[A Case of Conversion Surgery after Nivolumab Monotherapy as Third-Line Therapy for Advanced Gastric Cancer].

A 79-year-old man with unresectable advanced gastric cancer due to invasion to the pancreas and positive lavage cytology( T4b, N+, M1, CY1, cStage ⅣB; Japanese classification of gastric carcinoma, 15th edition)received standard chemotherapy, including 6 courses of S-1 plus cisplatin as first-line therapy and 2 courses of paclitaxel plus ramucirumab followed by 6 courses of paclitaxel monotherapy as second-line therapy. The primary lesion became PD with these treatments. Subsequently, nivolumab monotherapy was introduced as third-line therapy. After 9 courses, the primary tumor shrunk, and lavage cytology turned to negative on diagnostic laparoscopy. We judged that the tumor was resectable, and the patient underwent radical total gastrectomy and D2 lymphadenectomy as conversion surgery. The pathological stage was ypT3(SS), N0, M0, CY0, and the therapeutic effect was Grade 1b. R0 resection was accomplished. He has been alive without recurrence for 18 months after resection without adjuvant chemotherapy.

Nivolumab exerts therapeutic effects against metastatic lesions from early gastric adenocarcinoma with a small proportion of neuroendocrine carcinoma after gastrectomy: a case report.

Gastric neuroendocrine carcinoma (NEC) is an aggressive disease with high metastatic ability. Gastric cancer has intra-tumoral and intra-patient heterogeneity and may contain NEC. We discuss the case of a 75-year-old man who underwent distal gastrectomy for early gastric cancer. Tumor pathology revealed that nearly all of the tumor (> 95%) was well-differentiated adenocarcinoma, with NEC detected in a small area (< 5%) at the invasion front. No metastasis was identified in the dissected lymph nodes (LN). Multiple liver metastases were detected 3 months after surgery. The metastatic lesion was resistant to both chemotherapy regimens; namely, SOX (S-1 combined with oxaliplatin) and ramucirumab combined with paclitaxel. However, tumor regression was detected after nivolumab treatment. The tumor regression continued for 26 cycles (13 months). Irinotecan treatment was then administered. After 18 irinotecan treatment cycles for 11 months, the para-aortic LN rapidly enlarged. Following biopsy, the swollen para-aortic LN was diagnosed as the recurrence of NEC components of the gastric cancer. Treatment with carboplatin combined with etoposide has been effective and continued. We report a case of NEC para-aorta LN metastases from early gastric cancer with a low proportion of NEC (< 5%). A partial response of the distant metastatic lesions was observed with nivolumab therapy.

Efficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study.

BACKGROUND: In our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies. METHODS: We enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines. RESULTS: Patient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0-1/2/3-4: 24/4/2; Stage IIB-IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7-36.7), 8.7 (4.7-10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival. CONCLUSIONS: Concurrent chemotherapy is effective and safe for treating cancer patients with active MTB.

Laparoscopic omental filling with intraoperative endoscopy for a perforated duodenal ulcer.

As a surgical treatment for a perforated duodenal ulcer, duodenal omental filling is effective. However, filling the perforation site with a sufficient amount of omentum is difficult in some situations. We herein report that we successfully filled a perforated duodenal ulcer with a sufficient amount of omentum using intraoperative endoscopy. The operation was performed with three ports, the operation time was 110 min, and the estimated blood loss was small. The postoperative course was good. No stenosis of deformity of the duodenum was observed on follow-up endoscopy. Laparoscopic surgery has a shorter operation time, shorter postoperative hospital stay, and less postoperative pain than open surgery. The combined use of intraoperative endoscopy with laparoscopic surgery is effective for a large perforation, and it can be expected to reduce the rate of conversion to open surgery. This combined procedure is considered useful as a laparoscopic omental filling operation.

Case of cecal volvulus successfully treated with endoscopic colopexy.

We herein report a case of cecal volvulus successfully treated with endoscopic colopexy. A 73-year-old man with a high fever and abdominal fullness was diagnosed with ileus caused by cecal volvulus. CT showed a dilated cecum and small intestine without bowel strangulation as well as acute pneumonia. Because the pneumonia increased the risk associated with general anesthesia, we attempted decompression of the bowel using endoscopy to avoid surgery. On day 1, a transanal ileus tube was inserted to the terminal ileum through the dilated cecum. On day 7, the bowel torsion spontaneously released. On day 8, we performed percutaneous endoscopic colopexy to fix the cecum on the abdominal wall and prevent re-twisting. The patient was discharged on day 15 without postoperative complications. Percutaneous endoscopic colopexy for cecal volvulus may be a treatment option when the risk associated with general anesthesia or surgery is high because of a comorbidity.

Significance of lymph node metastasis in pancreatic neuroendocrine tumor.

PURPOSE: Pancreatic neuroendocrine tumor (PNET) is relatively rare and has a generally better prognosis than does pancreatic cancer. However, as its prognosis in patients with lymph node metastasis (LNM) is unclear, lymph node dissection for PNET is controversial. Our study aimed to clarify the significance of LNM in PNET. METHODS: We retrospectively examined 83 PNET patients who underwent pancreatic resections with lymph node dissection at Kumamoto University Hospital, Saiseikai Kumamoto Hospital, and Kumamoto Regional Medical Center from April 2001 to December 2014. Their clinicopathological parameters were analyzed by the absence or presence of LNM, and with regard to the disease-free survival (DFS) and overall survival (OS). A predictive score of LNM was also made using the age, tumor size, primary tumor location, and tumor function. RESULTS: Although the 5-year OS was 74.8% for LNM+ and 94.6% for LNM- (P = 0.002), LNM was not an independent risk factor for the OS in a multivariate analysis. However, tumors larger than 1.8 cm were found to be an independent prognostic factor, and the cut-off value for the predictive score was 1.69. CONCLUSIONS: Although LNM was not an independent prognostic factor, lymph node dissection is recommended for patients whose predictive score is larger than 1.69.

[The Experience of the Intensity Modulated Radiation Therapy for Abdominal Lymph Node Metastases from Gastric Cancer].

The recurrence ofgastric cancer has a poor prognosis in spite ofsystemic chemotherapy. We report three cases oflocal control ofdisease after the recurrence owing to intensity modulated radiation therapy(IMRT). The first case was a 66-yearsold man. He was received distal gastrectomy after neoadjuvant chemotherapy for advanced gastric cancer. Abdominal lymph node metastases appeared 1 year and 7 months after the surgery. IMRT was performed and he keeps CR for 1 year and 8 months. The second case was a 72-years-old man. He received proximal gastrectomy for early gastric cancer. Abdominal lymph node metastasis appeared 1 year and 9 months after the surgery. IMRT was performed and he keeps CR for 1 year. The third case was a 71-years-old woman. She received distal gastrectomy for advanced gastric cancer. Abdominal lymph node metastasis appeared 2 years after the surgery. IMRT was performed and she keeps CR for 10 months. We experienced longtime CR after IMRT against abdominal lymph node metastasis. IMRT could be one ofthe strategies ofthe comprehensive treatment for the recurrence of gastric cancer.

[A Case of Alpha-Fetoprotein-Producing Gastric Cancer with Synchronous Liver Metastasis Achieving Recurrence-Free Survival for Five Years by Gastrectomy, Hepatectomy, and Adjuvant Chemotherapy].

a-fetoprotein(AFP)-producing gastric cancer is relatively rare and tends to show a poor prognosis because of hepatic and lymph node metastasis. We experienced a case of AFP-producing gastric cancer with synchronous liver metastasis wherein the patient survived for 5 years without recurrence after undergoing surgery and adjuvant chemotherapy. A 39-year-old woman was admitted to our hospital complaining of tarry stool. Upper gastrointestinal endoscopy revealed a 40mm type 2 tumor in the greater curvature of the lower gastric body, and abdominal CT indicated a 50mm liver metastasis at the S2 segment. The AFP serum level had risen to 71,000 ng/mL. We performed distal gastrectomy and hepatic left lateral segmentectomy. The primary gastric tumor and the hepatic metastasis were both positive for AFP by immunohistochemistry. After conducting 3 courses of S-1/CDDP(SP)therapy as adjuvant chemotherapy, the serum level of AFP had decreased to normal levels. Be- cause the level had risen to 116 ng/mL after a change to S-1 oral administration alone, we decided to re-start SP therapy and carried out 16 courses through the third postoperative year. The patient is still alive without recurrence 5 years after surgery.

[A Case of Urothelial Carcinoma Who Underwent Pancreaticoduodenectomy and Was Diagnosed with Groove Pancreatitis and Preoperatively Suffered from Duodenal Stenosis].

We report a case of a highly advanced urothelial carcinoma accompanied by duodenal stenosis with pancreaticoduodenectomy. A6 6-year-old man presented with upper abdominal pain and vomiting. Acute pancreatitis and hydronephrosis were diagnosed with urgent hospitalization, but jaundice appeared, and stenosis of the duodenum was also found. Thus, we suspected groove pancreatitis or pancreatic cancer, and performed pancreaticoduodenectomy. However, poorly differentiated adenocarcinoma was observed in the retroperitoneal dissection surface in the intraoperative rapid tissue and right hemicolectomy, right nephrectomy, and right ureteral resection were added to the diagnosis. The final diagnosis was urothelial carcinoma. GEM plus CBDCAtherapy was administered as adjuvant chemotherapy. However, obstructive jaundice, acute cholangitis, and acute pancreatitis developed due to occlusion of the intestine due to local recurrence 4 months after surgery. We attempted to reduce yellowing by PTCD; perforation of the small intestine also occurred and a drainage tube was placed in the abdominal cavity. Although a lull condition was obtained, intestinal obstruction due to cancer peritonitis worsened and the patient died 8 months after the operation. In this case, there was no hematuria before surgery and cytology results of urine were negative, so a diagnosis of urinary tract cancer was difficult. There was no report of duodenal stenosis due to urothelial carcinoma.

[Multimodality Therapy for Cecal Cancer with Peritoneal Dissemination].

We report a case of cecal cancer with peritoneal dissemination. A 72-year-old man with cecal cancer(pT4N2M0H0P3, pStage IV )underwent ileocecal resection in 2010. The patient received 106 courses of chemotherapy(FOLFIRI plus Cmab) for peritoneal dissemination after surgery. However, follow-up CT performed 50 months after primary resection detected liver metastasis, which was resected in 2015. The patient received 19 courses of chemotherapy(FOLFIRI plus Cmab)after hepatectomy. The peritoneal dissemination with the diaphragm, retroperitoneal and right inguinal region, were growing 20 months after the 2nd operation. Surgical resection of the peritoneal dissemination was performed in 2016. The patient is alive 81 months after the 1st operation.

Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome.

The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed "X-SPINK1". Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3+/- mice rescued perinatal lethality, but the resulting Spink3-/-;XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3-/-;XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis.

First-line cetuximab-based chemotherapies for patients with advanced or metastatic KRAS wild-type colorectal cancer.

Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. A burgeoning number of studies have demonstrated that the addition of cetuximab to another standard first-line regimen markedly improves the outcome of CRC treatment. However, at present, the efficacy and safety of cetuximab-based combination chemotherapy has not been well described in Japan. The aim of the present study was to evaluate the efficacy and safety of first-line chemotherapies that included cetuximab for patients with advanced or metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type CRC in Japan. This prospective multicenter observational study was conducted at 13 affiliated medical institutions. A total of 64 patients were enrolled between 2010 and 2013. The patients met the following criteria for eligibility: i) histologically confirmed, advanced or metastatic KRAS wild-type CRC; and ii) cetuximab-based chemotherapies administered as a first-line treatment. First-line cetuximab-based treatments were administered as follows: 29 patients (45.3%) received a combination of infusional fluorouracil, leucovorin and oxaliplatin; 14 patients (21.9%) received a combination of capecitabine and oxaliplatin; and 10 patients (15.6%) received a combination of infusional fluorouracil, leucovorin and irinotecan. The overall response rate (including complete plus partial responses) was 50% (32/64 patients). Initially, 48 lesions were diagnosed as unresectable. Among those, 13 lesions (27.1%) were converted to a resectable status following cetuximab-based combination chemotherapy treatments. The median overall survival time and the progression-free survival time were 1,189 and 359 days, respectively. The most frequent grade 3/4 adverse event was neutropenia, which occurred in 20.3% of the patients. The incidence of grade 3/4 skin toxicity was 17.2% (11/64 patients). Cetuximab-based therapies may represent a promising first-line regimen for patients with advanced or metastatic KRAS wild-type CRC in Japan. In addition, this combination was associated with a low incidence of serious toxicities.

Crystalline Isotactic Polar Polypropylene from the Palladium-Catalyzed Copolymerization of Propylene and Polar Monomers.

Moderately isospecific homopolymerization of propylene and the copolymerization of propylene and polar monomers have been achieved with palladium complexes bearing a phosphine-sulfonate ligand. Optimization of substituents on the phosphorus atom of the ligand revealed that the presence of bulky alkyl groups (e.g. menthyl) is crucial for the generation of high-molecular-weight polypropylenes (Mw ≈10(4) ), and the substituent at the ortho-position relative to the sulfonate group influences the molecular weight and isotactic regularity of the obtained polypropylenes. Statistical analysis suggested that the introduction of substituents at the ortho-position relative to the sulfonate group favors enantiomorphic site control over chain end control in the chain propagation step. The triad isotacticity could be increased to mm=0.55-0.59, with formation of crystalline polar polypropylenes, as supported by the presence of melting points and sharp peaks in the corresponding X-ray diffraction patterns.

Successful surgical internal drainage of postoperative pancreatic pseudocyst through pancreaticojejunostomy with distal pancreatectomy: a case report.

Pancreatic pseudocyst is usually treated by percutaneous external drainage, endoscopic internal or external drainage, or surgical internal drainage such as cystogastrostomy. Surgical external drainage is an option if these procedures fail. We describe a case of a 70-year-old man with a pancreatic body pseudocyst that developed postoperatively. It was improved by endoscopic external drainage, and the stent was changed to an internal stent. However, surgery was required as the pseudocyst grew again. A direct approach to the pseudocyst was not possible because of severe adhesion. A distal pancreatectomy with pancreaticojejunostomy was performed, and an external pancreatic stent tube was inserted from the cut end into the duodenum to drain the pseudocyst. One month later, the pseudocyst disappeared, and the stent was removed.

Staging laparoscopy leads to rapid induction of chemotherapy for unresectable pancreatobiliary cancers.

Preoperatively evaluating the resectability of pancreatobiliary cancers is difficult. The aim of this study was to investigate the benefit of staging laparoscopy in unresectable pancreatobiliary cancers. Between 2010 and 2013, 25 patients with pancreatobiliary cancers underwent staging laparoscopy after conventional tumor staging; they were compared with 10 patients who had unresectable or metastatic tumors that were found during laparotomy. Staging laparoscopy did not show unresectable factors in 11 patients, and resections were performed in these patients. Unresectable factors were found in other 14 patients who underwent staging laparoscopy. In these patients, chemotherapy was started after median postoperative day 3 (range, 2-10 days). This period was significantly longer in patients who received unnecessary laparotomy; chemotherapy was started after median postoperative day 11 (range, 6-15 days). These results suggest that staging laparoscopy, while avoiding laparotomy with unsuccessful resection, can lead to rapid induction of chemotherapy for unresectable pancreatobiliary cancers.

Generation and analysis of serine protease inhibitor kazal type 3-cre driver mice.

Serine protease inhibitor Kazal type 1 (SPINK1; mouse homologue Spink3) was initially discovered as a trypsin-specific inhibitor in the pancreas. However, previous studies have suggested that SPINK1/Spink3 is expressed in a wide range of normal tissues and tumors, although precise characterization of its gene expression has not been described in adulthood. To further analyze Spink3 expression, we generated two mouse lines in which either lacZ or Cre recombinase genes were inserted into the Spink3 locus by Cre-loxP technology. In Spink3(lacZ) mice, ß-galactosidase activity was found in acinar cells of the pancreas and kidney, as well as epithelial cells of the bronchus in the lung, but not in the gastrointestinal tract or liver. Spink3(cre) knock-in mice were crossed with Rosa26 reporter (R26R) mice to monitor Spink3 promoter activity. In Spink3(cre);R26R mice, ß-galactosidase activity was found in acinar cells of the pancreas, kidney, lung, and a small proportion of cells in the gastrointestinal tract and liver. These data suggest that Spink3 is widely expressed in endoderm-derived tissues, and that Spink3(cre) knock-in mice are a useful tool for establishment of a conditional knockout mice to analyze Spink3 function not only in normal tissues, but also in tumors that express SPINK1/Spink3.

The modified Glasgow Prognostic Score (mGPS) is a good predictor of indication for palliative bypass surgery in patients with unresectable pancreatic and biliary cancers.

BACKGROUND: Patients with unresectable pancreatic and biliary cancers sometimes need decompression due to obstruction of the gastrointestinal tract and/or biliary tract. The aim of this study was to determine the prognostic factors associated with an indication for palliative bypass surgery in patients with unresectable pancreatic and biliary cancers. METHODS: Between April 2005 and September 2011, 37 patients with unresectable pancreatic and biliary cancers underwent palliative bypass surgery. Prognostic factors were searched for among clinical characteristics, operation-related factors, and tumor-related factors using a prospective database. RESULTS: The median survival time (MST) of these patients was 4.6 months, with a 6-month survival rate of 40.5 %. A multivariate Cox proportional hazards regression analysis revealed that mGPS >2 was the only independent prognostic factor for bypass surgery. Patients with an mGPS of 2 had an MST of 1.7 months, and they had a significantly worse prognosis than mGPS 0-1 patients with an MST of 6.3 months. CONCLUSIONS: The mGPS is useful for predicting survival after surgical decompression due to gastrointestinal obstruction in patients with unresectable pancreatic and biliary cancers. Patients with a poor mGPS may not be indicated for palliative bypass surgery.

Pancreatic cancer in the remnant pancreas following primary pancreatic resection.

PURPOSE: To clarify the clinical features of cancer in the pancreatic remnant. METHODS: We retrospectively reviewed the clinical and pathological findings of 10 patients who developed remnant pancreatic cancer in our hospital between 2002 and 2012. The KRAS sequences in both the initial pancreatic tumor and remnant pancreatic cancer were examined in two patients. RESULTS: Eight patients underwent a second pancreatectomy for remnant pancreatic cancer (resected group), while two patients were not operated on and underwent chemotherapy (unresected group). The remnant pancreatic cancer developed at the cut end of the pancreas (pancreaticogastrostomy site) in four patients. In the resected group, four patients died 17 months after the emergence of the remnant pancreatic cancer and four patients survived during the median 40.5-month observation period. The median survival of the unresected group after the emergence of the remnant pancreatic cancer was 10 months. The findings of the KRAS sequencing and immunohistological staining of the remnant pancreatic cancer for MUC1 and MUC2 in the two patients were consistent with those of the initial pancreatic tumor in one patient, and not consistent in the other. CONCLUSIONS: Our results suggest that both local recurrence and a new primary cancer can develop in the pancreatic remnant, and repeated pancreatectomy can prolong survival.

Reactive fibroinflammatory pseudotumor of the pancreas: report of three cases.

Reactive fibroinflammatory pseudotumor located in the pancreas is a rare condition. However, we experienced three cases of reactive fibroinflammatory pseudotumor of the pancreas over the previous 2 years. Immunohistochemical staining of immunoglobulin G4 (IgG4) confirmed that Cases 1 and 3 involved IgG4-related disease and that Case 2 did not. In Cases 1 and 3, the masses were formed through autoimmune reaction and were diagnosed as autoimmune pancreatitis (AIP). In Case 2, because only a few IgG4-positive cells were found, it was difficult to diagnose AIP or IgG4-related disease. Reactive fibroinflammatory pseudotumors can develop without the involvement of any autoimmune mechanisms. There seems to be partial overlap between reactive fibroinflammatory pseudotumors and AIP.

Adult transmesenteric hernia: report of two cases.

Transmesenteric hernia is a rare cause of bowel obstruction in adults. We herein describe two cases that occurred in adult women, ages 27 and 19. Both cases presented with abdominal pain without muscular defense signs. Computed tomography of both cases showed features of small bowel obstruction by an internal hernia. A laparotomy showed mesenteric defects of the mesentery of the ileum in the former case and the mesentery of the transverse colon in the latter case, with a herniating ileum. The involved small bowel was viable in both cases, and the bowel was pulled out of the mesenteric defect without resection. The mesenteric defects were then successfully repaired.