A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance.

PURPOSE: The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel. METHODS: Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed. RESULTS: The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted. CONCLUSIONS: The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.

Plasmablastic lymphoma presenting in a human immunodeficiency virus-negative patient: a case report.

Plasmablastic lymphoma (PBL), an aggressive non-Hodgkin's lymphoma that carries a poor prognosis, previously has been identified almost exclusively in patients infected with the human immunodeficiency virus (HIV). We present a case of a 42-year-old HIV-negative patient presenting with an isolated nasal cavity mass, the typical presentation for PBL. The patient was given systemic chemotherapy, central nervous system prophylaxis, and consolidative locoregional radiotherapy and achieved a complete clinical response. This case suggests PBL should be considered in HIV-negative patients with characteristic findings.

Impact of a program to diminish gender insensitivity and sexual harassment at a medical school.

PURPOSE: To measure the effect of an intervention to reduce gender insensitivity and sexual harassment at one medical school. METHOD: Stanford University School of Medicine undertook a multifaceted program to educate faculty and students regarding gender issues and to diminish sexual harassment. The authors developed a survey instrument to assess the faculty's perceptions regarding environment (five scales) and incidences of sexual harassment. Faculty were surveyed twice during the interventions (1994 and 1995). RESULTS: Between the two years, the authors measured significant improvements in mean ratings for positive climate (p = .004) and cohesion (p = .006) and decreases in the faculty's perceptions of sexual harassment (p = 0006), gender insensitivity (p = .001), and gender discrimination (p = .004). The faculty also reported fewer observations of harassing behavior during the study period. CONCLUSIONS: An intervention program to diminish gender insensitivity and sexual harassment can measurably improve a medical school's environment.

Outcome measurement in postgraduate year one of graduates from a medical school with a pass/fail grading system.

PURPOSE: To measure the performances of first-year residents who had graduated from a medical school with a pass/fail grading system and to compare the preparedness of these graduates with that of their peers. METHOD: All 169 graduates of Stanford University School of Medicine's classes of 1993 and 1994 were included in this study. First-year program directors rated the performance of each Stanford graduate in 11 areas, compared the graduate's clinical preparedness with that of his or her peer group, and rated the accuracy of the dean's letter in presenting the graduate's capabilities. RESULTS: Responses were obtained for 144 of the 169 graduates (85%). The program directors rated the overall clinical competencies of most of the graduates as "superior" (76%) or "good" (22%); they rated very few as "unsatisfactory" (2%). When the Stanford graduates were compared with their peers, their clinical preparedness was judged "outstanding" (33%), "excellent" (44%), and "good" (20%); very few were judged "poor" (3%). Stratification of programs by either hospital or medical specialty did not reveal significant differences in overall clinical competence. Ninety-one percent of the responses reported that the dean's letters had accurately presented the capabilities of the graduates. CONCLUSION: Graduates from a medical school with a two-interval, pass/fail system successfully matched with strong, highly-sought-after postgraduate training programs, performed in a satisfactory to superior manner, and compared favorably with their peer group.

[An examination program for prospective dental students]. / 'n keuringsprogram vir voornemende tandheelkunde studente.

The aim of this study was to develop a selection programme for prospective dental students at the University of Pretoria. A study of relevant literature was undertaken, and experts at universities in South Africa, Britain and Belgium were interviewed, in order to research and analyse existing selection procedures with a view to developing a concept selection programme. By means of a job analysis questionnaire relevant job requirements were ascertained, which were utilised as criteria for a concept selection programme.

The relationship of clinical knowledge to months of clinical training among medical students.

PURPOSE: To assess the correlation of the number of months of clinical training with clinical knowledge, as measured by the United States Medical Licensing Examination (USMLE) Step 2. METHOD: The total number of months of clinical training and percentile scores on USMLE Step 2 were determined for 217 Stanford. University School of Medicine graduates from 1992 through 1994. Percentile scores on each subsection of the Medical College Admission Test (MCAT) and the National Board of Medical Examiners Part 1 or USMLE Step 1 (Part 1/Step 1) for the graduates were also determined. For some analyses the graduates were separated into three groups according to the duration of clinical training. The Pearson product-moment correlation coefficient was used to quantify and define the significance of correlations. The Jorickheere-Terpstra nonparametric test was used to assess trends across the three groups. A multiple linear regression model was used to test the effects of confounding variables. RESULTS: The total numbers of clerkship months ranged from 12 to 23; the median was 18. A highly significant correlation was found between increasing months of clinical training and increasing scores on Step 2 (p = .002); a weaker significant correlation was found with scores on Part 1/Step 1 (p = .03). The correlation for Step 2 scores did not diminish appreciably (p = .004) when scores for Part 1/Step 1 and each MCAT subsection were introduced into the regression model. CONCLUSION: A highly significant correlation was found between the amount of clinical training and the acquisition and utilization of clinical knowledge. In the current climate of concerns about the rising costs of medical education, the impulse to solve these concerns by decreasing the amount of medical students' clinical training should be approached with caution.

A multicenter maintenance study of oral pilocarpine tablets for radiation-induced xerostomia.

Two hundred sixty-five patients with head and neck cancer who had previously participated in either a fixed-dose, dose-titration, or dose-ranging trial of oral pilocarpine hydrochloride tablets were enrolled in a 36-month multicenter maintenance study to evaluate the long-term safety and efficacy of oral pilocarpine for the treatment of radiation-induced xerostomia. In this open-label study, the initial drug dose was 5.0 mg tid, with possible adjustments from 2.5 to 10.0 mg tid or bid. Efficacy was evaluated by subjective measures of oral function. Safety evaluations were based on self-report of symptoms (or of adverse effects), various examinations, and laboratory tests. There was significant improvement in all criteria of oral function. Sweating was the most frequent adverse experience (55%). Less frequent side effects, mild to moderate in nature, included increased urinary frequency, lacrimation, and rhinitis. Side effects usually diminished within hours after the cessation of therapy. We conclude that oral pilocarpine at these doses effectively and safely reduces the symptoms of radiation-induced xerostomia.

A climate survey for medical students. A means to assess change.

An instrument was developed to assess the perceptions of students regarding six aspects of school climate and their experience of and attitudes toward sexual harassment and gender insensitivity. During clerkship orientation, 77 students (92% return rate), half female, were given the survey. Cronbach alpha reliabilities for the six scales ranged from .71 to .85. One significant female/male difference among the three scales of general school climate was observed; two significant female/male differences occurred among the three scales relating to gender concerns. Seventy percent of both males and females reported having observed sexually harassing behavior during the previous year; 46% of females and 15% of males reported experiencing sexually harassing behavior during the year. Observing and/or personally experiencing sexual harassment was associated with a decrease in positive climate ratings and an increase in negative climate ratings.

The value of medical student research: the experience at Stanford University School of Medicine.

At Stanford University School of Medicine, students are encouraged to conduct research, requiring a substantial amount of funding and effort on the part of teaching staff. We questioned one graduating class and all medical teachers to determine the value of the research experience to students, as well as staff satisfaction. Seventy-three per cent of students and 80% of teaching staff responded. Ninety per cent of students had performed research resulting in at least one published manuscript for 75% and a presentation at a national meeting for 52%. Almost all thought the experience taught them to ask questions, review the literature critically, and analyse data. Three-quarters responded that the experience motivated them to pursue further research, and 60% indicated that they plan a full-time academic career. The majority of teaching staff who worked with students found it rewarding and thought the student had had a valuable experience. We conclude that our curriculum provides a positive opportunity for students to develop an investigative approach to medical problems.

A phase IA/IB trial of anti-CD3 murine monoclonal antibody plus low-dose continuous-infusion interleukin-2 in advanced cancer patients.

Preclinical studies have shown that anti-CD3 antibodies can enhance the in vitro activation of human T lymphocytes in combination with low-dose interleukin-2 (IL-2) and induce the in vivo rejection of murine tumors. A Phase IA/IB trial combining a murine monoclonal antibody, anti-CD3 antibody (OKT3), with low-dose continuous-infusion IL-2 was conducted in cancer patients to define the toxicity and immunologic effects of this combination. OKT3 administered weekly as a 15-min infusion at dose levels of 10, 100, 200, 400, and 600 micrograms/m2 was followed 18 h later by a 100-h infusion of IL-2 at 3 MIU/m2/day for 3 consecutive weeks. When feasible, patients also received the IL-2 course without OKT3 to assess the effects of OKT3 on the IL-2 regimen within the same patient. Thirty patients were enrolled onto the study, with 24 completing the OKT3/IL-2 course and 18 completing both OKT3/IL-2 and IL-2 alone courses. OKT3 administration was associated with acute hypotension with fevers of > 40 degrees C and in two patients cerebral vascular infarcts. At 600 micrograms/m2 OKT3, these toxicities were dose limiting. In a dose-dependent manner, OKT3 induced the transient release of tumor necrosis factor (TNF) and IL-6 into the serum and a profound lymphopenia. OKT3 did not significantly enhance the toxicity of this schedule of IL-2 administration. All solid tumor patients treated at 100-600 micrograms/m2 OKT3 showed induction of a human anti-murine antibody response prior to the third week of treatment. A patient with renal cell cancer treated at the 600-micrograms/m2 OKT3 dose level experienced a 4-month partial remission, and two mixed responses were observed in a sarcoma and a melanoma patient treated at 100- and 400-micrograms/m2 OKT3 dose levels, respectively. Most importantly, we were unable to demonstrate that the addition of OKT3 enhanced immune activation within peripheral blood based upon the magnitude of rebound lymphocytosis, increase in CD56+ or CD3+, CD25+ lymphocytes, induction of natural killer, lymphokine activated killer, or cytolytic T lymphocyte cytotoxicity, or release of serum cytokines (TNF, IL-6) or soluble CD25 (as assayed 24 h following IL-2 infusion). Therefore, this approach was ineffective at enhancing the immunologic effects of a low-dose continuous-infusion IL-2 regimen and will not be pursued further in clinical trials.

School sexuality education and adolescent risk-taking behavior.

School sexuality education programs have been studied as a means to prevent sexual behavior that puts adolescents at risk for incurring an unwanted pregnancy or a sexually transmitted disease. This review examines and critiques research that measures effects of school sexuality education programs on the sexual risk-taking behavior of adolescents. First, methodological problems common in the literature are discussed. Second, studies measuring effects of school sexuality education programs are examined. Finally, suggestions for future research are made.

PIP: Studies measuring the impact of school-based sex education programs on the prevention of adolescent pregnancy and sexually transmitted diseases have produced inconsistent findings. In part, this may reflect the measurement problems inherent in subsuming under the term "sex education" programs that differ dramatically in terms of their goals, delivery agents, length, structure, and theoretical orientation. A reliance on self-report behavioral data and the infrequent use of unexposed control groups represent additional methodological weaknesses. Only one large-scale study has demonstrated that school sex education can be effective in delaying first intercourse. Although several studies have documented increases in knowledge among sex education course participants, they have failed to record significant increases in contraceptive usage. Most effective appear to be programs that combine a sex education curriculum with free school-based pregnancy prevention clinic services. Methodological refinements in terms of standardization of the definition of sex education, use of objective measures of behavioral change, and case-control studies are essential to facilitate the design of programs that will prevent sexual risk-taking among adolescents.

A phase II study of piritrexim in combination with methotrexate in recurrent and metastatic head and neck cancer.

Thirty patients with recurrent and/or metastatic head and neck cancer were treated with sequentially administered methotrexate (MTX) and piritrexim (PTX). The treatment schedule consisted of intravenous (IV) MTX (50 mg/m2) administered on day 1 and oral PTX (75 mg/m2) administered twice daily on days 8 to 12. Courses were repeated every 21 days with dose escalation in subsequent courses aimed at achieving Grade 1 toxicity. Two patients were not evaluable for response, 5 (17%; 95% confidence interval, 4% to 30%) had a partial response (PR), 10 had stable disease, and 13 had progressive disease. All five responses were seen in patients with regional lymph nodes as measurable disease. The median time to progression for all patients was 1.4 months, and the median survival was 6.7 months. Generally, this regimen was well tolerated with only mild toxicity seen during cycle 1 in the majority of patients. Dose escalation in subsequent cycles was possible in a high percentage of patients. Although the overall response rate and survival figures in this Phase II trial were disappointing, the doses and schedule used in this trial may have been suboptimal as reflected by the low incidence of moderate to severe toxicity. Additional evaluation of this combination of drugs in a more aggressive schedule may be warranted.

A phase II trial of carbetimer for the treatment of colorectal cancer. A trial of the Northern California Oncology Group.

Carbetimer (carboxyimamidate) was administered at a dose of 6,500 mg/m2/day intravenously for 5 consecutive days to 14 patients with measurable metastatic or recurrent colorectal cancer in a single institution phase II study of the Northern California Oncology Group. A total of 38 cycles of therapy were administered; nine patients completed at least three cycles of treatment. No partial or complete responses were observed. One patient did have a greater than 50% response in the liver while developing new retroperitoneal lymphadenopathy and is considered a nonresponder. Carbetimer was well tolerated with elevations of calcium from 10.2 to 12.5 mg/dl in nine patients, prolongation of prothrombin time and partial thromboplastin time in 14 patients, proteinuria in 10 patients, dizziness in six patients, nausea in two patients, and venous pain during infusion in three patients. Myelosuppression was not observed. Carbetimer at this dose and schedule is inactive in the treatment of colorectal cancer.

Head and neck squamous cancers.

Head and neck squamous cancers are a heterogeneous group of neoplasms with varying etiologic factors, presenting symptoms, staging, treatment, and expected outcome. In this monograph, we discuss principles of management common to all sites as well as individual differences. The presenting symptoms of disease are reviewed, stressing the importance of early diagnosis. Accurate pathologic diagnosis can be improved on in difficult cases by newer immunohistochemical techniques. Following diagnosis, accurate clinical staging must be performed, and the evaluation of an unknown primary in the neck is described. We review general considerations for planning the treatment of head and neck cancer, and then discuss specific guidelines for individual sites, stressing the optimal integration of surgery and radiation therapy, particularly brachytherapy. Controversial management issues and new, innovative approaches are discussed. The conventional use of chemotherapy in head and neck cancer is for palliation of recurrent disease. In recent years, chemotherapy has been added to the primary treatment program in an induction role, as a radiosensitizer, as an adjunct following standard therapy, and for organ preservation. The current status of these roles is reviewed. This is a cancer for which there are known etiologic agents. Future efforts in this disease should be directed toward early detection and prevention.

Cisplatin, doxorubicin, and 5-fluorouracil chemotherapy for salivary gland malignancies: a pilot study of the Northern California Oncology Group.

Seventeen patients with advanced or recurrent salivary gland cancer were treated with cisplatin, doxorubicin, and 5-fluorouracil combination chemotherapy (PAF). Two patients achieved a complete response and four patients achieved a partial response, for an overall response rate of 35%. Six of the nine patients who received PAF in the neoadjuvant setting did not respond and proceeded to surgery and/or radiation therapy. No difference in response rate was found between those patients treated for recurrent disease v those treated with neoadjuvant chemotherapy. All three patients with adenocarcinoma responded. The response duration in patients with metastatic or recurrent disease ranged from 6 to 15 months. The PAF regimen was delivered primarily in the outpatient setting and was associated with acceptable toxicity. PAF demonstrates activity in salivary gland malignancies, and further evaluation of this combination seems warranted.

The treatment advice of a computer-based cancer chemotherapy protocol advisor.

ONCOCIN is a chemotherapy protocol advisor used experimentally in a university oncology clinic. The program combines formal protocol guidelines with judgments of oncologists who have experience adjusting therapy in complex clinical situations. We compared the chemotherapy administered by clinic physicians with the treatment that would have been recommended by ONCOCIN in 415 visits for 39 patients with lymphoma seen before the program's introduction. In 189 visits the program agreed with the therapy actually administered. In a blinded evaluation, four experts on lymphoma failed to find a significant difference between the treatments selected by physicians and those proposed by ONCOCIN. Further analyses showed that ONCOCIN tended to attenuate drug doses or delay treatment more than the experts recommended, whereas the physicians were less likely to attenuate doses to the extent the experts suggested. Our results show that ONCOCIN provides advice on lymphoma treatment similar to the treatment provided in a university oncology clinic.

Improvements in data collection through physician use of a computer-based chemotherapy treatment consultant.

The impact of a computer-based data management system on the completeness of clinical trial data was studied before and after the system's introduction in an oncology clinic. Physicians use the system, termed ONCOCIN, to record data during patient visits and to receive advice about treatment and tests required by experimental cancer protocols. Although ONCOCIN does not force the user to enter all data expected by the protocol, after its introduction there was improvement in the recording frequency of such data. The percentage of expected physical findings recorded increased from 74% to 91% (P less than .05), toxicity history from less than 1% to 45% (P less than .01), general chemistry results from 36% to 82% (P less than .01), x-ray results from 44% to 73% (P less than .01), and physicians' assessments of overall disease activity and Karnofsky performance status from 73% to 91% (P less than .05). Analysis of the steps in data collection and their contribution to loss of data suggests that observations or test ordering which are dependent on the physician are most improved by the system. Furthermore, analysis of post-ONCOCIN visits when the system was unavailable suggests that the recording of physician-dependent data (physical findings and assessments of disease activity and performance status) is likely to revert to pre-ONCOCIN levels if the system is not used routinely. The results show that ONCOCIN can greatly enhance recovery of those data expected for chemotherapy protocol patients. The program's interaction with the physician is central to its effectiveness in data collection, especially for data that arise directly from the patient-physician encounter.