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Introduction: Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy., Methods: Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT., Results: CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature., Conclusion: These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brugiapaglia, Bulfamante, Curcio, Arigoni, Calogero, Bonello, Genuardi, Spadi, Satolli, Campra, Giordano, Cappello, Cordero and Novelli.)

Background: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC)., Objective: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting., Patients and Methods: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis., Results: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab., Conclusion: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis due to a lack of early diagnostic markers and effective therapy. In PDA patients, the glycolytic enzyme and plasminogen receptor alpha-enolase (ENO1) and the transcription factor far upstream element-binding protein 1 (FUBP1) are upregulated and elicit the production of autoantibodies (aAb) that discriminate healthy subjects from PDA patients, with the latter mostly directed to post-translational phosphorylated isoforms. Here, the correlation of prognosis with circulating ENO1 and FUBP1aAb, and their protein tissue expression was analyzed in PDA patients. Circulating ENO1 and FUBP1 aAb was analyzed in two cohorts of PDA patients by ELISA (n = 470), while tissues expression was observed by immunohistochemistry (n = 45). Overall survival (OS) was estimated using the Kaplan-Meier method, while the Cox model was used to estimate the hazard ratios (HR) adjusted for the main prognostic factors. Logistic models were applied to assess associations between death and its risk indicators. All statistical analyses were performed with Stata version 15. Unlike ENO1 aAb, there was a significant correlation between FUBP1 aAb and FUBP1 expression in tumors (p = 0.0268). In addition, we found that high ENO1 (p = 0.016) and intermediate FUBP1 aAb levels (p = 0.013) were unfavorable prognostic factors. Notably, it was found that high anti-FUBP1 aAb level is a good prognostic marker for tail-body PDA (p = 0.016). Our results suggest that different levels of circulating aAb to ENO1 and FUBP1 predict a poor outcome in PDA patients and can be used to improve therapeutic strategies., (© 2023. The Author(s).)

Background: The NAPOLI-I trial showed better outcome of nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) compared to 5-FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine-based therapy. This study aims to explore the real-world efficacy and safety of 5-FU/LV-nal-IRI., Methods: This is a retrospective multicenter analysis including advPDAC patients receiving 5-FU/LV-nal-IRI after failure of gemcitabine-based therapy. Survival analyses were performed using Kaplan-Meier method, univariate and multivariate analyses by Cox regression., Results: A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine-nabpaclitaxel as first line. 5-FU/LV-nal-IRI was administered as second-line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5-FU/LV-nal-IRI initiation was 3.2 and 7.1 months, respectively., Conclusions: These real-world data confirm the 5-FU/LV-nal-IRI efficacy and safety in advPDAC patients progressed to gemcitabine-based therapy, with outcomes comparable to NAPOLI-1, even in a less-selected population and with more modern therapeutic algorithm., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cholangiocarcinoma is a rare group of tumors that involve the hepatic biliary tree. Prognosis for patients with cholangiocarcinoma remains dismal. Herein, we present survival trends over a long time period spanning almost 20 years in patients with advanced cholangiocarcinoma receiving systemic chemotherapy. We retrospectively analyzed a large multicenter dataset of cholangiocarcinoma outpatients evaluated in 14 centers within the Cholangiocarcinoma Italian Group Onlus (Gruppo Italiano Colangiocarcinoma Onlus, G.I.C.O.) between 2000 and 2017 (first-line), and 2002 and 2017 (second-line). Three time periods were considered: 2000-2009, 2010-2013, and 2014-2017. A total of 922 patients (51.19% male) with cholangiocarcinoma undergoing first-line therapy were evaluated. The median durations of follow-up for progression-free survival (PFS) and overall survival (OS) were 37 and 57 months, respectively. PFS at 12 months in the three periods of starting first-line therapy was similar, ranging from 11.71% to 15.25%. OS at 12 months progressively improved (38.30%, 44.61% and 49.52%, respectively), although the differences were not statistically significant after adjusting for age, disease status, and primary tumor site. A total of 410 patients (48.5% male) underwent second-line chemotherapy. The median durations of follow-up for PFS and OS were 47.6 and 41.90 months, respectively. An OS of 24.3%, 32.3%, and 33.1% was observed in 2002-2009, 2010-2013, and 2014-2017, respectively. Despite incremental benefits across years, our clinical experience confirms that modest overall advances have been achieved with first- and second-line chemotherapy in advanced cholangiocarcinoma. Efforts should focus on the identification of patients who derive the greatest benefit from treatment., Competing Interests: FL: Advisory board participation for Merck Serono, Servier, Amgen, BMS, AstraZeneca. LFo: Advisory board participation and consulting for AstraZeneca, MSD, Tahio Oncology, BMS, EliLilly, Servier, Daiichi Sankyo. GB: Advisory board participation, consulting, or research funding from Incyte, Tahio, Ipsen, and Incyte. MS: Advisory board participation or research funding MERCK, MSD, Amgen, Servier, Eisai, GSK, Astra-Zeneca, Sanofi. NS: Advisory board participation for Servier, Lilly, Roche, Eisai. SL: Advisory board participation, consulting, or research funding (institutional) from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Hutchinson, Incyte, Lilly, Merck Serono, Nirati, MSD, Pierre-Fabre, Pfizer, Roche, Servier. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Casadei-Gardini, Leone, Brandi, Scartozzi, Silvestris, Santini, Faloppi, Aglietta, Satolli, Rizzo, Lonardi, Aprile and Fornaro.)

Biliary tract cancer's (BTC) treatment main stone for advanced stages is constituted by chemotherapy. Surgical centralization and physicians' confidence in the use of new technologies and molecular analysis turned out to be of interest and potentially influencing survival. After applying a random-effect model, the relationship between each clinical variable on the main outcome was investigated through multilevel mixed-effects logistic regression. The risk-standardized outcomes were calculated for each centre involved. In the unadjusted cohort the median survival was 8.6 months (95%C.I.: 7.8-9.3) with a 9-month survival rate of 48.3% (95%C.I.: 45.0-51.5). A substantial heterogeneity across hospitals was found (I 2 : 70.3%). In multilevel mixed effect logistic regression, male, being treated for gallbladder cancer, higher ECOG, increased NLR, CEA and Ca 19.9 and low value of haemoglobin showed to increase the odds for 9-month mortality. The model estimated that the residual variance observed in 9-month mortality was attributable for the 2.6% to the treating hospital. Through a multilevel mixed effect model, average risk-standardized mortality within 9 months was 50.1%. As noticeable, all hospital's risk-standardized mortality falls within 95%C.I., thus all participating centres provided similar outcomes when adjusted for patient case-mix. Heterogenicity between hospital did not affect the outcome in term of overall survival.

Aim: The aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens., Study Design and Methods: Clinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1-2), and intensity of chemotherapy regimen (doublet vs. triplet)., Results: Among 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users., Conclusion: In patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs., Competing Interests: APa reported receiving advisory board fees from GSK, Servier, Pharmamar. RG reported receiving fees from Amgen and Servier and advisory board fees from Amgen, Servier, Bayer and Merck-Serono. LS reported receiving fees from Pierre-Fabre, AstraZeneca, Bayer, Servier, Merck, Amgen. APe reported receiving fees from Eli-Lilly, MSD, BMS, Merck, Servier. BD has received fees from Ipsen, Eisai, Eli Lilly, AstraZeneca, Sanofi, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Bayer, Roche, and Amgen; and has received non-financial support from Ipsen, BMS. MG reported receiving fees by Amgen, Merck, Eli-Lilly, Servier, Italfarmaco. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parisi, Giampieri, Mammarella, Felicetti, Salvatore, Bensi, Maratta, Strippoli, Filippi, Satolli, Petrillo, Daniele, De Tursi, Di Marino, Giordano, Landriscina, Vitale, Zurlo, Dell’Aquila, Tomao, Depetris, Di Pietro, Zoratto, Ciardiello, Pensieri, Garrone, Galassi, Ferri, Berardi and Ghidini.)

Advanced biliary tract cancer (aBTC) comprises a heterogeneous group of rare malignancies with dismal prognosis. Given the scarcity of prospective evidence, the aim of this study was to derive clinically useful insights and prognostic factors from a large, real-world series of aBTC. Clinicopathologic variables and treatment outcomes were retrospectively collected involving 940 patients diagnosed with aBTC between 2001 and 2017, and treated with first-line chemotherapy (CT1) at 14 Italian medical oncology institutions. Median overall survival (OS) was 10.3 months (CI 95% 9.5-11.1). CT1 with gemcitabine-Platinum salts doublets achieved OS of 11.7 months vs 7.5 with gemcitabine alone (HR 0.67, p < 0.001). However, a clear temporal trend towards improved OS could not be demonstrated. Radical surgery of recurrent disease achieved a relapse-free survival of 5.9 months. A substantial minority (44.5%) of patients were able to receive a second-line chemotherapy, which achieved a response rate of 7.6%, and disease control in 30% of patients with no significant differences between combination regimens and monotherapies. In a large retrospective series of real-world aBTC, outcomes of standard CT1 closely resembled those of the registrational trials. A limited set of easily retrievable independent prognostic factors was defined. Further research is needed on second-line regimens.

Background: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone., Methods: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status., Results: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients., Conclusions: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets., (© 2021. The Author(s).)

Background: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1., Methods: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out., Results: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS ( p  <0.01). The prognostic score could generate a highly significant stratification (all between-group p values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI 95% 11.0-14.4), 7.1 (CI 95% 5.8-8.4), and 3.2 months (CI 95% 1.7-4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI 95% 11.0-14.3), 7.5 (CI 95% 6.1-8.9), and 1.4 months (CI 95% 0.1-2.7), respectively (all between-group p values ≤0.05)., Conclusion: A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment.