Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan.

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.

Accessory left gastric artery aneurysms in granulomatosis with polyangiitis: a case report and literature review.

Aneurysm formation is a potential complication of granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis. It is a very rare complication, but immediate diagnosis and therapy should be performed because an aneurysm can be life-threatening if it ruptures. An accessory left gastric artery (ALGA) is also a rare variant gastric artery that may obtain its blood supply from the left hepatic artery and left gastric artery. We herein describe a 57-year-old Japanese man who was diagnosed with GPA complicated by aneurysm rupture in an ALGA. Emergency surgery was performed after failure of arterial coil embolization to interrupt blood flow in the ALGA. The patient underwent partial resection of the lesser omentum, which contained all aneurysms. During partial resection of the lesser omentum, both the left gastric artery and ALGA were ligated because they were thought to be feeders of the aneurysms. Postoperative recovery was uneventful; no bleeding or recurrence of the aneurysms occurred. Immediate diagnosis and therapy should be performed for patients with GPA with symptoms of vascular ischemia or aortitis. Endovascular intervention is the first-choice therapy especially for hemodynamically stable patients with ruptured aneurysms or aneurysms located on variant arteries, which may have multiple blood supplies. In the present case, although endovascular treatment failed, the approach described herein was helpful during open surgery.

[A Case of Portal Vein Thrombosis Occurring during CapeOX and Bevacizumab Combination Therapy for Liver Metastasis].

A73 -year-old man underwent a sigmoidectomy for sigmoid colon cancer with liver metastasis. After the operation, he received CapeOX combined with bevacizumab therapy. After 6 courses, the liver metastasis was undetectable on computed tomography scans. After 15 courses, computed tomography revealed ascites, and chemotherapy was discontinued. Two months later, computed tomography revealed portal vein thrombosis. Owing to the chronic nature of the thrombosis, thrombolytic therapy was not initiated. However, preservation therapy using antiplatelet drugs for 1 month resolved the ascites and the thrombosis. The risk of serious thrombosis must be considered when using bevacizumab.

A comprehensive expression analysis of mucins in appendiceal carcinoma in a multicenter study: MUC3 is a novel prognostic factor.

BACKGROUND: Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma. METHODS: Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma. RESULTS: The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93-24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05-34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13-10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma. CONCLUSIONS: Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.

[Cetuximab-associated skin ulceration in patient with metastatic colorectal cancer: a case report].

An 82-year-old female was diagnosed with rectal cancer. Hartmann's procedure was performed and a curative resection was successfully achieved. Postoperative staging according to the classification of the Japanese Society for Cancer of the Colon and Rectum(The 7th Edition)was stage III. She received adjuvant chemotherapy after surgery with tegafur(UFT 300 mg/body/day)orally for 6 months. One year after the surgery, paraaortic lymph node metastasis and a local recurrence were diagnosed. She was treated with modified FOLFOX6 chemotherapy combined with bevacizumab. After 13 courses of treatment with FOLFOX6 and bevacizumab, multiple lung metastases were found. Therefore, we changed the chemotherapy regimens to FOLFIRI plus cetuximab. After 18 weeks of this new treatment she had two skin ulcerations around her stoma, a known side effect associated with cetuximab. We stopped cetuximab and continued chemotherapy with FOLFIRI alone. Seven weeks after cetuximab withdrawal, her skin ulcer healed with the support of a dermatologist and a wound ostomy continence nurse. We reintroduced cetuximab in a chemotherapy regimen with a reduced dose. After two infusions of cetuximab, skin ulceration recurred. We stopped cetuximab again and continued chemotherapy with FOLFIRI. Nine weeks later we resumed cetuximab, but this time the skin ulcer did not occur, and we were able to continue the chemotherapy regimen with FOLFIRI and cetuximab.

[Elderly patient with recurrent rectal cancer successfully responded to modified FOLFOX6 chemotherapy with bevacizumab--a case report].

An 80-year-old female visited our hospital with the chief complaint of lower abdominal pain and diarrhea. She was diagnosed to have rectal cancer. Hartmann operation was performed and curative resection was successfully achieved. Postoperative stage was III according to the classification of the Japanese Society for Cancer of the Colon and Rectum(The 7th Edition). She was treated with oral tegafur(UFT 300mg/body/day)as adjuvant chemotherapy for 6 months. Paraaortic lymph node metastasis and local recurrence were diagnosed by abdominal CT 1 year after the surgery. Her performance status score was 0. She was treated with modified FOLFOX6 chemotherapy combined with bevacizumab. Abdominal CT revealed a partial response after 5 courses. She experienced grade 2 leukocyopenia, grade 3 neutropenia, grade 2 proteinuria and grade 2 hypertension.

The efficacy and toxicity of FOLFOX regimen (a combination of leucovorin and fluorouracil with oxaliplatin) as first-line treatment of metastatic colorectal cancer.

BACKGROUND: Oxaliplatin is the third-generation platinum complex to be active in advanced colorectal cancer. In Japan, it was approved in April 2005. FOLFOX regimen(a combination of leucovorin and fluorouracil with oxaliplatin) has been one of the standard chemotherapy regimens for metastatic colorectal cancer. METHODS: To evaluate the efficacy and feasibility of FOLFOX4 and mFOLFOX6 regimens as first-line chemotherapy in Japanese patients with metastatic colorectal cancer, 23 consecutive patients with histologically confirmed colorectal cancer who were treated between June 2005 and August 2007 were investigated in this retrospective study. FOLFOX4 was used for treatment in 13 patients(57%), and mFOLFOX6 was in 10 patients(43%). RESULTS: The objective response rate was 50.0%. The median survival time was 17.4 months. The median number of cycles was 8.0, with a median relative dose intensity of 74.5% for oxaliplatin. Grade 3 or 4 hematological toxicities were leukocytopenia in four patients, and neutropenia in 12 patients, while non-hematological toxicities such as nausea, anorexia and sensory neuropathy occurred in only one patient each adverse event. No treatment-related deaths occurred. CONCLUSION: FOLFOX regimen has good efficacy in Japanese patients with metastatic colorectal cancer as first-line chemotherapy, with an acceptable overall toxicity profile.

[A case of advanced gastric cancer effectively treated with paclitaxel/S-1 as neoadjuvant chemotherapy].

We report a patient with advanced gastric cancer responding remarkably to neoadjuvant combination chemotherapy consisting of paclitaxel and S-1. The patient was a 65-year-old female who had large type 2 advanced gastric cancer with severe lymph node metastasis(cT3, cN3, cH0, cP0, cM0, cStage IV), treated with paclitaxel/S-1 as neoadjuvant chemotherapy. After the second course, according to UGI, gastroscope and CT findings, a significant tumor reduction was obtained. Distal gastrectomy with D2 nodal dissection were performed. The histological diagnosis was pT1, pN1, pStage IB. The histological effect of main tumor was judged to be Grade 2. The patient has now been in good health without a recurrence for 10 months after surgery. This case suggests that neoadjuvant chemotherapy with paclitaxel/ S-1 is a potential regimen for advanced gastric cancer.

Early detection of liver failure after hepatectomy by indocyanine green elimination rate measured by pulse dye-densitometry.

BACKGROUND/PURPOSE: Following a major hepatectomy, some degree of clinical and biochemical dysfunction occurs. Surgeons usually check serum total bilirubin levels to diagnose postoperative liver dysfunction. However, we cannot predict liver failure by biochemical data alone within the early postoperative period. Using newly developed pulse dye-densitometry (PDD), we measured serial postoperative indocyanine green elimination rate (ICG-K) values and investigated the possible relation between postoperative ICG-K values and complications. METHODS: Fifty-one patients scheduled for hepatectomy between January 2000 and December 2002 were enrolled. Pulse-dye densitometry was used to evaluate postoperative liver function. We analyzed the relation between postoperative ICG-K and postoperative outcome, assessed in terms of morbidity and mortality. RESULTS: Liver failure was seen in seven patients. The ICG-K value on postoperative day 1 in patients with liver failure was significantly lower than that in patients without liver failure (0.070 +/- 0.018 vs 0.152 +/- 0.056/min respectively; P < 0.001). There were no differences between preoperative ICG-K values in patients with and without liver failure. The sensitivity and specificity of an ICG-K value of less than 0.07 on postoperative day 1 were 71.4% and 95.5%, respectively, for predicting liver failure. CONCLUSIONS: We can measure the ICG-K value by PDD at the bedside without time delay, and we can predict liver failure in the early postoperative period by the ICG-K values on postoperative day 1. ICG-K values measured by PDD can provide important information for perioperative management.

Transhepatic portal venous angioplasty with stenting for bleeding jejunal varices.

A 54-year-old woman, who had undergone pancreatoduodenectomy with resection of the portal vein and intraoperative radiation therapy for cancer of the lower bile duct 16 months before, visited our institution complaining of melena. To identify the cause of bleeding and severe anemia, we performed gastrointestinal endoscopy but could detect no obvious source. The portal phase of the superior mesenteric arteriography and percutaneous transhepatic portography revealed severe stenosis of the extrahepatic portal vein, which corresponded to the end-to-end anastomosis of the portal vein, and hepatofugal collaterals. Extravasations into the afferent loop of the jejunum were detected only with portography. These findings suggested that portal hypertension due to extrahepatic portal obstruction led to bleeding varices. Subsequent to percutaneous transhepatic portography, we dilated the stenosis of the extrahepatic portal vein using a balloon catheter and placed an expandable metallic stent there. Portography after the treatment revealed the disappearance of the hepatofugal flow to collaterals and extravasations, and the patient has had no further episodes of gastrointestinal bleeding since. In conclusion, for patients with bleeding varices due to extrahepatic portal obstruction, especially after abdominal surgery, percutaneous transhepatic angioplasty is considered to be the treatment of choice because of its efficiency and minimal invasiveness.

Inflammatory myofibroblastic tumor (inflammatory fibrosarcoma) of the pancreas: a case report.

Inflammatory myofibroblastic tumors (inflammatory fibrosarcomas) of the pancreas are extremely rare. We report a 29-year-old woman who underwent pancreatoduodenectomy for a 6-cm tumor of the pancreas head causing obstructive jaundice. Tumor involvement was local, without apparent metastasis. The tumor was composed of proliferating fibroblastic/or myofibroblast-like spindle cells and aggregates of chronic inflammatory cells in a fibromyxoid matrix. Immunohistochemical examination demonstrated reactivity only to vimentin. This tumor has often been found in the peritoneal cavity, the retroperitoneum, or the pelvic cavity, but only very rarely in the pancreas.

Metachronous double cancer of the gallbladder and common bile duct.

We report a rare case of metachronous double cancer of the biliary tract. At age 59 years, a man had undergone a cholecystectomy and resection of the liver bed for gallbladder cancer pathologically diagnosed as papillary adenocarcinoma, in 1997. Four years later, he was admitted to our hospital with jaundice. At first, we suspected lymph node metastasis of the gallbladder cancer along the common bile duct. But abdominal computed tomography demonstrated circular wall thickness of the common bile duct, so primary bile duct cancer was strongly suspected. Thus, extended right hepatectomy and pancreaticoduodenectomy were performed after right portal vein embolization. The pathological diagnosis of the resected specimen was well-differentiated tubular adenocarcinoma, and this case was clarified to be metachronous double cancer. A review of the literature regarding double cancer of the biliary tract is presented following this case report. We showed that half of 30 cases of double cancer of the biliary tract were not associated with pancreaticobiliary maljunction, including all 6 metachronous cases.

Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor.

BACKGROUND/AIMS: The development of human malignancies can be attributed to aberrant regulation of intracellular signal transduction pathways. In the current study, we aimed to evaluate focal adhesion kinase (FAK), a non-receptor tyrosine kinase, expression in hepatocellular carcinoma (HCC), and to explore the prognostic significance of FAK. METHODS: We investigated FAK mRNA expression in 60 HCC specimens using quantitative real-time reverse transcription polymerase chain reaction analysis, and the correlation between FAK expression and clinicopathologic parameters. FAK protein expression was examined using Western blot analysis and an immunohistochemical study. RESULTS: We found that FAK mRNA was overexpressed in HCCs compared with the corresponding non-cancerous liver tissues (P=0.0008). The FAK overexpression correlated significantly with tumor size (P=0.034) and serum AFP level (P=0.030). Univariate and multivariate analyses revealed that FAK mRNA expression was an independent prognostic factor for disease-free (risk ratio 3.83; P=0.024) and overall (risk ratio 7.14; P=0.015) survival. Besides, we confirmed immunohistochemically that the FAK protein was detectable in cancer cells despite non-expression in corresponding non-cancerous tissues. CONCLUSIONS: Our results suggest that FAK mRNA expression has prognostic significance for the survival of patients with HCC.

Aberrant methylation of SOCS-1 was observed in younger colorectal cancer patients.

UNLABELLED: BACKGROUND Recently, it was demonstrated that sup-pressor of cytokine signaling-1 (SOCS-1) was frequently silenced by methylation of its CpG island inhuman hepatocellular carcinoma (HCC). To define the role of SOCS-1 in the tumorigenic pathway of the colorectum, we examined the methylation of SOCS-1 in tumors of colorectal cancer patients. METHODS: We examined 74 colorectal cancer patients, using a methylation-specific polymerase chain reaction (PCR;MSP) for SOCS-1 CpG island in primary tumors. RESULTS: Aberrant methylation of the SOCS-1 CpG island was detected in 6 of the 74 (8%) colorectal cancer specimens. No corresponding normal colorectal tissues showed SOCS-1 methylation. We then analyzed the correlation between the clinicopathological features and SOCS-1 aberrant methylation and found that younger age was significantly related to SOCS-1 methylation (P = 0.048). CONCLUSIONS: These findings suggested that SOCS-1 may act as a tumor suppressor in at least some colorectal cancers and that SOCS-1 methylation may be a particular phenomenon related to a nearly onset of colorectal cancer.

Detection of K-ras mutations in the plasma DNA of pancreatic cancer patients.

BACKGROUND: In pancreatic cancers, K-ras mutations have been found frequently (80%-100%), and they could be a good marker to detect tumor DNA in the plasma. Several studies have indicated that polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) analysis of K-ras mutation was a useful method for the detection of hepatic and lymph node metastasis of pancreatic cancer. However, this method sometimes exhibited false-positive results, and the rate of K-ras mutation might thus be overestimated in these tissues. To diagnose pancreatic cancer correctly at an early stage, we attempted to detect tumor DNA in the plasma of pancreatic cancer patients using a more sensitive and specific method. METHODS: We examined 28 pancreatic cancer patients using a sensitive mutation-specific mismatch ligation assay for K-ras gene mutations in primary tumors and paired plasma samples. RESULTS: K-ras gene mutations were detected in 26 of the 28 (93%) pancreatic cancers. We also found the same mutations in 9 of these 26 (35%) patients in their plasma DNA. This mutation was found even in the plasma of patients with TNM stage II cancer. CONCLUSIONS: Genetic alterations present in the tumors of pancreatic cancer patients can be detected in their plasma, and this approach is potentially applicable for cancer screening and the monitoring of this deadly disease.

Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis.

PURPOSE: Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of Janus kinase and signal transducer and activation of transcription pathway. Recently, it was demonstrated that SOCS-1 gene was silenced frequently by methylation of CpG island in human hepatocellular carcinoma (HCC). We examined the methylation-mediated silencing of SOCS-1 in tumors of HCC patients. EXPERIMENTAL DESIGN: Fifty patients with HCC were investigated in this study. We examined the methylation status of the SOCS-1 promoter region by methylation-specific PCR and then confirmed the methylation-mediated silencing of SOCS-1 by Northern blot analysis. Furthermore, this methylation status was compared with clinicopathological findings. RESULTS: Aberrant methylation of the SOCS-1 gene was detected in 30 of 50 (60%) HCC specimens. No corresponding nontumorous liver tissues showed SOCS-1 methylation. Subsequent Northern analysis proved that methylation of the SOCS-1 promoter inactivated translation and diminished expression of SOCS-1 mRNA. We then analyzed the correlation between the clinicopathological data and SOCS-1 aberrant methylation and found that HCC derived from liver cirrhosis had a significant relationship with SOCS-1 methylation (P = 0.0207). CONCLUSIONS: SOCS-1 may be a novel tumor suppressor, and its aberrant methylation may be a key event for HCC transformation of cirrhotic nodules.

Total pancreatectomy with segmental duodenectomy for benign or low-grade malignancy tumors of the whole pancreas.

Total pancreatectomy with segmental duodenectomy including major and minor papilla and preservation of the gastroduodenal artery is performed for low-grade malignancy tumor of the whole pancreas. Reconstruction of the alimentary tract was done by end-to-end duodenoduodenostomy and end-to-side choledochoduodenostomy. This is an easy, simple, safe and function-preserving operative procedure for benign or low-grade malignancy tumors of the whole pancreas.

Detection of mitochondrial DNA alterations in the serum of hepatocellular carcinoma patients.

PURPOSE: Somatic mutations in mitochondrial DNA (mtDNA) have recently been detected in various cancers. These mutations could possibly be detected in serum because mtDNA has a higher copy number than nuclear DNA. Thus, we examined genetic alterations in the D-loop region of mtDNA in hepatocellular carcinoma (HCC) patients. EXPERIMENTAL DESIGN: Fifty patients with HCC were investigated in this study. Somatic mutations in the D-loop region of tumor mtDNA were screened by direct sequencing, and then the paired serum samples were investigated using mutation-specific mismatch ligation assay. RESULTS: Fifteen of 100 sequence variants that were detected in tumor mtDNA have not been recorded previously. True somatic mutations in the D-loop region were detected in 17 of 50 patients (34%). Subsequent screening for paired serum by mismatch ligation assay revealed that 5 of 15 paired serum samples (33%) contained the same mutations as primary tumors. CONCLUSIONS: mtDNA mutation may be a novel tumor marker of HCC and may prove effective for detection of tumor DNA in the serum.

ICG pulse spectrophotometry for perioperative liver function in hepatectomy.

BACKGROUND: The indocyanine green (ICG) clearance test has been used to estimate liver functional reserve before hepatectomy. However, changes in ICG clearance after hepatectomy have not been investigated, and their extent remains unknown. PATIENTS AND METHODS: The ICG(K) value, signifying the ICG elimination rate constant, was measured with pulse-dye densitometry before operation and 1, 2, 3, 5, and 7 days postoperatively in 22 patients who underwent liver resection of various extent. CT volumetry was used to calculate the residual liver volume ratio. The relationship between the pre- and postoperative ICG(K) value and the residual liver volume ratio was examined statistically. RESULTS: There was a significant drop in ICG(K) value, from 0.193 +/- 0.011 before operation to 0.160 +/- 0.013 on Postoperative Day 1, and then it remained significantly low at the postoperative examination times. The residual liver volume ratio was 70.2 +/- 5.4%. The estimated ICG(K) value, calculated by the preoperative ICG(K) value and the residual liver volume ratio, showed a significant correlation with the actual postoperative value (r = 0.859 on Postoperative Day 1, P < 0.0001). In five patients with prolonged jaundice, the estimated ICG(K) value was significantly lower than in those without it (0.077 +/- 0.028 versus 0.153 +/- 0.012, P = 0.0136). CONCLUSIONS: The perioperative ICG(K) value measured by pulse-dye densitometry revealed a significant decrease in ICG(K) after operation depending on the reduction in liver volume, and the estimated ICG(K) based on the residual liver volume was useful in predicting postoperative morbidity.