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.

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.

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.

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.

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.

Inhibition of acid ceramidase elicits mitochondrial dysfunction and oxidative stress in pancreatic cancer cells.

Although the inhibition of acid ceramidase (AC) is known to induce antitumor effects in various cancers, there are few reports in pancreatic cancer, and the underlying mechanisms remain unclear. Moreover, there is currently no safe administration method of AC inhibitor. Here the effects of gene therapy using siRNA and shRNA for AC inhibition with its mechanisms for pancreatic cancer were investigated. The inhibition of AC by siRNA and shRNA using an adeno-associated virus 8 (AAV8) vector had antiproliferative effects by inducing apoptosis in pancreatic cancer cells and xenograft mouse model. Acid ceramidase inhibition elicits mitochondrial dysfunction, reactive oxygen species accumulation, and manganese superoxide dismutase suppression, resulting in apoptosis of pancreatic cancer cells accompanied by ceramide accumulation. These results elucidated the mechanisms underlying the antitumor effect of AC inhibition in pancreatic cancer cells and suggest the potential of the AAV8 vector to inhibit AC as a therapeutic strategy.

Claudin 7 as a possible novel molecular target for the treatment of pancreatic cancer.

BACKGROUND/OBJECTIVES: Pancreatic cancer consists of various subpopulations of cells, some of which have aggressive proliferative properties. The molecules responsible for the aggressive proliferation of pancreatic cancer may become molecular targets for the therapies against pancreatic cancer. METHODS: From a human pancreatic cancer cell line, MIA PaCa-2, MIA PaCa-2-A cells with an epithelial morphology and MIA PaCa-2-R cells with a non-epithelial morphology were clonogenically isolated by the limiting dilution method. Gene expression of these subpopulations was analyzed by DNA microarray. Gene knockdown was performed using siRNA. RESULTS: Although the MIA PaCa-2-A and MIA PaCa-2-R cells displayed the same DNA short tandem repeat (STR) pattern identical to that of the parental MIA PaCa-2 cells, the MIA PaCa-2-A cells were more proliferative than the MIA PaCa-2-R cells both in culture and in tumor xenografts generated in immunodeficient mice. Furthermore, the MIA PaCa-2-A cells were more resistant to gemcitabine than the MIA PaCa-2-R cells. DNA microarray analysis revealed a high expression of claudin (CLDN) 7 in the MIA PaCa-2-A cells, as opposed to a low expression in the MIA PaCa-2-R cells. The knockdown of CLDN7 in the MIA PaCa-2-A cells induced a marked inhibition of proliferation. The MIA PaCa-2-A cells in which CLDN7 was knocked down exhibited a decreased expression of phosphorylated extracellular signal-regulated kinase (p-Erk)1/2 and G1 cell cycle arrest. CONCLUSIONS: CLDN7 may be expressed in the rapidly proliferating and dominant cell population in human pancreatic cancer tissues and may be a novel molecular target for the treatment of pancreatic cancer.

Chemotherapy for alpha-fetoprotein producing gastric cancers expressing human epidermal growth factor receptor 2.

Although, gastric cancer is one of the most common cancers worldwide, alpha-fetoprotein (AFP) producing human epidermal growth factor receptor 2 (HER2) positive gastric cancers are rare. AFP producing gastric cancer has a poor prognosis and an appropriate treatment option has not been established to date. A 75-year-old woman with AFP- producing gastric cancer was treated with S-1, an oral fluoropyrimidine derivative, chemotherapy after distal gastrectomy. Recurrence of gastric cancer was observed after 18 months and immunohistochemistry analysis showed AFP and HER2 positive gastric cancer. The patient received combination therapy containing capecitabine, cisplatin, and trastuzumab. Computed tomography scans showed regression of the lymph node metastasis. The patient's quality of life substantially improved after the treatment. Thus, the present case suggests that AFP and HER2 positive gastric cancer can be effectively treated with, capecitabine, cisplatin, and trastuzumab combination therapy.

New treatment strategy with nuclear factor-κB inhibitor for pancreatic cancer.

BACKGROUND: Because of difficulties with early diagnosis, most patients with pancreatic cancer receive chemotherapy. The National Comprehensive Cancer Network guidelines (version 2.2015) suggest therapy with gemcitabine (GEM) plus nab-paclitaxel (nPTX) as a category 1 recommendation for metastatic pancreatic ductal adenocarcinoma. According to the results of many studies, the activation of chemotherapeutic agents-induced nuclear factor-κB (NF-κB) causes chemoresistance. Hence, we hypothesized that the addition of nafamostat mesilate (NM), a potent NF-κB inhibitor, to GEM/nPTX therapy could enhance the antitumor effect in the treatment of pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: In vitro, we assessed NF-κB activity and apoptosis under treatment with NM alone (80 µg/mL), with GEM/nPTX, or with a combination of NM and GEM/nPTX in human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1). In vivo, orthotopic pancreatic cancer mice (BALBc nu/nu) were divided into four groups: control (n = 13), NM (n = 13), GEM/nPTX (n = 13), and triple combination (n = 13). NM (30 mg/kg) was delivered intraperitoneally three times a week, and GEM/nPTX was injected intravenously once a week to orthotopic pancreatic cancer model mice. In the triple combination group, mice received NM followed by GEM/nPTX on the first day to avoid GEM/nPTX-induced NF-κB activation. RESULTS: In vitro and in vivo, NM inhibited GEM/nPTX-induced NF-κB activation, and a synergistic effect of apoptosis was observed in the triple combination group. Furthermore, tumor growth was significantly suppressed in the triple combination group compared with the other groups. CONCLUSIONS: NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation.

Effect of NF-κB inhibition on chemoresistance in biliary-pancreatic cancer.

Biliary cancer and pancreatic cancer are considered to be difficult diseases to cure. Although complete resection provides the only means of curing these cancers, the rate of resectability is not high. Therefore, chemotherapy is often selected in patients with advanced unresectable biliary-pancreatic cancer. Many combination chemotherapy regimens have been applied in clinical trials. However, the survival time is not satisfactory. On the other hand, most chemotherapeutic agents induce anti-apoptotic transcriptional factor nuclear factor kappa b (NF-κB) activation, and agent-induced NF-κB activation is deeply involved in the onset of chemoresistance. Recently, novel approaches to potentiating chemosensitivity in cases of biliary-pancreatic cancer using NF-κB inhibitors with cytotoxic agents have been reported, most of which comprise translational research, although some clinical trials have also been conducted. Nevertheless, to date, there is no breakthrough chemotherapy regimen for these diseases. As some reports show promising data, combination chemotherapy consisting of a NF-κB inhibitor with chemotherapeutic agents seems to improve chemosensitivity and prolong the survival time of biliary-pancreatic cancer patients.

[The current status of home palliative care for patients with advanced cancer at the Jikei University School of Medicine].

Medical oncologists are involved in cancer chemotherapy as well as end-of-life care. Recently, an increased number of patients with advanced cancer have expressed their preference to receive palliative care at their home during the end-of-life period, and several home medical care providers have aimed to provide such a service. The number of cancer patients who wish to receive home palliative care has also increased at our institution. We reviewed the characteristics of advanced cancer patients who received chemotherapy and who eventually received homecare from 2012 to 2014. The total number of patients was 22. Of these, 9 had breast cancer(40.9%)and 8 had colorectal cancer(36.4%). The median age was 68(range 36-90) years. Half of these patients died at home. The median duration of homecare to death was 64.5(range 12-252)days. Approximately 70% of patients were able to remain at home for over a month, but 3 patients died within 2 weeks at home and 1 patient returned to the hospital after 10 days of homecare due to disease progression. While palliative care in the home setting is valued by many cancer patients in the end-of-life period, close monitoring is needed for patients with rapidly progressing disease.

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.

Prognostic Impact of a Decrease in Serum Carbohydrate Antigen 19-9 Levels After Preoperative Therapy for 4 Months or More for Borderline Resectable Pancreatic Cancer Abutting Major Arteries.

Background: This study aimed to identify the prognostic factors after pancreatectomy for borderline resectable pancreatic cancer abutting major arteries (BR-A).Methods: We retrospectively investigated relationship between preoperative and intraoperative variables and overall survival (OS) through univariate and multivariate analyses. The cut-off points of preoperative therapy duration and response rates of serum carbohydrate antigen 19-9 (CA19-9) levels after preoperative therapy were determined through a minimum P-value approach using the log-rank test for OS. Overall survival was compared among patients stratified according to the independent prognostic factors and the presence or absence of pancreatectomy.Results: After pretreatment, 17 patients underwent pancreatectomy and four patients continued chemotherapy without surgery. Multivariate analysis in 17 resected BR-A patients demonstrated decreased serum CA19-9 levels and preoperative therapy duration of ≥4 months were the independent prognostic factors [hazard ratio (HR) 0.01; P = 0.002, HR 0.13; P = 0.02]. Patients who underwent surgery with decreased serum CA19-9 levels after preoperative therapy of ≥4 months had a significantly better prognosis than those without one or both of independent prognostic factors and those who did not undergo surgery (median survival time: not estimated, 23.3 months, 10.5 months, and 10.8 months; P = 0.02, P = 0.004, and P = 0.001, respectively). Furthermore, the prognosis did not significantly differ between the patients who underwent surgery without meeting either one or both criteria and those without surgery.Conclusions: Preoperative therapy duration of ≥4 months and decreased serum CA19-9 levels are independent prognostic factors among BR-A patients.

Impact of Preoperative Osteosarcopenia and Postoperative Administration of Pancrelipase on the Prognosis of Borderline Resectable and Unresectable Locally Advanced Pancreatic Cancer.

BACKGROUND: This study aimed to identify postoperative recurrence and prognostic factors, including osteosarcopenia for borderline resectable (BR) and unresectable locally advanced (UR-LA) pancreatic cancer and to examine the impact of postoperative pancreatic enzyme replacement therapy (PERT). METHODS: We retrospectively examined 32 resected patients with BR and UR-LA pancreatic cancer. We investigated independent factors in the disease-free survival and overall survival. The relation of osteosarcopenia with the clinicopathological factors was investigated. Additionally, the association of the administration of a standard dose of pancrelipase, the amount of lipase required for patients with pancreatic exocrine insufficiency, for ≥6 months postoperatively with improvement of sarcopenia, osteopenia, and osteosarcopenia and completion rate of adjuvant chemotherapy was investigated. RESULTS: Multivariate analyses identified osteosarcopenia (P = 0.049) and lymph node metastasis (P = 0.01) as independent recurrence predictors, and osteosarcopenia (P = 0.002), maximum tumor diameter ≥40 mm (P = 0.006), and no adjuvant therapy (P = 0.01) as independent prognostic predictors. In the osteosarcopenia group, serum CA19-9 levels were higher (P = 0.03). The administration of a standard dose of pancrelipase for ≥6 months postoperatively was none in the osteosarcopenia group (0% vs 42.9%, P = 0.01), while significantly improved postoperative sarcopenia (33% vs 0%, P = 0.004), increased number of cycles of adjuvant chemotherapy (n = 6 vs n = 3, P = 0.03), and the completion rate of adjuvant chemotherapy in excluding cases interrupted because of recurrence (86% vs 25%, P = 0.007). CONCLUSIONS: Osteosarcopenia was an independent recurrent and prognostic factor in patients after pancreatectomy for locally advanced pancreatic cancer. Appropriate postoperative PERT may contribute to a better prognosis by improving sarcopenia and increasing the completion rate of adjuvant chemotherapy.

Changes in Skeletal Muscle Volume During Preoperative Chemotherapy Affect the Outcome of Pancreatic Cancer.

BACKGROUND: This study aimed to investigate the effects of changes in clinicopathological factors during preoperative chemotherapy for pancreatic cancer, including skeletal muscle volume, on recurrence and prognosis after pancreatectomy. METHODS: Data from 41 patients who underwent resection for pancreatic cancer after preoperative chemotherapy from 2012 to 2021 were retrospectively reviewed. Skeletal muscle volume was substituted for the psoas muscle area (PMA) at the level of the third lumbar vertebra. We investigated the relationship of clinicopathological factors during preoperative chemotherapy with disease-free survival (DFS) and overall survival (OS). The association between clinicopathological factors and a decrease in PMA was investigated. RESULTS: In the multivariate analyses for DFS and OS, the factors associated with recurrence were as follows: decrease in PMA (P = 0.003) and the absence of adjuvant therapy (P = 0.03), and the factors associated with poor prognosis were as follows: decrease in PMA (P = 0.04) and the absence of adjuvant therapy (P = 0.008), and the resectability of borderline resectable and unresectable-locally advanced tumors (P = 0.033). All patients with partial response according to the Response Evaluation Criteria in Solid Tumors (version 1.1) had no decrease in PMA (P = 0.01). The proportion of patients with Evans classification ≥ II was significantly higher in the group without a decrease in PMA (P = 0.02). The proportion of patients with an average relative dose intensity of adjuvant therapy ≥0.6 was significantly higher in the group without a decrease in PMA (P = 0.02). CONCLUSION: Changes in preoperative skeletal muscle volume during preoperative chemotherapy for pancreatic cancer is a potential predictor of recurrence and prognosis after pancreatectomy.

Combination chemotherapy of nafamostat mesylate with gemcitabine for gallbladder cancer targeting nuclear factor-κB activation.

BACKGROUND: Gemcitabine is an effective chemotherapeutic agent for advanced gallbladder cancer. However, chemoresistance attributable to gemcitabine-induced nuclear factor-κB (NF-κB) activation has been reported. We previously reported that nafamostat mesylate inhibited NF-κB activation and induced apoptosis in pancreatic cancer. Therefore, we hypothesized that nafamostat mesylate inhibits gemcitabine-induced NF-κB activation and enhances apoptosis induced by gemcitabine in gallbladder cancer. MATERIALS AND METHODS: In vitro, we assessed NF-κB activation of a gallbladder cancer cell line (NOZ) treated with nafamostat mesylate, gemcitabine, or a combination of both. In vivo, we established a xenograft gallbladder cancer model in mice by subcutaneous injection of NOZ cells. Five weeks after implantation, the animals were treated with nafamostat mesylate three times a week in the nafamostat mesylate group, with gemcitabine once a week in the gemcitabine group, or with a combination of nafamostat mesylate three times a week and gemcitabine once a week in the combination group, respectively. In the control group, only the vehicle of gemcitabine and nafamostat mesylate was injected at the same time course. RESULTS: In the combination group, NF-κB activation was inhibited and apoptosis was enhanced compared with gemcitabine alone in vitro and vivo. Tumor growth in the combination group was significantly slower than that in the gemcitabine group (P < 0.001). At the end of the study, the tumor weight and volume in the combination group were significantly lower than those in the gemcitabine group (P = 0.039 and 0.028, respectively). CONCLUSIONS: Combination chemotherapy of gemcitabine with nafamostat mesylate enhances the anti-tumor effect against xenograft gallbladder cancer model in mice.

Inhibition of nuclear factor-κB enhances the antitumor effect of paclitaxel against gastric cancer with peritoneal dissemination in mice.

BACKGROUND: Intraperitoneal (i.p.) administration of paclitaxel is useful for treating malignant tumors with peritoneal dissemination, but the therapeutic efficacy is limited. Chemoresistance due to paclitaxel-induced nuclear factor-kappa B (NF-κB) activation is an important cause of suboptimal therapeutic efficacy. AIMS: The purpose of this study was to prove that addition of nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor and an NF-κB inhibitor, to i.p. paclitaxel enhances antitumor effects of paclitaxel against gastric cancer with peritoneal dissemination. METHODS: In vitro, we assessed NF-κB activity and apoptosis in response to treatment with FUT-175 alone, paclitaxel alone, or a combination of FUT-175 and paclitaxel in a human gastric cancer cell line (MKN-45). In vivo, we established peritoneal dissemination in nude mice by i.p. injection of MKN-45 cells. The animals received i.p. injections of FUT-175 alone three times a week (FUT-175 group), of paclitaxel alone once a week (paclitaxel group), or a combination of FUT-175 and paclitaxel (combination group) three times and once a week, respectively. RESULTS: In the combination group, paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. In the combination group, number and weight of peritoneal nodules were significantly lower than those in the paclitaxel group (p = 0.0009 and p = 0.0417, respectively). In the survival analysis, the combination group had a significantly better survival than the paclitaxel group (p = 0.0048). CONCLUSION: FUT-175 enhances the antitumor effect of i.p. paclitaxel against gastric cancer with peritoneal dissemination by inhibiting NF-κB activation in mice.