Prognostic value of preoperative geriatric nutritional risk index in intrahepatic cholangiocarcinoma after hepatectomy: a single­center retrospective cohort study.

AIM: Patients with malignant tumors are prone to develop nutritional disorders. The Geriatric Nutritional Risk Index (GNRI) is a new prognostic indicator for assessing the nutritional status. This study was performed to evaluate whether the preoperative GNRI can serve as a prognostic factor in patients with intrahepatic cholangiocarcinoma (ICC) undergoing curative surgery. METHODS: This study included 123 consecutive patients with ICC who were treated with curative surgery. Kaplan-Meier analysis was performed to calculate the recurrence-free survival (RFS) and overall survival (OS), and Cox regression analysis was used to evaluate prognostic factors. RESULTS: Of the 123 patients, 82 were male and 41 were female. The median age of the patients was 70 years, and the median follow-up period was 37.0 months (interquartile range, 16.2-71.7 months). The patients were classified by the median GNRI into a low GNRI group (GNRI < 105) and high GNRI group (GNRI ≥ 105). The patients in the low GNRI group had a significantly poorer prognosis in terms of RFS and OS than the patients in the high GNRI group (RFS, p = 0.0201; OS, p < 0.0001). Lymph node metastasis [hazard ratio (HR), 4.66; 95% confidence interval (CI), 2.46-8.85], postoperative complications (HR, 2.38; 95% CI, 1.32-4.31), and a low GNRI (HR, 2.53; 95% CI, 1.42-4.50) were independent poor prognostic factors for OS. CONCLUSION: The GNRI may be a useful prognostic indicator in patients with ICC undergoing curative hepatectomy.

Possible mechanisms and simulation modeling of FLASH radiotherapy.

FLASH radiotherapy (FLASH-RT) has great potential to improve patient outcomes. It delivers radiation doses at an ultra-high dose rate (UHDR: ≥ 40 Gy/s) in a single instant or a few pulses. Much higher irradiation doses can be administered to tumors with FLASH-RT than with conventional dose rate (0.01-0.40 Gy/s) radiotherapy. UHDR irradiation can suppress toxicity in normal tissues while sustaining antitumor efficiency, which is referred to as the FLASH effect. However, the mechanisms underlying the effects of the FLASH remain unclear. To clarify these mechanisms, the development of simulation models that can contribute to treatment planning for FLASH-RT is still underway. Previous studies indicated that transient oxygen depletion or augmented reactions between secondary reactive species produced by irradiation may be involved in this process. To discuss the possible mechanisms of the FLASH effect and its clinical potential, we summarized the physicochemical, chemical, and biological perspectives as well as the development of simulation modeling for FLASH-RT.

Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation.

Objective. FLASH radiotherapy (FLASH-RT) with ultra-high dose rate (UHDR) irradiation (i.e. > 40 Gy s-1) spares the function of normal tissues while preserving antitumor efficacy, known as the FLASH effect. The biological effects after conventional dose rate-radiotherapy (CONV-RT) with ≤0.1 Gy s-1have been well modeled by considering microdosimetry and DNA repair processes, meanwhile modeling of radiosensitivities under UHDR irradiation is insufficient. Here, we developed anintegrated microdosimetric-kinetic(IMK)model for UHDR-irradiationenabling the prediction of surviving fraction after UHDR irradiation.Approach.TheIMK model for UHDR-irradiationconsiders the initial DNA damage yields by the modification of indirect effects under UHDR compared to CONV dose rate. The developed model is based on the linear-quadratic (LQ) nature with the dose and dose square coefficients, considering the reduction of DNA damage yields as a function of dose rate.Main results.The estimate by the developed model could successfully reproduce thein vitroexperimental dose-response curve for various cell line types and dose rates.Significance.The developed model would be useful for predicting the biological effects under the UHDR irradiation.

Statins exert anti-growth effects by suppressing YAP/TAZ expressions via JNK signal activation and eliminate the immune suppression by downregulating PD-L1 expression in pancreatic cancer.

Statins are cholesterol-lowering agents that act as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzymeA (HMG CoA) reductase. Recently, statins have received a lot of attention, especially regarding how statins act on the immune system. Here, the clinical impact of statin intake was examined in patients with resected pancreatic cancer, and the underlying mechanisms were investigated in vitro and in vivo. We found that statin intake was associated with favorable prognostic outcomes in patients with resectable pancreatic cancer. Statins, especially lipophilic statins, exert anti-proliferative effects on pancreatic cancer cells in vitro (simvastatin > fluvastatin > atorvastatin > rosuvastatin > pravastatin). Simvastatin had an anti-proliferative effect on pancreatic cancer cells with decreased the yes-associated protein (YAP)/PDZ-binding motif (TAZ) expression by activating the JNK pathway, and simvastatin treatment with oxaliplatin revealed additive anti-growth effects. Furthermore, lipophilic and hydrophilic statins suppressed programmed cell death ligand 1 (PD-L1) expression by downregulating TAZ. Simvastatin treatment with an anti-PD-1 drug (BP0273) provided immediate anti-growth effects compared to controls, such as anti-PD-1 only and simvastatin only, and suppressed progressive disease during the early period of anti-PD-1 treatment in vivo. In conclusion, Statins display two distinct anti-cancer effects (direct anti-growth effect and elimination of immune suppression by downregulating PD-L1 expression) by targeting YAP/TAZ expression.

Prolonged door-to-antibiotics time is associated with high hospital mortality in patients with perforated colorectal peritonitis.

PURPOSE: Colorectal perforation is a fatal disease that presents with generalized peritonitis, leading to sepsis and septic shock. Recently, the association between prolonged door-to-antibiotics time and increased mortality in sepsis has been widely reported. In this study, we investigated the prognostic impact of a prolonged door-to-antibiotics time in patients with perforated colorectal peritonitis undergoing emergency surgery. METHODS: This retrospective study included 93 patients with perforated colorectal peritonitis who underwent emergency surgery at our institution between April 2015 and August 2019. Patients were divided into two groups depending on the door-to-antibiotics time (< 162 min or ≥ 162 min). The primary outcome was in-hospital mortality. The secondary outcomes were the length of hospital stay and severe complication rate. The logistic regression analysis was used to estimate the odds ratio for in-hospital mortality. RESULTS: We identified 38 patients who presented with an extended door-to-antibiotics time (≥ 162 min) and 55 patients who presented with a shortened door-to-antibiotics time (< 162 min). We found a strong association between the door-to-antibiotics time ≥ 162 min and in-hospital mortality. There were no significant differences between the two groups regarding the length of hospital stay and postoperative complication rate. However, in multivariate analysis, extended door-to-antibiotics time was an independent prognostic factor for in-hospital mortality (odds ratio = 244; 95% confidence interval, 11 -23,885). CONCLUSION: A prolonged door-to-antibiotics time (≥ 162 min) worsened hospital mortality rates in patients with perforated colorectal peritonitis.

A surgical resection of hepatic granuloma mimicking intrahepatic cholangiocarcinoma: a case report.

Hepatic granuloma is relatively rare, and benign tumor of the liver. Herein, we report an unusual case of hepatic granuloma mimicking intrahepatic cholangiocarcinoma (ICC). An 82-year-old woman with a history of viral hepatitis B was admitted for investigation of liver mass in the left lobe. Dynamic computed tomography revealed a mostly hypo-enhancing main tumor with a peripheral ring enhancement, and positron emission tomography demonstrated localized an abnormal accumulation of fludeoxyglucose. Considering the possibility of malignant disease, extended left hepatectomy was performed. The resected tumor was macroscopically a periductal infiltrating nodular type, 4.5 × 3.6 cm in diameter. The pathological findings showed that granuloma and coagulative necrosis were present, and diagnosis of hepatic granuloma was confirmed. Pathological studies demonstrated that periodic acid-Schiff stain, Grocott-Gomori stain and Ziehl-Neelsen stain were all negative in the lesion.

Biological and Clinical Impacts of Glucose Metabolism in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type as it is prone to metastases and is difficult to diagnose at an early stage. Despite advances in molecular detection, its clinical prognosis remains poor and it is expected to become the second leading cause of cancer-related deaths. Approximately 85% of patients develop glucose metabolism disorders, most commonly diabetes mellitus, within three years prior to their pancreatic cancer diagnosis. Diabetes, or glucose metabolism disorders related to PDAC, are typically associated with insulin resistance, and beta cell damage, among other factors. From the perspective of molecular regulatory mechanisms, glucose metabolism disorders are closely related to PDAC initiation and development and to late invasion and metastasis. In particular, abnormal glucose metabolism impacts the nutritional status and prognosis of patients with PDAC. Meanwhile, preliminary research has shown that metformin and statins are effective for the prevention or treatment of malignancies; however, no such effect has been shown in clinical trials. Hence, the causes underlying these conflicting results require further exploration. This review focuses on the clinical significance of glucose metabolism disorders in PDAC and the mechanisms behind this relationship, while also summarizing therapeutic approaches that target glycolysis.

Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.

BACKGROUND: Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). METHODS: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS: Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo. CONCLUSION: Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

[The Usefulness of RFA as a Conversion Therapy after Molecular Targeted Therapy for Advanced Hepatocellular Carcinoma-A Case of Long-Term Survival with Multidisciplinary Treatment].

In this study, we report a case in which molecular-targeted agents have been shown to be effective in the treatment of unresectable hepatocellular carcinoma(HCC), which has enabled a radical treatment, conversion therapy, and long-term survival with multimodality treatment including RFA. Case: A 61-year-old male, abdominal ultrasonography revealed a large liver tumor and multiple lesions mainly in the right lobe of the liver. He was diagnosed as having unresectable HCC, and treatment with sorafenib was initiated. After treatment, the tumor was clearly reduced in size and the lung metastases disappeared. Five years later, recurrence was observed at the treated site of S7/8, and RFA was performed again after TACE. The patient has survived for 8 years without recurrence.

Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-ß signal activation in pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-ß (TGF-ß) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-ß signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS: High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-ß signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-ß signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-ß activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS: TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-ß signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.