[The syndrome of inappropriate diuretic hormone secretion (SIADH) ending lethal during the use of paliperidon and lamotrigine]. / Het syndroom van inadequate secretie van het antidiuretisch hormoon (SIADH) met letale afloop tijdens gebruik van paliperidon en lamotrigine.

Hyponatremia, as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), is well known with the use of nearly all antipsychotics and mood stabilizers. The first symptoms are atypical and are not always mentioned by the patient. However, not recognising the syndrome in due time can be lethal. We describe a 35-year-old woman who died due to lack of recognition of SIADH. The patient, who had a bipolar disorder and was for a long time on a paliperidone depot, developed complaints of nausea, vomiting and thirst after lamotrigine was prescribed. A few days after increasing the dose, she died; no evidence was found of suicide. The SIADH was probably triggered by the use of lamotrigine and paliperidone. Paying sufficient attention to the symptoms that may cause this syndrome, as well as their early recognition, could save lives.

[Downbeat nystagmus - a rare side-effect of lithium carbonate]. / Downbeatnystagmus als zeldzame bijwerking van lithiumcarbonaat.

A 52-year-old woman who had been treated with lithium carbonate for 10 years developed a downbeat nystagmus. The literature describes downbeat nystagmus as a rare side-effect of lithium carbonate. In this patient other causes of downbeat nystagmus were ruled out. In most cases stopping lithium carbonate does not alleviate the symptoms, which are often debilitating. At the moment there is no adequate treatment for the condition. In some cases, however, the symptoms subside after the patient stops taking lithium. Therefore, we consider that early recognition of downbeat nystagmus in patients being treated with lithium carbonate is vitally important.

[Monumental books by Jelgersma and Rümke]. / Monumentale boeken van Jelgersma en Rümke en invloeden op hun werk.

BACKGROUND: Now that we are in the DSM-5 period, interest in the older psychiatric literature seems to be gradually waning. AIM: To provide a brief survey of important books by Jelgersma and Rümke, to show how these authors were influenced by Kraepelin, Bleuler, Jaspers, Lombroso and Pavlov, and thereby demonstrate how the older literature helped to shape the development of psychiatry. METHOD: The study is based on a selection of the older psychiatric literature in book form. RESULTS: It is evident that even today much of the older literature is still influencing current concepts and descriptions of symptoms and the development of concepts such as schizophrenia, and is still guiding psychiatrists on the best moment to begin psychiatric treatment. CONCLUSION: The older psychiatric literature should not be forgotten or overlooked. It is an invaluable source of in-depth knowledge about psychiatry.

Evolution of registry and tracking system for organ transplantation in Japan.

Previously, the renal and liver transplantation registry in Japan was enforced yearly using registration and tracking papers only on recipients. The input of all patient data and announcement of statistical analysis to the public required a long time. Following The Declaration of Istanbul 2008, the committees planned to establish new registry and tracking systems for renal and liver transplantations on both recipients and donors. As the first step, for renal transplantation, we established a new registry and tracking system, JARTRE (JApan Renal Transplantation REgistry), using flash (USB) memory in 2009. The recipient and donor data were inputted into the USB memory in the transplantation centers. The memory was collected once a year by the committees with performed at 3 months at 1 year and every year after, the operation. As the second step, for liver transplantation, we established an online registry and tracking system, LITRE-J (LIver Transplantation REgistry in Japan), using the Internet in 2011. The recipient and donor data are inputted online in the centers just after transplantation. The tracking is performed at 3 months, at 1 year and every year after the operation. In 2012, we will convert the JARTRE system to an online registration and tracking system using the Internet like LITRE-J. The advantages of these system are the ease of input, scope of the data, and rapidly for statistical processing. Herein we have reported the details of JARTRE and LITRE-J, as well as the evaluation of the registry and tracking systems for renal and liver transplantation in Japan.

[The complexity of repatriating psychiatric patients]. / Complexe psychiatrische repatriëring.

This article describes the method by which the repatriation to the Netherlands of psychiatric patients living abroad is carried out. On the basis of one case, namely that of a psychotic male with low Hb and fear of HIV, it is shown that the repatriation of psychiatric patients can be extremely complex and that a psychiatrist's active involvement in the patient's repatriation can be extremely important.

Heterogeneity of colorectal cancers and extraction of discriminator gene signatures for personalized prediction of prognosis.

Dissected specimens of colorectal cancer (CRC) have been intensively studied using molecular sketches (gene signatures) to obtain a set of discriminator gene signatures for accurate prognosis prediction in individual patients. The discriminators obtained so far are not universally applicable, as the gene sets reflect the method and site of the study. In this study, we show that dissected stage II and III CRC samples are significantly heterogeneous in molecular sketches, and are not appropriate sources for discriminator extraction unless handled individually. To search for an accurate discriminator gene set for prediction of metastases, we need to start with less heterogeneous stage II CRC. We examined 198 (92 stage II and 106 stage III) CRC dissected samples for the predictability of discriminator gene signatures by analyzing stage II CRC alone, stage III alone, or in combination. The best predictive power of discriminator genes was obtained only when these genes were extracted and validated with stage II CRC samples. An accurate discriminator gene set for the prediction of CRC metastases can be obtained by focusing on stage II CRC samples.

Recurrence-free survival more than 10 years after liver resection for hepatocellular carcinoma.

BACKGROUND: High recurrence rates after liver resection with curative intent for hepatocellular carcinoma (HCC) remain a problem. The characterization of long-term survivors without recurrence after liver resection may help improve the therapeutic strategy for HCC. METHODS: A nationwide Japanese database was used to analyse 20 811 patients with HCC who underwent liver resection with curative intent. RESULTS: The 10-year recurrence-free survival rate after liver resection for HCC with curative intent was 22.4 per cent. Some 281 patients were recurrence-free after more than 10 years. The HCCs measured less than 5 cm in 83.2 per cent, a single lesion was present in 91.7 per cent, and a simple nodular macroscopic appearance was found in 73.3 per cent of these patients; histologically, most HCCs showed no vascular invasion or intrahepatic metastases. Multivariable analysis revealed tumour differentiation as the strongest predictor of death from recurrent HCC within 5 years. CONCLUSION: Long-term recurrence-free survival is possible after liver resection for HCC, particularly in patients with a single lesion measuring less than 5 cm with a simple nodular appearance and low tumour marker levels.

Attitudes of medical professionals and transplantation facilities toward living-donor liver transplantation in Japan.

The Japan Society for Transplantation (JST) revised their guidelines in 2003 to specify that a living donor must be "a relative by blood within the sixth degree or an in-law within the third degree." Although several criticisms have been raised on this issue, these criteria have persisted without any empirical data showing the opinions and attitudes of people who are affected by the revision. Therefore, we performed a questionnaire survey to determine what Japanese medical professionals involved with living-donor liver transplantation (LDLT) regarded as eligible relationships for donation, as well as the kind of relationship for which they would be willing to donate their liver, and what donor eligibility criteria was currently used by their institutions. Among the 71 representatives of the Japanese Liver Transplantation Society, >90% answered that liver donations to emotionally close parents, siblings, children, or spouses were acceptable. However, the numbers were considerably lower for donation to emotionally close blood relatives, in-laws, friends, and strangers (78.2%, 52.1%, 18.6%, and 5.9%, respectively). This gap was more prominent when participants were questioned about their own willingness to donate. More than two-thirds of facilities that perform LDLTs have independent regulations for donor eligibility that are more conservative than the JST guidelines. No facility accepted friends or strangers as donors. When introducing policies or guidelines, it is important to carefully investigate the views of the people who are affected. The data obtained in this study should serve as a resource for ongoing discussions about the JST revised guidelines.

Age as an independent risk factor for surgical site infections in a large gastrointestinal surgery cohort in Japan.

A large scale survey was conducted to examine risk factors for surgical site infections (SSIs) among Japanese patients undergoing gastrointestinal surgery. The purposes of the study were: (i) to investigate age as a risk factor for SSIs in gastrointestinal surgery; and (ii) to examine the differences in risk factors for SSIs between laparoscopic cholecystectomy and open cholecystectomy. Surveillance data were prospectively collected from 20 participating hospitals in Japan between July 2003 and November 2007. SSIs were identified by use of the Centers for Disease Control and Prevention criteria. SSIs were identified in 1471 of 12 015 available cases, with an overall incidence of 12.2%. In the final logistic regression model, age was a risk factor in open cholecystectomy, gastrectomy and appendicectomy. Length of operation was a risk factor for SSIs for six surgical procedures, and wound class and drain use were also risk factors in most procedures. When comparing laparoscopic surgery against open procedure, use of silk sutures was a risk factor for SSIs in laparoscopic cholecystectomy. Drain use, wound class, operation duration, male gender and age were additional risk factors for SSIs in open cholecystectomy. In summary, patient age is a significant predictor for SSIs in some gastrointestinal procedures, although risk factors for SSIs in laparoscopic procedures appear quite different from those in open procedures.

A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer.

BACKGROUND: This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer. METHODS: Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m(-2) over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles. RESULTS: Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4 versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40-0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51-1.14); P=0.19). CONCLUSION: The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.

Significance of RRM1 and ERCC1 expression in resectable pancreatic adenocarcinoma.

The identification of molecular markers, useful for therapeutic decisions in pancreatic cancer patients, is crucial for advances in disease management. Gemcitabine, although a cornerstone of current therapy, has limited efficacy. RRM1 is a key molecule for gemcitabine efficacy and is also involved in tumor progression. We determined in situ RRM1 and excision repair cross complementation group 1 (ERCC1) protein levels in 68 pancreatic cancer patients. All had R0 resections without preoperative therapy. Protein levels were determined by automated quantitative analysis (AQUA), a fluorescence-based immunohistochemical method. The relationship between protein expressions and clinical outcomes, including response to gemcitabine at the time of disease recurrence, was determined. Patients with high RRM1 showed significantly better overall survival than patients with low expression (P=0.0196). There was a trend toward better overall survival for patient with high ERCC1 (P=0.0552). When both markers were considered together, patients with both high RRM1 and ERCC1 faired the best in terms of overall and disease-free survival (P=0.0066, P=0.0127). In addition, treatment benefit from gemcitabine in patients with disease recurrence was observed only in patients with low RRM1. The combination of RRM1 and ERCC1 expression is prognostic in pancreatic cancer patients after a complete resection. On disease recurrence, only patients with low RRM1 derive benefit from gemcitabine.

Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma.

Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). However, some IFNAR2-positive patients show no response to the therapy. This result suggests the possibility of other factors, which would be responsible for resistance to IFN-alpha/5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-alpha/5-FU therapy and search for a biological marker of chemoresistance to such therapy. Gene expression profiling and molecular network analysis were used in the analysis of non-responders and responders with IFNAR2-positive HCC. The Wnt/beta-catenin signalling pathway contributed to resistance to IFN-alpha/5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of Wnt/beta-catenin signalling, only in non-responders. In vitro studies showed that activation of Wnt/beta-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3'-oxime (BIO)) induced chemoresistance to IFN-alpha/5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-alpha/5-FU significantly to hepatoma cell cultures reduced the inhibitory effects of the latter two on DNA synthesis and accumulation of cells in the S-phase. The results indicate that activation of Wnt/beta-catenin signalling pathway induces chemoresistance to IFN-alpha/5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.

Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis.

Gene expression profiling is a valuable tool for identifying differentially expressed genes in studies of disease subtype and patient outcome for various cancers. However, it remains difficult to assign biological significance to the vast number of genes. There is an increasing awareness of gene expression profile as an important part of the contextual molecular network at play in complex biological processes such as cancer initiation and progression. This study analysed the transcriptional profiles commonly activated at different stages of gastric cancers using an integrated approach combining gene expression profiling of 222 human tissues and gene regulatory dynamic mapping. We focused on an inferred core network with CDKN1A (p21(WAF1/CIP1)) as the hub, and extracted seven candidates for gastric carcinogenesis (MMP7, SPARC, SOD2, INHBA, IGFBP7, NEK6, LUM). They were classified into two groups based on the correlation between expression level and stage. The seven genes were commonly activated and their expression levels tended to increase as disease progressed. NEK6 and INHBA are particularly promising candidate genes overexpressed at the protein level, as confirmed by immunohistochemistry and western blotting. This integrated approach could help to identify candidate players in gastric carcinogenesis and progression. These genes are potential markers of gastric cancer regardless of stage.

Long-term and short-term evaluation of esophageal reconstruction using the colon or the jejunum in esophageal cancer patients after gastrectomy.

For esophageal cancer patients, the gastric tube is the first choice as an esophageal substitute, with the colon or the jejunum being used when the stomach cannot be used. We retrospectively compared these two methods from the viewpoint of peri-operative complications and long-term bodyweight alteration. From 1998 to 2005 53 patients who had undergone subtotal esophagectomy due to thoracic esophageal cancers were given reconstruction with the colon (28 cases) or the jejunum (25 cases). Both intestines were reconstructed via the subcutaneous route and were anastomosed to the internal mammalian artery and vein for a supercharged blood supply. There was no difference in operating time and blood loss. Compared with the colon reconstruction group, the hospital stay of the jejunum reconstruction group was significantly shorter (65 days vs 45 days, P = 0.0120) and the incidence of anastomotic leakage tended to be less (13 cases, 46%vs 6 cases, 24%, P = 0.1507), while other operative morbidity did not differ between the two groups. Bodyweight loss, which is a serious postoperative sequela after esophagectomy, was less in the jejunum group than in the colon group, showing a significant difference at 12 months after surgery. Our retrospective study revealed the jejunum to be superior to the colon for the reconstruction after esophagectomy along with gastrectomy, with respect to anastomotic leakage and bodyweight loss. The next step will be to conduct a prospective large cohort study.

Evaluation of clinical significance of 18F-fluorodeoxyglucose positron emission tomography in superficial squamous cell carcinomas of the thoracic esophagus.

(18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used for pre-treatment staging and evaluation of response to pre-operative therapy in advanced thoracic esophageal cancers. To evaluate the clinical significance of PET diagnosis of superficial thoracic esophageal cancers, FDG-PET was conducted preoperatively in 41 patients with such cancers without pre-operative therapy. We compared the PET diagnosis with clinicopathological findings with respect to both the primary tumor and lymph node (LN) metastasis. Of the 41 superficial thoracic esophageal cancers, 21 (51.2%) were PET positive for primary tumors. Although tumor length and histological type did not correlate with FDG uptake by primary tumors, non-flat (elevated or depressed) tumors showed significantly stronger FDG uptake than flat ones. Of 28 tumors infiltrating the deep submucosal layer, 19 (67.9%) were PET positive, while only two (15.4%) of 13 tumors infiltrating only the mucosa or shallow submucosal layer were PET positive. Manova identified FDG uptake as the only independent risk factor for deep submucosal invasion (odds ratio, 7.407; P = 0.0279). In 13 patients with pathological LN metastasis, although no LN metastasis was detected by FDG-PET, FDG uptake by the primary tumors was the only risk factor for LN metastasis (P = 0.0318). PET-negative tumors tended to reflect longer disease-free survival than PET-positive tumors, although this was not significant. FDG-PET is useful for detecting tumors infiltrating the middle or deep submucosal layer (sm2/sm3), and for predicting LN metastasis in patients with superficial thoracic esophageal cancers. FDG-PET is helpful for decision-making regarding treatment of such patients.

Evaluation of the technical difficulty performing laparoscopic resection of a rectosigmoid carcinoma: visceral fat reflects technical difficulty more accurately than body mass index.

BACKGROUND: In general, visceral fat and adhesion greatly influence the technical difficulty in performing abdominal surgery. Body mass index (BMI) has been widely used to express the degree of obesity, but it does not always properly reflect the degree of visceral fat. This retrospective study investigated the impact of visceral fat on the operation time to examine whether a quantified visceral fat area (VFA) could be used as a sensitive predictor of technical difficulty in performing a laparoscopic resection of rectosigmoid carcinoma. METHODS: Between February 1999 and April 2004, 58 consecutive patients underwent a laparoscopically assisted sigmoidectomy or anterior resection. After a review of the medical charts, the relationship between the operation time and the following variables was analyzed: sex, depth of invasion, approach (medial-to-lateral, lateral-to-medial), subjectively graded degree of visceral fat and adhesion, history of previous abdominal surgery, and BMI. The correlations between VFA, VFA/body surface area (BSA) measured by the "FatScan," software package for quantifying the VFA from the preoperative CT images, and operation time were investigated. Next, the impact of the VFA amount on the early surgical outcome was examined. RESULTS: According to the intraoperative findings, two patients with a severe adhesion required a significantly longer operation time. A history of previous abdominal surgery was not a significant factor in the operation time. Instead, the VFA/BSA had a stronger correlation with the operation time than the BMI. A significantly longer operation time (209 +/- 42 vs 179 +/- 37 min; p = 0.031) was observed for the patients in the high VFA/BSA group (> or =85 cm(2)/m(2)) group than in the normal VFA/BSA group (<85 cm(2)/m(2)). CONCLUSION: For predicting the technical difficulty of performing a laparoscopic resection of rectosigmoid carcinoma, VFA/BSA may be a more useful index than BMI.

Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer.

Recent studies have identified vimentin, a type III intermediate filament, among genes differentially expressed in tumours with more invasive features, suggesting an association between vimentin and tumour progression. The aim of this study, was to investigate whether vimentin expression in colon cancer tissue is of clinical relevance. We performed immunostaining in 142 colorectal cancer (CRC) samples and quantified the amount of vimentin expression using computer-assisted image analysis. Vimentin expression in the tumour stroma of CRC was associated with shorter survival. Overall survival in the high vimentin expression group was 71.2% compared with 90.4% in the low-expression group (P=0.002), whereas disease-free survival for the high-expression group was 62.7% compared with 86.7% for the low-expression group (P=0.001). Furthermore, the prognostic power of vimentin for disease recurrence was maintained in both stage II and III CRC. Multivariate analysis suggested that vimentin was a better prognostic indicator for disease recurrence (risk ratio=3.5) than the widely used lymph node status (risk ratio=2.2). Vimentin expression in the tumour stroma may reflect a higher malignant potential of the tumour and may be a useful predictive marker for disease recurrence in CRC patients.

Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum.

Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.

Alpha-fetoprotein mRNA detection in peripheral blood for prediction of hepatocellular carcinoma recurrence after liver transplantation.

The aim of this study was to assess the value of alphafeto protein (AFP) mRNA-expressing cells detected in peripheral blood for predicting tumor recurrence after living donor liver transplantation (LDLT) in patients with hepatocellular carcinoma (HCC). The test group consisted of 25 patients who underwent LDLT for end-stage liver disease with HCC while the control group consisted of 37 living donors. Quantitative real-time reverse-transcriptase polymerase chain reaction was used for detection of AFP mRNA-expressing cells in peripheral blood. Nine (36%) of 25 patients developed tumor recurrences (four lung; one liver; one peritoneum; two bone; one adrenal gland) during the follow-up period. Perioperatively, AFP mRNA was positive in peripheral blood of eight patients (32.0%) but only in 1 (2.7%) of the control. Preoperative AFP mRNA was positive in three cases. Univariate analyses revealed that preoperative and perioperative AFP mRNA and microscopical vascular invasion were the significant predictors for HCC recurrence (P = .007, .037, and .005, respectively). In the patients with HCC exceeding Milan criteria (n = 15), the presence of AFP mRNA-positive cells in the peripheral blood correlated significantly with HCC recurrence (P = .033). We concluded that the presence of AFP mRNA-expressing cells could be a useful predictor of HCC recurrence in liver transplant patients.

Expression of PPARdelta in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology.

Whether peroxisome proliferator-activated receptor (PPAR) delta is a good target for the chemoprevention and/or treatment of colorectal cancer (CRC) remains controversial. Our goal was to examine PPARdelta expression in multistage carcinogenesis of the colorectum and to assess the relevance of PPARdelta in CRC. Immunohistochemical analysis indicated that PPARdelta expression increased from normal mucosa to adenomatous polyps to CRC. In cancer tissues, the PPARdelta protein was accumulated only in those cancer cells with highly malignant morphology, as represented by a large-sized nucleus, round-shaped nucleus, and presence of clear nucleoli. Interestingly, the cancer tissue often contained both PPARdelta-positive and -negative areas, each retaining their respective specific morphological features. Moreover, this pattern persisted even when PPARdelta-positive and -negative cells were aligned next to each other within a single cancer nest or gland and was present in the majority of CRC cases. Immunohistochemistry for Ki-67 proliferation marker showed no significant correlation between Ki-67 and PPARdelta in CRC samples. Based on Western blot analysis and quantitative RT-PCR, high PPARdelta protein expression correlated with high PPARdelta mRNA levels. Peroxisome proliferator-activated receptor delta may have a supporting role in tumorigenesis, and the close association between PPARdelta expression and malignant morphology of CRC cells suggests a pivotal role in cancer tissue.