Phase i/ii trial of 5-Fluorouracil, leucovorin, Zidovudine and dipyridamole for patients with metastatic colorectal-cancer, renal-cell carcinoma and malignant-melanoma

We conducted a phase I/II trial of 5-fluorouracil (5-FU), calcium leucovorin (LV), zidovudine (AZT) and dipyridamole (DP), (FLAP) in patients with metastatic colorectal cancer, renal cell carcinoma and malignant melanoma. AZT and DP were given to enhance the biochemical modulation and antitumor activity of 5-FU and LV. All patients received 5-FU (370 mg/m(2) i.v. bolus day 0-4), LV (50 mg/m(2) p.o. every 4 h day 0-4) and DP (50 mg/m(2) p.o. every 6 h days 0-27). In the phase I portion of the study, AZT was dose escalated in cohorts of 5 patients each, from 50 mg p.o. every 6 h days 0-27 to the MTD of 200 mg p.o. every 6 h days 0-27. Thirty-three patients received 200 mg of AZT in the phase II portion of the trial. Eleven patients developed grade III and 5 patients developed grade IV leukopenia. Four patients developed grade III and 21 patients developed grade IV neutropenia, with six febrile neutropenic episodes. Six patients experienced grade III anemia and four grade III thrombocytopenia. Diarrhea or stomatitis of greater than or equal to grade III occurred in six and four patients, respectively. Fifty-eight percent (19 of 33) of patients required dose reductions of AZT for hematologic toxicity (13 of 19 in the first treatment cycle). At the 200 mg AZT dose level, there were two partial responses in nine colorectal cancer patients (22%), no objective responses in 14 patients with renal cell carcinoma or in 14 patients with melanoma. FLAP does not have significant activity in melanoma, renal cell carcinoma or 5-FU-treated colorectal cancer patients, although it may have activity in untreated colon cancer.     

Prognostic-significance of chromosome 5q and 17p allelic deletion in colorectal adenocarcinomas

Patient survival was analysed for 75 patients after surgery for primary colorectal adenocarcinoma with regards to allelic loss of chromosome 17p and chromosome 5q. Allelic loss of chromosome 17p occurred in 69% of patients and was not significantly associated with a poorer patient prognosis as assessed by log rank analysis of Kaplan-Meier survival plots (p = 0.161). Allelic loss of chromosome 5q occurred in 32% of patients and was significantly associated with a poorer patient prognosis as assessed by log rank analysis of Kaplan-Meier survival plots (p = 0.014). Analysis of the two variables by Cox regression analysis indicated that allelic loss of chromosome 5q was an independent variable for patient prognosis. Entry of Dukes' stage into the model resulted in a final model with Dukes' stage and allelic loss of chromosome 5q as independent significant variables in assessing patient survival. These results show that allelic loss of chromosome 5q, but not chromosome 17p provides additional prognostic information for assessing patient survival, over and above Dukes' stage.     

The Effects of Fat Distribution on Resting Energy Expenditure in Premenopausal Morbidly Obese Females

Background: upper body, or abdominal, distribution of body fat is associated with a number of metabolic and hormonal aberrations that could influence resting energy expenditure REE. The purpose of our study was to examine the effects of fat distribution on REE of 96 morbidly obese premenopausal females. Methods: the study population consisted of three groups of study subjects, 32 with lower body fat distribution (LBD) and waist-to-hip circumference ratios WHR < 0.80, 20 with intermediate (INT) fat distribution and WHR between 0.80 and 0.85 and 34 females with upper body distribution of fat (UBD) and WHR > 0.85. Indices measured included: (1) REE; (2) maximal oxygen consumption during an exercise tolerance test (VO_2max); (3) basal respiratory quotient (RQ); (4) fasting blood glucose; and (5) serum cholesterol and triglycerides. Results: we found that morbidly obese women who store fat abdominally (WHR > 0.80) have significantly (p < 0.01) higher REE (kcal per h per BSA) than those with lower body obesity. Levels of triglyceride and glucose of the UBD group were also higher than those of the LBD subjects, i.e. 35% and 23%, respectively. VO_2max and RQ were similar between the study groups, suggesting that the elevated REE of the patients with abdominal adiposity were likely not the result of their greater muscle mass or differences in substrate utilization. Conclusion: fat distribution affects REE in morbidly obese premenopausal females, and further research is needed to identify the various entities regulating REE in the morbidly obese.     

Technical aspects of intraoperative monitoring of lower cranial nerve function

The efficacy of monitoring facial nerve activity in decreasing long-term morbidity has promoted an interest in monitoring other at-risk cranial nerves during procedures that involve manipulation of the basal cranial nerves. This presentation details practical techniques for monitoring the lower cranial nerves, which have been experientially developed over the past 9 years. Emphasis is placed on the selection of electrodes and procedural changes required for reliable and safe stimulation of the basal cranial nerves. Either paired hook-wire or tethered needle electrodes can be used for monitoring glossopharyageal, accessory, and hypoglossal nerve function. Several options for monitoring vagus nerve function are discussed. Of these, the transoral placement of paired hook-wire electrodes remains the most reliable, cost-effective, and least morbid technique. Electrical stimulation of the glossopharyngeal and vagus nerves carries the risk of unanticipated, potentially irreversible disturbances in cardiovascular function. Guidelines for type and optimal placement of stimulating electrodes and recommended intensity levels to prevent unfavorable reactions are presented.     

Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer

Epidemiologic and experimental data support a role for 1,25-dihydroxyvitamin D₃ in the growth regulation of prostate cancer. We conducted a phase II clinical trial evaluating calcitriol (1,25(OH)₂D₃) in patients with hormone refractory prostate cancer. We enrolled 14 patients in this study. 1,25(OH)₂D₃ was initiated at a daily oral dose of 0.5 μg and escalated to 1.5 μg daily. No objective responses were observed. However, in two patients decreases of 25% and 45% in prostate specific antigen levels were seen. Hypercalcemia was the predominant toxicity. We conclude that 1,25(OH)₂D₃ given in this manner is inactive in advanced prostate cancer. Dose escalation of oral 1,25(OH)₂D₃ is limited by hypercalcemia.     

Intraoperative radiotherapy in the treatment of neuroblastoma: Report of a pilot study

Background: External beam radiotherapy in advanced neuroblastoma is limited by the volume of normal radiosensitive tissues included in the radiation field. Limitations to external radiation are the late effects to these tissues. Intraoperative radiotherapy (IORT) delivers a single high-radiation dose to a tumor while displacing normal tissues that would have been included in an external field. Standard external radiotherapy can still be done after boost IORT. Methods: Eight advanced-stage neuroblastoma patients who received IORT as part of their multimodality therapy were reviewed to identify the impact of IORT on operative time, complications, and tumor control in the treatment field. The IORT was accomplished by patient transport from the OR to the radiation therapy suite; these were separated by three floors. Results: IORT added 30–75 min to the operative procedure. Tumors in the resection/IORT fields showed no evidence of disease (one), stable tumor size (six), and tumor recurrence (one). Two complications were identified: a urinary fistula and CO₂ retention, which was detected and corrected before the IORT. Neither of these complications was related to the IORT. Two patients who had subsequent tumor resection after IORT demonstrated tumor differentiation to ganglioneuromatous tissue. Conclusions: IORT usually can be completed in less than an hour. No IORT-associated complications were identified. IORT along with maximal tumor resection, external radiation, and chemotherapy enhances local tumor control.Presented in part at the 47th Annual Symposium of The Society of Surgical Oncology, Houston, TX, March 17–20, 1994.     

Dentists' responses to drug misusers

A survey among a sample of illicit drug misusers in 1993 indicated under-use of dental services, in spite of a high prevalence of dental problems, whilst a survey of dentists revealed reluctance to treat such patients. Most dentists use additional infection control procedures when they detect 'at-risk' patients, but their screening procedures are unlikely to be effective. Most dentists in the survey would welcome extra training focused on drug misuse.     

Establishing a new university department of rural health: the first 2 years of the South Australian Centre for Rural and Remote Health

ABSTRACT: This study aimed to describe the establishment of a new University Department of Rural Health (UDRH) in South Australia and to report early achievements. In May 1997, the UDRH was established, key staff were recruited, infrastructure was developed and in April 1998 a Joint University Committee on Rural and Remote Health was formed. By mid-1999, 14 full-time equivalent staff were employed in Whyalla and Adelaide. Early achievements include: review of undergraduate rural placements; increased rural clinical placements by 1000 student-weeks; partnership with the Dental School resulting in training opportunities and falling public dental waiting lists; multidisciplinary teaching practices in four rural sites; priority public health projects established; competitive research grants won; and a capital grant to strengthen Aboriginal health services infrastructure secured. These early achievements demonstrate UDRH potential to have a real impact on health worker education, service delivery, and public health status in rural and remote areas. This strong foundation must now be built on.     

PSYCHOSOCIAL PROFILE OF PREGNANT ADOLESCENTS IN A LARGE AUSTRALIAN REGIONAL AREA

A psychosocial profile was developed of 122 pregnant adolescents attending a public hospital antenatal clinic in a large regional Australian area. Participants completed the Rosenberg Self-Esteem Scale and the Support Behaviours Inventory and were interviewed to obtain psychosocial and demographic information. Results revealed that those who were most likely to have either or a combination of poor self-esteem, lack of social support, be unemployed or smoke, were more likely to be living alone or with friends, not have a partner or have a partner for a shorter period, have a partner who was older, have previous children, have not planned their pregnancy and have less education. The degree of social support was significantly associated with self-esteem. Over half of the sample smoked, and over half were unemployed. These results underscore the importance of addressing psychosocial factors in the implementation of care for the pregnant adolescent.     

How much global ill health is attributable to environmental factors?

Over the years, estimates have been made of the portions of human mortality and morbidity that can be attributed to environmental factors. Frustratingly, however, even for a single category of disease such as cancer, these estimates have often varied widely. Here we attempt to explain why such efforts have come to such different results in the past and to provide guidance for doing such estimates more consistently in the future to avoid the most important pitfalls. We do so by carefully defining what we mean by the terms "environmental," "ill health," and "attributable." Finally, based on these recommendations, we attempt our own estimate, appropriately qualified according to the many remaining uncertainties. Our estimate is that 25-33% of the global burden of disease can be attributed to environmental risk factors. Children under 5 years of age seem to bear the largest environmental burden, and the portion of disease due to environmental risks seems to decrease with economic development. A summary of these estimates first appeared in the 1997 report, "Health and Environment in Sustainable Development," which was the World Health Organization's contribution to the 5-year anniversary of the Rio Earth Summit. A full explanation of how these estimates were made is first presented here. We end with a call for a program of "strategic epidemiology," which would be designed to fill important gaps in the understanding of major environmental health risks in important population groups worldwide.