Clinical Efficacy of the GnRH Agonist (Deslorelin) in Dogs Affected by Benign Prostatic Hyperplasia and Evaluation of Prostatic Blood Flow by Doppler Ultrasound.

In six German Shepherds dogs, GnRH agonist implants (Deslorelin) were inserted subcutaneously one month after histological confirmation of benign prostatic hyperplasia (BPH). Prostatic volume (PV), characteristics of ejaculate, serum testosterone concentrations and Doppler parameters of prostatic and subcapsular arteries were detected at different time intervals, for 6 month. The prostatic volume showed a significantly reduction starting at day 37. The decrease in sperm concentration, motility and increase in morphological abnormal sperm were observed from day 22 to day 37, when it was no longer possible to obtain the ejaculate. The values of peak systolic velocity and end-diastolic velocity in prostatic and subcapsular arteries showed from day 11 a gradual decrease, significant at day 22 until day 37 and reaching the lowest values at day 52 until the end of observation. The power Doppler pixel intensity of both arteries showed a gradual decrease from day 5 until day 52. In particular, a significant decrease was observed for both arteries from day 11. Testosterone serum concentration decreased to undetectable levels by day 11 until the end of the observations. All these Doppler parameters and testosterone values were positively correlated with the prostatic volume. Furthermore, testosterone values were positively correlated with peak systolic velocity, end diastolic velocity and pixel numbers. The use of implants containing GnRH analogues, even in asymptomatic subjects, is effective for the control of BPH and the application of Doppler exam of prostatic blood flow represent an non-invasive tool for monitoring the response of medical treatment

Clinical pharmacokinetics and metabolism of irinotecan (CPT-11)

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent

Molecular medicine of inherited arrhythmias

科学研究費補助金研究成果報告書研究種目: 基盤研究(B)研究期間: 2002～2003課題番号: 14370225研究代表者: 堀江 稔（滋賀医科大学・医学部・教授

Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation

Background Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. Methods The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. Results Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. Conclusion EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment

Invasive Micropapillary Breast Carcinoma

Invasive micropapillary morphology is associated with clinically meaningful staging and outcome implications in patients with breast cancer. The characteristic micropapillary morphology is seen focally in the tumor in most cases. In contrast to other special subtypes of breast cancer, any proportion of invasive micropapillary growth confers to the tumor a “special” aggressive behaviour characterised by lymphovascular invasion, high propensity for lymph node metastases and high stage at presentation. At the molecular and immunohistochemical level, tumors with mixed invasive micropapillary and invasive carcinoma NST display striking similarities to those with pure invasive micropapillary carcinomas. Moreover, these tumors are classified in most cases in the category of luminal B molecular subtype. Invasive micropapillary carcinoma has been described in other organ systems, although less frequently as in breast. In the urinary tract, gastrointestinal tract, lungs and salivary glands, this tumor pattern is in general admixed with a more conventional tumor growth pattern, and same as in breast, presents as a locally advanced disease and is associated with an aggressive behaviour. To date there are few molecular studies performed on IMPCa of the breast. None of them shows characteristic genetic alteration that could explain the special morphology of the tumor or its aggressive course. In other terms, IMPCa is not defined by highly recurrent specific mutations or fusion genes. In few cases reported in the literature as well as in the study that we presented, hotspot point mutations of the PIK3CA gene, and the TP53 gene were identified however at a rate similar to that seen in invasive breast carcinoma NST. In addition we saw in one of our IMPCa cases a MET-T1010I germline mutation, which is usually very rare in breast cancer, occurring in 2% of patients with metastatic breast carcinoma. Because of the therapeutic consequences (with MET inhibitors) we suggest a more extensive testing of the MET gene in this aggressive type of breast cancer