Conversion Surgery After Chemotherapy Plus Nivolumab as the First-Line Treatment for Unresectable Advanced or Recurrent Gastric Cancer and a Biomarker Study Using the Gustave Roussy Immune Score: A Multicenter Study.

BACKGROUND: There are few reports on conversion surgery (CS) after chemotherapy plus nivolumab as a first-line treatment in patients with unresectable advanced or recurrent gastric cancer (GC). This multicenter study was conducted to analyze real-world data on CS after chemotherapy plus nivolumab as a first-line treatment and to identify predictive biomarkers. METHODS: This multicenter study included 104 patients who received chemotherapy plus nivolumab as primary treatment for unresectable advanced recurrent GC from 12 institutes. We investigated and analyzed patient characteristics and blood test data in the presence or absence of CS, the relationship between the Gustave Roussy Immune Score (GRIm-s) and CS, and the characteristics of CS cases. RESULTS: CS was performed in 12 patients (11.5%). Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was significantly better in patients who underwent CS (p < 0.0001). There were no CS cases with high-risk GRIm-s (0%), however there were 22 non-CS cases (23.9%). No high-risk GRIm-s cases were converted to CS. Minimally invasive surgery was performed in 50.0% of the cases, with R0 resection in all cases and only one case of urinary retention (Grade II) as a postoperative complication, indicating a good postoperative short-term outcome. There were two cases of postoperative recurrence (16.7%), both of which were grade 1b. CONCLUSIONS: The short-term postoperative results of CS after chemotherapy plus nivolumab as the first-line treatment for GC were acceptable in this study. There were no high-risk GRIm-s cases among those who underwent CS, suggesting that the GRIm-s may be a predictor of CS.

Identification of Biomarkers for Assessing Treatment Efficacy of Chemotherapy plus Nivolumab as the First Line in Patients with Unresectable Advanced or Recurrent Gastric Cancer: A Multicenter Study.

INTRODUCTION: In this study, we aimed to identify biomarkers for predicting treatment outcomes and efficacy of chemotherapy plus nivolumab, as well as predict immune-related adverse events (irAEs) characteristics of immune checkpoint inhibitors. METHODS: This multicenter study included 104 patients who received chemotherapy plus nivolumab as the primary treatment for unresectable advanced recurrent gastric cancer. Blood test results were collected before the start and after two courses of treatment. The neutrophil-lymphocyte ratio, prognostic nutritional index, and lactate dehydrogenase/albumin ratio (LAR) were examined after treatment in each case to determine changes compared to values before the start of treatment. RESULTS: A total of 57 (54.8%) patients experienced a complete or partial response. The LAR of the stable disease/progressive disease group significantly increased (p = 0.018). An examination of the presence of grade ≥3 irAEs and changes in related factors showed that the LAR of all patients increased. CONCLUSION: The LAR was correlated with the best therapeutic response; therefore, it may be a potential biomarker of treatment outcomes and efficacy.

Clinical significance of ß2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma.

The ß2-adrenergic receptor (ß2-AR) is highly expressed in various human neoplasms and has been considered a novel therapeutic target of cancer treatment. However, the clinicopathological significance of ß2-AR expression in patients with gastric cancer (GC) remains unclear. The aim of this study was to explore ß2-AR expression and its prognostic significance. A total of 331 patients with surgically resected GC were evaluated. Tumor sections were stained immunohistochemically for ß2-AR. And, we confirmed ß2-AR expression in the GC cell lines by Western blot. ß2-AR was highly expressed in 30.5 % of GC patients. Expression was significantly associated with age, T factor, tumor differentiation, histology of non-signet cells, lymphatic permeation, and vascular invasion. And, all the GC cell lines expressed ß2-AR. On univariate analysis, age, disease stage, T factor, N factor, lymphatic permeation, vascular invasion, and ß2-AR expression were significantly associated with overall survival. Although the multivariate analysis did not indicate that ß2-AR expression was independently prognostic of survival, high-level ß2-AR expression was associated with significantly poorer survival of GC patients with well or moderately differentiated tumors. ß2-AR expression was a significant predictor of tumor aggressiveness in, and poorer survival of, patients with GC.

[A case of long-term survival after peritoneal recurrence of rectal cancer achieved by tumorectomy and adjuvant chemotherapy].

The patient was a 40-year-old woman.She began experiencing abdominal pain and constipation in July 2005.S he underwent endoscopy in August, which revealed rectal cancer.She was referred to our hospital for surgery and underwent anterior resection with lymph node dissection in September. The pathological diagnosis was tub2, SS, N2, ly1, v1, stage III b. After discharge, she began oral chemotherapy. However, in April 2006, computed tomography (CT) revealed recurrence in the Douglas pouch. She began FOLFOX4 treatment in May.On follow-up CT performed in July, the recurrent sites were limited to 2 nodules and were deemed resectable. The patient underwent peritoneal dissemination resection, and the pathological diagnosis was metastatic tumor.She subsequently received 11 postoperative FOLFOX4 courses. The chemotherapy regimen was changed to the de Gramont regimen because of peripheral neuropathy. After 56 courses of the de Gramont regimen, the chemotherapy regimen was further changed to UFT/UZEL. The patient received 28 additional courses but experienced hair loss and requested treatment cessation. To date, she remains alive without recurrence.

[A case of advanced pancreas cancer successfully treated by using combined modality therapy].

A 62-year-old woman visited a nearby hospital with chief complaints of diarrhea and weight loss.A computed tomography (CT)scan showed a hypovascular tumor approximately 2 cm in diameter in the pancreatic uncus, and the patient was referred to our department for thorough examination and treatment.The patient was diagnosed with cT4 (A) N0M0, cStage IV a cancer of the pancreatic uncus.The treatment consisted of 3 weeks of gemcitabine and 1 week of drug withdrawal; after completion of 4 courses, concomitant administration of S-1 (ie GS therapy) was initiated.The tumor gradually shrank, and it was not observed on a CT scan 1 year and 8 months later.Although no obvious distant metastasis was observed, a low density area around the superior mesenteric artery still remained.Possibility of viable tumor could not be completely ruled out; therefore, a pancreaticoduodenectomy was scheduled.However, because sclerosis around the superior mesenteric artery was quite severe, bled easily, and was difficult to separate, we decided that excision was impossible and resumed the GS therapy. The primary lung cancer that developed subsequently was resected, and the GS therapy was continued.The tumor in the pancreatic uncus was resected after growth was observed 3 years and 9 months after the initiation of chemotherapy.The patient is currently receiving chemotherapy as an outpatient.

[Retrospective analysis of the bevacizumab and CapeOX combination in untreated metastatic/recurrent colorectal cancer].

In recent years, there has been significant progress in systemic chemotherapy for metastatic or recurrent colorectal cancer. We investigated the clinical efficacy and feasibility of the bevacizumab and capecitabine /oxaliplatin(CapeOX)combination for untreated colorectal cancer. From October 2009 to June 2012, 38 patients were included, 18 receiving CapeOX alone and 20 receiving CapeOX plus bevacizumab. The response rate and disease-control rate were 16% and 5 0%, respectively, in the CapeOX arm, and 5 5% and 8 5%, respectively, in the CapeOX plus bevacizumab arm. Median progression-free survival was 8.0 months in the CapeOX arm and 1 2.8 months in CapeOX plus bevacizumab arm. The median overall survival was 21.6 months in the CapeOX arm and 3 4.0 months in CapeOX plus bevacizumab arm. Our results suggest that CapeOX treatment can be useful in the outpatient setting and more effective when combined with bevacizumab. Except in cases of bevacizumab intolerance, addition of bevacizumab to CapeOX treatment is considered useful as first-line therapy for metastatic or recur- rent colorectal cancer.

[Subset analysis of preoperative lymphocyte ratio in stage II or III colorectal cancer patients treated with oral tegafur-uracil and protein-bound polysaccharide K].

PURPOSE: We have reported, in a randomized, controlled study, that tegafur-uracil(UFT)and protein-bound polysaccharide K(PSK)combination therapy significantly improves the 5-year disease-free survival rate and reduces the risk of recurrence compared to UFT alone for Stage II or III colorectal cancer. In this study, we examined the efficacy of PSK by stratifying patients according to the preoperative lymphocyte ratio(Lym). METHODS: In a randomized, controlled study, 205 patients were eligible(137 in the UFT/PSK group and 68 in the UFT group). Of these, 193 patients with available preoperative Lym data were analysed(131 in the UFT/PSK group and 62 in the UFT group). RESULTS: Among patients with a preoperative Lym of <35%, the relapse-free survival(RFS)rate was 76.5% in the UFT/PSK group and 55.8% in the UFT group(p=0.008). However, in patients with a preoperative Lym of ≥35%, the RFS rate did not differ between the 2 groups. Similarly, overall survival was significantly higher in the UFT/PSK group than in the UFT group in patients with a preoperative Lym of <35%, whereas no intergroup difference was found among patients with a preoperative Lym of ≥35%. CONCLUSION: This study suggests that a low preoperative Lym is a good predictor for response to PSK in patients with Stage II or III colorectal cancer.

[Pathological complete remission using low-dose cisplatin plus S-1 for gastric cancer patient with liver metastases].

A 70-year-old female presented with epigastralgia. Gastrointestinal endoscopic examination showed advanced gastric cancer type 2. Computed tomography(CT)showed a liver tumor of 37mm in segment 6. She was treated with oral S-1, 80 mg/body for 14 days, followed by a 7-day rest, and CDDP 20mg/m2(day 1 and 8). After ten courses of treatment, CT showed reduction of the primary cancer, the liver tumor, and the affected lymph nodes. Then, distal gastrectomy, lymph node dissection, and partial liver resection were performed. The histological diagnosis was no viable cancer cells found in stomach, liver or lymph nodes. One year and 1 month postoperatively, the patient is alive without recurrence.

[A case of advanced colon cancer with peritoneal dissemination effectively treated with modified FOLFOX6 chemotherapy].

A 50-year-old woman was diagnosed with ascending colon cancer with bilateral ovarian metastases, carcinomatous peritonitis, and carcinomatous pleurisy. Nine courses of mFOLFOX6 treatment resulted in the disappearance of her ascites and pleural effusion and a marked decrease in her serum CEA and CA19-9 levels. Additionally, the primary tumor and ovarian metastases became smaller. Therefore, a right hemicolectomy with D3 lymph node dissection, total hysterectomy, and bilateral salpingo-oophorectomy were performed. Postoperatively, we changed the chemotherapy from mFOLFOX6 to bevacizumab+FOLFIRI because the patient had an allergic reaction to oxaliplatin, and we suspected lung metastasis. Because the lung metastasis grew after ten courses of bevacizumab+FOLFIRI, we changed to cetuximab+FOLFIRI. Unfortunately, 28 months after her diagnosis, the patient died of carcinomatous pleurisy.

[A case of pancreatic cancer with celiac trunk and common hepatic artery invasion successfully resected after gemcitabine+S-1therapy].

We present a case of a 59-year-old female who was admitted to our hospital for upper abdominal pain. She was diagnosed with pancreatic body carcinoma by computed tomography and magnetic resonance imaging. We started gemcitabine+S-1 chemotherapy because the tumor had invaded the celiac trunk, common hepatic artery, superior mesenteric vein, and splenic vein. We reduced the S-1 to 100mg/body after the third course of gemcitabine(1, 000mg/m2 on days 1 and 8, every 21 days)+S-1(120mg/body on days 1-14, every 21 days)because of side effects. The tumor became smaller, and the celiac trunk and common hepatic artery were released. Thus, we conducted a distal pancreatectomy with a D2 lymph node dissection.

[A case of gastric cancer with lung, Virchow and para-aortic lymph node metastases treated successfully using PTX/5'-DFUR].

A 6 3-year-old male presented with dysphagia. Gastrointestinal endoscopic examination showed advanced gastric cancer type 3, which was diagnosed as well-differentiated adenocarcinoma. Computed tomography(CT)showed bilateral lung tumors, hugely enlarged Virchow and para-aortic lymph nodes. He was treated with combination chemotherapy of weekly paclitaxel(PTX)and doxifluridine(5'-DFUR). PTX was administered at a dose of 80mg/m2 on day 1, 8 and 15, and 5'- DFUR was orally administered at a dose of 533mg/m / 2day for 5 days followed by withdrawal for 2 days. After four courses of treatment, CT showed an almost complete disappearance of the lung and lymph node metastases. After 13 courses of treatment, total gastrectomy and lymph node dissection were performed. One year postoperatively, the patient died of a recur- rence.

[An elderly gastric cancer patient with multiple-node metastases treated successfully using S-1].

A n 83-year-old male presented with a leg edema. Gastrointestinal endoscopic examination showed advanced gastric cancer type 2, which was diagnosed as mod~well-differentiated adenocarcinoma. Computed tomography (CT) showed enlarged multiple lymph nodes. He was treated with oral S-1, 80 mg/day for 14 days, followed by a 7-day rest. After two courses of treatment, CT showed reduction of the lymph nodes. After 8 courses of treatment, total gastrectomy and lymph node dissection were performed. The histological diagnoses were tub 2>tub 1, pSS, pN0, pStage I B. One year and 10 months postoperatively, the patient is alive without recurrence.

[A case of gastric cancer with Virchow and para-aortic node metastases treated successfully using S-1].

A 64-year-old female presented with a left cervical tumor. Gastrointestinal endoscopic examination showed advanced gastric cancer type 3, which was diagnosed as poorly-differentiated adenocarcinoma. Computed tomography (CT) showed hugely enlarged Virchow and para-aortic lymph nodes. She was treated with oral S-1, 100 mg/day for 28 days, followed by a 2-week rest. After two courses, S-1 was administered for 14 days followed by a 7-day rest because of side effects. After five courses of treatment, CT showed complete disappearance of the lymph node metastases. Total gastrectomy and lymph node dissection were performed. The histology was judged as Grade 2. The residual cancer in the stomach was only 2mm in size, and there were no viable cancer cells in any lymph nodes. One year postoperatively, the patient is alive without recurrence.

Effects of the COX-2 inhibitor FK3311 on ischemia - reperfusion injury in the rat lung.

Ischemia-reperfusion injury is induced by activation of the arachidonic acid cascade following the induction of cyclooxygenase-2. This study evaluated the effects of a selective cyclooxygenase-2 inhibitor, FK3311, on warm ischemia-reperfusion injury in the lung. Male Wistar rats were divided into two groups. In the FK3311 group (n = 27), FK3311 (4 mg/kg) was administered intravenously 5 min before ischemia, while in the control group (n = 27) only vehicle was injected. Warm ischemia was induced for 1 h by clamping the left hilus. The arterial oxygen pressure (PaO(2)) and saturation (SaO(2)) were measured 30 and 120 min after reperfusion. Serum thromboxane B(2) and 6-keto-prostaglandin F(1alpha) were also measured 30 min after reperfusion. Lung specimens were harvested 120 min after reperfusion for histologic examination and polymorphonuclear counts, and immunostained with cyclooxygenase-2. The 1-week survival rate in the two groups was compared. PaO(2) and SaO(2) 30 and 120 min after reperfusion were significantly (p < .05) better in the FK3311 group. Serum thromboxane B(2) levels were significantly (p < .05) lower in the FK3311 group. However, there was no significant difference in 6-keto-prostaglandin F(1alpha). Histologically, tissue damage was mild and polymorphonuclear infiltration was reduced in the FK3311 group compared to the control group. The expression of cyclooxygenase-2 in the alveolar epithelium based on immunostaining was suppressed in the FK3311 group. The 1-week survival rate was significantly (p < .05) higher in the FK3311 group. We conclude that FK3311 has protective effects on pulmonary ischemia-reperfusion injury, and results in improvement in the 1-week survival rate.

Prognostic role of BiP/GRP78 expression as ER stress in patients with gastric adenocarcinoma.

PURPOSE: The glucose-regulated protein 78 (GRP78), also referred to as immunoglobulin heavy chain binding protein (BiP) (BiP/GRP78), is a major molecular chaperone in the endoplasmic reticulum (ER) and is extensively expressed in human neoplasms. Although the enhanced expression of BiP/GRP78 has been described to be associated with poor prognosis in gastric cancer (GC), details regarding its prognostic significance remain unclear. The aim of this study was to elucidate the prognostic role of BiP/GRP78 in patients with GC. METHODS: Study subjects included 328 patients who underwent surgical resection. Tumor specimens of primary tumors underwent immunohistochemical staining for BiP/GRP78. RESULTS: BiP/GRP78 was highly expressed in 57% (188/328) of patients. High expression of BiP/GRP78 was significantly associated with older age, male, disease staging, T factor, lymph node metastases, differentiation, lymphatic permeation, and vascular invasion. According to univariate analysis, age, disease staging, T factor, N factor, lymphatic permeation, vascular invasion, and BiP/GRP78 expression were significant prognostic factors for OS. In particular, high BiP/GRP78 expression was proven to be a significant predictor of prognosis in patients with older age, female sex, early disease stage, T1-2 factor, well or moderately differentiated tumors, and negative vascular invasion. CONCLUSION: BiP/GRP78 is significantly associated with tumor aggressiveness and progression. The increased expression of BiP/GRP78 was identified as an independent factor for predicting poor OS in patients with early stage of disease, especially T1-2 factor.

Spontaneous isolated dissection of the superior mesenteric artery and aneurysm formation resulting from segmental arterial mediolysis: a case report.

BACKGROUND: Spontaneous isolated dissection of the superior mesenteric artery (SMA) can lead to bowel ischemia, aneurysm rupture, or even death. Studies have suggested that mechanical or hemodynamic stress on the vascular wall of the SMA may be a contributor, but its pathogenesis is unclear. CASE PRESENTATION: A 57-year-old Japanese man with a history of untreated hypertension and hyperuricemia was admitted to our hospital with the sudden onset of severe epigastric pain. Laboratory findings showed elevated white blood cell count and C-reactive protein, and contrast-enhanced computed tomography (CT) of the abdomen demonstrated arterial dissection with luminal stenosis and aneurysm formation at the distal portion of the SMA after the branching of the jejunal artery, and intravenous nicardipine was administered. The patient's epigastric pain resolved spontaneously but recurred on day 6 of his hospital stay. Contrast-enhanced abdominal CT revealed an enlarged aneurysm with wall thinning. Because of the risk of aneurysm rupture, the decision was made to perform aneurysmectomy and bowel resection on day 6. Histologic examinations revealed two separate dissecting lesions: one latent and the other resulting in aneurysm formation. Both lesions showed characteristics of segmental arterial mediolysis (SAM) with lack of arterial media, absence of internal and external elastic laminae and intimal proliferation. CONCLUSIONS: Histologic findings in the present case suggest that mechanical or hemodynamic stress on the vascular wall and SAM-related vascular vulnerability may concomitantly contribute to the onset of isolated SMA dissection.

The role of mitogen-activated protein kinases and the participation of intestinal congestion in total hepatic ischemia-reperfusion injury.

BACKGROUND/AIMS: The mitogen-activated protein kinase (MAPK) pathways are comprised of key regulatory proteins that control the cellular responses to both proliferation and stress signals. This study was performed to examine the degree of liver damage and MAPK activation induced by ischemia of varying durations, and the association between intestinal congestion and liver dysfunction after hepatic ischemia-reperfusion injury. METHODOLOGY: Male Sprague-Dawley rats were divided into five groups: sham-operated controls (no hepatic ischemia); 15, 30, or 45 min of total hepatic ischemia; or 45 min of total hepatic ischemia with a portosystemic shunt. Serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, interleukin-1beta and tumor necrosis factor-alpha, as well as liver tissue blood flow were measured. Liver was also sampled for MAPK analysis and histopathological examination. RESULTS: Total hepatic ischemia for over 30 min, with intestinal congestion, caused severe liver damage and an inflammatory cytokine response. A portosystemic shunt attenuated ischemia-reperfusion injury and inhibited inflammatory cytokine expression. Extracellular signal-regulated kinase was markedly phosphorylated in all groups other than the sham-operated group. p38 MAPK and c-Jun N-terminal kinase were highly phosphorylated in all groups receiving 30 min or more of ischemia. CONCLUSIONS: Prolonged warm total hepatic ischemia-reperfusion injury is associated with small intestinal congestion; a portosystemic shunt reduces liver damage by inhibiting inflammatory cytokine expression. MAPKs are markedly phosphorylated after reperfusion.

2-Arachidonoylglycerol increases in ischemia-reperfusion injury of the rat liver.

Several studies have implicated endocannabinoids in various forms of shock. However, the role of endocannabinoids in hepatic ischemia-reperfusion injury remains unclear. The purpose of this study was to evaluate the changes of two endocannabinoidsin hepatic ischemia-reperfusion injury: anandamide (ANA) and 2-arachidonoylglycerol (2-AG). Male Sprague-Dawley rats were divided into 2 groups: the short (15 min) ischemic group and the long (60 min)ischemic group in the segmental (70%) hepatic tissue. Blood levels of aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), ANA, and 2-AG were examined. Serum lev-els of AST, ALT, and LDH were significantly higher in the long-ischemia group than in the short-ischemia group. Plasma levels of 2-AG showed similar augmentation prior to and after reperfusion in both the short- and long-ischemia groups, although plasma 2-AG lev-els tended to be higher in the long-ischemia group than in the short-ischemia group. Plasma levels of ANA were augmented in the early phase of reperfusion in the short-ischemia group and did not differ significantly from the normal level with time after reperfusion in the long-ischemia group. These results suggest that the endocannabinoid 2-AG increases in hepatic ischemia-reperfusion injury of rats, rather than ANA.

NO donor ameliorates ischemia-reperfusion injury of the rat liver with iNOS attenuation.

This study investigated the effect of a spontaneous nitric oxide (NO) donor, FK409 (FK), in a rat model of segmental hepatic ischemia. Rats were allocated to four experimental groups. Two of the groups underwent segmental hepatic ischemia of 60 min duration and received FK (0.4 mg/kg, iv) or vehicle alone before inducing ischemia and again 5 min before reperfusion. Sham-FK and sham groups were treated identically, but did not have vascular occlusion. Serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) were measured, and the livers were examined for histological evidence of injury, polymorphonuclear neutrophil (PMN) infiltration, and immunohistochemical expression of inducible NO synthase (iNOS) before and 6 h after reperfusion. AST, ALT, and LDH levels were significantly (p < .05) reduced 6 h after reperfusion in the FK-treated group compared with the vehicle-treated control group. FK treatment also reduced the degree of hepatic damage apparent on histopathology and reduced PMN infiltration and iNOS expression. Thus, FK treatment is protective against hepatic ischemia reperfusion injury and attenuates neutrophil infiltration and iNOS expression.