Prognostic factors to predict the survival in patients with advanced gastric cancer who receive later-line nivolumab monotherapy-The Asahikawa Gastric Cancer Cohort Study (AGCC).

BACKGROUND: Chemotherapy for advanced gastric cancer is recommended in the guidelines; however, later-line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens. PATIENTS AND METHODS: A regional cohort study was undertaken to determine the real-world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated. RESULTS: In total, 70 patients who received nivolumab as ≥third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8-10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68-0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2-positive status (27.3%) or microsatellite instability-high (27.3%) status. CONCLUSIONS: The regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

IgG4-related Disease Manifesting as Gastroduodenal Ulcer Diagnosed by an Endoscopic Biopsy.

A 26-year-old man was admitted to our hospital due to upper abdominal pain. He had previously been diagnosed with gastroduodenal ulcer at 23 and 25 years old and had been treated with proton-pump inhibitors. Endoscopic hemostasis and a biopsy were performed on the hemorrhagic gastroduodenal ulcers. Laboratory and pathologic examinations demonstrated elevated serum IgG4 levels and the infiltration of IgG4-positive plasma cells into the gastroduodenal tissues. Based on the clinicopathologic findings and after excluding other causes, he was diagnosed with IgG4-related gastroduodenal ulcer. We herein report a rare case of IgG4-related disease manifesting as a gastroduodenal ulcer diagnosed by an endoscopic biopsy.

Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis.

BACKGROUND: Angiotensin II type 1 receptor blockers (ARBs) have been reported to attenuate hepatic fibrosis in non-alcoholic steatohepatitis (NASH). However, it is uncertain whether ARBs prevent hepatocarcinogenesis in NASH even after hepatic fibrosis has developed. METHODS: Male Wistar rats were fed with a choline-deficient, L-amino acid-defined (CDAA) diet for 24 weeks, and then fed with the CDAA diet with telmisartan (2 mg/kg/day), a novel ARB, or vehicle for another 24 weeks. The liver histology and the expression of genes and proteins related to angiogenesis were investigated. RESULTS: The 24-week CDAA diet induced liver cirrhosis. The 48-week CDAA diet exacerbated liver cirrhosis, and developed hepatocellular carcinoma (HCC) in 54.6 % of the rats concurrently with increases of hypoxia-inducible factor-1α (HIF-1α) protein and vascular endothelial growth factor (VEGF) mRNA, which are potent angiogenic factors in the liver. Telmisartan inhibited hepatic fibrosis and preneoplastic lesions and prevented the development of HCC along with inducing decreases in HIF-1α protein and VEGF mRNA. CONCLUSIONS: These data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.

Possibility of oral feeding after induction of percutaneous endoscopic gastrostomy.

BACKGROUND AND AIM: Although percutaneous endoscopic gastrostomy (PEG) has become established as a useful enteral nutrition technique, the associated risks must always be kept in mind. Recently, we experienced several patients who could orally ingest after PEG. To avoid unnecessary PEG, we investigated patients who could orally ingest after PEG, and analyzed predictive factors of postoperative oral feeding. METHODS: We retrospectively analyzed data of 302 patients who underwent PEG at our hospital. After all patients were divided according to postoperative oral feeding status, we assessed factors of patients' backgrounds. In patients who could orally ingest after PEG, we investigated the course of oral feeding status. We attempted to identify predictive factors for postoperative oral feeding using logistic regression analysis. RESULTS: Mean age was high in both groups, and overall condition was markedly poor. Forty-four patients (15%) were able to ingest orally after PEG. Enteral nutrition could be avoided during our observation period in 15 cases, because sufficient oral intake was achieved. Conversely, oral feeding was reduced or discontinued in 14 cases. Multivariate analysis identified the following independent predictive factors for postoperative oral feeding: (i) absence of dysphagia or aphagia; (ii) younger age; (iii) favorable performance status; (iv) presence of post-traumatic encephalopathy; and (v) preoperative swallowing training. CONCLUSIONS: A total of 15% of PEG cases were able to ingest orally after PEG. In patients showing positive predictive factors, indications for PEG should be carefully considered.

[Risk factors of early mortality after percutaneous endoscopic gastrostomy: a retrospective study].

When performing percutaneous endoscopic gastrostomy (PEG), the associated risks must always be kept in mind. We investigated and analyzed early mortality after PEG, retrospectively. Of the 302 patients (63% males, mean age 75 years) who underwent PEG at our center from 1999 to 2008, 7 patients (2.3%) were dead within 30 days of the procedure. Only one death could be directly related to the procedure. By a logistic regression analysis, the following 3 factors were identified as independent preoperative risk factors for death within 30 days of the PEG: (1) high serum creatinine level [mg/dl, p=0.006, odds ratio (OR)=8.472]; (2) past history of ischemic heart disease [p=0.008, OR=9.985]; (3) low serum albumin level [g/dl, p=0.017, OR=0.096]. In patients with poor renal function, poor cardiac function, severe malnutrition or exhaustion, the indications for PEG need to be very carefully investigated.

Investigation and prediction of enteral nutrition problems after percutaneous endoscopic gastrostomy.

AIM: To investigate and predict enteral nutrition problems after percutaneous endoscopic gastrostomy (PEG). METHODS: We retrospectively analyzed data for 252 out of 285 patients who underwent PEG at our hospital from 1999 to 2008. Enteral nutrition problems after PEG were defined as: (1) patients who required > or = 1 mo after surgery to switch to complete enteral nutrition, or who required additional parenteral alimentation continuously; or (2) patients who abandoned switching to enteral nutrition using the gastrostoma and employed other nutritional methods. We attempted to identify the predictors of problem cases by using a logistic regression analysis that examined the patients' backgrounds and the specific causes that led to their problems. RESULTS: Mean age of the patients was 75 years, and in general, their body weight was low and their overall condition was markedly poor. Blood testing revealed that patients tended to be anemic and malnourished. A total of 44 patients (17.5%) were diagnosed as having enteral nutrition problems after PEG. Major causes of the problems included pneumonia, acute enterocolitis (often Clostridium difficile-related), paralytic ileus and biliary tract infection. A multivariate analysis identified the following independent predictors for problem cases: (1) enteral nutrition before gastrectomy (a risk reduction factor); (2) presence of esophageal hiatal hernia; (3) past history of paralytic ileus; and (4) presence of chronic renal dysfunction. CONCLUSION: Enteral nutrition problems after PEG occurred at a comparatively high rate. Patient background analysis elucidated four predictive factors for the problem cases.

[Clinical utility of angiotensin II receptor antagonist].

Non-alcoholic steatohepatitis (NASH) can potentially progress to liver cirrhosis and hepatocellular carcinoma. The causes of this disease are not well defined, and although several therapies have been tried, the optimal treatment has not been established. Recently, a role for angiotensin II in insulin resistance, oxidative stress and hepatic stellate cell activation has been reported. We treated patients who had NASH and hypertension with losartan, an angiotensin II receptor antagonist for 48 weeks. The losartan treatment improved hepatic necroinflammation and fibrosis in NASH patients. Moreover, a disappearance of iron deposition in hepatocytes, and a decrease in activated hepatic stellate cells were detected after treatment. Our results suggest the therapeutic efficacy of angiotensin II receptor antagonist in patients with NASH.

Macrophage inflammatory protein-1alpha plays a crucial role in concanavalin A-induced liver injury through induction of proinflammatory cytokines in mice.

BACKGROUND/AIMS: : The chemokines play roles in the development of immune mediated liver diseases. In this study, we investigate the involvement of macrophage inflammatory protein-1alpha (MIP-1alpha), one of the CC chemokines in concanavalin A (Con A)-induced liver injury in mice. METHODS: : Liver injury was induced by intravenous injection of Con A. Anti-mouse MIP-1alpha antibody, recombinant murine-MIP-1alpha and gadolinium chloride (GdCl(3)) were administrated prior to Con A injection. Plasma alanine aminotransferase (ALT), MIP-1alpha, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) levels were determined and histological assessment of the liver was performed. RESULTS: : Plasma MIP-1alpha level was elevated after Con A injection. The elevated plasma ALT level, mortality rate and histological change after Con A injection were inhibited by anti-MIP-1alpha antibody pretreatment. The elevated plasma ALT level after Con A injection was further enhanced by recombinant murine-MIP-1alpha. The elevated plasma TNF-alpha and IFN-gamma levels after Con A injection were inhibited by anti-MIP-1alpha antibody, and enhanced by recombinant murine-MIP-1alpha. GdCl(3) pretreatment inhibited the elevated plasma MIP-1alpha and ALT levels. CONCLUSIONS: : These findings suggest that MIP-1alpha is produced from Kupffer cells after Con A injection, and this CC chemokine plays a crucial role in Con A-induced liver injury through induction of proinflammatory cytokines.

High, but not low, molecular weight hyaluronan prevents T-cell-mediated liver injury by reducing proinflammatory cytokines in mice.

BACKGROUND: The extracellular matrix component hyaluronan (HA) modulates the production of various cytokines and chemokines by activated inflammatory cells. In this study, we investigated whether exogenous administration of HA influences T-cell-mediated liver injury and cytokine production. METHODS: Liver injury was induced by administration of concanavalin A (Con A) or D-galactosamine/lipopolysaccharide (GalN/LPS), and 0.05%-0.35% (v/v) HA (MW 250, 470, 780, 900, and 1200 kDa) was administered intravenously 18 h before Con A or GalN/LPS injection. Plasma ALT level was determined enzymatically and plasma cytokine levels were determined by ELISA. RESULTS: The elevated plasma levels of ALT at 8 h after Con A and at 7 h after GalN/LPS injection were significantly decreased by pretreatment with high molecular weight HAs (780, 900, and 1200 kDa) but not low molecular weight HAs (250 and 470 kDa). High molecular weight HA (900 kDa) significantly reduced plasma tumor necrosis factor-alpha, interferon gamma, macrophage inflammatory protein 2, and interleukin 4 levels after Con A injection. However, this inhibitory effect on plasma cytokines was not observed with low molecular weight HA (250 kDa) pretreatment. CONCLUSIONS: The present results suggest that high molecular weight but not low molecular weight HA prevents liver injury by reducing proinflammatory cytokines in a T-cell-mediated liver injury model. The extracellular matrix component hyaluronan (HA) modulates the production of various cytokines and chemokines by activated inflammatory cells. In this study, we investigated whether exogenous administration of HA influences T-cell-mediated liver injury and cytokine production.

Antithrombin III prevents concanavalin A-induced liver injury through inhibition of macrophage inflammatory protein-2 release and production of prostacyclin in mice.

BACKGROUND/AIMS: Recently, we have reported that macrophage inflammatory protein-2 (MIP-2) plays a pivotal role in concanavalin A (Con A)-induced liver injury. In this study, we investigated the effect of antithrombin III (AT-III) on liver damage, and production of MIP-2 and prostacyclin in this model. METHODS: Liver injury was induced by intravenous injection of Con A (15 mg/kg) and AT-III was administered (50, 250 and 500 units/kg, iv) 30 mm before Con A injection. Plasma levels of alanine aminotransferase (ALT), MIP-2 and 6-keto-prostaglandin F1alpha (6k-PG-F1alpha), stable metabolite of prostaglandin I(2) (prostacyclin), were determined. RESULTS: The elevated plasma ALT levels 8, 16, 24 h after Con A injection were inhibited by AT-III pretreatment. The elevated plasma MIP-2 levels were significantly inhibited by AT-III pretreatment compared with vehicle treatment. The inhibitory effect of AT-III on plasma ALT and MIP-2 in Con A-induced liver injury was attenuated by indomethacin (5 mg/kg, ip). Plasma concentration of 6k-PG-F1alpha at 2 h after AT-III injection was significantly elevated compared with baseline and vehicle pretreatment. CONCLUSIONS: These findings suggest that AT-III prevents Con A-induced liver injury through an inhibition of MIP-2 release and a production of prostacyclin.