Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?

Apoptosis is an essential physiological process for the selective elimination of cells, which is involved in a variety of biological events. The Bcl-2 family is the best characterized protein family involved in the regulation of apoptotic cell death, consisting of anti-apoptotic and pro-apoptotic members. The anti-apoptotic members of this family, such as Bcl-2 and Bcl-x_L, prevent apoptosis either by sequestering proforms of death-driving cysteine proteases called caspases (a complex called the apoptosome) or by preventing the release of mitochondrial apoptogenic factors such as cytochrome c and AIF (apoptosis-inducing factor) into the cytoplasm. After entering the cytoplasm, cytochrome c and AIF directly activate caspases that cleave a set of cellular proteins to cause apoptotic changes. In contrast, pro-apoptotic members of this family, such as Bax and Bak, trigger the release of caspases from death antagonists via heterodimerization and also by inducing the release of mitochondrial apoptogenic factors into the cytoplasm via acting on mitochondrial permeability transition pore, thereby leading to caspase activation. Thus, the Bcl-2 family of proteins acts as a critical life–death decision point within the common pathway of apoptosis.     

PRIMARY MALIGNANT FIBROUS HISTIOCYTOMA OF THE ENDOMETRIUM

Malignant fibrous histiocytoma (MFH) has become one of the most common malignancies occurring in soft tissue. To our knowledge, the present case is the first of MFH occurring in the endometrium. The uterus removed from a 47-year-old woman demonstrated a large multinodular endometrial lesion with gross invasive foci in the myometrium and the left oviduct. Microscopically, the endometrial tumor and the invasive lesions were composed of dense sheets of markedly pleomorphic cells consisting of fibroblast-like cells, histiocyte-like cells, foamy histiocytes, benign appearing multinucleated giant cells resembling either osteoclasts or Touton giant cells, and bizarre tumor giant cells. Some of the tumor cells showed phagocytic activities. The tumor cells were oriented in a random or haphazard fashion and classical storiform and fascicular patterns were not observed. The tumor was diagnosed as MFH consisting exclusively of so-called pleomorphic pattern. The patient is alive without evidence of disease, months following total hysterectomy and bilateral salpingo-oophorectomy.     

Primary malignant fibrous histiocytoma of the ascending colon: Report of a case

We report herein an unusual case of primary malignant fibrous histiocytoma (MFH) of the ascending colon. A 47-year-old man was admitted to our hospital for further investigations following the discovery of a mass in the right lower quadrant of the abdomen during a medical checkup. Abdominal ultrasonography (US) and computed tomography (CT) demonstrated a mass extending to the right lateral side from the ascending colon. At laparotomy, a tumor was found originating in the ascending colon and infiltrating the right lateral peritoneum. A right hemicolectomy and partial peritoneal dissection were performed followed by an ileotransverse colostomy reconstruction. The resected specimen contained a tumor measuring 7×5×4 cm, the cut surface of which was yellowish white, and the mucosa of the colon was intact. Based on histological and immunohistochemical inspection, the tumor was diagnosed as MFH of the ascending colon. We reviewed the total 18 known cases of colorectal MFH documented in the literature including our case. After surgery, 4 of 17 patients died of local recurrence, all within 42 months, indicating that early and complete excision of tumor is essential to achieve cure.     

Effects of antihistamines,ebastine and terfenadine,on electrocardiogram in conscious dogs and cats

The purpose of this study was to evaluate the effects of ebastine and terfenadine on the electrocardiogram of conscious dogs and cats. In dogs, terfenadine at oral doses of 30 mg/kg twice a day for 7 days prolonged the electrocardiographic QT interval and the corrected QT (QTc) interval on the seventh day, whereas the drug did not affect these parameters on the first day. Plasma concentrations of terfenadine and its active metabolite, fexofenadine, reached 306 and 8,541 ng/mL, respectively, on the seventh day. Ebastine at oral doses of 30 and 100 mg/kg once a day for 7 days was without effect on the QT and QTc intervals, whereas the drug slightly shortened the RR interval. On the seventh day following the dose of 100 mg/kg, plasma concentrations of ebastine and its active metabolite, carebastine, reached 36 and 1,939 ng/mL, respectively. In conscious cats, terfenadine at oral doses of 30 mg/kg twice a day for 7 days prolonged the QT and QTc intervals, QRS duration, JT and the corrected JT intervals. Unexpectedly, terfenadine induced ventricular tachyarrhythmia and premature beats. On the other hand, ebastine at oral doses of 100 mg/kg once a day for 7 days was without effect on the electrocardiographic parameters in cats. These results suggest that the electrocardiographic changes indicative of the proarrhythmic potential of terfenadine can be evaluated in conscious dogs and especially in conscious cats by repeated oral administration, and that ebastine does not induce such changes. 58:209–217, 2003. © 2003 Wiley‐Liss, Inc.     

Factors that influence the eligibility of cases for inclusion in clinical trials. The Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group

BACKGROUND: It is important to minimize the incidence of ineligible cases to improve the quality of clinical trials. To determine factors which may influence the incidence of ineligible cases, the incidence of and reasons for ineligibility in clinical trials were retrospectively analyzed. METHODS: We retrospectively examined the incidence of and reasons for ineligibility for inclusion in eight clinical trials conducted by the Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group and four trials financed by trust funds from a pharmaceutical company. RESULTS: In these 12 clinical studies, the incidence of ineligibility was 4.2% (32/762) (range 0-10.6%). Specific factors that might influence the incidence of ineligible cases were then analyzed. There was a significant difference in the incidence of ineligibility between the methods of registration (P < 0.05). The incidences using a central registration and without using a central registration system were 2.8% (9/322) and 5.2% (23/440) respectively. We also analyzed ineligible cases in clinical studies published in the Journal of Clinical Oncology. In clinical studies published in the Journal of Clinical Oncology recently and 10 years ago, the incidences of ineligible cases were 5.0% (942/18 878) and 4.1% (206/4995) respectively. In clinical studies on lung cancer published in the Journal of Clinical Oncology from 1984 to 1995, the incidence of ineligible cases was 4.7% (900/19,116). There was no significant difference in the incidence of ineligible cases between our 12 studies and the Journal of Clinical Oncology clinical studies by the chi 2 test (P > 0.05). CONCLUSIONS: We conclude that the incidence of ineligible cases in our studies is similar to that in clinical trials published in the Journal of Clinical Oncology. Central registration systems are useful for checking for ineligibility, and to increase the quality of clinical trials.      

Spontaneous closure of ventricular septal defects followed up from <3 months of age

BACKGROUND: This study evaluates the incidence and timing of spontaneous closure (SC) of ventricular septal defect (VSD) using Doppler color flow mapping. METHODS: A total of 225 infants (mean age 30 days) were diagnosed with uncomplicated VSD: 31 (14%) subpulmonary VSD, 159 (70%) perimembranous, and 35 (16%) muscular. The patients were divided into two groups according to the presence or absence of congestive heart failure (CHF). SC was confirmed with color Doppler. RESULTS: Surgical closure was performed in 59 patients (26%). SC occurred in 107 patients (48%); three (10%) of 31 with subpulmonary VSD, 75 (47%) of 159 with perimembranous VSD, and 29 (83%) of 35 with a muscular VSD. Average age at SC was 19 months. In three SC patients with a subpulmonary VSD, there was no aortic valve prolapse and no aortic regurgitation. SC occurred in 96% of SC patients with a perimembranous VSD by the age of 6 years, and in 93% of those with a muscular VSD by the age of 3 years. In patients without CHF, the rate of SC was 72%; 23% in subpulmonary VSD, 74% in perimembranous, and 85% in muscular. SC occurred in only 23% of patients with a perimembranous VSD with CHF. Mean age at the final examination was 6.9 years in 59 patients with a VSD remaining open, and 63% of patients with a perimembranous VSD remaining open had an aneurysm of the ventricular membranous septum. CONCLUSIONS: The SC rate of VSD by mean age of 6.9 years was 48%, but it was 72% in patients without CHF. In patients with CHF, SC was seen only in patients with a perimembranous VSD. The rate of SC was 10% in subpulmonary VSD. The authors contend that SC probably occurred by growth of muscular septum surrounding VSD. Muscular VSD spontaneously closed earlier than perimembranous VSD.     

Safety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance

Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.