Prognostic Significance of Sarcopenia and Eicosapentaenoic Acid (EPA) Levels in Patients With Unresectable Pancreatic or Biliary Tract Cancer.

Background/Aim: This study aimed to investigate the relationship between prechemotherapy blood eicosapentaenoic acid (EPA) levels, sarcopenia, and overall survival in patients with pancreatic and biliary tract cancer undergoing chemotherapy. Patients and Methods: Forty-five patients with recurrent, non-resected pancreatic or biliary tract cancer undergoing chemotherapy were retrospectively analyzed. The skeletal muscle mass was measured at the third lumbar vertebra. Sarcopenia cut-off values were based on the Japanese Society of Hepatology sarcopenia assessment criteria. Two months after starting chemotherapy, the patients received enteral nutrition containing omega-3 fatty acids. Results: Patients with pancreatic and biliary tract cancers with low pre-treatment blood EPA levels had significantly more intense sarcopenia than those with high EPA levels (p=0.023). Patients with sarcopenia before chemotherapy had significantly lower overall survival than those without sarcopenia. Multivariate analysis revealed blood EPA concentration as an independent prognostic factor (p<0.01). Lumbar muscle volume, a marker of sarcopenia, showed a clear positive correlation with prechemotherapy EPA concentration (p=0.008). In patients administered with enteral nutrition containing omega-3 fatty acids, both EPA concentration and lumbar muscle volume were significantly higher than those prior to intervention, indicating sarcopenia improvement due to the intervention. Conclusion: In patients with recurrent non-resected pancreatic and biliary tract cancer, low blood EPA levels before chemotherapy are associated with sarcopenia and poor prognosis.

The prognosis-based classification model in resectable pancreatic cancer.

AIM: Pancreatic ductal adenocarcinoma treatment is mainly based on the anatomical resectability classification. However, prognosis-based classification may be more reasonable. In this study, we stratified resectable pancreatic ductal adenocarcinoma according to preoperative factors and reconsidered treatment strategies. METHODS: We retrospectively evaluated 131 patients who underwent upfront surgery for resectable pancreatic ductal adenocarcinoma between 2007 and 2019. Recurrence within 1 year after surgery was defined as early recurrence, and the risk factors for early recurrence were identified using preoperative factors. Subsequently, we calculated the scores and stratified the participant groups. RESULTS: Fifty-five (42 %) patients who relapsed within 1 year showed significantly poorer survival than those without recurrence (median overall survival, 14.0 vs. 80.6 months; p < 0.01). Multivariate analysis revealed that a tumor diameter of ≥24 mm (p < 0.01) and preoperative serum carbohydrate antigen 19-9 level of ≥380 U/mL (p = 0.04) were the independent risk factors for early recurrence. Early recurrence score was created using these factors, stratifying the participant group into three groups of 0-2 points, and the prognosis was significantly different (median overall survival, 49.3 vs. 31.2 vs. 16.0 months; p < 0.01). CONCLUSION: We stratified the upfront surgical cases of resectable pancreatic ductal adenocarcinoma. The group with a score of 0 had a good prognosis, and upfront surgery was possibly not futile on patients in poor general condition. The group with a score of 2 had a poor prognosis and may require stronger preoperative treatment.

Osteosarcopenia is a significant predictor of recurrence and the prognosis after resection for extrahepatic bile duct cancer.

PURPOSE: This study examined the impact of osteosarcopenia on recurrence and the prognosis after resection for extrahepatic biliary tract cancer (EBTC). METHODS: We retrospectively analyzed 138 patients after resection for perihilar cholangiocarcinoma (11), distal cholangiocarcinoma (54), gallbladder carcinoma (30), or ampullary carcinoma (43). Osteosarcopenia is defined as the concomitant occurrence of osteopenia and sarcopenia. We investigated the relationship between osteosarcopenia and the overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analyses. RESULTS: Osteosarcopenia was identified in 38 patients (27.5%) before propensity score (PS) matching. In the multivariate analysis, the independent recurrence factors were the prognostic nutrition index (p = 0.015), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.004), perineural invasion (p = 0.002), and non-curability (p = 0.008), whereas the independent prognostic factors were prognostic nutrition index (p = 0.030), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.007), lymphatic invasion (p = 0.018), and non-curability (p = 0.004). After PS matching, there was no significant difference in the variables between the patients with and without osteosarcopenia (n = 34 each). The 5-year DFS and OS after PS matching in patients with osteosarcopenia were significantly worse than in patients without osteosarcopenia (17.6% vs. 38.8%, p = 0.013 and 20.6% vs. 57.4%, p = 0.0005, respectively). CONCLUSIONS: Preoperative osteosarcopenia could predict the DFS and OS of patients after resection for EBTC.

Systemic inflammation adversely affects response to anamorelin in patients with pancreatic cancer.

PURPOSE: Anamorelin, a selective ghrelin receptor agonist, has been approved for pancreatic cancer treatment in Japan. We aimed to investigate whether systemic inflammation, represented by the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP)-albumin ratio (CAR), could predict the effect of anamorelin in patients with advanced pancreatic cancer. METHODS: This study included 31 patients who had received anamorelin for advanced pancreatic cancer between 2021 and 2023. Patients' NLR, PLR, LMR, and CAR were evaluated before anamorelin administration. The patients were classified as responders and non-responders based on whether they gained body weight after 3 months of anamorelin administration. We investigated the association between systemic inflammation and anamorelin efficacy using a univariate analysis. RESULTS: Twelve (39%) patients were non-responders. A high serum CRP level (p = 0.007) and high CAR (p = 0.013) was associated with non-response to anamorelin. According to the receiver operating characteristics analysis, the CAR cutoff value was 0.06, and CAR ≥ 0.06 was a risk factor (odds ratio, 5.6 [95% confidence interval 1.2-27.1], p = 0.032) for non-response to anamorelin. CONCLUSION: CAR can be a predictor of non-response to anamorelin in patients with advanced pancreatic cancer, suggesting the importance of a comprehensive assessment of the inflammatory status.

Superior mesenteric vein/portal vein contact in preoperative imaging indicates biological malignancy in anatomically resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer in contact with the superior mesenteric vein/portal vein is classified as resectable pancreatic cancer; however, the biological malignancy and treatment strategy have not been clarified. METHODS: Data from 186 patients who underwent pancreatectomy for pancreatic cancer were evaluated using a prospectively maintained database. The patients were classified as having resectable tumors without superior mesenteric vein/portal vein contact and with superior mesenteric vein/portal vein contact of ≤180°. Disease-free survival, overall survival, and prognostic factors were analyzed. RESULTS: In the univariate analysis, superior mesenteric vein/portal vein contact in resectable pancreatic cancer was a significant prognostic index for disease-free survival and overall survival. In the multivariate analysis for poor disease-free survival, the superior mesenteric vein/portal vein contact remained significant (hazard ratio = 2.13, 95% confidence interval: 1.29-3.51; p < 0.01). In the multivariate analysis, superior mesenteric vein/portal vein contact was a significant independent prognostic index for overall survival (hazard ratio = 2.17, 95% confidence interval: 1.27-3.70; p < 0.01), along with sex, tumor differentiation, nodal involvement, and adjuvant chemotherapy. Portal vein resection for superior mesenteric vein/portal vein contact did not improve the overall survival (p = 0.86). CONCLUSIONS: Superior mesenteric vein/portal vein contact in resectable pancreatic cancer was found to be an independent predictor of disease-free survival and overall survival after elective resection. Thus, pancreatic cancer in contact with the superior mesenteric vein/portal vein may be considered as borderline resectable pancreatic cancer.

Effect of duration of adjuvant chemotherapy with S-1 (6 versus 12 months) for resected pancreatic cancer: the multicenter clinical randomized phase II postoperative adjuvant chemotherapy S-1 (PACS-1) trial.

BACKGROUND: Six-month adjuvant chemotherapy with S-1 is standard care for resected pancreatic cancer in Japan; however, the optimal duration has not been established. We aimed to evaluate the impact of duration of adjuvant chemotherapy with S-1. METHODS: We performed a multicenter, randomized, open-label, phase II study. Patients with histologically proven invasive pancreatic ductal carcinoma, pathological stage I-III, and no local residual or microscopic residual tumor were eligible. Patients were randomized 1:1 to receive 6- or 12-month adjuvant chemotherapy with S-1. The primary endpoint was 2-year overall survival (OS). Secondary endpoints were disease-free survival (DFS) and feasibility. RESULTS: A total of 170 patients were randomized (85 per group); the full analysis set was 82 in both groups. Completion rates were 64.7% (6-month group) and 44.0% (12-month group). Two-year OS was 71.5% (6-month group) and 65.4% (12-month group) (hazard ratio (HR): 1.143; 80% confidence interval CI 0.841-1.553; P = 0.5758). Two-year DFS was 46.4% (6-month group) and 44.9% (12-month group) (HR: 1.069; 95% CI 0.727-1.572; P = 0.6448). In patients who completed the regimen, 2-year DFS was 56.5% (6-month group) and 75.0% (12-month group) (HR: 0.586; 95% CI 0.310-1.105; P = 0.0944). Frequent (≥ 5%) grade ≥ 3 adverse events comprised anorexia (10.5% in the 6-month group) and diarrhea (5.3% vs. 5.1%; 6- vs. 12-month group, respectively). CONCLUSIONS: In patients with resected pancreatic cancer, 12-month adjuvant chemotherapy with S-1 was not superior to 6-month therapy regarding OS and DFS.

Preoperative Therapy for Unresectable Locally Advanced Pancreatic Cancer for ≥6 Months Improves Prognosis After Pancreatectomy.

BACKGROUND/AIM: This study aimed to identify the optimal duration of pretreatment for unresectable locally advanced (UR-LA) pancreatic cancer and analyze its effect on the prognosis. PATIENTS AND METHODS: This retrospective study included 39 patients with UR-LA pancreatic cancer after pancreatectomy. The cutoff period of preoperative therapy was determined using a receiver operating characteristic curve. We investigated the relationship between preoperative and intraoperative clinical variables and overall survival (OS) in univariate and multivariate analyses. The relationship between the preoperative therapy duration and the clinicopathological variables was investigated. OS was compared according to preoperative therapy duration and the presence or absence of adjuvant surgery. RESULTS: After pretreatment, 15 patients underwent adjuvant surgery and 24 patients continued on chemotherapy without surgery. The multivariate analysis demonstrated preoperative therapy duration ≥6 months was an independent prognostic factor [hazard ratio (HR)=0.10, p=0.04]. No significant difference in the clinicopathological variables was observed between the two groups according to preoperative therapy duration. The OS was significantly better in patients who underwent adjuvant surgery after preoperative therapy duration ≥6 months than in those after preoperative therapy duration <6 months and in those without adjuvant surgery (5-year OS rates: 80% vs. 0%; p=0.01 and 5-year OS rates: 80% vs. 0%; p=0.004, respectively). The OS was not significantly better in patients with adjuvant surgery after preoperative therapy duration <6 months than in those without adjuvant surgery (2-year OS rates: 45.7% vs. 38.1%; p=0.98). CONCLUSION: Preoperative therapy for UR-LA pancreatic cancer for ≥6 months is necessary to improve prognosis after adjuvant surgery.

The impact of C-reactive protein-albumin-lymphocyte (CALLY) index on the prognosis of patients with distal cholangiocarcinoma following pancreaticoduodenectomy.

Aim: The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a novel inflammation-based biomarker, which has been associated with long-term outcomes in patients with hepatocellular carcinoma. We aimed to investigate whether the CALLY index can predict the prognosis for distal cholangiocarcinoma after pancreaticoduodenectomy. Methods: The study comprised 143 patients who had undergone primary pancreaticoduodenectomy for distal cholangiocarcinoma between 2002 to 2019. The CALLY index was defined as (albumin × lymphocyte)/ (CRP × 104). We investigated the association of CALLY index with disease-free survival and overall survival by univariate and multivariate analyses. Results: Eighty-seven (61%) patients had a preoperative CALLY index <3.5. In multivariate analysis, obstructive jaundice drainage (P < .01), poorly differentiated tumor (P < .01), and CALLY index<3.5 (P = .02) were independent predictors of disease-free survival, while obstructive jaundice drainage (P < .01), poorly differentiated tumor (P < .01), and CALLY index <3.5 (P = .02) were independent predictors of overall survival. Conclusion: The CALLY index may be an independent and significant indicator of poor long-term outcomes in patients with distal cholangiocarcinoma after pancreaticoduodenectomy, suggesting the importance of comprehensive assessment for inflammatory status.

Multimodal Management for Refractory Biliary Stricture After Living Donor Liver Transplantation.

BACKGROUND: Biliary stricture is a common complication of living donor liver transplantation (LDLT). Endoscopic retrograde biliary drainage (ERBD) is the primary treatment of biliary stricture, which is sometimes refractory. This study aimed to evaluate the risk factors for biliary stricture after LDLT and present successful management for refractory biliary stricture. METHODS: Data from 26 patients who underwent LDLT were retrospectively analyzed. The relationship between the incidence of biliary strictures and clinical variables, including pre/intra/postoperative factors, was assessed. RESULTS: Univariate analysis showed that ABO incompatibility (P = .037) was a significant risk factor for biliary strictures. Case 1 was a 57-year-old woman who underwent LDLT using a left-lobe graft for primary biliary cholangitis (PBC) and developed a biliary stricture 1 month after surgery. Percutaneous transhepatic cholangiodrainage (PTCD) and embolization of the portal vein and hepatic artery were performed. Thereafter, ethanol was injected into the biliary duct, and the intervention was successfully completed. Case 2 was a 54-year-old woman who underwent LDLT using a right-lobe graft and duct-to-duct biliary reconstruction for PBC. Internal plastic stent insertion by ERBD was unsuccessful due to the significantly bending bile duct. After PTCD, the gun-site technique for the posterior branch and dual hepatic vascular embolization of the anterior branch was performed. The patient was followed up without an external fistula tube. CONCLUSION: ABO incompatibility was a risk factor for refractory biliary stricture. Appropriate procedures should be chosen based on stricture types.

Liver Only Living Donor Transplantation for Polycystic Disease in a Patient on Chronic Hemodialysis: Case Report.

BACKGROUND: Polycystic liver disease (PLD) is characterized by the progressive development of polycystic lesions in the kidney and the liver, possibly resulting in dual organ failure. We indicated living donor liver transplantation (LDLT) for a patient with end-stage liver and kidney disease (ELKD) due to PLD on uncomplicated chronic hemodialysis. CASE PRESENTATION: A 63-year-old man with ELKD and uncontrolled massive ascites due to PLD and hepatitis B on uncomplicated chronic hemodialysis was referred to us with a single possible 47-year-old female living donor. Because of the necessity of right lobe liver procurement from this small middle-aged donor and uncomplicated hemodialysis on this recipient, we considered LDLT, rather than dual organ transplantation, could be the most well-balanced option to save the life of this recipient with acceptable risk limits for this donor. A right lobe graft with 0.91 for graft recipient weight ratio was implanted with an uneventful operative procedure under intra- and postoperative continuous hemodiafiltration. The recipient was rescheduled on routine hemodialysis on day 6 after transplantation and recovered with a gradual decrease in ascites output. He was discharged on day 56. He continues to have a very good liver function and quality of life without ascites and uncomplicated routine hemodialysis 1 year after transplantation. The living donor was discharged 3 weeks after surgery and is also doing well. CONCLUSION: Although combined liver-kidney transplantation from a deceased donor could be the best option for ELKD due to PLD, LDLT can also be an acceptable option for ELKD with uncomplicated hemodialysis, considering the double equipoise theory for both lifesaving of the recipient and acceptable donor risk.

Open Thoracic Drainage Followed by Proximal Splenic Artery Embolization for Massive Hydrothorax Before Living Donor Liver Transplantation.

BACKGROUND: Hepatic hydrothorax is associated with postoperative infectious complications and mortality in patients undergoing living-donor liver transplantation (LDLT). Thus, preoperative management of massive hepatic hydrothorax is essential for improving the outcomes of LDLT. This study aimed to demonstrate our successful cases and strategy for treating massive hepatic hydrothorax. METHODS: Our strategy for hepatic hydrothorax includes (a) mini-thoracotomy under general anesthesia for the drainage of hydrothorax, (b) preoperative hepatic inflow modulation by proximal splenic arterial embolization, and (c) nutritional and physical intervention to improve the general condition. RESULTS: Two patients with massive hepatic hydrothorax were treated with our strategy. Both patients had end-stage liver disease secondary to primary biliary cholangitis. Their performance status deteriorated due to massive hydrothorax. After the intervention, their performance status significantly improved. After that, LDLTs with right lobe grafts were performed. The duration of the operation was 440 and 343 minutes, with an intraoperative blood loss of 1,700 and 1,600 g, respectively. Their postoperative courses were uneventful, and they were discharged on postoperative days 16 and 14. CONCLUSION: Our pre-LDLT multimodal management strategy for massive hepatic hydrothorax, including preoperative open thoracic drainage, pre-LDLT portal inflow modulation, and nutritional intervention, improved the preoperative condition of patients undergoing LDLT, resulting in successful outcomes.

Zero Mortality in Living-Donor Liver Transplantation for Primary Biliary Cholangitis in Patients With a Meld Score of <20.

BACKGROUND: Although primary biliary cholangitis (PBC) is considered a good indication for living-donor liver transplantation (LDLT), the postoperative results are not well known. METHODS: At Jikei University Hospital, 14 patients with PBC underwent LDLT from February 2007 to June 2022. We consider PBC with a Model for End-Stage Liver Disease (MELD) score of <20 to indicate LDLT. We performed a retrospective analysis of the patients' clinical records. RESULTS: The patients' median age was 53 years, and 12 of the 14 patients were female. A right graft was used in 5 patients, and 3 ABO-incompatible transplants were performed. The living donors were children in 6 cases, partners in 4 cases, and siblings in 4 cases. The preoperative MELD scores ranged from 11 to 19 (median, 15). The graft-to-recipient weight ratio ranged from 0.8 to 1.1 (median, 1.0). The median operative time for donors and recipients was 481 and 712 minutes, respectively. The median operative blood loss of donors and recipients was 173 and 1,800 mL, respectively. The median postoperative hospital stay of donors and recipients was 10 and 28 days, respectively. All recipients recovered satisfactorily and remained well during a median follow-up of 7.3 years. Three patients underwent a liver biopsy after LDLT because of acute cellular rejection without histologic findings of PBC recurrence. CONCLUSIONS: Living-donor liver transplantation provides satisfactory long-term survival for patients with PBC with a graft-to-recipient weight ratio of >0.7 and MELD score of <20 without hepatocellular damage and only portal vein hypertension.

A Multidisciplinary Treatment Strategy With Conversion Surgery for Hepatocellular Carcinoma.

BACKGROUND/AIM: Sorafenib was previously the only targeted therapy for hepatocellular carcinoma (HCC). However, pharmaceutical therapy for HCC has undergone remarkable advances in recent years. Herein, we report cases of unresectable advanced HCC responding to pharmaceutical therapy resulting in improved prognosis through surgical intervention. PATIENTS AND METHODS: Five patients with intermediate and advanced stage HCC treated with lenvatinib followed by hepatectomy between October 2019 and September 2022 were retrospectively reviewed. Patient characteristics, tumor factors, and treatment factors were compared. RESULTS: The median patient age was 66 (60-79) years, and all patients (100%) were male. The median follow-up period was 10.4 months. All five patients received lenvatinib treatment for more than 2 months before surgery. Three patients achieved partial responses and 2 patients had stable disease with modified RESIST in response to lenvatinib. Three patients had a partial pathological response (50% or more tumor necrosis). Four patients underwent R0 resection and 3 cases had no recurrence. CONCLUSION: Lenvatinib might be useful for intermediate and advanced HCC and long-term survival may be obtained by combining lenvatinib therapy with surgery.

Impact of C-reactive protein-albumin-lymphocyte (CALLY) index on prognosis after hepatectomy for colorectal liver metastasis.

AIM: The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a novel inflammation-based biomarker. We aimed to investigate whether the CALLY can predict the prognosis in patients with colorectal liver metastases (CRLM) after hepatic resection. METHODS: We included 183 patients with CRLM who underwent hepatectomy. The CALLY index was defined as (albumin × lymphocytes)/(CRP × 104). We investigated the association of the CALLY index with overall survival by univariate and multivariate analyses. RESULTS: In total, 101 (55%) patients had a low CALLY index (<4). In the univariate analysis, overall survival was significantly worse in patients with lymph node metastases (p = 0.02), extrahepatic lesions (p < 0.01), and a low CALLY index (p < 0.01). In the multivariate analysis, independent and significant predictors of overall survival were lymph node metastases (p = 0.04), extrahepatic lesions (p = 0.03), and a low CALLY index (p = 0.03). Patients with a low CALLY index had significantly more postoperative complications than those with a high CALLY index (29% vs. 11%, p < 0.01). CONCLUSION: The CALLY index may be an independent and significant indicator of outcomes in patients who underwent liver resection for CRLM.

Blood loss in laparoscopic distal pancreatectomy could be underestimated.

BACKGROUND: Previous studies have reported that laparoscopic distal pancreatectomy (LDP) has an advantage in reducing blood loss over open distal pancreatectomy (ODP). This study was performed to investigate whether blood loss is truly reduced in LDP. METHODS: A total of 113 patients undergoing DP from 2014 to 2022 were classified into Open and LDP groups and compared by statistical analysis. Estimated blood loss (EBL) was calculated from the perioperative changes in the hematocrit, hemoglobin, or red blood cell volume, and actual blood loss (ABL) was taken from the operative record. RESULTS: ABL was significantly lower in the LDP than ODP group (50[5-1350] vs 335 [5-1950] ml, P < .01). However, there were no significant differences in EBL calculated from the hematocrit (406 [66-1990] vs 540 [23-1490] ml, P = .14), hemoglobin, or red blood cell volume. EBL showed more linear correlations with ABL in the ODP group (r = 0.64-0.73) than in the LDP group (r = 0.52-0.57). In the multivariate analysis for ABL, ODP (P = .02) and operative time (P < .01) were significant factors. In contrast, no significant factors were found for EBL. CONCLUSIONS: Intraoperative blood loss may be underestimated in LDP, and a new evaluation method needs to be established.

The effectiveness of adjuvant chemotherapy for Stage I pancreatic cancer based on the UICC 8th edition.

BACKGROUND: Adjuvant chemotherapy is recommended for patients with pancreatic cancer after curative resection. However, there is limited evidence regarding the efficacy and prognostic factors for adjuvant chemotherapy in patients with stage I pancreatic cancer. This study aimed to identify patients in whom chemotherapy was effective and to detect prognostic factors for stage I pancreatic cancer based on guidelines of the 8th edition of the Union for International Cancer Control (UICC). METHODS: Between 2009 and 2017, 108 patients diagnosed with stage I pancreatic cancer were enrolled in this study. They were distributed into invasion (n = 68) and non-invasion (n = 40) groups. The relationship between clinicopathological variables, including various prognostic factors, disease-free survival (DFS), and overall survival (OS), were investigated by univariate and multivariate analyses. RESULTS: Five-year survival in all patients with stage I pancreatic cancer was 38.9%. Adjuvant chemotherapy failed to improve DFS or OS in patients with stage I cancer (DFS, p = 0.26; OS, p = 0.30). In subgroup analysis, adjuvant chemotherapy significantly improved DFS (multivariate-adjusted hazard ratio (HR), 0.40; 95% confidence interval [CI], 0.21-0.78; p = 0.007) and OS (multivariate-adjusted HR, 0.32; 95% CI, 0.15-0.68; p = 0.003) in the invasion group than in non-invasion group. In contrast, in the non-invasion group, adjuvant chemotherapy failed to improve DFS and OS in univariate analysis (DFS, p = 0.992; OS, p = 0.808). CONCLUSION: For stage I pancreatic cancer, based on guidelines of the UICC 8th edition, adjuvant chemotherapy may benefit patients with extrapancreatic invasion.

Inhibition of lysosomal acid ß-glucosidase induces cell apoptosis via impairing mitochondrial clearance in pancreatic cancer.

Sphingolipid metabolism plays an important role in the formation of cellular membranes and is associated with malignant potential and chemosensitivity of cancer cells. Sphingolipid degradation depends on multiple lysosomal glucosidases. We focused on acid ß-glucosidase (GBA), a lysosomal enzyme the deficiency of which is related to mitochondrial dysfunction. We analyzed the function of GBA in pancreatic ductal adenocarcinoma (PDAC). Human PDAC cell lines (PANC-1, BxPC-3 and AsPC-1) were examined under conditions of GBA knockdown via the short interfering RNA (siRNA) method. We assessed the morphological changes, GBA enzyme activity, GBA protein expression, cell viability, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) and mitophagy flux of PDAC cells. The GBA protein level and enzyme activity differed among cell lines. GBA knockdown suppressed cell proliferation and induced apoptosis, especially in PANC-1 and BxPC-3 cells, with low GBA enzyme activity. GBA knockdown also decreased the MMP and impaired mitochondrial clearance. This impaired mitochondrial clearance further induced dysfunctional mitochondria accumulation and ROS generation in PDAC cells, inducing apoptosis. The antiproliferative effects of the combination of GBA suppression and gemcitabine were higher than those of gemcitabine alone. These results showed that GBA suppression exerts a significant antitumor effect and may have therapeutic potential in the clinical treatment of PDAC.

Phase II trial of nafamostat mesilate/gemcitabin/S-1 for unresectable pancreatic cancer.

PURPOSE: To assess the efficacy of combination chemotherapy with nafamostat mesilate, gemcitabine and S-1 for unresectable pancreatic cancer patients. MATERIALS AND METHODS: The study was conducted as a single-arm, single center, institutional review board-approved phase II trial. Patients received nafamosntat mesilate (4.8 mg/kg continuous transregional arterial infusion) with gemcitabine (1000 mg/m2 transvenous) on days 1 and15, and with oral S-1 [(80 mg/day (BSA<1.25 m2), 100 mg/day (1.25 ≤ BSA<1.5 m2), or 120 mg/day (BSA ≥1.5 m2)] on days 1-14 or, days 1-7 and 15-21. This regimen was repeated at 28-day intervals. RESULTS: Forty-seven evaluable patients (Male/Female: 31/16, Age (median): 66 (range 35-78) yrs, Stage III/IV 10/37.) were candidates in this study. Two patients in stage III (20%) could undergo conversion surgery. Twenty-four patients (51%) underwent subsequent treatment (1st line/ 2nd line / 4th line, 13/ 10/ 1, FOLFIRINOX: 12, GEM/nab-PTX: 18, TAS-118: 3, chemoradiation with S-1: 2, GEM/Erlotinib: 1, nal-IRI: 1, surgery: 2). Median PFS and OS were 9.7 (95% CI, 8.9-14.7 mo) and 14.2 months (99% CI, 13.3-23.9 mo), respectively. Median PFS in stage IV patients was 9.2 months (95% CI, 8.4-12.0 mo). Median OS in patients without subsequent treatment was 10.8 months (95% CI, 9.1-13.8 mo). Median OS in patients with subsequent treatment was 19.3 months (95% CI, 18.9-31.9 mo). Grade 4 treatment-related hematological toxicities were encountered in 7 patients. Two patients developed grade 3 allergic reaction after 6 cycles or later. No febrile neutropenia has been observed. CONCLUSION: NAM/GEM/S-1 therapy is safe and could be promising option for unresectable pancreatic cancer, especially for stage IV cancer.

The impact of S-1 for the patient with lymph nodal metastasis biliary tract cancer as adjuvant chemotherapy: a multicenter database analysis.

INTRODUCTION: Although adjuvant chemotherapy is expected to improve the prognosis for patients with biliary tract cancer after curative resection, there is limited evidence regarding the efficacy and prognostic factors of adjuvant chemotherapy. We investigated the effective subgroups for whom adjuvant chemotherapy with S-1 in biliary tract cancer patients. METHODS: 413 patients who underwent curative resection for biliary tract cancer at our four affiliated hospitals between 2009 and 2019 were included in this study. The association of adjuvant chemotherapy with long-term outcomes in overall and patient subgroups were investigated by univariate and multivariate analyses. RESULTS: Among overall patients, adjuvant chemotherapy with S-1 did not improve disease free survival (p = 0.29) and overall survival (p = 0.83). In the subgroup analysis, adjuvant chemotherapy with S-1 improved both disease-free and overall survival in patients with lymph node metastasis, advanced Stage (III and IV), and microscopic residual tumor. In 135 patients with lymph node metastasis, adjuvant chemotherapy with S-1 was given in 67 patients (50%). In the patients with lymph node metastasis, preoperative bile duct drainage (p = 0.01) and adjuvant chemotherapy (p = 0.04) were independent and significant predictors of disease-free survival, while preoperative bile duct drainage (p = 0.03), tumor differentiation (p = 0.03), and adjuvant chemotherapy (p = 0.03) were independent and significant predictors of overall survival. CONCLUSION: After resection of biliary tract cancer, adjuvant chemotherapy with S-1 appears to benefit those who had lymph node metastasis.

Effects of an enteral nutrient-rich therapy with omega-3 fatty acids in patients with unresectable or recurrent biliary tract cancer or pancreatic cancer during chemotherapy: a case-control study.

To evaluate omega-3 fatty acid-rich enteral nutrient effects in patients with unresectable or recurrent biliary tract or pancreatic cancers during chemotherapy. Enteric nutritional supplements containing omega-3 fatty acids (Racol®) was administered to aforementioned patients with cancers during chemotherapy. The skeletal muscle mass and blood test data were obtained pre-administration and 28 and 56 days after. Patients with pancreatic cancer were administered the digestive enzyme supplement pancrelipase (LipaCreon®) 28 days after the start of Racol® administration. The number of chemotherapies skipped due to neutropenia was recorded for 2 months before and after enteral nutrient initiation. In all 39 patients, the skeletal muscle mass increased on day 56 versus baseline (median 17.3 kg vs. 14.8 kg, p < 0.01), number of chemotherapies skipped decreased (mean: 0.65 times/month vs. 1.3 times/month, p = 0.03), and retinol-binding protein (mean: 2.56 mg/dL vs. 2.42 mg/dL, p = 0.05) increased. Patients with pancreatic cancer showed increased blood eicosapentaenoic acid concentration on day 56 versus baseline (median: 48.1 µg/mL vs. 37.0 µg/mL, p = 0.04) and increased skeletal muscle mass (median 16.8 kg vs. 14.4 kg, p = 0.006). Baseline median neutrophil count increased significantly from 2200/µL at baseline to 2500/µL (p = 0.04). Patients with biliary tract cancer during chemotherapy also exhibited increased skeletal muscle mass following omega-3 supplementation (median 17.3 kg vs. 15.8 kg, p = 0.01). In patients undergoing chemotherapy for unresectable or post-recurrence pancreatic and biliary tract cancers, high-omega-3 fatty acid nutrition therapy use improved skeletal muscle maintenance and chemotherapy dosing intensity.