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Objectives: The local renin-angiotensin system promotes angiogenesis and proliferation via vascular endothelial growth factor or epidermal growth factor receptor expression. In this study, we aimed to evaluate the impact of angiotensin system inhibitors (ASIs) on long-term outcomes in patients undergoing surgical resection of pancreatic ductal adenocarcinoma (PDAC)., Methods: A single institutional retrospective analysis was performed using the medical records of patients who underwent pancreatic resection with curative intent for PDAC between January 2005 and December 2018. Patient characteristics and surgical outcomes were compared between patients taking ASIs and those who are not., Results: A total of 272 patients were included in the study and classified into the ASI group (n = 121) and the non-ASI group (n = 151). The median overall survival times in the ASI group and non-ASI group were 38.0 and 34.0 months ( P = 0.250), and the median recurrence-free survival times were 24.0 and 15.0 months ( P = 0.025), respectively. Multivariate analysis for recurrence-free survival identified the use of ASIs ( P = 0.020), CA19-9 level >500 IU/L ( P = 0.010), positive lymph node metastasis ( P < 0.001), and no adjuvant chemotherapy ( P < 0.001) as independent prognostic factors., Conclusions: The use of ASI may improve long-term outcomes after surgery for PDAC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Mirogabalin, a selective voltage-gated calcium channel α2δ ligand, improves peripheral neuropathic pain; however, its effects on patients with cancers including pancreatic ductal adenocarcinoma (PDAC) remain unknown. We analyzed the effects of mirogabalin on a KPPC ( LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ) mouse model of PDAC. Six-week-old KPPC mice received oral mirogabalin (10 mg/kg/day) (n = 10) or vehicle water (n = 14) until the humane end point. Cancer-associated pain was evaluated using the scores of hunching and mouse grimace scale (MGS). Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. The effects of mirogabalin on the proliferative ability of PDAC cell lines were determined. The scores of the hunching and MGS improved after mirogabalin administration with a decrease in the plasma levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Although no significant difference in the survival rate was observed, mirogabalin significantly increased pancreatic tumor size and proliferative index of Ki-67 and cyclins. Local arginase-1 + M2-like tumor-associated macrophages and CD31 + tumor blood vessels increased after mirogabalin administration. By contrast, the number of α-smooth muscle actin + cancer-associated fibroblasts, desmoplastic stroma, and CD8 + T cells decreased. Local myeloperoxidase + tumor-associated neutrophils and CD45R + B cells were unaltered. Mirogabalin enhanced the proliferative ability of PDAC cell lines with the upregulation of cyclins and cyclin-dependent kinases; however, it inhibited the potential of pancreatic stellate cells in vitro. Therefore, our results suggest that mirogabalin improves cancer-associated pain but enhances the proliferative potential of PDAC in vitro and in vivo., (Copyright © 2023 International Association for the Study of Pain.)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Patients with inoperative PDAC require effective chemotherapy and pain control to increase their quality of life. We investigated whether duloxetine, a serotonin-noradrenaline reuptake inhibitor, improves quality of life in a KPPC (LSL-Kras;Trp53;Pdx1-cre) mouse model of PDAC. Six-week-old KPPC mice were orally administered 4 mg/kg/d duloxetine (n = 12); 4 mg/kg/d duloxetine with 0.15 mg/kg/d atipamezole, a synthetic α2 adrenergic receptor antagonist (n = 9); or vehicle water (n = 11). Body weight and food intake were measured daily, and cancer pain was evaluated by the hunching score and mouse grimace scale. At the endpoint, the tumor status, angiogenesis, and immunoinflammatory condition were analyzed. The pain level using the hunching and mouse grimace scale scores improved by duloxetine in KPPC mice (P < 0.01), whereas the scores that had been reduced by duloxetine were elevated by administration of atipamezole. Kaplan-Meier analysis demonstrated that duloxetine-treated mice had significantly prolonged survival (P < 0.05) with delayed appetite loss, cachexia, and body weight loss. Duloxetine inhibited the proliferation of PDAC cells and cancer-associated fibroblasts in vivo with a shift into an antitumor immunoinflammatory condition and the corresponding plasma cytokine levels. The migrative/invasive potentials of PDAC were inhibited by duloxetine in vitro. Meanwhile, atipamezole did not inhibit the antitumor effects of duloxetine in vitro and in vivo. Therefore, our results indicate that duloxetine mainly improves cancer-associated pain by enhancement of the noradrenergic pathway rather than the serotonergic pathway, whereas duloxetine modulates antitumor effects on PDAC without involvement of the noradrenergic pathway.

Objectives: Pancreatic cystic lesions (PCLs) are considered precursors of pancreatic cancer. Diabetes mellitus (DM) and obesity are known as risk factors for pancreatic cancer. We investigated the prevalence of PCLs in the general population and the relationship between PCLs and DM/obesity., Methods: This cross-sectional analysis included 5296 individuals who underwent a preventive medical examination between October 2006 and June 2013 at our institution. Magnetic resonance imaging, including magnetic resonance cholangiopancreatography, was performed using a 3.0-T system as part of a comprehensive health screening program. We investigated the prevalence and risk factors of PCLs., Results: The prevalence of PCLs was 13.7%, which was increased according to age. Individuals with PCLs were more prone to obesity (body mass index, 24.0 vs 23.7 kg/m [P = 0.015]; waist circumference, 87.4 vs 85.5 cm [P < 0.001]). DM was more prevalent in individuals with PCLs (18.4% vs 10.5%, P < 0.001). In a multivariate analysis, age (odds ratio [OR], 1.06; P < 0.001), excess body mass index (OR, 1.26; P = 0.039), and DM (OR, 1.39; P = 0.005) were associated with PCLs., Conclusions: The prevalence of PCLs detected by magnetic resonance imaging in a preventive medical examination was 13.7%. Pancreatic cystic lesions were significantly associated with DM and obesity.

Objectives: Malignant ascites (MA) caused by peritoneal carcinomatosis is not uncommon in patients with pancreatic cancer. However, the clinical features and outcomes in these patients remain to be elucidated., Methods: Baseline characteristics and overall survival (OS) of consecutive patients with advanced pancreatic cancer who presented with MA were retrospectively evaluated., Results: Of 494 patients with advanced pancreatic cancer, 73 (15%) presented with MA. Patients with synchronous MA (n = 21), compared with those with metachronous MA (n = 52), had better performance status (P = 0.02), smaller amount of ascites (P < 0.01), and higher chance of receiving chemotherapy (57% vs 17%, P < 0.01), and resulted in longer OS (115 vs 42 days, P < 0.01). Overall survival was significantly longer in patients receiving chemotherapy than in those with best supportive care alone (124 vs 50 days, P < 0.01). In a multivariate analysis, chemotherapy was prognostic in addition to performance status, CRP, and small amount of MA; the hazard ratio of chemotherapy was 0.46, compared with best supportive care alone (P = 0.02)., Conclusions: Although the prognosis of pancreatic cancer patients with MA remains poor, selected patients may be candidate for chemotherapy, regardless of the timing of appearance of MA.

Objectives: The aim of this study was to examine the association of risk factors including diabetes mellitus (DM) with the age of onset in Japanese pancreatic cancer (PC) patients., Methods: We retrospectively reviewed 688 PC patients diagnosed at our institute. We analyzed the association between the age of onset of PC and the following variables: sex, smoking, alcohol, DM, and a family history of cancer especially PC., Results: The mean age of PC diagnosis was 67.6 years. The onset of PC occurred earlier in current smokers (63.6 years old, P < 0.001) compared with past smokers (69.5 years old) and never smokers (68.6 years old). Patients with long-standing DM (>2 years) were older (70.5 years, P < 0.001) when diagnosed with PC than patients with new-onset DM (within 2 years) (66.9 years old) and patients without DM (66.7 years old). In the multivariate analysis, current smokers and a family history of cancer other than PC were associated with earlier onset. Conversely, long-standing DM was associated with later onset., Conclusions: In Japanese PC patients, current smokers and a family history of cancer other than PC were associated with a younger age of onset. Conversely, long-standing DM was associated with a later onset.

Objectives: The long-term prognosis in patients with intraductal papillary mucinous neoplasm (IPMN) has not been determined. The aim of this study was to elucidate the risk for nonpancreatic cancer-specific mortality in patients with IPMN., Methods: Seven hundred ninety-three patients with IPMN who were followed up more than 1 year were included in this study. Fine and Gray competing risk regression was used to assess the risk for mortality unrelated to pancreatic cancer. A comorbidity score at diagnosis was assigned using the Adult Comorbidity Evaluation 27., Results: After a median follow-up of 50 months, a high comorbidity score and age at diagnosis were significantly associated with a risk for mortality unrelated to pancreatic cancer. Adjusted hazards ratio and 95% confidence interval of each comorbidity burden were as follows: none, 1; mild, 2.68 (0.76-9.45; P = 0.124); moderate, 10.9 (3.19-37.1; P < 0.001); and severe, 32.0 (9.41-108.8; P < 0.001). Comorbidity burden did not affect the risk for pancreatic cancer-specific mortality., Conclusions: Comorbidity and age at diagnosis was significantly related to mortality unrelated to pancreatic cancer in patients with IPMN. For patients at high risk for nonpancreatic cancer mortality, a follow-up management may be more reasonable than surgery.

Objectives: The aim of this study was to clarify the impact of diabetes mellitus (DM) as well as antidiabetic, antihypertensive, and antihyperlipidemic medications such as metformin and statins on survival in patients with advanced pancreatic cancer receiving chemotherapy., Methods: We retrospectively reviewed the medical records of 250 patients with advanced pancreatic cancer receiving chemotherapy. Multivariate analyses of prognostic factors for survival were performed both in overall population and in subgroups with and without DM., Results: Diabetes mellitus was diagnosed in 124 patients (50%) who had less distant metastasis and more hypertension. Thirty patients received statin for hyperlipidemia. Overall survival was 13.3 versus 10.0 months with and without DM (P = 0.084), but hazard ratio of DM was 1.05 (P = 0.758) in the multivariate analysis. Subgroup analysis of diabetic patients, but not in non-diabetic patients, demonstrated use of statins (hazard ratio, 0.40; P = 0.010) as a prognostic factor, as well as distant metastasis, performance status, combination therapy with gemcitabine and S-1, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. No antidiabetic medications were prognostic factors., Conclusions: Neither DM nor antidiabetic treatment had prognostic impact on advanced pancreatic cancer. Statin use was associated with better survival in the diabetic patients.

Background: Female liver to male recipient is a well-accepted risk factor for graft loss in cadaveric liver transplantation. However, gender matching is infeasible because of an insufficient number of available donors. No studies have been performed on the role of gender in the field of living donor liver transplantation. This report investigates the effect of gender mismatch on the outcome of living donor liver transplantation., Methods: A total of 335 patients and donors were classified into four groups according to the following gender combinations: male donor to male recipient group (n=104), male donor to female recipient group (n=120), female donor to male recipient (FM) group (n=59), and female donor to female recipient group (n=52). Patient and graft survival were compared among the groups. We performed a multivariable analysis to identify the factors associated with patient mortality., Results: The 1-, 3-, 5-, and 10-year patient survival rates in the FM group were 80.6%, 66.8%, 61.8%, and 47.7%, respectively. The FM group showed significantly shorter patient survival compared with the other three groups. Independent risk factors for patient mortality were: FM group (P=0.006), pretransplant diabetes mellitus (P=0.001), and a model for end-stage liver disease score more than or equal to 20 (P=0.004)., Conclusions: Male recipients of transplants from female donors, pretransplant diabetes mellitus, and a model for end-stage liver disease score more than or equal to 20 have poor survival rates.

Objective: The aim of this study was to investigate the effect of S-1 on the prognosis of advanced pancreatic cancer., Methods: In total, 112 patients with pancreatic cancer who received chemotherapy between April 2001 and April 2007 were divided into 2 groups: PreS-1 (53 patients who started chemotherapy before January 2005) and PostS-1 (59 patients who started chemotherapy after February 2005, the time of S-1 introduction). Patient characteristics and clinical outcomes were compared, and prognostic factors were analyzed., Results: Patient characteristics did not significantly differ between the 2 groups. S-1 was administered as a second-line monotherapy in 5.7% of the PreS-1 group and combined with gemcitabine as a first-line therapy in 27.1% or as second-line monotherapy in 23.7% in the PostS-1 group. Both progression-free survival and overall survival improved after introduction of S-1 (median progression-free survival, 4.4 and 5.3 months; P = 0.043; median overall survival, 9.5 and 13.1 months; P = 0.048 in PreS-1 and PostS-1 groups, respectively). Multivariate analysis revealed that the PostS-1 group (hazards ratio, 0.52; P = 0.003), performance status, and carcinoembryonic antigen were significant prognostic factors for survival., Conclusions: Introduction of S-1 may improve the prognosis of Japanese patients with advanced pancreatic cancer.

Background: Although it is generally considered that livers with moderate steatosis can be safely used in the setting of living-donor liver transplantation, the effect of the regenerative process of such a graft on postoperative liver function is incompletely understood. We assessed the morphologic and functional alterations during the regeneration of fatty liver, with special reference to the biliary system., Methods: Wistar rats with normal or fatty livers induced by a choline-deficient diet were subjected to 70% partial hepatectomy (PH). The regenerated liver weight and serum parameters were compared. Furthermore, to assess the spatial alterations of bile canalicular networks, the distribution of AGp110, a fibronectin receptor that localizes on the apical (bile canalicular) membrane of the hepatocytes, was analyzed immunohistochemically., Results: The serum albumin levels of the fatty-liver rats decreased significantly after 24 hours, and this continued until day 7. The increase in the total bile acid levels of the fatty-liver group was higher and more prolonged compared with that of the normal-liver group. At 24 hours after PH, discontinuity of the AGp110-positive canalicular network was evident in both groups. At 7 days after PH, the typical AGp110-positive canalicular network was almost restored in the normal-liver group. In contrast, the fatty-liver group showed sustained discontinuity of canalicular networks at the same time point., Conclusions: The livers with moderate steatosis are associated with prolonged cholestasis after 70% PH, and this was caused, in part, by sustained spatial disturbance of bile canalicular networks during the regenerative process.

The role of the calcium ion in central cardiovascular regulation was investigated by injecting a calcium channel blocker, diltiazem, intracerebroventricularly (i.c.v.) in urethane-anaesthetized, DOCA-salt hypertensive rats. This produced a fall in blood pressure and bradycardia with corresponding decreases in abdominal sympathetic nerve activity. However, a similar amount of diltiazem injected intravenously (i.v.) did not affect abdominal sympathetic nerve activity despite an accompanying vasodepression. The responses to i.v. injections of diltiazem were not different between the two groups; however, the magnitude of the blood pressure fall, bradycardia and sympathetic inhibition with i.c.v. injections was greater in the DOCA rats than in the sham-operated animals. These results suggest that diltiazem causes the central nervous system to decrease the sympathetic nerve outflow. The augmented central vasodepressor responses to diltiazem in DOCA-salt hypertensive rats may indicate that calcium metabolism in the central nervous system is disrupted and that this is of importance in the pathogenesis of DOCA-salt hypertension in rats.

The origin of an endogenous digitalis-like substance in rats was investigated. The tissue content of the substance measured by radio-immunoassay was highest in the pituitary gland, with a decreasing gradient through the hypothalamus, forebrain, cerebellum, brain stem, heart, liver and kidney. Sodium loading decreased the content in the hypothalamus and increased the urinary excretion of the substance. The urinary output of the substance decreased after electrical lesions of the anteroventral third ventricle in the brain. The content increased in the hypothalamus and decreased in the plasma when the axonal flow of neurosecretion was interrupted with intracerebroventricular injections of colchicine. These results suggest that the digitalis-like substance could be produced in the hypothalamus and secreted from the pituitary gland like vasopressin, and that sodium loading increases the turnover of the substance in the hypothalamus.

When tripamide was added to the food of spontaneously hypertensive rats (SHR), there were no appreciable effects on heart rate, body weight, or food intake. Tail-cuff systolic pressures measured weekly were also unaffected in normotensive control rats (WKY), but the elevation expected in SHR was significantly reduced. Pressor responses to hypothalamic stimulation were also reduced selectively only in SHR. A peripheral inhibition of cardiovascular reactivity was considered unlikely, since pressor responses to injected norepinephrine, tyramine, or vasopressin were unaltered. Diminished pressor responsiveness was considered to be due to concurrent reduction of central sympathetic vasomotor activity, because sympathetic nerve responses to hypothalamic stimulation were appreciably lessened in tripamide-treated SHR. Although neither the site nor the mechanism causing sympathetic inhibition was determined exactly, our results are in accord with the interpretation that antihypertensive effects of tripamide in SHR depend, at least partly, on sympathetic inhibition.

Hypertonic NaCl solution injected into the cisterna magna of anesthetized rats produced dose-dependent pressor responses accompanied by slight tachycardia. Similar injections of hypertonic urea solution were ineffective. Because the early phase of the pressor response to hypertonic NaCl was always accompanied by increased sympathetic nerve firing and was inhibited following alpha-adrenergic blockade with phentolamine, initial pressor response was attributed to sympathetic hyperactivity. On the other hand, because the later phase of the pressor response was unaffected either by adrenalectomy or by alpha-adrenergic blockade, but was significantly inhibited by hypophysectomy or by pretreatment with a vasopressin antagonist, the later pressor response was ascribed to an increased release of endogenous vasopressin. Thus, our findings indicate that central pressor responses to hypertonic NaCl solution involve two different mechanisms: sympathetic hyperactivity in the early phase and vasopressin release during the later phase. In spontaneously hypertensive rats (SHR), both pressor and sympathetic responses to intracisternally injected NaCl were greater than in Wistar-Kyoto rats (WKY). Our results further indicate hypersensitivity to NaCl around the brain stem in SHR, which could account for the increased sympathetic activity and cause SHR to develop hypertension.