Deciphering the role of Enterococcus faecium cytidine deaminase in gemcitabine resistance of gallbladder cancer.

Gemcitabine-based chemotherapy is a cornerstone of standard care for gallbladder cancer (GBC) treatment. Still, drug resistance remains a significant challenge, influenced by factors such as tumor-associated microbiota impacting drug concentrations within tumors. Enterococcus faecium, a member of tumor-associated microbiota, was notably enriched in the GBC patient cluster. In this study, we investigated the biochemical characteristics, catalytic activity, and kinetics of the cytidine deaminase of E. faecium (EfCDA). EfCDA showed the ability to convert gemcitabine to its metabolite 2',2'-difluorodeoxyuridine. Both EfCDA and E. faecium can induce gemcitabine resistance in GBC cells. Moreover, we determined the crystal structure of EfCDA, in its apo form and in complex with 2', 2'-difluorodeoxyuridine at high resolution. Mutation of key residues abolished the catalytic activity of EfCDA and reduced the gemcitabine resistance in GBC cells. Our findings provide structural insights into the molecular basis for recognizing gemcitabine metabolite by a bacteria CDA protein and may provide potential strategies to combat cancer drug resistance and improve the efficacy of gemcitabine-based chemotherapy in GBC treatment.

PARP inhibitor and immune checkpoint inhibitor have synergism efficacy in gallbladder cancer.

Gallbladder cancer (GBC) is an aggressive cancer with poor prognosis. PARP inhibitors (PARPi) target PARP enzymes and have shown efficacy in patients with breast cancer gene (BRCA) mutations. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has transformed cancer treatment. However, the combined impact of PARPi and ICIs in GBC remains unclear. We present a groundbreaking case of a GBC patient with BRCA2 mutations who received combination therapy with PARPi and ICIs after failing multiple lines of treatment. Next-generation sequencing (NGS-Seq) identified BRCA gene mutations. To further investigate potential mechanisms, we developed a PARP1-BRCA1-BRCA2 pathway-related risk score (PBscore) system to evaluate the impact of PARPi on the tumor immune microenvironment via RNA-Seq data. Gene expression and functional analysis identified potential mechanisms associated with the PBscore. Experimental validation assessed the impact of the combination therapy on the tumor microenvironment using multiplexed immunofluorescence imaging and immunohistochemistry in patients with BRCA gene wild type or mutations. RNA-Seq analysis revealed correlations between PBscore, immune checkpoint levels, tumor-infiltrating immune cells (TIICs), and the cancer-immunity cycle. Multiplexed immunofluorescence imaging validated that low PBscore patients might have an active tumor microenvironment. Furthermore, upon drug resistance, we observed an upregulation of negative immune checkpoints such as CEACAM1, indicating that the tumor immune microenvironment becomes suppressed after resistance. Our study revealed that PBscore could serve as a biomarker to predict immunotherapy efficacy, offering a promising alternative for BRCA2-mutated GBC patients.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer.

BACKGROUND: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC). METHODS: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety. RESULTS: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported. CONCLUSION: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

Prognostic Impact of Neoadjuvant Chemotherapy in Localized or Locoregionally Advanced Gallbladder Cancer: A Population-Based and Propensity Score Matched SEER Analysis.

BACKGROUND: The effect of neoadjuvant chemotherapy (NACT) in gallbladder cancer (GBC) patients remains controversial. The aim of this study was to assess the impact of NACT on overall survival (OS) and cancer specific survival (CSS) in patients with localized or locoregionally advanced GBC, and to explore possible protective predictors for prognosis. METHODS: Data for patients with localized or locoregionally advanced GBC (i.e., categories cTx-cT4, cN0-2, and cM0) from 2004 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients in the NACT and non-NACT groups were propensity score matched (PSM) 1:3, and the Kaplan-Meier method and log-rank test were performed to analyze the impact of NACT on OS and CSS. Univariable and multivariable Cox regression models were applied to identify the possible prognostic factors. Subgroup analysis was conducted to identify patients who would benefit from NACT. RESULTS: Of the 2676 cases included, 78 NACT and 234 non-NACT patients remained after PSM. In localized or locoregionally advanced GBC patients, the median OS of the NACT and non-NACT was 31 and 16 months (log-rank P < 0.01), and the median CSS of NACT and non-NACT was 32 and 17 months (log-rank P < 0.01), respectively. Longer median OS (31 vs 17 months, log-rank P < 0.01) and CSS (32 vs 20 months, log-rank P < 0.01) was associated with NACT compared with surgery alone. Multivariable Cox regression analysis showed that NACT, stage, and surgery type were prognostic factors for OS and CSS in GBC patients. Subgroup analysis revealed that the survival hazard ratios (HRs) of NACT vs non-NACT for localized or locoregionally advanced GBC patients were significant in most subgroups. CONCLUSIONS: NACT may provide therapeutic benefits for localized or locoregionally advanced GBC patients, especially for those with advanced stage, node-positive, poorly differentiated or undifferentiated disease. NACT combined with radical surgery was associated with a survival advantage. Therefore, NACT combined with surgery may provide a better treatment option for resectable GBC patients.

Surgical Resection Alone is Associated With Higher Long-Term Survival Than Multiagent Chemotherapy Alone for Patients With Localized Biliary Tract Cancers.

INTRODUCTION: We compared long-term survival of patients with localized biliary tract cancers (BTCs) treated with either surgical resection or multiagent chemotherapy. METHODS: Patients with localized BTC [gallbladder adenocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma] were identified within the National Cancer Database (2010-2017). Piecewise-constant hazard modeling was used to estimate hazard ratios (HRs) at prespecified intervals: 0-30 d, 31-60 d, 61-90 d, and >90 d post-treatment. RESULTS: A total of 5988 patients with localized BTC were identified: 2697 (45.0%) received multiagent chemotherapy and 3291 (55.0%) underwent surgical resection. Patients with gallbladder adenocarcinoma or extrahepatic cholangiocarcinoma who were treated with surgical resection had an associated decline in overall survival (OS) as compared to those treated with multiagent chemotherapy within 0-30 d of treatment initiation (gallbladder adenocarcinoma [adjusted HR = 3.94, 95% confidence interval [CI]: 1.77-8.80]; extrahepatic cholangiocarcinoma [adjusted HR = 4.88, 95% CI: 2.76-8.61]). However, there was an associated improvement in OS for patients treated with surgical resection after 90 d from treatment initiation (gallbladder adenocarcinoma [adjusted HR = 0.36, 95% CI: 0.28-0.46]; extrahepatic cholangiocarcinoma [adjusted HR = 0.27, 95% CI: 0.24-0.32]). Among patients with intrahepatic cholangiocarcinoma, those who underwent surgical resection had an associated improvement in OS at 31-60 d (adjusted HR = 0.63, 95% CI: 0.40-0.99) and a further associated increase in OS at 61-90 d (adjusted HR = 0.34, 95% CI: 0.21-0.54) and after 90 d (HR = 0.23, 95% CI: 0.21-0.27) of treatment initiation. CONCLUSIONS: For patients with localized BTC, surgical resection alone is associated with improved long-term survival outcomes compared to multiagent chemotherapy alone.

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics.

The aim of this investigation was to evaluate the differential expression of the sterol O-acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC-996, NOZ, and gallbladder cancer (GBC)-SD using Western blot and q-PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC-996 and GBC-SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer.

Propofol Modulates Gallbladder Cancer Progression via miR-4430/SLC19A3 Axis.

Background/Aim: Propofol is a common anesthetic used during surgery. MircoRNA (miRNA), especially miR-4430, is currently a research hotspot in GBC. This study investigates whether propofol regulates GBC through the miR-4430/SLC19A3 axis. Materials and methods: NOZ and SGC996 cells, human gallbladder cancer cell lines, were obtained from BLUEFBIO (Shanghai, China). The cells were treated with propofol, and the experimental setup included a control group. qRT-PCR was used to measure the content of miR-4430 and solute carrier family 19 member 3 (SLC19A3). The cell viability, migration, and apoptosis were analyzed by colony formation assay, wound healing assay, and flow cytometry, respectively. Western blot tested the levels of SLC91A3, cyclin D-dependent kinases 6 (CDK6), and Bax proteins. Mechanically, dual-luciferase reporter assay notarized the link of miR-4430 with SLC19A3. Results: Propofol significantly repressed the proliferation of GBC cells, as indicated by a pronounced reduction in colony formation in both NOZ and SGC996 cells (P = .025, 95% CI:1.2, 2.4). The inhibitory effect of propofol was reversed by the enhanced expression of miR-4430 in GBC cells. Furthermore, SLC19A3 was identified as a direct target of miR-4430. Silencing SLC19A3 reversed the altered cell behavior observed in propofol-treated GBC cells (P = .019, 95% CI:1.6, 3.5). Additionally, overexpression of SLC19A3 significantly attenuated both cell proliferation and migration influenced by miR-4430 in propofol-treated GBC cells (P = .034, 95% CI:1.4, 2.8). Conclusion: Propofol changed the cell behaviors of GBC by modulating the miR-4430/SLC19A3 axis.

A Case of Gallbladder Metastasis of Malignant Melanoma.

In the clinical course of malignant melanoma, which can metastasize to multiple organs, gallbladder metastases are rarely detected. A 69-year-old man who underwent resection of a primary malignant melanoma was subsequently treated with nivolumab for lung metastases and achieved complete response. Seven years after surgery, multiple nodules were found in the gallbladder, and he underwent laparoscopic cholecystectomy. The postoperative diagnosis was metastases of malignant melanoma. He has been recurrence-free 8 months after surgery. If radical resection is possible, such surgery should be performed for gallbladder metastases found in patients with other controlled lesions of malignant melanoma.

[A Case of Radical Hepatectomy in a Patient with Recurrent Liver Metastasis of Gallbladder Cancer after Successful Chemotherapy with GC+Durvalumab].

A 49-year-old man underwent an open cholecystectomy for advanced gallbladder cancer in 2021. Three months after surgery, the patient underwent an additional resection, which showed no malignant findings, but 12 months after surgery, contrast-enhanced CT and MRI showed a new mass lesion in segment 8 of the liver, and the patient was diagnosed with postoperative hepatic metastatic recurrence of gallbladder cancer. After referral to our institution, he received 1 course of gemcitabine+cisplatin(GC)therapy and 8 courses of gemcitabine+cisplatin+durvalumab(GCD)therapy. Contrast- enhanced CT and MRI showed that the metastases had shrunk, and PET scan showed no FDG accumulation. Two months after completion of chemotherapy, there was no evidence of metastatic enlargement and new metastasis including distant metastasis, and the patient was referred to our department. Since curative resection was expected, a laparoscopic partial hepatectomy of segment 8 of the liver was performed. Pathological diagnosis revealed no residual tumor. If the metastases could be well controlled by systemic chemotherapy, hepatectomy for hepatic metastases of biliary tract cancer could be a treatment option.

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

Trends in Receipt of Adjuvant Chemotherapy and its Impact on Survival in Resected Biliary Tract Cancers.

BACKGROUND: Resection remains the cornerstone of curative-intent treatment for biliary tract cancers (BTCs). However, recent randomized data also support a role for adjuvant chemotherapy (AC). This study aimed to characterize trends in the use of AC and subsequent outcomes in gallbladder cancer and cholangiocarcinoma (CCA). METHODS: The National Cancer Database (NCDB) was queried for patients with resected, localized BTC from 2010 to 2018. Trends in AC were compared among BTC subtypes and stages of disease. Multivariable logistic regression was used to identify factors associated with receipt of AC. Survival analysis was performed with Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: The study identified 7039 patients: 4657 (66%) with gallbladder cancer, 1159 (17%) with intrahepatic CCA (iCCA), and 1223 (17%) with extrahepatic CCA (eCCA). Adjuvant chemotherapy was administered to 2172 (31%) patients, increasing from 23% in 2010 to 41% in 2018. Factors associated with AC included female sex, year of diagnosis, private insurance, care at an academic center, higher education, eCCA (vs iCCA), positive margins, and stage II or III disease (vs stage I). Alternatively, increasing age, higher comorbidity score, gallbladder cancer (vs iCCA), and farther travel distance for treatment were associated with reduced odds of AC. Overall, AC was not associated with a survival advantage. However, subgroup analysis showed that AC was associated with a significant reduction in mortality among patients with eCCA. CONCLUSIONS: Among the patients with resected BTC, those who received AC were in the minority. In the context of recent randomized data and evolving recommendations, emphasis on guideline concordance with a focus on at-risk populations may improve outcomes.

A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance.

Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.

Isoalantolactone suppresses gallbladder cancer progression via inhibiting the ERK signalling pathway.

CONTEXT: Gallbladder cancer (GBC) is the most common malignant tumour of the biliary tract. Isoalantolactone (IAL), an active sesquiterpene lactone compound isolated from the roots of Inula helenium L. (Asteraceae), has antitumour effects. OBJECTIVE: This study investigates the effects of IAL on GBC. MATERIALS AND METHODS: In vitro, NOZ and GBC-SD cells were treated with IAL (0, 10, 20 and 40 µM) for 24 h. The DMSO-treated cells were selected as a control. Cell proliferation, migration, invasion and apoptosis were measured by the CCK-8 assay, transwell assay, flow cytometry and western blot. In vivo, subcutaneous tumour xenografts were constructed by injecting nude mice (BALB/C) with 5 × 106 NOZ cells. Mice were divided into the control group (equal amount of DMSO), the IAL group (10 mg/kg/day) and the IAL + Ro 67-7476 group (IAL, 10 mg/kg/day; Ro 67-7476, 4 mg/kg/day). The study duration was 30 days. RESULTS: Compared with the DMSO group, cell proliferation of NOZ (IC50 15.98 µM) and GBC-SD (IC50 20.22 µM) was inhibited by about 70% in the IAL 40 µM group. Migration and invasion were suppressed by about 80%. Cell apoptosis rate was increased about three-fold. The phosphorylation level of ERK was decreased to 30-35%. Tumour volume and weight (about 80% reduction) were suppressed by IAL in vivo. Moreover, the effects of IAL were abolished by Ro 67-7476 in vitro and in vivo. DISCUSSION AND CONCLUSIONS: Our findings indicate that IAL could inhibit GBC progression in vitro and in vivo by inhibiting the ERK signalling pathway.

[A Case of Conversion Surgery for Gallbladder Cancer with Para-Aortic Lymph Node Metastasis].

The study presents the case of a 71-year-old woman who visited a nearby hospital for epigastric pain and weight loss. A CT scan showed a mass in the gallbladder, and the CEA level was high, so she was referred to our hospital for further investigation. Abdominal US, CT, and MRI suggested gallbladder cancer with para-aortic metastasis, and the histological findings on the EUS-FNA confirmed the diagnosis. Since surgical resection was not indicated, chemotherapy was performed(gemcitabine plus cisplatin). After 10 courses of chemotherapy, CT and MRI showed downsizing of para-aortic lymph nodes, and no accumulation of FDG was found on FDG-PET. Confirming the downstaging of cancer, conversion surgery, comprising an extended cholecystectomy and a lymph node resection, was performed. The pathological diagnosis showed no lymph node metastasis. No recurrence was observed after 12 months of surgery. Initially, unresectable gallbladder cancer with para-aortic lymph node metastasis was indicated to be compatible with preoperative chemotherapy and conversion surgery.

[Conversion Surgery Following Systemic Chemotherapy for Advanced Gallbladder Cancer with Peritoneal Dissemination-A Case Report].

A 73-year-old female was diagnosed with gallbladder cancer, but the future liver remnant volume was deemed insufficient for curative resection. Consequently, transileocolic portal vein embolization was performed. During laparotomy, multiple nodules were palpable on the peritoneal surface of the pelvic floor. Subsequently, staging laparoscopy confirmed the pathological diagnosis of adenocarcinoma in the resected nodules, indicating peritoneal dissemination of gall bladder cancer. Due to this peritoneal dissemination, surgical resection was deemed inappropriate, and the patient was initiated on systemic chemotherapy consisting of gemcitabine and cisplatin. Following 22 courses of chemotherapy, contrast-enhanced computed tomography demonstrated no significant changes in the size of the primary tumor or its location relative to the main vessels, although a small metastatic lesion was identified in the gallbladder bed. At the second staging laparoscopy, any nodules suggesting peritoneal dissemination were observed. Based on these findings, we decided to perform curative resection. The surgical procedure involved right hepatectomy plus segment 4a resection, extrahepatic bile duct resection, and hepaticojejunostomy. Pathological examination revealed ypT3bN0M1(HEP), ypStage ⅣB, with the achievement of R0 resection. The patient survived with no recurrences for 40 months after surgery. These results suggest that aggressive therapeutic strategies, including conversion surgery following systemic chemotherapy, may be beneficial for patients initially deemed unresectable due to gallbladder cancer.

[Three Cases of Conversion Surgery for Unresectable Advanced Gallbladder Cancer with Distant Metastasis Treated with Gemcitabine plus CDDP].

All three patients were female, one in her 50s, and the other two in their 60s. The one in her 50s had liver metastasis and the other two had unresectable advanced cholecystic carcinomas with peritoneal dissemination. All three received 8-12 courses of gemcitabine plus CDDP(GC). After GC, all three were deemed to be candidates for R0 resection and underwent resection of two central liver segments. In addition, the second patient required an extrahepatic cholangiectomy; an extended cholecystectomy, plus an extrahepatic cholangiectomy, plus a complete omental resection; and the third needed an extended cholecystectomy, plus an extrahepatic cholangiectomy with a partial transverse colon resection, plus a partial duodenectomy. The pathologic response to chemotherapy was moderate in the patient with liver metastases, mild in the one who underwent the omental resection, and moderate in the patient who had the partial resection of the digestive tract. All three patients continued with postoperative chemotherapy. The patient with liver metastases and the one with the partial gastrointestinal tract resection have survived without recurrence for 52 months and 43 months, respectively, after the initial treatment. The patient with the omental resection has survived 44 months after the initial treatment with recurrent peritoneal dissemination and is continuing chemotherapy as an outpatient. Although further study is needed to accumulate more cases, the results suggest the usefulness of multidisciplinary treatment including conversion surgery in cases such as these.

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience].

BACKGROUND: Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer. METHODS: GEM plus CDDP combination therapy was administered to 29 patients with unresectable biliary tract cancer from 2016 to 2021. RESULTS: The mean age was 71.9 years, male/ female 19/10. The target of chemotherapy was below, local progression was 3 cases, first distant metastasis 7 cases, metastatic recurrence 19 cases. The type of cancer was below, intrahepatic bile duct carcinoma was 8 cases, hepatic hilar bile duct carcinoma 6 cases, gallbladder carcinoma 5 cases, cystic duct carcinoma 1 case, distal bile duct carcinoma 6 cases, and papilla Vater's cancer 3 cases. The dosing period was 23.1 weeks(range 2-52 weeks). The relative dose intensities of GEM and CDDP were 73.7% and 75.1%. The adverse events were below, the hematological toxicities of Grade 3 or higher were neutropenia(65.5%), leukopenia(3.4%), and thrombocytopenia(10.3%). Non-hematological toxicities of Grade 2 or higher were fatigue(13.7%)and skin rash(6.9%). There was no interstitial pneumonia. The disease control rate was 66.7 %(complete response, n=0; partial response, n=6; stable disease, n=10; progressive disease, n=8). CONCLUSION: GEM plus CDDP combination therapy was safe to perform and was an effective treatment for unresectable biliary tract cancer.

A real-world study of the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer.

BACKGROUND: Anti-PD-1 antibodies plus lenvatinib therapeutic regimens have demonstrated a relatively high antitumor response in many solid cancers; however, the efficacy and safety of anti-PD-1 antibodies plus lenvatinib in patients with advanced gallbladder cancer (GBC) has not been reported. METHODS: Advanced GBC patients who received anti-PD-1 antibodies plus lenvatinib were retrospectively screened. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), PD-L1 expression and safety were evaluated to identify efficacy biomarkers. RESULTS: A total of 31 GBC patients were included in this study. After a median follow-up of 8 months and 23 deaths were observed. The median PFS was 5.0 months (95% CI: 4.1-8.0 months), and the median OS was 11.3 months (95% CI: 7.5-20.9 months). Overall, the ORR was 32.3%, the DCR was 83.9%, and the CBR was 41.9%. Moreover, after treatment, 3 patients received conventional surgery, in which 1 patient achieved a pathological complete response. All patients (100%) experienced adverse events (AEs), and 58.1% of the patients experienced grade 3 AEs. The most commonly observed grade 3 AEs included fatigue (5/31, 16.1%), decreased appetite (5/31, 16.1%), hypertension (4/31, 12.9%) and bilirubin elevation (4/31, 12.9%). Subgroup analysis revealed that positive PD-L1 expression maybe associate with a longer PFS. CONCLUSION: Anti-PD-1 antibodies plus lenvatinib represent an effective and tolerable therapy for patients with advanced gallbladder cancer.