Search

Riccardo Carloni,1,2 Simone Sabbioni,1,2 Alessandro Rizzo,3 Angela Dalia Ricci,4 Andrea Palloni,1,2 Cataldo Petrarota,3 Antonio Cusmai,3 Simona Tavolari,1,2 Gennaro Gadaleta-Caldarola,5,* Giovanni Brandi1,2,* 1Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy; 2Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 3Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Bari, Italy; 4Medical Oncology Unit, National Institute of Gastroenterology, “Saverio de Bellis” Research Hospital, Bari, Italy; 5Unità Operativa Complessa di Oncologia Medica, Ospedale “Mons. A.R. Dimiccoli”, Barletta, Italy*These authors contributed equally to this workCorrespondence: Alessandro Rizzo, Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, Bari, 70124, Italy, Tel +39-051-2144078, Fax +39-051-6364037, Email rizzo.alessandro179@gmail.comAbstract: Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related death worldwide. HCC frequently presents as advanced disease at diagnosis, and disease relapse following radical surgery is frequent. In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC, particularly with the introduction of atezolizumab/bevacizumab as the new standard of care for first-line treatment. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective first-line treatment for advanced HCC and most of the research is currently focused on developing combination treatments based mainly on ICIs. In this review, we will discuss the rationale and ongoing clinical trials of immune-based combination therapies for the treatment of advanced HCC, also focusing on new immunotherapy strategies such as chimeric antigen receptor T cells (CAR-T) and anti-cancer vaccines.Keywords: hepatocellular carcinoma, VEGF, PD-1, tislelizumab, atezolizumab, durvalumab

The success of vegetative propagation programmes strongly depends on adventitious rooting, a postembryonic developmental process whereby new roots can be induced from differentiated cells in positions where normally they do not arise. This auxin-dependent organogenesis has been studied at molecular, cellular, and developmental levels, and our knowledge of the process has improved in recent years. However, bioactive compounds that enhance adventitious root formation and possibly reduce undesirable auxinic side effects are still needed to ameliorate this process. From this point of view, our structure−activity relationship studies concerning urea derivatives revealed that some of them, more specifically, the N,N′-bis-(2,3-methylenedioxyphenyl)urea (2,3-MDPU), the N,N′-bis-(3,4-methylenedioxyphenyl)urea (3,4-MDPU), the 1,3-di(benzo[d]oxazol-5-yl)urea (5-BDPU), and the 1,3-di(benzo[d]oxazol-6-yl)urea (6-BDPU), constitute a category of adventitious rooting adjuvants. The results of our studies are presented here, in order either to highlight the positive effects of the supplementation of these urea derivatives, or to better understand the nature of their interaction with auxin.

Introduction: Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches., Areas Covered: In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials., Expert Opinion: At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients.

Background: Although early-stage gastric cancer is a candidate for curative surgical resection, the absence of specific early symptoms results in a late diagnosis and consequently most patients present advanced or metastatic disease. Identifying noveland tumor-specific biomarkers is needed to increase early detection and match patients to the appropriate treatment. The present study focused on the possible prognostic role of Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2)/Autotaxin (ATX) and lysophosphatidic acid (LPA) in Gastro-Esophageal Adenocarcinoma (GEA). High levels of ATX/LPA are associated with several malignancies including gastrointestinal tumors., Methods: Using a bioinformatics analysis, the incidence of ENPP2 mutations together with its expression in the tumor tissues and the correlation between the presence of mutations and the survival rate were examined in databases of GEA patients. Furthermore, circulating levels of ATX and LPA were studied retrospectively and longitudinally both in patients receiving frontal surgery and in patients receiving preoperative chemotherapy., Results: Overall findings suggested that although ENPP2 mutations occur at low incidence, their presence was associated with a particular poor Overall Survival (OS). Furthermore, removal of the tumour by surgery resulted in a decrease in serum ATX and LPA levels within five days, regardless of any previous chemotherapy. Basal circulating ATX were associated with the aggressive diffuse GEA and could be considered of negative prognostic value, mainly in combination models with circulating Carcino-Embryonic Antigen (CEA)., Conclusions: Based on these observations, clinical trials with ATX-targeted drugs and standard chemotherapy regimens may benefit from selecting GEA patients based on their levels of ATX, LPA and CEA., Competing Interests: Declaration of Competing Interest Dr Michael Lahn is Chief Medical Officer at iOnctura SA and holds stocks in the company; Dr Gianluigi Giannelli is an Editorial Member for Journal Experimental Clinical Cancer Research and was not involved in the editorial review or the decision to publish this article. Dr Rosalba D’Alessandro is Guest Editor for Cancers and was not involved in the editorial review or the decision to publish this article. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: We declare no competing interests.

Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase ( ENPP ) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.

Metastatic gastric cancer (mGC) often has a poor prognosis and may benefit from a few targeted therapies. Ramucirumab-based anti-angiogenic therapy targeting the VEGFR2 represents a milestone in the second-line treatment of mGC. Several studies on different cancers are focusing on the major VEGFR2 ligand status, meaning VEGFA gene copy number and protein overexpression, as a prognostic marker and predictor of response to anti-angiogenic therapy. Following this insight, our study aims to examine the role of VEGFA status as a predictive biomarker for the outcome of second-line therapy with Ramucirumab and paclitaxel in mGC patients. To this purpose, the copy number of the VEGFA gene, by fluorescence in situ hybridization experiments, and its expression in tumor tissue as well as the density of micro-vessels, by immunohistochemistry experiments, were assessed in samples derived from mGC patients. This analysis found that amplification of VEGFA concomitantly with VEGFA overexpression and overexpression of VEGFA with micro-vessels density are more represented in patients showing disease control during treatment with Ramucirumab. In addition, in the analyzed series, it was found that amplification was not always associated with overexpression of VEGFA, but overexpression of VEGFA correlates with high micro-vessel density. In conclusion, overexpression of VEGFA could emerge as a potential biomarker to predict the response to anti-angiogenic therapy.

Background: Trypanosoma cruzi, the agent of Chagas disease, displays a highly structured population, with multiple strains that can be grouped into 6-7 evolutionary lineages showing variable eco-epidemiological traits and likely also distinct disease-associated features. Previous works have shown that antibody responses to 'isoforms' of the polymorphic parasite antigen TSSA enable robust and sensitive identification of the infecting strain with near lineage-level resolution. To optimize the serotyping performance of this molecule, we herein used a combination of immunosignaturing approaches based on peptide microarrays and serum samples from Chagas disease patients to establish a deep linear B-cell epitope profiling of TSSA., Methods/principle Findings: Our assays revealed variations in the seroprevalence of TSSA isoforms among Chagas disease populations from different settings, hence strongly supporting the differential distribution of parasite lineages in domestic cycles across the Americas. Alanine scanning mutagenesis and the use of peptides of different lengths allowed us to identify key residues involved in antibody pairing and the presence of three discrete B-cell linear epitopes in TSSAII, the isoform with highest seroprevalence in human infections. Comprehensive screening of parasite genomic repositories led to the discovery of 9 novel T. cruzi TSSA variants and one TSSA sequence from the phylogenetically related bat parasite T. cruzi marinkellei. Further residue permutation analyses enabled the identification of diagnostically relevant or non-relevant substitutions among TSSA natural polymorphisms. Interestingly, T. cruzi marinkellei TSSA displayed specific serorecognition by one chronic Chagas disease patient from Colombia, which warrant further investigations on the diagnostic impact of such atypical TSSA., Conclusions/significance: Overall, our findings shed new light into TSSA evolution, epitope landscape and modes of recognition by Chagas disease patients; and have practical implications for the design and/or evaluation of T. cruzi serotyping strategies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Romer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

(1) Background: Biliary tract cancers (BTCs) are a heterogeneous group of neoplasms with dismal prognosis and the role of adjuvant chemoradiotherapy in high-risk resected patients is unclear. (2) Methods: We retrospectively analyzed the outcomes of BTC patients who received curative intent surgery with microscopically positive resection margins (R1) and adjuvant chemoradioradiotherapy (CCRT) or chemotherapy (CHT) from January 2001 to December 201. (3) Results: Out of 65 patients who underwent R1 resection, 26 received adjuvant CHT and 39 adjuvant CCRT. The median recurrence-free survival (RFS) in the CHT and CHRT groups was 13.2 and 26.8 months, respectively ( p = 0.41). Median overall survival (OS) was higher in the CHRT group (41.9 months) as compared to the CHT group (32.2 months), but the difference was not statistically significant (HR 0.88; p = 0.7). A promising trend in favor of CHRT was observed in N0 patients. Finally, no statistically significant differences were observed between patients undergoing adjuvant CHRT after R1 resection and patients treated with chemotherapy alone after R0 surgery. (4) Conclusions: Our study did not show a significant survival benefit with adjuvant CHRT over CHT alone in BTC patients with positive resection margins, while a promising trend was observed.

Following the practice-changing results observed in several hematological and solid tumors, immunotherapy with immune checkpoint inhibitors (ICIs) has been tested in cholangiocarcinoma (CCA) patients. However, ICI monotherapy has had disappointing results in CCA, and phase I-III clinical trials have assessed whether combinatorial strategies including immunotherapy plus other anticancer agents may have a synergistic activity. The TOPAZ-1 trial has recently highlighted improved survival in CCA patients receiving first-line durvalumab plus gemcitabine-cisplatin compared with gemcitabine plus cisplatin alone, and several guidelines consider adding durvalumab to the reference doublet as standard of care. This article provides an overview of durvalumab pharmacology, safety and efficacy in CCA, highlighting current and future research directions in this setting.

Despite representing some of the most common and investigated molecular changes in intrahepatic cholangiocarcinoma (iCCA), the prognostic role of FGFR and IDH1/2 alterations still remains an open question. In this review we provide a critical analysis of available literature data regarding this topic, underlining the strengths and pitfalls of each study reported. Despite the overall poor quality of current available studies, a general trend toward a better overall survival for FGFR2 rearrangements and, possibly, for FGFR2-3 alterations can be inferred. On the other hand, the positive prognostic role of IDH1/2 mutation seems much more uncertain. In this scenario, better designed clinical trials in these subsets of iCCA patients are needed in order to get definitive conclusions on this issue., Competing Interests: GB received a research grant from INCYTE and IPSEN and he is a member of the advisory board for INCYTE, LILLY and TAIHO. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Brandi, Deiana, Galvani, Palloni, Ricci, Rizzo and Tavolari.)

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

Anaplastic classic Kaposi sarcoma (CKS) is an extremely rare pathologic variant of CKS characterized by high aggressiveness and poor prognosis. We report the clinical course of this malignant histologic form in an otherwise healthy 67-year-old male from Apulia in Southern Italy. The anaplastic progression arose during a long history of CKS and developed after multiple local and systemic treatments. The extremely aggressive and chemorefractory nature of the disease dictated amputation of a lower limb and, later, surgery for metastatic pulmonary involvement. At subsequent relapse, therapy with the anti-PD-1 inhibitor pembrolizumab was started. The immunotherapy was selected based on the PD-L1 expression in the tumor and tumor microenvironment. Remarkably, PD-1 blockade induced a complete and durable response in the patient, with a disease-free survival that has exceeded 18 months, and follow-up is still ongoing.

During an infection the immune system produces pathogen-specific antibodies. These antibody repertoires become specific to the history of infections and represent a rich source of diagnostic markers. However, the specificities of these antibodies are mostly unknown. Here, using high-density peptide arrays we examined the human antibody repertoires of Chagas disease patients. Chagas disease is a neglected disease caused by Trypanosoma cruzi, a protozoan parasite that evades immune mediated elimination and mounts long-lasting chronic infections. We describe a proteome-wide search for antigens, characterised their linear epitopes, and show their reactivity on 71 individuals from diverse human populations. Using single-residue mutagenesis we revealed the core functional residues for 232 of these epitopes. Finally, we show the diagnostic performance of identified antigens on challenging samples. These datasets enable the study of the Chagas antibody repertoire at an unprecedented depth and granularity, while also providing a rich source of serological biomarkers., (© 2023. The Author(s).)

Background: Despite all the improvements achieved over the last decade, the use of immune checkpoint inhibitors (ICIs) has been associated to a wide range of adverse drug events, which are frequently markedly different from those observed with cytotoxic chemotherapy and targeted therapies, such as sorafenib., Research Design and Methods: We performed a meta-analysis with the aim to compare grade 3/4 treatment-related adverse events (TRAEs), grade 5 TRAEs, serious TRAEs, and TRAEs leading to discontinuation in ICIs versus sorafenib across phase III clinical trials of first-line treatment for advanced hepatocellular carcinoma (HCC)., Results: Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients treated with ICIs showed higher risk of serious TRAEs (OR 1.48, 95% CI = 1.16-1.9) while sorafenib treatment was associated with higher risk of TRAEs leading to discontinuation (OR 0.65, 95% CI = 0.48-0.89). No differences in grade 3/4 TRAEs and grade 5 TRAEs., Conclusions: Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

Recent years have observed the emergence of novel therapeutic opportunities for advanced hepatocellular carcinoma (HCC), such as combination therapies including immune checkpoint inhibitors. We performed a meta-analysis with the aim to compare median overall survival (OS), median progression-free survival (PFS), complete response (CR) rate, and partial response (PR) rate in advanced HCC patients receiving immune-based combinations versus sorafenib. A total of 2176 HCC patients were available for the meta-analysis (immune-based combinations = 1334; sorafenib = 842) and four trials were included. Immune-based combinations decreased the risk of death by 27% (HR, 0.73; 95% CI, 0.65−0.83; p < 0.001); similarly, a PFS benefit was observed (HR, 0.64; 95% CI, 0.5−0.84; p < 0.001). In addition, immune-based combinations showed better CR rate and PR rate, with ORs of 12.4 (95% CI, 3.02−50.85; p < 0.001) and 3.48 (95% CI, 2.52−4.8; p < 0.03), respectively. The current study further confirms that first-line immune-based combinations have a place in the management of HCC. The CR rate observed in HCC patients receiving immune-based combinations appears more than twelve times higher compared with sorafenib monotherapy, supporting the long-term benefit of these combinatorial strategies, with even the possibility to cure advanced disease.

Background: The albumin levels may potentially be used as a prognostic biomarker in patients with cancertreated with immune checkpoint inhibitors (ICIs) due to its close relationship with nutritional and inflammatory status. However, the available data is limited with heterogeneous patient cohorts, sample sizes and variable cut-offs. Therefore, we conducted a systematic review and meta-analysis to evaluate the association between survival outcomes and albumin levels in patients treated with ICIs. Methods: We conducted a systematic review using the PubMed, Web of Science, and Embase databases to filter the published studies up to 1 June 2022. The meta-analyses were performed with the generic inverse-variance method with a random-effects model due to the high degree of heterogeneity. The primary outcome measure was hazard ratio (HR) with 95% confidence intervals (CI). The study protocol was registered with the PROSPERO registry (Registration Number: CRD42022337746). Results: Thirty-six studies encompassing 8406 cancer patients with advanced disease were included in the meta-analyses. Almost half of the studies were conducted in NSCLC cohorts (n = 15), and 3.5 gr/dL was the most frequently used albumin cut-off in the included studies (n = 20). Patients with lower albumin levels had a significantly increased risk of death (HR: 1.65, 95% CI: 1.52-1.80, p < 0.0001) than patients with higher albumin levels. Subgroup analyses for study location, sample size, tumor type and albumin cut-off were demonstrated consistent results. Furthermore, in the subgroup analysis of eight studies using albumin levels as a continuous prognostic factor, every 1 gr/dL decrease in albumin levels was associated with significantly increased risk of death by a factor of 10% (HR: 1.10, 95% CI: 1.05-1.16, p = 0.0002). Similar to analyses with overall survival, the patients with lower albumin levels had an increased risk of progression or death compared to patients with higher albumin levels (HR: 1.76, 95% CI: 1.40-2.21, p < 0.001). Conclusion: The available evidence demonstrates that albumin levels may be a prognostic biomarker in advanced cancer patients treated with ICIs. Further research is needed to delineate the role of albumin levels in patients treated with ICIs in the adjuvant setting, as well as the possible benefit of therapeutic approaches to improve hypoalbuminemia., 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., (Copyright © 2022 Guven, Sahin, Erul, Rizzo, Ricci, Aksoy and Yalcin.)

Systemic treatments (e.g., chemotherapy and targeted therapies) have limited efficacy for patients with locally advanced - unresectable - and metastatic cholangiocarcinoma (CCA), with an overall survival of less than a year. Tumor microenvironment (TME) represents the ecosystem surrounding the tumor which comprises immune cells, fibroblasts, endothelial cells, and a wide range of soluble factors. CCA TME is characterized by an abundant desmoplastic stroma, exhibits a high heterogeneity and it plays a central role in cancer onset and progression. There is growing evidence suggesting that it is possible to target TME in association with other treatment modalities, such as cytotoxic chemotherapy or targeted therapies, paving the way to possible combination strategies with a synergistic effect. Herein, we describe the components of CCA TME - such as cancer-associated fibroblasts and other cells of pivotal importance - with their most relevant interactions, focusing on the preclinical rationale for the development of effective anticancer treatments., Competing Interests: Declaration of Competing Interest All authors declared that there are no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Recent years have seen the advent of novel treatment options for hepatocellular carcinoma (HCC). Given a strong biological rationale supporting this strategy, multiple studies have explored the role of combination treatments including locoregional plus systemic therapies to produce a synergistic effect and enhance antitumor activity. Among locoregional therapies, several clinical trials assessing trans-arterial chemoembolization (TACE) have been recently presented and published. In the current paper, we discuss available evidence and current and future research on combined TACE and systemic treatments, including antiangiogenic agents, immune checkpoint inhibitors, and immune-based combinations for HCC patients.

Objectives: The ABC-06 and the NIFTY trials recently established the role of second-line chemotherapy (2L) in patients with advanced biliary tract cancer (BTC). Our real-world study aimed to explore 2L in BTC patients aged ≥ 70 years old and to compare their outcomes with younger subjects. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. The Kaplan−Meier methods were used to estimate survival, and the log-rank test was used to make comparisons. Results: A total of 190 BTC patients treated with 2L were identified and included in the analysis. Among them, 52 (27.3%) were aged ≥ 70 years (range 70−87 years). No statistically significant differences in both median overall survival (mOS) and median progression-free survival (mPFS) were recorded between the elderly and younger patients. Absolute lymphocyte count < 1000/mmc (p < 0.001) and albumin level < 3 g/dL (p < 0.001) were independently associated with worse prognoses. Conclusions: The results of this real-world study suggest that for patients aged ≥ 70 years, 2L could be equally effective for younger patients with survival outcomes aligned to those from the ABC-06 and NIFTY trials. The delivery of 2L should be carefully evaluated and monitored in this patient subset.

Background: Recent years have witnessed the advent of molecular profiling for intrahepatic cholangiocarcinoma (iCCA), and new techniques have led to the identification of several molecular alterations. Precision oncology approaches have been widely evaluated and are currently under assessment, as shown by the recent development of a wide range of agents targeting Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF. However, several knowledge gaps persist in the understanding of the genomic landscape of this hepatobiliary malignancy., Methods: In the current study, we aimed to comprehensively analyze clinicopathological features of BAP1 -mutated iCCA patients in public datasets to increase the current knowledge on the molecular and biological profile of iCCA., Results: The current database study, including 772 iCCAs, identified BAP1 mutations in 120 cases (15.7%). According to our analysis, no differences in terms of overall survival and relapse-free survival were observed between BAP1 -mutated and BAP1 wild-type patients receiving radical surgery. In addition, IDH1, PBRM1, and ARID1A mutations were the most commonly co-altered genes in BAP1 -mutated iCCAs., Conclusions: The genomic characterization of iCCA is destined to become increasingly important, and more efforts aimed to implement iCCA genomics analysis are warranted.

Aim: The aim of this research was to assess the impact of an intensive follow-up program on BTC patients who had received surgery with curative intent at a tertiary referral hospital., Methods: BTC patients were followed-up every three months during the first two years after their first surgery and every six months from the third to the fifth post-operative year., Results: A total of 278 BTC patients who received R0/R1 surgery were included. A total of 17.7% of patients underwent a second surgery following disease relapse, and none of these patients experienced additional disease relapse., Conclusions: An intensive follow-up after surgical resection may help in the early identification of disease relapse, leading to early treatment and prolonged survival in selected cases.

Introduction: Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated., Areas Covered: The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed., Expert Opinion: Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.

Introduction: Immune checkpoint inhibitors (ICIs) have recently entered into the therapeutic scenario of metastatic breast cancer. However, only a proportion of patients benefit from ICIs and immune-based combinations, so the identification of reliable predictors of response remains an unmet need., Areas Covered: We discuss potential predictors of response to ICIs in breast cancer, including PD-L1 expression, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and several other biomarkers and suggest future directions of research in this setting. A literature search was conducted in October 2021 of Pubmed/Medline, Cochrane library and Scopus databases; in addition, abstract of international cancer meetings were reviewed., Expert Opinion: In terms of predictors of response to immunotherapy in TNBC patients, several biomarkers are being evaluated. Valuable data on predictive biomarkers have recently emerged, including host-related factors, immune-related cells, and protein and genetic markers. Data supporting immunotherapy in the metastatic triple-negative breast cancer setting are not concordant, but there have been some positive phase III trials including IMpassion130 and KEYNOTE-355. Phase II and III (neo)adjuvant trials are supportive of this therapeutic strategy. Further investigations are warranted in this challenging area.

Background: Immune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy., Methods: We performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC., Results: Two studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31-1.84) and 1.43 (95% CI, 1.23-1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs., Conclusions: The current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs.

Introduction: Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed malignancy worldwide, accounting for millions of deaths annually. Despite immune checkpoint inhibitors (ICIs) reported important results, only a minority of HCC patients benefit from these treatments, and the identification of predictive biomarkers of response still remains a highly unmet need., Areas Covered: Herein, we provide a timely overview of available evidence on biochemical predictors of response to immunotherapy in advanced HCC patients; we speculate on how PD-L1, TMB, and other emerging biomarkers could assist drug clinical trials in the near future. A literature search was conducted in June 2021 using Pubmed/Medline, Cochrane library, and Scopus databases., Expert Opinion: Reliable predictors of response to ICIs are of pivotal importance to allow a proper stratification and selection of HCC patients that could derive more benefit from immunotherapy. Well-designed, multicenter clinical trials specifically focused on predictive biomarkers are warranted in this setting, where most of evidence currently derives from retrospective, single-center studies with small sample size.

Introduction: While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination therapies have recently produced unprecedented paradigm shifts. The combination of lenvatinib plus pembrolizumab is now being evaluated as a front-line treatment in advanced HCC patients; early phase clinical trials have already reported promising results., Areas Covered: This paper reviews the combination of lenvatinib plus pembrolizumab for the treatment of advanced HCC. The preclinical rationale and completed and ongoing trials are examined and later, the authors reflect on biomarkers of predictive of response to immune-based combinations and future treatment decision-making on the basis of tolerability and clinical benefits provided by these novel therapeutics. A literature search was conducted in April 2021 of Pubmed/Medline, Cochrane library and Scopus databases; moreover, abstracts of international cancer meetings were reviewed., Expert Opinion: The landscape of new agents and combinations continues to expand. Recently, immune-based combinations have reported important results in advanced HCC, as witnessed by the landmark IMbrave150 trial. Based on the promising results of early phase clinical trials, lenvatinib plus pembrolizumab has the potential to represent a novel treatment option in this setting.

Hepatocellular carcinoma (HCC) represents the fourth most common cause of cancer-related death. Surgery, local ablative therapies and liver transplantation are the only potentially curative strategies, but the majority of patients present with advanced disease at diagnosis or develop recurrence after surgery. In recent years, immunotherapy for HCC has received growing interest, and one of the most promising strategies is the association of two immune checkpoint inhibitors (ICIs), which has already demonstrated its potential in other solid tumors such as melanoma and renal cell carcinoma. Herein, we discuss the role and the biologic rationale of dual immune checkpoint blockade in HCC patients, focusing on the two ICI combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab.

Context: Immune checkpoint inhibitors (ICIs) have reported unprecedented results in the treatment of metastatic renal cell carcinoma (mRCC) patients, as monotherapy or in combination with other anticancer agents. However, little information is available regarding the association between different clinicopathological features and survival in this setting., Objective: We performed a meta-analysis aimed at exploring the predictive value of routinely collected clinicopathological data in randomized controlled trials (RCTs) evaluating ICIs plus tyrosine kinase inhibitors (TKIs) in treatment-naïve patients with mRCC., Evidence Acquisition: We retrieved all the relevant RCTs through PubMed/Medline, Cochrane Library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs assessing first-line ICI-TKI versus sunitinib in treatment-naïve mRCC patients; the primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI)., Evidence Synthesis: Overall, three phase III RCTs involving 1769 patients with advanced or metastatic RCC were included. Compared with sunitinib, the ICI-TKI combination significantly decreased the risk of death in patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 (HR, 0.66; 95% CI, 0.57-0.76) and ECOG-PS 1 (HR, 0.64; 95% CI, 0.54-0.77). Similarly, the combination was associated with prolonged OS in patients who were <65 yr old (HR, 0.57; 95% CI, 0.49-0.67), in mRCC patients ≥65 yr old (HR, 0.75; 95% CI, 0.61-0.90), as well as in male (HR, 0.66; 95% CI, 0.56-0.78) and female (HR, 0.66; 95% CI, 0.52-0.83) patients., Conclusions: According to our results, the magnitude of benefit of the ICI-TKI combination over sunitinib monotherapy in treatment-naïve mRCC patients was consistent across the clinicopathological subgroups. Despite the limitations affecting the analysis, we believe that the results of the current meta-analysis could assist clinicians and researchers in the design and interpretation of future clinical trials on combination therapies in this setting., Patient Summary: First-line combinations of an immune checkpoint inhibitor plus a tyrosine kinase inhibitor improved survival in metastatic renal cell carcinoma (mRCC) patients. This survival benefit was consistent across all subgroups of mRCC patients irrespective of clinicopathological features such as patient performance status, age <65 and ≥65 yr, and male and female gender., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Aims: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma. The authors performed a meta-analysis aiming to evaluate the predictive value of Eastern Cooperative Oncology Group performance status, age, sex, liver metastasis and histology in trials comparing first-line ICI-based combinations with chemotherapy in metastatic urothelial carcinoma patients. Methods: Hazard ratios were analyzed. Results: ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including patients with no liver metastases (hazard ratio: 0.84; 95% CI: 0.74-0.95) and those with an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio: 0.84; 95% CI: 0.72-0.97). Conclusion: The benefit of ICI-based combinations over chemotherapy in metastatic urothelial carcinoma was consistent across several clinicopathological subgroups, although a proportion of patients responded to chemotherapy alone.

Rectal neuroendocrine tumors (r-NETs) are rare tumors with overall good prognosis after complete resection. However, there is no consensus on the extension of lymphadenectomy or regarding contraindications to extensive resection. In this study, we aim to identify predictive factors that correlate with nodal metastasis in patients affected by G1-G2 r-NETs. A retrospective analysis of G1-G2 r-NETs patients from eight tertiary Italian centers was performed. From January 1990 to January 2020, 210 patients were considered and 199 were included in the analysis. The data for nodal status were available for 159 cases. The nodal involvement rate was 9%. A receiver operating characteristic (ROC) curve analysis was performed to identify the diameter (>11.5 mm) and Ki-67 (3.5%), respectively, as cutoff values to predict nodal involvement. In a multivariate analysis, diameter > 11.5 mm and vascular infiltration were independently correlated with nodal involvement. A risk scoring system was constructed using these two predictive factors. Tumor size and vascular invasion are predictors of nodal involvement. In addition, tumor size > 11.5 mm is used as a driving parameter of better-tailored treatment during pre-operative assessment. Data from prospective studies are needed to validate these results and to guide decision-making in r-NETs patients in clinical practice.

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarcinoma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Here, we aim at describing the pattern of care, survival outcome and prognostic factors of ABC patients (pts) receiving third-line chemotherapy., Methods: Institutional registries across three academic medical centers were retrospectively reviewed. Kaplan-Meier estimators were used to calculate survival, the log-rank test to make comparisons, and the Cox proportional hazard models to assess the progostic impact of variables., Results: Among 101 pts included in the analysis. 68 (67.3%), 19 (18.8%) and 14 (13.8%) had intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, respectively. Atotal of 63 (62.3%) pts received monochemotherapy, while 38 (37.6%) were treated with adoublet. The median OS and PFS were 5 and 3 months, respectively. Disease control rate was achieved in 23 (22.7%) pts, with 2 (2%) partial responses. Grade 3-4 treatment-related adverse events were reported in 22 (21.7%) pts. At multivariate analysis, ECOG PS (p < 0.001), tumor burden (p = 0.01) and lymphocyte-to-monocyte ratio (p =0.02) were independent predictors of survival., Conclusions: Third-line chemotherapy displayed limited activity in this real-world cohort, although prognostic factors have been identified that may assist in treatment decision. The results of this multicenter experience, highlight the need for more effective therapies and provide a benchmark for future trials in this setting.

Hepatocellular carcinoma (HCC) remains the sixth most commonly diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Over the next few years, novel systemic treatment options have emerged. Among these, immune checkpoint inhibitors (ICIs) have been widely evaluated and are under assessment, as monotherapy or in combination with other anticancer agents in treatment-naïve and previously treated patients. In particular, the approval of the PD-L1 inhibitor atezolizumab plus the antiangiogenic agent bevacizumab as front-line treatment for advanced HCC has led to the adoption of this combination in this setting, and the IMbrave 150 phase III trial has established a novel standard of care. However, several questions remain unanswered, including the identification of reliable predictors of response to ICIs in HCC patients. In the current paper, we will provide an updated overview of potentially useful predictive biomarkers of response to immunotherapy in advanced HCC. A literature search was conducted in September 2021 of Pubmed/Medline, Cochrane library and Scopus databases., 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., (Copyright © 2021 Rizzo, Ricci, Di Federico, Frega, Palloni, Tavolari and Brandi.)

Competing Interests: The authors have no conflicts of interest to declare.

Biliary tract cancer (BTC) includes a heterogeneous group of aggressive and rare hepatobiliary malignancies, including gallbladder cancer, ampullary carcinomas, intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma, further subclassified into distal (dCCA) and perihilar cholangiocarcinoma (pCCA) [...].

Introduction: Immunotherapy has recently taken on an extremely important role in medical oncology, as first- or later-line treatment in several tumor types, and recent years have seen the emerging of clinical trials assessing immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC)., Areas Covered: Herein, we provide an overview of recently published studies exploring the dual immune checkpoint blockade or the combination of ICIs plus biological treatments as first-line treatment in HCC patients with advanced disease, especially focusing on the biological rationale behind these therapeutic strategies, and ongoing active and recruiting clinical trials., Expert Opinion: Results of studies on monotherapy with ICIs have suggested that this strategy could be beneficial only in a minority of patients; conversely, the recently published IMbrave150 study has reported an overall survival benefit in HCC receiving the combination of atezolizumab plus bevacizumab compared to sorafenib as first-line treatment. A wide number of clinical trials is evaluating ICI-based combinations in advanced HCC, a strategy which is supported by robust preclinical and early-phase clinical data, and results of these studies are highly awaited.

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.

Ampullary carcinomas (ACs) represent a rare entity, accounting for approximately 0.2% of all gastrointestinal solid tumors and 20% of all periampullary cancers (PACs). Unfortunately, few data are available regarding the optimal therapeutic strategy for ACs due to their rarity, and physicians frequently encounter significant difficulties in the management of these malignancies. In this review, we will provide an overview of current evidence on AC, especially focusing on biological features, histological characteristics, and available data guiding present and future therapeutic strategies for these rare, and still barely known, tumors.

Availability of highly parallelized immunoassays has renewed interest in the discovery of serology biomarkers for infectious diseases. Protein and peptide microarrays now provide a rapid, high-throughput platform for immunological testing and validation of potential antigens and B-cell epitopes. However, there is still a need for tools to prioritize and select relevant probes when designing these arrays. In this work we describe a computational method called APRANK (Antigenic Protein and Peptide Ranker) which integrates multiple molecular features to prioritize potentially antigenic proteins and peptides in a given pathogen proteome. These features include subcellular localization, presence of repetitive motifs, natively disordered regions, secondary structure, transmembrane spans and predicted interaction with the immune system. We trained and tested this method with a number of bacteria and protozoa causing human diseases: Borrelia burgdorferi (Lyme disease), Brucella melitensis (Brucellosis), Coxiella burnetii (Q fever), Escherichia coli (Gastroenteritis), Francisella tularensis (Tularemia), Leishmania braziliensis (Leishmaniasis), Leptospira interrogans (Leptospirosis), Mycobacterium leprae (Leprae), Mycobacterium tuberculosis (Tuberculosis), Plasmodium falciparum (Malaria), Porphyromonas gingivalis (Periodontal disease), Staphylococcus aureus (Bacteremia), Streptococcus pyogenes (Group A Streptococcal infections), Toxoplasma gondii (Toxoplasmosis) and Trypanosoma cruzi (Chagas Disease). We have evaluated this integrative method using non-parametric ROC-curves and made an unbiased validation using Onchocerca volvulus as an independent data set. We found that APRANK is successful in predicting antigenicity for all pathogen species tested, facilitating the production of antigen-enriched protein subsets. We make APRANK available to facilitate the identification of novel diagnostic antigens in infectious diseases., 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., (Copyright © 2021 Ricci, Brunner, Ramoa, Carmona, Nielsen and Agüero.)