Causal roles of gut microbiota in cholangiocarcinoma etiology suggested by genetic study.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with poor prognosis. Previous studies have implicated the gut microbiota in CCA, but evidence for causal mechanisms is lacking. AIM: To investigate the causal relationship between gut microbiota and CCA risk. METHODS: We performed a two-sample mendelian randomization study to evaluate potential causal associations between gut microbiota and CCA risk using genome-wide association study summary statistics for 196 gut microbial taxa and CCA. Genetic variants were used as instrumental variables. Multiple sensitivity analyses assessed result robustness. RESULTS: Fifteen gut microbial taxa showed significant causal associations with CCA risk. Higher genetically predicted abundance of genus Eubacteriumnodatum group, genus Ruminococcustorques group, genus Coprococcus, genus Dorea, and phylum Actinobacteria were associated with reduced risk of gallbladder cancer and extrahepatic CCA. Increased intrahepatic CCA risk was associated with higher abundance of family Veillonellaceae, genus Alistipes, order Enterobacteriales, and phylum Firmicutes. Protective effects against CCA were suggested for genus Collinsella, genus Eisenbergiella, genus Anaerostipes, genus Paraprevotella, genus Parasutterella, and phylum Verrucomicrobia. Sensitivity analyses indicated these findings were reliable without pleiotropy. CONCLUSION: This pioneering study provides novel evidence that specific gut microbiota may play causal roles in CCA risk. Further experimental validation of these candidate microbes is warranted to consolidate causality and mechanisms.

Safety and Efficacy Analysis of PD-1 Inhibitors in Combination with Gemcitabine Plus Nab-Paclitaxel for Advanced Pancreatic Cancer: A Real-World, Single-Center Study.

Background: Pancreatic cancer is a deadly disease with a low five years survival rate, and chemotherapy remains the standard treatment for advanced cases. However, the efficacy of chemotherapy alone is limited, and there is a need for new treatment options. Recently, immune checkpoint inhibitors (ICIs), particularly programmed death-1 (PD-1) inhibitors, have shown promising results in various cancers, including pancreatic cancer. In this study, we explore the safety and efficacy of PD-1 inhibitors in combination with chemotherapy for advanced pancreatic cancer. Materials and Methods: A retrospective analysis was conducted on clinical data from 27 patients with advanced pancreatic cancer who were administered a combination of anti-PD-1 antibody and gemcitabine plus nab-paclitaxel (GnP) regimen. The study evaluated the safety of the treatment as well as the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: In this study, treatment with a combination of anti-PD-1 antibody and GnP regimen for pancreatic cancer resulted in partial response (PR) for 10 out of 27 (37.04%) patients, stable disease (SD) for 10 (37.04%) patients, and progressive disease (PD) for 7 (25.92%) patients. The study found that the median OS (mOS) for these patients was 16.4 months [standard error (SE) = 1.117, 95% confidence interval (CI) 14.211-18.589], while the median PFS (mPFS) was 6.4 months (SE = 1.217, 95% CI 3.981-8.752). Subgroup analysis revealed that pancreatic cancer patients' Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs 1) and treatment cycles (≤6 cycles vs >6 cycles) significantly affected OS and PFS. Patients experienced mostly grade 1-2 adverse events (AEs), which were relieved through clinical treatment. Conclusion: The combination of GnP with anti-PD-1 antibodies shows promise as a potential treatment option for advanced pancreatic cancer.

Nanosecond pulsed electric field stimulates CD103+ DC accumulation in tumor microenvironment via NK-CD103+ DC crosstalk.

CD103+ DC is crucial for antitumor immune response. As a promising local therapy on cancers, nanosecond pulsed electric field (nsPEF) has been widely reported to stimulate anti-tumor immune response, but the underlying relationship between intratumoral CD103+ DC and nsPEF treatment remains enigmatic. Here, we focused on the behavior of CD103+ DC in response to nsPEF treatment and explored the underlying mechanism. We found that the nsPEF treatment led to the activation and accumulation of CD103+ DC in tumor. Depletion of CD103+ DC via Batf3-/- mice demonstrated CD103+ DC was necessary for intratumoral CD8+ T cell infiltration and activation in response to nsPEF treatment. Notably, NK cells recruited CD103+ DC into nsPEF-treated tumor through CCL5. Inflammatory array revealed CD103+ DC-derived IL-12 mediated the CCL5 secretion in NK cells. In addition, the boosted activation and infiltration of intratumoral CD103+ DC were abolished by cGAS-STING pathway inhibition, following IL-12 and CCL5 decreasing. Furthermore, nsPEF treatment promoting CD103+ DC-mediated antitumor response enhanced the effects of CD47 blockade strategy. Together, this study uncovers an unprecedented role for CD103+ DC in nsPEF treatment-elicited antitumor immune response and elucidates the underlying mechanisms.

Advanced hepatocellular carcinoma with MET-amplified contained excellent response to crizotinib: a case report.

Introduction: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Several novel therapeutic strategies have been developed to prolong the survival of patients with advanced HCC. However, therapeutic decision-making biomarkers owing to the extensive heterogeneity of HCC. Next-generation sequencing (NGS) is generally used in treatment decisions to help patients benefit from genome-directed targeting. Case presentation: A 56 year-old male with type-B hepatitis for more than 20 years was admitted to our department and underwent laparoscopic left lateral hepatic lobectomy for hepatocellular carcinoma. Unfortunately, the tumor recurred 1 year later. Despite multiple treatments, the tumor continued to progress and invaded the patient's 5th thoracic vertebras, leading to hypoesthesia and hypokinesia below the nipple line plane 2 years later. NGS revealed MET amplification, and crizotinib, an inhibitor of MET, was recommended. After administration for a month, tumor marker levels decreased, and the tumor shrunk. The patient has remained in remission since that time. Conclusions: We report that a patient with high MET amplification benefited from its inhibitor, which was recommended by NGS. This indicates the potential clinical decision support value of NGS and the satisfactory effect of MET inhibitors.

Isolated pancreatic tuberculosis masquerading as malignancy in an immunocompetent host: a case report and review of the literature.

A 41-year-old man was admitted to our department with a 7-day history of jaundice of the skin. He was misdiagnosed with carcinoma because imaging tests showed a space-occupying lesion in the pancreatic head, and laboratory examinations showed elevated liver enzymes, and elevated serum bilirubin, alpha-fetoprotein, carbohydrate antigen 19-9, and ferroprotein levels. However, there was slight calcification in the lesion and a subsequent T-Spot test result was positive. The patient then underwent endoscopic retrograde cholangiopancreatography for biopsy and bile drainage. Histologically, the pancreatic mass showed granulomatosis, and the pathologic diagnosis of the isolated pancreatic neoplasm was tuberculosis. The patient accordingly received anti-tuberculosis agents, resulting in a significant decrease in the size of the pancreatic mass. The patient recovered well. Pancreatic tuberculosis can masquerade as malignancy; however, careful attention to a differential diagnosis can prevent the need for laparotomy.

Association between gut microbiota and hepatocellular carcinoma from 2011 to 2022: Bibliometric analysis and global trends.

Background: Hepatocellular carcinoma (HCC) is a primary malignant tumor responsible for approximately 90% of all liver cancers in humans, making it one of the leading public health problems worldwide. The gut microbiota is a complex microbial ecosystem that can influence tumor formation, metastasis, and resistance to treatment. Therefore, understanding the potential mechanisms of gut microbiota pathogenesis is critical for the prevention and treatment of HCC. Materials and methods: A search was conducted in the Web of Science Core Collection (WoSCC) database for English literature studies on the relationship between gut microbiota and HCC from 2011 to 2022. Bibliometric analysis tools such as VOSviewer, CiteSpace, and R Studio were used to analyze global trends and research hotspots in this field. Results: A total of 739 eligible publications, comprising of 383 articles and 356 reviews, were analyzed. Over the past 11 years, there has been a rapid increase in the annual number of publications and average citation levels, especially in the last five years. The majority of published articles on this topic originated from China (n=257, 34.78%), followed by the United States of America (n=203, 27.47%), and Italy (n=85, 11.50%). American scholars demonstrated high productivity, prominence, and academic environment influence in the research of this subject. Furthermore, the University of California, San Diego published the most papers (n=24) and had the highest average citation value (value=152.17) in the study of the relationship between gut microbiota and HCC. Schnabl B from the USA and Ohtani N from Japan were the authors with the highest number of publications and average citation value, respectively. Conclusion: In recent years, research on the gut microbiota's role in HCC has made rapid progress. Through a review of published literature, it has been found that the gut microbiota is crucial in the pathogenesis of HCC and in oncotherapy.

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 diffuse-type 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.

Shulan Estimation Model: A New Formula for Estimation of Standard Liver Volume In Chinese Adults.

BACKGROUND: To establish a new and accurate model for standard liver volume (SLV) estimation and graft size prediction in liver transplantation for Chinese adults. METHODS: In this study, the data of morphologic indices and liver volume (LV) were retrospectively obtained on 507 cadaveric liver transplantation donors between June 2017 and September 2020 in Shulan (Hangzhou) Hospital. Linear regression analysis was performed to evaluate the impact of each parameter and develop a new SLV formula. The new formula was then validated prospectively on 97 donors between October 2020 and June 2021, and the prediction accuracy was compared with previous formulas. RESULTS: The average LV in all subjects was 1445.68 ± 309.94 mL. Body weight (BW) showing the strongest correlation (r = 0.453, P < .001). By stepwise multiple linear regression analysis, BW and age were the only 2 independent correlation factors for LV. Shulan estimation model derived: SLV (mL) = 13.266 × BW (kg) - 4.693 × age + 797.16 (R2 = 0.236, P < .001). In the validation cohort, our new model achieved no significant differences between the estimated SLV and the actual LV (P > .05), and showed the lowest mean percentage error of 0.33%. The proportions of estimated SLV within the actual LV ± 20%, ± 15%, and ± 10% percentage errors were 69.1%, 55.7%, and 40.2%, respectively. DISCUSSION: The Shulan SLV estimation model predicted LV more accurately than previous formulas on Chinese adults, which could serve as a simple screening tool during the initial assessment of graft volume for potential donors.

ABO-Incompatible Liver Transplantation under the Desensitization Protocol with Rituximab: Effect on Biliary Microbiota and Metabolites.

Background: ABO-incompatible liver transplantation (ABOi LT) under the desensitization protocol with rituximab had excellent survival outcomes comparable to those of ABO-compatible liver transplantation (ABOc LT). In this work, we explored the effect of ABOi LT on recipients from the perspective of biliary microbiota and metabonomics. Methods: Liver transplant (LT) recipients treated at our center were enrolled in the study. In total, 6 ABOi LT recipients and 12 ABOc LT recipients were enrolled, and we collected their bile five times (during LT and at 2 days, 1 week, 2 weeks and 1 month after LT). The collected samples were used for 16S ribosomal RNA sequencing and liquid chromatography mass spectrometry analysis. Results: We obtained 90 bile samples. Whether in group ABOi LT or ABOc LT, the most common phyla in all of the samples were Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria. The most common genera were Lactobacillus, Weissella, Klebsiella, Pantoea and Lactococcus. There was no significant difference in the diversity between the two groups at 1 week, 2 weeks and 1 month after LT. However, the biggest disparities between the ABOi LT recipients and ABOc LT recipients were observed 2 days after LT, including increased biodiversity with a higher ACE, Chao1, OBS and Shannon index (p < 0.05), and more Staphylococcus in ABOi LT and binary−Jaccard dissimilarity, which indicated varying ß-diversity (p = 0.046). These differences were not observed at 1 week, 2 weeks and 1 month after LT. The principal coordinate analysis (PCoA) revealed that the composition of the bile microbiota did not change significantly within 1 month after LT by longitudinal comparison. In an analysis of the bile components, the metabolites were not significantly different every time. However, four enrichment KEGG pathways were observed among the groups. Conclusion: These findings suggest that ABOi LT under the desensitization protocol with rituximab did not significantly affect the biliary microbiota and metabolites of recipients.

Identification of Key mRNAs as Prediction Models for Early Metastasis of Pancreatic Cancer Based on LASSO.

Pancreatic cancer is a highly malignant and metastatic tumor of the digestive system. Even after surgical removal of the tumor, most patients are still at risk of metastasis. Therefore, screening for metastatic biomarkers can identify precise therapeutic intervention targets. In this study, we analyzed 96 pancreatic cancer samples from The Cancer Genome Atlas (TCGA) without metastasis or with metastasis after R0 resection. We also retrieved data from metastatic pancreatic cancer cell lines from Gene Expression Omnibus (GEO), as well as collected sequencing data from our own cell lines, BxPC-3 and BxPC-3-M8. Finally, we analyzed the expression of metastasis-related genes in different datasets by the Limma and edgeR packages in R software, and enrichment analysis of differential gene expression was used to gain insight into the mechanism of pancreatic cancer metastasis. Our analysis identified six genes as risk factors for predicting metastatic status by LASSO regression, including zinc finger BED-Type Containing 2 (ZBED2), S100 calcium-binding protein A2 (S100A2), Jagged canonical Notch ligand 1 (JAG1), laminin subunit gamma 2 (LAMC2), transglutaminase 2 (TGM2), and the transcription factor hepatic leukemia factor (HLF). We used these six EMT-related genes to construct a risk-scoring model. The receiver operating characteristic (ROC) curve showed that the risk score could better predict the risk of metastasis. Univariate and multivariate Cox regression analyses revealed that the risk score was also an important predictor of pancreatic cancer. In conclusion, 6-mRNA expression is a potentially valuable method for predicting pancreatic cancer metastasis, assessing clinical outcomes, and facilitating future personalized treatment for patients with ductal adenocarcinoma of the pancreas (PDAC).

Influence of dialysis duration on outcomes of simultaneous pancreas-kidney transplant.

OBJECTIVE: The objective of this study was to assess how pre-transplant dialysis duration affects transplant outcomes after simultaneous pancreas-kidney transplant (SPK) in patients with type 1 diabetes mellitus (T1DM). METHODS: Data of 6887 T1DM patients who underwent SPK transplantation between 2008 and 2018 were obtained from the Scientific Registry of Transplant Recipients database. According to pre-transplant dialysis duration, the patients were divided into the preemptive SPK, 0-2 years, 2-5 years, and >5 years dialysis groups. Kaplan-Meier survival analysis was performed to compare patient and graft survival among the groups. Univariate and multivariate Cox regression analyses were used to identify predictors of transplant outcomes. RESULTS: The mean follow-up period was 56.7 ± 34.7 months. Compared with no dialysis or preemptive SPK, dialysis for 0-2 years was not significantly associated with patient or kidney graft survival, while long-term dialysis of 2-5 years and >5 years was significantly associated with increased risk of death and kidney graft failure. However, the duration of dialysis was not associated with pancreas graft survival. CONCLUSION: Long-term dialysis duration before SPK transplant is an independent predictor of patient death and kidney graft failure in T1DM patients.

Outcomes of liver-kidney transplantation in patients with primary hyperoxaluria: an analysis of the scientific registry of transplant recipients database.

BACKGROUND: Primary hyperoxaluria (PH) is an inherited disease lacking of hepatic oxalic acid metabolic enzymes which could lead to irreverisible renal damage. Currently, liver-kidney transplantation is a curative but highly invasive therapy used to treat patients with PH. However, limited studies have focused on combined liver-kidney transplantation (CLKT) and sequential liver and kidney transplantation (SLKT) in patients with PH. METHODS: The present study included 201 patients with PH who received both liver and kidney transplants and who were listed on the Scientific Registry of Transplant Recipients from 1987 to 2018. According to the liver-kidney transplant procedure, patients were separated into a CLKT group and a SLKT group. Patient demographics and transplant outcomes were assessed in each group. RESULTS: Compared with the SLKT group, The CLKT group got a worse pretransplant dialysis condition in both the proportion of patients under pretransplant dialysis (p = 0.048) and the duration of the pretransplant dialysis (p < 0.001). The SLKT group got higher human leukocyte antigen mismatch score of kidney donor (p < 0.001) and liver donor (p = 0.003). The CLKT group utilized higher proportion (98.9%) of organs from a single deceased donor, while the SLKT group utilized 75.0% of organs from deceased liver donors and only 35.0% of organs from deceased kidney donors (p < 0.001). Kidney function measured by serum creatinine concentration before liver transplantation (LT) or CLKT was similar (p = 0.305) between groups. Patient survival was not significantly different between the two groups (p = 0.717) and liver (p = 0.685) and kidney (p = 0.464) graft outcomes were comparable between the two groups. CONCLUSIONS: SLKT seems to be an alternative option with strict condition for CLKT, further exploration about the SLKT is still required.

Influence of duration of type 1 diabetes on long-term pancreatic transplant outcomes.

BACKGROUND: There are no multicenter studies on the influence of diabetes duration on pancreatic transplant outcomes. Our study aimed to determine how type 1 diabetes duration influenced survival of pancreatic grafts. METHODS: The data of 8,139 patients who received pancreas transplants during 2006-2015 were extracted from the Scientific Registry of Transplant Recipients database. Patients were separated into two groups according to duration of diabetes: S group (diabetes ≤20 years) and L group (>20 years). RESULTS: Compared to S group, L group were older and prone to be male, to have higher body mass index, to receive pancreas after kidney transplantation (PAK), and to be White. Patient survival was not significantly different between the two groups, but pancreatic survival was better in the L group (hazard ratio 0.88; P = 0.012). Pancreatic survival of L group was better than S group in pancreas transplant alone and simultaneous pancreas-kidney transplantation (SPK). Graft survival was not significant different between the two groups in PAK. Diabetes duration was an independent predictor of graft survival in SPK patients (hazard ratio 0.86; P = 0.012). CONCLUSIONS: Diabetes duration has no influence on patient survival. However, long duration of type 1 diabetes mellitus appears to be protective against pancreatic graft loss.

Pancreas grafts for transplantation from donors with hypertension: an analysis of the scientific registry of transplant recipients database.

BACKGROUND: With the rising demands for pancreas transplantation, surgeons are trying to extend the donors pool and set up a more appropriate assessment system. We aim to evaluate the effect of donor hypertension on recipient overall and graft survival rates. METHODS: Twenty-four thousand one hundred ninety-two pancreas transplantation patients from the Scientific Registry of Transplant Recipients database were subdivided into hypertension group (HTN, n = 1531) and non-hypertension group (non-HTN, n = 22,661) according to the hypertension status of donors. Recipient overall and graft survival were analyzed and compared by log rank test, and hazard ratios of predictors were estimated using Cox proportional hazard models. RESULTS: Patient overall and graft survival of non-HTN group were higher than that of the HTN group (both p < 0.001). The duration of hypertension negatively influenced both overall and graft survival rates (both p < 0.001). Multivariate analyses demonstrated that hypertension was an independent factor for reduced survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.01-1.18; p < 0.001). Other independent factors included recipient body mass index (HR, 1.02; 95% CI, 1.01-1.05; p < 0.001) and transplant type (pancreas after kidney transplants / pancreas transplant alone vs. simultaneous pancreas-kidney transplants; HR, 1.41; 95% CI, 134-1.55; p < 0.001). CONCLUSIONS: Donor hypertension is an independent factor for recipient survival after pancreas transplantation and could be considered in donor selection as well as post-transplant surveillance in clinical practice.

Potential roles of eosinophils in cancer therapy: epidemiological studies, experimental models, and clinical pathology.

Eosinophils play important roles in allergic diseases as well as during helminth infection. As multifunctional leukocytes, eosinophils have also been indicated in anti-cancer immunity. Published studies have suggested an association between allergic conditions and a trend of decreased risk in numerous malignances. Moreover, eosinophil infiltration in tumor tissue is considered an independent prognostic factor. Eosinophils are often recruited to tumor sites, where eosinophil granule proteins and cytokines are released upon activation, which in turn damage and kill tumor cells. In the last decade, a number of patents based on potential cancer therapy using eosinophilic cytokines have been awarded. In this article, we review the current findings on epidemiology, experimental models, clinical pathology, and molecular mechanisms involved in the response of eosinophils towards cancer. Moreover, we discuss promising targeted therapies with eosinophilic cytokines as a novel perspective to combat cancer.