Decreased 5-HT1A receptor binding in amygdala of schizophrenia.

BACKGROUND: On the basis of postmortem data and the pharmacological action of atypical antipsychotics, serotonin-1A receptors are of interest in the study of the pathophysiology of schizophrenia. To investigate serotonin-1A receptors in schizophrenia and their relation to symptoms, we measured the availability of serotonin-1A receptors in patients with schizophrenia using positron emission tomography with [carbonyl-(11)C]WAY-100635. METHODS: Serotonin-1A receptor binding of 11 patients with schizophrenia (8 drug-naive and 3 drug-free) was compared with that of 22 age-matched and gender-matched healthy control subjects. Symptoms were assessed using the Positive and Negative Syndrome Scale. Serotonin-1A receptor binding in selected regions of interest was quantified by binding potential obtained by the reference tissue method. RESULTS: The regional binding potential value was lower in the amygdala by about 19% in patients with schizophrenia than in normal controls. A significant negative correlation was observed between binding potential in the amygdala and the negative and depression/anxiety symptom scores on the five-symptom subscale of the Positive and Negative Syndrome Scale. CONCLUSIONS: Decreased serotonin-1A receptor binding in the amygdala may underlie the affective components included in the symptoms of negative and depression/anxiety in schizophrenia.     

Two cases of unusual acral melanocytic tumors: illustration of molecular cytogenetics as a diagnostic tool

The differential diagnosis between benign Spitz nevus and malignant melanoma may present considerable difficulties in some cases. Here we report 2 unusual melanocytic tumors with spitzoid features developing in acral sites of Japanese patients to illustrate the use of comparative genomic hybridization (CGH) to classify these lesions. Case 1 was a 12-mm-thick, >2 cm-diameter nodule on the sole of a 37-year-old man. Case 2 was a subungual tumor of the left index finger in a 13-year-old boy. CGH showed absence of chromosomal aberrations in case 1 and multiple aberrations in case 2, including focused amplification as previously described in acral melanomas. Case 1 was free of disease after 2.5 years of follow-up, whereas case 2 developed lymph node metastasis. We conclude that molecular techniques such as CGH can be of diagnostic help in the classification of histologically ambiguous lesions.     

Determinants of BRAF mutations in primary melanomas

The RAS/mitogen-activated protein kinase pathway sends external growth-promoting signals to the nucleus. BRAF, a critical serine/threonine kinase in this pathway, is frequently activated by somatic mutation in melanoma. Using a cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common in melanomas occurring on skin subject to intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, two-sided Fisher's exact test). By contrast, BRAF mutations in melanomas on chronically sun-damaged skin (1 of 12 patients) and melanomas on skin relatively or completely unexposed to sun, such as palms, soles, subungual sites (6 of 39 patients), and mucosal membranes (2 of 21 patients) are rare. We found no association of mutation status with clinical outcome or with the presence of an associated melanocytic nevus. The mutated BRAF allele was frequently found at an elevated copy number, implicating BRAF as one of the factors driving selection for the frequent copy number increases of chromosome 7q in melanoma. In summary, the uneven distribution of BRAF mutations strongly suggests distinct genetic pathways leading to melanoma. The high mutation frequency in melanomas arising on intermittently sun-exposed skin suggests a complex causative role of such exposure that mandates further evaluation.     

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes

The effect of chemotherapy on peritoneal carcinomatosis (PC) of gastric cancer remains unclear. Recently, the intraperitoneal (IP) administration of taxanes [e.g., paclitaxel (PTX) and docetaxel (DOC)] during the perioperative period has shown promising results. Herein, we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results. IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h. The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects, making it ideal for IP chemotherapy. There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy (SPIC). In SPIC, patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery (CRS) until disease progression. Usually, a taxane dissolved in 500-1000 mL of saline at ordinary temperature is administered through an IP access port on an outpatient basis. According to phase I studies, the recommended doses (RD) are as follows: IP DOC, 45-60 mg/m²; IP PTX [without intravenous (IV) PTX], 80 mg/m²; and IP PTX (with IV PTX), 20 mg/m². Phase II studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%. A phase III study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011. The prognosis of patients who underwent CRS was better than that of those who did not; however, this was partly due to selection bias. Although several phase II studies have shown promising results, a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.     

Ursodeoxycholic acid protects concanavalin A-induced mouse liver injury through inhibition of intrahepatic tumor necrosis factor-alpha and macrophage inflammatory protein-2 production

Ursodeoxycholic acid (UDCA) is widely used for the therapy of liver dysfunction. In this study, we investigated the protective effect of UDCA in concanavalin A-induced mouse liver injury. The treatment with UDCA at oral doses of 50 and 150 mg/kg at 2 h before concanavalin A injection significantly reduced the elevated plasma levels of aminotransferases and the incidence of liver necrosis compared with concanavalin A-injected control group without affecting the concentrations of liver hydrophobic bile acids. UDCA significantly inhibited elevated levels of tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and interleukin 6 (IL-6) in blood of concanavalin A-injected mice. To clarify the influence of UDCA on production of cytokines, we examined intrahepatic mRNA expressions and the protein levels of TNF-alpha, MIP-2, interferon-gamma (IFN-gamma), IL-4, IL-6, and IL-10 at 1 h after concanavalin A injection. The treatment with UDCA significantly decreased the intrahepatic levels of TNF- alpha and MIP-2, whereas this compound showed no clear effect on IFN-gamma, IL-4, IL-6, or IL-10. Furthermore, UDCA significantly decreased myeloperoxidase activity as well as MIP-2 level in the liver and histological examination of liver tissue revealed that intrasinusoidal accumulation of neutrophils was decreased markedly by UDCA. In addition, UDCA significantly inhibited the production of TNF-alpha and MIP-2 when cultured with nonparenchymal and lymph node cells. In conclusion, these findings suggest that UDCA protects concanavalin A-induced liver injury in mice by inhibiting intrahepatic productions of TNF-alpha and MIP-2, and the infiltration of neutrophils into the liver.     

Characteristics of a purified dog hepatic microsomal N, O-acyltransferase

Dog liver microsomes have at least three different enzymes thatare capable of the deacylation of amides, N-aryl-hydroxamicacids and carboxylesters, the acyltransfer of N-arylhydroxamicacids and the N-acetylation of arylamines. As judged by SDS-PAGEstained with silver nitrate, one of these enzymes was purifiedto homogeneity by sequential treatment with Triton X-100, ion-exchangecolumn chromatography, gel filtration and chromatofocusing.The protein was a glycoprotein trimer with a subunit weightof 60 kDa. It showed microheterogeneity on analytical isoelectricfocusing (IEF) in polyacrylamide with pls of 5.4–5.6.Following digestion with endoglycosidase H, its subunit weightwas reduced to 58 kDa, and it appeared to be homogeneous onIEF with a pl of 5.6. A monoclonal antibody prepared againstthis enzyme also reacted with the pl 6.0 carboxyl-esterase ofrat liver microsomes, but did not react with the other two doghepatic acyltransferases. Conversely, a polyclonal antibodyraised against the rat esterase reacted with the dog enzyme.The N-terminal sequence of the enzyme was Y-P-S-L-P-P-V-V-D-T-V-Q-G-K-V-,which was homologous to the form 1 carboxylesterase of rabbitliver and the pl 6.0 carboxylesterase of rat liver. Immunohistochemicalanalyses showed the presence of this enzyme in the epitheliumof dog liver and urinary bladder, human liver and rat liver,esophagus, forestomach, glandular stomach, small and Large intestines,renal tubules, trachea and prostate and alveolar cells of lung.Since this enzyme is present in the urothelium, it may be importantfor the activation of urinary metabolites of carcinogenic arylaminesfor the initiation of bladder carcinogenesis in the dog.     

Oncological benefit of lateral pelvic lymph node dissection for rectal cancer treated without preoperative chemoradiotherapy: a multicenter retrospective study using propensity score analysis

Purpose

We aimed to clarify the prognostic impact of lateral pelvic lymph node (LPN) dissection (LPND) for rectal cancer through a multicenter retrospective study using propensity score analysis.

Methods

A total of 1238 patients with pathological T2-4, M0 rectal cancer who had undergone curative operation between 2007 and 2008 were examined. Majority of the patients (96 %) were treated without preoperative chemoradiotherapy (CRT). Clinical background data of the patients treated with LPND and those treated without LPND were matched using propensity scores, and hazard ratios (HRs) for cancer-specific mortality were compared.

Results

LPND was performed more frequently for lower rectal cancers and in patients with more advanced disease, and 29 % of the patients were treated with LPND. After matching background features by propensity scores, LPND did not correlate with improved cancer-specific survival (CSS) among the entire study population [HR, 0.73; 95 % confidence interval (CI) 0.41–1.31; P?=?0.28]; however, LPND was correlated with significantly improved CSS in female patients (HR, 0.23; 95 % CI, 0.06–0.89; P?=?0.04) but not in male patients (HR, 0.95; 95 % CI, 0.48–1.89; P?=?0.89). The results were similar when patients treated with LPND finally diagnosed as pathologically negative for LPN metastasis were compared with those curatively treated without LPND.

Conclusions

It is suggested that the prognostic impact of LPND for rectal cancer treated without CRT might be different between sexes, and LPND should be considered for female rectal cancer patients although they are diagnosed as clinically negative for LPN metastasis.