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Biomedical subjects

R Phelps

Publications and source records attributed to R Phelps.

At least 37 records · Page 2Linked to original sources
PubMed1993

Individualized chemotherapy for patients with non-small cell lung cancer determined by prospective identification of neuroendocrine markers and in vitro drug sensitivity testing.

We attempted to prospectively select individualized chemotherapy for 165 non-small cell lung cancer patients based on in vitro analysis of neuroendocrine (NE) markers and drug sensitivity testing (DST) using fresh tumor. The chemotherapy used for small cell lung cancer (SCLC) was selected when NE marker expression determined by L-dopa decarboxylase assay was documented. Selection of chemotherapy for other patients was guided by DST results using a modified dye exclusion assay when available; otherwise etoposide and cisplatin was administered. A total of 112 of 165 (68%) specimens were assayed for L-dopa decarboxylase and 36 patients (22%) had DST. In vitro data directed management for 27 of 96 (28%) patients given chemotherapy: 6 with NE markers were treated with the SCLC regimen; and 21 (58% of those with DST) received their DST-selected chemotherapy regimen. There were no significant differences in response rate among all 3 treatment arms (P = 0.076). However, response to chemotherapy for the patients treated prospectively with a SCLC regimen was 3 of 6 (50%), marginally better than patients given their DST-selected chemotherapy regimen (2 of 21; 9%; P = 0.056) or those treated with etoposide and cisplatin (10 of 69; 14%; P = 0.061). When patients whose NE markers were identified retrospectively are included, 4 of 9 (44%) responded to administered chemotherapy, compared to 7 of 55 (13%) with no NE markers present (P = 0.04). There were no differences in survival among the three treatment groups. Cisplatin and etoposide comprised the most active regimen in vitro for tumors from 16 of 36 (44%) patients, potentially limiting the benefit of DST since this is often the empiric therapy for non-SCLC. Furthermore, the correlation between in vitro and clinical response is nonsignificant for all drugs tested, highlighting the overall relative resistance of non-SCLC tumors to currently available chemotherapy.

Antineoplastic Agents↗
PubMed1993

Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking-related second primary cancers.

OBJECTIVE: To determine the incidence of second primary cancers developing in patients surviving free of cancer for 2 or more years after treatment for small-cell lung cancer and to assess the potential effect of smoking cessation. DESIGN: Retrospective review of 540 patients from a single institution with a median follow-up of 6.1 years. SETTING: A single government institution (the National Cancer Institute). PATIENTS: Consecutive sample of 540 patients with histologically confirmed small-cell lung cancer treated from 1973 through 1989 on therapeutic clinical trials. MEASUREMENTS: The relative risk for second primary cancers and death were calculated in patients who remained free of cancer for 2 years after initiation of therapy. The relation of these end points to smoking history was also determined. RESULTS: Fifty-five patients (10%) were free of cancer 2 years after initiation of therapy. Eighteen of these patients developed one or more second primary cancers, including 13 who developed second primary non-small-cell lung cancer. The risk for any second primary cancer compared with that in the general population was increased four times (relative risk, 4.4; 95% CI, 2.5-7.2), with a relative risk of a second primary non-small-cell lung cancer of 16 (CI, 8.4-27). Forty-three patients discontinued smoking within 6 months of starting treatment for small-cell lung cancer, and 12 continued to smoke. In those who stopped smoking at time of diagnosis, the relative risk of a second lung cancer was 11 (CI, 4.4 to 23), whereas, in those who continued to smoke, it was 32 (CI, 12 to 69). CONCLUSIONS: Patients with small-cell lung cancer who survive cancer-free for more than 2 years have a significantly increased risk for development of a second primary smoking-related cancer. Cigarette smoking cessation after successful therapy is associated with a decrease in risk for a second smoking-related primary cancer.

Aged↗
PubMed1993

Atrial natriuretic factor and arginine vasopressin production in tumor cell lines from patients with lung cancer and their relationship to serum sodium.

Patients with lung cancer (n = 263) were studied to determine the relationship among ectopic production of atrial natriuretic factors (ANF) and arginine vasopressin (AVP), serum sodium, and patient outcome. Of 133, 21 (16%) patients with small cell lung cancer (SCLC) had hyponatremia (serum sodium, < 130 mmol/liter), compared to none of 130 (0%) patients with non-small cell lung cancer (P < 0.0001). Patients with extensive-stage SCLC and hyponatremia had shorter survival than patients with extensive stage SCLC and normal serum sodium values (P = 0.012). Of the 11 hyponatremic patients with SCLC and tumor cell lines available for study, 9 produced ANF mRNA, 7 of 11 produced AVP mRNA, and 5 of 11 produced both ANF mRNA and AVP mRNA. All 11 cell lines produced either ANF mRNA and ANF peptide or AVP mRNA and AVP peptide, or both. The quantity of AVP peptide in the tumor cell lines was more closely associated with hyponatremia in the patients (P = 0.0026, r2 = 0.28) than was the production of ANF peptide (P = 0.066, r2 = 0.12), although neither association was strong. All tumor cell lines studied from SCLC patients with hyponatremia produce ANF and/or AVP mRNA and peptides.

Arginine Vasopressin↗
PubMed1993

Phase I trial of dihydrolenperone in lung cancer patients: a novel compound with in vitro activity against lung cancer.

Antitumor activity of the butyrophenone dihydrolenperone in non-small cell lung cancer was initially suggested by in vitro screening against tumor cells derived from fresh surgical samples using the human tumor colony-forming assay. We have completed a directed phase I trial in patients with lung cancer. Thirty-two patients with lung cancer have completed 25 courses of therapy at doses of 10 to 60 mg/square meter orally on a twice daily schedule. Twenty-three men and 9 women with a median age of 55 (range 24-69) were entered. Twenty-four were performance status 0 or 1 and 8 were 2. The maximum tolerated dose was 50 mg/square meter orally twice daily and the dose limiting toxicity was somnolence. Of the 32 patients, 18 developed symptomatic hypotension (grade 1 or 2). There was no significant hematologic, renal, or hepatic toxicity. In vitro drug testing using the MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (thiazolyl blue)] assay confirmed 50% inhibition of non-small cell and small cell lung cancer cell line growth at 70-450 micromolar concentrations. Plasma dihydrolenperone levels were at least 75-fold less than levels at which in vitro activity was observed. We conclude: 1) the maximum tolerated dose in our study is 50 mg/square meter orally twice daily, 2) the dose-limiting side effect of dihydrolenperone is somnolence, and 3) the concentrations of dihydrolenperone observed in plasma are significantly lower than those associated with in vitro activity.

Adult↗
PubMed1993

Cutaneous reactions to vitamin K1 injections.

Cutaneous reactions to vitamin K1 injections are reported infrequently. Most previously reported cases have been associated with liver disease, primarily alcoholic cirrhosis and viral hepatitis. Four new cases are reported. One patient had polycythemia vera and the Budd-Chiari syndrome, the second such report in the literature. The other three patients had no known hepatic disease. The reactions consisted of erythematous plaques at the injection site without progression to sclerodermatous plaques. Histopathologic examination in three cases showed spongiotic changes and mononuclear infiltrates typical of cutaneous reactions to vitamin K1. In one instance a neutrophilic infiltrate was associated with the reaction site. Our findings support the observation that liver disease is not a necessary condition for the occurrence of vitamin K1 hypersensitivity.

Adult↗
PubMed1992

High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors.

We analysed the p53 open reading frame (ORF) in 16 small-cell lung cancer (SCLC) cell lines by direct sequencing of cDNA/PCR products and in 20 SCLC tumors by chemical cleavage and single-strand conformation polymorphism analyses of genomic DNA/PCR products. Abnormalities of p53 were found in 16/16 cell lines (100%) and in 16/20 tumors (80%). In the SCLC cell lines, mutations (59% missense, 18% nonsense and 23% splicing) changing the coding sequence were dispersed between amino acids 68 and 342. In the tumor samples, while the mutations occurred predominantly in exons 5-8, other mutations were located outside these regions. G to T transversions were common, occurring in 32% of the cases. We found no p53 mutations in the corresponding normal tissue from 19 patients whose tumors had p53 lesions, indicating that the mutations were all somatically acquired. In analysing the clinical data of the patients we found no correlation between tumor response to therapy or survival and the location or type of mutations. We conclude from these data that: (1) p53 mutations are found in SCLC with high frequency; (2) p53 mutations in a significant fraction of cases generate cDNAs with nonsense or splicing mutations; and (3) to date, these mutations have all been somatically acquired events.

Base Sequence↗
PubMed1991

ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent.

We analyzed 66 non-small cell lung cancer cell lines for mutations at codons 12, 13, and 61 of all three ras genes and correlated the findings with patient survival. We used designed restriction fragment-length polymorphisms to detect mutations after amplification of ras-specific sequences by the polymerase chain reaction. We found 19 mutations of ras genes (29%), and 11 of these 19 (58%) were at codon 12 of the K-ras gene. By univariate analysis, the presence of any ras mutation in cell lines from patients who received curative intent treatment was associated with a shorter survival (P2 = 0.002). For patients who received only palliative treatment, detection of K-ras mutations at codon 12 was associated with a shortened survival (P2 = 0.0103), but this analysis was not statistically significant for the group with any ras mutation (P2 = 0.093). The Cox proportional hazards model also predicted a higher risk for patients with any type of ras mutations. We conclude that ras mutations, present in a subset of non-small cell lung cancers, are independently associated with the shortened survival of patients, irrespective of treatment intent.

Analysis of Variance↗
PubMed1991

Lung cancer: rational strategies for early detection and intervention.

The current mortality rate for lung cancer, which approaches 90% at two years, is not decreasing despite intensive clinical trials attempting to improve systemic therapy. New drug discoveries and dose intensification approaches have not resulted in more effective anti-tumor control. An alternative approach using sputum immunocytology for early lung cancer detection was recently reported. The proposed basis for this early detection reflects the underlying biology of immunodominant carbohydrate tumor-associated antigens, which are recognized as a class of oncofetal antigens. The process of bronchial epithelial carcinogenesis is associated with an evolution of carbohydrate display which reverses the sequence originally associated with fetal organ development. By elucidating this pattern of fetal carbohydrate display, a precise map of stage of bronchial carcinogenesis may emerge.

Antigens, Neoplasm↗
PubMed1990

Tumor cell lines established in vitro: an independent prognostic factor for survival in non-small-cell lung cancer.

OBJECTIVE: To determine the relation between in-vitro establishment of tumor cell lines and survival in patients with non-small-cell lung cancer. DESIGN: Cohort study. SETTING: Single-institution tertiary care center. PATIENTS: One hundred twenty-three consecutive patients with non-small-cell lung cancer from whom a viable tumor specimen could be obtained. INTERVENTION: Tumor tissue was removed at the time of entry into a therapeutic protocol. The tumor tissue was processed in the laboratory for attempted cell-line establishment. Patients classified as potentially curable (stages I, II, and IIIA) were treated with surgical resection, radiation therapy, or a combination. Patients suitable for palliative therapy only (stages IIIB and IV) were treated with radiation therapy with or without chemotherapy. Chemotherapy was based on in-vitro drug sensitivity when available. Cell-line establishment was correlated to clinical outcome. MEASUREMENTS AND MAIN RESULTS: Univariate analysis of survival was done using the log-rank test; multivariate analysis was done by Cox modeling step-up and step-down techniques. Cell lines were established from the tumor specimens of 25 patients (20%). Those patients experienced a median survival of 7 months compared with 18 months in patients from whom cell lines could not be established (P less than 0.001). In the 61 patients with potentially curable disease, 8 patients (13%) with cell lines established had a median survival of 8 months compared with 32 months for those without cell lines established (P = 0.001). In the 62 palliative group patients, the median survival of the 17 patients (27%) from whom tumor cell lines were established was 5 months compared with 7 months for those without cell lines (P = 0.15). Multivariate analysis in both groups showed cell-line establishment to be a significant indicator of prognosis (P less than 0.0001 for curable group; P less than 0.01 for palliative group). CONCLUSION: In-vitro tumor growth is related to decreased patient survival, which in turn reflects the biologic aggressiveness of cancers giving rise to these tumor cell lines.

Analysis of Variance↗
PubMed1990

Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sézary syndrome.

We previously demonstrated that recombinant interferon alfa-2a (IFN-alfa) in a dose of 50 X 10(6) U million units (MU)/m2 intramuscularly (IM) three times per week has efficacy against mycosis fungoides (MF) and the Sézary syndrome (SS). However, this regimen given to patients with refractory disease was uniformly complicated by toxicities requiring major dose reductions. The present study was designed to determine if intermittent high-dose IFN-alfa would preserve efficacy and decrease toxicity in a similar patient population. Twenty-four patients with advanced disease refractory to one or more standard therapies received IFN-alfa, 10 MU/m2 IM on day 1 followed by 50 MU/m2 IM on days 2 to 5 every 3 weeks; after the first four cycles, stable and partially responding patients underwent dose escalation to twice the starting dose. One complete (CR) and six partial responses (PRs) were observed (response rate, 29%; 95% confidence interval, 13% to 51%) lasting 4 to 19 months (median, 8 months). No improvement in objective response was seen in the eight patients who received dose escalation. Dose reductions were necessary in eight of 22 patients receiving one or more cycles of therapy. Weighted mean dose rate intensity for patients on this study over the first four cycles of treatment was 65.5 MU/m2/wk compared with 73.2 MU/m2/wk over the first 12 weeks of treatment in patients from the previous study, in which all 19 patients receiving more than 1 week of treatment required dose reduction. IFN-alfa is effective against previously treated MF and the SS and is better tolerated on this intermittent schedule.

Combined Modality Therapy↗
PubMed1990

Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years.

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.

Adult↗
PubMed1988

Female patients with small cell lung cancer live longer than male patients.

PURPOSE: The incidence of lung cancer is rising in women in the United States, and recent reports have suggested that female patients treated for small cell lung cancer have an improved survival compared with their male counterparts. In view of these findings, we decided to determine if, in our patient population, women live longer than men and if a higher proportion of female patients are entering our trials. PATIENTS AND METHODS: The survival of women entering therapeutic clinical trials for small cell lung cancer from 1973 through 1986 at the National Cancer Institute-Navy Medical Oncology Branch was evaluated and compared with the survival of similarly treated men during the same time period. RESULTS: The survival of female patients was longer than that of male patients (median of 13 months versus 10 months). Cox proportional hazards modeling incorporating multiple prognostic factors indicated that women survived significantly longer than men (p = 0.002) when adjustment for other significant factors was made. This survival advantage for women was consistent in both early and late time periods analyzed. In addition, women constituted a larger proportion of patients entering clinical trials in the later time period, as is consistent with the rising incidence of lung cancer in women nationwide. CONCLUSION: We believe it will be important that comparisons of current clinical trials with older trials that enrolled fewer women control for the favorable prognostic factor of the female sex.

Carcinoma, Small Cell↗
PubMed1985

Psychosocial childbearing stress and metabolic control in pregnant diabetics.

The authors tested the relationship between psychosocial childbearing stress factors and metabolic control in a research sample of 39 pregnant insulin-dependent diabetic women. Subjects were selected using rigorous exclusion criteria from a population of more than 200 pregnant diabetic patients assessed in a University National Institutes of Health Center. Metabolic control was determined by plasma levels of preprandial day, night, and early morning fasting glucose, urinary ketones, and glycosylation of hemoglobin. Differences in plasma glucose concentrations and urinary ketone levels at several times during the day and night were associated with psychosocial stress factors. A similar relationship between stress and levels of diabetic control could not be demonstrated by hemoglobin A1 assay, a result contradicting most prior studies of adolescent populations. These findings are compatible with a biopsychosocial model of diabetes mellitus and emphasize the importance of using several different measures of diabetic control to determine stress-control relationships.

Adaptation, Psychological↗