Clinicopathological significance of ASC amino acid transporter-2 expression in pancreatic ductal carcinoma.

AIMS: ASC amino acid transporter-2 (ASCT2) is highly expressed in cancer cells. However, the clinicopathological significance of ASCT2 expression in pancreatic cancer remains unclear. The aim of this study was to investigate the clinical significance of ASCT2 expression in pancreatic cancer. METHODS AND RESULTS: Ninety-seven patients with surgically resected pancreatic ductal adenocarcinoma were evaluated. Tumour sections were stained by immunohistochemistry for ASCT2, Ki67, CD34 (to determine microvessel density), phospho-AKT (p-AKT) and phospho-mammalian target of rapamycin (p-mTOR) expression. ASCT2 was expressed in 54% (52/97) of tumours. Statistically significant differences in patient age, T stage, N stage, lymphatic permeation, vascular invasion, Ki67, and CD34 and p-mTOR expression were observed between tumours with and without ASCT2 expression. Multivariate analysis confirmed that vascular invasion, ASCT2 expression and Ki67 expression were independent predictive factors for a poorer prognosis. CONCLUSIONS: ASCT2 expression plays an important role in tumour cell growth, and is a promising pathological marker for predicting a worse outcome in pancreatic cancer.

Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma.

AIM: Amino acid transporters play an important role in tumor progression and survival of cancer cells. However, the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino acid transporter-2 (ASCT2) and xCT expression in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC. METHODS: We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67 and microvessel density (MVD) determined by CD34. RESULTS: LAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and α-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery. CONCLUSION: LAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery.

[A case of long-term survival after peritoneal recurrence of rectal cancer achieved by tumorectomy and adjuvant chemotherapy].

The patient was a 40-year-old woman.She began experiencing abdominal pain and constipation in July 2005.S he underwent endoscopy in August, which revealed rectal cancer.She was referred to our hospital for surgery and underwent anterior resection with lymph node dissection in September. The pathological diagnosis was tub2, SS, N2, ly1, v1, stage III b. After discharge, she began oral chemotherapy. However, in April 2006, computed tomography (CT) revealed recurrence in the Douglas pouch. She began FOLFOX4 treatment in May.On follow-up CT performed in July, the recurrent sites were limited to 2 nodules and were deemed resectable. The patient underwent peritoneal dissemination resection, and the pathological diagnosis was metastatic tumor.She subsequently received 11 postoperative FOLFOX4 courses. The chemotherapy regimen was changed to the de Gramont regimen because of peripheral neuropathy. After 56 courses of the de Gramont regimen, the chemotherapy regimen was further changed to UFT/UZEL. The patient received 28 additional courses but experienced hair loss and requested treatment cessation. To date, she remains alive without recurrence.

[A case of advanced pancreas cancer successfully treated by using combined modality therapy].

A 62-year-old woman visited a nearby hospital with chief complaints of diarrhea and weight loss.A computed tomography (CT)scan showed a hypovascular tumor approximately 2 cm in diameter in the pancreatic uncus, and the patient was referred to our department for thorough examination and treatment.The patient was diagnosed with cT4 (A) N0M0, cStage IV a cancer of the pancreatic uncus.The treatment consisted of 3 weeks of gemcitabine and 1 week of drug withdrawal; after completion of 4 courses, concomitant administration of S-1 (ie GS therapy) was initiated.The tumor gradually shrank, and it was not observed on a CT scan 1 year and 8 months later.Although no obvious distant metastasis was observed, a low density area around the superior mesenteric artery still remained.Possibility of viable tumor could not be completely ruled out; therefore, a pancreaticoduodenectomy was scheduled.However, because sclerosis around the superior mesenteric artery was quite severe, bled easily, and was difficult to separate, we decided that excision was impossible and resumed the GS therapy. The primary lung cancer that developed subsequently was resected, and the GS therapy was continued.The tumor in the pancreatic uncus was resected after growth was observed 3 years and 9 months after the initiation of chemotherapy.The patient is currently receiving chemotherapy as an outpatient.

CD98 is a promising prognostic biomarker in biliary tract cancer.

CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman's rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 (LAT1, r=0.562, P<0.001), Ki-67 (r=0.230, P=0.006) and CD34 (r=0.290, P=0.005). Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.

[A case of pathological complete response of advanced rectal cancer with liver metastasis accompanied by tumor thrombus following treatment with bevacizumab/FOLFOX4 chemotherapy].

A 58-year-old man underwent low anterior resection for type 2 rectal cancer with liver metastasis. An abdominal computed tomography (CT) scan showed multiple hepatic tumors (in S2, S3, S4, and S6) and a filling defect in the left portal vein. Pathological examination revealed a moderately differentiated adenocarcinoma, pSS, pN0, ly0, v3, with a tumor thrombus in the portal vein. After surgery, the patient was treated with combined chemotherapy of bevacizumab/Leucovorin and fluorouracil with oxaliplatin (FOLFOX4). After 11 courses of chemotherapy, tumor marker levels normalized, and the sizes of the liver metastases and thrombus in the left portal vein remarkably decreased. Resection of the left hepatic lobe and a partial resection of S6 were performed. Pathological examination revealed no residual cancer cells and indicated that the histological classification due to the chemotherapy regimen was Grade 3. The patient was alive for 5 years after the initial surgery, without recurrence.

[Retrospective analysis of the bevacizumab and CapeOX combination in untreated metastatic/recurrent colorectal cancer].

In recent years, there has been significant progress in systemic chemotherapy for metastatic or recurrent colorectal cancer. We investigated the clinical efficacy and feasibility of the bevacizumab and capecitabine /oxaliplatin(CapeOX)combination for untreated colorectal cancer. From October 2009 to June 2012, 38 patients were included, 18 receiving CapeOX alone and 20 receiving CapeOX plus bevacizumab. The response rate and disease-control rate were 16% and 5 0%, respectively, in the CapeOX arm, and 5 5% and 8 5%, respectively, in the CapeOX plus bevacizumab arm. Median progression-free survival was 8.0 months in the CapeOX arm and 1 2.8 months in CapeOX plus bevacizumab arm. The median overall survival was 21.6 months in the CapeOX arm and 3 4.0 months in CapeOX plus bevacizumab arm. Our results suggest that CapeOX treatment can be useful in the outpatient setting and more effective when combined with bevacizumab. Except in cases of bevacizumab intolerance, addition of bevacizumab to CapeOX treatment is considered useful as first-line therapy for metastatic or recur- rent colorectal cancer.

Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer.

BACKGROUND: The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer. METHODS: A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line. RESULTS: In total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU. CONCLUSIONS: High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

[Subset analysis of preoperative lymphocyte ratio in stage II or III colorectal cancer patients treated with oral tegafur-uracil and protein-bound polysaccharide K].

PURPOSE: We have reported, in a randomized, controlled study, that tegafur-uracil(UFT)and protein-bound polysaccharide K(PSK)combination therapy significantly improves the 5-year disease-free survival rate and reduces the risk of recurrence compared to UFT alone for Stage II or III colorectal cancer. In this study, we examined the efficacy of PSK by stratifying patients according to the preoperative lymphocyte ratio(Lym). METHODS: In a randomized, controlled study, 205 patients were eligible(137 in the UFT/PSK group and 68 in the UFT group). Of these, 193 patients with available preoperative Lym data were analysed(131 in the UFT/PSK group and 62 in the UFT group). RESULTS: Among patients with a preoperative Lym of <35%, the relapse-free survival(RFS)rate was 76.5% in the UFT/PSK group and 55.8% in the UFT group(p=0.008). However, in patients with a preoperative Lym of ≥35%, the RFS rate did not differ between the 2 groups. Similarly, overall survival was significantly higher in the UFT/PSK group than in the UFT group in patients with a preoperative Lym of <35%, whereas no intergroup difference was found among patients with a preoperative Lym of ≥35%. CONCLUSION: This study suggests that a low preoperative Lym is a good predictor for response to PSK in patients with Stage II or III colorectal cancer.

[Pathological complete remission using low-dose cisplatin plus S-1 for gastric cancer patient with liver metastases].

A 70-year-old female presented with epigastralgia. Gastrointestinal endoscopic examination showed advanced gastric cancer type 2. Computed tomography(CT)showed a liver tumor of 37mm in segment 6. She was treated with oral S-1, 80 mg/body for 14 days, followed by a 7-day rest, and CDDP 20mg/m2(day 1 and 8). After ten courses of treatment, CT showed reduction of the primary cancer, the liver tumor, and the affected lymph nodes. Then, distal gastrectomy, lymph node dissection, and partial liver resection were performed. The histological diagnosis was no viable cancer cells found in stomach, liver or lymph nodes. One year and 1 month postoperatively, the patient is alive without recurrence.

[A case of pancreatic cancer with celiac trunk and common hepatic artery invasion successfully resected after gemcitabine+S-1therapy].

We present a case of a 59-year-old female who was admitted to our hospital for upper abdominal pain. She was diagnosed with pancreatic body carcinoma by computed tomography and magnetic resonance imaging. We started gemcitabine+S-1 chemotherapy because the tumor had invaded the celiac trunk, common hepatic artery, superior mesenteric vein, and splenic vein. We reduced the S-1 to 100mg/body after the third course of gemcitabine(1, 000mg/m2 on days 1 and 8, every 21 days)+S-1(120mg/body on days 1-14, every 21 days)because of side effects. The tumor became smaller, and the celiac trunk and common hepatic artery were released. Thus, we conducted a distal pancreatectomy with a D2 lymph node dissection.

[A case of advanced colon cancer with peritoneal dissemination effectively treated with modified FOLFOX6 chemotherapy].

A 50-year-old woman was diagnosed with ascending colon cancer with bilateral ovarian metastases, carcinomatous peritonitis, and carcinomatous pleurisy. Nine courses of mFOLFOX6 treatment resulted in the disappearance of her ascites and pleural effusion and a marked decrease in her serum CEA and CA19-9 levels. Additionally, the primary tumor and ovarian metastases became smaller. Therefore, a right hemicolectomy with D3 lymph node dissection, total hysterectomy, and bilateral salpingo-oophorectomy were performed. Postoperatively, we changed the chemotherapy from mFOLFOX6 to bevacizumab+FOLFIRI because the patient had an allergic reaction to oxaliplatin, and we suspected lung metastasis. Because the lung metastasis grew after ten courses of bevacizumab+FOLFIRI, we changed to cetuximab+FOLFIRI. Unfortunately, 28 months after her diagnosis, the patient died of carcinomatous pleurisy.

[A case of Barrett's esophageal carcinoma treated with combined therapy].

During a routine health examination, a 50-year-old man was found to have an elevated lesion at the esophagogastric junction. Poorly differentiated adenocarcinoma was diagnosed from the biopsy findings. Computed tomography showed metastases in the mediastinal, intra-abdominal, and paraaortic lymph nodes. The clinical stage diagnosis was cT2, cN4, cM0, cStage IVa. Combination chemotherapy with docetaxel, CDDP, and 5-FU (DCF) was started initially. After 2 courses of DCF, the primary lesion and mediastinal lymph nodes had decreased in size, but the intra-abdominal lymph node had grown. A curative operation with paraaortic lymph node dissection was considered possible; thus, video-assisted thoracoscopic surgery of the esophagus with 3-field lymph node dissection was performed. The final findings revealed Barrett's esophageal carcinoma, EG, 0-III,23×18 mm, mod-por, CT-pT1b (sm3) pN4, sM0, fStage IV. Histologically, the mediastinal lymph node metastases disappeared with chemotherapy, but no reduction was observed in the abdominal lymph nodes. After surgery, 2 courses of combination adjuvant chemotherapy with CDDP and 5-FU were administered along with 50 Gy of radiotherapy. Subsequently, the treatment was changed to tegafur-gimeracil-oteracil potassium alone on an outpatient basis. The patient remains recurrence free 22 months postsurgery.

Large cell neuroendocrine carcinoma of the ampulla of vater with adenocarcinoma and squamous cell carcinoma components.

A 73-year-old woman visited our hospital complaining of general fatigue and jaundice. Laboratory tests revealed an elevated total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and γ-glutamyltransferase. Computed tomography and magnetic resonance imaging demonstrated a mass lesion at the ampulla of Vater with dilatation of the common bile duct and main pancreatic duct. Percutaneous transhepatic cholangiography revealed dilatation of the bile duct and a negative filling defect due to the tumor. Pancreatoduodenectomy was performed. The specimen included an ulcerated firm tumor of the papilla Vater. The surface of the ampulla consisted of well-differentiated papillary adenocarcinoma, whereas the deep layer, such as submucosal or muscular layer, contained large cell neuroendocrine carcinoma and squamous cell carcinoma. Immunohistochemistry revealed that the large cell neuroendocrine carcinoma component was positive for chromogranin A, synaptophysin and CD56. The patient died from multiple liver and bone metastases 13 months after surgery. This is a very rare case of a large cell neuroendocrine carcinoma accompanied by adenocarcinoma and squamous cell carcinoma components.

[A case of gastric cancer with lung, Virchow and para-aortic lymph node metastases treated successfully using PTX/5'-DFUR].

A 6 3-year-old male presented with dysphagia. Gastrointestinal endoscopic examination showed advanced gastric cancer type 3, which was diagnosed as well-differentiated adenocarcinoma. Computed tomography(CT)showed bilateral lung tumors, hugely enlarged Virchow and para-aortic lymph nodes. He was treated with combination chemotherapy of weekly paclitaxel(PTX)and doxifluridine(5'-DFUR). PTX was administered at a dose of 80mg/m2 on day 1, 8 and 15, and 5'- DFUR was orally administered at a dose of 533mg/m / 2day for 5 days followed by withdrawal for 2 days. After four courses of treatment, CT showed an almost complete disappearance of the lung and lymph node metastases. After 13 courses of treatment, total gastrectomy and lymph node dissection were performed. One year postoperatively, the patient died of a recur- rence.

[An elderly gastric cancer patient with multiple-node metastases treated successfully using S-1].

A n 83-year-old male presented with a leg edema. Gastrointestinal endoscopic examination showed advanced gastric cancer type 2, which was diagnosed as mod~well-differentiated adenocarcinoma. Computed tomography (CT) showed enlarged multiple lymph nodes. He was treated with oral S-1, 80 mg/day for 14 days, followed by a 7-day rest. After two courses of treatment, CT showed reduction of the lymph nodes. After 8 courses of treatment, total gastrectomy and lymph node dissection were performed. The histological diagnoses were tub 2>tub 1, pSS, pN0, pStage I B. One year and 10 months postoperatively, the patient is alive without recurrence.

[A case of gastric cancer with Virchow and para-aortic node metastases treated successfully using S-1].

A 64-year-old female presented with a left cervical tumor. Gastrointestinal endoscopic examination showed advanced gastric cancer type 3, which was diagnosed as poorly-differentiated adenocarcinoma. Computed tomography (CT) showed hugely enlarged Virchow and para-aortic lymph nodes. She was treated with oral S-1, 100 mg/day for 28 days, followed by a 2-week rest. After two courses, S-1 was administered for 14 days followed by a 7-day rest because of side effects. After five courses of treatment, CT showed complete disappearance of the lymph node metastases. Total gastrectomy and lymph node dissection were performed. The histology was judged as Grade 2. The residual cancer in the stomach was only 2mm in size, and there were no viable cancer cells in any lymph nodes. One year postoperatively, the patient is alive without recurrence.

[Remarkable effect of gemcitabine-oxaliplatin (GEMOX) therapy in a patient with advanced metastatic mucinous cystic neoplasm of the pancreas].

Gemcitabine(GEM)is the standard therapy for advanced pancreatic cancer. GEM-oxaliplatin (GEMOX) combination treatment has been reported to be superior to GEM alone in terms of clinical progression-free survival, but it is not the therapy of choice for pancreatic cancer. We report a case of advanced mucinous cystic neoplasm (MCN) of the pancreas with multiple hepatic metastases in a 39-year-old female. She was treated with 16 courses of GEMOX (GEM 1,500 mg/day at a rate of 10 mg/m2/min on the first day and oxaliplatin 150 mg/day at 100 mg/m2 on the second day, every 3 weeks). The pharmacist helped her to avoid severe side effects. When the hepatic metastases disappeared after 13 courses, the primary MCN was removed surgically after 16 courses of GEMOX treatment. No recurrence has been observed 22 months postoperatively. GEMOX might be effective for the treatment of MCN of the pancreas.

Primary liver cancers with nonalcoholic steatohepatitis.

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.

Factors affecting the prognosis of anatomical liver resection for liver metastases from colorectal cancer.

BACKGROUND/AIMS: Liver resection has improved the survival of colorectal cancer patients with metastases. However, there are groups at high risk of recurrence after liver resection. This report reviews our results using anatomical liver resection and analyzes the prognostic factors. METHODOLOGY: We analyzed 78 patients who underwent anatomical liver resection of liver metastases from colorectal cancer between June 1988 and March 2002. RESULTS: Twenty-nine patients had synchronous metastases, and 49 had metachronous. The 5-year overall survival rate was 43%. Patients with more than three metastatic tumors had a significantly poorer 5-year recurrence-free survival rate. There was no statistical difference in the 5-year overall survival rate between patients with metachronous metastases (41%) and those with synchronous (44%) metastases. The 5-year overall survival rate was significantly poorer for patients with an interval of 1 year or less between colorectal and liver resections than for patients with a longer interval. Recurrence after liver resection occurred in 38 patients (49%). The recurrences occurred in the lung in 18 patients, in remnant liver in 15 patients, in lymph nodes in 7 patients, and in other organs in 6 patients. CONCLUSIONS: We conclude that anatomical liver resection of liver metastases from colorectal cancer improves survival. Liver metastases that occur within 1 year of colorectal resection may need an interval of observation before liver resection.