Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway.

Vestigial-like 3 (VGLL3) is a member of the VGLL family, whose members serve as cofactors for TEA domain-containing transcription factors (TEADs). TEADs promote tissue and tumor development together with the cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although VGLL3 is involved in tumor cell proliferation, its relationship with TEADs and YAP/TAZ remains largely unknown. To close this research gap, here we established tumor cells stably expressing VGLL3 and found that they exhibit enhanced proliferation. Notably, YAP and TAZ were inactivated in the VGLL3-expressing cells, coinciding with activation of the Hippo pathway, which suppresses YAP/TAZ activities. VGLL3 in combination with TEADs promoted expression of the Hippo pathway components large tumor suppressor kinase (LATS2) and angiomotin-like 2 (AMOTL2). VGLL3 was highly expressed in malignant breast tumor cells and osteosarcoma cells, and VGLL3 knockdown increased nuclear localization of YAP and TAZ. Knockdown of LATS2 or AMOTL2, as well as VGLL3 knockdown, repressed proliferation of breast tumor cells. Together, these results suggest that VGLL3 together with TEADs promotes cell proliferation by activating the Hippo pathway through LATS2 and AMOTL2, leading to YAP/TAZ inactivation.

Oral nutritional supplements versus a regular diet alone for body weight loss after gastrectomy: a phase 3, multicenter, open-label randomized controlled trial.

BACKGROUND: Body weight loss (BWL) after gastrectomy is associated with not only a deteriorated quality of life but also a poor prognosis. Oral nutritional supplements (ONS) may be used to minimize BWL, which is observed in the first 3 months after gastrectomy and becomes stable thereafter, although the results of several randomized trials remain controversial. METHODS: We performed a multicenter, open-label randomized controlled trial including 1003 gastric cancer patients undergoing curative gastrectomy. Patients were assigned to the ONS group or the control group. In the former, 400 ml (400 kcal) per day for 12 weeks as enteral nutrition was planned, and the actual intake amount was recorded daily by patients themselves. The primary endpoint was BWL 1 year after gastrectomy. RESULTS: BWL data were available in 880 patients (ONS 437, control 443). BWL at 3 months was significantly lower in the ONS group than in the control group (7.1 ± 5.6% and 8.5 ± 5.8%, p = 0.0011). However, the difference gradually declined after 6 months and was not significant 1 year after surgery (9.3 ± 8.2% and 9.8 ± 8.7%, p = 0.37). In the ONS group, 50.4% of patients took more than 200 ml/day of ONS (average 301 ml) and showed significantly less BWL (8.2 ± 7.2%) at 1 year than the control (p = 0.0204). CONCLUSION: The administration of ONS for 12 weeks after gastrectomy did not improve BWL at 1 year. However, the improvement in BWL remained until 1 year after surgery in patients who took more than 200 kcal/day of ONS.

[A Resected Case of Adeno-Squamous Carcinoma of Gallbladder with Liver Invasions].

A patient was 70-year-old female. Because unknown fever following operation of left knee in December 20XX-1, abdominal simple CT was performed, diagnosed as cholecystitis and liver abscesses. However, her unknown fever did not improve with antibiotics therapy. Abdominal enhanced CT and MRI revealed to gallbladder cancer with liver invasion and metastases. These lesions were relatively localized in liver S4a/S5 and gallbladder, hepatoduodenal mesentery. Because unknown fever was exhausting, cholecystectomy, S4a+S5 hepatectomy with extrahepatic bile duct resection and lymph node dissemination were performed in January 20XX+1. In these pathological findings, there were moderate to poorly differentiated adenocarcinoma with squamous cell differentiation in almost area of gallbladder, diagnosed as adeno-squamous carcinoma with liver invasion and metastasis(pT3a[SI][H-inf], int, INF-ß, ly1, v3, pn1, pN1, pM1, pStage ⅣB). One months after operation, abdominal CT revealed multiple liver metastatic recurrences. She died 7 months after operation. Although gallbladder adeno-squamous carcinoma has a poor prognosis, these many cases had a tendency to local infiltration accompanied with tumor fever. If curative resection might be obtained and the symptoms might be improved, aggressive resection should be performed.

[A Case of Mesh Infection Due to Transverse Colon Cancer].

A 69-year-old female underwent a mesh repair for an abdominal incisional hernia 4 years previously in our hospital. She visited local hospital for abdominal pain and fever. Abdominal CT showed a localizes abscess formation above the mesh, then she was taken to our hospital. We suspected mesh infection and performed emergent mesh removal. After the operation, we examined for her anemia. Her colonoscopy and CT findings pointed to transverse colon cancer. We performed right hemicolectomy, and final diagnosis was transverse colon cancer pT4aN0M0, pStage Ⅱb. She underwent adjuvant chemotherapy, and 9 months after surgery, no recurrence was found.

[A Case of Laparoscopic Assisted Resection for Small Intestinal Cancer Diagnosed Preoperatively].

A 50-year-old woman was admitted to our hospital due to intermittent epigastric pain and vomiting for 2 months. Contrast enhanced CT scan showed stenosis in the upper jejunum. She was diagnosed with small intestinal ileus. A small enteroscopy revealed a peripheral type 2 lesion in the upper jejunum, approximately 10 cm from the Treitz's ligament. Upon biopsy, she was diagnosed with a well-differentiated adenocarcinoma. A laparoscope-assisted extracorporeal operation was performed due to the ease of raising the umbilical wound. Swollen lymph nodes were found in the mesentery. A surgical margin of 5 cm on the oral side and 20 cm on the anal side was secured. We performed partial resection of the small intestine, including the mesentery with the enlarged lymph nodes. The histopathological diagnosis was a Type 2, 3×2 cm, tub2, pT4aN1aM0, pStage Ⅲb small intestinal cancer. Due to the development of small intestinal ileus, the small bowel cancer was diagnosed preoperatively. Hence, it was slightly we will report including the literature consideration of.

[Hyperprogressive Disease during Treatment with Nivolumab for Recurrence of Gastric Cancer].

A man in his 60s with a large Type 3 gastric cancer presented with the chief complaint of epicardial discomfort. We decided to perform laparoscopy. The patient was diagnosed with cT4aN2M1(CY1), cStage Ⅳ disease and was treated with XP(capecitabine plus cisplatin[CDDP])plus trastuzumab(HER). After chemotherapy, CY0 was confirmed using laparoscopy. The patient underwent total gastrectomy and D2 lymph node dissection. Histopathological examination revealed ypT4aN3M0, ypStage ⅢC disease. Therefore, adjuvant treatment with XP plus HER was continued. Four months after surgery, liver, lung, and # 16b1latLN metastases were observed on CT. The metastatic foci were observed even after 3 courses of ramucirumab plus paclitaxel. Nivolumab was administered as the third-line treatment; after 3 courses, the liver metastasis increased markedly. Hence, our final diagnosis was hyperprogressive disease(HPD).

[Bilateral Multiple Liver Metastases after Pancreatoduodenectomy for a Duodenal Neuroendocrine Tumor-A Case Report].

The patient was a 79-year-old woman. In January 20XX, upper gastrointestinal endoscopy revealed a duodenal tumor with bleeding and ulceration. This tumor was diagnosed as a duodenal neuroendocrine tumor(NET)based on biopsy findings. In March 20XX, the patient underwent pancreatoduodenectomy with lymph node dissemination. Based on these pathological findings, the tumor was diagnosed as a duodenal NET(G2)with a lymph node metastasis(T2, N1, M0, Stage Ⅲ). Twenty months after the operation, abdominal CT revealed multiple liver metastases(S4, S7, and S8). After this recurrence, she underwent the subcutaneous somatostatin analogue injection therapy every 28 days, and transarterial chemoembolization( TACE)when these recurrent tumors showed remarkable regrowth, once a year, accounting for her age. She has maintained good disease control for 5 years.

[Resection of the Acinar Cell Carcinoma of the Pancreas with Lymph Node Recurrence along the Lesser Curvature of the Stomach-A Case Report].

A 78-year-old woman had undergone subtotal stomach-preserving pancreatoduodenectomy for acinar cell carcinoma (ACC)of the pancreatic head approximately 2 years before presentation, and the pathological diagnosis had been pT2pN0pM0, fStageⅠB(JPS 7th). Adjuvant chemotherapy was discontinued after 3 months because of side effects. Contrast- enhanced CT and PET-CT 2 years postoperatively revealed a tumor measuring 2 cm with a high concentration of FDG in the minor curvature of the stomach. During laparotomy, a 3 cm large lymph node was palpated in the minor curvature of the stomach, and a small lymph node was found adjacently. We diagnosed the patient with multiple lymph node recurrences and performed gastric lymph node dissection of the minor curvature. The pathological diagnosis was a single 2 cm large ACC lymph node metastasis. The patient did not consent to postoperative adjuvant chemotherapy and showed no recurrence for 1 year and 7 months postoperatively. Pancreatic ACC is a rare pancreatic tumor, and its clinicopathologic features are still largely unknown. In recent years, there have been reports of active resection or long-term survival with anti-cancer drug treatment even in recurrent cases, such as the present case. However, the indication and method of anti-cancer treatment are unclear and might need the accumulation of many more cases.

[A Case of Mature Teratoma in the Hepatoduodenal Ligament].

A 60's woman was admitted to our hospital because of palpitations that occurred with exertion. Coronary angiography computed tomography(CT)of suspected angina detected a tumor in the pancreatic head region. Abdominal CT showed a poorly enhanced 40×32 mm solid tumor in the hepatoduodenal ligament that contained a fatty component and calcification. During surgery, the tumor was located in the hepatoduodenal ligament, adhered to the pancreatic head, common hepatic artery, gastroduodenal artery, portal vein and common bile duct. However, the tumor was resected by preserving them. The tumor contained stratified squamous epithelium, a sebaceous gland, nerve, a pancreatic gland, and an adrenal gland. The histological diagnosis was a mature cystic teratoma. The patient showed no recurrence in 2 years and 10 months post-surgery. Mature teratomas in the hepatoduodenal ligament are extremely rare. Some reports showed that combined resection was performed when the tumor was in contact with the common bile duct, portal vein, and arteries. However, in our case, the tumor was removed relatively safely without combined resection.

[A Case of Appendix Torsion with Low-Grade Appendiceal Mucinous Neoplasm].

An 84-year-old woman with a chief complaint of right lower abdominal pain was admitted to our hospital in November 20XX. Abdominal CT scan revealed a 9.6×4.1 cm diameter low density area proximal to the 13 mm diameter appendix, which led to perforated appendicitis with a huge abscess. The patient underwent an open appendectomy with partial cecum resection. The appendix was found to be twisted by 540°. The pathological diagnosis was low-grade appendiceal mucinous neoplasm(LAMN). Recent research has found that the use of laparoscopic surgery for the treatment of LAMN has been increasing. Appropriate surgical intervention should be considered for LAMN because it is a borderline malignancy. Careful treatment with laparoscopic surgery might be considered as one of the treatment options for LAMN. We hope to accumulate more cases of LAMN to confirm our results.

[A Case of Intestinal Obstruction Caused by Peritoneal Metastatic Recurrence One Year after Radical Operation for Pancreatic Cancer].

In December 20XX-1, abdominal enhanced CT of a 73-year-old female patient showed a 28mm-in-diameter pancreatic tail cancer with splenic venous invasion. She underwent neoadjuvant GEM/TS-1 combination chemotherapy but abandoned this chemotherapy due to melena and exanthema. She underwent a distal pancreatectomy with lymph node dissemination. In these pathological findings, the tumor was diagnosed as a pancreatic tail cancer with splenic venous invasion(T3, N0, M0, Stage ⅡA). She underwent adjuvant GEM chemotherapy, but she abandoned this chemotherapy due to exanthema and was managed with observation. In September 20XX, she had a postoperative bowel obstruction and was treated with natural light. However, she had a postoperative bowel obstruction again in July, 20XX+1. Fluoroscopic images revealed stenosis in the intestine located 170 cm from the nasal cavity. She underwent open surgery to manage the bowel obstruction. There was a peritoneal tumor with adhesion to each intestine serosa in 3 areas located 80 cm, 100 cm, and 150 cm from the Treitz ligament. Therefore, she underwent a small intestine resection and anastomosis 70 cm to 110 cm from the Treitz ligament. Pathological findings showed that there was a 3mm-in-diameter adenocarcinoma in this peritoneal tumor. In these findings, this final diagnosis was an adhesive intestinal obstruction caused by peritoneal metastasis. Curative resection for single peritoneal recurrent metastasis might be useful for prognosis prolongation.

[A Case of Long Survival with Hilar Lymph Node Metastasis from Gastric Cancer Successfully Treated with Nivolumab Immunotherapy].

A 74-year-old man underwent distal gastrectomy for gastric cancer(CY1, fStage Ⅳ). About 18 months after surgery, abdominal CT scans revealed multiple lymph node metastases along the portal vein. Systemic chemotherapy was administered comprising a capecitabine/oxaliplatin(CAPOX)regimen. After 4 courses of chemotherapy, an adverse reaction of Grade 2 diarrhea and peripheral neuropathy occurred, although regression of the lymph node metastasis was confirmed. Ramucirumab was administered as the second-line regimen, but CT imaging revealed lymph node progression after several courses. Although irinotecan(CPT-11)was selected as the third-line chemotherapy, the lymph node progression remained uncontrolled. Nivolumab was selected as the fourth-line chemotherapy. After 23 courses, nivolumab immunotherapy induced a partial response to the lymph node metastasis. Nivolumab immunotherapy continues to be administered until now, 5 years after the operation. We experienced a case of lymph node metastasis from gastric cancer successfully treated with nivolumab chemotherapy.

[A Case of Unresectable Advanced Esophageal Cancer Treated with Chemoradiotherapy Resulting in Complete Response].

A70s man was admitted to our hospital complaining of chest discomfort. Endoscopic examination showed mucosal erythema and irregularity and an area unstained by iodine in the middle esophagus 21 to 41 cm from the incisors. The biopsy specimen showed moderately differentiated squamous cell carcinoma. An abdominal computed tomographic(CT)scan revealed swelling of the lymph nodes along the celiac artery and abdominal aorta. The patient was diagnosed with unresectable advanced esophageal cancer(cT2N4M0, cStage Ⅳa). Systemic chemotherapy was initiated using a regimen of 5-FU and cisplatin(FP). After 2 courses of chemotherapy, an abdominal CT scan showed reduction of the lymph node swelling along the abdominal aorta, but the lymph node swelling remained along the celiac artery. Therefore, chemoradiotherapy(CRT; FP plus RT 60 Gy/30 Fr at the main tumor and the swelling of lymph nodes along the celiac artery)was administered. An abdominal CT scan showed reduced swelling of the lymph nodes along the abdominal aorta and the celiac artery after CRT. In addition, FP chemotherapy was also administered. APET -CT scan showed no increased FDG up take in the main tumor and swollen lymph nodes after 2 courses of chemotherapy. The complete response(CR)has been maintained for 30 months without therapy.

[Long-Term Survival after Palliative Surgery for Advanced Gastric Cancer with Bone Marrow Metastasis-A Case Report].

A 57-year-old woman was diagnosed with advanced gastric cancer with bone marrow metastasis(cT4aN1pM1[MAR], pStage Ⅳ). After 18 courses of S-1 and cisplatin and 18 courses of ramucirumab and paclitaxel, the chemotherapy was stopped because of stenosis. We performed endoscopic metallic stent placement, but stenosis reappeared after a month. Subsequently, distal gastrectomy was performed as a palliative surgery. She had no complications and improved appetite, therefore, she resumed chemotherapy after 3 postoperative months and continued for 4 years and 9 months from the first visit. In general, gastric cancer with bone marrow metastasis has a poor prognosis, however, in this case, long-term survival was achieved with palliative surgery.

[XELIRI plus Bmab Therapy as a Secondary Treatment for Recurrent Colorectal Cancer with Long-Term Survival].

A 71-year-old woman complained of melena, and laparoscopic right hemicolectomy was performed for advanced colorec- tal cancer. Pathological examination revealed pStage Ⅲa(RAS-positive)disease. After the operation, UFT/LV was administered. However, peritoneal recurrence was confirmed. We changed the chemotherapeutic regimen to CapeOX plus Bmab and capecitabine plus Bmab. After 5 years and 9 months, pulmonary metastasis was observed. Therefore, we again changed the chemotherapeutic regimen to biweekly XELIRI plus Bmab. After 43 courses, the patient had stable disease. During biweekly XELIRI plus Bmab therapy, Grade 4 neutropenia occurred, so we reduced the CPT-11 dose by 20%. After dose reduction the patient experienced no more Grade 3/4 adverse events. We experienced a case of colorectal cancer wherein biweekly XELIRI plus Bmab therapy contributed to disease control as second-line treatment.

Optimal Cutoff Values of Skeletal Muscle Index to Define Sarcopenia for Prediction of Survival in Patients with Advanced Gastric Cancer.

BACKGROUND: Sarcopenia, characterized by loss of skeletal muscle mass, is recognized as a prognostic factor in patients with gastric cancer. However, wide variability exists in the cutoff values of muscle mass for defining sarcopenia across previous studies, and the best cutoff values to predict survival remain unknown. This study aimed to determine the optimal cutoff values for sarcopenia to predict survival in patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with clinical stage II/III gastric cancer who underwent gastrectomy at Kyoto University Hospital were included in the study. The cross-sectional area of skeletal muscle at the third lumbar vertebra level was measured using preoperative computed tomography scan. The skeletal muscle index (SMI) was calculated by dividing the area by height in meters squared. Five sex-specific cutoffs of SMI, which were significantly associated with prognosis in patients with gastric and nongastric cancers, were examined as a threshold to define sarcopenia. RESULTS: In the 177 eligible patients, the five cutoffs of SMI resulted in an incidence of sarcopenia between 6 (3%) and 114 (64%). The 5-year overall survival was 48% in patients with sarcopenia based on the cutoffs reported by Martin et al., compared with 68% in those without sarcopenia (p = 0.013). A multivariate regression model demonstrated that sarcopenia based on the cutoffs was significantly associated with overall survival (hazard ratio 2.00, 95% confidence interval 1.24-3.24, p = 0.005). CONCLUSIONS: The cutoff values reported by Martin et al. were optimal to predict survival in patients with advanced gastric cancer.

[A Case of Hyperammonemia Induced by Chemotherapy with 5-Fluorouracil for Metastatic Colon Cancer].

Systemic chemotherapy based on 5-fluorouracil(5-FU)is a standard treatment for unresectable or recurrent colon cancers. Here, we report a case of hyperammonemia induced by chemotherapy using 5-FU for metastatic colon cancer. An 84-yearold male patient with past histories of liver cirrhosis related to hepatitis C virus and renal dysfunction underwent an operation for the rectosigmoid colon cancer 8 years ago. Three years after that operation, a local recurrence of the colon cancer was diagnosed, and chemotherapy using sLV5FU2 was initiated. The recurrence lesion reduced markedly by this chemotherapy, which was ceased 2 years ago. Two years after the cessation the recurrent tumor had been enlarged, and the chemotherapy using the same drugs at the same dose was performed. On the treatment day 3, he was emergently transported to our hospital due to the disturbance of consciousness. Since laboratory tests showed the high concentration of plasma ammonia and the progressed renal dysfunction with no other definite cause of obnubilation, he was diagnosed as the hyperammonemia induced by 5-FU. He was treated by administrating the branched-chain amino acids solutions combined with fluid therapy, which quickly recovered him from the encephalopathy. He is followed up without any chemotherapy because of his high age. When a patient treated with the chemotherapy using 5-FU is sent with the disturbance of consciousness, we should take hyperammonemia into consideration, especially when he or she has the hepatic or renal dysfunction.

[A Case of Chemotherapy with FOLFOXIRI plus Cetuximab for Liver Metastasis of Sigmoid Colon Cancer].

We report a case of chemotherapy with FOLFOXIRI plus cetuximab for liver metastasis of sigmoid colon cancer. The patient was a 40's man who was diagnosed with sigmoid colon cancer with liver metastasis. Colonoscopy revealed a type 2 tumor with stenosis in the sigmoid colon. He underwent sigmoidectomy under laparotomy, and after the operation, received 7 courses of chemotherapy with FOLFOXIRI plus cetuximab. The liver tumor was sufficiently reduced, and laparotomy and liver right lobectomy were performed. Histopathology revealed a modified, Grade 2 tumor regression. He has been followed for 1 year 4months after the operation.

[A Case of Primary Duodenal Cancer with Duodenocolic Fistula Treated with Pancreatoduodenectomy and Right Hemicolectomy].

A patient was 59-year-old female. She presented our hospital with weight loss, anorexia and lower abdominal bloating. Abdominal computed tomography(CT), gastrointestinal endoscopy, colonoscopy and duodenal fistulagram showed duodenal cancer or colon cancer with duodenocolic fistula and ovary metastasis. She underwent subtotal stomach preserving pancreatoduodenectomy and right hemicolectomy. In these pathological findings, tumor was diagnosed as a duodenal cancer with duodenocolic fistula. She was surviving 12 months after the last surgery. In cases of cancer with duodenocolic fistula, pancreatoduodenectomy with right hemicolectomy would be necessary for nutrition improvement and cancer treatment.

[A Case of Advanced Esophageal Cancer Successfully Treated with DCF Chemotherapy Followed by Conversion Surgery].

A 66-year-old man was admitted to our hospital complaining of dysphagia. Endoscopic examination showed type 1 tumor in the middle intrathoracic esophagus. The biopsy specimen showed moderately differentiated squamous cell carcinoma. Abdominal CT scan revealed the swelling of lymph nodes along the celiac artery. We diagnosed unresectable advanced esophageal cancer(cT3N4M0, cStage IV a). Systemic chemotherapy was initiated using a regimen of docetaxel, CDDP, and 5- FU(DCF). Abdominal CT scan indicated regression of the swelling lymph nodes after 3 courses. Subtotal esophagectomy with 3 field lymph nodes dissection was performed, because the bulky lymph node could not be resected. Histological effect of chemotherapy diagnosed from resected specimen was Grade 2. In summary, we experienced a case of esophageal cancer successfully treated with DCF chemotherapy followed by conversion surgery.