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Biliary tract cancer incidence is increasing and the prognostic remains dismal. The development of personalized medicine is a pivotal issue in proposing therapeutic options for biliary tract cancer patients. Whole exome sequencing identifies approximately 15% of IDH1 mutations and 15% of FGFR2 fusions in intrahepatic cholangiocarcinoma. Other patients are not currently eligible for targeted therapy. Here, we present a patient treated for a metastatic cholangiocarcinoma with an unexpected response to a mammalian target of rapamycin (mTOR) targeting agent. Whole exome sequencing enabled the identification of TSC1 and ARID1A mutations. Reintroduction of mTOR inhibitors with similar results sustains the main role of these targeted agents in the control of the disease. These results suggest the existence of an mTOR oncogenic addiction in biliary tract cancer. Our results support the interest in performing exome sequencing in liver cancers and the potential to identify actionable mutations with important therapeutic issues. [ABSTRACT FROM AUTHOR]

Background: There is a strong rational of using anti-programmed cell death protein-1 and its ligand (anti-PD-1/L1) antibodies in human papillomavirus (HPV)-induced cancers. However, anti-PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti-PD-1/L1 is therefore of interest. Combining anti-PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non-small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV+ cancers. Methods: Patients with HPV+ cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously. Discussion: Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific TH1 CD4 T cells sustain the quality and homing of an antigen-specific CD8+ T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based TH1 inducing vaccine (UCPVax) and an anti-PD-L1 (atezolizumab) immunotherapy in HPV+ cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Surgical resection with adjuvant chemotherapy is the only treatment that can provide long term survival in localized pancreatic ductal adenocarcinoma (LPDAC). Notwithstanding, recurrence occurs in the vast majority of patients and a better stratification of preoperative therapies is required. This study aimed to investigate preoperative immunological and nutritional factors to predict relapse-free survival (RFS) in patients with LPDAC. Methods: Analyses were derived from all consecutive LPDAC patients treated with surgical resection at Besancon University Hospital, France, between January 2006 and December 2014 (n=146). Biological and nutritional parameters were recorded before and after surgery. The association of 24 baseline parameters with RFS was evaluated using univariate and multivariate Cox analyses. Based on the final model, a prognostic score was developed. Results: Lymphocyte count and body composition were available for 94 patients. In multivariate analysis, preoperative lymphopenia and sarcopenia (or a low muscle mass) were identified as independent prognostic factors for RFS. The score determined three groups with a median RFS of 5.6 months (95% confidence interval [CI] = 4.3 to 9.6 months) for high-risk group, corresponding to patients with lymphopenia; 11.5 months (95%CI = 9.8 to 13.9 months), and 21.2 months (95%CI = 9.9 to 55.3 months), for intermediate-(patient with sarcopenia without lymphopenia), and low-risk groups (no risk factor), respectively (p <0.001). Preoperative sarcopenia predicts the occurrence of postoperative lymphopenia in patients with a preoperative lymphocyte count above 1,000/mm3 (p = 0.0029). Conclusions: Preoperative lymphopenia and sarcopenia are pejorative prognostic factors in LPDAC and should be considered in the preoperative evaluation to stratify death risk in patients with LPDAC. [ABSTRACT FROM AUTHOR]

Background and objectives: Practices in end‐of‐life platelet transfusions in haematologic malignancies are variable. Our aim was to describe the platelet transfusion burden and parameters linked to this indication in such a setting and thereby contribute to defining optimal practices. Materials and methods: From July 2015 to December 2016, all consecutive deceased adult patients with a haematologic malignancy receiving a platelet transfusion in the last 6 months of their life from the Etablissement Français du Sang Bourgogne Franche‐Comté were included retrospectively. The outcome criteria were changes in the number of platelet transfusions, percent platelet recovery, platelet transfusion interval, reported bleeding with its grade and recipient adverse events in the last 6 months of life. Results: Among the 1125 patients monitored, 119 were included in our study. Bleeding prophylaxis (versus treatment) was the reason for 55% of transfusions. 18% of platelet concentrates (n = 1999) were transfused during the last two weeks of life. As death approached, the transfusion and haemorrhage burden increased (P < 0·0001 in both cases), whereas platelet recovery and transfusion interval decreased (P = 0·02 in both cases). Recipient adverse events were rare (0·6%) and of minor severity. Conclusion: In end‐of‐life transfused patients with haematologic malignancies, approaching death is associated with an increased number of platelet transfusions and bleeding events, while platelet recovery and transfusion intervals are reduced. Such findings, together with further evaluations, may contribute to informing best practices for these patients. [ABSTRACT FROM AUTHOR]

Résumé: Les cancers des voies biliaires (CVB) sont un groupe hétérogène de tumeurs au pronostic sombre dont la prise en charge connaît des évolutions ces dernières années. Dans cette revue, nous donnons un aperçu des options thérapeutiques pouvant être proposées dans les CVB avancés et leur application dans la pratique clinique. Une part importante de patients ne peut recevoir de traitements spécifiques et n'est traitée que par des soins de support (dont le drainage biliaire), qui occupent une place centrale dans la prise en charge des CVB. La chimiothérapie à base de gemcitabine et de platine est le traitement standard en première ligne dans les CVB avancés. Récemment, le schéma FOLFOX (5-fluorouracile, acide folinique plus oxaliplatine) est devenu le seul traitement de deuxième ligne à être validé de manière prospective dans une étude de phase III après échec de la combinaison gemcitabine plus cisplatine, malgré une amélioration modeste de la survie par rapport aux soins de support. Les questions du meilleur traitement à proposer en deuxième ligne et de la sélection des patients susceptibles de bénéficier le plus de ces traitements restent non résolues. Depuis 2015, les connaissances sur l'hétérogénéité moléculaire des CVB ont considérablement augmenté avec l'avènement des analyses génomiques et transcriptomiques à large échelle, ouvrant de nouvelles perspectives pour les stratégies de thérapies dites ciblées et posant la question de la réalisation d'un profil moléculaire pour tous les patients en bon état général en pratique courante. Parmi les développements en cours, le ciblage des altérations du gène codant pour le récepteur du facteur de croissance des fibroblastes (FGFR) et de l'isocitrate déshydrogénase (IDH) sont les pistes les plus avancées, et les immunothérapies sont en cours d'évaluation dans des essais cliniques. Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis, with therapeutic evolutions in recent years. In this review, we provide an overview of the treatment options that can be proposed in advanced BTC and their application in clinical practice. A large number of patients cannot receive specific treatments and are only treated with supportive care (including biliary drainage), which is central to the management of BTC. Gemcitabine and platinum-based chemotherapy is the standard first-line therapy in advanced BTC. Recently, FOLFOX (5-fluorouracil, folinic acid plus oxaliplatin) regimen became the only second-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase III study, even though chemotherapy yielded modest survival improvement over best supportive care. The question of the best second-line treatment to offer and the selection of patients likely to benefit the most from these treatments remains unresolved. Since 2015, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyzes, opening up new perspectives for so-called targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice. Among the ongoing developments, the targeting of fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase (IDH) gene alterations are the most promising avenues, and immunotherapies are being evaluated in clinical trials. [ABSTRACT FROM AUTHOR]

Fluoropyrimidine (FP) plus platinum chemotherapy has been recently established as a second‐line (L2) preferred option in advanced biliary tract cancer (aBTC) (ABC‐06 phase III trial). However, the overall survival (OS) benefit was limited and comparison with FP monotherapy was not available. Our aim was to assess the OS of patients treated with a FP monotherapy compared to a doublet with irinotecan or platinum in L2. We performed a retrospective analysis of two large multicenter prospective cohorts: a French cohort (28 centers) and an Italian cohort (9 centers). All consecutive patients with aBTC receiving FP‐based L2 after gemcitabine plus cisplatin/gemcitabine plus oxaliplatin L1 between 2003 and 2016 were included. A subgroup analysis according to performance status (PS) and an exploratory analysis according to platinum sensitivity in L1 were planned. In the French cohort (n = 351), no significant OS difference was observed between the FP monotherapy and doublet groups (median OS: 5.6 vs 6.8 months, P =.65). Stratification on Eastern Cooperative Oncology Group (ECOG) PS showed similar results in PS 0‐1 and 2. Median OS was not different between FP monotherapy, platinum‐ and irinotecan‐based doublets (5.6 vs 7.1 vs 6.7 months, P =.68). Similar findings were observed in the Italian cohort (n = 174) and in the sensitivity analysis in pooled cohorts (n = 525). No L2 regimen seemed superior over others in the platinum resistant/refractory or sensitive subgroups. Our results suggest that FP monotherapy is as active as FP doublets in aBTC in L2, regardless of the patient PS and country, and could be a therapeutic option in this setting. What's new?: Advanced biliary tract carcinoma is usually diagnosed at an advanced stage, and requires first‐line chemotherapy. For those patients who go on to second‐line chemotherapy, most receive fluoropyrimidine (FP) alone or in combination. Here, the authors compared overall survival between patients given a second‐line treatment of FP monotherapy versus those given FP plus either irinotecan or platinum. They stratified patients by therapy regimen and by ECOG performance status, which is considered the best prognostic factor for second‐line treatment. They found that overall survival was comparable, whether patients received FP alone or in combination, even after controlling for performance status. [ABSTRACT FROM AUTHOR]

Résumé: Le cancer du canal anal représente 2,7 % des cancers digestifs et son incidence est en constante augmentation. Dans la grande majorité des cas, il s'agit d'un carcinome épidermoïde, qui est associé à l'infection par HPV notamment au génotype 16 dans 90 % des cas. Environ 30-40 % des patients présentent soit une maladie métastatique au diagnostic, soit une évolution vers une maladie avancée non résécable suite à une radiochimiothérapie pour une maladie initialement localisée. La chimiothérapie systémique est donc le traitement de choix. En France, la collaboration de groupes coopérateurs a permis de mener des essais de phase II dans les cancers du canal anal avancés, aboutissant à un changement de paradigme avec une validation prospective des protocoles dans cette situation orpheline. Le premier fruit de ce travail fut l'étude Epitopes-HPV02, qui a permis de valider le schéma modifié du DCF (docétaxel, cisplatine et 5-fluoruracile) comme un nouveau standard. Plus récemment, un réseau international a également validé l'intérêt des taxanes en première ligne. En deuxième ligne, les immunothérapies anti-PD1/PD-L1 semblent prometteuses, surtout en association. Plusieurs essais cliniques sont actuellement en cours. Anal canal carcinoma represents 2.7% of gastrointestinal cancers, and its incidence is steadily increasing. Squamous cell carcinoma is by far the most frequent subtype, and is associated with HPV infection, mostly the genotype 16 in 90% of cases. Approximately 30 to 40% of patients are in an advanced stage, either with metastatic disease at diagnosis or with non resectable recurrence after chemoradiotherapy for an initially localized disease. Systemic chemotherapy is then the standard of choice. In France, a national network was settled and made possible to perform large phase II trials in advanced anal carcinomas. This is a paradigm shift with prospective validation of new strategies in this rare clinical setting thanks to the collaboration of different groups. Its first fruit was the Epitopes-HPV02 trial which validated the modified DCF (docetaxel, cisplatin, and 5-fluorouracil) regimen as a new standard. More recently, an international network has also validated the interest of taxanes in first-line. In second-line, results with anti-PD1/PD-L1 check point inhibitors are encouraging, especially in association, and could be the next standard. Several clinical trials are ongoing [ABSTRACT FROM AUTHOR]

Résumé: Les cancers des voies biliaires (CVB) sont un groupe hétérogène de tumeurs au pronostic sombre. Dans cette revue, nous donnons un aperçu des options thérapeutiques systémiques pouvant être proposées dans les CVB avancés et des nouvelles stratégies en développement. La chimiothérapie à base de gemcitabine et de platine est le traitement standard en première ligne (L1) dans les CVB avancés. Le niveau de preuve est insuffisant pour recommander un schéma de chimiothérapie spécifique en deuxième ligne (L2), et les anticorps anti-récepteurs du facteur de croissance épidermique (EGFR) et anti-angiogéniques n'ont pas montré d'amélioration de la survie chez des patients non sélectionnés. Ces dernières années, les connaissances sur l'hétérogénéité moléculaire des CVB ont considérablement augmenté avec l'avènement des analyses génomiques et transcriptomiques à large échelle, ouvrant de nouvelles perspectives pour les stratégies de thérapies dites ciblées. Parmi les développements en cours, le ciblage des altérations du gène codant pour le récepteur du facteur de croissance des fibroblastes (FGFR) et de l'isocitrate déshydrogénase (IDH), et les immunothérapies sont les pistes les plus prometteuses. Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. In this review, we provide an overview of the systemic treatment options that can be proposed in advanced BTC and new strategies under development. Gemcitabine and platinum-based chemotherapy is the standard first-line therapy (L1) in advanced BTC. The level of evidence is insufficient to recommend a specific second-line chemotherapy regimen (L2), and anti-epidermal growth factor receptor (EGFR) and anti-angiogenic antibodies have not demonstrated any improvement in survival in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyzes, opening up new perspectives for so-called targeted therapies. Among the ongoing developments, the targeting of fibroblast growth factor receptor (FGFR) and isocitrate dehydrogenase (IDH) gene alterations, and immunotherapies are the most promising avenues. [ABSTRACT FROM AUTHOR]

Background: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial. Better discrimination for overall survival (OS) at diagnosis is needed. We address this issue by developing and validating a prognostic nomogram and a score for OS in LAPC (PROLAP).Methods: Analyses were derived from 442 LAPC patients enrolled in the LAP07 trial. The prognostic ability of 30 baseline parameters was evaluated using univariate and multivariate Cox regression analyses. Performance assessment and internal validation of the final model were done with Harrell's C-index, calibration plot and bootstrap sample procedures. On the basis of the final model, a prognostic nomogram and a score were developed, and externally validated in 106 consecutive LAPC patients treated in Besançon Hospital, France.Results: Age, pain, tumour size, albumin and CA 19-9 were independent prognostic factors for OS. The final model had good calibration, acceptable discrimination (C-index=0.60) and robust internal validity. The PROLAP score has the potential to delineate three different prognosis groups with median OS of 15.4, 11.7 and 8.5 months (log-rank P<0.0001). The score ability to discriminate OS was externally confirmed in 63 (59%) patients with complete clinical data derived from a data set of 106 consecutive LAPC patients; median OS of 18.3, 14.1 and 7.6 months for the three groups (log-rank P<0.0001).Conclusions: The PROLAP nomogram and score can accurately predict OS before initiation of induction chemotherapy in LAPC-untreated patients. They may help to optimise clinical trials design and might offer the opportunity to define risk-adapted strategies for LAPC management in the future. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies. [ABSTRACT FROM AUTHOR]

Stratification of the prognosis of pancreatic cancer (PDAC) patients treated by surgery is based solely on clinical variables, such as tumor stage and node status. The development of biomarkers of relapse is needed, especially to drive administration of adjuvant therapy in this at-risk population. Our study evaluates the prognostic performance of a CD3- and CD8-based immune score. CD3, CD8 and Foxp3 expression were evaluated on whole slides in two retrospective PDAC cohorts totaling 334 patients. For this study, we developed an immune score to estimate CD3 and CD8 infiltration in both tumor core and invasive margin using computer-guided analysis with QuPath software. Variables were combined in a dichotomous immune score. The association between immune and clinical scores, and both PFS and OS was investigated. We observed that a dichotomous immune score predicts both PFS and OS of localized PDAC. By univariate and multivariate analysis, immune score, tumor grade, adjuvant therapy, lymph node status, and adjuvant chemotherapy administration were associated with PFS and OS. We subsequently associated the PDAC immune score and clinical variables in a combined score. This combined score predicted patient outcomes independently of adjuvant or neoadjuvant treatment, and improved patient prognostic prediction compared to clinical variables or immune score alone., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: There is a strong rational of using anti-programmed cell death protein-1 and its ligand (anti-PD-1/L1) antibodies in human papillomavirus (HPV)-induced cancers. However, anti-PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti-PD-1/L1 is therefore of interest. Combining anti-PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non-small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV + cancers., Methods: Patients with HPV + cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously., Discussion: Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific T H 1 CD4 T cells sustain the quality and homing of an antigen-specific CD8 + T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based T H 1 inducing vaccine (UCPVax) and an anti-PD-L1 (atezolizumab) immunotherapy in HPV + cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials., Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier NCT03946358., Competing Interests: CB: Research grant from Bayer and Roche, advisory board for Bayer, Sanofi, MSD. FB: Novartis, Seagen, Daiichi Sankyo, Pierre Fabre, Astra-Zeneca, Clovis. SK: reports a consulting or advisory role for Ipsen, Incyte, Boehringer Ingelheim, Sanofi and BeiGene and has received research funding from Pfizer, Roche, Novartis, Bristol-Myers Squibb, Boehringer Ingelheim and Sanofi. 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 Rebucci-Peixoto, Vienot, Adotevi, Jacquin, Ghiringhelli, de la Fouchardière, You, Maurina, Kalbacher, Bazan, Meynard, Clairet, Fagnoni-Legat, Spehner, Bouard, Vernerey, Meurisse, Kim, Borg and Mansi.)