[A Case Report of R0 Resection after Chemotherapy for Locally Advanced Pancreatic Head Cancer with Ureter Invasion].

A 60-year-old woman was referred to our hospital due to pancreatic head cancer with right ureter invasion. We considered that it was difficult to achieve R0 resection for the patient by operation because of a wide range of retroperitoneal invasions involving the right ureter. She was treated with chemotherapy(gemcitabine plus nab-paclitaxel: GnP). GnP therapy was administered 3-weeks on/1-week off for 1 course. After 3 courses, we performed pancreaticoduodenectomy, right nephrectomy and partial transverse colectomy. We achieved R0 resection and considered the GnP therapy to be effective.

[A Case of Liver Metastasis 28 Years after Resection for Gastrointestinal Stromal Tumor of Duodenum].

A 69-year-old woman underwent a pancreaticoduodenectomy at the age of 41 years for a submucosal tumor of duodenum, which was diagnosed as leiomyoma at that time. Twenty eight years later, a liver tumor, which is 10 cm in a diameter, was identified on an abdominal ultrasonography. The left hepatectomy was undertaken. Immunohistochemical examination indicated that the tumor was positive for c-kit and diagnosed as a gastrointestinal stromal tumor(GIST). The pathological reexamination revealed the primary tumor was also positive for c-kit and diagnosed as GIST. Therefore, the liver tumor was considered as a metastasis of the duodenal GIST, which was resected 28 years earlier.

[Laparoscopic Local Gastrectomy for Gastric Schwannoma and Extramurally Developed Gastric GIST].

Among gastric submucosal tumors, neurogenic tumors are considered to be rare diseases. We experienced a case of laparoscopic local gastrectomy of gastric schwannoma coexisting with extramurally developed gastric GIST found accidentally during surgery. A 61-year-old man was pointed out a gastric submucosal tumor with a diameter of 15 mm in a medical checkup. Endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)was performed, and immunostaining showed that c-kit(-), CD34(-), S-100(+), SMA(-), MIB-1<2%. Diagnosis was gastric schwannoma. We performed laparoscopic local gastrectomy. During the surgery another extramural nodule was accidentally found with a diameter of 8 mm at the anterior wall of the gastric body near lesser curvature. Immunostaining showed c-kit(+), CD34(+)and was diagnosed GIST. Because a gastric schwannoma coexisting with GIST is a rare case, we decided to report it by adding discussion with some literatures.

[A Case of Jejunal Ectopic Pancreatic Cancer with Small Bowel Obstruction].

Were port a caseof an 82-year-old man who presented with vomiting. Computed tomography(CT)revealed a jejunum tumor and small bowel obstruction. Enteroscopy revealed a protruded lesion and biopsy indicated adenocarcinoma. PET-CT revealed nothing without jejunal tumor. Therefore, with a preoperative diagnosis of primary small bowel cancer, we performed operation. Surgery indicated peritoneal disseminations and a jejunal tumor 40 cm distal from the ligament of Treitz, and we performed small bowel partial resection. Pathological examination revealed adenocarcinoma originating from a Heinrich type I ectopic pancreas in the jejunum. Ectopic pancreatic cancer in the jejunum is rare, and we review case reports in the literature.

[A Case of Successful Curative Resection Following Downsizing Chemotherapy in Initially Unresectable Locally Advanced Gallbladder Carcinoma].

A 58-year-old woman was referred to our hospital with high fever and right upper abdominal pain. Abdominal computed tomography (CT) revealed a bulky tumor of the gallbladder with liver invasion, metastases to para-aortic lymph nodes, and extensive infiltration to Glisson's sheath. The tumor was initially considered to be unresectable locally advanced gallbladder carcinoma with inflammation, and she received 6 courses of chemotherapy with gemcitabine plus cisplatin. Subsequently, the inflammation was extinguished, and CT showed the main tumor shrunk and the Glisson's sheath infiltration disappeared; however, a liver metastasis existed in segment 5. Thus, S4a plus S5 hepatic segmentectomy with extrahepatic bile duct resection and regional and para-aortic lymphadenectomy was performed. The pathological diagnosis was pT3a, pN1, pM1 (Hep, LYM), fStage ⅣB. Curative resection was then performed. If selected according to their response to downsizing chemotherapy, conversion therapy might therefore be an effective multidisciplinary treatment for patients with initially unresectable locally advanced gallbladder carcinoma.

[A case of effective multidisciplinary treatment for advanced gallbladder carcinoma with distant lymph node metastases].

A 59-year-old woman with upper abdominal pain was diagnosed as having an advanced-stage gallbladder carcinoma with significant metastases in the para-aortic lymph nodes to the more distant right external iliac nodes by imaging studies. These findings suggested that the tumor was unresectable, and therefore, palliative cholecystectomy with lymph node biopsy was performed. Furthermore, we initiated chemoradiotherapy with linac radiotherapy( 50 Gy) and weekly gemcitabine (GEM 300 mg/body) for 6 weeks. Partial response (PR) was achieved after chemoradiotherapy. Subsequently, we initiated chemotherapy with GEM alone (1,000 mg/m2) on days 1, 8, and 15, every 28 days for 15 courses. Following disease progression, we initiated chemotherapy with S-1 alone( 80 mg/m2/day) on days 1-14, every 21 days for 9 courses, as second-line treatment. Two years later, following re-progression of the disease, we performed best supportive care with retrograde ureteral stenting for hydronephrosis and retrograde biliary stenting for obstructive jaundice. The patient survived for 35 months after palliative surgery. Moreover, she remained well and performed normal activities for 34 months. This experience indicates that, in patients with unresectable gallbladder carcinoma, multidisciplinary treatment could extend survival and improve the quality of life.

[A case of long-term survival after aggressive surgery for Stage IV gallbladder carcinoma].

A 67-year-old woman was referred to our hospital because of a gallbladder mass. Abdominal computed tomography revealed a protruding mass 34 mm in diameter in the body of the gallbladder with wall thickening and enhancement. Advanced gallbladder carcinoma was diagnosed by image analysis, with liver metastasis in segment 5 and lymph node metastasis in the hepatoduodenal ligament. Subsequently, S4a+S5 hepatic segmentectomy was performed with extrahepatic bile duct resection and regional lymphadenectomy. The final pathological diagnosis was pT2 pN1 pM1, Stage IV,according to the International Union against Cancer classification system. Curative resection was then performed. In addition, we performed adjuvant chemotherapy with 15 courses of 1,000 mg/m2 gemcitabine on days 1, 8, and 15 at every 28 days. At 5 years after the operation, the patient was alive and free of disease. Therefore, in cases of limited liver metastasis (within segments 4a and 5), aggressive surgery should be considered even for Stage IV gallbladder carcinoma. In such cases, long-term patient survival may be expected only when curative resection is achieved.

[Histological complete response in a case of advanced gastric cancer treated by neoadjuvant TS-1 combined with CDDP therapy].

A 63-year-old woman with advanced gastric cancer was referred to our hospital.Upper gastrointestinal endoscopy revealed a type 2 tumor in the lesser curvature of the angle of stomach. Moderately-differentiated adenocarcinoma was found in the biopsy specimens. Lymph node metastases of No.3 and No.7 were suspected by abdominal CT. We diagnosed the tumor as cStage III A (cT2N2H0P0M0) gastric cancer.For better curability, we selected neoadjuvant chemotherapy with TS-1/ CDDP. Two courses were completed without serious side effects. Upper gastrointestinal endoscopy and abdominal CT revealed that the primary tumor and metastatic lymph nodes had become smaller, suggesting that a partial response had been achieved. The patient underwent curative surgery, including distal gastrectomy and D2 lymph node dissection.No cancer cells were found by pathological evaluation of the resected stomach and all the regional lymph nodes, confirming a pathological complete response. It is suggested that the neoadjuvant chemotherapy is a useful therapeutic strategy for advanced gastric cancer.

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97 and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis.

Tumor lymphangiogenesis is now known to play a causal role in lymph node metastasis, and thus its inhibition would have great significance for the prevention of lymph node metastasis in cancer therapy. VEGF-C has recently been identified as a key molecule that involved in tumor lymphangiogenesis and lymphatic metastasis. However, the expressional regulation of VEGF-C is not fully understood. We investigated the role of mTOR, which is a downstream kinase of the phosphatidylinositol 3-kinase/Akt pathway, and the MAPK family (MEK1/2, p38, and JNK) in the regulation of VEGF-C and VEGF-A expression in B13LM cells, a lymphatic metastasis-prone pancreatic tumor cell line. We also investigated the antilymphangiogenic effect of rapamycin, a specific inhibitor of mTOR in vivo using male BALB/c nu/nu mice. VEGF-C expression was inhibited by the inhibitors for mTOR, p38, and JNK, but not by the inhibitor for MEK1/2, whereas VEGF-A expression was inhibited by all four of these inhibitors. The serum starvation-induced expression of VEGF-C was inhibited by rapamycin, whereas that of VEGF-A was incompletely inhibited. The metastatic experiment in vivo demonstrated that the number and the area of lymphatic vessels in the primary tumors were significantly decreased by rapamycin. Finally, the lymph node metastasis was significantly suppressed in rapamycin-treated mice. Our results suggest that mTOR, p38, and JNK play important roles in VEGF-C expression, and that rapamycin has an antilymphangiogentic effect and exerts the expected inhibition of lymphatic metastasis.