Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition.

Onset of the mitochondrial permeability transition (MPT) causes both necrotic and apoptotic cell death in cultured hepatocytes. Salicylate lowers the threshold for onset of the MPT. In this study, our aim was to determine whether nontoxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and tert-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2 microM), a specific inhibitor of the MPT. In hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), salicylate accelerated cell killing after low-dose TNF-alpha (1 ng/ml), which by itself induced little apoptosis. Salicylate enhancement of apoptosis was associated with onset of the MPT and accelerated caspase 3 activation. Salicylate also augmented killing of MCF-7 human breast tumor cells by etoposide and PLC/PRF/5 human hepatoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, salicylate potentiates both necrotic and apoptotic cell killing by promoting onset of the MPT. Enhancement by salicylate of MPT-dependent apoptosis may play a role in protection by aspirin and other nonsteroidal anti-inflammatory drugs against colon, lung, and breast cancer.     

Dural repair using acellular human dermis: experience with 200 cases: technique assessment

OBJECTIVE: Many craniotomies require a watertight dural closure. When primary dural repair is not possible, a graft is necessary. Autograft material is not always easily accessible or available, necessitating the use of other material. We performed 200 craniotomies using an acellular human dermal graft (AlloDerm; LifeCell Corp., The Woodlands, TX) to determine its suitability as a dural substitute. METHODS: From June 1996 through March 1998, all patients at Allegheny General Hospital who required a dural substitute graft and in whom autograft harvest was impractical or impossible received the acellular dermal autograft. The running suture technique was used to form a watertight seal. RESULTS: After follow-up for a minimum of 1 year, seven patients have required subsequent surgery. Three patients developed cerebrospinal fluid leaks that were repaired without removing the dermal graft. Four patients developed wound infections that required debridement. In each patient, the graft seemed to be uninvolved in the infectious process and was left in place. The patients were administered antibiotics postoperatively, and there have been no recurrent infections. No adhesion formation or scarring was noted around or underneath the graft in any patient. CONCLUSION: AlloDerm is a reasonable alternative to the available dural graft materials. Its handling characteristics are similar to those of dura, it is biologically inert, and it does not produce adhesion formation.     

A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer.

PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m(2)/day. Dose escalation up to 60 mg/m(2)/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent. RESULTS: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident. CONCLUSIONS: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.     

Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal cancer.

BACKGROUND: Since 1990, we have treated patients with advanced nasopharyngeal cancer with induction chemotherapy and concomitant chemoradiotherapy. We herein report the results of our experience. PATIENTS AND METHODS: From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated with induction chemotherapy followed by concomitant chemoradiotherapy. Using the American Joint Committee on Cancer's 1992 stage classification, all patients were stage III (11%) or IV (89%). By histology, 63% were poorly differentiated carcinoma and 37% squamous cell carcinoma. The median age was 42 years. Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin and interferon-alpha2b were administered, followed by concomitant chemoradiotherapy consisting of seven cycles of 5-fluorouracil, hydroxyurea and once-daily radiotherapy (FHX) on a week-on week-off schedule. The median radiotherapy dose was 70 Gy. RESULTS: Clinical response to induction chemotherapy was 100%, 54.2% complete response (CR) and 45.8% partial response. Clinical and/or pathological (37% of all patients had post-treatment biopsy with or without neck dissection) CR after FHX was 100%. At a median follow-up of 52 months, three failures were observed. Two patients have died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis. At 5 years, actuarial locoregional control is 93% and actuarial distant control 92%. The overall survival at 3 and 5 years is 88% and 77%, respectively. Four patients died of unrelated illnesses and had no evidence of disease with respect to their nasopharyngeal cancer. The progression-free survival at 3 and 5 years is 92% and 86%, respectively. Thirty-three per cent of patients required a reduction in the chemotherapy dose due to acute toxicity. Chronic toxicity was not observed, with all patients able to eat orally without dietary restrictions. CONCLUSIONS: Treatment of locoregionally advanced nasopharyngeal cancer with induction chemotherapy followed by concomitant chemoradiotherapy resulted in excellent overall survival with acceptable toxicity. These results are encouraging and warrant further investigation of intensified approaches.     

cAMP-induced stellation in primary astrocyte cultures with regional heterogeneity

It is well known that increased cAMP levels in cultured astrocytes can convert flat polygonal shaped astrocytes into process-bearing, stellate astrocytes. In this study, we have examined the possible existence of astrocyte regional heterogeneity in morphological changes in response to cAMP stimulation. Primary astrocyte cultures were prepared from six different regions of neonatal rat brains, including cerebral cortex, hippocampus, brain stem, mid brain, cerebellum, and hypothalamus. After about 2 weeks in culture, the astrocyte culture medium was changed to DMEM containing various concentrations of 8-CPT-cAMP, a membrane permeable cAMP analog, for 2 h. We found that 250 microM 8-CPT-cAMP produced a maximum effect causing >95% stellation in all regional astrocytes except hypothalamic astrocytes (56% stellation). At lower cAMP concentrations, cell stellation most effectively occurred in cerebellar astrocytes. To examine further the regional heterogeneity of astrocyte morphological changes, glutamate was added together with 8-CPT-cAMP to block cAMP-induced astrocyte stellation. Interestingly, glutamate blockage on cAMP-induced astrocyte stellation was brain region-specific in that cerebral and hippocampal astrocytes were effectively blocked by glutamate when compared to other regional astrocytes. Furthermore, glutamate inhibited isoproterenol-induced astrocyte stellation in a region-specific manner similarly as in cAMP-induced stellation. The present study demonstrates that astrocytes derived from different regions of the neonatal rat brain maintain different levels of morphological plasticity in culture.     

Frequent genotype changes at -308, and 488 regions of the tumor necrosis factor-alpha (TNF-alpha) gene in patients with prostate cancer

PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is involved in oncogenesis of several cancers. The purpose of this study was to investigate whether genotype changes of TNF-alpha promoter regions (-238, -308) and at the 488 region are associated with human prostate cancer. MATERIALS AND METHODS: The DNA from 73 cases of human prostate cancer was analyzed by allele-specific polymerase chain reaction to characterize the genotype changes of three regions of the TNF-alpha gene in prostate cancer patients. We also determined the genotype frequency in these patients. The relative risk of variant genotype was calculated by comparing with our previous data from healthy controls. RESULTS: Genetic changes were detected in 15.1% (11/73) of prostate cancer samples at 488 region of TNF-alpha. Seventy-three percent (53/73) of the patients showed genotype GA at -308 region of TNF-alpha. Genotype GA at 488 region in TNF-alpha was observed in 73% (53/73) of the cancer and 71% (52/73) of the normal tissue. The relative risks of incidence for prostate cancer was 14-fold higher in people with genotype GA at -308 region of TNF-alpha. The relative incidence for prostate cancer was a 17-fold higher in-patient with genotype GA at 488 region of TNF-alpha. Genotype GA at -308 of TNF-alpha was related to higher clinical tumor stage of prostate cancer than genotype G (p <0.05). CONCLUSIONS: The present study demonstrates, for the first time, that the genotype changes in -308 and 488 regions of TNF-alpha are associated with prostate cancer.     

Bilateral eventration of the diaphragm with perforated gastric volvulus in an adolescent

Bilateral congenital eventration of the diaphragm almost uniformly presents in infancy with respiratory compromise and is associated with a high mortality rate. Delayed presentation of diaphragmatic eventration in older children and adults may be associated with acute gastric volvulus. Thus, any patient with abdominal pain, vomiting, or nonspecific gastrointestinal symptoms in association with abnormal diaphragmatic findings on chest x-ray should undergo further diagnostic workup with upper gastrointestinal series or computed tomography (CT) scan. Treatment of gastric volvulus requires immediate surgical repair to prevent subsequent necrosis and perforation. The authors describe a case report of bilateral congenital diaphragmatic eventration complicated by a perforated gastric volvulus in a 13-year-old boy. Emergent reduction of the volvulus, closure of the perforated stomach, plication of the diaphragm, and placement of gastrostomy was performed successfully.     

Tailgut cyst in a neonate

Tailgut cyst is a rare lesion of developmental origin located in the retrorectal space, which usually presents as a multilocular cystic mass. It is usually found in adults, and neonatal cases are extremely rare. The authors report a tailgut cyst in a neonate that was found by prenatal ultrasonogram, which was like a teratoma in gross appearance.