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The tetraspanin family of membrane proteins is essential for controlling different biological processes such as cell migration, penetration, adhesion, growth, apoptosis, angiogenesis and metastasis. The present review summarized the current knowledge regarding the expression and roles of tetraspanins in different types of cancer of the digestive system, including gastric, liver, colorectal, pancreatic, esophageal and oral cancer. Depending on the type and context of cancer, tetraspanins can act as either tumor promoters or suppressors. In the present review, the importance of tetraspanins in serving as biomarkers and targets for different types of digestive system‑related cancer was emphasized. Additionally, the molecular mechanisms underlying the involvement of tetraspanins in cancer progression and metastasis were explored. Furthermore, the current challenges are addressed and future research directions for advancing investigations related to tetraspanins in the context of digestive system malignancies are proposed.

Background: Primary care (PC) is essential to overall wellness and management of comorbidities. In turn, patients without adequate access to PC may face healthcare disparities. We sought to characterize the impact of established PC on postoperative outcomes among patients undergoing a surgical procedure for a digestive tract cancer., Methods: Medicare beneficiaries with a diagnosis of hepatobiliary, pancreas, and colorectal cancer between 2005 and 2019 were identified within the Surveillance, Epidemiology, and End Results program and Medicare-linked database. Individuals who did versus did not have PC encounters within 1-year before surgery were identified. A postoperative textbook outcome (TO) was defined as the absence of complications, no prolonged hospital stay, no readmission within 90 days, and no mortality., Results: Among 63,177 patients, 50,974 (80.7%) had at least one established PC visit before surgery. Patients with established PC were more likely to achieve TO (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.09-1.19) with lower odds for complications (OR, 0.85; 95% CI, 0.72-0.89), extended hospital stay (OR, 0.86; 95% CI, 0.81-0.94), 90-day readmission (OR, 0.94; 95% CI, 0.90-0.99), and 90-day mortality (OR, 0.87; 95% CI, 0.79-0.96). In addition, patients with established PC had a 4.1% decrease in index costs and a 5.2% decrease in 1-year costs. Notably, patients who had one to five visits with their PC in the year before surgery had improved odds of TO (OR, 1.21; 95% CI, 1.16-1.27), whereas individuals with more than 10 visits had lower odds of a postoperative TO (OR, 0.91; 95% CI, 0.84-0.98)., Conclusion: Most Medicare beneficiaries with digestive tract cancer had established PC within the year before their surgery. Established PC was associated with a higher probability of achieving ideal outcomes and lower costs. In contrast, patients with more than 10 PC appointments, which was likely a surrogate of overall comorbidity burden, experienced no improvement in postoperative outcomes., (© 2024. The Author(s).)

Theragnostic biomarkers are still needed to select patients with digestive neuroendocrine neoplasms (NENs) for an optimal management. The PD-1/PD-L1 pathway plays a pivotal role in T cells activation and host immune response to cancer and PD-L1 expression in tumor and/or immune cells is used to identify patients who would benefit of treatment with immune checkpoint inhibitors. However, its role as a biomarker is still unclear in digestive NENs. We investigated PD-L1 expression in 68 well-characterized digestive NENs (32 NETs, 32 NECs and 4 MiNENs) and TPS and CPS scores were calculated. In addition, tumor infiltrating T-lymphocytes and mismatch repair protein expression (MMR) were evaluated. All results were correlated with clinicopathological features. PD-L1 expression was higher in NECs than in NETs: TPS > 1% and/or CPS > 1 were observed in 16% of NETs, 68.8% of NECs and 50% of MiNENs (p: 0.05). The mean TPS score in positive cases was 6.3% in NETs, 16.2% in NECs and 5% in MiNENs. The CPS score was 4.8 in NETs, 8.1 in NECs and 6 in MiNENs. MMR-deficient neoplasms were more frequently observed in NECs than in NETs (p: < 0.05) as well as intra-tumor immune infiltration (p: 0.00001). No correlation between PD-L1 expression and survival or other clinicopathological parameters was observed. Our results suggest that treatment with immune checkpoint inhibitors may have a potential role only in selected cases, mainly in NECs and MiNENs., Competing Interests: Declarations This study was performed according to the clinical standards of the 1975 and 1983 Declaration of Helsinki and was approved by the local ethical committee (Comité d’éthique sur la recherche humaine du canton de Vaud, ref ID 2019–02259). Conflicts of interest The authors have no financial or non-financial conflicts of interest to disclose., (© 2024. The Author(s).)

Competing Interests: Conflict of interest I declare that I have not any conflict of interest regarding my commentary about the article by Bo Gao et al. entitled “Role of pathological tumor regression grade of lymph node metastasis following neoadjuvant chemotherapy in locally advanced gastric cancer”. In this commentary I highlight the more accurate TRG, proposed by Bo Gao et al. encompassing both the primary and the corresponding lymph nodes. It may reinforce the use of a revisited pathologic response as an end point in neoadjuvant clinical trials of digestive oncology, especially in this era of innovative targeted treatments. Consequently, the design of future projects in digestive oncology may welcome this approach, for a more precise evaluation of treatments and outcome of patients.

Glutamine is one of the most abundant non-essential amino acids in human plasma and plays a crucial role in many biological processes of the human body. Tumor cells take up a large amount of glutamine to meet their rapid proliferation requirements, which is supported by the upregulation of glutamine transporters. Targeted inhibition of glutamine transporters effectively inhibits cell growth and proliferation in tumors. Among all cancers, digestive system malignant tumors (DSMTs) have the highest incidence and mortality rates, and the current therapeutic strategies for DSMTs are mainly surgical resection and chemotherapy. Due to the relatively low survival rate and severe side effects associated with DSMTs treatment, new treatment strategies are urgently required. This article summarizes the glutamine transporters involved in DSMTs and describes their role in DSMTs. Additionally, glutamine transporter-target drugs are discussed, providing theoretical guidance for the further development of drugs DSMTs treatment., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 The Authors.)

Long non‑coding RNA (lncRNA) is a class of non‑coding RNA molecules located in the cytoplasm or nucleus, which can regulate chromosome structure and function by interacting with DNA, RNA, proteins and other molecules; binding to mRNA bases in a complementary manner, affecting the splicing, stabilization, translation and degradation of mRNA; acting as competing endogenous RNA competitively binds to microRNAs to regulate gene expression and participate in the regulation of various vital activities of the body. The PI3K/AKT signalling pathway plays a key role in numerous biological and cellular processes, such as cell proliferation, invasion, migration and angiogenesis. It has been found that the lncRNA/PI3K/AKT axis regulates the expression of cancer‑related genes and thus tumour progression. The abnormal regulation of lncRNA expression in the lncRNA/PI3K/AKT axis is clearly associated with clinicopathological features and plays an important role in regulating biological functions. In the present review, the expression and biological functions of PI3K/AKT‑related lncRNAs both in vitro and in vivo over recent years, were comprehensively summarized and analyzed. Their correlation with clinicopathological features was also evaluated, with the objective of furnishing a solid theoretical foundation for clinical diagnosis and the monitoring of efficacy in digestive system neoplasms. The present review aimed to provide a comprehensive overview of the expression and biological functions of PI3K/AKT‑related lncRNAs in digestive system neoplasms and to assess their correlation with clinicopathological features. This endeavor seeks to establish a solid theoretical foundation for the clinical diagnosis and efficacy monitoring of digestive system tumors.

Digestive system cancers rank among the most prevalent malignant tumors, maintaining persistently high incidence and mortality rates. Notch signaling activity, often aberrant in esophageal, gastric, hepatic, pancreatic, and colorectal cancers, plays a pivotal role in the initiation, progression, and therapy resistance of these malignancies. As a highly conserved pathway, Notch signaling is integral to cell differentiation, survival, proliferation, stem cell renewal, development, and morphogenesis. Its dysregulation has been increasingly linked to various diseases, particularly digestive system cancers. In these malignancies, altered Notch signaling influences multiple biological processes, including cell proliferation, invasion, cell cycle progression, immune evasion, drug resistance, and stemness maintenance. Understanding the mechanisms of Notch signaling in digestive system cancers is essential for the development of novel targeted therapies. Numerous Notch pathway-targeting drugs are currently in preclinical studies, demonstrating promising efficacy both as monotherapies and in combination with conventional anti-cancer treatments. This review summarizes recent high-quality findings on the involvement of Notch signaling in digestive system cancers, focusing on the expression changes and pathological mechanisms of its dysregulated components. Special emphasis is placed on the potential of translating Notch-targeted approaches into therapeutic strategies, which hold promise for overcoming the limitations of existing treatments and improving the poor prognosis associated with these cancers., Competing Interests: Declaration of competing interest All authors declare no competing interests related to this review., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The incidence of tumors in the human digestive system is relatively high, including esophageal cancer, liver cancer, pancreatic cancer, gastric cancer and colorectal cancer. These malignancies arise from a complex interplay of environmental and genetic factors. Among them, long non‑coding RNAs (lncRNAs), which cannot be translated into proteins, serve an important role in the development, progression, migration and prognosis of tumors. Small nucleolar RNA host gene 16 (SNHG16) is a typical lncRNA, and its relationship with digestive system tumors has been widely explored. The prevailing hypothesis suggests that the principal molecular mechanism of SNHG16 in digestive system tumors involves it functioning as a competitive endogenous RNA that interacts with other proteins, regulates various genes and influences a downstream target molecule. The present review summarizes recent research on the relationship between SNHG16 and numerous types of digestive system cancer, encompassing its biological functions, underlying mechanisms and potential clinical implications. Furthermore, it outlines the association between SNHG16 expression and pertinent risk factors, such as smoking, infection and diet. The present review indicated the promise of SNHG16 as a potential biomarker and therapeutic target in human digestive system cancer.

The role of skeletal muscle and adipose tissue in the progression of cancer has been gradually discussed, but it needs further exploration. The objective of this study was to provide an in-depth analysis of skeletal muscle and fat in digestive malignancies and to construct novel predictors for clinical management. This is a retrospective study that includes data from Cancer Center, the First Hospital of Jilin University. Basic characteristic information was analyzed by T tests. Correlation matrices were drawn to explore the relationship between CT-related indicators and other indicators. Cox risk regression analyses were performed to analyze the association between the overall survivals (OS) and various types of indicators. A new indicator body composition score (BCS) was then created and a time-dependent receiver operating characteristic curve was plotted to analyze the efficacy of the BCS. Finally, a nomogram was produced to develop a scored-CT system based on BCS and other indicators. C-index and calibration curve analyses were performed to validate the predictive accuracy of the scored-CT system. A total of 575 participants were enrolled in the study. Cox risk regression model revealed that VFD, L3 SMI and VFA/SFA were associated with prognosis of cancer patients. After adjustment, BCS index based on CT was significantly associated with prognosis, both in all study population and in subgroup analysis according to tumor types (all study population: HR 2.036, P < 0.001; colorectal cancer: HR 2.693, P < 0.001; hepatocellular carcinoma: HR 4.863, P < 0.001; esophageal cancer: HR 4.431, P = 0.008; pancreatic cancer: HR 1.905, P = 0.016; biliary system malignancies: HR 23.829, P = 0.035). The scored-CT system was constructed according to tumor type, stage, KPS, PG-SGA and BCS index, and it was of great predictive validity. This study identified VFD, L3 SMI and VFA/SFA associated with digestive malignancies outcomes. BCS was created and the scored-CT system was established to predict the OS of cancer patients., (© 2024. The Author(s).)

Tumor-mediated immunosuppression is a fundamental obstacle to the development of dendritic cell (DC)-based cancer vaccines, which despite their ability to stimulate host anti-tumor CD8 T cell immunity, have not been able to generate meaningful therapeutic responses. Exosomes are inactive membrane vesicles that are nanoscale in size and are produced by the endocytic pathway. They are essential for intercellular communication. Additionally, DC-derived exosomes (DEXs) contained MHC class I/II (MHCI/II), which is frequently complexed with antigens and co-stimulatory molecules and is therefore able to prime CD4 and CD8 T cells that are specific to particular antigens. Indeed, vaccines with DEXs have been shown to exhibit better anti-tumor efficacy in eradicating tumors compared to DC vaccines in pre-clinical models of digestive system tumors. Also, there is room for improvement in the tumor antigenic peptide (TAA) selection process. DCs release highly targeted exosomes when the right antigenic peptide is chosen, which could aid in the creation of DEX-based antitumor vaccines that elicit more targeted immune responses. Coupled with their resistance to tumor immunosuppression, DEXs-based cancer vaccines have been heralded as the superior alternative cell-free therapeutic vaccines over DC vaccines to treat digestive system tumors. In this review, current studies of DEXs cancer vaccines as well as potential future directions will be deliberated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Claudin 18.2-targeted therapy has shown significant efficacy in treating claudin 18.2-positive cancers. However, limited systematic studies have investigated characteristics of claudin 18.2 expression in neuroendocrine neoplasms (NENs)., Methods: Data and specimens from 403 cases of digestive NENs were retrospectively collected, and claudin 18.2 expression was detected using immunochemical staining., Results: Claudin 18.2 was positive in 19.6% (79/403) of the digestive NENs. The highest positive rate of claudin 18.2 was observed in gastric NENs (72/259, 27.8%), accounting for 91.1% (72/79) of all positive cases. The positivity rate was significantly higher in gastric NENs compared to pancreatic (2/78, 2.6%) or colorectal NENs (2/38, 5.3%; p < 0.05). For digestive NENs, claudin 18.2 positivity was significantly higher in neuroendocrine carcinomas (NECs) (37/144, 25.7%) than in neuroendocrine tumours (NETs; 14/160, 8.8%; p < 0.001), but no significant difference was found between gastric NECs (59/213, 27.7%) and gastric NETs (13/46, 28.3%; p > 0.05). The positivity was significantly higher in large-cell NECs (LCNECs; 28/79, 35.4%) and MiNEN (mixed neuroendocrine-non- neuroendocrine neoplasms)-LCNECs (23/66, 34.8%) compared to small-cell NECs (SCNECs; 9/65, 13.8%) and MiNEN-SCNECs (5/33, 15.2%; p < 0.05). Claudin 18.2 expression was more prevalent in gastric NENs than in pancreatic (12.5 ×; p = 0.001) and colorectal NENs (5.9 ×; p = 0.021). Claudin 18.2 staining was a useful method for identify the gastric origins of NETs, with a sensitivity of 28.3% and a specificity of 99.1%., Conclusion: The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: The presence of cancer cachexia is a significant adverse prognostic indicator in patients with malignant tumors. Cancer cachexia is a multifactorial syndrome characterized by a constant loss of skeletal muscles with or without a loss of weight, leading to immune dysfunction. We performed a retrospective study to investigate the influence of cachexia on the immunotherapy efficacy and prognosis for malignant tumors of the digestive system., Methods: The present study adopts a cross-sectional design. The prognosis data of patients with advanced cancer of the digestive system who received immunotherapy from September 2021 to December 2022 were analyzed. Cachexia was calculated using the change of the area of the psoas major muscle (PMMA) or the weight. We measured the change at the beginning of immunotherapy and at least 2 cycles afterward. The participants were categorized into the cachexia group and control group based on the evaluation criteria. Kaplan-Meier and Log-rank methods were used for survival analysis. Cox proportional hazard model as a method to assess the contribution of different clinical factors to overall survival (OS) and progression-free survival (PFS)., Results: A total number of 98 patients, including esophageal carcinoma (4, 4%), gastric (36, 37%), colorectal (51, 52%), and other cancer types (7, 7%), were enrolled. Fifty-four patients were diagnosed with non-cancer cachexia, and the cancer cachexia group included 44 patients. The median PFS in the cachexia group was shorter than that in the control group (130 days vs. 212 days). Their difference was not significant (p = .321). The survival rate of the patients without cachexia was longer than of those with cachexia (p = .027). The level of albumin and the number of metastatic organs were related to PFS (p = .020, p = .029). The albumin level was significantly associated with the OS of patients (p = .003)., Conclusions: The presence of cachexia was significantly associated with poor OS in patients with malignant tumors of the digestive system who received immunotherapy, not with PFS or the response to immunotherapy., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Background: Panel gene sequencing is an established diagnostic tool for precision oncology of solid tumors, but its utility for the treatment of cancers of the digestive system in clinical routine is less well documented., Methods: We retrospectively identified patients with advanced or metastatic gastrointestinal, pancreaticobiliary or hepatic cancers who received panel gene sequencing at a tertiary university hospital from 2015 to 2022. For these cases, we determined the spectrum of genetic alterations, clinicopathological parameters and treatment courses. Assessment of actionability of genetic alterations was based on the OncoKB database, cancer-specific ESMO treatment guidelines, and recommendations of the local molecular tumor board., Results: In total, 155 patients received panel gene sequencing using either the Oncomine Focus (62 cases), Comprehensive (91 cases) or Childhood Cancer Research Assay (2 cases). The mean age of patients was 61 years (range 24-90) and 37% were female. Most patients suffered from either colorectal cancer (53%) or cholangiocellular carcinoma (19%). 327 genetic alterations were discovered in 123 tumor samples, with an average number of 2.1 alterations per tumor. The most frequently altered genes were TP53, KRAS and PIK3CA. Actionable gene alterations were detected in 13.5-56.8% of tumors, according to ESMO guidelines or the OncoKB database, respectively. Thirteen patients were treated with targeted therapies based on identified molecular alterations, with a median progression-free survival of 8.8 months., Conclusions: Actionable genetic alterations are frequently detected by panel gene sequencing in patients with advanced cancers of the digestive tract, providing clinical benefit in selected cases. However, for the majority of identified actionable alterations, sufficient clinical evidence for targeted treatments is still lacking., (© 2024. The Author(s).)

Tumors of the digestive system pose a significant threat to human health and longevity. These tumors are associated with high morbidity and mortality rates, leading to a heavy economic burden on healthcare systems. Several intratumoral microorganisms are present in digestive system tumors, and their sources and abundance display significant heterogeneity depending on the specific tumor subtype. These microbes have a complex and precise function in the neoplasm. They can facilitate tumor growth through various mechanisms, such as inducing DNA damage, influencing the antitumor immune response, and promoting the degradation of chemotherapy drugs. Therefore, these microorganisms can be targeted to inhibit tumor progression for improving overall patient prognosis. This review focuses on the current research progress on microorganisms present in the digestive system tumors and how they influence the initiation, progression, and prognosis of tumors. Furthermore, the primary sources and constituents of tumor microbiome are delineated. Finally, we summarize the application potential of intratumoral microbes in the diagnosis, treatment, and prognosis prediction of digestive system tumors. Video Abstract., (© 2024. The Author(s).)

Aims: Criteria for the interpretation of digestive system neuroendocrine neoplasms (NENs) continue to evolve. Although there are some literature recommendations regarding workup and diagnosis of these lesions, different practice patterns exist among pathologists when signing out these specimens. The aim of this study was to assess practice trends among pathologists worldwide when reporting these neoplasms., Methods and Results: We created an online survey with multiple questions pertaining to digestive NENs. The results were analysed based on type of practice setting, years of sign-out experience, and practice location. Respondents included 384 practicing pathologists: 70% academic, 30% private practice; 63% gastrointestinal (GI) pathology-subspecialised, 37% not; 39% North American, 42% European, 19% others; 45% with ≤10 years in practice; 55% with >10 years. Some question responses were chosen by the majority (e.g. 85% use both mitotic count and Ki67 index for grading NENs, 82% complete a synoptic, and Ki67 stain even for small incidental appendiceal neuroendocrine tumours [NETs], and 96% utilize the diagnosis of grade 3 NET). However, some questions showed varying responses, including counting mitotic figures, Ki67 stain interpretation, and pancreatic grade 3 NEN workup. Pathologists also had some variability in interpreting regional metastatic foci of small bowel NETs and in choosing blocks for Ki67 staining in multifocal lesions., Conclusion: There existed scenarios wherein practice patterns varied despite recommendations in the literature, and there were also scenarios lacking clear guidelines wherein pathologists used varying judgement. This survey highlights current key grey areas in digestive system NEN evaluation, leading to variation in practice patterns., (© 2022 John Wiley & Sons Ltd.)

Digestive system cancers account for nearly half of all cancers around the world and have a high mortality rate. Cell culture and animal models represent cornerstones of digestive cancer research. However, their ability to enable cancer precision medicine is limited. Cell culture models cannot retain the genetic and phenotypic heterogeneity of tumors and lack tumor microenvironment (TME). Patient-derived xenograft mouse models are not suitable for immune-oncology research. While humanized mouse models are time- and cost-consuming. Suitable preclinical models, which can facilitate the understanding of mechanisms of tumor progression and develop new therapeutic strategies, are in high demand. This review article summarizes the recent progress on the establishment of TME by using tumor organoid models and microfluidic systems. The main challenges regarding the translation of organoid models from bench to bedside are discussed. The integration of organoids and a microfluidic platform is the emerging trend in drug screening and precision medicine. A future prospective on this field is also provided., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: HOXB7 is abnormally expressed in a variety of tumors, but its prognostic value remains unclear due to sample size limitation and outcome inconsistency in previous studies. This meta-analysis was performed to explore the effect of HOXB7 expression on prognoses and clinicopathological factors in range of the whole solid tumors., Methods: PubMed, EMBASE, and Web of Science databases were searched to identify included studies. Hazard ratios (HR) with its 95% confidence interval (CI) and clinicopathological factors were extracted. Subgroup analyses were performed according to histopathological type, tumor occurrence systems, and HOXB7 detection methods., Results: A total of 3430 solid tumors patients from 20 studies (21 cohorts) were included in the meta-analysis. The results showed that high HOXB7 expression was significantly associated with worse survival (overall survival: HR = 1.98, 95%CI: 1.74-2.26, P < .001 and disease-free survival: HR = 1.59, 95%CI: 1.21-2.09, P = .001), more advanced tumor-node-metastasis (TNM) stage (odds ratio [OR] = 2.14, 95%CI: 1.68-2.73, P < .001), positive lymph node metastasis (OR = 2.16, 95%CI: 1.74-2.70, P < .001), more distant metastasis (OR = 1.63, 95%CI: 1.01-2.63, P = .048), poorer differentiation (OR = 1.48, 95%CI: 1.14-1.91, P = .003), and higher Ki-67 expression (OR = 2.53, 95%CI: 1.68-3.84, P < .001). Subgroup analysis showed that survival of patients with HOXB7 high expression was worse in either squamous cell carcinomas or non-squamous cell carcinomas, digestive tumors or non-digestive tumors, and protein level or mRNA level., Conclusion: High HOXB7 expression might be a valuable biomarker of poor prognosis for solid tumors. HOXB7 promotes tumor proliferation and metastasis, and is associated with poorer differentiation, more advanced stage, even the chemotherapy resistance, suggesting that HOXB7 is a potential therapeutic target for solid tumors., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

The physin family of proteins, synaptophysin (SYP), synaptophysin like 1 (SYPL1), synaptophysin like 2 (SYPL2) and synaptoporin (SYNRP), are tetratransmembrane transport vesicle proteins distributed throughout the digestive system. Of these, SYP is a required marker for histopathologic identification of neuroendocrine neoplasms (NENs), especially in gastroenteropancreatic NENs (GEP-NENs). Recently, bloodstream SYP, i.e., on platelets and circulating tumor cells, has been correlated to clinicopathologic features of GEP-NENs and may have prognostic significance. Serum SYPL1 also represents a promising biomarker for colorectal cancer. This chapter provides an overview of physin structures and potential use as diagnostic, prognostic and therapeutic tools for digestive tract neoplasms., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: Extensive abdominal surgery is associated with the risk of postoperative pulmonary complications. This study aims to explore the incidence and risk factors for developing postoperative pulmonary complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and to analyze how these complications affect overall survival., Methods: Data were collected on 417 patients undergoing surgery between 2007 and2017 at Uppsala University Hospital, Sweden. Postoperative pulmonary complications were graded according to the Clavien-Dindo classification system where Grade ≥ 3 was considered a severe complication. A logistic regression analysis was used to analyze risk factors for postoperative pulmonary complications and a Cox proportional hazards model to assess impact on survival., Results: Seventy-two patients (17%) developed severe postoperative pulmonary complications. Risk factors were full thickness diaphragmatic injury and/or diaphragmatic resection [OR 5.393, 95% CI 2.924-9.948, p = < 0.001]. Severe postoperative pulmonary complications, in combination with non-pulmonary complications, contributed to decreased overall survival [HR 2.285, 95% CI 1.232-4.241, p = 0.009]., Conclusions: Severe postoperative pulmonary complications were common and contributed to decreased overall survival. Full thickness diaphragmatic injury and/or diaphragmatic resection were the main risk factors. This finding emphasizes the need for further research on the mechanisms behind pulmonary complications and their association with mortality., Competing Interests: The authors have declared that no competing interests exist.

Background: The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177 Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results., Methods: This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177 Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg ( 177 Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177 Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239., Findings: From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the 177 Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the 177 Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177 Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177 Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177 Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up., Interpretation: 177 Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177 Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up., Funding: Advanced Accelerator Applications, a Novartis company., Competing Interests: Declaration of interests JRS has provided consulting or advisory services for Novartis, speakers bureau services for Ipsen, Lexicon and has received research funding from Novartis. MEC has provided consulting or advisory services for Advanced Accelerator Applications (a Novartis company), Ipsen, Sirtex Medical, Novartis, speakers bureau services for Advanced Accelerator Applications, Ipsen, Sirtex Medical, and Pfizer, and has received research funding from Advanced Accelerator Applications. PLK has provided consulting or advisory services for Ipsen, Lexicon, and Advanced Accelerator Applications, and has received research funding from Advanced Accelerator Applications, Lexicon, Ipsen, Xencor, and Brahms. PLK owns stock in Guardant Health. PBR has provided consulting or advisory services for Ipsen, Advanced Accelerator Applications, ITM, and Novartis; has received research funding from Advanced Accelerator Applications, Ipsen, and ITM; and has received travel or accommodation expenses from Ipsen. LB has provided consulting services (non-remunerated) for Advanced Accelerator Applications, ITM, Clovis Oncology, Curium, and Iba; has provided speaker's bureau services (non-remunerated) for Advanced Accelerator Applications, ITM, and Iba; and has received research funding from Advanced Accelerator Applications. AH has provided consulting or advisory services for Novartis, Ipsen, Perthera, Celgene and AbbVie, and has received travel or accommodation expenses from Halozyme and research funding from Ipsen. EM has provided consulting or advisory services for Ipsen and Advanced Accelerator Applications, has received honoraria from Advanced Accelerator Applications and Curium, and has received research funding from Advanced Accelerator Applications and Nordic Nanovector. EMW has provided consulting or advisory services for Advanced Accelerator Applications, Lexicon, and Progenics. JCY has provided consulting or advisory services for Advanced Accelerator Applications, Ipsen, Chiasma, Crinetics, and Hutchinson Medi Pharma, and has received research funding from Advanced Accelerator Applications and Novartis. MEP has provided consulting or advisory services for Advanced Accelerator Applications and Ipsen, and has received honoraria from Ipsen, Hutchison MediPharma, Advanced Accelerator Applications, Riemser, and Boehringer Ingelheim, and travel or accommodation expenses from Ipsen and Hutchison. EG has provided consulting or advisory services for MSD, Pfizer, Ipsen, Roche, and Bristol Myers Squibb; has received honoraria from Pfizer, Bristol Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, and Lilly; has received travel or accommodation expenses from Bristol Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, and Ipsen; and has received research funding from Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, and Astellas Pharma. EVC has provided consulting or advisory services for Bayer, Lilly, Roche, Servier, Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, and Incyte, and has received research funding from Amgen, Bayer, Boehringer Ingelheim, Lilly, Novartis, Roche, Celgene, Ipsen, Merck, Merck KGaA, Servier, and Bristol Myers Squibb. GG is an employee of Novartis, owns stock in Novartis, and receives travel or accommodation expenses from Novartis. AB is an employee of Novartis, owns stock in Novartis, and receives travel or accommodation expenses from Novartis. MFM is an employee of Novartis and owns stock in Novartis. AD is an employee of Novartis and owns stock in Novartis. SM is an employee of Novartis and owns stock in Novartis. EPK has an employment interest in Cyclotron Rotterdam BV; has stock or other ownership interest in AstraZeneca, GlaxoSmithKline, Merck and Roche; has patent or intellectual property interest in Advanced Accelerator Applications; and receives travel or accommodation expenses from Advanced Accelerator Applications. ES and HD declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim of Study: The conclusions on the association between the rs2736100 polymorphisms of telomerase reverse transcriptase (TERT) gene polymorphism and digestive cancers risk are still debated. This meta-analysis was conducted to update the association between the TERT rs2736100 polymorphisms and the risk of digestive cancers., Materials and Methods: The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using the meta-analysis method., Results: Eight case-control studies were included in this meta-analysis for associating TERT rs2736100 gene polymorphism and digestive cancer susceptibility. Pooled odds ratio with 95% confidence interval was calculated using a fixed or random-effects model. Overall, no evidence has shown that the TERT rs2736100 polymorphism was associated with the susceptibility to digestive cancers. Besides, stratified analysis with ethnicity also indicated no significant association between TRET rs2736100 and the risk of digestive cancers under all genetic models in both Asian and Caucasian populations were observed., Conclusion: According to the meta-analysis, TERT rs2736100 polymorphism might be unrelated to digestive cancer susceptibility. Evidence with adequate sample size is still needed., Competing Interests: None

Background and Aim: Cost-effectiveness comparison between endoscopic ultrasound (EUS)-guided acquisition techniques by fine-needle aspiration (FNA) and fine needle biopsy (FNB) in gastrointestinal lesions is still scarce. EUS-FNB has been shown to be more cost-effective than EUS-FNA, however, when adding rapid on-site evaluation (ROSE) to EUS-FNA, it is unclear whether EUS-FNB remains more cost-effective. Our aim was to assess cost-efficacy of EUS-FNB as compared to EUS-FNA with ROSE in gastrointestinal lesions., Method: All patients who underwent EUS-FNA with ROSE or EUS-FNB at Galilee Medical Center were retrospectively reviewed. Cost-effectiveness analysis was based on the additional EUS sessions needed and on the average cost expenditure to achieve one final pathological diagnosis., Results: Seventy-four cases were included in the final analysis. Of them, 21 patients (28.4%) were in the EUS-FNB group (group A), as compared to 53 patients (71.6%) who underwent EUS-FNA with ROSE (group B). Additional EUS sessions needed to achieve one final pathological diagnosis were needed in 14.3% of group A patients vs 9.4% in group B patients (P = .5). and, the average cost for achieving one final pathological diagnosis was similar in both groups (1226 ± 369$ for group A vs 1158 ± 309.6.7$ for group B, P = .2). Notably, even after analyzing pancreatic and non-pancreatic gastrointestinal lesions separately, there was no cost benefit of EUS-FNB over EUS-FNA with ROSE., Conclusions: Cost-effectiveness analysis was not different between EUS-FNB vs EUS-FNA with ROSE. Thus, the preference of one modality over the other should be based on availability and local expertise., (© 2021 Wiley Periodicals LLC.)

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Human leukocyte antigen-G (HLA-G) conveys immunological tolerance at the maternal-foetal interface. HLA-G expression by tumour cells may also play such a role, resulting in tumour immune evasion, making HLA-G a potential target for immunotherapies. The aim of this review was to determine to what extent it is justified that HLA-G expression is considered as a target for immune checkpoint inhibiting therapy by critically assessing the association between HLA-G expression by carcinomas and clinical outcome of patients. The used HLA-G-detecting mAb, HLA-G quantification methods and statistically significant HLA-G-associated clinicopathological parameters are discussed. Tumour HLA-G expression correlated with poor clinical outcome in breast, esophageal, gastric and hepatocellular carcinoma patients. Tumour HLA-G expression was not associated with clinical outcome in ovarian and oral carcinoma patients. Cervical, colorectal, lung, and pancreatic carcinoma patients presented discrepant and therefore inconclusive results regarding the association between tumour HLA-G expression and clinical outcome. These disparities might partly be the result of differences in the methodological approach to quantify HLA-G expression between studies. Therefore, implementation of universal methodological procedures is strongly advised. Overall, HLA-G expression did not univocally result in poor clinical outcome of carcinoma patients. This implies that tumour HLA-G expression is not necessarily part of an inhibited tumour-immune response and tumour progression. Consequently, it remains elusive whether HLA-G expression by carcinomas functions as an immune checkpoint molecule affecting a tumour-immune response. It may also reflect derailed control of gene expression in tumours, with no real functional consequences.

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases ( n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the Idylla TM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.

Objective: Owing to its rarity and heterogeneity, the biological behavior and optimal therapeutic management of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) have not been established. Herein, we aimed to evaluate the clinicopathological characteristics and metastatic patterns of MiNEN., Methods: Continuous clinicopathological data of MiNEN patients treated at our hospital were retrospectively collected and analyzed., Results: This study had enrolled 169 patients since January 2010 to January 2020. Pathological components were assessed in 129 patients with MiNEN (76.3%), and a focal (non-)neuroendocrine component was observed in 40 patients (23.7%; <30% of the tumor). Among the enrolled patients, 80 underwent surgical removal of the primary tumor and lymph nodes (LNs), and 34 with distant metastasis underwent biopsy of both primary tumor and metastatic lesions. In patients with LN metastasis, 68.8% (55/80) exhibited a pure component of either neuroendocrine (NE) or adenocarcinoma/squamous carcinoma (AS) in metastatic LNs, while 20% (16/80) showed different components in different LNs, and only 11.2% (9/80) exhibited both NE and AS components in the same LN. In patients with distant metastases, 26.5% (9/34) possessed coexisting NE and AS components in the distant metastases, 70.6% (24/34) were regarded as a pure NE component, and 2.9% (1/34) were comprised of a pure AS component., Conclusion: Lymph node and distant metastases exhibited distinct metastatic patterns in patients with MiNEN. The major pathological component in regional LNs may have influenced the proportion of the two components within the primary tumor, but distant metastases were dominated by the NE component., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m 2 /dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m 2 , and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

Background: Digestive tumor is one of the most common cancers, its symptoms and treatment will bring patients with anxiety, depression and other negative emotions, and cause cancer-related fatigue. As a new complementary replacement therapy, music therapy can greatly reduce cancer-related fatigue, anxiety and depression, and achieve good clinical results, but there is a lack of evidence-based medicine. The purpose of this study is to evaluate the effect of music therapy on cancer-related fatigue, anxiety, and depression in patients with digestive tumors by meta-analysis., Method: Computer search of Chinese and English databases: Wanfang, VP Information Chinese Journal Service Platform, China National Knowledge Infrastructure, Chinese BioMedicine Literature Database and pubmed, embase, cochrane, web of science. A comprehensive collection of relevant studies on the effects of music therapy on digestive tract cancer-related fatigue, anxiety and depression, the retrieval time is from the date of establishment to March 2021. According to the inclusion and exclusion criteria, the literature is selected, the quality of the literature is evaluated and the data are extracted. The data are analyzed by meta-analysis., Result: The purpose of this study is to evaluate the effect of music therapy on digestive tract cancer-related fatigue, anxiety, and depression by European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire, Hamilton Depression Scale, and Hamilton Anxiety Scale ., Conclusion: This study will provide reliable evidence-based evidence for the clinical application of music therapy in the treatment of digestive tract cancer-related fatigue and anxiety and depression., Osf Registration Number: DOI 10.17605/OSF.IO/UR4GV., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Context.—: The 5th edition of the World Health Organization classification of digestive system tumors discusses several advancements and developments in understanding the etiology, pathogenesis, and diagnosis of several digestive tract tumors., Objective.—: To provide a summary of the updates with a focus on neuroendocrine neoplasms, appendiceal tumors, and the molecular advances in tumors of the digestive system., Data Sources.—: English literature and personal experiences., Conclusions.—: Some of the particularly important updates in the 5th edition are the alterations made in the classification of neuroendocrine neoplasms, understanding of pathogenesis of appendiceal tumors and their precursor lesions, and the expanded role of molecular pathology in establishing an accurate diagnosis or predicting prognosis and response to treatment.

Tissue biopsies are the gold-standard for investigating the molecular characterization of tumors. However, a "solid" biopsy is an invasive procedure that cannot capture real-time tumor dynamics and may yield inaccurate information because of intratumoral heterogeneity. In this review, we summarize the current state of knowledge about surgical treatment-associated "liquid" biopsy for patients with digestive organ tumors. A liquid biopsy is a technique involving the sampling and testing of non-solid biological materials, including blood, urine, saliva, and ascites. Previous studies have reported the potential value of blood-based biomarkers, circulating tumor cells, and cell-free nucleic acids as facilitators of cancer treatment. The applications of a liquid biopsy in a cancer treatment setting include screening and early diagnosis, prognostication, and outcome and recurrence monitoring of cancer. This technique has also been suggested as a useful tool in personalized medicine. The transition to precision medicine is still in its early stages. Soon, however, liquid biopsy is likely to form the basis of patient selection for molecular targeted therapies, predictions regarding chemotherapy sensitivity, and real-time evaluations of therapeutic effects.

Context.—: The World Health Organization Classification of Tumours: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition., Objective.—: To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities., Data Sources.—: The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition., Conclusions.—: The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary., (© 2021 College of American Pathologists.)

Context.—: Epstein-Barr virus is a ubiquitous oncogenic virus. During the past 5 decades, the virus has been linked to several disease entities, both neoplastic and nonneoplastic. Several Epstein-Barr virus-associated conditions affect the digestive organs, ranging from mild transient inflammatory conditions to more debilitating and even fatal diseases., Objective.—: To discuss the clinicopathologic aspects of some newly or recently recognized Epstein-Barr virus-related conditions encountered in the digestive system and their therapeutic implications., Data Sources.—: Published peer-reviewed literature was reviewed., Conclusions.—: This article highlights the importance of recognizing the discussed lesions because they influence the direct clinical management or serve as a potential predictive marker for therapy., (© 2021 College of American Pathologists.)

During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals., 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 Albertelli, Grillo, Lo Calzo, Puliani, Rainone, Colao, Faggiano and NIKE group.)

Background: The impact of the stage of cancer on perioperative mortality remains obscure. The purpose of this study was to investigate whether cancer stage influences 30-d mortality for gastric, pancreatic, and colorectal cancers., Methods: Data were collected from the National Cancer Database for patients undergoing resections for cancers of the stomach, pancreas, colon, or rectum between 2004 and 2015. The main analysis was conducted among patients with cancer stages 1-3. A sensitivity analysis also included cancer stage 4. Descriptive statistics were used to compare the patients' baseline characteristics. Generalized linear mixed models were used to evaluate the relationship between stage and 30-d mortality, controlling for other disease-, patient- and hospital-level factors. Pseudo R2 statistics (%Δ pseudo R 2 ) were used to quantify the relative explanatory capacity of the variables to the model for 30-d mortality. All analyses were performed using SAS 9.4., Results: The cohort included 24,468, 28,078, 176,285, and 64,947 patients with stomach, pancreas, colon, and rectal cancers, respectively. After adjusting for other variables, 30-d mortality was different by stage for all cancer types examined. The factor most strongly associated with 30-d mortality was age (%Δ pseudo R 2 range 14%-39%). The prognostic impact of cancer stage (Stages 1, 2, or 3) on 30-d mortality was comparable to that of the Charlson comorbidity index., Conclusions: Cancer stage contributes to explaining differences observed in short-term mortality for gastrointestinal cancers. Short-term mortality models would benefit by including more granular cancer stage, beyond disseminated status alone., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. Dr. Ferris has the following financial disclosures: Aduro Biotech, Inc (consulting); Astra-Zeneca/MedImmune (clinical trial, research funding); Bristol-Myers Squibb (advisory board, clinical trial, research funding); EMD Serono (advisory board); MacroGenics, Inc (advisory board); Merck (advisory board, clinical trial); Novasenta (consulting, stock, research funding); Numab Therapeutics AG (advisory board); Pfizer (advisory board); Sanofi (consultant); Tesaro (research funding) and Zymeworks, Inc (consultant). All other authors have no conflicts to disclose.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare neoplasm. Immunohistochemically, GNET typically demonstrates neural differentiation but lacks melanocytic differentiation, making it distinct from clear cell sarcoma of the soft tissues (CCS). Herein we report for the first time the cytomorphologic features of lymph node metastasis from presumably liver GNET. A 36-year-old female presented with fevers, night sweats, loss of appetite, and a 20-lbs weight loss. Radiographic imaging showed a 13 cm heterogeneously enhancing mass in the right lobe of the liver and a hypermetabolic 0.9 cm periportal lymph node on positron emission tomography-computed tomography (PET/CT). Initially, a CT-guided liver biopsy was performed followed by right hepatic lobectomy and portal lymphadenectomy. The liver biopsy and resection showed an S100-protein and SOX10 positive malignant neoplasm and genomic profiling of liver biopsy revealed EWSR1-CREB1gene rearrangement. These findings in conjunction with the morphologic and immunohistochemical profile were diagnostic of GNET. Two months later, she presented with recurrent lymphadenopathy in the upper abdomen. Fine needle aspiration of the periportal nodal mass revealed single and clusters of primitive, large to medium-sized neoplastic cells with round to oval nuclei, high nuclear-cytoplasmic ratio, vesicular chromatin, and prominent nucleoli. The tumor cells were S100 protein and SOX10 positive, consistent with metastasis of the patient's recently diagnosed malignant digestive system GNET. Palliative chemotherapy was administered but the patient died a few days later, 4 months from the initial diagnosis. Awareness of this entity and judicial use of ancillary studies including molecular testing are essential for achieving accurate diagnosis., (© 2020 Wiley Periodicals LLC.)

The SARS-CoV-2 (COVID-19) pandemic requires an analysis in the field of oncological surgery, both on the risk of infection, with very relevant clinical consequences, and on the need to generate plans to minimize the impact on possible restrictions on health resources. The AEC is making a proposal for the management of patients with hepatopancreatobiliary (HPB) malignancies in the different pandemic scenarios in order to offer the maximum benefit to patients, minimising the risks of COVID-19 infection, and optimising the healthcare resources available at any time. This requires the coordination of the different treatment options between the departments involved in the management of these patients: medical oncology, radiotherapy oncology, surgery, anaesthesia, radiology, endoscopy department and intensive care. The goal is offer effective treatments, adapted to the available resources, without compromising patients and healthcare professionals safety., (Copyright © 2020 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.)

A circRNA is a type of endogenous noncoding RNA that consists of a closed circular RNA molecule formed by reverse splicing; these RNAs are widely distributed in a variety of biological cells. In contrast to linear RNAs, circRNAs have no 5' cap or 3' poly(A) tail. They have a stable structure, a high degree of conservation, and high stability, and they are richly and specifically expressed in certain tissues and developmental stages. CircRNAs play a very important role in the occurrence and progression of malignant tumors. According to their origins, circRNAs can be divided into four types: exon-derived circRNAs (ecRNAs), intron-derived circRNAs (ciRNAs), circRNAs containing both exons and introns (EIciRNAs) and intergenic circRNAs. A large number of studies have shown that circRNAs have a variety of biological functions, participate in the regulation of gene expression and play an important role in the occurrence and progression of tumors. In this paper, the structure and function of circRNAs are reviewed, along with their biological role in malignant tumors of the digestive tract, in order to provide a reference for the diagnosis and treatment of digestive system neoplasms.

Aim: This study aimed to evaluate the clinical values of platelet parameters in patients with digestive tumors. Patients & methods: A total of 974 people were classified into three groups: malignant group, patients with digestive malignant tumors; benign group, patients with benign tumors; and normal group: healthy individuals. Results: Compared with the benign and normal groups, the malignant group showed significantly increased platelet count (PLT) and plateletcrit (PCT) and significantly reduced mean platelet volume (MPV) and platelet-large cell rate (P-LCR, p < 0.001). Elevated PLT and PCT and reduced MPV and P-LCR indicated poor overall survival in patients with digestive tumors. Conclusion: PLT, PCT, MPV and P-LCR were proven to be predictive biomarkers for patients with digestive malignant tumors. Elevated PLT and PCT or decreased MPV and P-LCR indicated poor overall survival.

Cancers evolve as a result of the accelerated proliferation of cancer cells in a complicated, enriched, and active microenvironment. Tumor microenvironment (TME) components are the master regulators of any step of cancer development. The tumor microenvironment is composed of many cellular and noncellular components that contribute to the evolution of cancer cells. Cancer-associated fibroblasts (CAFs) are activated fibroblasts in the TME that implicate in tumor progression and metastasis dissemination through secretion of oncogenic factors which are carried to the secondary metastatic sites through exosomes. In this review, we aimed to assess the role of CAF-derived exosomes in TME construction and pre-metastatic niche formation in different cancers of the digestive system in order to better understand some important mechanisms of metastasis and provide possible targets for clinical intervention. This review article is divided into two thematic parts explaining the general mechanisms of pre-metastatic niche formation and metastasis and the role of CAF-derived exosomes in different digestive system cancers including colorectal, gastric, esophageal, pancreatic, and liver cancers.

High-throughput sequencing analysis represented both a medical diagnosis and technological revolution. Gene panel analysis is now routinely performed in the exploration of hereditary predisposition to cancer, which is becoming increasingly heterogeneous, both clinically and molecularly. We present 1530 patients with suspicion of hereditary predisposition to cancer, for which two types of analyses were performed: a) oriented according to the clinical presentation (n = 417), or b) extended to genes involved in hereditary predisposition to adult cancer (n = 1113). Extended panel analysis had a higher detection rate compared to oriented analysis in hereditary predisposition to breast / ovarian cancer (P < .001) and in digestive cancers (P < .094) (respectively 15% vs 5% and 19.3%, vs 12.5%). This higher detection is explained by the inclusion of moderate penetrance genes, as well as the identification of incident mutations and double mutations. Our study underscores the utility of proposing extended gene panel analysis to patients with suspicion of hereditary predisposition to adult cancer., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Molecular predictive biomarkers represent an essential tool for the future of personalized oncotherapy. Gastro- entero-pancreatic neuroendocrine neoplasms are a heterogeneous group of epithelial tumors with a steady increase in incidence and prevalence. Their effective management depends on early diagnosis, personalized risk stratification, and monitoring response to therapy. A crucial element is identifying accurate biomarkers to predict/monitor therapeutic responses, assess drug resistance, and quantify residual disease in a reproducible and less invasive way. Taking into consideration their role in cell differentiation, cell proliferation, apoptosis and tumor development, microRNAs have gained interest as potential prognostic markers and treatment response predictors in neuroendocrine neoplasms. This review is the first to summarize the available data on the possible role of microRNAs in evaluating the efficacy of somatostatin analogs treatment in gastro- entero-pancreatic neuroendocrine neoplasms. Although the literature is scarce, the let-7 family targeting phosphoinositide 3 kinase - protein kinase B 1 - mammalian target of rapamycin signaling pathway might represent a promising biomarker with potential clinical benefit, but further research is required before their eventual clinical application. Furthermore, the ambiguous molecular mechanisms of neuroendocrine proliferation and the undefined signaling pathway of somatostatin analogs should encourage future research in this field that may lead to a different clinical approach to neuroendocrine disease.

MicroRNAs (miRNAs) are a group of highly conserved, short (18-25 nucleotide long) non-coding RNAs which play important functional roles in cellular differentiation, biological development, pathogenesis and disease susceptibility and have been linked to both tumorigenesis and the malignant progression of various cancers. miRNAs primarily exert their function through the negative regulation of their target gene's transcription via the specific recognition of their 3' untranslated region. A single miRNA can regulate multiple target genes and most miRNAs are controlled by several factors. Recent studies have shown that microRNA-149 (miR-149) plays a pivotal role in the pathogenesis of digestive system cancers and may act as a potential diagnostic marker and therapeutic target. In this review, we summarize and discuss the most recent reports describing miR-149 in digestive system cancers, including its single nucleotide polymorphisms, expression levels, target genes, drug sensitivity and clinical significance., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Digestive system cancers are the most frequent cancers worldwide and often associated with poor prognosis because of their invasive and metastatic characteristics. Recent studies have found that the plasticity of cancer cells can impart cancer stem-like properties via the epithelial-mesenchymal transition (EMT). Cancer stem-like properties such as tumor initiation are integral to the formation of metastasis, which is the main cause of poor prognosis. Numerous markers of cancer stem cells (CSCs) have been identified in many types of cancer. Therefore, CSCs, via their stem cell-like functions, may play an important role in prognosis after surgery. While several reports have described prognostic analysis using CSC markers, few reviews have summarized CSCs and their association with prognosis. Herein, we review the prognostic potential of eight CSC markers, CD133, CD44, CD90, ALDH1A1, EPCAM, SOX2, SOX9, and LGR5, in digestive cancers including those of the pancreas, colon, liver, gastric, and esophagus.

Mixed neuroendocrine - nonneuroendocrine neoplasms (MiNENs) of the digestive system represent a challenge for both pathologists and clinicians. Their nomenclature has changed several times, and their diagnostic criteria, classification and clinical behaviour have been matter of debate over the years. Although several attempts have been made to elucidate the pathogenesis and biology of MiNENs, some issues remain open. This review will provide: a historical background that helps in understanding the evolution of the concept and nomenclature of mixed neoplasms; a revision of the knowledge on this topic, including molecular aspects, to give the reader a comprehensive and practical overview on this challenging field of pathology; a focus on the diagnostic criteria and on the determination of prognostic and predictive factors; and a description of the different tumour types in the different sites of origin., (© 2020 John Wiley & Sons Ltd.)