Ral GTPase-activating protein regulates the malignancy of pancreatic ductal adenocarcinoma.

The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common ß subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC. We generated RalGAPß-deficient PDAC cells by CRISPR-Cas9 genome editing to investigate how increased Ral activity affects malignant phenotypes of PDAC cells. RalGAPß-deficient PDAC cells exhibited several-fold higher Ral activity relative to control cells. They had a high migratory and invasive capacity. The RalGAPß-deficient cells grew more rapidly than control cells when injected subcutaneously into nude mice. When injected into the spleen, the RalGAPß-deficient cells formed larger splenic tumors with more liver metastases, and unlike controls, they disseminated into the abdominal cavity. These results indicate that RalGAPß deficiency in PDAC cells contributes to high activities of RalA and RalB, leading to enhanced cell migration and invasion in vitro, and tumor growth and metastasis in vivo.

[A Case of Aortitis Caused by a Granulocyte-Colony-Stimulating Factor during Chemotherapy for Pancreatic Cancer].

BACKGROUND: Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor(G-CSF), has been used as prophylaxis for severe hematotoxicity induced by chemotherapy. We report a case of aortitis induced by pegfilgrastim administration during modified FOLFIRINOX(mFOLFIRINOX)chemotherapy for metastatic pancreatic cancer. CASE REPORT: A 65-year-old woman underwent a distal pancreatectomy for pancreatic tail cancer. Liver metastases appeared 2 years after the surgery. mFOLFIRINOX chemotherapy was started with prophylactic administration of pegfilgrastim. Eight days after the first administration and 6 days after administration of the 8th course, the patient developed a fever. The blood test results indicated severe inflammation. Computed tomography revealed a thickened aorta indicating aortitis. The symptoms rapidly improved with antibiotic therapy. We diagnosed aortitis induced by pegfilgrastim administration. CONCLUSION: Aortitis should be considered when a patient has unidentified inflammatory findings after receiving pegfilgrastim.

[A Case of Initially Locally Advanced Pancreatic Cancer Curatively Resected after Carbon-Ion Radiotherapy with Gemcitabine].

BACKGROUND: The neoadjuvant therapy against locally advanced pancreatic cancer(LAPC)have been developed by combining radiation with chemotherapy. We experienced a case of LAPC performed R0 resection and obtained high histopathological effect by carbon-ion radiotherapy with gemcitabine(GEM). CASE PRESENTATION: A 65-year-old male with epigastric and back pain was suspected as pancreas cancer by FDG-PET/CT scan, and was referred to our hospital. CT scan revealed a tumor in pancreatic body with poor contrast effect and with invasion to celiac artery, common hepatic artery and portal vein, and diagnosed as pancreatic adenocarcinoma by endoscopic ultrasound-fine needle aspiration(EUS-FNA). Therefore we diagnosed the tumor as pancreatic body cancer, cT4, cN1a, cM0, cStage Ⅲ, UR-LA. GEM plus nab-paclitaxel(GnP)were administered for 4 months followed by carbon-ion radiotherapy with GEM at other hospital. Distal pancreatectomy with en bloc celiac axis resection(DP-CAR)was performed 3 months after irradiation. High therapeutic effect was obtained histopathologically( Evans grade Ⅲ), and lesions outside the pancreas disappeared except for metastasis to one lymph node (ypT1c, ypN1a, ycM0, ypStage ⅡB), and R0 resection was performed. CONCLUSION: Carbon-ion radiotherapy with chemotherapy for LAPC may improve curative resection rate.

[Laparoscopic Lymphadenectomy without Gastrectomy for Lymph Nodes Recurrence after Endoscopic Submucosal Dissection (ESD)].

A case oflaparoscopic lymphadenectomy in a patient with lymph node recurrence after endoscopic submucosal dissection (ESD)is presented. A 77-year-old man underwent ESD for gastric cancer. After 2 years, the patient was referred to our hospital with the diagnosis of lymph node recurrence. We offered radical surgery, including gastrectomy and lymphadenectomy; however, this suggestion was denied by the patient because ofstrong anxiety for gastrectomy. As an alternative therapy, laparoscopic lymphadenectomy for the limited area of high recurrence, without gastrectomy, was performed. Postoperative course was uneventful. The patient was discharged on the 10th postoperative day and remains cancer-free over 2 years after the operation. Laparoscopic lymphadenectomy for high risk area of recurrence may be considered in frail elderly patients to avoid the high burden ofgastrectomy.

[A Case of Curatively Resected Goblet Cell Carcinoid of the Appendix Diagnosed via Intraoperative Frozen Sectional Examination].

A 52-year-old patient presented with epigastric pain.An enhanced CT scan showed a strongly enhanced appendix with abscess formation.Appendectomy was performed under the diagnosis of acute appendicitis with perityphlitic abscess.The stump of the appendix was white and hard, suggesting malignant transformation.Intraoperative frozen sectional examination indicated goblet cell carcinoid(GCC)of the appendix.Thereafter, we performed ileocecal resection with lymphadenectomy (D3).The final pathological diagnosis was GCC, pSS, pN1, Stage III a by the Japanese classification of colorectal carcinoma. Immunohistochemical examination was consistent with GCC including synaptophysin(+), chromogranin A(+), somatostatin receptor(SSTR)2(±), SSTR5(+), and cytokeratin 20(+).The patient received adjuvant chemotherapy and remains cancer-free over 5 years after the operation.

[Simultaneous Laparoscopic Resection of Gastric Cancer and Hepatocellular Carcinoma].

A report of simultaneous laparoscopic resection for a patient with synchronous gastric cancer and hepatocellular carcinoma (HCC)is presented.A 76-year-old man was referred to our hospital for gastric cancer located in the antrum.In the preoperative examination, enhanced CT and MRI revealed a liver tumor located at S2 that had high contrast enhancement in the arterial phase but that was not washed out in the delayed phase.An early HCC was suspected, and simultaneous laparoscopic distal gastrectomy and partial resection of the liver was performed.The postoperative course was uneventful, and the patient was discharged on the 14th postoperative day.Simultaneous laparoscopic resection of gastric cancer and HCC is possible with special attention to surgical procedures and port settings.

[A Case of Advanced Gastric Cancer with Extensive Lymph Node Metastases Treated by Capecitabine plus Cisplatin plus Trastuzumab Chemotherapy,Followed by Conversion Surgery].

An 82-year-old woman underwent upper gastrointestinal endoscopy to evaluate upper abdominal pain.A type 2 tumor (adenocarcinoma, por, HER2+)was found in the lesser curvature of the gastric antrum.Abdominal CT showed bulky lymph node metastases and pancreatic invasion of lymph node No.6 , resulting in a diagnosis of cT3N3M0, Stage III B.Radical resection was not possible by gastrectomy, and chemotherapy(capecitabine plus cisplatin plus trastuzumab)was administered. The primary lesion and lymph node showed significant regression on CT after the administration of 8 courses of chemotherapy, which also clarified the border between the lymph node and pancreas.At this stage, it was determined that radical resection was feasible; distal gastrectomy(Roux-en-Y reconstruction)and D2 dissection and cholecystectomy were performed.No cancer cells were found in the primary lesion on histopathology.The therapeutic effect of preoperative chemotherapy was assessed as Grade 3, pCR, and retained tumor was only found in lymph node No.5 . On follow-up observation, the patient is alive 11 months after surgery, with no evidence of recurrence without neoadjuvant chemotherapy.