Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas

Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart.Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing(NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC(LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes.Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas.Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC(TERT amplification),colorectal NEC(KRAS mutation), and bile tract NEC(ARID1A mutation). The gene disparities between small-cell NEC(SCNEC) and large-cell NEC(LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in22.2% of the patients, and they had longer progression-free survival(PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40(0.21-0.75), P=0.006].Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

Classificatory updates in verrucous and cuniculatum carcinomas:Insights from the 5^(th) edition of WHO-IARC head and neck tumor classification

The International Agency for Research on Cancer(IARC)and World Health Organization(WHO)collaboratively produce the'WHO Blue Books'essential tools standardizing the diagnostic process for human cancers.Regular updates in this classification accommodate emerging molecular discoveries,advances in immunohistochemical techniques,and evolving clinical insights.The 5th edition of the WHO/IARC classification of head and neck tumors refines the'Oral Cavity and Mobile Tongue'chapter,including sections for non-neoplastic lesions,epithelial tumors,and tumors of uncertain histogenesis.Notably,the epithelial tumors section is rearranged by tumor behavior,starting with benign squamous papillomas and progressing through potentially malignant oral disorders to oral squamous cell carcinoma(OSCC).The section on OSCC reflects recent information on epidemiology,pathogenesis,and histological prognostic factors.Noteworthy is the specific categorization of verrucous carcinoma(VC)and carcinoma cuniculatum(CC),both associated with the oral cavity and distinct in clinical and histologic characteristics.This classification adjustment emphasizes the oral cavity as their predominant site in the head and neck.Designating specific sections for VC and CC aims to provide comprehensive insights into these unique subtypes,elucidating their clinical features,distinct histological characteristics,prevalence,significance,and clinical relevance.By categorizing these subtypes into specific sections,the 5th edition of the WHO classification aims to provide a more nuanced and detailed account,enhancing our understanding of these specific variants within the broader spectrum of head and neck tumors.

Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

The “No-touch” technique improves the survival of patients with advanced hepatocellular carcinomas treated by liver transplantation: A single-center prospective randomized controlled trial

Background:Liver transplantation(LT)is the best treatment for patients with hepatocellular carcinoma(HCC).However,the surgical technique needs to be improved.The present study aimed to evaluate the“no-touch”technique in LT.Methods:From January 2018 to December 2019,we performed a prospective randomized controlled trial on HCC patients who underwent LT.The patients were randomized into two groups:a no-touch technique LT group(NT group,n=38)and a conventional LT technique group(CT group,n=46).Operative outcomes and survival in the two groups were analyzed.Results:The perioperative parameters were comparable between the two groups(P>0.05).There was no significant difference between the two groups in disease-free survival(DFS)(P=0.732)or overall survival(OS)(P=0.891).Of 36 patients who were beyond the Hangzhou criteria for LT,the DFS of the patients in the NT group was significantly longer than that in the CT group(median 402 vs.126 days,P=0.025).In 31 patients who had portal vein tumor thrombosis(PVTT),DFS and OS in the NT group were significantly better than those in the CT group(median DFS 420 vs.167 days,P=0.022;2-year OS rate 93.8%vs.66.7%,P=0.043).In 14 patients who had diffuse-type HCCs,DFS and OS were significantly better in the NT group than those in the CT group(median DFS 141 vs.56 days,P=0.008;2-year OS rate 75.0%vs.33.3%,P=0.034).Multivariate analysis showed that for patients with PVTT and diffusetype HCCs,the no-touch technique was an independent favorable factor for OS(PVTT:HR=0.018,95%CI:0.001-0.408,P=0.012;diffuse-type HCCs:HR=0.034,95%CI:0.002-0.634,P=0.024).Conclusions:The no-touch technique improved the survival of patients with advanced HCC compared with the conventional technique.The no-touch technique may provide a new and effective LT technique for advanced HCCs.

A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma

Noncoding RNAs instruct the Cas9 nuclease to site speifillyl cleave DNA in the CRISPR/Cas9 system.Despite the high incidence of hepatocellular carcinoma(HCC),the patient's outcome is poor.As a result of the emergence of therapeutic resistance in HCC patients,dlinicians have faced difficulties in treating such tumor.In addition,CRISPR/Cas9 screens were used to identify genes that improve the dlinical response of HCC patients.It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer,with a particular emphasis on HCC as part of the current state of knowledge.Thus,in order to locate recent developments in oncology research,we examined both the Scopus database and the PubMed database.The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs.Drug resistance can be overcome with the help of the CRISPR/Cas9 system.HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening although this method is not without limitations.It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy.CRISPR and its applications to tumor research,particularly in HCC,are examined in this study through a review of the literature.

Early esophageal carcinomas in achalasia patient after endoscopic submucosal dissection combined with peroral endoscopic myotomy:A case report

BACKGROUND Achalasia is associated with high risk of esophageal carcinoma.However,the optimal endoscopic surgery for patients with early esophageal carcinoma concomitant with achalasia remains unclear.CASE SUMMARY A combination of concurrent endoscopic submucosal dissection(ESD)and modified peroral endoscopic myotomy(POEM)was performed on a 62-year-old male,who presented with multiple early esophageal carcinomas concomitant with achalasia.The patient exhibited an improvement in feeding obstruction,and presented no evidence of disease during the 3-year follow-up.CONCLUSION The combination of ESD and POEM is a feasible treatment modality for patients with early esophageal carcinoma concomitant with achalasia.

Downstaging strategies for unresectable hepatocellular carcinoma

A significant number of patients with hepatocellular carcinoma(HCC)are usually diagnosed in advanced stages,that leads to inability to achieve cure.Palliative options are focusing on downstaging a locally advanced disease.It is wellsupported in the literature that patients with HCC who undergo successful conversion therapy followed by curative-intent surgery may achieve a significant survival benefit compared to those who receive chemotherapy alone or those who are successfully downstaged with conversion therapy but not treated with surgery.Hepatic artery infusion chemotherapy can be a potential downstaging strategy,since recent studies have demonstrated excellent outcomes in patients with colorectal liver metastatic disease as well as primary liver malignancies.

Small Cell Neuroendocrine Carcinoma of the Vulva: Case Report and Literature Review

Background: Neuroendocrine neoplasms are those that develop from a neuroendocrine cell. They most commonly affect the lungs, gastrointestinal tract, and pancreas, being rare conditions in the female genital tract. When present, these neoplasms often manifest with nonspecific signs and symptoms such as pain, itching, swelling, single-focus lesions, bleeding, and enlargement of inguinal lymph nodes, in addition to the presence of progressively enlarging vulvar nodules. Consequently, the diagnostic investigation involves histopathological examination and confirmation through immunohistochemistry. Objective: To present a comprehensive understanding of this rarely studied pathology. The primary objective is to provide valuable insights that could aid in the future development of universally applicable treatment guidelines. Case Presentation: A 57-year-old female, with no prior comorbidities, menopause at 36, who presented with a left vulvar nodule accompanied by intense pain and swelling, later diagnosed with small cell neuroendocrine carcinoma in the vulva. Conclusion: This case report highlights the importance of enhancing our knowledge regarding small cell neuroendocrine carcinoma in the vulva, given its scarcity in medical literature. The information presented here underscores the need for standardized diagnostic and treatment approaches, paving the way for future consensus on managing this uncommon but challenging neoplasm.

Nrf2 and Her3 co-expression in cholangiocarcinoma:Possible biological pathways for potential therapeutic approach

To the Editor:Cholangiocarcinomas(CCAs)are heterogeneous group of malignancies,encompassing intrahepatic CCA(iCCA),and extrahepatic CCA(eCCA);they are also classified into common hepatic duct cholangiocarcinoma(CHDCCA),choledocus extrapancreatic cholangiocarcinoma(EPCCA)and choledocus intrapancreatic cholangiocarcinoma(IPCCA)and,finally,gallbladder carcinoma(GBCCA).CCAs are relatively uncommon but.

3-Epi-betulinic acid 3-O-β-D-glucopyranoside(eBAG)induces autophagy by activation of AMP-activated protein kinase in hepatocellular carcinoma

3-Epi-betulinic acid 3-O-β-D-glucopyranoside(eBAG)is a pentacyclic triterpene mainly distributed in food and medicinal plants,which exhibits various pharmacological properties.However,whether these functions are attributed to eBAG or additional components in these plants remain unknown.Herein,we report that eBAG exerted an inhibitory activity against hepatocellular carcinoma and esophageal cancer cells.EBAG induced non-apoptotic cell death in hepatocellular carcinoma cells.The eBAG-induced cell death was inhibited by knock-down of autophagy related gene(ATG)5 and ATG7,by administration of 3-methyladenine,a selective autophagy inhibitor that suppresses phosphoinositide 3-kinase(PI3K),and by chloroquine,a classic autophagy flux inhibitor.We demonstrated that eBAG induced an autophagy-mediated cell death.Application of eBAG mimicked cellular bioenergetics depletion leading to the reduction of intracellular ATP,activation of AMP-activated protein kinase(AMPK),and inhibition of mTOR.Co-treatment with compound C,an AMPK inhibitor,abrogated cell death induced by eBAG.We further validated the anti-tumor effect of eBAG in the murine xenograft model of hepatocellular carcinoma and found that eBAG treatment promoted the induction of autophagy and reduction of tumor growth in mice.As a functional food ingredient,eBAG is a potential therapeutic agent for the treatment of hepatocellular carcinoma and esophageal cancer.

Retraction: Knockdown of Gab1 Inhibits Cellular Proliferation, Migration, and Invasion in Human Oral Squamous Carcinoma Cells

Following the publication,concerns have been raised about a number of figures in this article.The Western Blot data shown in Figs.2a,2b were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published.The authors were contacted and invited to comment on the concerns raised and to provide the original,unmodified figures,but did not respond.The Editors-in-Chief therefore no longer have confidence in the integrity of the data in this article and decided to retract this article.

Investigation of the feasibility of NRAV as a biomarker for hepatocellular carcinoma

The long non-coding RNA,Negative Regulator of Antiviral Response(NRAV)has been identified as a participant in both respiratory virus replication and immune checkpoints,however,its involvement in pan-cancer immune regulation and prognosis,particularly those of hepatocellular carcinoma(HCC),remains unclear.To address this knowledge gap,we analyzed expression profiles obtained from The Cancer Genome Atlas(TCGA)database,comparing normal and malignant tumor tissues.We found that NRAV expression is significantly upregulated in tumor tissues compared to adjacent nontumor tissues.Kaplan-Meier(K-M)analysis revealed the prognostic power of NRAV,wherein overexpression was significantly linked to reduced overall survival in a diverse range of tumor patients.Furthermore,noteworthy associations were observed between NRAV,immune checkpoints,immune cell infiltration,genes related to autophagy,epithelial-mesenchymal transition(EMT),pyroptosis,tumor mutational burden(TMB),and microsatellite instability(MSI)across different cancer types,including HCC.Moreover,NRAV upregulation expression was associated with multiple pathological stages by clinical observations.Furthermore,our investigation revealed a substantial elevation in the expression of NRAV in both HCC tumor tissues and cells compared to normal tissues and cells.The inhibition of NRAV resulted in the inhibition of cell proliferation,migration,and invasion in HCC cells,while also influencing the expression of CD274(PD-L1)and CD44,along with various biomarkers associated with EMT,autophagy,and pyroptosis.The aforementioned results propose NRAV as a promising prognostic biomarker for HCC.

Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice

Hepatocellular carcinoma(HCC)is one of the most common causes of cancerrelated mortality.This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease.This makes the management of patients more challenging,since physicians must take into consideration two different conditions,the chronic liver disease and the tumor.The underlying liver disease has several implications in clinical practice,because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC,obstacles in surveillance,and differences in the efficacy of the treatment against HCC.A shift in the prevalence of liver diseases has been evident over the last few years,with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance.Therefore,in an era of personalized medicine,it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

Endobronchial metastasis secondary to renal clear cell carcinoma:A case report

BACKGROUND Endobronchial metastases(EBMs)are tumours that metastasise from a malignant tumour outside the lungs to the central and subsegmental bronchi,and are visible under a bronchofibrescope.Most EBMs are formed by direct invasion or metastasis of intrathoracic malignant tumours,such as lung cancer,oesophageal cancer or mediastinum tumours.Renal cell carcinoma(RCC),accounting for 2%to 3%of all tumours,is a common malignant tumour of the urinary system.Renal clear cell carcinoma(RCCC)constitutes the predominant pathological subtype of RCC,comprising approximately 70%to 80%of all RCC cases.RCCC can spread and metastasise through arterial,venous and lymphatic circulation to almost all organs of the body.Moreover,lung,bone,liver,brain and local recurrence are the most common metastatic neoplasms of RCCC.However,EBM from RCCC has a low complication rate and is often misdiagnosed as primary lung cancer.CASE SUMMARY A 71-year-old male patient who had undergone radical left nephrectomy 7 years prior due to RCCC was referred to our hospital due to a 1-mo history of productive cough.The results of an enhanced chest CT scan indicated the presence of a soft tissue nodule in the upper lobe of the left lung,and flexible bronchoscopy revealed a hypervascular lesion in the bronchus of the left lung's superior lobe.Therefore,the patient underwent thoracoscopic left superior lobe wedge resection,and pathology confirmed EBM from the RCCC.CONCLUSION EBM from RCCC has a low incidence and no characteristic clinical manifestations in the early stage.If a bronchial tumour is found in a patient with RCCC,the possibility of bronchial metastatic cancer should be considered.

Retraction: Knockdown of Urothelial Carcinoma-Associated 1 Suppressed Cell Growth and Migration Through Regulating miR-301a and CXCR4 in Osteosarcoma MHCC97 Cells

Following the publication,concerns have been raised about a number of figures in this article.The western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.The authors were contacted and invited to comment on the concerns raised and to provide the original,unmodified figures,but did not respond.The Editors-in-Chief therefore no longer have confidence in the integrity of the data in this article and decided to retract this article.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma:a multicenter cohort study in China

Objective:Sex-specific differences are observed in various liver diseases,but the influence of sex on the outcomes of hepatocellular carcinoma(HCC)after liver transplantation(LT)remains to be determined.This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC.Methods:Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed.The associations between donor,recipient,or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching(PSM).The survival associated with different sex-based donor-recipient transplant patterns was further studied.Results:Among 3,769 patients enrolled in this study,the 1-,3-,and 5-year overall survival(OS)rates of patients with HCC after LT were 96.1%,86.4%,and 78.5%,respectively,in female recipients,and 95.8%,79.0%,and 70.7%,respectively,in male recipients after PSM(P=0.009).However,the OS was comparable between recipients with female donors and male donors.Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival(HR=1.381,P=0.046).Among the donor-recipient transplant patterns,the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival(P<0.05).Conclusions:Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients,and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival.Livers from male donors may provide the most benefit to female recipients.Our results indicate that sex should be considered as a critical factor in organ allocation.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma:A case report

BACKGROUND Multiple primary carcinomas(MPCs)are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual.Synchronous MPCs are rarer than solitary cancers or metachronous MPCs.Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases.CASE SUMMARY A 64-year-old patient presented with dysphagia,without obvious cause.A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results.After multi-disciplinary consultations,combination chemotherapy(a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14)and esophageal cancer radiotherapy were initiated.Based on the results of genetic testing,we switched to a regimen of leucovorin+fluorouracil+oxaliplatin and cetuximab regimen for 8 cycles.Subsequently,capecitabine and bevacizumab were administered until the most recent follow-up,at which the tumor remained stable.CONCLUSION Successful cetuximab chemotherapy treatment provides a reference for the nonoperative and homogeneous treatment of different pathological types of synchronous MCPs.

Epidemio-Clinical-Histopathological Aspects and Therapeutics of Squamous Cell Carcinoma of the Conjunctival at the University Hospital Center of Bouake

Introduction: Squamous cell carcinoma of the conjunctiva is one of the most common malignancies in the elderly. Purpose: To describe the specific aspects of squamous cell carcinoma of the conjunctiva and to determine the therapeutic modalities. Materials and Methods: Descriptive cross-sectional retrospective study carried out at the University Hospital Center of Bouake over a period of 9 years (From January 2015 to December 2023). We identified all malignant oculo-adnexal and orbital tumors whose histopathological diagnosis was confirmed;monitoring the sorting of squamous cell carcinomas of the conjunctiva among these cancers and studying the different parameters linked to them. Results: The average age of patients is 44.3 years. Male predominance with a sex ratio of 1.12. HIV was the majority ATCD with 64.7%. The main reason for consultation was exophthalmos (36.11%). The average consultation time was 10 months 13 days. Invasive differentiated conjunctival squamous cell carcinoma was predominant at 55.56%. Enucleation was the most performed surgical method. Conclusion: Squamous cell carcinoma of the conjunctiva is a malignant ocular tumor of the elderly whose frequency increases in young adults infected with HIV-AIDS. Invasive differentiated forms are increasingly encountered, limiting treatment to mutilating surgery.

Clinical analysis of 12 cases of ovarian neuroendocrine carcinoma

BACKGROUND Neuroendocrine neoplasms of the female genital tract are rare.AIM To enhance our clinical understanding of neuroendocrine carcinoma(NEC)of the ovary.METHODS A retrospective review was conducted on 12 patients diagnosed with NEC of the ovary,analyzing clinicopathological characteristics,treatment modalities,and survival status.RESULTS The median age at diagnosis was 34.5 years(range:20 to 62 years).Among the 12 cases,9 were small cell carcinoma of the ovary and 3 were large cell NEC.Five cases were stage I tumors,one case was stage IV,and six cases were stage III.Eleven patients underwent surgery as part of their treatment.All patients received adjuvant chemotherapy.Among the 12 patients,one patient received radiotherapy,and one patient with a BRCA2 mutation was administered PARP inhibitor maintenance after chemotherapy.The median progression-free survival was 13 months,and the median overall survival was 19.5 months.Four cases remained disease-free,while eight cases experienced tumor recurrence,including three cases that resulted in death due to disease recurrence.CONCLUSION NEC of the ovary is a rare condition that is more common in women of childbearing age and is associated with aggressive behavior and poor clinical outcomes.Surgical resection remains the mainstay of treatment,with some patients benefiting from adjuvant chemoradiation therapy.

Development of a diagnostic nomogram for alpha-fetoproteinnegative hepatocellular carcinoma based on serological biomarkers

BACKGROUND Hepatocellular carcinoma(HCC)is the third leading cause of cancer-related death worldwide.Serum biomarkers play an important role in the early diagnosis and prognosis of HCC.Because a certain percentage of HCC patients are negative for alpha-fetoprotein(AFP),the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC.AIM To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers.METHODS A total of 180 HCC patients were enrolled in this study.The expression levels of GP73,des-γ-carboxyprothrombin(DCP),CK18-M65,and CK18-M30 were detected by a fully automated chemiluminescence analyser.The variables were selected by logistic regression analysis.Several models were constructed using stepwise backward logistic regression.The performance of the models was compared using the C statistic,integrated discrimination improvement,net reclassification improvement,and calibration curves.The clinical utility of the nomogram was assessed using decision curve analysis(DCA).RESULTS The results showed that the expression levels of GP73,DCP,CK18-M65,and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls(P<0.001).Multivariate logistic regression analysis revealed that GP73,DCP,and CK18-M65 were independent factors for diagnosing AFP-negative HCC.By comparing the diagnostic performance of multiple models,we included GP73 and CK18-M65 as the model variables,and the model had good discrimination ability(area under the curve=0.946)and good goodness of fit.The DCA curves indicated the good clinical utility of the nomogram.CONCLUSION Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC.The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC.