Ocular manifestations of AIDS

AIDS causes severe depression of the immune system through selective infection of CD4+ T lymphocytes. As such, certain infections and neoplasms occur in these patients often with ocular involvement. Among these, cytomegalovirus retinitis is by far the most common and remains a leading cause of visual loss. Intravenous ganciclovir and foscarnet, the two Food and Drug Administration-approved treatments for cytomegalovirus retinitis, are effective in most cases, but recurrences are the rule. In addition, these virustatic drugs require lifelong administration and dose-limiting toxicity affects many of these patients. Ongoing investigation into current and alternative therapies has produced some promising developments which are discussed here. Also reviewed are recent findings associated with other opportunistic pathogens and neoplasms that affect the eye in AIDS, including varicella-zoster virus, Toxoplasma gondii, and lymphoma.     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

Natural helping functions of lay health advisors in breast cancer education

Summary The Save Our Sisters Project builds on the roles of 95 natural helpers to increase mammography screening among older African American women in a NC county. Natural helpers are lay people to whom others naturally turn for advice, emotional support, and tangible aid. Findings from 14 focus group interviews showed that older women seek out these individuals when they have a female-specific concern, rather than or before seeking help from professionals. The characteristics of natural helpers, revealed in the findings, were used to identify and recruit them to become trained lay health advisors in breast cancer education. Through the SOS Project, natural helpers provide a community-based system of care and social support that complements the more specialized role of health professionals; linking them to women through places and ways that no health professional could begin to acquire. The three roles of lay health advisors are: (1) to assist individuals in their social networks with needs that are difficult for professionals to address; (2) to negotiate with professionals for support from the health system; and (3) to mobilize the resources of associations in their community to sustain support from the health system.     

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.