Mary Bartholomew

Clinical signs of androgen excess as risk factors for coronary artery disease

Women with androgen excess have been found to have higher triglycerides and lower high-density lipoprotein cholesterol concentrations than nonhirsute women and are presumed to be at increased risk of coronary artery disease. However, definitive data linking androgen excess with coronary artery disease is lacking. We evaluated 102 women coming to coronary artery catheterization for signs and symptoms of androgen excess. Hirsutism was found more commonly in those women with confirmed coronary artery disease (chi 2 = 10.11). Waist:hip ratio (an index of android fat distribution) was associated with hirsutism (by ANOVA, F-test) and with coronary artery disease (t-test). The strongest associations were found in older women (aged greater than or equal to 60). Androgen excess in women may signal risk for coronary artery disease.

Aromatase activity in primary and metastatic human breast cancer

Aromatase activity was measured in 104 primary and 24 metastatic breast cancer patients. The assay employed quantitates the production of 3H water release from 1β‐[3H] androstenedione after aromatization. Of 104 human primary breast tumors studied, 64 contained measurable aromatase activity, ranging from 5–70.5 pmol estrone formed/g protein/hour. In primary breast cancers there was no difference in levels of aromatase activity when analyzed by menstrual status or age by decade. Aromatase activity was similar in small and large primary tumors. The median aromatase activity of primary breast tumors (8.6 pmol/g/h) was similar to that found in metastatic breast cancer deposits (12.0 pmol/g/h). Aromatase activity did not correlate with either estrogen (ER) or progesterone (PR) receptor concentration in the tissues assayed. In this regard there were 33 ER− PR− tumor biopsies. Twelve of these 33 tumors contained aromatase activity greater than 10 pmol/g/hour. Cancer 59:779‐782, 1987.

Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome.

We conducted a randomized clinical trial in men with stage D2 prostate cancer to test whether androgen priming potentiates the efficacy of cytotoxic chemotherapy. Eighty-five men with progressive prostate cancer refractory to orchiectomy were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were administered cyclic intravenous (IV) chemotherapy. The patients were randomized to receive either androgen priming or no additional treatment for three days before and on the day of chemotherapy. Median duration of follow-up was 43 months. Response rate (remission plus disease stabilization) was not significantly different between the stimulation and control arm when the analysis was restricted to evaluable patients (79% v 73%, respectively) or when it was extended to all patients (46% v 61%). Median duration of response was similar for the stimulation and control arm (9 and 10 months, respectively). Median survival was 10 months in the stimulation and 15 months in the control group (P = .0047). The androgen sensitivity of the tumors was supported by the greater toxicity in the stimulation arm associated with androgen administration. Factors found to be independently associated with improved clinical outcome included a high Karnofsky score and hematocrit, long duration of response to the initial castration, and normalization of an elevated serum acid phosphatase on treatment. We conclude that in this group of patients with advanced disease, androgen priming does not potentiate the efficacy of chemotherapy and is actually associated with a worse outcome. Furthermore, our data emphasize the heterogeneity of biologic behavior of prostate cancer.

Unmet needs of persons with cancer in pennsylvania during the period of terminal care

A stratified random sample of recent cancer deaths was drawn from the Pennsylvania death registry, and 433 family members or close friends were interviewed concerning unmet needs during the last month of life. It was estimated that 72% of persons who died of cancer in Pennsylvania experienced at least one unmet service need during this period. The most frequently reported was help with activities of daily living, estimated at 42% of cancer deaths, involving over 11,000 persons each year in the state. There were significantly more unmet needs during the terminal period, compared with just after diagnosis, in activities of daily living, obtaining health care, transportation, and problems with medical staff. Our findings indicate a need to increase a broad range of support programs during the terminal period, especially of home‐care services.

Bladder and rectal complications following radiotherapy for cervix cancer

One-hundred and thirty-two patients with cervix carcinoma who were treated with whole pelvis irradiation and two intracavitary applications had bladder and rectal dosimetry during brachytherapy with contrast agents placed into the bladder and rectum prior to orthogonal simulator radiographs. Doses were computer calculated at points A and B, F (bladder), R1 (rectum), and R2 (rectosigmoid). Late occurring bladder and rectal complications were graded on a severity scale of 1 to 3, and 14% had grade 2 or 3 injuries (9% developed fistulas). Statistical evaluation of the data showed that severe bladder and rectal injuries occur more commonly in stage IIIA and IIIB disease and in those receiving high external beam doses (5000 rad +). Analysis of variance tests revealed a significant correlation of brachytherapy dose to points R1 and R2 with severe rectal injuries but there was not a correlation of dose to F with bladder injuries. Nor was there correlation of injuries with dose to point A or the milligram-hour dose. We conclude that our technique for rectal dosimetry is adequate but that an improved technique of bladder dosimetry is needed. Also, when combining whole pelvis irradiation with two intracavitary applications (4000 rad to point A), the whole pelvis dose should probably not exceed 4000-4500 rad.

Treatment with 13-cis-Retinoic Acid in Transfusion- Dependent Patients with Myelodysplastic Syndrome and Decreased Toxicity with Addition of Alpha-Tocopherol

PURPOSE The purpose of this study was to determine the response and tolerance to long-term treatment using 13-cis-retinoic acid (13-CRA) in transfusion-dependent patients with the myelodysplastic syndrome (MDS) and to determine the effects of therapy on the natural history of the disease. PATIENTS AND METHODS Sixty-six consecutive patients with transfusion-dependent MDS seen in a medical school hospital and outpatient clinic from 1981 to 1988 were studied. The first 21 patients were treated with 13-CRA alone and the next 45 patients with 13-CRA plus alpha-tocopherol (AT). We compared responses to and toxicities of therapy, rates of transformation, and survival from onset of therapy in 20 evaluable patients treated with 13-CRA alone and 43 patients treated with 13-CRA plus AT. RESULTS Four patients responded (20%) at 4 to 8 months to 13-CRA alone, but this response was associated with considerable toxicity and resulted in cessation of therapy. Among the responders, only one continued therapy and is currently in remission, whereas three discontinued therapy because of toxicity and have had a relapse and died. In the 13-CRA plus AT group, we observed one prolonged complete remission and 10 partial remissions (26%), with a decrease in skin and constitutional toxicities by the addition of AT, which enabled the continuation of 13-CRA indefinitely. Although the response rates were similar in both groups, fewer patients (28% versus 60%) experienced progression to acute leukemia in the 13-CRA plus AT group than in the group receiving 13-CRA alone, who terminated treatment (p = 0.018). A twofold increase in median survival of the RA/RARS and RAEB/CMML patient groups was observed with 13-CRA plus AT but was not significant (p greater than 0.5). CONCLUSION This study shows a 20% to 26% response rate to 13-CRA and suggests that 13-CRA, if given continuously, decreases the rate of progression or transformation to acute leukemia in patients with MDS. The addition of AT ameliorates the toxicity of 13-CRA and allows for long-term treatment with 13-CRA. Since the standard treatment for MDS is currently unsatisfactory, these findings indicate that longer treatment with a non-marrow-suppressive agent such as 13-CRA is important, and further trials to determine the role of 13-CRA plus AT in combination with new recombinant growth factors in the therapy for transfusion-dependent MDS should offer a new approach to a disease common in the elderly population.

Correlation of afferent pupillary defect with visual field loss on automated perimetry.

The study was designed to ascertain the relationship between visual loss in the central 30 degrees of vision and the density of the relative afferent pupillary defect (APD). The APD of 26 patients was quantified using a neutral log density filter. The mean threshold light sensitivity on Humphrey automated perimetry (Program 30-1) of one eye was substracted from the fellow eye total to yield the interocular visual field difference (VFD). A direct correlation was noted such that the log density of the APD increased linearly with an increase in VFD (r = 0.69, P = 0.0001). In the absence of ptosis or ocular media opacification, a VFD greater than 8.7 that is not associated with an APD is suggestive of functional visual loss. Four patients had an APD despite normal static automated perimetry, indicating that an APD may be one of the earliest signs of retinal ganglion cell or axonal dysfunction.

Pelvic exenteration: A morbidity and mortality analysis of a seven-year experience

Twenty patients have undergone pelvic exenteration at the University Hospital of the Pennsylvania State University from 1979 to 1985. The majority of operations were performed for cancers of the cervix or vagina that recurred following radiotherapy. Operative mortality was 5.0%. Of those surviving the procedure, 16 patients (84%) were rehospitalized for complications that occurred more than 30 days after exenteration. The majority of these involved the gastrointestinal or urinary tracts. Fifty-eight percent of the complications requiring surgical intervention occurred more than 1 year after surgery while 74% of the complications managed conservatively occurred within 1 year of surgery. The 2-year survival for all patients was 70%; survival decreased to 58% at 5 years. The most important risk factor for reduced survival was the extension of tumor laterally into the surgical margins.

Colonic polyamine content and ornithine decarboxylase activity as markers for adenomas.

Polyamine content (putrescine, spermidine, and spermine) or ornithine decarboxylase (ODC) activity was measured in normal‐appearing colonic mucosa from patients undergoing colonoscopy. Comparisons were made between those with and those without adenomatous polyps. Colonic mucosal polyamine content was measured in 44 persons. Mean putrescine content was 1.25 ± 0.26 (SE) nmol/mg protein in 22 patients with adenomatous polyps compared with 0.53 ± 0.12 nmol/mg protein in patients without polyps (P < 0.02). Tissue content of spermidine and spermine did not differ between these two groups. Ornithine decarboxylase activity was measured in tissue from 45 patients. Mean ODC activity was 2.84 ± 0.73 pmol/hr/mg protein in 23 persons with adenomatous polyps compared with 1.15 ± 0.18 pmol/hr/mg protein in persons without polyps (P < 0.05). Mucosal putrescine and ODC activity are elevated in patients with adenomatous polyps compared with patients without polyps. These biochemical markers may prove helpful in improving surveillance methods for colorectal cancer and premalignant adenomatous polyps.

Polyamine involvement in basal and estradiol-stimulated insulin-like growth factor I secretion and action in breast cancer cells in culture

Recent evidence indicates that the polyamine pathway may play a significant role in the autocrine/paracrine control of breast cancer cell proliferation by hormones. To directly test this hypothesis, in the present experiments, we evaluated the polyamine involvement in immunoactive insulin-like growth factor I (IGF-I) secretion and IGF-I action using MCF-7 breast cancer cells cultured in serum-free medium in the presence and absence of estradiol (E2). Administration of the polyamine biosynthetic inhibitor, alpha-difluoromethylornithine (DFMO) induced a marked suppression of cellular ornithine decarboxylase (ODC) activity and polyamine levels which was associated with significant, although partial, inhibition of E2-stimulated growth. Exogenous putrescine administration repleted cellular polyamine pools and completely reversed the growth-inhibitory effect of DFMO. Despite these parallel changes in polyamine levels and proliferative activity, basal as well as E2-stimulated levels of immunoactive IGF-I measured in the conditioned media were unaffected by DFMO with and without exogenous putrescine administration. On the other hand, induction of polyamine depletion and repletion by the same treatments significantly (although partially) affected the proliferative action of exogenously added IGF-I. These findings indicate that polyamines, while not involved in immunoactive IGF-I production, play an important role, at least in part, in IGF-I action in this experimental system. Furthermore, we observed that the administration of a monoclonal antibody directed against IGF-I was able to partially block basal as well as of a monoclonal antibody directed against IGF-I was able to partially block basal as well as E2-stimulated MCF-7 cell proliferation. We conclude that immunoactive IGF-I is an important but not sole mediator of MCF-7 breast cancer growth under our experimental conditions. The polyamine pathway plays an important role in the expression of its proliferative action.