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Objective: In this study we aimed to comprehensively evaluate the clinical features and treatment outcomes of Chinese patients with autoimmune pancreatitis (AIP) through a single-center real-world study., Methods: Patients diagnosed with AIP in Changhai Hospital, Naval Medical University from January 2014 to December 2021 were included. Baseline characteristics, laboratory test results, cross-sectional imaging and endoscopic ultrasound (EUS) findings, and long-term follow-up data were obtained. The differences in these characteristics between type 1 and type 2 AIP patients were analyzed., Results: Among all 320 patients, 271 (84.7%) and 49 (15.3%) had type 1 and type 2 AIP, respectively. The most common initial symptom was abdominal discomfort (58.1%), followed by obstructive jaundice (32.5%). Extrapancreatic organ involvement was identified in 126 (39.4%) patients, with the biliary system being the most commonly involved (36.6%). Elevated serum IgG4 level was rare in type 2 AIP patients. The diagnostic accuracy of computed tomography (CT), magnetic resonance imaging (MRI), and EUS for definitive and probable AIP were 78.0%, 68.7%, and 80.5%, respectively. EUS-guided tissue acquisition with immunohistochemical staining helped establish a final diagnosis in 39.7% of patients. During the follow-up period of 60 months, 18.6% of patients experienced relapse. The 1-, 3-, and 5-year relapse rates were higher in type 1 AIP patients, with an accumulated rate of 8.0%, 12.6%, and 15.1%, when compared with those with type 2 AIP., Conclusions: Type 2 AIP is not uncommon in Chinese population. The diagnostic accuracy of CT and EUS for AIP might be superior to that of MRI., (© 2024 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Globally, hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers. Hepatitis B virus (HBV) infection is an important etiology and disease progression factor for HCC. Hepatectomy is a widely accepted curative treatment for HCC, but the long-term survival rate is still unsatisfactory due to the high recurrence rate after resection. Preoperative or postoperative antiviral therapy plays an important role in improving the prognosis for HBV-related HCC patients who underwent hepatectomy. However, many patients miss out on the chance to receive long-term preoperative antiviral medication because their HBV and HCC infections are discovered concurrently, necessitating the start of remedial antiviral therapy in the perioperative phase. Therefore, it is of great value to know when antiviral therapy is more appropriate and whether perioperative rescue antiviral therapy can achieve the effect of preoperative long-term antiviral therapy., Competing Interests: Conflict-of-interest statement: All authors declare that they have no competing interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have greatly improved the survival in several cancers. Immune-related adverse events (irAEs) are common in patients on ICI therapy, as inhibition of cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death protein 1 (PD-1) leads to non-selective activation of the immune system. ICI-induced enterocolitis is highly prevalent and corticosteroid administration is the first-line treatment. Selective immunosuppressive therapy was employed for steroid-refractory patients. The monoclonal antibody vedolizumab exhibits gut-specific immunosuppressive effects by targeting the α4β7 integrin., Case Description: We report a case of corticosteroid-dependent camrelizumab-induced enterocolitis in a 58-year-old man with hepatocellular carcinoma (HCC) who was treated with vedolizumab. The patient's diarrhea resolved following the administration of two doses of vedolizumab (300 mg), and he was able to stop using corticosteroids. He later underwent surgery and HCC treatment, including appropriate management of ICI-induced enterocolitis, and achieved a complete pathological response., Conclusions: This report illustrates the valuable role of vedolizumab in treating ICI-induced enterocolitis that is refractory to corticosteroid treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-222/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses., 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 B.V. All rights reserved.)

Genetic variants in Epstein-Barr virus (EBV) have been strongly associated with nasopharyngeal carcinoma (NPC) in South China. However, different results regarding the most significant viral variants, with polymorphisms in EBER2 and BALF2 loci, have been reported in separate studies. In this study, we newly sequenced 100 EBV genomes derived from 61 NPC cases and 39 population controls. Comprehensive genomic analyses of EBV sequences from both NPC patients and healthy carriers in South China were conducted, totaling 279 cases and 227 controls. Meta-analysis of genome-wide association study revealed a 4-bp deletion downstream of EBER2 (coordinates, 7188-7191; EBER-del) as the most significant variant associated with NPC. Furthermore, multiple viral variants were found to be genetically linked to EBER-del forming a risk haplotype, suggesting that multiple viral variants might be associated with NPC pathogenesis. Population structure and phylogenetic analyses further characterized a high risk EBV lineage for NPC revealing a panel of 38 single nucleotide polymorphisms (SNPs), including those in the EBER2 and BALF2 loci. With linkage disequilibrium clumping and feature selection algorithm, the 38 SNPs could be narrowed down to 9 SNPs which can be used to accurately detect the high risk EBV lineage. In summary, our study provides novel insight into the role of EBV genetic variation in NPC pathogenesis by defining a risk haplotype of EBV for downstream functional studies and identifying a single high risk EBV lineage characterized by 9 SNPs for potential application in population screening of NPC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wong 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.)

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV + NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30-150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell-cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease.

Introduction: The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive., Objectives: To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T-cells and response to chemotherapy., Methods: In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T-cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T-cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment., Results: NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8 + effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched., Conclusion: Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T-cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy., 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. Production and hosting by Elsevier B.V.)

Generative pre-trained transformer 4 (GPT-4) is an artificial intelligence (AI) system with a chat interface. The number of studies testing GPT-4 in clinical applications has been increasing. We hypothesized that GPT-4 would be able to suggest management strategies for medical issues in elderly oncology patients, similar to those provided by geriatricians. We compared the responses of GPT-4 to those of a geriatrician for four oncological patients. After these case conferences, none of the patients required admission for medical consultation. In three out of four scenarios, GPT-4 was able to offer a multidisciplinary approach in the first prompt. In all three scenarios, GPT-4 identified medication-related side effects and suggested appropriate medications in the first prompt. However, GPT-4 was unable to suggest initial dosages of medications to be used in the first prompt and was unable to suggest a more humanistic and non-pharmacological approach to anorexia, even with a follow-up prompt. In conclusion, GPT-4 may be used as a screening tool to provide potential rudimentary directions for management, which can then be reviewed by medical professionals before considering a formal consultation for more tailored and refined opinions from specialists., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Purpose: Extranodal extension (ENE) has the potential to add value to the current nodal staging system (N 8th ) for predicting outcome in nasopharyngeal carcinoma (NPC). This study aimed to incorporate ENE, as well as cervical nodal necrosis (CNN) to the current stage N3 and evaluated their impact on outcome prediction. The findings were validated on an external cohort., Methods & Materials: Pre-treatment MRI of 750 patients from the internal cohort were retrospectively reviewed. Predictive values of six modified nodal staging systems that incorporated four patterns of ENE and two patterns of CNN to the current stage N3 for disease-free survival (DFS) were compared with that of N 8th using multivariate cox-regression and concordance statistics in the internal cohort. Performance of stage N3 for predicting disease recurrence was calculated. An external cohort of 179 patients was used to validate the findings., Results: Incorporation of advanced ENE, which infiltrates into adjacent muscle/skin/salivary glands outperformed the other five modifications for predicting outcomes (p < 0.01) and achieved a significantly higher c-index for 5-year DFS (0.69 vs 0.72) (p < 0.01) when compared with that of N 8th staging system. By adding advanced ENE to the current N3 increased the sensitivity for predicting disease recurrence from 22.4 % to 47.1 %. The finding was validated in the external cohort (5-year DFS 0.65 vs. 0.72, p < 0.01; sensitivity of stage N3 increased from 14.0 % to 41.9 % for disease recurrence)., Conclusion: Results from two centre cohorts confirmed that the radiological advanced ENE should be considered as a criterion for stage N3 disease in NPC., 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 © 2023 Elsevier B.V. All rights reserved.)

We investigated the clinical significance of CTCs in cancer progression by detecting multiple cancer driver genes associated with epithelial-to-mesenchymal transition (EMT) at the transcript level. The 10-gene panel, comprising CCND1 , ECT2 , EpCAM , FSCN1 , KRT5 , KRT18 , MET , TFRC , TWIST1 , and VEGFC , was established for characterizing CTCs from mouse ESCC xenograft models and clinical ESCC peripheral blood (PB) samples. Correlations between gene expression in CTCs from PB samples ( n = 77) and clinicopathological features in ESCC patients ( n = 55) were examined. The presence of CTCs at baseline was significantly correlated with tumor size ( p = 0.031). The CTC-high patients were significantly correlated with advanced cancer stages ( p = 0.013) and distant metastasis ( p = 0.029). High mRNA levels of TWIST1 (Hazard Ratio (HR) = 5.44, p = 0.007), VEGFC (HR = 6.67, p < 0.001), TFRC (HR = 2.63, p = 0.034), and EpCAM (HR = 2.53, p = 0.041) at baseline were significantly associated with a shorter overall survival (OS) in ESCC patients. This study also revealed that TWIST1 facilitates EMT and enhances malignant potential by promoting tumor migration, invasion, and cisplatin chemoresistance through the TWIST1-TGFBI-ZEB1 axis in ESCC, highlighting the prognostic and therapeutic potential of TWIST1 in clinical ESCC treatment.

Most mature B cells can be divided into four subtypes based on the expression of the surface markers IgD and CD27: IgD + CD27 - naïve B cells, IgD + CD27 + unswitched memory B cells, IgD - CD27 + switched memory B cells, and IgD - CD27 - double-negative (DN) B cells. Despite their small population size in normal peripheral blood, DN B cells play integral roles in various diseases. For example, they generate autoimmunity in autoimmune conditions, while these cells may generate both autoimmune and antipathogenic responses in COVID-19, or act in a purely antipathogenic capacity in malaria. Recently, DN B cells have been identified in nasopharyngeal carcinoma and non-small-cell lung cancers, where they may play an immunosuppressive role. The distinct functions that DN B cells play in different diseases suggest that they are a heterogeneous B-cell population. Therefore, further study of the mechanisms underlying the involvement of DN B cells in these diseases is essential for understanding their pathogenesis and the development of therapeutic strategies. Further research is thus warranted to characterize the DN B-cell population in detail., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma., (© 2023. The Author(s).)

Bigelovin (BigV), as traditional Chinese medicine, has been shown to inhibit the malignant progression of hepatocellular carcinoma (HCC). This study aimed to investigate whether BigV affects the development of HCC by targeting the MAPT and Fas/FasL pathway. Human HCC cell lines HepG2 and SMMC-7721 were used for this study. Cells were treated with BigV, sh-MAPT, and MAPT. The viability, migration, and apoptosis of HCC cells were detected by CCK-8, Transwell, and flow cytometry assays, respectively. Immunofluorescence and immunoprecipitation were used to verify the relationship between MAPT and Fas. Subcutaneous xenograft tumor and tail vein-injected lung metastases mouse models were constructed for histological observation. Hematoxylin-eosin staining was used to assess lung metastases in HCC. Western blotting was used to measure the expression of migration, apoptosis, and epithelial-mesenchymal transition (EMT) marker proteins, as well as Fas/FasL pathway-related proteins. BigV treatment inhibited the proliferation, migration, and EMT of HCC cells, whereas enhanced cell apoptosis. Moreover, BigV downregulated MAPT expression. The negative effects of sh-MAPT on HCC cell proliferation, migration, and EMT were enhanced by BigV treatment. Conversely, BigV addition attenuated the positive effects of MAPT overexpression on the malignant progression of HCC. In vivo experiments showed that BigV and/or sh-MAPT reduced tumor growth and lung metastasis while promoting tumor cell apoptosis. Furthermore, MAPT could act with Fas and inhibit its expression. sh-MAPT upregulated the expression of Fas/FasL pathway-associated proteins, which were enhanced by BigV administration. BigV suppressed the malignant progression of HCC via activating the MAPT-mediated Fas/FasL pathway.

Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3 + T, B cells, and immunosuppressive cells such as APOC1 + APOE + macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor-prognostic epithelial-immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74 + CXCR4 + and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1 + APOE + macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph-node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhang 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.)

The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment., Competing Interests: Declaration of interests VH-FL reports personal fees and grants from AstraZeneca; and personal fees from AQUILAB, Amgen, Boston Scientific, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, and Takeda, all outside this Policy Review. GFH reports fees paid to the institution from Eli Lilly, Regeneron, Merck Sharp and Dohme, AB Science, Astellas, Tessa Therapeutics, Roche, Arcus Bioscience, AstraZeneca, and Pfizer; and personal fees from Merck Sharp and Dohme, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Pfizer, Ipsen, Bristol Myers Squibb, Janssen, and Taiho, all outside the scope of this Policy Review. WKJL is a shareholder of Illumina/GRAIL. Q-TL reports personal fees from the RTOG Foundation and NRG Oncology, outside the scope of this Policy Review, and is supported by the US National Institutes of Health (2U10CA180868-06, 1R01DE029672-01A1, P30CA124435, and R01DE030894-01A1). NYL is supported by the US National Institutes of Health (R01 CA238392-02A1 and 5UG1CA233290-02). DW-TL reports institutional fees from Bristol Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, Janssen, and Novartis, outside the scope of this Policy Review. RM reports personal fees from Merck Pharmaceuticals, Merck Sharp and Dohme, Bristol Myers Squibb, Roche, Amgen, AstraZeneca, Nanobiotix, Seattle Genetics, and Boehringer Ingelheim, all outside the scope of this Policy Review. RK-CN reports personal fees from Pfizer, Novartis, Sanofi, AstraZeneca, Eli Lilly, Merck Sharp and Dohme, Zai Lab, Roche, Eisai, Merck Pharmaceutical, Astellas, and Nuance (China), outside the scope of this Policy Review. RK-YT is the President of Hong Kong Society of Otolaryngology, Head and Neck Surgery, and past President of Hong Kong Head and Neck Society. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

(1) Background: SMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare sinonasal malignancy; since its discovery and description in 2014, less than 200 cases have been identified. It is almost impossible to perform randomized-controlled trials on novel therapy to improve treatment outcomes in view of its rarity. We performed a systematic review of all the published case reports/series and included our patients for survival analysis. (2) Methods: In this systematic review, we searched from PubMed-MEDLINE, EMBASE, Scopus, Cochrane Library, CINAHL, and Google Scholar for individual patient data to identify and retrieve all reported SMARCB1-deficient sinonasal carcinoma. Clarification on treatment details and the most updated survival outcomes from all authors of the published case reports/series were attempted. Survival analysis for overall survival (OS) and identification of OS prognostic factors were performed. This systematic review was registered with PROSPERO (CRD42022306671). (3) Results: A total of 67 publications were identified from the systematic review and literature search. After excluding other ineligible and duplicated publications, 192 patients reported were considered appropriate for further review. After excluding duplicates and patients with incomplete pretreatment details and survival outcomes, 120 patients were identified to have a complete set of data including baseline demographics, treatment details, and survival outcomes. Together with 8 patients treated in our institution, 128 patients were included into survival analysis. After a median follow up of 17.5 months (range 0.3-149.0), 50 (46.3%) patients died. The 1-year, 2-year and 3-year OS rates were 84.3% (95% CI % 77.6-91.0), 62.9% (95% CI 53.1-72.7), and 51.8% (95% CI 40.8-62.8), respectively, and the median OS was 39.0 months (95% CI 28.5-49.5). Males ( p = 0.029) and T4b disease ( p = 0.013) were significant OS prognostic factors in univariable analysis, while only T4b disease ( p = 0.017) remained significant in multivariable analysis. (4) Conclusions: SMARCB1-deficient sinonasal carcinoma is an extremely aggressive sinonasal malignancy with a dismal prognosis. Early diagnosis and a multimodality treatment strategy are essential for a better treatment and survival outcome.

Cancer stem cells (CSCs) are responsible for tumorigenesis, therapeutic resistance, and metastasis in hepatocellular cancer (HCC). Cancer/testis antigen Maelstrom (MAEL) is implicated in the formation of CSC phenotypes, while the exact role and underlying mechanism remain unclear. Here, we found the upregulation of MAEL in HCC, with its expression negatively correlated with survival outcome. Functionally, MAEL promoted tumor cell aggressiveness, tumor stem-like potentials, and resistance to sorafenib in HCC cell lines. Transcriptional profiling indicated the dysregulation of stemness in MAEL knockout cells and identified PTGS2 as a critical downstream target transactivated by MAEL. The suppression effect of MAEL knockout in tumor aggressiveness was rescued in PTGS2 overexpression HCC cells. A molecular mechanism study revealed that the upregulation of PTGS2 by MAEL subsequently resulted in IL-8 secretion and the activation of AKT/NF-κB/STAT3 signaling. Collectively, our work identifies MAEL as an important stemness regulation gene in HCC. Targeting MAEL or its downstream molecules may provide a novel possibility for the elimination of CSC to enhance therapeutic efficacy for HCC patients in the future.

Background: Previous in vitro hepatocyte differentiation model showed that TROY was specifically expressed in liver progenitor cells and a small proportion of hepatocellular carcinoma cells, suggesting that TROY may participate in hepatocellular carcinoma (HCC) stemness regulation. Here, we aim to investigate the role and mechanism of TROY in HCC pathogenesis., Method: Bioinformatics analysis of the TCGA dataset has been used to identify the function and mechanism of TROY. Spheroid, apoptosis, and ALDH assay were performed to evaluate the stemness functions. Validation of the downstream pathway was based on Western blot, co-immunoprecipitation, and double immunofluorescence., Results: HCC tissue microarray study found that a high frequency of TROY-positive cells was detected in 53/130 (40.8%) of HCC cases, which was significantly associated with poor prognosis and tumor metastasis. Functional studies revealed that TROY could promote self-renewal, drug resistance, tumorigenicity, and metastasis of HCC cells. Mechanism study found that TROY could interact with PI3K subunit p85α, inducing its polyubiquitylation and degradation. The degradation of p85α subsequently activate PI3K/AKT/TBX3 signaling and upregulated pluripotent genes expression including SOX2, NANOG, and OCT4, and promoted EMT in HCC cells. Interestingly, immune cell infiltration analysis found that upregulation of TROY in HCC tissues was induced by TGF-β1 secreted from CAFs. PI3K inhibitor wortmannin could effectively impair tumor stemness to sorafenib., Conclusion: We demonstrated that TROY is an HCC CSC marker and plays an important role in HCC stemness regulation. Targeting TROY-positive CSCs with PI3K inhibitor wortmannin combined with chemo- or targeted drugs might be a novel therapeutic strategy for HCC patients., (© 2022. The Author(s).)

Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells., (© 2021. The Author(s).)

(1) Background: NPC patients with de novo distant metastasis appears to be a heterogeneous group who demonstrate a wide range of survival, as suggested by growing evidence. Nevertheless, the current 8th edition of TNM staging (TNM-8) grouping all these patients into the M1 category is not able to identify their survival differences. We sought to identify any anatomic and non-anatomic subgroups in this study. (2) Methods: Sixty-nine patients with treatment-naive de novo M1 NPC (training cohort) were prospectively recruited from 2007 to 2018. We performed univariable and multivariable analyses (UVA and MVA) to explore anatomic distant metastasis factors, which were significantly prognostic of overall survival (OS). Recursive partitioning analysis (RPA) with the incorporation of significant factors from MVA was then performed to derive a new set of RPA stage groups with OS segregation (Set 1 Anatomic-RPA stage groups); another run of MVA was performed with the addition of pre-treatment plasma EBV DNA. A second-round RPA with significant prognostic factors of OS identified in this round of MVA was performed again to derive another set of stage groups (Set 2 Prognostic-RPA stage groups). Both sets were then validated externally with an independent validation cohort of 67 patients with distant relapses of their initially non-metastatic NPC (rM1) after radical treatment. The performance of models in survival segregation was evaluated by the Akaike information criterion (AIC) and concordance index (C-index) under 1000 bootstrapping samples for the validation cohort; (3) Results: The 3-year OS and median follow-up in the training cohort were 36.0% and 17.8 months, respectively. Co-existence of liver-bone metastases was the only significant prognostic factor of OS in the first round UVA and MVA. Set 1 RPA based on anatomic factors that subdivide the M1 category into two groups: M1a (absence of co-existing liver-bone metastases; median OS 28.1 months) and M1b (co-existing liver-bone metastases; median OS 19.2 months, p = 0.023). When pre-treatment plasma EBV DNA was also added, it became the only significant prognostic factor in UVA (p = 0.001) and MVA (p = 0.015), while co-existing liver-bone metastases was only significant in UVA. Set 2 RPA with the incorporation of pre-treatment plasma EBV DNA yielded good segregation (M1a: EBV DNA ≤ 2500 copies/mL and M1b: EBV DNA > 2500 copies/mL; median OS 44.2 and 19.7 months, respectively, p < 0.001). Set 2 Prognostic-RPA groups (AIC: 228.1 [95% CI: 194.8−251.8] is superior to Set 1 Anatomic-RPA groups (AIC: 278.5 [254.6−301.2]) in the OS prediction (p < 0.001). Set 2 RPA groups (C-index 0.59 [95% CI: 0.54−0.67]) also performed better prediction agreement in the validation cohort (vs. Set 1: C-index 0.47 [95% CI: 0.41−0.53]) (p < 0.001); (4) Conclusions: Our Anatomic-RPA stage groups yielded good segregation for de novo M1 NPC, and prognostication was further improved by incorporating plasma EBV DNA. These new RPA stage groups for M1 NPC can be applied to countries/regions regardless of whether reliable and sensitive plasma EBV DNA assays are available or not.

Background: Tuberculosis (TB) reactivation has been increasingly identified following immune checkpoint inhibitor (ICI) therapy for cancer patients. However there has been no report on TB reactivation in the gastrointestinal tract. In the report, we describe a patient who developed TB ileitis after pembrolizumab for her metastatic nasopharyngeal carcinoma (NPC). Rechallenge with pembrolizumab after its temporary interruption together with anti-TB therapy produced continuous tumor response but without further TB reactivation., Case Presentation: A 29-year-old lady with metastatic NPC involving the cervical nodes, lungs and bones started pembrolizumab after failure to multiple lines of chemotherapy. She complained of sudden onset of abdominal pain, vomiting and bloody diarrhea with mucus 21 months after pembrolizumab. Colonoscopy revealed terminal ileitis with multiple caseating granulomas with Langerhan cells. Serum interferon gamma release assay was strongly positive. She was treated with anti-TB medication and was later rechallenged with pembrolizumab for her progressive lung metastases without further TB relapse while her lung metastases were brought under control again., Conclusion: To date, this is the first gastrointestinal TB reactivation after ICI therapy for cancer. Guidelines to screen for TB before initiation of ICIs in endemic areas should be established., (© 2021. The Author(s).)

Background: Cigarette smoking is associated with nasopharyngeal cancer (NPC) risk. Whether quitting reduces the risk is unclear. We investigated the associations of NPC with duration of and age at quitting in an endemic region., Methods: We investigated the associations between NPC and quitting in a multicenter case-control study in Hong Kong with 676 newly diagnosed NPC cases and 1,285 hospital controls between 2014 and 2017, using a computer-assisted self-administered questionnaire. Multivariable unconditional logistic regression yielded adjusted odds ratios (AORs) of NPC by quitting status, duration and age of quitting, combinations of duration and age of quitting, and quitting to smoking duration ratio, compared with current smoking., Results: Quitting (AOR: 0.72; 95% CI: 0.53-0.98) and never smoking (0.73, 0.56-0.95) were associated with lower NPC risk. NPC risk decreased with (i) longer quitting duration ( p < 0.01), reaching significance after 11-20 (0.62, 0.39-0.99) and 21+ years (0.54, 0.31-0.92) of quitting; (ii) younger quitting age ( p = 0.01), reaching significance for quitting at <25 years (0.49, 0.24-0.97); and (iii) higher quitting to smoking duration ratio ( p < 0.01), reaching significance when the ratio reached 1 (0.60, 0.39-0.93). Quitting younger (age <25) appeared to confer larger reductions (49% for ≤10 years of quitting, 50% for 11+ years) in NPC risk than quitting at older ages (25+) regardless of quitting duration (16% for ≤10 years, 39% for 11+ years)., Conclusions: We have shown longer duration and younger age of quitting were associated with lower NPC risk, with dose-response relations. Our findings support including smoking as a cause of NPC. Stronger tobacco control measures and quitting services are needed to prevent NPC., 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 Wang, Mai, Ngan, Ng, Lin, Kwong, Chiang, Yuen, Ng, Ip, Chan, Lee, Lung, Ho and Lam.)

The evolution of the tumor microenvironment (TME) is a cancer-dependent and dynamic process. The TME is often a complex ecosystem with immunosuppressive and tumor-promoting functions. Conventional chemotherapy and radiotherapy, primarily focus on inducing tumor apoptosis and hijacking tumor growth, whereas the tumor-protective microenvironment cannot be altered or destructed. Thus, tumor cells can quickly escape from extraneous attack and develop therapeutic resistance, eventually leading to treatment failure. As an Epstein Barr virus (EBV)-associated malignancy, nasopharyngeal carcinoma (NPC) is frequently infiltrated with varied stromal cells, making its microenvironment a highly heterogeneous and suppressive harbor protecting tumor cells from drug penetration, immune attack, and facilitating tumor development. In the last decade, targeted therapy and immunotherapy have emerged as promising options to treat advanced, metastatic, recurrent, and resistant NPC, but lack of understanding of the TME had hindered the therapeutic development and optimization. Single-cell sequencing of NPC-infiltrating cells has recently deciphered stromal composition and functional dynamics in the TME and non-malignant counterpart. In this review, we aim to depict the stromal landscape of NPC in detail based on recent advances, and propose various microenvironment-based approaches for precision therapy., 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 Gong, Kwong, Dai, Wu, Wang, Lee and Guan.)

Background & Aims: Little is known about the risk of nasopharyngeal carcinoma (NPC) in relation to vitamin D exposure. The aim of this study was to examine the associations of NPC risk with serum level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD, and potential effect modification by several putative risk factors of NPC., Methods: Our multicenter case-control study in Hong Kong recruited 815 NPC cases and 1502 frequency-matched (by sex and age) hospital controls from five major regional hospitals, and recruited 299 healthy subjects from blood donation centers (2014-2017). Circulating level of 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD (rs12785878, rs11234027, rs12794714, rs4588 and rs6013897) were measured by validated enzyme immunoassay and the iPLEX assay on the MassARRAY System, respectively. Data were also collected on demographics, lifestyle factors, ultraviolet radiation exposure, and potential confounders using a computer-assisted, self-administered questionnaire with satisfactory test-retest reliability. Unconditional logistic regression models were used to estimate ORs and 95% CIs., Results: Despite no significant association of NPC risk with circulating 25OHD and genetic predicted 25OHD, there was evidence for an inverse association in participants with normal body mass index (between 18.5 and 27.5) across categories of 25OHD (P trend  = 0.003), and a positive association in those with low socioeconomic status across categories based on the genetic score (P trend  = 0.005). In addition, risk of NPC diagnosed at an early stage was higher for genetically lower 25OHD level (adjusted OR = 3.09, 95% CI = 1.04-9.21, P trend  = 0.022)., Conclusions: Findings of this first comprehensive study to investigate the positive association of NPC risk with vitamin D deficiency need to be confirmed and be best interpreted with results of further similar studies. Our findings may inform possible etiological mechanisms of the associations with several putative risk/protective factors of NPC., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis.&nbsp;A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI).&nbsp;A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations.

Background: This study investigated the feasibility of using a computer-assisted method to evaluate and differentiate the carotid plaque characteristics in radiation-induced and non-radiation-induced carotid atherosclerosis., Methods: This study included 107 post-radiotherapy (post-RT) nasopharyngeal carcinoma (NPC) patients and 110 subjects with cardiovascular risk factors (CVRFs). Each participant had a carotid ultrasound examination, and carotid plaques and carotid intima-media thickness (CIMT) were evaluated with grey scale ultrasound. The carotid plaque characteristics were evaluated for grey-scale median (GSM) and detailed plaque texture analysis (DPTA) using specific computer software. In DPTA, five different intra-plaque components were colour-coded according to different grey scale ranges. A multivariate linear regression model was used to evaluate the correlation of risk factors and carotid plaque characteristics., Results: Post-RT NPC patients have significantly higher CIMT (748±15.1 µm, P=0.001), more patients had a plaque formation (80.4%, P<0.001) and more plaque locations (2.3±0.2, P<0.001) than CVRF subjects (680.4±10.0 µm, 38.2% and 0.5±0.1 respectively). Among the five intra-plaque components, radiation-induced carotid plaques had significantly larger area of calcification (4.8%±7.7%, P=0.012), but lesser area of lipid (42.1%±16.9%, P=0.034) when compared to non-radiation-induced carotid plaques (3.0%±5.7% and 46.3%±17.9% respectively). Age, radiation and number of CVRF were significantly associated with the carotid atherosclerosis burden (P<0.001). Besides, age was significantly associated with the amount of lipid and calcification within carotid plaques (P<0.001)., Conclusions: Radiation caused more severe carotid artery disease than CVRF with larger CIMT and more prevalent of carotid plaque. Radiation-induced carotid plaques tended to have more intra-plaque calcifications, whereas non-radiation-induced carotid plaques had more lipids. Ultrasound aided by computer-assisted image analysis has potential for more accurate assessment of carotid atherosclerosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-1012). The authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

A new polysaccharide (cDFP-W1) with high immunostimulatory activities was isolated from the stems of Dendrobium fimbriatum Hook. The analysis of the physicochemical properties showed that cDFP-W1 consisted of mannose and glucose in a molar ratio of 1 : 3.84, and its relative molecular weight was 4.0 × 10 4 Da. Structural analysis implied that the linear backbone of cDFP-W1 was composed of α-1,4-d-Glcp, β-1,4-d-Manp, 3-O-acetyl-α-1,4-d-Glcp and α-1,4,6-d-Glcp, and its branches were the terminal β-d-Manp that was attached to the C-6 position of α-1,4,6-d-Glcp. An in vivo immunostimulatory assay exhibited that cDFP-W1 at 200 mg kg -1 could significantly increase the proportions of CD4 + T-cell subpopulations, B cells, natural killer cells and dendritic cells, decrease the proportion of CD8 + T-cell subpopulations, and upregulate the percentage of activated macrophages (p < 0.01) in the spleen of mice. An in vitro immunostimulatory assay revealed that cDFP-W1 could effectively promote the proliferation of spleen lymphocytes, enhance the proliferation and phagocytosis of macrophage RAW264.7 cells, and stimulate the mRNA expression and extracellular release of NO, TNF-α and IL-1β of RAW264.7 cells. The western blot experiment suggested that the immunostimulatory activities of cDFP-W1 were closely related to the activation of MAPKs, NF-κB and PI3K/Akt signaling pathways.

The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.

Purpose: We compared, in this pooled analysis, the differences in efficacy and safety between three induction chemotherapy regimens including gemcitabine plus cisplatin (GP), cisplatin plus fluorouracil (PF) and cisplatin plus capecitabine (PX) in patients recruited into our two prospective studies for previously untreated locoregionally advanced nasopharyngeal carcinoma (NPC)., Methods: GP, PF or PX followed by radical concurrent chemoradiotherapy was given to patients with previously untreated locoregionally advanced (stage III to IVA) NPC prospectively recruited into our two prospective studies. The study endpoints included progression-free survival (PFS) and overall survival (OS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and major acute and late treatment-related toxicities (grade ≥ 3)., Results: From 2006 to 2016, 278 patients were enrolled (84, 94 and 100 patients in GP, PF and PX group respectively). After a median follow-up of 80 months, the 3-year PFS, OS, LRFS, DMFS and CSS of the whole population were 78.7%, 88.1%, 84.9%, 80.9% and 89.8%, respectively. There were no significant differences in prespecified survival endpoints among GP, PF and PX in both stage III and stage IVA patients. GP had lower incidences of severe (grade ≥ 3) anemia and diarrhea in stage III patients, as well as severe anemia, dehydration, renal impairment and vomiting in stage IVA patients. The incidences of grade ≥ 3 late toxicities were similar among these 3 induction regimens., Conclusion: GP had similar efficacy and potentially fewer treatment-related complications compared with PF and PX as induction chemotherapy for previously untreated locoregionally advanced NPC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The role of dietary fiber intake on risk of nasopharyngeal carcinoma (NPC) remains unclear. We examined the associations of dietary fiber intake on the risk of NPC adjusting for a comprehensive list of potential confounders., Methods: Using data from a multicenter case-control study, we included 815 histologically confirmed NPC incident cases and 1502 controls in Hong Kong, China recruited in 2014-2017. Odds ratios (ORs) of NPC (cases vs controls) for dietary fiber intake from different sources at different life periods (age 13-18, age 19-30, and 10 years before recruitment) were evaluated using unconditional logistic regression, adjusting for sex, age, socioeconomic status, smoking and drinking status, occupational hazards, family history of cancer, salted fish, and total energy intake in Model 1, Epstein-Barr virus viral capsid antigen serological status in Model 2, and duration of sun exposure and circulating 25-hydroxyvitamin D in Model 3., Results: Higher intake of total dietary fiber 10 years before recruitment was significantly associated with decreased NPC risk, with demonstrable dose-response relationship (P-values for trend = 0.001, 0.020 and 0.024 in Models 1-3, respectively). The adjusted ORs (95% CI) in the highest versus the lowest quartile were 0.51 (0.38-0.69) in Model 1, 0.48 (0.33-0.69) in Model 2, and 0.48 (0.33-0.70) in Model 3. However, the association was less clear after adjustment of other potential confounders (e.g. EBV) in the two younger periods (age of 13-18 and 19-30 years). Risks of NPC were significantly lower for dietary fiber intake from fresh vegetables and fruits and soybean products over all three periods, with dose-response relationships observed in all Models (P-values for trend for age 13-18, age 19-30 and 10 years before recruitment were, respectively, 0.002, 0.009 and 0.001 for Model1; 0.020, 0.031 and 0.003 for Model 2; and 0.022, 0.037 and 0.004 for Model 3). No clear association of NPC risk with dietary fiber intake from preserved vegetables, fruits and condiments was observed., Conclusion: Our study has shown the protective role of dietary fiber from fresh food items in NPC risk, but no association for total dietary fiber intake was observed, probably because total intake also included intake of preserved food. Further studies with detailed dietary information and in prospective settings are needed to confirm this finding, and to explore the possible underlying biological mechanisms.

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (T rs2517664  = 4.6%, P = 6.38 × 10 -21 ) and rs117495548 (G rs117495548  = 3.0%, P = 4.53 × 10 -13 ), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10 -36 ). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10 -21 ) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.

Objective: The transcription factor forkhead box protein O1 (FOXO1) is critical for regulating cytokine and chemokine secretion. However, its function in the tumor microenvironment (TME) remains largely unexplored. In this study, we characterized the prognostic value of FOXO1 and the interaction between tumor-derived FOXO1 and M2 macrophages in esophageal squamous cell carcinoma (ESCC). Methods: FOXO1 expression and macrophage infiltration in clinical samples and mouse models were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry staining. Western blotting, qRT-PCR, and enzyme-linked immunosorbent assay were used to evaluate chemokine ligand 20 (CCL20) and colony stimulating factor 1 (CSF-1) expression in FOXO1(+) and FOXO1(-) tumor cells. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and RNA sequencing. Transcriptional activity was measured using chromatin immunoprecipitation (ChIP)-qPCR. Tumor viability was investigated using XTT proliferation and foci formation assays. Results: FOXO1 upregulation in tumor tissues was found to drive the polarization of M0 macrophages and infiltration of M2 macrophages into the TME, resulting in worse prognosis in ESCC patients. CSF-1, a vital factor inducing M0-to-M2 polarization, was upregulated via a FOXO1-mediated mechanism. RNA sequencing results corroborated that the FOXO1-induced macrophages exhibited similar molecular signatures to the IL4-stimulated M2 macrophages. The transwell assays showed that FOXO1 promoted the migration of M2 macrophages via CCL20 secretion, which could be inhibited using an anti-CCL20 antibody. FOXO1(+) tumor-induced M2 macrophages promoted tumor proliferation via the FAK-PI3K-AKT pathway and the PI3K inhibitor could effectively impede the oncogenical process. Conclusions: FOXO1 facilitated M0-to-M2 polarization and the recruitment of M2 macrophages in the TME via the transcriptional modulation of CCL20 and CSF-1. Our data deciphered the FOXO1-dependent mechanism in M2 macrophage infiltration in the TME of ESCC, which has implications for the development of novel prognostic and therapeutic targets to optimize the current treatment against ESCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: We investigated the relationship of Epstein-Barr virus viral capsid antigen (EBV VCA-IgA) serostatus with ambient and personal ultraviolet radiation (UVR) and vitamin D exposure., Methods: Using data from a multicenter case-control study, we included 1026 controls subjects in 2014-2017 in Hong Kong, China. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between UVR exposure and EBV VCA-IgA (seropositivity vs seronegativity) were calculated using unconditional logistic regression models adjusted for potential confounders., Results: We observed a large increase in seropositivity of EBV VCA-IgA in association with duration of sunlight exposures at both 10 years before recruitment and age 19-30 years (adjusted OR = 3.59, 95% CI = 1.46-8.77; and adjusted OR = 2.44, 95% CI = 1.04-5.73 for ≥8 vs <2 hours/day; P for trend = .005 and .048, respectively). However, no association of EBV VCA-IgA serostatus with other indicators of UVR exposure was found. In addition, both circulating 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD were not associated with EBV VCA-IgA serostatus., Conclusions: Our results suggest that personal UVR exposure may be associated with higher risk of EBV reactivation, but we did not find clear evidence of vitamin D exposure (observational or genetic), a molecular mediator of UVR exposure. Further prospective studies in other populations are needed to confirm this finding and to explore the underlying biological mechanisms. Information on photosensitizing agents, and serological markers of EBV, and biomarkers related to systemic immunity and inflammation should be collected and are also highly relevant in future studies., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: The prognostic role of plasma Epstein-Barr virus (EBV) DNA clearance when intensity-modulated radiotherapy (IMRT) and the 8th edition of American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM Staging Classification are fully implemented remains undeciphered. We investigated if its half-life clearance during radical treatment for non-metastatic nasopharyngeal carcinoma (NPC) was an early prognosticator. Patients and methods: Patients with previously untreated non-metastatic NPC were prospectively treated with radical IMRT and concurrent chemotherapy +/- induction/adjuvant chemotherapy from 2014 to 2018. Their plasma EBV DNA was measured immediately before treatment followed by weekly schedules until 0 copy/ml in two consecutive measurements. Cox regression models were employed to identify prognostic factors. Results: Forty-five patients were prospectively recruited and analyzed. After a median follow-up of 30.3 months, 2 (4.5%), 1 (2.3%), and 6 (13.6%) patients experienced local, regional, and distant relapses, respectively. The median half-life clearance of plasma EBV DNA was 7.92 days. Those with half-life clearance of >15 days had a worse 3-years progression-free survival (PFS) (79.5 vs. 25.0%, p = 0.005), distant metastasis-free survival (DMFS) (85.0 vs. 31.3%, p = 0.009), and overall survival (OS) (91.3 vs. 75.0%, p = 0.024) when compared to those with a shorter half-life. Multivariable analyses demonstrated that only half-life (>15 days) was prognostic of DMFS [HR (95% CI): 4.91 (1.31; 18.39), p = 0.01] and OS [HR (95% CI): 5.24 (1.06; 26.05)] while half-life (>15 days) [HR (95% CI): 5.14 (1.28; 22.73), p = 0.02] and sum of pretreatment gross tumor volumes of the primary nasopharyngeal tumor and the radiologically positive neck nodes (GTV&#95;P+N) [HR (95% CI): 1.01 (1.00; 1.03), p = 0.02] were prognostic of PFS. Conclusion: The half-life clearance of plasma EBV DNA was prognostic in non-metastatic NPC staged and treated in the contemporary era. Earlier biomarker surveillance during treatment should be considered. Clinical Trial Registration: This study has been registered with ClinicalTrials.gov (Identifier: NCT03830996)., (Copyright © 2020 Chan, Chan, Choi, Tong, Lam, Kwong, Vardhanabhuti, Leung, Luk, Lee and Lee.)

Introduction: Pancreaticoduodenectomy (PD) has been widely applied as a standard surgical procedure to treat periampullary diseases. The placement of a pancreaticojejunal anastomotic stent is considered an effective and safe method for preventing pancreatic fistula after PD. Recently, the role of pancreaticojejunal anastomotic stents has been challenged, as gradually increasing complications have been observed. Stent-related small bowel perforation has only occurred in 2 cases as long-term complications but has not been reported to occur within 1 week after surgery., Patient Concerns: Here, we report the case of a 71-year-old female patient complaining of painless jaundice who underwent PD with a pancreaticojejunal anastomotic stent for a duodenal papillary adenocarcinoma (T4N1M0). Four days after surgery, she had a sudden rise in temperature, high white blood cell count, significantly elevated C-reactive protein and 400 ml green-brown drainage fluid. Enhanced computed tomography showed hydrops abdominis., Diagnosis: Small bowel perforation caused by stent migration was considered first., Interventions: An emergency exploratory laparotomy was performed. We located the pancreaticojejunal anastomotic stent, which extended 2 cm from the small bowel, and sutured the jejunum hole after cutting away the protruding part of the stent., Outcomes: The patient recovered smoothly and was discharged on the 7th day after the second surgery. After more than 12 months of follow-up, the patient is doing well and is free of any symptoms related to the procedure., Conclusion: We caution that stent-related complications can occur when perioperative patients suffer from unexplained or sudden changes in vital signs after PD. In addition, the function of the pancreaticojejunal anastomotic stent needs to be reevaluated by future studies.

Background: Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease., Method: Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines., Results: The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis., Conclusions: We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.

Purpose: Craniopharyngioma is a rare low-grade neoplasm in children. Tumor progression occurs frequently, and survivors are at risk of long-term disease and treatment-related morbidities. We reviewed the population-based experience of managing pediatric craniopharyngioma in Hong Kong., Methods: The Hong Kong Pediatric Hematology/Oncology Study Group database was interrogated for patients with craniopharyngioma younger than 18 years between 1999 and 2018. Patient demographics, clinical characteristics, outcomes, and long-term morbidities were summarized., Results: Twenty-eight patients with craniopharyngioma were included (approximate incidence of 1.1 per 1,000,000 individuals). The treatment approaches were heterogeneous and included surgery only, surgery with adjuvant radiation, and surgery with intracystic interferon. With a median follow-up of 6.1 years, 12 (43%) patients experienced disease progression, and 3 patients died of progression, postoperative complication, and gastrointestinal bleeding. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 56.8% (± 10.0%) and 92.0% (± 5.4%), respectively. The 10-year PFS and OS rates were 37.3% (± 11.4) and 92.0% (± 5.4%), respectively. Patients receiving treatment in a high-volume center had significantly better outcomes than did those treated at other centers (PFS, p = 0.007; OS, p = 0.029). Period of diagnosis, sex, age at diagnosis, greatest tumor dimension, extent of resection, and radiotherapy use did not significantly affect patient survival. Long-term visual impairment (60%) and endocrinopathies (92%) were common., Conclusion: Prognosis of pediatric craniopharyngioma in Hong Kong compares unfavorably with published reports. Centralization and standardization of treatment may prove valuable in mitigating patient outcomes.

Background: Primary hepatic neuroendocrine neoplasms (PHNENs) are extremely rare and few articles have compared the prognosis of PHNENs with other neuroendocrine neoplasms (NENs). This study aimed to investigate the different prognosis between PHNENs and pancreatic NEN (PanNENs) and evaluate the relevant prognosis-related factors., Methods: From January 2012 to October 2016, a total of 44 NENs patients were enrolled and divided into two groups according to the primary tumor location which were named group PHNENs (liver; n = 12) and group PanNENs (pancreas; n = 32). Demographic, clinical characteristics and survival data were compared between the two groups with Kaplan-Meier method and log-rank tests. Prognostic factors were analyzed using the Cox regression model., Results: The overall survival of group PHNENs and group PanNENs were 25.4 ± 6.7 months and 39.8 ± 3.7 months, respectively (P = 0.037). The cumulative survival of group PanNENs was significantly higher than that of group PHNENs (P = 0.029). Univariate analysis revealed that sex, albumin, total bilirubin, total bile acid, aspartate aminotransferase, alkaline phosphatase, α-fetoprotein and carbohydrate antigen 19-9, histological types, treatments and primary tumor site were the prognostic factors. Further multivariate analysis indicated that albumin (P = 0.008), histological types NEC (P = 0.035) and treatments (P = 0.005) were the independent prognostic factors. Based on the histological types, the cumulative survival of patients with well-differentiated neuroendocrine tumor was significant higher than that of patients with poorly differentiated neuroendocrine carcinoma in group PHNENs (P = 0.022), but not in group PanNENs (P > 0.05). According to the different treatments, patients who received surgery had significantly higher cumulative survival than those with conservative treatment in both groups (P < 0.05)., Conclusions: PHNENs have lower survival compared to PanNENs. Histological types and treatments affect the prognosis. Surgical resection still remains the first line of treatment for resectable lesions and can significantly improve the survival., (Copyright © 2019 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) in endemic regions may have undetectable plasma EBV DNA., Methods: We prospectively recruited 518 patients with non-metastatic NPC and measured their pre-treatment plasma EBV DNA. The stage distribution and prognosis between pre-treatment plasma EBV DNA-negative (0-20 copies/ml) and EBV DNA-positive (>20 copies/ml) patients following radical treatment were compared., Results: Seventy-eight patients (15.1%) were plasma EBV DNA-negative, and 62 in this subset (12.0%) had 0 copy/ml. Only 23/78 (29.5%) plasma EBV DNA-negative patients with advanced NPC (stage III-IVA) had strong EBV encoded RNA (EBER) positivity (score 3) in their tumours compared to 342/440 (77.7%) EBV DNA-positive patients of the same stages (p < 0.001). Though EBV DNA-negative patients had more early-stage disease (p < 0.001) and smaller volumes of the primary tumour and the positive neck nodes (p < 0.001), they had similar 5-year overall survival and cancer-specific survival to those EBV DNA-positive counterparts by stage. Similar results were also seen when plasma EBV DNA cut-off was set at 0 copy/ml., Conclusions: Patients with low-volume NPC may not be identified by plasma/serum tumour markers and caution should be taken in its utility as a screening tool for NPC even in endemic regions., Clinical Trial Registration: Clinicaltrials.gov Identifier: NCT02476669.

Deletion of Chromosome 3p is one of the most frequently detected genetic alterations in nasopharyngeal carcinoma (NPC). We reported the role of a novel 3p26.3 tumor suppressor gene (TSG) CHL1 in NPC. Down-regulation of CHL1 was detected in 4/6 of NPC cell lines and 71/95 (74.7%) in clinical tissues. Ectopic expressions of CHL1 in NPC cells significantly inhibit colony formation and cell motility in functional study. By up-regulating epithelial markers and down-regulating mesenchymal markers CHL1 could induce mesenchymal-epithelial transition (MET), a key step in preventing tumor invasion and metastasis. CHL1 could also cause the inactivation of RhoA/Rac1/Cdc42 signaling pathway and inhibit the formation of stress fiber, lamellipodia, and filopodia. CHL1 could co-localize with adhesion molecule Integrin-β1, the expression of CHL1 was positively correlated with Integrin-β1 and another known tumor suppressor gene (TSG) Merlin. Down-regulation of Integrin-β1 or Merlin was significantly correlated with the poor survival rate of NPC patients. Further mechanistic studies showed that CHL1 could directly interact with integrin-β1 and link to Merlin, leading to the inactivation of integrin β1-AKT pathway. In conclusion, CHL1 is a vital tumor suppressor in the carcinogenesis of NPC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The much higher incidence of nasopharyngeal carcinoma (NPC) in men suggests sex hormones as a risk factor, and dairy products contain measurable amounts of steroid hormones. Milk consumption has greatly increased in endemic regions of NPC. We investigated the association between NPC and milk consumption across life periods in Hong Kong. Methods: A multicentre case-control study included 815 histologically confirmed NPC incident cases and 1,502 controls who were frequency-matched on age and sex at five major hospitals in Hong Kong in 2014-2017. Odds ratios (ORs) of NPC (cases vs. controls) for milk consumption at different life periods were estimated by unconditional logistic regression, adjusting for sex, age, socioeconomic status score, smoking and alcohol drinking status, exposure to occupational hazards, family history of cancer, IgA against Epstein-Barr virus viral capsid antigen, and total energy intake. Results: Compared with abstainers, lower risks of NPC were consistently observed in regular users (consuming ≥5 glasses of milk [fresh and powdered combined] per month) across four life periods of age 6-12 (adjusted OR 0.74, 95% CI 0.54-0.86), 13-18 (0.68, 0.55-0.84), 19-30 (0.68, 0.55-0.84), and 10 years before recruitment (0.72, 0.59-0.87). Long-term average milk consumption of ≤2.5, >2.5, and ≤12.5, >12.5 glasses per month yielded adjusted OR (95% CI) of 1.00 (0.80-1.26), 0.98 (0.81-1.18), 0.95 (0.76-1.18), and 0.55 (0.43-0.70), respectively (all P -values for trend < 0.05). Conclusion: Consumption of milk across life periods was associated with lower risks of NPC. If confirmed to be causal, this has important implications for dairy product consumption and prevention of NPC.

The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity-modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein-Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five-year progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA-I (T1-T4 N0-N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA-II (T1-T4 N0-N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA-III (T1-T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA-IVA (T3-T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1-T2 N0-N2; II: T3-T4 N0-N2 or T1-T2 N3 and III: T3-T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA-based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups., (© 2018 UICC.)

Nasopharyngeal carcinoma is an Epstein-Barr Virus (EBV) associated malignancy which is highly prevalent in Southeast Asia. EBV-related antibodies have been widely used as screening markers for early nasopharyngeal carcinoma (NPC) detection. However, due to its low positive predictive rate, it is essential to develop new biomarkers to facilitate NPC early diagnosis or triage EBV serological high-risk individuals to improve the chance of NPC early detection. BART microRNAs, which are encoded by BamHI region of EBV, were reported to be abundant in NPC and have potential value in early diagnosis of NPC. Here, we quantified circulating level of 17 BART microRNAs in discovery stage based on previous microarray and sequencing data and, in particular, BART 2-5p, the sole candidate whose area under curve (AUC) was higher than 0.8, has been chosen for further study. In validation stage, the sensitivity, specificity and AUC of BART 2-5p was 93.9%, 89.8%, 0.972 (95%CI: 0.954-0.989), respectively, in Cohort 1 constituted by NPC patients and controls from Hong Kong. For validation Cohort 2 consisting of patients and controls from Guangzhou, the sensitivity, specificity and AUC was 94.2%, 83.5%, 0.959 (95%CI: 0.939-0.980), respectively. To evaluate its ability to distinguish preclinical NPC patients, we established a nested case-control study with serum samples prospectively collected from 22 NPC patients prior to their clinical diagnosis and 88 matched healthy high-risk controls in a screening trial. The sensitivity and specificity were 90.9% and 54.5%. Collectively, EBV microRNA BART2-5p may be a valuable biomarker for early detection of NPC., (© 2018 UICC.)