CHOP versus intensive regimens in non-Hodgkin's lymphoma.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
R C Young
Publications and source records attributed to R C Young.
Geriatric depression: age of onset and dementia.
Age of depression onset was studied in 183 consecutively hospitalized elderly patients with major depression. Patients with both depression and dementia had onset of depression at a significantly later age than patients with depression alone. Depressives with reversible dementia had age of onset comparable to that of depressives with irreversible dementia. These findings suggest that late-onset depression is a heterogeneous syndrome and includes a considerable number of patients who develop depression as part of a dementing illness.
Age Factors↗
Mechanisms and modulation of resistance to chemotherapy in ovarian cancer.
Chemotherapy for advanced ovarian cancer remains suboptimal. Despite the improvements in objective response rates realized with cisplatin-based combination chemotherapeutic regimens, most patients still die of refractory cancer. Drug resistance has emerged as the single most important determinant of treatment outcome. Laboratory studies have provided substantial insights into the cellular mechanisms of resistance to the commonly used chemotherapeutic agents. Decreased drug accumulation, metabolic drug inactivation, and repair or tolerance to drug-induced cellular injury all contribute to resistance at the cellular level. Identification of these mechanisms has facilitated the development of specific treatment strategies, many of which are in or nearing clinical trials. These strategies include dose intensification, inhibition of P-glycoprotein function, inhibition of cellular glutathione synthesis, and inhibition of cellular DNA repair. The initial results from clinical trials that use these strategies provide reasonable grounds for optimism. In addition, efforts to identify new drugs with activity against resistant cells continue. One such drug, taxol, has significant activity in tumors refractory to conventional therapy. These approaches offer hope that intensive laboratory and clinical efforts ultimately will translate into real improvements in the efficacy of chemotherapy for ovarian cancer.
Alkylating Agents↗
Localized ovarian cancer in the elderly. The Gynecologic Oncology Group experience.
BACKGROUND: The appropriate therapy for patients with localized (FIGO Stage I and II) ovarian cancer has been poorly defined for all age groups and particularly for the elderly. Few prospective randomized comparisons of adjuvant therapy after careful surgical staging have been performed. The Gynecologic Oncology Group (GOG) has performed a series of trials testing adjuvant treatment in carefully staged patients with early-stage ovarian cancer. Early trials included few elderly patients but the most recent trial (GOG 95) included 18% over the age of 65 years. METHODS: Comprehensive surgical staging defined by protocol is performed before randomization. Patients with predefined stages and histologies are included and the patients are randomized prospectively to receive either intraperitoneal phosphorus-32 or three monthly cycles of cyclophosphamide and cisplatin. Assessment of the value of this adjuvant therapy will depend on survival, disease-free survival, and relapse pattern differences between the two adjuvant therapies. RESULTS: This is an ongoing clinical trial and insufficient numbers of patients have been randomized for definitive conclusions. There have been seven recurrences on both arms of the trial with a median time to recurrence of 14 months. There currently are no significant age differences between relapsed patients and disease-free patients. At this point, 12 elderly patients have been randomized to each of the arms of therapy. CONCLUSIONS: Although no apparent survival differences exist for elderly patients in the most recent adjuvant chemotherapy trial of early ovarian cancer, the number of patients with cancer randomized and follow-up are insufficient to establish such a difference. Currently there is no evidence that elderly patients display a significant difference in relapse frequency or pattern.
Adult↗
Cancer prevention.
Increasing attention is being paid to cancer prevention as the best and most cost-effective way to address the cancer problem. Efforts have focused on the modification of high-risk behavior as well as the development of chemoprevention agents that may reduce or modify the development of cancer. In each of the areas of cancer prevention research, specific studies and trials have been and are being performed in oropharyngeal cancers. These include extensive programs of behavior modification such as smoking cessation and studies of synthetic retinoids and other chemopreventative agents in head and neck cancers, esophageal cancer, and other oropharyngeal cancers. One of the problems that compromises this effort is the distorted public perception of risk where rare risk factors are often given more emphasis than the more important dangers such as alcohol and tobacco use.
Alcohol Drinking↗
Timing breast cancer surgery to menstrual cycles: fact or artifact?
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Artifacts↗
T-type and L-type calcium currents in freshly dispersed human uterine smooth muscle cells.
OBJECTIVE: Our purpose was to characterize the types of voltage-activated calcium currents that are found in human uterine myocytes and to determine the effects of magnesium and nifedipine on these currents. STUDY DESIGN: Electrophysiologic experiments were performed on freshly isolated human uterine smooth muscle cells by means of the nystatin modification of the whole-cell patch clamp technique. RESULTS: Two types of voltage-activated calcium currents that are similar to the T-type and L-type calcium currents observed in cardiac myocytes were identified in freshly dispersed, pregnant human uterine myocytes. Magnesium at 8 mmol/L reduced uterine myocyte T-type currents by 68% +/- 17% but did not reduce L-type currents. Nifedipine at 10(-6) mol/L blocked the L-type currents but had no effect on T-type currents. CONCLUSION: Freshly isolated human uterine smooth muscle cells exhibit subtypes of calcium currents that are analogous to those found in cardiac myocytes. The uterine myocyte T-type current may be primarily involved with action potential transmission and the L-type current primarily with increasing intracellular free calcium by bulk calcium transport. The differing physiologic effects of magnesium and nifedipine on the calcium current subtypes suggest that for the treatment of preterm labor the primary effect of magnesium therapy is to decrease the frequency of contractions and of nifedipine the strength.
Action Potentials↗
The course of geriatric depression with "reversible dementia": a controlled study.
OBJECTIVE: The goals of this longitudinal investigation were 1) to study the rate of development of irreversible dementia in elderly depressed patients with a dementia syndrome that subsided after improvement of depression and 2) to compare it with that of depressed, never-demented patients. METHOD: The subjects were 57 elderly patients consecutively hospitalized for major depression. At entry into the study, 23 subjects also met criteria for "reversible dementia," while 34 were without dementia. After a systematic clinical evaluation, the subjects were followed up at approximately yearly intervals for an average of 33.8 months. RESULTS: Irreversible dementia developed significantly more frequently in the depressed group with reversible dementia (43%) than in the group with depression alone (12%). Survival analysis showed that the group with reversible dementia had a 4.69-times higher chance of having developed dementia at follow-up than the patients with depression alone. No clinical characteristics at entry into the study were found to discriminate the subjects who developed irreversible dementia during the follow-up period from those who remained nondemented. CONCLUSIONS: These findings suggest that geriatric depression with reversible dementia is a clinical entity that includes a group of patients with early-stage dementing disorders. Therefore, identification of a reversible dementia syndrome is an indication for a thorough diagnostic workup and frequent follow-ups in order to identify treatable neurological disorders.
Aged↗
High-dose carboplatin and recombinant granulocyte-macrophage colony-stimulating factor in advanced-stage recurrent ovarian cancer.
PURPOSE: We investigated whether carboplatin myelosuppression could be favorably modulated by the administration of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in patients with advanced-stage ovarian cancer. PATIENTS AND METHODS: Thirty-four patients with advanced-stage recurrent ovarian cancer were treated with high-dose carboplatin (800 mg/m2 per 35-day cycle) and rGM-CSF. rGM-CSF was administered as a daily subcutaneous injection starting 72 hours after the carboplatin dose and continuing until 7 days beyond the WBC nadir. rGM-CSF was administered in a phase I fashion. Seven patients were treated at an rGM-CSF dose of 3 micrograms/kg, 11 at 5 micrograms/kg, 10 at 10 micrograms/kg, and six at 20 micrograms/kg. RESULTS: rGM-CSF-related toxicities that were not dose-related included nonneutropenic fever, rib pain, acute hypersensitivity reaction, and pericarditis. At the rGM-CSF dose of 20 micrograms/kg, debilitating malaise was seen in four of six patients and this was the dose-limiting toxicity. Patient tolerance of the 3-micrograms/kg and 5-micrograms/kg doses was good, but tolerance was limited for the 10-micrograms/kg dose. Febrile neutropenia was seen in four of seven patients at 3 micrograms/kg, two of 11 at 5 micrograms/kg, two of 10 at 10 micrograms/kg, and one of six at 20 micrograms/kg. Cumulative carboplatin myelotoxicity was blunted only in respect to WBC count, and not for platelets or RBCs. Gastrointestinal bleeding was seen in seven patients. The administered dose-intensity of carboplatin averaged 134 mg/m2/wk for the cohort, or 670 mg/m2 per 35-day cycle. There were two clinical complete responses and eleven partial responses, for a response rate of 38%. CONCLUSION: rGM-CSF appears to be effective and tolerable at 5 micrograms/kg/d administered subcutaneously, if given with carboplatin doses up to approximately 600 mg/m2 over 35 days. The use of rGM-CSF with high-dose carboplatin is associated with a substantial response rate in poor-prognosis ovarian cancer patients.
Adult↗
Management of mania in the elderly: an update.
Manic syndromes in the geriatric population present special issues in management. The authors review the state of the art, with particular emphasis on assessment and pharmacotherapy. Research needs are emphasized.
Acute Disease↗
Gynecologic malignancies.
No new publication appeared in the past year on early stage ovarian cancer. The current GOG study will help determine the relative benefits and toxicities of intraperitoneal P32 versus cyclophosphamide and cisplatin in this group of patients. Recent studies in advanced ovarian carcinoma suggest a modest additional benefit for multidrug regimens, but cisplatin and cyclophosphamide remains an acceptable first line treatment for stage III and IV disease. Additional information on the use of carboplatin in advanced disease has been published, and this agent is now accepted as part of standard first line treatment programs. Platinum-based chemotherapy continues to be the mainstay of treatment for recurrent disease. With the commercial availability of taxol, a new salvage treatment is now available. Taxol will be increasingly studied as a part of front-line therapy as well as its role in the salvage setting. Altretamine and ifosfamide appear to have activity even in some patients with platinum-resistant disease, but these drugs will not likely have a major impact on ovarian cancer treatment. The use of high-dose chemotherapy with autologous bone marrow or peripheral stem cell support offers an exciting and potentially beneficial approach for patients with poor prognosis disease. The use of intraperitoneal chemotherapy and biologic agents continues to be problematic, and additional improvements are needed before they are considered useful outside of a research setting. With the exception of P32 for early stage disease, radiation therapy is likely to continue to play a minor role in the treatment of ovarian cancer. Few studies involving non-epithelial ovarian carcinomas were published during the past year. A definitive report was published demonstrating the activity of cisplatin-based chemotherapy (BEP) in patients with advanced dysgerminoma. Chemotherapy which preserves fertility provides an effective alternative to irradiation. Cisplatin-based chemotherapy was active in mixed mullerian tumors of the ovary although the prognosis of these patients was worse than patients with epithelial ovarian cancer. Concurrent chemotherapy added to irradiation has not improved survival over radiotherapy alone in patients with cancer of the uterine cervix. Patients still failed locally and distantly. Extended field irradiation to involved paraaortic lymph nodes with weekly cisplatin generated promising pilot data. Randomized trials evaluating the use of neoadjuvant chemotherapy prior to pelvic radiotherapy showed no benefit and increased toxicity. Ifosfamide alone or in combination regimens is an active drug but with serious side effects which require careful monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)
Combined Modality Therapy↗
The stereoselective recognition of substrates by phosphoinositide kinases. Studies using synthetic stereoisomers of dipalmitoyl phosphatidylinositol.
Soluble phosphatidylinositol (PtdIns) 4- and 3-kinase activities were partially purified and characterized from human placental extracts. The placental PtdIns 4-kinase (type 3) has a Km for ATP of 460 microM and is kinetically different to a partially purified human erythrocyte, membrane-bound, PtdIns 4-kinase (type 2). These three inositol lipid kinases were then used to compare their substrate specificities against the four synthetic stereoisomers of dipalmitoyl PtdIns. Only the placental 4-kinase was influenced by the chirality of the glycerol moiety of PtdIns. However, neither of the 4-kinases was able to phosphorylate L-PtdIns and, therefore, these kinases have an absolute requirement for the inositol ring to be linked to the glyceryl backbone of the lipid through the D-1 position. Phosphoinositide 3-kinase, on the other hand, was found to phosphorylate both D- and L-PtdIns. While the 3-kinase phosphorylated exclusively the D-3 position of D-PtdIns, further analyses demonstrated that the same enzyme phosphorylated two sites on L-PtdIns, namely the D-6 and D-5 positions of the inositol ring. Some implications of these findings are discussed.
1-Phosphatidylinositol 4-Kinase↗
Tendering for veterinary service contracts.
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Animals↗
Brain computed tomography findings in geriatric depression and primary degenerative dementia.
Brain computed tomography (CT) scans were performed in hospitalized geriatric patients with major depression (n = 45) or primary degenerative dementia (n = 21). Depressed patients with onset of illness at age 60 years or older (n = 32) had greater ventricular size than geriatric depressives with earlier age of illness onset (n = 13). CT parameters of late-onset depressives were comparable to those of patients with primary degenerative dementia. However, early-onset geriatric depressives had significantly smaller ventricles and less sulcal widening than demented patients. The findings suggest that late-onset depression may have a stronger association with neurological dementing disorders than early-onset depression.
Aged↗
Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results.
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Adult↗
Evaluation of in vitro drug screening leads using experimental models of human ovarian cancer.
Five compounds which were identified as potential new anticancer drugs in in vitro screening with the human tumor colony forming assay were selected for further evaluation using in vitro and in vivo models of human ovarian cancer. Three of five compounds were found to inhibit in vitro colony formation of ovarian cancer cell lines derived from both untreated and combination chemotherapy refractory patients. One compound was also found to prolong survival in a human ovarian carcinoma xenograft model system. This compound, chloroquinoxaline sulfonamide, was selected for development and has shown preliminary indication of activity in phase I clinical testing.
Animals↗
Stage II carcinoma of the ovary: an analysis of survival after comprehensive surgical staging and adjuvant therapy.
Ninety-three women with FIGO stage II epithelial ovarian carcinoma underwent comprehensive surgical staging and were randomized prospectively to therapy consisting of either intraperitoneal radioactive phosphorus or oral melphalan. No patient had gross residual disease at the time of randomization. Ten of the forty-five women treated with melphalan experienced severe bone marrow depression at some time during therapy and two women expired from leukemia. Four of the forty-eight women treated with intraperitoneal phosphorus required surgical reexploration for intestinal obstruction or bowel injury. Twenty-one women died of their disease. Survival was not statistically different between the two treatment arms. The 5-year actuarial survival was 78%.
Adolescent↗
5-Fluorouracil (5-FU) and leucovorin in platinum-refractory advanced stage ovarian carcinoma.
Twenty-nine patients with recurrent advanced stage ovarian cancer were treated with 5-fluorouracil (5-FU) and leucovorin by intravenous bolus on 5 consecutive days, repeated every 3 weeks. Twenty-one of these patients had experienced disease progression while receiving a cisplatin- or carboplatin-based regimen. There were 2 clinical complete responders and 1 partial responder to therapy (10% response rate; 95% confidence interval, 2 to 27%) and 11 individuals who experienced stable disease for periods ranging from 5 to 27 months. Of 204 cycles of therapy administered, 9 cycles were associated with hospitalization. These occurred in the more heavily pretreated members of the cohort. 5-FU and leucovorin appear to have activity in platinum-refractory ovarian cancer and form a well-tolerated regimen in most patients.
Adult↗