CA125 Kinetics as a Potential Biomarker for Peritoneal Metastasis Progression following Taxane-Plus-Ramucirumab Administration in Patients with Advanced Gastric Cancer.

Currently, no established marker exists for predicting peritoneal metastasis progression during chemotherapy, although they are major interruptive factors in sequential chemotherapy in patients with advanced gastric cancer (AGC). This multicenter retrospective study was conducted from June 2015 to July 2019, analyzing 73 patients with AGC who underwent taxane-plus-ramucirumab (TAX/RAM) therapy and had their serum carbohydrate antigen 125 (CA125) concentrations measured. Of 31 patients with elevated CA125 levels above a cutoff of 35 U/mL, 25 (80.6%) had peritoneal metastasis. The CA125 concentrations before TAX/RAM treatment were associated with ascites burden. The overall survival was significantly shorter in the CA125-elevated group. CA125 kinetics, measured at a median of 28 days after chemotherapy, were associated with the ascites response (complete or partial response: -1.86%/day; stable disease: 0.28%/day; progressive disease: 2.33%/day). Progression-free survival in the CA125-increased group, defined by an increase of 0.0067%/day using receiver operating characteristic curve analysis, was significantly poorer among patients with peritoneal metastases. In conclusion, this study highlights that CA125 kinetics can serve as an early predictor for the progression of peritoneal metastasis during TAX/RAM treatment.

Clinical Impact of the Charlson Comorbidity Index on the Efficacy of Salvage Photodynamic Therapy Using Talaporfin Sodium for Esophageal Cancer.

Introduction Photodynamic therapy (PDT) is a salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Salvage PDT is the treatment available for vulnerable patients with various comorbidities at risk of salvage esophagectomy. This study assessed the impact of the Charlson comorbidity index (CCI) on the outcomes of salvage PDT using talaporfin sodium (TS) for esophageal cancer. Metohds Consecutive patients with esophageal cancer who underwent salvage TS-PDT from 2016 to 2022 were included in this retrospective study. We investigated the local complete response (L-CR), progression-free survival (PFS) and overall survival (OS) and evaluated the relationship between the CCI and therapeutic efficacy. Results In total, 25 patients were enrolled in this study. Overall, 12 patients (48%) achieved an L-CR, and the 2-year PFS and OS rates were 24.9% and 59.4%, respectively. In a multivariate analysis, a CCI ≥1 (p=0.041) and deeper invasion (p=0.048) were found to be significant independent risk factors for not achieving an L-CR. To evaluate the efficacy associated with comorbidities, we divided the patients into the CCI=0 group (n=11) and the CCI ≥1 group (n=14). The rate of an L-CR (p=0.035) and the 2-year PFS (p=0.029) and OS (p=0.018) rates in the CCI ≥1 group were significantly lower than those in the CCI=0 group. Conclusion This study found that the CCI was negatively associated with the efficacy of salvage TS-PDT for esophageal cancer.

Liver metastasis affects progression pattern during immune checkpoint inhibitors monotherapy in gastric cancer.

Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is heterogeneous at each metastatic site, and tumor progression pattern is associated with survival; however, it remains unclear in gastric cancer (GC). Therefore, we aimed to clarify the progression pattern in response to ICIs in patients with GC, and we analyzed its mechanism focusing on the intratumoral immune cells. Methods: Patients who received ICIs were retrospectively classified into non-systemic and systemic progression groups based on their radiological assessments. Moreover, the best percentage change in target lesions from each organ was compared. Results: Among 148 patients, the non-systemic progression group showed a significant improvement in overall survival (OS) compared with the systemic progression group (median, 5.6 months vs. 3.3 months; HR, 0.53; 95%CI, 0.32-0.89; p = 0.012). Poor performance status (HR, 1.73, 95%CI, 1.00-2.87) and systemic progression (HR, 3.09, 95%CI, 1.95-4.82) were associated with OS. Of all metastatic sites, the liver showed the poorest percentage change, and liver metastasis (OR, 2.99, 95%CI, 1.04-8.58) was associated with systemic progression. Hence, intratumoral CD8+ T-cell density was lower in patients with liver metastasis than in those without liver metastasis after ICIs, although the density of CD4+ T-cells (Th1, Th17, and Treg) and CD163+ cells (TAM) were not significantly different. Conclusion: The new progression pattern was associated with OS in GC. Liver metastasis may be a predictive factor of systemic progression during ICIs by regulating intratumoral CD8+ T-cells.

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Feasibility of edoxaban for asymptomatic cancer-associated thrombosis in Japanese patients with gastrointestinal cancer: ExCAVE study.

BACKGROUND: Although initial therapy with a parenteral anticoagulant is required before edoxaban, this strategy is frequently avoided in actual clinical practice because of its complexity. This study assessed the feasibility of edoxaban without initial heparin usage for asymptomatic cancer-associated thrombosis (CAT) in Japanese patients with gastrointestinal cancer (GIC) at high risk of bleeding. METHODS: In this multicenter prospective feasibility study conducted at 10 Japanese institutions, patients with active GIC who developed accidental asymptomatic CAT during chemotherapy were recruited. Edoxaban was orally administered once daily without initial parenteral anticoagulant therapy within 3 days after detecting asymptomatic CAT. The primary outcome was the incidence of major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) during the first 3 months of edoxaban administration. RESULTS: Of the 54 patients enrolled from October 2017 to September 2020, one was excluded because of a misdiagnosis of CAT. In the remaining 53 patients, the primary outcome occurred in six patients (11.3%). MB occurred in four patients (7.5%), including gastrointestinal bleeding in three patients and intracranial hemorrhage in one patient. CRNMB occurred in two patients (3.8%), including bleeding from the stoma site and genital bleeding in one patient each. There were no deaths attributable to bleeding, and all patients who experienced MB or CRNMB recovered. CONCLUSIONS: The risk of bleeding after edoxaban without heparin pretreatment was acceptable, demonstrating new treatment options for asymptomatic CAT in patients with GIC.

Efficacy and Safety of FOLFOX in Advanced Gastric Cancer Initially Presenting With Disseminated Intravascular Coagulation.

BACKGROUND/AIM: Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis. Chemotherapy should be selected in consideration of hematological toxicities because these patients are at high risk of hemorrhagic complications. The leucovorin, fluorouracil, and oxaliplatin (FOLFOX) regimen is an effective and less toxic regimen for patients with AGC and poor performance status. PATIENTS AND METHODS: The present study assessed overall survival of all patients receiving first-line chemotherapy with and without DIC using Kaplan-Meier methods and examined the clinicopathological factors, DIC parameters, response, and survival of five patients with AGC and DIC who received FOLFOX in the first-line setting between February 2017 and February 2020. RESULTS: Among the patients, four patients (80%) recovered from DIC after a median of 12 days of FOLFOX therapy (range=12-25), and their platelet count gradually increased within 1 week after the start of chemotherapy. The median progression-free survival and overall survival were 46 (range=22-296) and 115 days (range=83-324), respectively. No patients experienced adverse events necessitating treatment discontinuation, including gastrointestinal bleeding and thrombocytopenia. Moreover, all patients received second-line treatment after progression, and one patient exhibited improvement of DIC symptoms following nab-paclitaxel and ramucirumab treatment. CONCLUSION: FOLFOX therapy is well tolerated and effective in patients with AGC initially presenting with DIC and subsequent second-line treatment might be crucial for better prognosis.

Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. PATIENTS AND METHODS: In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. RESULTS: GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. CONCLUSION: GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

Hematochezia Due to Panitumumab-induced Colitis with Vitamin K Deficiency.

Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be useful in treating either advanced or recurrent KRAS/NRAS/BRAF wild-type colorectal cancer. We herein report the case of a 60-year-old man with short bowel syndrome who developed hematochezia due to panitumumab-induced colitis with vitamin K deficiency during third-line chemotherapy. The cause of vitamin K deficiency was the lack of intravenous vitamin K supplementation following a change from central venous nutrition to peripheral venous nutrition. We advise clinicians to carefully check for colitis and manage the infusions of chemotherapy patients with short bowel syndrome.

Transcriptomic response of HepG2 cells exposed to three common anti-inflammatory drugs: Ketoprofen, mefenamic acid, and diclofenac in domestic wastewater effluents.

The biological impacts of residual pharmaceuticals in the complex wastewater effluents have not been fully understood. Here, we investigated changes in the transcriptomic responses of hepatobrastoma (HepG2) cells exposed to a single or partially combined three common non-steroidal anti-inflammatory drugs (NSAIDs); ketoprofen (KPF), mefenamic acid (MFA) and diclofenac (DCF), in domestic wastewater effluents. After 48 h sub-lethal exposure to single compounds, the DNA microarray analysis identified 57-184 differently expressed genes (DEGs). The hierarchical clustering analysis and GO enrichment of the DEGs showed that gene expression profiles of the NSAIDs were distinct from each other although they are classified into the same therapeutic category. Four maker genes (i.e., EGR1, AQP3, SQSTM1, and NAG1) were further selected from the common DEGs, and their expressions were quantified by qPCR assay in a dose-dependent manner (ranging from µg/L to mg/L). The results revealed the insignificant induction of the marker genes at 1 µg/L of KPF, MFA, and DCF, suggesting negligible biological impacts of the NSAIDs on gene expression (early cellular responses) of HepG2 at typical concentration levels found in the actual wastewater effluents. Based on the quantitative expression analysis of the selected marker genes, the present study indicated that the presence of wastewater effluent matrix may mitigate the potentially adverse cellular impacts of the NSAIDs.

Rare resected eight cases of duodenal adenocarcinomas.

INTRODUCTION: Duodenal adenocarcinoma is a rare malignancy; recently, it has been found to be accompanied by operative indications. METHODS: Nine consecutive rare cases were diagnosed with duodenal carcinoma (DC), in which clinicopathological characteristics were retrospectively examined. Age was ranged over middle-aged males and females. No clinical onset with severe symptoms was observed, and the specific treatment for accompanied diseases or habits was not found. OUTCOMES: One case of two T1 stage DCs that underwent pancreas-sparing duodenectomy. Stage II DC was diagnosed in three cases, and stage III DC was diagnosed in four cases. Pancreaticoduodenectomy (PD) mainly occurred in seven patients, and duodenectomy was limited in two patients. All operations were safely performed, and the postoperative course showed no severe morbidity. Histological findings showed R0 resection in eight cases and R1 at the retroperitoneal dissecting part in one case. Five patients with advanced-stage DC underwent adjuvant chemotherapy; however, four patients showed tumor recurrence within 12 months. With additional strong chemotherapy, eight patients survived up to 84 months, and one died of liver metastasis at 43 months after surgery. Three representative cases of mucosal invasion with widespread pancreas-sparing duodenectomy and advanced-stage DC cases undergoing duodenectomy or PD are shown. CONCLUSION: In the field of upper digestive tract surgery, duodenal adenocarcinoma and various applications of surgery or adjuvant chemotherapy for long-term survival are important.

Antiparkinsonian drugs as potent contributors to nocturnal sleep in patients with Parkinson's disease.

OBJECTIVE: To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD). BACKGROUND: Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients. METHODS: The study participants consisted of 112 PD patients (median age 72.5 years [inter-quartile range: IQR 65-79]; mean disease duration 8.44 years [standard deviation: 7.33]; median Hoehn and Yahr stage 3 [IQR 2-3.75]) taking one of three types of non-ergot extended-release DAs (rotigotine 32; pramipexole 44; ropinirole 36) with or without L-dopa (median daily total dosage of antiparkinsonian drugs 525.5 mg [IQR 376.25-658] levodopa equivalent dose [LED]). Participants were assessed using the PD Sleep Scale-2 (PDSS-2). RESULTS: For the whole PD patient cohort, the PDSS-2 sleep disturbance domain score and the scores for item 1 assessing sleep quality and item 8 assessing nocturia were positively correlated with daily total dosage of antiparkinsonian drugs and dosage of L-dopa, but not with the dosage of DAs. Sub-analysis according to DA treatment revealed that DA dosage was not correlated with item 1 or 8 score in any of the subgroups. The LED ratio of rotigotine to the total dosage of antiparkinsonian drugs was inversely correlated with the item 1 score. CONCLUSIONS: These data suggest that antiparkinsonian drugs, in particular L-dopa, adversely affect nocturnal sleep in PD patients, especially in terms of sleep quality and nocturia. Thus, adjusting both the total dosage of antiparkinsonian drugs and the dose-ratio of L-dopa might be key actions for alleviating poor sleep quality in patients with PD. Among DAs, we found a clear positive correlation between the dose-ratio of rotigotine and sleep quality. Thus, partial L-dopa replacement with rotigotine could improve sleep quality in patients with PD.

Phase II clinical trial of gemcitabine plus oxaliplatin in patients with metastatic pancreatic adenocarcinoma with a family history of pancreatic/breast/ovarian/prostate cancer or personal history of breast/ovarian/prostate cancer (FABRIC study).

BACKGROUND: A family/personal history of breast, ovarian, or pancreatic cancer is a useful predictive marker for response to platinum-based chemotherapy in treating patients with pancreatic cancer. These cancers, and prostate cancer, are known as BRCA-related malignancies. We evaluated the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with metastatic pancreatic cancer with a family/personal history of these cancers. METHODS: Chemotherapy-naïve patients with metastatic pancreatic cancer with a family history of pancreatic/breast/ovarian/prostate cancer or a personal history of breast/ovarian/prostate cancer were included. Patients received fixed dose-rate gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks. The primary endpoint was 1-year survival, and the threshold and expected values were set at 30 and 50%, respectively. The target sample size was determined to be 43, with a one-sided alpha value of 5% and power of 80%. A total of 45 patients were enrolled. RESULTS: Among the first 43 enrolled patients, the 1-year survival rate was 27.9% [90% confidence interval (CI) 17.0-41.3], which did not meet the primary endpoint. Median overall survival, progression-free survival, and response rates were 7.6 months (95% CI 6.0-10.7), 4.0 months (95% CI 2.0-4.6), and 26.7% (95% CI 14.6-41.9), respectively, in all registered patients. The GEMOX regimen was generally tolerated; the most common grade three or higher adverse events were hematological toxicities. CONCLUSION: GEMOX did not show the expected efficacy in patients with metastatic pancreatic cancer with a family or personal history of pancreatic/breast/ovarian/prostate cancer. Selection of GEMOX based on family/personal history is not recommended. TRIAL REGISTRATION NUMBER: UMIN000017894.

Comparison of the effects of three kinds of glucose-lowering drugs on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open-label, three-arm, active control study.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. MATERIALS AND METHODS: We carried out a prospective clinical trial (a randomized and open-label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end-point was the change of the liver-to-spleen ratio on abdominal computed tomography. RESULTS: There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver-to-spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver-to-spleen ratio were comparable. CONCLUSIONS: The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

Practical application of short-term intensive insulin therapy based on the concept of "treat to target" to reduce hypoglycaemia in routine clinical site.

The aim is to devise a new short-term intensive insulin therapy (N-SIIT) based on the concept of "treat to target" to avoid hypoglycaemia and was applied it to various diabetic state. We determined dosage of 1 basal and 3 bolus "treat" insulin based on "target" blood glucose level and changed each insulin dose by small units (2 units) every day for 2 weeks. We evaluated the effects of N-SIIT in 74 subjects with type 2 diabetes (male 45, female 29, 64.9 ± 16.6 years old, HbA1c 10.4 ± 2.6%). Glargine U300 ("treat") and morning blood glucose level ("target") was significantly correlated with increasing insulin dose and decreasing blood glucose level in day 1-7, indicating that insulin amount was determined by target blood glucose level and lowered next target blood glucose level. Remission rates were 67.3% (Hypoglycaemia rate 5.6 %) in N-SIIT and 47.3% (Hypoglycaemia rate 38.1%) in conventional SIIT. Required amount of insulin would be automatically determined, depending on each patient pathophysiology and life style. This method is pretty simple, flexible and cheap, and provides information about the dynamic pathophysiological alteration of insulin resistance and glucotoxicity from the profile of blood glucose levels and insulin shot.

Two cases of bile duct carcinoma patients who underwent the photodynamic therapy using talaporfin sodium (Laserphyrin®).

The efficacy of adjuvant photodynamic therapy (PDT) using the new photosensitizer, talaporfin sodium (TPS) has been clinically examined in some patients with bile duct carcinoma (BDC). Based on our previous cohorts, a prospective clinical trial was attempted; however, only two cases were ultimately enrolled in 27 months. A 664-nm semiconductor laser (100 J/cm2) was applied through an endoscope to the tumor lesion within 6 h of an intravenous injection of 40 mg/m2 TPS according to the protocol for lung cancer. Case 1 was an 82-y.o. female patient with BDC at the left hepatic duct with biliary obstruction, percutaneous transhepatic biliary drainage (PTBD) was achieved, and the patient did not consent to surgery. She was followed up for 15 months to search for non-surgical treatments and eventually received PDT. Although mild photosensitivity occurred, she was discharged without severe adverse events. Biliary stenosis markedly extended and a PTBD tube was scheduled at 1 month. However, cancer immediately metastasized to the liver and she died 155 days after PDT. Case 2 was a 70-y.o. female with perihilar BDC and multiple biliary stenoses. Multiple biliary stenting was considered to be difficult. She received PDT and no adverse events were observed. Biliary stenoses markedly improved and multiple stenting was successfully performed. On day 132, she died of cancer progression. These two cases demonstrated the safety and efficacy of biliary malignant stenosis soon after PDT; however, long-term survival and a sufficient quality of life were not achieved. The combination of the PDT protocol and system chemotherapy or brachytherapy needs to be examined in clinical trials for advanced stage BDC.

Adrenomedullin: A Novel Therapy for Intractable Crohn's Disease with a Loss of Response to Infliximab.

A 35-year-old man with refractory Crohn's disease showed a loss of response to infliximab after requiring treatment with infliximab at 10 mg/kg together with steroid to maintain remission. His symptoms recurred, and colonoscopy showed extensive active ulcers in the colon. Adrenomedullin therapy was started in addition to the conventional infliximab therapy. A few days after, his symptoms went into remission. Endoscopy at 2 and 7 weeks revealed significant mucosal remission without steroid therapy. Adrenomedullin promoted mucosal healing and led to the re-induction of remission in Crohn's disease in a patient with a loss of response to infliximab.

Phase II study of S-1 plus oxaliplatin 130 mg/m2 in Japanese patients with advanced gastric cancer.

PURPOSE: Although oxaliplatin 130 mg/m2 every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m2 (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer. METHODS: Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0-1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin. RESULTS: Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8-86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1-19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9-8.5) and 13.1 months (95% confidence interval 7.4-19.0), respectively. CONCLUSION: Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

Pancreatic alpha cells in diabetic rats express active GLP-1 receptor: Endosomal co-localization of GLP-1/GLP-1R complex functioning through intra-islet paracrine mechanism.

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic beta cells and suppresses glucagon secretion from alpha cells. It remains controversial, however, whether GLP-1 receptor (GLP-1R) is expressed in mature alpha cells. In this study, unlike previous studies using non-diabetic animals, we demonstrated using diabetic model rats and confocal laser scanning microscopy that the GLP-1/GLP-1R complex was located in the endosome of diabetic islets. In addition, we showed that GLP-1 and GLP-1R co-localized with various endosomal markers and adenylate cyclase in the alpha cells of diabetic rats. Diabetic rats had endosomal signaling pathway but normal rats had classical signaling pathway for activated GLP-1R. Furthermore, we performed pancreatic perfusion to assess the functional activity of GLP-1R when stimulated by exendin-4 (EX4). In a pancreas perfusion study, EX4 significantly stimulated glucagon secretion in diabetic rats but not normal rats. However, such glucagon secretion was immediately suppressed, probably due to concomitantly secreted insulin. The GLP-1/GLP-1R complex appears to function through an intra-islet paracrine mechanism in diabetic conditions which could explain, at least in part, the mechanism of paradoxical hyperglucagonaemia in type 2 diabetes.

Multiple-endpoints gene alteration-based (MEGA) assay: A toxicogenomics approach for water quality assessment of wastewater effluents.

Wastewater effluents contain a significant number of toxic contaminants, which, even at low concentrations, display a wide variety of toxic actions. In this study, we developed a multiple-endpoints gene alteration-based (MEGA) assay, a real-time PCR-based transcriptomic analysis, to assess the water quality of wastewater effluents for human health risk assessment and management. Twenty-one genes from the human hepatoblastoma cell line (HepG2), covering the basic health-relevant stress responses such as response to xenobiotics, genotoxicity, and cytotoxicity, were selected and incorporated into the MEGA assay. The genes related to the p53-mediated DNA damage response and cytochrome P450 were selected as markers for genotoxicity and response to xenobiotics, respectively. Additionally, the genes that were dose-dependently regulated by exposure to the wastewater effluents were chosen as markers for cytotoxicity. The alterations in the expression of an individual gene, induced by exposure to the wastewater effluents, were evaluated by real-time PCR and the results were validated by genotoxicity (e.g., comet assay) and cell-based cytotoxicity tests. In summary, the MEGA assay is a real-time PCR-based assay that targets cellular responses to contaminants present in wastewater effluents at the transcriptional level; it is rapid, cost-effective, and high-throughput and can thus complement any chemical analysis for water quality assessment and management.

Primary Cardiac Leiomyosarcoma: A 27-Month Survival with Surgery and Chemotherapy.

The patient was a 39-year-old man hospitalized due to the presence of a cardiac mass and heart failure. Emergency tumor resection and mitral valve replacement were performed. The pathological findings of the tumor led to a diagnosis of cardiac leiomyosarcoma. After the operation, multiple metastases were found. The patient underwent three courses of chemotherapies: adriamycin, ifosfamide, dacarbazine, and mesna (MAID therapy), gemcitabine plus docetaxel, and sunitinib. During MAID therapy, the patient underwent resection of gastrointestinal metastases twice due to gastrointestinal hemorrhaging. Although he died 27 months after the initial treatment, use of multimodal therapy was effective in achieving a longer survival for the patient.