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PubMed1988

Job strain, work place social support, and cardiovascular disease: a cross-sectional study of a random sample of the Swedish working population.

This cross-sectional study investigates the relationship between the psychosocial work environment and cardiovascular disease (CVD) prevalence in a randomly selected, representative sample of 13,779 Swedish male and female workers. It was found that self-reported psychological job demands, work control, and co-worker social support combined greater then multiplicatively in relation to CVD prevalence. An age-adjusted prevalence ratio (PR) of 2.17 (95% CI-1.32, 3.56) was observed among workers with high demands, low control, and low social support compared to a low demand, high control, and high social support reference group. PRs of approximately 2.00 were observed in this group after consecutively controlling for the effects of age together with 11 other potential confounding factors. The magnitude of the age-adjusted PRs was greatest for blue collar males. Due to the cross-sectional nature of the study design, causal inferences cannot be made. The limitations of design and measurement are discussed in the context of the methodological weaknesses of the work stress field.

Adolescent↗
PubMed1979

Renin-angiotensin system in phlorhizin compared with alloxan diabetes in the rat.

In alloxan-treated diabetic rats, plasma renin activity (PRA) is decreased. One possible mechanism that may explain the decreased PRA is an increased delivery of sodium to the macula densa produced by the glucose osmotic diuresis, resulting in decreased renin release. To evaluate this possible mechanism, rats with phlorhizin diabetes, which produces a glucose osmotic diuresis without hyperglycemia, were studied and compared with rats with alloxan-induced diabetes. Whereas phlorhizin-treated rats had low blood glucose and alloxan-treated rats had elevated glucose, the glucose osmotic diuresis was similar in the two groups. PRA and plasma renin concentration (PRC) were significantly increased in the phlorhizin group. In the alloxan group, PRA was decreased and angiotensin II sensitivity increased, both significantly. Plasma renin substrate (PRS) remained adequate in each group. These results suggest that the decreased PRA in alloxan-induced diabetes is due neither to factors associated with the glucose osmotic diuresis including changes in renal tubular sodium not to decreased PRS.

Alloxan↗
PubMed2003

Progesterone receptor-regulated gene networks in implantation.

The steroid hormone progesterone (P) plays a pivotal role in the establishment and maintenance of pregnancy. The well-known function of P during early pregnancy is to regulate (i) uterine receptivity for blastocyst attachment, (ii) progressive phases of embryo-uterine interactions, and (iii) differentiation of the endometrial stroma that maintains an environment conducive for the growth and development of the implanting embryo. The cellular actions of P are mediated through intracellular progesterone receptors (PRs), which are well-studied gene regulators. It is postulated that hormone-occupied PRs trigger the expression of specific gene networks in different cell types within the uterus and the products of these genes mediate the hormonal effects during early pregnancy. In the present article, we provide a brief description of the molecules that have emerged as candidate markers of progesterone action in rodents and humans during implantation.

Animals↗
PubMed1983

Effects on the renin-angiotensin system of the administration of prostaglandin E1 and E2 in second trimester human pregnancy.

We have measured evoked changes in plasma renin concentration (PRC), plasma renin substrate (PRS) amd plasma aldosterone concentration (ALD) during the infusion of angiotensin II (AII) with and without the simultaneous administration of prostaglandin E2, 5 micrograms min-1 i.v. (PGE2) or prostaglandin E1, 15 ng kg-1 min-1 (PGE1). Experiments have been carried out using PGE2 in 20 patients, and in 5 patients to date with PGE1. AII alone (16 ng kg-1 min-1 i.v.) significantly reduced PRC in both groups of patients without altering PRS, while ALD concentrations more than doubled. The infusion of PGE2 stimulated basal PRC; PGE1 at the dose used did not alter PRC. Neither prostaglandin altered basal RS or ALD concentrations. When AII was infused simultaneously, PRC was again suppressed, in the presence of PGE2. However, only minimal feedback suppression occurred when PGE1 was being used. Furthermore, AII was still associated with a more than two-fold rise in ALD concentration when given together with PGE2, but the rise was considerably smaller and not significant in the presence of PGE1. PGE2 is a known stimulus to renin secretion, apparently acting directly at the juxtaglomerular apparatus. These preliminary results suggest that while a similar mechanism exists in second trimester human pregnancy, PGE1 may have a different effect. The apparent blockade of the normal feedback suppression of PRC in the presence of increased PGE1 concentrations by raised concentrations of AII is especially interesting.

Adult↗
PubMed1997

Progesterone and estrogen receptors in meningiomas: prognostic considerations.

Meningiomas often contain steroid hormone receptors, but the correlation of receptor presence with patient outcome or mitotic index is unclear. Intracranial meningiomas from 70 patients (27 males and 43 females, mean age 52.9 + 1.7 years [mean +/- standard error of the mean], range 15-78 years) were evaluated immunocytochemically for female sex hormone receptors using specific monoclonal antibodies. Prognostic correlations were determined using statistical analyses that included clinical and histological variables. Twenty-eight tumors were benign, 27 had atypical features, and 15 were malignant. Thirty tumors were meningotheliomatous, 11 were fibroblastic, 28 were transitional, and one was secretory. Twenty-nine of the 70 primary tumors recurred (mean interval to recurrence 50.1 +/- 10 months). The mean progression-free follow-up period for patients without recurrence was 82.1 +/- 7.7 months. Nuclear staining for the progesterone receptor (PR) was found in 58 cases (83%) and PR status was scored as 0 (0% nuclei positive), 1 (< 1%), 2 (1-9%), 3 (10-49%), or 4 (> 50%). Only six tumors (8.6%) contained nuclear estrogen receptor (ER) staining, which was limited to a small number of nuclei (< 1%). Fisher's exact test (two-tailed) showed an inverse correlation between tumor grade and PR staining score (p < or = 0.001), with 96% of benign and 40% of malignant meningiomas containing PR-positive nuclei. No correlation between age or histological subtype and PR score was detected. Meningiomas from female patients had more PRs (p < or = 0.05). Analysis of variance revealed that the mitotic index (total counts of mitoses per 10 high-power fields) for tumors with 0 PR staining (18 +/- 4.4) was higher (p < or = 0.0001) than for those with PR scores of 1 to 4 (4.3 +/- 1.9, 5.1 +/- 2, 2.2 +/- 0.8, and 1.7 +/- 0.9, respectively). Univariate analysis indicated that the absence of PR, high mitotic index, and higher tumor grade were significant factors for shorter disease-free intervals. Multivariate analysis showed that a three-factor interaction model, with a PR score of 0, mitotic index greater than 6, and malignant tumor grade, was a highly significant predictor (p < or = 0.0001) for worse outcome in patients harboring meningiomas. These data indicate that the presence of PRs, even in a small number of tumor cells, is a favorable prognostic factor for meningiomas.

Analysis of Variance↗
PubMed2003

Resveratrol induces apoptosis in human esophageal carcinoma cells.

AIM: To investigate the apoptosis in esophageal cancer cells induced by resveratrol, and the relation between this apoptosis and expression of Bcl-2 and Bax. METHODS: In in vitro experiments, MTT assay was used to determine the cell growth inhibitory rate. Transmission electron microscope and TUNEL staining method were used to quantitatively and qualitively detect the apoptosis status of esophageal cancer cell line EC-9706 before and after the resveratrol treatment. Immunohistochemical staining was used to detect the expression of apoptosis-regulated gene Bcl-2 and Bax. RESULTS: Resveratrol inhibited the growth of esophageal cancer cell line EC-9706 in a dose-and time-dependent manner. Resveratrol induced EC-9706 cells to undergo apoptosis with typically apoptotic characteristics, including morphological changes of chromatin condensation, chromatin crescent formation, nucleus fragmentation and apoptotic body formation. TUNEL assay showed that after the treatment of EC-9706 cells with resveratrol (10 mmol/L) for 24 to 96 hours, the AIs were apparently increased with treated time (P<0.05). Immunohistochemical staining showed that after the treatment of EC-9706 cells with resveratrol (10 mmol/L) for 24 to 96 hours, the PRs of Bcl-2 proteins were apparently reduced with treated time (P<0.05) and the PRs of Bax proteins were apparently increased with treated time (P<0.05). CONCLUSION: Resveratrol is able to induce the apoptosis in esophageal cancer. This apoptosis may be mediated by down-regulating the apoptosis-regulated gene Bcl-2 and up-regulating the expression of apoptosis-regulated gene bax.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430).

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.

Clinical Trial↗
PubMed2005

Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.

BACKGROUND: To date, few large studies have been reported of patients with peritoneal mesothelioma, and treatment of this disease has been largely extrapolated from the treatment of pleural disease. Hence, it was considered important to study and report on this specific patient population. Before the regulatory approval of pemetrexed, an expanded access program (EAP) provided access to eligible patients with malignant pleural or peritoneal mesothelioma. PATIENTS AND METHODS: Patients received pemetrexed 500 mg/m2 alone or in combination with cisplatin 75 mg/m2 once every 21 days for > or = 6 cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Serious adverse events (SAEs) were compiled in a pharmacovigilance database, which included all patients in the EAP with pleural or peritoneal mesothelioma. From June 12, 2002 to February 18, 2004, 1056 patients with malignant mesothelioma were enrolled and received > or = 1 dose of treatment at 462 sites in the United States. Of these patients, 98 (9.3%) had peritoneal mesothelioma (57 previously treated, 38 chemotherapy-naive, and 3 with missing data). RESULTS: Response data were available for 73 patients (43 previously treated, 28 chemotherapy-naive, and 2 not classified), indicating response rates of 23.3% for previously treated patients (0 complete responses [CRs], 10 partial responses [PRs], 21 cases of stable disease [SDs], 12 cases of progressive disease [PDs]) and 25% for chemotherapy-naive patients (3 CRs, 4 PRs, 12 SDs, and 9 PDs). Median survival was 13.1 months for previously treated patients and has not been reached for chemotherapy-naive patients. The most commonly reported SAEs for the total EAP were dehydration (7.2%), nausea (5.2%), and vomiting (4.9%). CONCLUSION: Pemetrexed with or without cisplatin had a favorable safety profile, and the disease control rate (CR + PR + SD) of 71.2% in the subset of patients with peritoneal mesothelioma indicated activity in this patient population.

Adult↗
PubMed2000

[The effects of sleep position change in sleep apnea syndrome].

Changing the sleep position from supine to non-supine is a simple but effective treatment for some patients with sleep apnea syndrome. In the present study, we compared the clinical data for good responders (GRs), those who responded well to the sleep position change, with those for poor responders (PRs), and also evaluated the effect of surgical treatment on the positional improvement of ventilation in the PR group. Forty-one adult patients with sleep apnea syndrome (mean age: 47.1 years, mean obesity index: 125.8%) were divided into two groups based on their polysomnographic responses to sleep position change. Thirty-two patients were classified as the GR group, whose apnea-hypopnea index (AHI) in the non-supine position declined to less than half of their AHI in the supine position, and nine whose non-supine AHI remained greater than half of their supine AHI were classified as the PR group. The AHI and the desaturation index (DI) for the PR group were significantly higher than those for the GR group, and the obesity index was also higher in the PR group. For the eight PRs who had surgical therapy, their polysomnographic data improved much more in the non-supine position than in the supine position. Of six patients whose total AHI was still 10 or more after surgery, four changed into GRs. The combination of surgery and sleep position change seemed to be an effective treatment even for patients with a little improvement before surgery.

Female↗
PubMed2026

MyGeneRisk Colon: A Web-Based Tool for Personalized Colorectal Cancer Risk Prediction Based on Genetics and Lifestyle.

Colorectal cancer (CRC) is a leading cause of cancer-related death, with incidence rising substantially among individuals under 50 years of age. Polygenic risk scores (PRS) hold promise for identifying high-risk individuals; when combined with lifestyle factors, they substantially improve prediction accuracy compared with models based on lifestyle factors alone. However, few clinical tools currently exist that facilitate this integrated, PRS-enhanced risk assessment. To bridge this gap, we developed MyGeneRisk Colo n, a publicly accessible web portal that delivers individualized CRC risk prediction by incorporating genetic, demographic, family history, and lifestyle factors. This paper details the development of the underlying risk prediction model, the portal's architecture and data security, our reporting framework, and engagement with a community advisory panel. Designed as a user-friendly platform, MyGeneRisk Colon aims to effectively communicate personalized CRC risk profiles and educate users and healthcare providers about prevention strategies.

Journal Article↗
PubMed1976

Multidisciplinary curative treatment for disseminated carcinoma of the breast.

Eighty-four patients with disseminated breast carcinoma were treated with the combination of hormonal therapy and combination chemotherapy from the time of diagnosis. Hormonal treatment included castration for women still menstruating, estrogens for women menopausal for greater than 5 years, and androgens or progesterone for women menopausal for less than 5 years. Combination chemotherapy consisted of monthly 5-day courses of 5-fluorouracil (500 mg/day, Days 1-5), cyclophosphamide (300 mg/day, Days 1 and 4), vincristine (1 mg/day, Days 2 and 5), and methotrexate (100 mg, Day 1) followed by citrovorum factor (12 mg/day, Days 2 and 3). The overall response rate was 83.3%: 43 CRs (51%) and 27 PRs. The median survival time was 17 months: 6 months for the failures, 12 months for the 27 PRs, and 27 months for the 43 CRs. Fifteen patients with CR are still alive: one after 16 months, one after 17 months, two after 19 months, and one each after 23, 24, 25, 31, 35, 37, 38, 43, 48, 68 and 70 months.

Androgens↗
PubMed1999

A typology of parent rated child behavior for a national U.S. sample.

The purpose of the current study was to build on the emerging effort to produce a meaningful typology of child behavior for school-aged children. The Behavior Assessment System for Children (BASC) Parent Rating Scales for Children (PRS-C) norming data were collected for 2029 6- to 11-year-old children at 116 sites representing various regions of the United States. The PRS-C has 130 items that are rated by the parent on a 4-point scale of frequency, ranging from "never" to "almost always". The Ward method of cluster analysis was used to identify the initial centroids or cluster seeds in this norming sample. An iterative clustering method, a K-means procedure, was used to refine the Ward cluster solution. A nine-cluster solution was selected based on both rational and empirical considerations. The resulting clusters were labeled adapted, physical complaints/worry, average, well-adapted, minimal problems, attention problems, internalizing, general psychopathology-severe, and disruptive behavior problems. The nine-cluster solution is similar to those of Achenbach (1991), Thompson, Kronenberger, and Curry (1989), and other researchers. At the same time, some significant differences exist. The resulting typology points the way toward future cluster studies of child psychopathology and normal behavioral development by delineating additional research and theoretical directions.

Caregivers↗
PubMedDate not supplied

[A system of multidimensional behavior assessment. A scale for parents of children from 6 to 11 years of age. Colombian version].

INTRODUCTION: Behavioral Assessment System for Children (BASC) has demonstrated to be useful in the diagnosis of Attention Deficit Disorder (ADD). PATIENTS AND METHODS: A randomized sample of 120 children, 6 to 11-year-old, participants from the school of the city of Medellín, Colombia, was selected. The sample was stratified by sex and two socioeconomic status (SES). Parents were asked to answer the BASC Parent Rating Scale (PRS) 6-11, authorized Spanish version. RESULTS: Cronbach's alpha coefficient was 0.85 for the clinical scale (9 items). It was 0.75 for the Adaptive Scale (3 items). A scale designed with 4 items to assess ADD (hyperactivity, attention problems, aggression, and conduct problems) showed an alpha coefficient of 0.82. Male children scored significantly higher than female (ANOVA, p < 0.05) in hyperactivity, conduct problems, and atypicality. Children from low SES scored significantly higher than children of high SES on the most of clinical measures (p < 0.05) and lower on the three adaptive measures. Cluster analysis selecting six clusters found a prevalence of 61.6% for normal male children. In the total sample there were a 4% at risk of DDA type II (inattentive) and 14% at risk of DDA type I (combined). CONCLUSIONS: BASC PRS (6-11) showed reliability and validity to assessing the behavior in Spanish speaking Colombian children.

Attention Deficit Disorder with Hyperactivity↗
PubMedDate not supplied

[Use of multidimensional scale for parents of children aged 6 to 11 for the diagnosis of attention deficit with hyperactivity].

INTRODUCTION: The BASC is a multidimensional approach to evaluate the child behavior and it has been validated on the diagnosis of ADD/+H in North American children. OBJECTIVE: Validating BASC-PRS 6-11 on the diagnosis of ADD/+H. PATIENTS AND METHODS: We selected 25 male DSM IV-ADD/+H (combined type), 6 to 11-years-old children, and 25 age, gender, and socioeconomic status matched controls. Mean ages of both groups 8.16 (1.5), schooling of controls 2.64 (1.4), and cases 2.6 (1.9). RESULTS: On the Clinical Scale ADD/+H children had significant (Anova p < 0.01) higher scores in hyperactivity, conduct problems, and attention problems. On the Adaptive Scale only significant differences on social skills and leadership were found, with lower score in the ADD/+H group. A crosstab analysis between group code and each rating variable transformed into categorical (0 and 1) variable, cut-off point = 85 percentile, found that the case children's parents qualified as clinically in higher risk the variables attention problems (OR = 24.4; 95% CI = 4.5-130), conduct problems (OR = 9.0; 95% CI = 1.7-46.9) and hyperactivity (OR = 6.8; 95% CI = 1.6-28.5) (p < 0.01). A discriminant analysis selected attention problems as discriminant function (p < 0.0001). Classification capability 84% for each group. CONCLUSION: Our results proved the validity of the BASC-PRS 6-11 questionnaire for the screening diagnosis of ADD/+H children in a Spanish speaking population.

Adult↗
PubMedDate not supplied

Simultaneous determination of residues of chloramphenicol, florfenicol, florfenicol amine, and thiamphenicol in shrimp tissue by gas chromatography with electron capture detection.

A gas chromatographic (GC) method is presented for determining residues of chloramphenicol (CAP), florfenicol (FF), florfenicol amine (FFa), and thiamphenicol (TAP) in shrimp tissues, with meta-nitrochloramphenicol (mCAP) as the internal standard. The composited shrimp is extracted with basic ethyl acetate, followed by an acetonitrile-basic ethyl acetate mixture. This extract is centrifuged, filtered, evaporated, and reconstituted in water; the reconstituted extract is acidified, defatted with hexane, and passed through a propylsulfonic acid (PRS) and C18 solid-phase extraction (SPE) system. The C18 SPE column is eluted with methanol, and the PRS SPE column is eluted with basic MeOH plus counter ion. The combined eluates are evaporated, reconstituted in acetonitrile, and derivatized with Sylon BFT. After derivatization, the addition of toluene directly to the sample, followed by the addition of basic water, quenches the derivatization process. After centrifugation, the organic layer is carefully removed, and the analytes are determined by GC with electron capture detection. Shrimp tissues were fortified with fenicols (i.e., CAP, FF, FFa, and TAP) at 5, 10, 20, 40, and 80 ng/mL. Overall recoveries were 88, 101, 91, and 84% with overall interassay (between-day) variabilities (i.e., relative standard deviations) of 5.3, 9.4, 12.8, and 7.4% for CAP, FF, FFa, and TAP, respectively. The method detection limits were calculated as 0.7, 1.4, 2.4, and 1.3 ng/g (ppb) for CAP, FF, FFa, and TAP, respectively, based on a 10 g sample. The quantitation limit as determined empirically by this method is the lower limit of the standard curve, which is about 5 ng/g (ppb) for each analyte.

Acetates↗
PubMedDate not supplied

A sequential chemo-radiotherapeutic treatment for patients with malignant gliomas: a phase II pilot study.

BACKGROUND: The purpose of our study was to evaluate the activity and toxicity of a sequential chemo-radiotherapeutic treatment on the basis of an earlier report by The Johns Hopkins Oncology Center. MATERIALS AND METHODS: Eighteen patients with histologically diagnosed malignant gliomas entered the study. Fifteen patients had glioblastoma multiforme (83%). BCNU (40 mg/sqm/die) and Cisplatin (40 mg/sqm/die) were administered concurrently for 3 days every 3-4 weeks. Radiotherapy consisted of 45 Gy whole cranial irradiation plus a 15 Gy boost on the preoperative volume. RESULTS: Thirteen patients had measurable disease and were evaluable for response. After chemotherapy we obtained 3 CRs (complete remission) and 4 PRs (partial remission) (RR (response rate 54%). Three PRs were converted to CRs after radiotherapy, for a complete remission rate of 46% (6/13). The median duration of response was 10 months. The median survival of the entire patients population was 9 months with 33% survival rates at 1 year. Hematological toxicity grade 4 in one patient and grade 3 in two patients were the major complications due to chemotherapy. CONCLUSIONS: Our sequential chemo-radiotherapeutic regimen appears to have significant activity in adults with newly diagnosed high-grade gliomas.

Adult↗
PubMed2000

Phase I/II trial of irinotecan, carboplatin, and paclitaxel in advanced or metastatic NSCLC.

This multicenter study enrolled 73 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). The study design was based on the hypothesis that the non-overlapping toxicities of a 3-drug combination of irinotecan (Camptosar, CPT-11), carboplatin (Paraplatin), and paclitaxel (Taxol) would allow them to be dosed at recommended or standard doses, respectively. Of the 32 patients in phase I portion of the trial, six received irinotecan 40 mg/m2 plus carboplatin at an area-under-curve (AUC) of 6 and paclitaxel 225 mg/m2 on an every-3-week schedule (regimen A). Due to the unexpectedly severe toxicity associated with this regimen, the carboplatin and paclitaxel doses were reduced, while the irinotecan doses were escalated from 40 to 80 to 125 mg and reduced to 100 mg/m2 (regimen B). In the phase II portion of the trial, irinotecan was dosed at 100 mg/m2 because 3 of 8 patients who received the 125 mg/m2 dose in phase I experienced first-course grade 3/4 toxicities. However, the toxicity of regimen B proved unacceptably severe in phase II; 13 of the 40 patients (35%) experienced grade 3/4 neutropenia and 30% suffered febrile or septic neutropenia. The unconfirmed objective response rate in phase I was 64.5%; median time to progression and median survival were 7.1 months and 11.6 months, respectively, and 1-year survival was 46.9%. The unconfirmed objective response rate in phase II was 60.6%, including one complete response (CR) and 19 partial responses (PRs); one CR and 16 PRs were subsequently confirmed. The efficacy and toxicity of this triple combination strongly suggest significant pharmacokinetic and/or pharmacodynamic interactions, warranting continued clinical investigation.

Adult↗
PubMed2000

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.

Adult↗