are available., Methods: Using the ONKOTEV validation dataset (n = 425), we applied generalized decision curve analysis (gDCA) which integrates the principles of evidence-based medicine with treatment effects, model accuracy and patient preferences (weighted as the relative value [RV] of avoiding VTE versus major bleeding [MB]). The aim is to select the most optimal treatment strategy among multiple options: "no treatment", "treat all patients with DOAC/LMVH", or "use ONKOTEV/KHORANA scores to guide PP with DOAC/LMWH"., Results: Results showed that ONKOTEV-guided PP (using DOAC or LMWH) remained the most optimal strategy for wide range assumption of treatment efficacy and patient's preference. For those patients, who value avoiding VTE more than MB, then offering DOAC to all patients represents the best strategy. When MBs are feared more than the morbidity of VTE, ONKOTEV-guided PP (DOAC) represents the best management strategy. In all cases, ONKOTEV outperformed Khorana for individualized VTE prevention., Conclusions: When the two predictive models are integrated within a decision analysis framework, ONKOTEV appears superior to Khorana Score in guiding individualized prevention of cancer-related VTE in outpatients with cancer. The findings herein reported provide cutting edge insights in cancer care and support the spread of ONKOTEV score in the ambulatory cancer setting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CAC reports personal fees from BMS and Leo Pharma; and a research grant from IPSEN (institutional). BD has no conflict of interest to declare. IH has no conflict of interest to declare. FL received fees for lectures, expert appraisal or consulting services from Amgen GmbH, Astellas Pharma GmbH, AstraZeneca GmbH, Bayer AG, BioNTech SE, Bristol-Myers Squibb GmbH & Co. KGaA, Daiichi Sankyo Deutschland GmbH, Lilly Deutschland GmbH, Elsevier GmbH, Falk Foundation e.V., Incyte Inc, Merck KGaA, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, Roche Deutschland Holding GbmH, Servier Deutschland GmbH, Springer Nature AG & Co. KGaA, StreamedUp! GmbH; research projects are supported by Bristol-Myers Squibb GmbH und Co. KGaA and Gilead Science GmbH. VB has no conflict of interest to declare. SF has no conflict of interest to declare. LG has no conflict of interest to declare. NF received personal fees from AAA, Hutchinson MediPharma, Merck, Novartis; has financial interest with 4SC, Astellas, Beigene, FIBROGEN, Incyte, IPSEN, MSD and NUCANA; and has received research grant form IPSEN (institutional)., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Background: Carcinoma of unknown primary (CUP) with a gastrointestinal profile is categorized by the European Society of Medical Oncology (ESMO) guidelines into favorable and unfavorable subsets. Favorable CUPs benefit from site-specific chemotherapy (CT), while the optimal treatment for unfavorable CUPs is still undefined., Materials and Methods: We conducted a single-center retrospective study to describe outcomes of patients with CUP with a gastrointestinal profile referred to our center from January 2000 to August 2023. Favorable CUPs were defined as CK7-/CK20+/CDX2+ by immunohistochemistry, according to the ESMO definition; all other cases were considered unfavorable. The main endpoint was the progression-free survival (PFS) of first-line CT for advanced disease in all patients and in the unfavorable group., Results: A total of 56 patients were included, of whom 46 (82%) had unfavorable CUPs. After a median follow-up of 43.9 months, the median overall survival (mOS) was 11.8 months [95% confidence interval (CI) 8.3-15.3 months]. At univariate analysis, the presence of peritoneal metastases and residual tumor after primary surgery were associated with a shorter OS. The median PFS (mPFS) was 6.1 months (95% CI 3.6-8.7 months). In the unfavorable CUP subgroup, the mOS was 12.6 months (95% CI 8.7-16.5 months), the mPFS was 6.1 months (95% CI 3.5-8.9 months) and none of the CT regimens used showed to portend better PFS. The most relevant altered genes included: KRAS (9/29; 31%), BRAF (1/26; 4%), NRAS (1/25; 4%), TP53 (9/23; 39%)., Conclusions: CUPs with a gastrointestinal profile are characterized by poor prognosis and the absence of biomarker for treatment personalization. No CT regimen was superior in terms of PFS in patients with unfavorable CUPs., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...

Textbook outcome (TO) has been proposed as a tool to evaluate surgical quality. Textbook oncological outcome (TOO) adds chemotherapeutic compliance to TO. This study was conducted to analyze the TO and TOO of patients with gastric adenocarcinoma who underwent surgery at our center. Data from a prospective database of patients operated on for gastric adenocarcinoma between September 2018 and September 2022 were analyzed. Postoperative management followed Enhanced Recovery After Surgery guidelines. The Dutch Upper Gastrointestinal Cancer Audit group defined TO as a multidimensional measure (10 items). TOO also considers guideline-accordant chemotherapeutic compliance. Three hundred patients underwent surgery during the study period (167 men, 133 women). One hundred seventy-six (58.7%) reached TO. Achieving TO was influenced by patients' comorbidities, calculated via the Charlson Comorbidity Score (3 vs. 4; p = 0.002) and surgery type (subtotal gastrectomy; p < 0.001), but not by the American Society of Anesthesiologists (ASA) score (p = 0.057) or surgical approach (laparoscopic vs. open; p = 0.208). The analysis of TOO included 213 patients. Of these, 71 (33%) underwent complete adequate systemic treatment. Compared with the non-TOO group, patients who achieved TOO had a lower median age (64 vs. 73 years; p < 0.001) and lower ASA score (p < 0.001) and more frequently underwent preoperative chemotherapy (p < 0.001). Our results represent the experience of a single team at a high-volume Western institute. Patients' comorbidities and surgery type influenced whether TO was achieved. Conversely, younger age, lower ASA score and preoperative chemotherapy were associated with TOO., (© 2023. Italian Society of Surgery (SIC).) more...

Background: The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy., Objectives: We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes., Design: Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery., Methods: Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS)., Results: Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10-1.26), p  = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02-1.07), p  = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63-8.36, p  = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35-4.06, p  = 0.79)., Conclusion: Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.) more...

Immune checkpoint inhibitors (ICIs) revolutionized the management of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers. Based on notable results observed in the metastatic setting, several clinical trials investigated ICIs as neoadjuvant treatment (NAT) for localized dMMR/MSI-H GI cancers, achieving striking results in terms of clinical and pathological responses and creating the opportunity to spare patients from neoadjuvant chemotherapy and/or radiotherapy and even surgical resection. Nevertheless, these impressive findings are mainly derived from small proof of concept phase II studies and there are still several open questions to address. Moreover, dMMR/MSI-H represents a limited subgroup accounting for less than 10% of GI cancers. Consequently, many efforts have been produced to investigate neoadjuvant ICIs also in mismatch repair-proficient/microsatellite stable (MSS) cancers, considering the potential synergistic effect in combining immune-targeted agents with standard therapies such as chemo and/or radiotherapy. However, results for combining ICIs to the standard of care in the unselected population are still unsatisfactory, without improvements in event-free survival in esophago-gastric adenocarcinoma for the addition of pembrolizumab to chemotherapy, and sometimes limited benefit in patients with locally advanced rectal cancer. Therefore, a major challenge will be to identify among the heterogenous spectrum of this disease, those patients that could take advantage of neoadjuvant immunotherapy and deliver the most effective treatment. In this review we discuss the rationale of NAT in GI malignancies, summarize the available evidence regarding the completed trials that evaluated this treatment strategy in both MSI-H and MSS tumors. Finally, we discuss ongoing studies and future perspectives to render neoadjuvant immunotherapy another arrow in the quiver for the treatment of locally advanced GI tumors., Competing Interests: Competing interests: DC received travel support from Sanofi, BMS and Merck KgA. NF declares Personal Financial Interests for ADACAP, Ipsen (Invited speaker), for ADACAP, Merck, MSD, Novartis, Pfizer, Boehringer (Advisory Board); Institutional Financial Interests: local PI of trials for 4SC, Astellas, Beigene, Fibrogen, Incyte, Ipsen, Nucana; research grants from ADACAP, Ipsen, MSD, Merck. Other Authors declare no conflict of interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Background: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting., Material and Methods: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included., Results: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs., Conclusions: These results confirm the effectiveness and safety of pemigatinib in a real-world setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Introduction: A significant proportion of locally-advanced esophago-gastric adenocarcinoma (EGA) is diagnosed in patients ≥70 years old (y.o.) who are commonly underrepresented in clinical trials., Materials and Methods: The PubMed database was searched for phase 2/3 clinical trials enrolling patients ≥70 y.o and reporting efficacy/safety information of chemotherapy for resectable EGA. The main outcomes were overall survival (OS) and recurrence-free survival (RFS)., Results: Among 6,128 records, only seven studies reported these outcomes (three peri-operative, three adjuvant, and one neoadjuvant), including 1004 older patients, <20% of the overall population. No significant benefit in terms of OS and RFS was observed for perioperative or adjuvant chemotherapy vs surgery alone. No trial reported safety endpoints in this subgroup., Discussion: This work did not show any significant benefit in OS or RFS for chemotherapy vs surgery alone or conventional vs de-escalated chemotherapy in the curative setting of EGA in ≥70 y.o patients. Specific ad hoc trials should be performed to derive reliable data., Competing Interests: Declaration of Competing Interest LG, SC, and SG have no conflicts of interest to disclose. ANR reports to be IPSEN speaker and travel, accommodations, and expenses by Pfizer, IPSEN, Gilead. CAC Reports personal fees from BMS and Leo Pharma; and a research grant from IPSEN (institutional). NF reports to be AAA, IPSEN, and Sanofi speaker, besides advisory board for AAA, Hutchmed, Merck, MSD, Novartis, and Pfizer., (Copyright © 2023. Published by Elsevier Ltd.) more...

Purpose: Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced gastric cancer (LAGC). Several biomarkers, including HER2 and MMR/MSI are crucial for treatment decisions in the advanced stage but, currently, no biomarkers can guide the choice of NAC in clinical practice. Our aim was to evaluate the role of MSI and HER2 status on clinical outcomes., Methods: We retrospectively collected LAGC patients treated with NAC and surgery +/- adjuvant chemotherapy from 2006 to 2018. HER2 and MSI were assessed on endoscopic and surgical samples. Pathologic complete response (pCR) rate, overall survival (OS), and event-free survival (EFS) were estimated and evaluated for association with downstaging and MSI., Results: We included 76 patients, 8% were classified as MSI-H, entirely consistent between endoscopic and surgical samples. Six percent of patients were HER2 positive on endoscopic and 4% on surgical samples. Tumor downstaging was observed in 52.5% of cases, with three pCR (5.1%), none in MSI-H cancers. According to MSI status, event-free survival (EFS) and overall survival (OS) were higher for MSI-H patients to MSS [EFS not reached vs 30.0 months, p = 0.08; OS not reached vs 39.6 months, p = 0.10]., Conclusion: Our work confirms the positive prognostic effect of MSI-H in the curative setting of LAGC, not correlated with pathologic tumor downstaging. Prospective ad-hoc trial and tumor molecular profiling are eagerly needed., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).) more...

Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing in vitro and in vivo models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescence-activated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both in vitro and in vivo models. On this basis, we envisage future research to further investigate along these promising lines. more...

Introduction: In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development., Areas Covered: We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs., Expert Opinion: Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors. more...

Non-metastatic neuroendocrine carcinoma of the cervix (NECC) is a rare and aggressive disease. Lacking prospective studies, the optimal multimodal treatment approach has not yet been clearly defined. This study aims to assess the clinical outcomes of patients with non-metastatic NECC treated with surgery and (neo)adjuvant chemotherapy, according to pathologic prognostic factors and multimodal treatments received. We retrospectively examined data from patients with non-metastatic NECC candidate to receive surgery and (neo)adjuvant chemotherapy and discussed at the European Institute of Oncology's Multidisciplinary Neuroendocrine Tumor Board, between January 2003 and December 2021. Primary endpoints were event-free survival and overall survival. A total of 27 consecutive patients were evaluated, 15 with early stage NECC and 12 with a locally advanced NECC. Eight patients received neoadjuvant and 19 adjuvant platinum-based chemotherapy; 14 received adjuvant pelvic radiotherapy, half with external-beam radiation therapy alone, and half combined with brachytherapy. No patients progressed or relapsed during (neo)adjuvant chemotherapy. The median event-free survival was 21.1 months and the median overall survival was 33.0 months. Pathological FIGO stage ≥ IIB, adjuvant external-beam radiation therapy with or without brachytherapy emerged as significant and independent prognostic factors for event-free survival. Brachytherapy was also prognostic for overall survival. Non-metastatic NECC requires a multimodal approach, mainly weighted on the FIGO stage. The addition of brachytherapy should be considered, especially in patients with locally advanced disease. Because of the scarcity of robust clinical data, treatment strategy should be discussed in multidisciplinary board, taking into account patient. more...

Importance: The assessment of the risk of venous thromboembolism (VTE) among outpatients with cancer represents an unsolved topic. Current international guidelines recommend primary prophylaxis for patients at intermediate to high risk of VTE, indicated by a Khorana score of 2 or more. A previous prospective study developed the ONKOTEV score, a 4-variable risk assessment model (RAM) consisting of a Khorana score of more than 2, metastatic disease, vascular or lymphatic compression, and previous VTE event., Objective: To validate the ONKOTEV score as a novel RAM to assess the risk of VTE among outpatients with cancer., Design, Setting, and Participants: ONKOTEV-2 is a noninterventional prognostic study conducted in 3 European centers located in Italy, Germany, and the United Kingdom among a prospective cohort of 425 ambulatory patients with a histologically confirmed diagnosis of a solid tumor who were receiving active treatments. The total study duration was 52 months, with an accrual period of 28 months (from May 1, 2015, to September 30, 2017) and an overall follow up-period of 24 months (data were censored September 30, 2019). Statistical analysis was performed in October 2019., Exposures: The ONKOTEV score was calculated for each patient at baseline by collecting clinical, laboratory, and imaging data from tests performed for routine practice. Each patient was then observed to detect any thromboembolic event throughout the study period., Main Outcomes and Measures: The primary outcome of the study was the incidence of VTE, including deep vein thrombosis and pulmonary embolism., Results: A total of 425 patients (242 women [56.9%]; median age, 61 years [range, 20-92 years]) were included in the validation cohort of the study. The cumulative incidences for the risk of developing VTE at 6 months were 2.6% (95% CI, 0.7%-6.9%), 9.1% (95% CI, 5.8%-13.2%), 32.3% (95% CI, 21.0%-44.1%), and 19.3% (95% CI, 2.5%-48.0%), respectively, among 425 patients with an ONKOTEV score of 0, 1, 2, and greater than 2 (P < .001). The time-dependent area under the curve at 3, 6, and 12 months was 70.1% (95% CI, 62.1%-78.7%), 72.9% (95% CI, 65.6%-79.1%), and 72.2% (95% CI, 65.2%-77.3%), respectively., Conclusions and Relevance: This study suggests that, because the ONKOTEV score has been validated in this independent study population as a novel predictive RAM for cancer-associated thrombosis, it can be adopted into practice and into clinical interventional trials as a decision-making tool for primary prophylaxis. more...

The coronavirus disease-19 (COVID-19) pandemic dramatically impacted oncological patients' care. Since the introduction of vaccines and the demonstration of their benefit on frail patients, COVID-19 vaccinations were indicated to also be beneficial to oncological population. However, data about the impact of anticancer-treatments and the timing between vaccinations and systemic therapy delivery were not available. We aimed to evaluate potential factors influencing the outcome of the COVID-19 vaccination in cancer patients. We prospectively collected data of patients undergoing the COVID-19 vaccination with gastro-entero-pancreatic and neuroendocrine neoplasms, treated at our institute, between 03/2021 and 12/2021. We enrolled 46 patients, 63.1% males; at the time of data collection, 86.9% had received two-doses of Pfizer-BioNTech and the rest had received the Moderna vaccine. All patients obtained a subsequent immune-response. Chemotherapy seems to determinate a significantly lower antibody response after vaccination compared to the other anti-cancer agents ( p = 0.004). No significant effect on immune-response was reported for both vaccinations performed ≤7 vs. >7 days from the last systemic treatment ( p = 0.77) and lymphocytes count ( p = 0.11). The findings suggest that the optimal timing for COVID-19 vaccination and lymphocytes count are not the issue, but rather that the quality of the subset of lymphocytes before the vaccination determine the efficacy level of immune-response in this population. more...

Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0-68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8-79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5-95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0-97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data. more...

Background: The success of targeted therapies in the treatment of pancreatic neuroendocrine tumors has emphasized the strategy of targeting angiogenesis and the PI3K/AKT/mTOR pathway. However, the major challenge in the targeted era remains the early identification of resistant tumors especially when the efficacy is rarely associated to a clear tumor shrinkage at by imaging assessment., Methods: In this prospective study (NCT02305810) we investigated the predictive and prognostic role of soluble biomarkers of angiogenesis turnover (VEGF, bFGF, VEGFR2, TSP-1) circulating endothelial cells and progenitors, in 43 patients with metastatic panNET receiving everolimus., Results: Among all tested biomarkers, we found a specific subpopulation of circulating cells, CD31+CD140b-, with a significantly increased tumor progression hazard for values less or equal to the first quartile., Conclusion: Our study suggested the evidence that circulating cells might be surrogate biomarkers of angiogenesis activity in patients treated with everolimus and their baseline levels can be correlated with survival. However, further studies are now needed to validate the role of these cells as surrogate markers for the selection of patients to be candidates for antiangiogenic treatments. more...

Background: EOX (epirubicin, oxaliplatin, and capecitabine) is one of the standard regimens for metastatic or locally advanced gastric cancer (GC). A new combination based on fractional docetaxel (low-TOX) has been developed in an attempt to increase the efficacy of EOX and reduce the heavy toxicity of classical docetaxel regimens., Methods: Overall, 169 previously untreated GC patients were randomized between EOX (arm A) and low-TOX (arm B). The primary endpoint was progression-free survival (PFS), while secondary ones were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and tolerability. The study was designed to detect a 35% (80% power at a two-sided 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events., Results: At the cut-off date of interim analysis, median PFS was 6.3 months [95% confidence interval (CI) 5.0-8.1] in arm A vs 6.3 months (95% CI 5.0-7.8) in arm B, without statistical difference. OS was comparable in the two arms: 12.4 in arm A (95% CI 9.1-19.2) vs 11.5 months in arm B (95% CI 8.6-15.0). ORR was 33% and 24%, while DCR was 68% and 67%, respectively. Treatment modification (91% vs 78%, P = 0.017) and number of patients with CTC grade ≥ 3 adverse events (42 vs 35) were higher in arm B., Conclusions: A triplet regimen based on the fractional dose of docetaxel achieves no improvement over EOX which remains a potential standard treatment in many patients with inoperable, locally advanced or metastatic GC., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.) more...

Background: In pancreatic ductal adenocarcinoma cytoreduction can be curative, or palliative. FOLFIRINOX and GEM-NAB are the two FDA/EMA approved regimens for advanced disease. We aim to identified the most cytoreductive regimen on the basis of current literature., Material and Methods: PUBMED was searched for studies published to April 2021. Abstracts of annual meetings ASCO 2009-2021, and ESMO 2015-2020, were searched as well. Phase II, phase III clinical trials, prospective, observational and retrospective studies, reporting overall response rate (complete + partial response) (ORR) in patients treated either with FOLFIRINOX or GEM-NAB were included. The meta-analysis was performed using a randomized-effects model. Main outcome was cytoreduction with each regimen reported as ORR according to RECIST., Results: Among 2183 studies identified, 40 fulfilled the selection criteria (22 FOLFIRINOX, 18 GEM-NAB), totaling 2883 patients. Pooling of data found similar ORR between regimens: FOLFIRINOX [30% (95 CI 26-34%)] and GEM-NAB [30% (95 CI 26-35%),] P = 0.928. Disease control rate (DCR) was significantly higher with FOLFIRINOX [85% (95CI 82-88%)] compared to GEM-NAB [80% (95CI 77-84%)], P = 0.012. A significantly higher ORR irrespective of the regimen was observed in stage IV [36% (95CI 32-40%)] versus stage II-III [25% (95CI 20-31%)], P = 0.002., Conclusions and Relevance: Our meta-analysis did not find significant superiority of one regimen over the other in terms of RECIST-based cytoreduction both in palliative and curative setting of patients with pancreatic adenocarcinoma. The significantly better DCR with FOLFIRINOX compared with GEM-NAB deserves further investigation including waterfall plot and correlations with potential predictive factors., (Copyright © 2022 Elsevier Ltd. All rights reserved.) more...

Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced resectable gastric cancer but, despite important progresses, relapse-related death remains a major challenge. Therefore, it appears crucial to understand which patients will benefit from peri-operative treatment. Biomarkers such as human epidermal growth factor receptor-2 (HER2), microsatellite instability (MSI), and Epstein-Barr Virus (EBV) have been widely studied; however, they do not yet guide the choice of perioperative treatment in clinical practice. We performed a narrative review, including 23 studies, addressing the value of tissue- or blood-based biomarkers in the neoadjuvant setting. Ten studies (43.5%) were prospective, and more than half were conducted in East-Asia. Biomarkers were evaluated only post-NAC (on surgical samples or blood) in seven studies (30.4%), only pre-NAC (on endoscopic specimens or blood) in 10 studies (43.5%), and both pre- and post-NAC (26.1%) in six studies. Among the high variety of investigated biomarkers, some of these including MSI-H or enzymatic profile (as TS, UGT1A1, MTHFR, ERCC or XRCC) showed promising results and deserve to be assessed in methodologically sound clinical trials. The identification of molecular biomarkers in patients treated with NAC for locally advanced resectable gastric or EGJ cancer remains crucial., Competing Interests: Conflict of interest statement: FLorian Lordick declares COI for: Amgen Advisory Board Astellas Advisory Board Astra Zeneca Invited Speaker Bayer Advisory Board Beigene Advisory Board Biontech Expert Testimony BMS Invited Speaker BMS Advisory Board BMS Expert Testimony Eli Lilly Invited Speaker Eli Lilly Advisory Board Elsevier Expert Testimony Iomedico Writing Engagement Medscape Invited Speaker MedUpdate Invited Speaker Merck Serono Invited Speaker MSD Invited Speaker MSD Advisory Board MSD Expert Testimony Roche Invited Speaker Roche Advisory Board Promedicis Invited Speaker Servier Invited Speaker Servier Advisory Board Springer-Nature Writing Engagement StreamedUp! Invited Speaker Zymeworks Advisory Board Imedex Invited Speaker Deutscher Ärzteverlag Writing Engagement Nicola Fazio declares COI for Novartis Consulting and advisory services, speaking engagements, Steering committee Ipsen Consulting and advisory services, speaking engagements, Steering committee Pfizer Advisory services Merck Serono Advisory services, Speaking engagements Advanced Accelerator Applications Advisory services MSD Advisory services Sanofi-Aventis Speaking engagements ACCMED Speaking engagements Wren Laboratories Europe Advisory services EANM Advisory services Springer Writing engagements Pensiero Scientifico EditoreWriting engagements All other authors declare no COIs., (© The Author(s), 2021.) more...

Background: After the results reported by the "Chemoradiotherapy for esophageal Cancer Followed by Surgery Study" (CROSS) trial, neo-adjuvant chemoradiotherapy became the standard treatment for locally advanced cancers of esophagus and gastroesophageal junction (GEJ). Excellent results were reported for squamocellular carcinomas (SCCs). Since the advent of the CROSS regimen, the results of surgery for esophageal adenocarcinomas (EAC) have cast some doubts about its efficacy on overall survival (OS) even in the presence of local response. This study evaluated the relation between pathological (yp) stage after CROSS regimen followed by surgery for adenocarcinoma of cardia and overall (OS) and disease-free survival (DFS). Sites of relapse after surgery were also analyzed. Methods: Patients submitted to the CROSS regimen for locally advanced EAC of the cardia followed by transthoracic esophagectomy were analyzed. Actuarial OS and DFS were analyzed and stratified according to yp stage. The site of relapse, distal and local, was also analyzed. Results: The study included 132 patients. The 50-month OS and DFS were 45% and 6.7%, respectively. No differences emerged analyzing OS according to yp stage. Time to relapse was significantly longer for yp Stage I and II, and for yp N0, compared with yp N+. Recurrence occurred in 48 cases (36.3%) with a 9 months median time to relapse. Local and distal relapse were 10 (7.5%) and 38 (28.7%) cases, respectively ( p ≦ 0.001). Conclusions: Pathological stage after CROSS regimen does not relate to OS and DFS. Time to recurrence is significantly longer for yp Stages I and II and ypN0. Chemoradiotherapy in a neoadjuvant setting may influence the site of relapse, significantly reducing local recurrences. more...

Highly proliferative lung carcinoids (HPLC) have been recently reported but information about this subset remains scarce., Objectives: Clinical and pathological data of 630 patients with lung carcinoids (LC) referred to Gustave Roussy Institute (GR) and European Institute of Oncology (IEO) were retrospectively reviewed to select HPLC and analyze their frequency, behavior and compare their outcome to conventional LC with Ki-67 ≤ 20 % and mitotic count (MC)≤10/2 mm 2 ., Materials and Methods: Selection criteria were: diagnosis of LC confirmed by local pathologist, and available clinical and follow-up data. Patients with Ki-67 > 20 % and/or MC > 10/ 2 mm2 in primary or metastatic specimens were identified as HPLC., Results: 30/514 patients (6%) met the selection criteria of HPLC. Based on primary tumor evaluation, 22/25 (88 %) were classified as atypical carcinoids (AC). Median MC was 4.5/2 mm 2 (1-11) 6/2 mm 2 (3-15) in primary tumors and metastasis, respectively. Median Ki-67 was respectively 23 % (15-65) and 25 % (8-60). Recurrence rate was 66 % (12/18) in HPLC and 9 % (33/352) in conventional LC. Median RFS was 24 (10-NR) months in HPLC, 288 (141-NR) months in LC with Ki-67 index≤5 % and NR (148-NR) months in LC with Ki-67 6-20% (p < 001). Median OS was 203 (83-NR) months in LC with Ki-67 index≤5%, 101 (79-NR) months in LC with Ki-67 index 6-20 % and 53 (39-NR) months in HPLC (p = 002). Among 20 metastatic patients with HPLC, median PFS under platinum-based chemotherapy, everolimus, alkylating-based chemotherapy, FOLFOX and PRRT was 5.1 (95 % CI 0.7-9.4), 12.1(95 %CI 0.3-24), 6.8 (95 % CI 0-14.9), 10.2 (95 % CI 0.4-19.9) and 14.2 months (95 % CI 0-30) respectively. Best response was stable disease (SD) under platinum-based chemotherapy and partial response (PR) under alkylating-based chemotherapy and FOLFOX., Conclusion: This study confirms the existence and rarity of HPLC. Their characteristics and clinical behavior are more similar to LC rather than neuroendocrine carcinomas (NECs), suggesting that this entity could be managed accordingly., (Copyright © 2020 Elsevier B.V. All rights reserved.) more...

Background: Venous thromboembolism (VTE) is a common complication of cancer. This study aimed to evaluate immature platelet fraction (IPF), mean platelet volume (MPV), P-selectin, D-dimer, and thrombin generation (TG) as predictive biomarkers for VTE and further the improvement of existing risk assessment models (RAMs)., Methods: A prospective, observational, exploratory study was conducted on ambulatory cancer patients with indication for systemic chemotherapy. Baseline RAMs included the Khorana-, Vienna Cancer, Thrombosis-, Protecht-, ONKOTEV-, and Catscore. IPF, MPV, P-selectin, D-dimer, and TG were analysed at baseline and 3-month follow-up., Results: We enrolled 100 patients, of whom 89 completed the follow-up. Frequent tumour types were breast (30%), gastric (14%), gynaecological (14%), and colorectal (14%) cancer. Ten of the 89 patients (11.2%) developed VTE. The highest VTE rate was observed in patients with cholangiocarcinoma (3/5; 60%). Baseline D-dimer levels but not IPF, MPV, or P-selectin were associated with the risk of developing VTE (HR 6.9; p = 0.021). None of the RAMs showed statistical significance in predicting VTE. Peak thrombin and endogenous thrombin potential were lower in patients who developed VTE. Biomarker changes between baseline and follow-up were not associated with VTE risk., Conclusions: VTE risk was well predicted by baseline D-dimer levels. Adding D-dimer could improve existing RAMs to better identify patients who may benefit from primary VTE prophylaxis. The VTE risk among patients with cholangiocarcinoma should be further evaluated., (© 2020 The Author(s) Published by S. Karger AG, Basel.) more...

Introduction : Pancreatic neuroendocrine tumors (panNETs) represent a rare group of malignancies. For decades, chemotherapy, somatostatin analogs and interferon represented the only systemic therapies; however, over the latest years, new options were registered, including Everolimus, Sunitinib (SUN), and Peptide Receptor Radionuclide Therapy. Areas covered : This review discusses the role of tyrosine kinase inhibitors (TKIs) in advanced panNETs. Expert opinion : TKIs showed an antiangiogenic and antiproliferative impact on advanced panNETs. Sunitinib is the only TKI currently available in clinical practice, having been approved on the basis of relevant results of a specific panNET phase III trial. New TKIs, such as Cabozantinib, Lenvatinib, Pazopanib, Surufatinib are still on investigation in panNETs. Although some phase II studies with the new TKIs yielded better PFS and RR compared with SUN, different study designs and tumor populations may have induced selection biases. However, it was reported that panNETs resistant to SUN could respond to a new TKI, indicating a possible further therapeutic line in this context. The global investigation plan of TKIs in panNETs is not homogeneous and it is difficult to understand what kind of development this can have in the near future for clinical practice. more...

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh)., Material and Methods: The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC., Results: Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence)., Conclusion: Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings., (Copyright © 2019 Elsevier Ltd. All rights reserved.) more...

Introduction: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available., Methods: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays., Conclusions: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices. more...

Introduction: Cytoreduction is sometimes an important aim of systemic anti-tumor therapies in well-differentiated pancreatic neuroendocrine tumors (PanNETs). As there is not a gold standard treatment for these tumors in this field, we conducted a literature review in order to identify objective criteria for treatment choice., Materials and Methods: We critically reviewed and performed a meta-analysis of all published clinical studies of systemic therapies in patients with well-differentiated unresectable PanNETs, selecting only those articles which reported tumor shrinkage (TS) with a waterfall plot (WP). Tumor downsizing of ≥10% was considered as objective response., Results: We selected 17 out of 2758 studies, comprising 1118 patients with tumor response reported as WP. Proliferation index, tumor burden and anti-tumor therapies were heterogeneous. Chemotherapy alone (mainly, capecitabine/temozolomide) or in combination showed the best results, with ≥10% TS ranging from 65% to 93%. Peptide receptor radionuclide therapy combined with chemotherapy (Chemo-PRRT) and sunitinib appeared promising by inducing objective response in a significant proportion of patients (93% and 60%, respectively). Time to tumor response was reported in only two trials. No clear clinical and/or biological predictive factors emerged., Conclusion: Based on response criteria used in our retrospective analysis, systemic chemotherapy alone or in combination appeared to have the main cytoreductive impact. However no conclusions regarding either a specific regimen or combination can be drawn. Furthermore, tumor population selection and/or choice of regimen may have a significant influence. Further analysis should be also conducted to identify potential predictive biomarkers of responses, in order to design future prospective interventional clinical trials enrolling more homogenous populations of advanced well-differentiated PanNETs., (Copyright © 2018 Elsevier Ltd. All rights reserved.) more...

Objectives: Two issues were put forth by clinicians in the management of the advanced stages of rare variants of pancreatic ductal adenocarcinoma and other exocrine histotypes with peculiar clinical and pathological features: Do chemotherapy regimens recommended in pancreatic ductal adenocarcinoma patients have a clinical activity in rare pancreatic tumors? Or should other chemotherapy combinations be considered in this subset of patients?, Methods: We conducted a multicenter retrospective study that collected data from 2005 to 2016 at 14 Italian cancer centers with the aim to evaluate tumor response and time to progression for first- and second-line and overall survival., Results: Of approximately 4300 exocrine pancreatic cancer patients, 79 advanced cases affected by rare histological types were identified, with pancreatic acinar cell cancer (n = 23), pancreatic adenosquamous cancer (n = 16), and mucinous cystic neoplasm with an associated invasive mucinous cystadenocarcinoma (n = 15) most represented. Survival analyses for each subgroup in relation with the different chemotherapy regimens showed the lack of statistical significance correlations., Conclusions: Because of the lack of clinical trials in patients affected by these rare pancreatic histotypes, only their molecular classification would help clinicians in future therapeutic choice. more...

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare. more...

Background: The efficacy of risk model scores to predict venous thromboembolism (VTE) in ambulatory cancer patients is under investigation, aiming to stratify on an individual risk basis the subset of the cancer population that could mostly benefit from primary thromboprophylaxis., Materials and Methods: We prospectively assessed 843 patients with active cancers, collecting clinical and laboratory data. We screened all the patients with a duplex ultrasound (B-mode imaging and Doppler waveform analysis) of the upper and lower limbs to evaluate the right incidence of VTE (both asymptomatic and symptomatic). The efficacy of the existing Khorana risk model in preventing VTE was also explored in our population. Several risk factors associated with VTE were analyzed, leading to the construction of a risk model. The Fine and Gray model was used to account for death as a competing risk in the derivation of the new model., Results: The risk factors significantly associated with VTE at univariate analysis and further confirmed in the multivariate analysis, after bootstrap validation, were the presence of metastatic disease, the compression of vascular/lymphatic structures by tumor, a history of previous VTE, and a Khorana score >2. Time-dependent receiving operating characteristic (ROC) curve analysis showed a significant improvement in the area under the curve of the new score over the Khorana model at 3 months (71.9% vs. 57.9%, p  = .001), 6 months (75.4% vs. 58.6%, p  < .001), and 12 months (69.8% vs. 58.3%, p  = .014)., Conclusion: ONKOTEV score steps into history of cancer-related-VTE as a promising tool to drive the decision about primary prophylaxis in cancer outpatients. The validation represents the goal of the prospective ONKOTEV-2 study, endorsed and approved by the European Organization for Research and Treatment of Cancer Young Investigators Program. The Oncologist 2017;22:601-608 IMPLICATIONS FOR PRACTICE: Preventing venous thromboembolism in cancer outpatients with a risk model score will drive physicians' decision of starting thromboprophylaxis in high-risk patients., (© AlphaMed Press 2017.) more...

Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9-34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8-27.1 %) vs. 4.8 % (95 % CI 0-14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7-46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials. more...

A major challenge for the management of advanced-colorectal-cancer is the multidisciplinary approach required for the treatment of liver metastases. Reducing the burden of liver metastases with liver-directed therapy has an important impact on both survival and health-related quality of life. This paper debates the rationale and current liver-directed approaches for colorectal liver metastases based on the evidence of literature and new clinical trials. Surgery is the gold standard, when feasible, and it's the main treatment goal for patients with potentially-resectable disease as a means of prolonging progression-free survival. Better tumor response rates with modern systemic therapy mean that more unresectable patients are now down-staged for radical resection following conversion therapy but for other patients, additional procedures are needed. In multiple unilobar disease, when the projected remnant liver is <30% of the total liver, portal embolization or selective-internal-radiation-therapy (SIRT) can induce hypertrophy of the healthy liver, leading to resectability. In multiple bilobar disease, in situ destruction of non-resectable lesions by minimally invasive techniques may be associated with liver resection to achieve potential curative intent. Other palliative liver-directed approaches, such as SIRT or intra-hepatic chemotherapy (HAI), which are associated with higher response rates, may also have role in down-staging patients for resection. Until recently, such technologies have not been validated in prospective controlled trials. However in the light of new Phase 3 data for SIRT as well as for HAI combined with modern therapies or radiofrequency ablation in the first- and second-line setting, the clinical value of these treatments needs to be re-appraised., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.) more...

We report a case of a 74-year-old man with a metastatic anaplastic pancreatic carcinoma (APC). After an early tumour progression on first-line chemotherapy with cisplatin and gemcitabine, even though it was badly tolerated, he was treated with a combination of systemic modified FOLFIRI and high-intensity focused ultrasound (HIFU) on the pancreatic mass. A tumour showing partial response with a clinical benefit was obtained. HIFU was preferred to radiotherapy because of its shorter course and minimal side effects, in order to improve the patient's clinical conditions. The patient is currently on chemotherapy, asymptomatic with a good performance status. In referral centres, with specific expertise, HIFU could be safely and successfully combined with systemic chemotherapy for treatment of metastatic pancreatic carcinoma. more...

Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.) more...

Purpose: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs., Methods: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples., Results: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome., Conclusion: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors., (© 2016 S. Karger AG, Basel.) more...

After years of limited progress in the treatment of neuroendocrine neoplasms (NENs), an increasing number of therapeutic targets have recently emerged as potential tools to improve disease outcome. The mammalian target of rapamycin (mTOR) pathway and vascular endothelial growth factor (VEGF) signalling are implicated in the regulation of cell growth, proliferation, neo-angiogenesis and tumour cell spread. Their combined blockade, in a simultaneous or sequential strategy, represents an intriguing biological rationale to overcome the onset of resistance mechanisms. However, is becoming increasingly imperative to find the optimal sequential strategy according to the best toxicity profile, and also to identify predictive biomarkers. We will provide an overview of the pre-clinical and clinical data relating to mTOR pathway/VEGF signalling as a potential targets of treatment in NENs., (Copyright © 2015 Elsevier Ltd. All rights reserved.) more...

Background: Basaloid squamous cell carcinoma (BSCC) is a high-grade variant of squamous cell carcinoma usually localized in the aerodigestive tract, with a poor prognosis. Surgical resection is generally recommended, even if no standard treatment has been established yet., Case Report: Here, we report the case history of a patient diagnosed with BSCC at the esophagogastric junction who was successfully treated with chemotherapy alone, leading to a durable complete response., Conclusions: The presented case illustrates the diagnostic challenges associated with BSCC of the esophagus and reports an unexpected chemosensitivity of this histotype to the combination of a platinum salt plus 5-fluorouracil, which could represent an optimal treatment strategy in unfit patients., (© 2014 S. Karger GmbH, Freiburg.) more...

Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer. more...

Tumor-to-tumor metastasis is a rare phenomenon, with around 150 cases being reported in the literature. Breast cancer is the second most commonly reported donor tumor after lung cancer, but thymic epithelial tumors have never been reported as recipient tumors. Furthermore, the thymus is rarely affected by metastases. To our knowledge, the present report is the first case of breast cancer metastatic to thymic epithelial tumor. more...

Primary hepatic lymphoma is an extremely rare malignancy accounting for 0.016% of all cases of non-Hodgkin lymphomas. Approximately 1-4% of histologies described show a follicular pattern. We report a case of primary hepatic non-Hodgkin lymphoma that developed in a middle-aged woman 3 years after radical treatment (neoadjuvant chemoradiotherapy and surgery) for a rectal adenocarcinoma. Abdomen ultrasound showed a single nodule in the liver, which raised the issue of differential diagnosis with a metastasis from rectal cancer. After surgical removal of the nodule, histology revealed a primary B cell, stage IE follicular non-Hodgkin lymphoma, confined to the liver; indeed, no foci of lymphoma were found elsewhere in the body. more...