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OBJECTIVE: To determine the utilization rate of a weight-based heparin nomogram and to assess the performance of the nomogram outside of experimental conditions. STUDY DESIGN: Prospective cohort analysis. PATIENTS AND METHODS: A total of 747 consecutive patients treated with intravenous heparin therapy for any indication on an internal medicine service were evaluated for the utilization rate of the weight-based nomogram, the time needed to exceed heparin's therapeutic threshold (activated partial thromboplastin time [aPTT] of > 1.5 times the control value), and the time needed to achieve heparin's therapeutic range (aPTT of 1.5 to 2.4 times the control value). Physicians were encouraged to use the weight-based nomogram by using conventional continuing medical education techniques and by configuring the computerized order entry system to give physicians an equally easy and voluntary choice between choosing the weight-based nomogram or ordering heparin in the traditional fashion. RESULTS: The study program had no effect in increasing the utilization rate of the nomogram; this rate remained the same as before the program was initiated (10%). Less time was needed both to exceed the therapeutic threshold and to achieve a therapeutic range with the weight-based nomogram compared with physician-guided dosing (P < .001 and P = .021, respectively). No difference was demonstrated between the weight-based and physician-guided groups in incidence of bleeding complications or in the proportion of patients with one or more supratherapeutic aPTTs. CONCLUSIONS: The weight-based nomogram led to superior intermediate outcomes compared with physician-guided dosing. However, despite efforts intended to modify physician behavior, the utilization rate remained so low that it was ineffective. Further research into the reasons why physicians chose not to use the weight-based nomogram and further research into methods to translate efficacious therapies into effective patient care are indicated.

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BACKGROUND: The sizable increase in the United States physician workforce over the last 25 years has led to a concern by health policy analysts that we are training too few generalist physicians, too many specialists and too many doctors altogether. Nearly all analysts' studies report that the United States currently has an adequate or more than adequate supply of physicians; however, few reports discuss practicing physicians' view of the issues. OBJECTIVE: To determine internists' opinion regarding the current and future physician supply and specialty mix. DESIGN: Analysis of results of a mailed questionnaire. SETTING: Nine hundred bed academic medical center in southern Connecticut. PARTICIPANTS: Three hundred seventy eight internal medicine attendings, fellows and residents. MEASURES: Seventeen questions that covered 4 domains: is there or will there be a surplus of general internists, internal medicine subspecialists or total physicians in Connecticut or the United States; which internal medicine subspecialties have a current surplus; what is the correct primary care/specialty care mix for our physician workforce; and what subspecialties are current internal medicine residents planning to pursue? RESULTS: A total of 378 of 686 (55%) mailed surveys were returned. The majority of physicians reported that there is currently no surplus of physicians (68%) or general internists (90%) in the Unites States, but that there is a surplus of internal medicine subspecialists (68%). The majority of the physicians who responded that there is no current surplus reported that there would not be a surplus in 10 years. Subspecialties most frequently indicated to have a surplus in the United States were cardiology (70%) and gastroenterology (57%). A majority of internal medicine residents (66%) indicated that they planned to pursue subspecialty fellowship; the fellowship most commonly indicated was cardiology (23%). CONCLUSIONS: In contrast to the opinion of most health policy analysts, the majority of internists associated with our institution do not believe that there is or will be a physician surplus in the United States. Reasons for a difference of opinion between practicing internists and health policy analysts are worthy of further study.

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An educational Web site on the topic of risk management and medical-legal issues was designed. The site incorporates a 25-question multiple-choice quiz where resident responses were stored in a database for quantitative analysis. Residents who browsed the educational module scored significantly higher on the quiz (81%) than those who did not (62%). The authors conclude that the Web site and accompanying quiz database offer a practical solution for the uniform delivery of risk management in graduate medical education.

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The academic physician-investigator faces many challenges. Obtaining funding to support research is the greatest impediment. The National Institutes of Health, the single largest source of grants for the academic physician-investigator, approved only 14.2% of new investigator grant applications in 1990, compared with 40% in 1965 and 1975. Physicians submitted 25% of all applications, and they have priority scores similar to those applications submitted by investigators with PhD degrees. The 14.2% funding rate for new investigator-initiated grants is considerably less than the 56% success rate of amended renewal investigator-initiated grants. These trends in funding can be discouraging to the new physician-investigator. In addition, more emphasis is placed on clinical practice to generate money to support the new academic physician. These two facts, reduced probability of obtaining a grant and the perceived need to see more patients for salary support, may jeopardize retention of young faculty members. Moreover, training to prepare physicians for academic careers has been poor, with no attention given to the projected needs of the academic centers or the nation. This article describes the dilemma facing young physician-investigators and provides recommendations for improvement to the leaders of American medicine.

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PURPOSE: To report on the deployment of the syringe tracking and testing system in the New Haven needle exchange program, which is the first federally funded evaluation of a needle exchange program conducted in the United States. PATIENTS AND METHODS: A legal needle exchange for intravenous drug users began in New Haven, Connecticut, in November 1990. All syringes distributed by the program received unique tracking codes. Syringes were tracked and HIV-1 proviral DNA prevalence in returned syringes was assessed using polymerase chain reaction and Southern blotting. RESULTS: At the outset of the program, the prevalence of HIV-1 proviral DNA in syringes exceeded two thirds. Prevalence decreased rapidly to less than 45% during the first 3 months of the program and remained at this level for the following 10 months. During the periods of decreasing prevalence and subsequent steady state, no changes in the demographics of program participants or in the drug use habits of newly enrolling clients that could account for the decrease in HIV-1 prevalence in needles were detected. In addition, the program referred almost 20% of its clients to drug treatment programs. CONCLUSION: The needle exchange program in New Haven has decreased the percentage of syringes testing positive for HIV-1 proviral DNA among needle exchange clients while simultaneously serving as an entry point for drug treatment.

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The cytotoxic interactions between etoposide and two fluoropyrimidines (FP), 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd), were determined in L1210 cells by soft agar clonogenic assay and in five human adenocarcinoma cell lines by colony growth assay. The administration of etoposide prior to FP resulted in synergistic cytotoxicity in L1210, HCT-8, Mia PaCa, MCF-7, and T47-D cells while the reverse sequence resulted in additive or antagonistic cytotoxicity in L1210, HCT-8, and Mia PaCa cells. Etoposide prior to FdUrd produced more DNA single strand breaks than expected in L1210 cells, while the reverse sequence produced fewer than expected. The sequence--dependent synergistic cytotoxicity of etoposide--FP correlates with relative DNA single strand break production in L1210 cells.

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From 1969 through 1982, 184 patients with advanced Hodgkin's disease (HD) were treated with combined modality therapy (CMT) at Yale University. The data were reanalyzed in November 1986, with a mean follow-up of 10 years. The patient population consisted of 102 newly diagnosed stages IIIB and IV patients, and 82 patients who had relapsed after initial radical radiotherapy. From 1969 through 1978, the treatment program was induction chemotherapy with nitrogen mustard, vincristine, vinblastine, procarbazine, and prednisone (MVVPP) for three cycles (6 months) followed by low-dose radiation (1,500 to 2,500 cGy) for patients who had achieved complete remission (CR), to all disease sites present before the onset of chemotherapy. From 1978 to 1982, selected "poor-risk" advanced-stage patients received nitrogen mustard, vincristine, procarbazine, prednisone plus Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (MOPP-ABVD) induction chemotherapy, while the remaining patients were randomized between MVVPP and MOPP. One hundred fifty-one patients have achieved CR (82%); 23 (15%) of these 151 have relapsed, with the remaining 128 patients in continuous CR. A total of 62 patients have died, 45 due to HD, and 17 due to other causes. Twelve of these 17 patients died of second malignancies. The 15-year actuarial survival of all patients is 54%. It is 71% if deaths due only to HD are considered. Within the overall group of advanced HD patients, age and multiple extranodal sites of involvement continue to constitute adverse risk factors. The three drug programs used were all equivalent. No improvement resulted from the use of MOPP-ABVD in the poor-risk patients. These results compare favorably with those recently published by the National Cancer Institute (NCI). CMT resulted in an approximate 20% improvement in survival with no increase in second malignancies when compared with chemotherapy alone.

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The cytotoxic effects of ketoconazole, an antifungal agent known to have some activity against human prostate cancer, adrenal cancer, and male metastatic breast cancer, were evaluated using colony-growth and clonogenic assays in eight malignant cell lines. The cytotoxicity of ketoconazole showed a dose- and time-dependent pattern, with the following concentrations inhibiting 90% of the growing colonies (IC90): MCF 7 (human breast cancer) 7.25 micrograms/ml, T 47 D (human breast cancer) 9.0 micrograms/ml, MiaPaCa (human pancreatic carcinoma) 10.0 micrograms/ml, COLO 357 (human pancreatic carcinoma), 9.5 micrograms/ml, HCT 8 (human colonic adenocarcinoma) 27.1 micrograms/ml, DU 145 (human prostatic cancer) 40.0 micrograms/ml, AR 42 J (rat pancreatic carcinoma) 9.0 micrograms/ml, and L1210 (murine leukemia) 8.6 micrograms/ml. Since a concentration of 10 micrograms/ml can be achieved in humans, the use of ketoconazole in human malignancies might be worthy of clinical evaluation.

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The relationship between cytotoxicity and fluoropyrimidine effects on the production of mature cytoplasmic 28S and 18S ribosomal RNA was studied in S-180 cells for the fluoropyrimidines: 5-fluorouracil (FUra), 5-fluorouridine (FUrd), 5-fluorodeoxyuridine (FdUrd), and 5'-deoxy-5-fluorouridine (5'-dFUrd). After a 6-hr drug exposure, the total cytotoxicity in the absence of added thymidine (dThd) was determined by soft-agar cloning and resulted in LC90 (lethal concentration to 90% of cells) values of 0.6 microM FdUrd, 0.7 microM FUrd, 5.3 microM FUra and 93 microM 5'-dFUrd. The RNA-directed (dThd-nonreversible) cytotoxicity was assessed by cloning the cells in the presence of 10 microM dThd. This resulted in an altered order of potency and increased LC90 values to 5.5 microM FUrd, 20 microM FUra, 265 microM FdUrd and 870 microM 5'-dFUrd. The production of mature cytoplasmic rRNA was determined by measuring the amount of [3H]cytidine incorporated into the 28S and 18S rANA species following their separation by agarose gel electrophoresis, compared with the level of [3H]cytidine incorporated into the nuclear rRNA. When all four fluoropyrimidines were compared together, the degree of inhibition of cytoplasmic rRNA production was poorly predictive of the total cytotoxicity in the absence of dThd (correlation coefficient, r = 0.77). FdUrd, in particular, had a very minor effect on rRNA production even at very toxic drug concentrations. When toxicity was assessed in the presence of dThd, however, there was a strong and significant correlation between rRNA production and RNA-directed cytotoxicity (r = 0.95, P less than 0.001), for all the fluoropyrimidines tested, including FdUrd. Thus, when the inhibition of thymidylate formation was eliminated as a site of drug action and only RNA-directed cytotoxicity was assessed, the impaired production of cytoplasmic rRNA was strongly associated with cytotoxicity. These results demonstrate that the inhibition of mature cytoplasmic rRNA production may be an important common mechanism of RNA-directed cytotoxicity for all the fluoropyrimidines, and not limited to FUrd or FUra.

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Since 1979 a protocol of total body electron beam therapy (3,600 rads; 6 MeV), followed by six monthly cycles of chemotherapy (doxorubicin, 30 mg/M2 given intravenously once monthly, and cyclophosphamide, 100 mg/M2 given orally each day for 14 days), has been used to treat fifty patients with mycosis fungoides (primarily Stages I and II). A group of twenty-four patients, treated by identical high-dose electron beam therapy alone, served as control subjects. Actuarial analysis by the Kaplan-Meier method and statistical analysis by the generalized Wilcoxon test of Gehan demonstrated a significant difference (p = 0.008) in the probability of Stages I and II patients' remaining in complete clinical remission when combination therapy was compared with high-dose electron beam therapy alone. No statistically significant difference was demonstrated in patients in Stages III and IV mycosis fungoides. Although 60% of patients were in "complete clinical remission," the longest follow-up being 75 months, all continued to show karyotypic abnormalities of circulating lymphocytes, and 70% had intermittently and abnormally elevated blood levels of Sézary cells.

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Pretreatment hematocrit in 117 advanced-stage Hodgkin's disease patients treated with a combined modality therapy program was evaluated as an independent prognostic variable with regard to survival and relapse-free survival. Age greater than 40 years, and multiple extranodal sites of involvement were found to be statistically significant independent negative prognostic factors with regard to survival. Pretreatment hematocrit, however, was not an independent negative prognostic variable.

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The distribution and level of 5-fluorouracil (FUra) incorporation into RNA were studied in S-180 murine tumor cells for two different fluoropyrimidine nucleosides: 5-fluorouridine (FUrd) and 5'-deoxy-5-fluorouridine (5'-dFUrd) under both cytotoxic (thymidine nonreversible) and nontoxic conditions. Exposure of cells to 200 microM 5'-dFUrd for 6 hr resulted in minor thymidine-nonreversible toxicity (11% cell kill) and produced an FUra incorporation level of 12.5 pmol of FUra/microgram of RNA. Exposure of cells to 1 microM FUrd for 6 hr resulted in considerably more toxicity (74% cell kill) but was found to produce less FUra incorporation (7.8 pmol of FUra/microgram of RNA) than the nontoxic concentration of 5'-dFUrd. Subcellular fractionation (i.e., nucleolar, nucleoplasmic, cytoplasmic) was completed, and the density of FUra incorporation from 5'-dFUrd was found to be approximately equally distributed between nucleoplasmic RNA and nucleolar RNA, independent of toxicity or concentration levels (average nucleolar/nucleoplasmic FUra ratio = 0.75). FUrd, however, was preferentially incorporated into nucleolar RNA (average nucleolar/nucleoplasmic FUra ratio = 22). The nontoxic accumulation of FUra in RNA of cells treated with 200 microM 5'-dFUrd was also associated with the mature cytoplasmic 28 S and 18 S rRNA, the levels of which increased considerably with exposure time. In contrast, in cells exposed to 1 microM FUrd, there was very little FUra measured in the mature 28 S and 18 S rRNA, consistent with an inhibition of rRNA processing. It is concluded that 5'-dFUrd can produce large nontoxic levels of FUra accumulation in cellular RNA compared with FUrd because total FUra incorporation in nuclear RNA was almost equally dispersed between nucleoplasmic and nucleolar RNA, whereas nuclear FUra incorporation from FUrd was preferential for nucleolar RNA. Also, for nontoxic doses of 5'-dFUrd, unaltered rRNA processing over time can result in the large accumulation of FUra-containing rRNA in the cytoplasm.

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Studies were completed in C3-L5178Y cells, in which the DNA-coding region for dihydrofolate reductase messenger RNA (DHFR-mRNA) is amplified, to determine the acute effect of 5-fluorouracil (FUra) on DHFR-mRNA metabolism. There was minimal to no effect of 100 microM FUra on total cytoplasmic DHFR-mRNA levels by 6 and 12 h and only a 25% reduction by 24 h. These results contrasted with the nuclear DHFR-mRNA levels which by 6 h following exposure to FUra increased by 80% in a dose-dependent manner. Furthermore, some of the increased nuclear DHFR-mRNA was found to be in a non-polyadenylated form. Under conditions to examine only RNA synthesized during the drug exposure, FUra was found to markedly enhance the level of newly synthesized nuclear DHFR-mRNA in a dose-dependent manner, while also producing an apparent dose-dependent reduction in the cytoplasmic DHFR-mRNA. RNA fractionated by 1.5% agarose-urea gel electrophoresis revealed two major cytoplasmic DHFR-mRNA species approximately 1.8 and 0.8 kilobases in size. Following a 24-h FUra exposure, a dose-dependent loss of the 0.8-kilobase DHFR-mRNA was observed. The combined results of these experiments indicate that FUra treatment reduces the ability of nascent DHFR-mRNA to relocate to the cytoplasm, suggesting either an inhibition of mRNA processing or nuclear-cytoplasmic transport.

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Studies were completed to examine the effects of the antineoplastic agent 5-Fluorouridine (FUrd) on the metabolism of the small molecular weight nuclear RNA (snRNA). Cultured Sarcoma-180 murine tumor cells were exposed to FUrd concurrent with [3H]cytidine for 6 h, the drug was removed, and the RNA was isolated at 0, 24, or 48 h following the drug treatment. The results of these studies demonstrated that FUrd produced three dose-dependent changes in snRNA metabolism. The electrophoretic migration of the U4 and U6 snRNA was altered in nondenaturing 10% polyacrylamide slab gels. These results were not observed in denaturing gels or when RNA was extracted at temperatures exceeding 25 degrees C, suggesting that the incorporation of 5-fluorouracil induced secondary structural changes in these RNA. A dose- and time-dependent selective reduction in the turnover of the U1 snRNA synthesized in the presence of FUrd was observed as well, with levels over 100% higher than control cells at 48 h after exposure to 10 microM FUrd. These changes in snRNA metabolism may contribute to the reported alterations in large molecular weight RNA metabolism that also result in fluoropyrimidine-treated cells, or to cytotoxicity.

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Due to the high frequency of micro- or macrometastatic disease at the time of diagnosis of cancer, and to the increasing prevalence of cancer in this country, the use of chemotherapy to evoke cure or prolongation of survival has become critically important. In addition, the growth kinetics of large tumor burdens and the high probability of drug-resistant cells in a tumor mass at the time of diagnosis necessitate combinations of chemotherapeutic agents rather than single agents as the most effective mode of treatment. Since there are 40 to 50 active anticancer drugs now utilized, and since synergy between drug combinations is often dose and/or schedule dependent, the number of possible drug combinations and permutations is vast. Thus, screening for effective drug combinations requires a rational approach which will allow for accurate predictions of synergy. Most advances in this scientific approach have utilized biochemical modulation in conjunction with in vitro cytotoxicity assays, in particular, clonogenic assays. Such an approach has generated a number of drug combinations, such as sequential MTX-5FU, with widely applicable clinical efficacy. The continued use of biochemical modulation should rapidly generate new effective drug combinations which will, hopefully, allow us to cure even those cancers presently considered incurable.

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