Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.

BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. RESULTS: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. CONCLUSION: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).

Six National University Consortium in Liver Transplant Professionals Training (SNUC-LT) Program in Japan.

BACKGROUND: There has been no public structured training program for transplant surgeons in Japan. However, such a program is crucial for optimizing liver transplant surgery and training young professionals in liver transplant surgery. A comprehensive training program was recently developed and the underlying concepts, structure and curriculum, and results of this program are described here. METHODS: We developed a 3-year training program in 2014 called the Six National University Consortium in Liver Transplant Professionals Training (SNUC-LT) program supported by the Ministry of Education, Culture, Sports, Science, and Technology. This program is based on strong cooperation among 6 national universities (Kumamoto, Okayama, Nagasaki, Kanazawa, Niigata, and Chiba Universities). The program includes various courses to help trainees learn transplant theory and practice as well as to teach surgical skills required to safely perform transplant surgery. RESULTS: Three trainees completed the specially designed 3-year curriculum. They attended lectures on transplant theory for an average of 59 hours and participated in an average of 44 liver transplant surgeries and 51 liver resections for transplant practice. Trainees from low-volume centers had sufficient opportunities to attend operations in high-volume centers because of the cooperative agreement among the universities. After finishing the program, the trainees were certified as talent-proven liver transplant surgeons. CONCLUSIONS: The SNUC-LT program is the first national program in Japan to have strong professional support. Our multicenter program enables young surgeons to have more abundant knowledge, more extensive experience, better surgical skills, and smoother communication skills in the field of liver transplantation.

Chylous ascites after hepatopancreatobiliary surgery.

BACKGROUND: Postoperative chylous ascites following abdominal surgery is uncommon. It potentially induces malnutrition and immunodeficiency, contributing to increased mortality. In the field of hepatopancreatobiliary (HPB) surgery, no large studies have been conducted that focused on postoperative chylous ascites. The aim of this study was to determine the incidence, risk factors and management of chylous ascites following HPB surgery, with particular emphasis on pancreatic resection. METHODS: Consecutive patients who had HPB surgery between 2000 and 2011 at a single institution were reviewed retrospectively. Chyle leak was defined as 100 ml/day or more of milky, amylase-free peritoneal fluid with a triglyceride concentration of 110 mg/dl or above. Risk factors for chylous ascites associated with pancreatic resection and the clinical efficacy of octreotide in treating chylous ascites were evaluated. RESULTS: Of 2002 consecutive patients who underwent HPB surgery during the study period, 21 (1·0 per cent) developed chylous ascites. Chylous ascites occurred relatively frequently in patients who had a pancreatic resection, such as pancreaticoduodenectomy (3·3 per cent) or distal pancreatectomy (3·8 per cent). Multivariable analysis revealed that manipulation of the para-aortic area (P < 0·001), retroperitoneal invasion (P = 0·031) and early enteral feeding after operation (P < 0·001) were independent risk factors for chylous ascites following pancreatic resection. Octreotide treatment decreased drainage output of chylous ascites on day 1 after initiation of treatment (P = 0·002). CONCLUSION: Chylous ascites is a rare complication following HPB surgery. It is more common after pancreatic resection. Treatment with octreotide combined with total parenteral nutrition is recommended.

Increased circulating cell signalling phosphoproteins in sera are useful for the detection of pancreatic cancer.

BACKGROUND: Intracellular phosphoprotein activation significantly regulates cancer progression. However, the significance of circulating phosphoproteins in the blood remains unknown. We investigated the serum phosphoprotein profile involved in pancreatic cancer (PaCa) by a novel approach that comprehensively measured serum phosphoproteins levels, and clinically applied this method to the detection of PaCa. METHODS: We analysed the serum phosphoproteins that comprised cancer cellular signal pathways by comparing sera from PaCa patients and benign controls including healthy volunteers (HVs) and pancreatitis patients. RESULTS: Hierarchical clustering analysis between PaCa patients and HVs revealed differential pathway-specific profiles. In particular, the components of the extracellular signal-regulated kinase (ERK) signalling pathway were significantly increased in the sera of PaCa patients compared with HVs. The positive rate of p-ERK1/2 (82%) was found to be superior to that of CA19-9 (53%) for early stage PaCa. For the combination of these serum levels, the area under the receiver-operator characteristics curves was showing significant ability to distinguish between the two populations in independent validation set, and between cancer and non-cancer populations in another validation set. CONCLUSION: The comprehensive measurement of serum cell signal phosphoproteins is useful for the detection of PaCa. Further investigations will lead to the implementation of tailor-made molecular-targeted therapeutics.

Significance of repeated resection for recurrent intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Management of patients with recurrent intrahepatic cholangiocarcinoma (ICC) following surgical resection is difficult, and surgical resection is rarely indicated. We retrospectively reviewed patients with recurrent intrahepatic cholangiocarcinoma. METHODOLOGY: Between April 1998 and March 2007, 57 consecutive patients with ICC underwent surgical resection. Mode of recurrence and treatment of recurrent tumors, especially surgical resection for these tumors, in patients with cancer recurrence were evaluated. RESULTS: 37 (65%) patients experienced tumor recurrence. Out of these patients, 24 underwent some type of cancer-directed therapy, including 9 patients (24%) for whom surgical resection was attempted: the latter included 4 hepatic resections, 2 pulmonary resections, 2 tumor resections, and 1 gastric resection. For 6 patients with recurrent tumor in the liver or the lung, microscopic complete resection was achieved, while incomplete resection was resulted in the remaining 3 patients. No postoperative mortality was encountered. Among patients with complete resection, 3 are alive without disease 32, 39 and 77 months after the second operation, one has lived with disease for 13 months, and 2 died of disease after 22 and 26 months. No significant difference in overall survival was observed between patients undergoing primary and second surgical resections, calculated from the primary and the second operations, respectively. CONCLUSIONS: Repeated surgical resection for recurrent ICC can be performed with acceptable morbidity, and affords selected patients a chance for long-term survival.

Detection of post-menopausal women with low bone mineral density and elevated biochemical markers of bone turnover by panoramic radiographs.

OBJECTIVES: The detection of an eroded mandibular cortex on panoramic radiographs and questionnaire-based screening tools show similar diagnostic efficacies for identifying osteoporosis in post-menopausal women. We evaluated whether both tools also have similar diagnostic performances in identifying women with osteoporosis and elevated biochemical markers of bone turnover who have a high risk of fracture. METHODS: Urinary N-telopeptide cross-links of type I collagen (NTx) (corrected for creatinine) and serum levels of total non-bone-specific alkaline phosphatase (ALP) were measured in 99 post-menopausal women aged 44-70 years (mean +/- standard deviation (SD), 54.6 +/- 5.2 years) who underwent bone mineral density (BMD) assessment and panoramic radiography. BMD was measured at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. The Female Osteoporosis Self-assessment Tool for Asia (FOSTA), which is based on age and weight, was used as the questionnaire-based screening tool. Osteoporosis was defined as a BMD T-score of -2.5 or less at either the lumbar spine or the femoral neck. RESULTS: Urinary NTx and serum ALP were significantly associated with cortical erosion, but not with the FOSTA. The areas under the receiver operating characteristics (ROC) curve for identifying participants with osteoporosis were 0.784 for FOSTA and 0.827 for the detection of cortical erosion, and for identifying participants with osteoporosis and elevated urinary NTx they were 0.700 for FOSTA and 0.807 for the detection of cortical erosion. CONCLUSIONS: Our results suggest that panoramic radiography is superior to questionnaire-based screening for identifying women who are at high risk of fracture.

FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer.

Pancreatic cancer has one of the highest mortalities among all malignancies and there is an urgent need for new therapy. This might be achieved by resolving the detailed biological mechanism, and in this study we examined how pancreatic cancer cells develop aggressive properties by focusing on signalling through the fibroblast growth factor (FGF)10 and FGF receptor (FGFR)2, which play important roles in pancreatic organogenesis. Immunostaining of pancreatic cancer tissues showed that FGFR2 was expressed in cancer cells, whereas FGF10 was expressed in stromal cells surrounding the cancer cells. Patients with high FGFR2 expression in cancer cells had a shorter survival time compared to those with low FGFR2 expression. Fibroblast growth factor 10 induced cell migration and invasion of CFPAC-1 and AsPC-1 pancreatic cancer cells through interaction with FGFR2-IIIb, a specific isoform of FGFR2. Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)-beta1, and increased secretion of TGF-beta1 protein from these cell lines. These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis. This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

Observer performance in diagnosing osteoporosis by dental panoramic radiographs: results from the osteoporosis screening project in dentistry (OSPD).

Mandibular cortical erosion detected on dental panoramic radiographs (DPRs) may be useful for identifying women with osteoporosis, but little is known about the variation in diagnostic efficacy of observers worldwide. The purpose of this study was to measure the accuracy in identifying women at risk for osteoporosis in a worldwide group of observers using DPRs. We constructed a website that included background information about osteoporosis screening and instructions regarding the interpretation of mandibular cortical erosion. DPRs of 100 Japanese postmenopausal women aged 50 years or older who had completed skeletal bone mineral measurements by dual energy X-ray absorptiometry were digitized at 300 dpi. These were displayed on the website and used for the evaluation of diagnostic efficacy. Sixty observers aged 25 to 66 years recruited from 16 countries participated in this study. These observers classified cortical erosion into one of three groups (none, mild to moderate, and severe) on the website via the Internet, twice with an approximately 2-week interval. The diagnostic efficacy of the Osteoporosis Self-Assessment Tool (OST), a simple clinical decision rule based on age and weight, was also calculated and compared with that of cortical erosion. The overall mean sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the 60 observers in identifying women with osteoporosis by cortical erosion on DPRs were 82.5, 46.2, 46.7, and 84.0%, respectively. Those same values by the OST index were 82.9, 43.1, 43.9, and 82.4%, respectively. The intra-observer agreement in classifying cortical erosion on DPRs was sufficient (weighted kappa values>0.6) in 36 (60%) observers. This was significantly increased in observers who specialized in oral radiology (P<0.05). In the 36 observers with sufficient intra-observer agreement, the overall mean sensitivity, specificity, PPV, and NPV in identifying women with osteoporosis by any cortical erosion were 83.5, 48.7, 48.3, and 85.7%, respectively. The mean PPV and NPV were significantly higher in the 36 observers with sufficient intra-observer agreement than in the 24 observers with insufficient intra-observer agreement. Our results reconfirm the efficacy of cortical erosion findings in identifying postmenopausal women at risk for osteoporosis, among observers with sufficient intra-observer agreement. Information gathered from radiographic examination is at least as useful as that gathered from the OST index.

Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases.

OBJECTIVES: KL-6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL-6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL-6 are associated with increased mortality, and to identify the most suitable cut-off level of KL-6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL-6 levels in patients with stable-state ILDs. METHODS: Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL-6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. RESULTS: During the follow-up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL-6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL(-1) as the most suitable cut-off level by which to distinguish between the two groups of patients. The 95% specificity serum KL-6 level with poor outcome was 2750 U mL(-1). In univariate and multivariate analysis, elevated serum KL-6 (>1000 U mL(-1)) in the stable state indicated poor prognosis (P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). CONCLUSIONS: Elevated KL-6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.

Atelectasis of the right medial basal segment mimicking primary lung cancer in an asthmatic patient.

A segmental collapse due to mucous plug in the bronchus tree may mimic malignant pathological conditions. We present a case of 58-year-old asthmatic patient with an obstruction of right medial basal bronchus due to mucous plug, which was simulating mediastinal mass. To the best knowledge, a similar case is not reported in the English medical literature.

Significantly lower rate of smoking in female compared to male patients with lung adenocarcinoma.

To examine the relationship between smoking and lung adenocarcinoma in female patients, we performed a retrospective chart review for 470 patients with lung adenocarcinoma at our hospital. The proportions of non-smokers were higher in female patients than those of male patients. A significant difference in smoking history was found between female and male patients. Not only active smoking but also passive smoking may influence the development of female lung adenocarcinoma, which reinforces the need for effective programmes aimed refraining from smoking and cessation among men as well as women.

Bone metastasis as the first manifestation of lung cancer.

Bone metastasis usually occurs late in the course of the disease, but in some patients it is the first manifestation of lung cancer. To evaluate the characteristics of patients with bone metastasis as a first manifestation of lung cancer, the medical records of 1063 patients with lung cancer between 1976 and 2001 were reviewed retrospectively. Twenty-four (2.3%) lung cancer patients presented symptoms of bone metastasis as a first manifestation; 11 patients had bone metastasis as the only site of spread in lung cancer; 16 had adenocarcinoma; five had a primary lesion <30 mm, and nine had N0-1 disease. Patients with sole bone metastasis did not have a more favourable survival rate than patients with bone and other systemic metastases (p=0.2938). Whether metastasis is the first manifestation of lung cancer or not, the occurrence of bone metastasis generally means a poor prognosis.

Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival.

BACKGROUND: The results of surgical treatment for intrahepatic cholangiocarcinoma (ICC) and specific factors influencing survival are still unclear. METHODS: Between 1984 and 2001, 62 patients with ICC underwent laparotomy, with a 77 per cent (48 patients) resectability rate. The tumours in these 48 patients were reviewed retrospectively to examine the relationship between gross appearance (mass forming, periductal infiltrating, intraductal growth, and mass forming plus periductal infiltrating) and patient survival, as well as the manner of recurrence. In patients with mass-forming and mass-forming plus periductal infiltrating types, univariate and multivariate analyses of potential prognostic factors were performed. RESULTS: The 1-, 3- and 5-year survival rates were 62, 38 and 23 per cent respectively. All patients with the intraductal growth type remained alive after intervals ranging from 8 to 72 months. Univariate analysis showed multiple hepatic lesions, liver capsule invasion, presence of cancer cells in the resection margin, and high serum carbohydrate antigen (CA) 19-9 level to be significant negative prognostic factors. Lymph node involvement, however, was not identified as a significant prognostic factor. With multivariate analysis, multiple hepatic lesions and high serum CA19-9 concentration were found to be significantly related to prognosis. The most frequent recurrence site was the remnant liver. CONCLUSION: These results suggest that the intraductal growth type of tumour should be treated as a distinct entity compared with other types of ICC. Multiple tumours and high serum CA19-9 level were signs of dismal prognosis, whereas not all patients with lymph node involvement had a poor prognosis.