Biomedical subjects
Publications and source records attributed to R Ravi.
Explore the source record for details and available documents.
OBJECTIVE: To review our experience in management of residual masses after chemotherapy for metastatic seminoma. PATIENTS AND METHODS: The study comprised a review of 107 patients with metastatic seminoma, treated with initial chemotherapy from 1978 to 1996. Forty-three patients had residual masses detected by computed tomography after chemotherapy, while 64 achieved a complete response. Residual masses were classified radiologically as <3 cm or >/=3 cm and as well- or poorly defined. Of the patients with residual masses, 19 underwent surgery, while 24 were observed. RESULTS: Viable cancer was present in six of 11 patients with well-defined residual masses of >/=3 cm (positive histology in three of six undergoing surgery and site relapses in three of five observed), one of 14 patients with poorly defined masses of >/=3 cm (negative histology in nine undergoing surgery and site relapse in one of five observed), and in none of 17 patients with residual masses of <3 cm (negative histology in four undergoing surgery and no site relapses in 13 observed; one additional patient in this group died from treatment complications). CONCLUSION: Patients with a complete response after chemotherapy, a residual mass of <3 cm and a poorly defined residual mass of >/=3 cm can be observed, reserving intervention for recurrent or progressive disease. Well-defined residual masses of >/=3 cm should be resected because there is a 55% likelihood of persistent tumour.
The p53 tumor suppressor gene plays an instrumental role in transcriptional regulation of target genes involved in cellular stress responses. p53-dependent transactivation and transrepression require its interaction with p300/CBP, a coactivator that also interacts with the RelA subunit of nuclear factor-kappaB. We find that p53 inhibits RelA-dependent transactivation without altering RelA expression or inducible kappaB-DNA binding. p53-mediated repression of RelA is relieved by p300 overexpression and the increased RelA activity conferred by p53-deficiency is counteracted by either transactivation domain-deficient p300 fragments that bind RelA or a transdominant mutant of IkappaB alpha. Our results suggest that p53 can regulate diverse kappaB-dependent cellular responses.
Activation of the nuclear factor (NF)-kappaB transcription factor is instrumental for the immune response and the survival of peripheral activated T cells. We demonstrate that ligation of CD95 (Fas/APO1), a potent apoptotic stimulus in lymphocytes, results in repression of NF-kappaB activity in Jurkat T cells by inducing the proteolytic cleavage of NF-kappaB p65 (Rel A) and p50. Inhibition of caspase-3-related proteases by a specific acetylated aldehyde (Ac-DEVD-CHO) prevented CD95-induced cleavage of p65 (RelA) or p50 and restored the inducibility of NF-kappaB in cells treated with an antibody against CD95. The addition of recombinant caspase-3 also resulted in proteolytic cleavage of RelA p65 and p50 in vitro. TNF-alpha treatment, unlike CD95 ligation, did not result in the death of Jurkat cells but did so in the presence of I kappaB alphaM, a transdominant inhibitor of NF-kappaB. These results suggest that intact, functional NF-kappaB maintains the survival of activated T cells, and that CD95-induced cleavage of NF-kappaB subunits sensitizes T cells to apoptosis and, hence, facilitates the decay of an immune response.
OBJECTIVE: To review our experience of surgical staging for residual masses after chemotherapy in patients with nonseminomatous germ cell tumour (NSGCT) and positive tumour markers. PATIENTS AND METHODS: Of 107 patients with metastatic NSGCTs treated surgically after chemotherapy from 1978 to 1995, 30 (median age 30.5 years, range 20-52) had positive tumour markers. These patients were reviewed and the outcome compared with 77 patients who had normal tumour marker values. RESULTS: Of the 77 patients with negative markers undergoing surgical/pathological staging, 71 (92%) became continuously disease-free, including 37 of 50 (74%) with viable NSGCT in excised specimens. Seventeen of 30 (57%) with raised marker levels undergoing similar surgery for chemotherapy-resistant tumour became disease-free, including 11 of 22 with viable NSGCT in the excised specimens. CONCLUSION: Although the outcome after surgery is better in patients with negative tumour markers, it is clear that surgery is curative for patients with localized chemotherapy-resistant masses. There is a need for continued debate on the timing of salvage surgery and subsequent chemotherapy.
Caspases are a family of cysteine proteases implicated in the biochemical and morphological changes that occur during apoptosis (programmed cell death). The loop domain of Bcl-2 is cleaved at Asp34 by caspase-3 (CPP32) in vitro, in cells overexpressing caspase-3, and after induction of apoptosis by Fas ligation and interleukin-3 withdrawal. The carboxyl-terminal Bcl-2 cleavage product triggered cell death and accelerated Sindbis virus-induced apoptosis, which was dependent on the BH3 homology and transmembrane domains of Bcl-2. Inhibitor studies indicated that cleavage of Bcl-2 may further activate downstream caspases and contribute to amplification of the caspase cascade. Cleavage-resistant mutants of Bcl-2 had increased protection from interleukin-3 withdrawal and Sindbis virus-induced apoptosis. Thus, cleavage of Bcl-2 by caspases may ensure the inevitability of cell death.
OBJECTIVE: To review the impact of surgical staging after treatment on the late malignant events in an unselected group of patients treated with chemotherapy for germ cell cancer of the testis over the last 16 years. PATIENTS AND METHODS: The study comprised 256 patients treated between 1978 and 1994 who were reviewed for late relapse and development of second germ cell and non-germ cell cancer. RESULTS: At diagnosis, 142 patients had clinical stage 2, 30 stage 3 and 84 stage 4 disease; 57 patients relapsed within 20 months of treatment, while late germ-cell cancer relapses (> or = 24 months after treatment) occurred in six patients. Of patients relapsing early or late, 42% and 33%, respectively, received surgery after treatment. Only two of those relapsing late remain progression-free with further treatment. Four patients developed germ cell cancer in the contralateral testis, while six developed second non-germ cell cancers. CONCLUSION: Late events occurred in 6.2% of 256 patients in this series, from 29 to 141 months after treatment. Given that the late relapse rate of six of 256 (2.3%) is less than the incidence of mature teratoma at routine retroperitoneal lymph node dissection, more patients may eventually relapse. These results suggest that there might be a case to evaluate the use of ultrasonographic surveillance of the retroperitoneum and testis at 5, 10 and 20 years, in addition to extending routine surveillance.
We found that a single 600 mg/kg subcutaneous dose of the chelating agent diethyldithiocarbamate (DDTC) in rats caused severe damage of the olfactory epithelium. Damage was characterized by degeneration of the receptor cells but sparing of basal cells. This degeneration was characterized centrally (in the olfactory bulb) by 50% shrinkage of glomeruli. Reactive gliosis, as judged by immunoreactivity for glial fibrillary acidic protein, was prominent in the glomeruli at one week. Glomeruli areas had recovered to control values and gliosis in glomeruli had decreased by five weeks after injection. This recovery corresponds to sparing of the regenerative cell of the olfactory epithelium. We hypothesized that DDTC may act by disrupting xenobiotic metabolic pathways requiring divalent cations.
The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.
Continuous ambulatory peritoneal dialysis (CAPD) was used as renal replacement therapy in 55 patients for 666 patient months. Thirty five patients had Type II diabetes. They ranged in age from 1-83 years. Majority of the patients were above 50 years of age who could not be transplanted due to various comorbid conditions. The incidence of peritonitis was 1 episode every 20 patient months. Twenty five patients dropped out during the observation period. The major cause of drop-out was death due to underlying coronary artery disease. Three patients underwent renal transplantation.
This investigation was undertaken to explain the possible, mechanism(s) of protection by diethyldithiocarbamate (DDTC) against cisplatin ototoxicity. Male Wistar rats (250-275 g) underwent pretreatment auditory brain stem-evoked responses (ABRs). The different groups of rats were injected as follows: (1) cisplatin (16 mg/kg i.p.), (2) cisplatin plus DDTC (16 mg/kg i.p. + 600 mg/kg, s.c.), and (3) control rats. Post-treatment ABRs were performed after 3 days and the rats were euthanized and cochleae were harvested. The cochleae were analyzed for glutathione (GSH) and oxidized glutathione, by HPLC, and for the activities of the antioxidant enzymes, and malondialdehyde levels, by spectrophotometry. The cisplatin-injected rats showed a threshold elevation of 36 +/- 3.05 dB above the pretreatment thresholds using click stimulus. Rats treated with cisplatin and then DDTC did not show a significant elevation of hearing threshold. DDTC-mediated protection was associated with higher levels of GSH (0.81 +/- 0.11 nmol/mg tissue), compared to 0.45 +/- 0.02 nmol/mg tissue following administration of cisplatin alone. Administration of cisplatin + DDTC restored the cochlear GSH-Px activity to control level. Cisplatin-treated rats were found to have decreased GSH-Px activity (75% of control). Cochlear SOD and CAT activities and MDA levels showed a decreasing trend in the animals injected with cisplatin + DDTC, compared to cisplatin-alone-treated rats. These data suggest that the protection conferred by DDTC against cisplatin ototoxicity is associated with sparing of the cochlear GSH/GSH-Px.
BACKGROUND: Meningiomas are generally solid tumors and are easily diagnosed by CT scans and MRI scans. Rarely are these tumors associated with cysts that can cause a confusion in the pre- and intraoperative diagnosis. Cysts associated with meningiomas may be intratumoral or peritumoral. METHODS: The authors conducted a retrospective study of the seventeen meningiomas, out of a total number of 232, which were associated with cysts. The cysts were classified based on their relationship to the tumor. The patients' sex, age group, location of the tumor, and pathological type of tumor were also analyzed. RESULTS: The 17 cases of cystic meningioma formed 7.3% of the meningiomas seen between 1984 and 1993. Eleven of these were intratumoral and 6 peritumoral. One case had both intra- and peritumoral cysts. The tumors were found mostly in the fourth and fifth decades of life. Histologically, all the peritumoral cysts except one were associated with meningotheliomatous meningiomas. Tumors with peritumoral cysts were more common in males. Intratumoral cysts, more common in females, were angioblastic or meningotheliomatous on histopathology. Only one case was an anaplastic meningioma. CONCLUSION: Cysts associated with meningiomas, although uncommon, are certainly not rare. The peritumoral and the intratumoral cysts form distinct subtypes needing separate consideration. Cystic meningiomas are only rarely malignant.
The purpose of this investigation was to determine whether any alterations in antioxidant enzyme activities and levels of glutathione (GSH) in brain regions occurred following exercise training. Sprague-Dawley rats were given exercise training on a treadmill for 7.5 weeks and sacrificed 18 h after the last exercise along with the sedentary control rats. Different brain regions-cerebral cortex (CC), brainstem (BS), corpus striatum (CS), and hippocampus (H)-were isolated; GSH, oxidized glutathione (GSSG), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined. The exercise training increased SOD activity significantly (130% of sedentary control) in BS and in CS. SOD activity in H was the lowest of all four brain regions. Different brain regions showed GSH-Px activity in decreasing order for CS < BS < CC < H. GSH levels were 43% less in BS than CC and CS. The ratio of GSH/GSSG significantly increased from 6.8 to 8.3 in CC, and from 9.4 to 13.5 in BS as a result of exercise training. Different brain regions contained different activities of antioxidant enzymes, as well as GSH and GSSG levels, which were preferentially altered as a result of exercise training to cope with oxidative stress.
Explore the source record for details and available documents.
OBJECTIVE: To study the role of tobacco in squamous cell carcinoma of the penis. SUBJECTS AND METHODS: The use of tobacco in the form of cigarettes, chewing tobacco and snuff was studied in a total of 503 patients and age-matched controls. RESULTS: By multivariate analysis, a significant association was found between smoking (P = 0.002) or chewing tobacco (P < 0.001) and the use of snuff (P = 0.004) in patients with penile carcinoma as compared with controls. A dose-response relationship was observed for both smoking and chewing. CONCLUSIONS: The use of tobacco is a significant risk factor for penile carcinoma, and the use of more than one form of tobacco increases this risk.
The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post-treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats were sacrificed and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45 +/- 0.012 nmol/mg] after cisplatin administration compared to 0.95-012 nmol/mg in control cochleae (P < 0.05). Superoxide dismutase, catalase activities and malondialdehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Five patients with a second penile cancer following irradiation of a primary squamous cell carcinoma of the penis were treated at our cancer. The first cancers had completely regressed within 4 months of irradiation. The second cancers developed in the radiation field at a mean latent period of 158 months (range 124-242). Further, all patients had experienced early radiation reaction and showed late radiation stigmata, pointing to the possible radiation-induced nature of the second cancer. Although all cancers were squamous cell carcinomas, the second cancers were uniformly invasive and of a higher grade than the first. Radiation-induced second cancers, although rare, should be considered a late complication of primary irradiation of squamous cell carcinoma of the penis.
Four patients with advanced testicular seminoma and > or = 3 cm postchemotherapy residual retroperitoneal masses underwent retroperitoneal lymph node dissection (RPLND) followed by intraoperative irradiation (IORT) to a dose of 20 Gy. The RPLND was incomplete in all cases and hence all patients received IORT. Two patients showed viable carcinoma in the resected specimen and were administered additional chemotherapy. There were no complications of IORT (bowel, ureteric, haematologic, neurogenic). All patients are alive and disease-free at a mean follow-up period of 19 months (range 10-26). IORT is an attractive treatment alternative in this situation. Further, this approach also identifies patients with viable carcinoma, who are candidates for additional chemotherapy.