Can fenretinide protect women against ovarian cancer?
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Female↗
Biomedical subjects
C Boni
Publications and source records attributed to C Boni.
Chemotherapy of advanced non-small-cell lung cancer: a comparison of three active regimens. A randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.).
BACKGROUND: Cisplatin-based chemotherapy is generally considered the most active treatment for advanced non-small-cell lung cancer. The combination of cisplatin and etoposide had for some time been the standard treatment at our center. Of the other active regimens, cisplatin in combination with mitomycin-C, vindesine or ifosfamide (MVP or MIC) showed the highest response rates. We decided to perform a comparative trial of the three 'best' regimens in order to define a possible standard regimen in advanced NSCLC. MATERIALS AND METHODS: From May 1989 to April 1992, 393 consecutive, previously untreated NSCLC patients, stages IIIB and IV, were randomized to receive either cisplatin (120 mg/sqm day 1) + etoposide (100 mg/sqm days 1-3) every 3 weeks (PE) or cisplatin (120 mg/sqm every 4 weeks) + mitomycin-C (8 mg/sqm days 1-29-71) + vindesine (3 mg/sqm days 1-8-15-22) (MVP) or cisplatin (120 mg/sqm day 1) + mitomycin-C (6 mg/sqm day 1) + ifosfamide (3 mg/sqm day 2) every 3 weeks (MIC). Of these, 382 were evaluable for survival and 360 for response. RESULTS: Response rates were statistically higher for both MIC (40%) and MVP (36%) than for the PE arm (23%). Survival estimates analyzed by the log-rank test showed a significant benefit (p < 0.04) for patients treated with three-drug regimens (MVP; MIC) as compared to those in the PE arm. The main toxicity was myelosuppression; thrombocytopenia WHO grade 3-4 was worse in the MIC arm; nephrotoxicity grade 3-4 was also more frequent in the MIC arm. CONCLUSIONS: A three-drug cisplatin-based regimen (MVP; MIC) should be considered as reference treatment in NSCLC.
Aged↗
Postnatal development and localization of 5-HT1A receptor mRNA in rat forebrain and cerebellum.
The localization of the rat brain 5-HT1A receptor mRNA was analyzed by RNAse mapping and in situ hybridization during postnatal development, particularly in the cerebellum. The regional distribution of 5-HT1A mRNA during the first 2 postnatal weeks was different from that found in adults. In some areas of the immature brain (hippocampus, cerebral cortex), 5-HT1A mRNA was found in lower density than in the adult brain. In contrast, high concentrations of the transcript were present in other brain structures only during the first days after birth. Thus, in the cerebellum, the density of 5-HT1A mRNA decreased markedly from day 2 to day 9 after birth and could hardly be detected in the adult animal. The localization of the mRNA in the molecular/Purkinje cell layer of the immature cerebellum agreed with that of the 5-HT1A receptor protein visualized by immunocytochemistry and was consistent with the hypothesis that Purkinje cells express this receptor.
Animals↗
Effect of chronic ACE inhibition on glucose tolerance and insulin sensitivity in hypertensive type 2 diabetic patients.
We studied 14 moderately overweight Type 2 diabetic patients with essential hypertension in stable metabolic control after a run-in period, and again after 3 months of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor captopril. Glucose tolerance was tested with a 75g oral glucose load (OGTT) and insulin sensitivity was measured by the insulin suppression test (IST) while dietary and drug treatment of the hyperglycemia was maintained constant. In the whole group, mean blood pressure (MBP) fell progressively over 3 months from a baseline value of 123 +/- 3 mmHg (1 mmHg = 0.133 kpa) to a final value of 115 +/- 2 mmHg (P < 0.005). After treatment, fasting plasma glucose, insulin, free fatty acid (FFA), potassium, and glycosylated hemoglobin concentrations were unchanged from baseline. There were no significant differences in glucose tolerance and insulin sensitivity between pre- and post-treatment values. Neither endogenous (oral glucose) nor exogenous (IST) insulin caused any change in plasma potassium concentration. This resistance to the hypokalemic action of insulin was not affected by captopril.
Blood Glucose↗
Insulin sensitivity in familial hypercholesterolemia.
Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The quail tyrosine hydroxylase gene promoter contains an active cyclic AMP-responsive element.
A 1.5-kb genomic DNA fragment situated upstream from the quail tyrosine hydroxylase (TH) gene transcription site was isolated. This upstream region starts 15 bp from the translation initiation site. It contains two canonical TATA boxes, at positions -37 and -297, three putative glucocorticoid-responsive elements, at positions -1487, -1329, and -1268, and one putative cyclic AMP (cAMP)-responsive element (CRE) at position -53, as well as a putative negative regulatory element consensus sequence at position -735. The consensus POU-Oct site is partly conserved. Comparison of the 5' flanking sequences of quail and mammalian (bovine, human, and rat) TH genes revealed a strong sequence conservation within the 230 nucleotides upstream of the TATA box, with a distinct conservation of the CRE region. Constructs in which the bacterial chloramphenicol acetyltransferase (CAT) reporter gene was linked to promoter stretches of increasing lengths were transfected into three cell lines, two of them originating from quail and rat neural crest and the third derived from mouse fibroblasts. Reporter gene expression was specifically high in the quail and rat neural crest-derived cells compared to the fibroblast cell line. The physiological activity of this putative quail CRE was analyzed further in transfected neural crest cells of quail origin. Both cAMP analogues and agents that enhance intracellular cAMP increased CAT activity. The physiological relevance of this finding is sustained by the presence, in quail nuclear extracts, of a protein(s) that binds CRE consensus sequences.
Animals↗
Immunoradiometric assay of serum myosin as a marker of myocardial cell damage: methodological and clinical evaluation.
We evaluated the performance and analytical parameters of a one-step magnetic IRMA kit for the measurement of myosin in serum. The method uses two monoclonal antibodies selected for their high affinity to the heavy chains of human ventricular myosin. The first antibody is coupled to a magnetic solid phase and the second one is labeled with 125I. The working range of the IRMA (range of myosin concentrations measured with an imprecision < 10% CV) was 250-3600 microU/L and the sensitivity 20.8 +/- 7.2 microU/L. The between-assay variability, evaluated from replicate measurements in different runs of two serum pools was 14.6 CV% for the first pool (259.1 +/- 37.8 microU/L) and 14.3 CV% for the second pool (442.0 +/- 63.1 microU/L), respectively. To evaluate the clinical usefulness of myosin as a marker of myocardial cell damage, serum myosin was measured in patients with acute myocardial infarction (AMI) (n = 9) or subarachnoid hemorrhage (n = 20). The results obtained with the myosin assay were compared with those of two other markers considered specific for myocardial necrosis (CK-MB and myoglobin). In eight patients with AMI, serum myosin was elevated 24-36 hours after the onset of chest pain and reached a maximum at 4-7 days, returning to control levels at 8-11 days. The one remaining AMI patient showed two subsequent peaks in serum CK-MB and myoglobin concentrations (thus suggesting an extension of myocardial necrosis), the myosin concentrations reaching their peak only after 9 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Biomarkers↗
Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen.
BACKGROUND: Endocrine factors may affect the clinical course of malignant melanoma and the response to the treatment of this disease. The presence of estrogen receptors in melanomas has been suggested, and occasional responses to antiestrogen therapy have been reported. METHODS AND RESULTS: We randomly assigned 117 patients with metastatic malignant melanoma to treatment with dacarbazine alone or dacarbazine in combination with tamoxifen. The overall rate of response, measured objectively, was higher (28 percent vs. 12 percent, P = 0.03) and survival was longer (median, 48 vs. 29 weeks, P = 0.02) among the patients who received dacarbazine plus tamoxifen than among those who received dacarbazine alone. Among women, both the response rate (38 percent vs. 10 percent, P = 0.04) and the median survival (69 vs. 30 weeks, P = 0.008) were better with dacarbazine plus tamoxifen than with dacarbazine alone, whereas among men the differences were smaller and not statistically significant. Among the patients given dacarbazine alone, there were no significant differences between women and men in response rate (10 percent vs. 13 percent) or survival (30 vs. 27 weeks), whereas among those given dacarbazine plus tamoxifen, women had better outcomes, as indicated by both response rate (38 percent vs. 19 percent, P = 0.15) and survival (69 vs. 31 weeks, P = 0.02). When we analyzed the Quetelet body-mass index (the weight in kilograms divided by the square of the height in meters) as an indirect indicator of the levels of endogenous estrogens in postmenopausal women and in men, survival was not affected by the body-mass index in the group given dacarbazine alone, whereas in the group given dacarbazine plus tamoxifen, survival was longer among patients whose Quetelet index was above the median value than among those with a Quetelet index lower than the median value (60 vs. 26 weeks, P less than 0.001). CONCLUSIONS: In the treatment of metastatic malignant melanoma, dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated by both the response rate and the median survival; the difference in efficacy is among women.
Adult↗
Fluorouracil-alone versus high-dose folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research (GOIRC).
One hundred eighty-one patients with measurable recurrent or metastatic colorectal cancer, who had not received prior chemotherapy, were randomized in a prospective controlled trial to receive 5-fluorouracil (5FU), 13.5 mg/kg, for five days (arm A) or high-dose folinic acid [Cyanamid-Lederle, Italy] (FA), 200 mg/m2, for five days and 5FU, 400 mg/m2 for five days (arm B). The treatments were repeated every four weeks. One hundred fifty-five patients were evaluable for response. The two arms were balanced for all potential prognostic factors studied. The response rate (CR+PR) was 18% in the 5FU arm and 16% in the 5FU plus FA arm. Median duration of response was 56 weeks for 5FU alone and 42 weeks for the combination (p = 0.48). Median time to failure (TTF) was 20 weeks for arm A and 21 for arm B (p = 0.62). Median survival was 62 weeks on the 5FU arm and 53 weeks on the FA plus 5FU arm (p = 0.14). Dose intensity (DI) delivered was the same in both arms. Diarrhea and mucositis were the most frequent adverse reactions in arm B; 20% of the patients in arm A and 38% of those in arm B experienced diarrhea (p = 0.008). Mucositis occurred in 34% of patients in arm A and 42% in arm B (p = 0.04). In general nausea and vomiting were moderate. Hematological toxicity was more severe in patients treated with 5FU alone: 31% in arm A and 14% in arm B developed leukopenia (p = 0.015). In the combination arm one patient died due to gastrointestinal and hematological toxicity after the seventh cycle. This study indicates that, in advanced colorectal cancer, the combination of high-dose FA and 5FU is not superior to 5FU alone when utilized at standard high-dose intensity.
Adult↗
Effect of chronic ACE inhibition on glucose tolerance and insulin sensitivity in hypertensive type 2 diabetic patients.
The question, of whether long-term treatment of essential hypertension with angiotensin-converting enzyme (ACE) inhibitors is capable of modifying glucose tolerance or insulin sensitivity in Type 2 (non-insulin dependent) diabetes, is still unsolved. We studied 14 moderately overweight Type 2 diabetic patients with essential hypertension in stable metabolic control after a run-in period and again after 3 months of antihypertensive treatment with the ACE inhibitor, captopril. Glucose tolerance was tested with a 75-g oral glucose load and insulin sensitivity was measured by the insulin suppression test, while dietary and drug treatment of the diabetes remained constant. In the whole group, mean blood pressure (MBP) fell progressively over 3 months from a baseline value of 123 +/- 3 mmHg to a final value of 115 +/- 2 mmHg (p < 0.005); in six patients, the change in MBP was < 5 mmHg (non-responders), thus giving a clinical response rate of approximately 60%. After treatment, fasting plasma glucose, insulin, free fatty acid (FFA), potassium, and glycated haemoglobin concentrations were unchanged from baseline. During the oral glucose tolerance test, the incremental glucose area-under-curve was 0.75 +/- 0.05 mol 120 min l-1 before and 0.76 +/- 0.06 mol 120 min l-1 after treatment (p = ns). Endogenous insulin response and suppression of plasma FFA levels were superimposable on the two occasions. During the insulin suppression test, steady-state plasma glucose levels were 14.4 +/- 1.3 vs 14.2 +/- 1.1 mmol l-1 before and after chronic ACE inhibition, respectively, at comparable hyperinsulinaemic plateaux (291 +/- 21 vs 287 +/- 14 pmol l-1).(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
Low-dose aminoglutethimide with and without hydrocortisone replacement as a first-line endocrine treatment in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research.
PURPOSE: A randomized study comparing low-dose aminoglutethimide (AG) with and without hydrocortisone (HC) was performed to investigate whether corticosteroid replacement contributes to the therapeutic effects of the drug administered as a front-line endocrine therapy in postmenopausal advanced breast cancer. PATIENTS AND METHODS: Postmenopausal patients who had not had prior endocrine therapy for advanced disease and with estrogen receptor (ER) or progesterone receptor (PgR) status positive or unknown were eligible. AG was administered at a dose of 250 mg twice a day orally (125 mg twice a day during the first month) with or without HC (20 mg twice a day orally). Seventy-nine and 74 patients were assessable for response on the AG plus HC arm and on the AG arm, respectively. The two treatment groups were well balanced and patients were largely untreated. Approximately 60% had not received any adjuvant treatment, and approximately 75% had not received any medical treatment after relapse. RESULTS: The overall responses (complete response [CR] plus partial response [PR]) were 44% and 41% for the AG plus HC and the AG arm, respectively, showing no significant difference. Time to progression (median, 8.1 and 6.3 months), duration of response (median, 15.8 and 13.7 months), and duration of survival (median, 34.2 and 36.3 months) were not significantly different between the two treatment arms. Side effects were infrequent and mild in both arms, with no significant differences. CONCLUSION: We conclude that half of the conventional daily dose of AG has optimal therapeutic activity as a front-line endocrine treatment of postmenopausal advanced breast cancer and that HC does not significantly contribute to the therapeutic effects.
Adenocarcinoma↗
Cisplatin and etoposide in advanced colorectal carcinoma.
The cisplatin (P) and etoposide (E) combination has been found to be active in several types of solid tumors. It has never been previously tested in advanced colorectal cancer. Thirty-three patients with advanced colorectal cancer were treated with this combination. Five patients responded (1 complete and 4 partial responses) with an overall response rate of 15% (95% confidence limits, 3%-27%). Responses were seen in both untreated (3/16) and pretreated (2/17) patients. The median duration of response was 28 weeks (range: 23; 80), the median time to progression was 16 weeks (range 2; 80) and the median survival time for all entered patients was 38 weeks (range: 2; 187+). These results suggest that the PE combination has a low but definite activity in advanced colorectal carcinoma, particularly in previously untreated patients.
Adenocarcinoma↗
Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research.
In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.
Adenocarcinoma↗
Insulin resistance after surgery: normalization by insulin treatment.
1. Injury is known to be associated with variable degrees of tissue insensitivity to insulin. We measured insulin resistance in a group of non-obese, glucose-tolerant patients undergoing major elective surgery with an uncomplicated post-operative course. 2. Shortly after surgery, hyperglycaemia (7.3 +/- 0.6 versus 4.2 +/- 0.3 mmol/l glucose pre-surgery, mean +/- SEM, P less than 0.01) with normal insulin concentrations (73 +/- 15 versus 64 +/- 18 pmol/l) suggested the presence of insulin resistance. Counter-regulatory hormones were raised, whole-body protein oxidation was doubled (P less than 0.01) and energy expenditure was up by 18% (P less than 0.01). 3. Insulin sensitivity was quantified by clamping plasma glucose concentrations at 5.6 mmol/l during 24 h of total parenteral nutrition (15% protein, 55% glucose and 30% fat, supplying 1.25 times the measured resting energy expenditure) with a variable infusion of exogenous insulin. After surgery, eight times more insulin was needed than before surgery (14.14 +/- 1.15 versus 1.78 +/- 0.29 pmol min-1 kg-1, P less than 0.001) to maintain euglycemia. 4. After surgery, stimulation of net carbohydrate oxidation (18.8 +/- 1.4 versus 17.2 +/- 1.8 mumol min-1 kg-1 preoperatively, not significant), suppression of lipolysis and lipid oxidation and inhibition of ketogenesis occurred to the same extent as before surgery. Of the infused nutrients, the glucose was all oxidized, amino acids replaced endogenous protein losses (= neutral nitrogen balance) and lipids were stored. Insulin administration caused no further increment in oxygen consumption or energy expenditure.(ABSTRACT TRUNCATED AT 250 WORDS)
Carbohydrate Metabolism↗
Operation of Randle's cycle in patients with NIDDM.
It has been suggested that the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) may be caused by substrate competition between glucose and free fatty acids (FFAs) (Randle's cycle). We measured substrate oxidation and energy metabolism in 10 nonobese untreated NIDDM patients with fasting glucose levels of 7-8 mM with indirect calorimetry in the basal state and during an isoglycemic-hyperinsulinemic (approximately 100 mU/L) clamp without (control) and with a concomitant infusion (approximately 0.35 mmol/min) of Intralipid, a triglyceride emulsion. In the control study, fasting rates of total glucose turnover [( 3-3H]glucose) and glucose and lipid oxidation (9.4 +/- 1.4, 7.3 +/- 1.3, and 3.0 +/- 0.4 mumol.kg-1.min-1, respectively) were comparable with those of nondiabetic individuals. After insulin administration, lipid oxidation was normally suppressed (to 1.3 +/- 0.3 mumol.kg-1.min-1, P less than 0.01), as were the circulating levels of FFA, glycerol, and beta-hydroxybutyrate, whereas glucose oxidation doubled (14.1 +/- 1.8 mumol.kg-1.min-1, P less than 0.01). Because glycemia was clamped at 7.5 mM, endogenous glucose production (EGP) was completely suppressed, and total glucose disposal was stimulated (to 25.7 +/- 5.2 mumol.kg-1.min-1, P less than 0.01 vs. baseline), but glucose clearance (3.6 +/- 0.8 ml.kg-1.min-1) was 30% reduced compared with normal. With concomitant lipid infusion, FFA, glycerol, and beta-hydroxybutyrate all rose during the clamp; correspondingly, lipid oxidation was maintained at fasting rates (3.6 +/- 0.2 mumol.kg-1.min-1, P less than 0.01 vs. control).(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
Combination therapy with platinum and etoposide of brain metastases from breast carcinoma.
Twenty-two consecutive patients with brain metastases from breast carcinoma were treated with a combination of platinum (100 mg/m2 day 1) and etoposide (100 mg/m2 days 4, 6, 8) every three weeks. Five (23%) achieved a complete response (CR) while 7 (32%) obtained a partial response (PR) for an overall response rate of 55%. The 95% confidence interval for combined CR and PR was 34-76%. Five patients received brain irradiation after reaching the maximum degree of objective remission by chemotherapy. Median duration of combined CR plus PR was 40 weeks (12+; 152). Median duration of survival was 58 weeks (2; 208+). Fifty-five percent of the patients were alive at one year. Our study demonstrates that this combination treatment is highly effective in the management of brain metastases from breast carcinoma.
Adult↗
Exacerbation of metastatic disease shortly after administration of tamoxifen in ER negative advanced breast carcinoma. A case report.
In a patient with long untreated slow-growing osteoblastic bone metastases from an ER/PgR negative breast carcinoma, new metastatic sites in many lymphnodes pleura and massively in liver have been observed 4 weeks after receiving tamoxifen. Cause-effect relationship between administration of the drug and this unusually rapid spreading of the disease may be considered only as a hypothesis, as it is based wholly on clinical outcome. However, reporting of any exacerbation of breast cancer apparently induced by tamoxifen, even if only anecdotal, is advisable.
Breast Neoplasms↗
Bone marrow biopsy in the staging of small cell lung cancer.
From April 1982 to December 1987, 71 patients with small cell lung cancer entered a randomized clinical trial, and underwent bone marrow biopsy (BMB) as part of staging procedures. We identified 8 patients (11%) with bone marrow metastases, 6 with extensive disease independently of BMB, and 2 with extensive disease on the basis of the BMB only. BMB determined a change in the stage in only 3% (2/71) of the cases. No differences were found in the hematological parameters of the patients with or without bone marrow metastases. The median survival of the patients with bone marrow involvement was the same (41 weeks) as those with extensive disease but without bone marrow involvement. We conclude that unilateral BMB without aspiration detects a substantial proportion of bone marrow metastases in patients with extensive disease. This fact does not worsen the prognosis. A small proportion of patients with apparently limited disease has bone marrow involvement. The technique therefore contributes, to a small extent, to the definition of the clinical stage of the disease. However, bone marrow involvement is an important data of natural history, and therefore new methods to better assess this peculiar site of the disease are needed.
Adult↗