Loss of retinoic acid receptors in mouse skin and skin tumors is associated with activation of the ras(Ha) oncogene and high risk for premalignant progression.

Retinoic acid receptor transcripts (RARalpha and RARgamma) are decreased in benign mouse epidermal tumors relative to normal skin and are almost absent in carcinomas. In this report, the expression of RARalpha and RARgamma proteins was analyzed by immunoblotting in benign skin tumors induced by two different promotion protocols designed to yield tumors at low or high risk for malignant conversion. RARalpha was slightly reduced in papillomas promoted with 12-O-tetradecanoylphorbol-13-acetate (low risk) and markedly decreased or absent in papillomas promoted by mezerein (high risk). However, mezerein also caused substantial reduction of RARalpha in nontumorous skin. RARgamma was not detected in tumors from either protocol and was greatly reduced in skin treated by either promoter. Both RARalpha and RARgamma proteins were decreased in keratinocytes overexpressing an oncogenic v-ras(Ha) gene, and RARalpha was underexpressed in a benign keratinocyte cell line carrying a mutated c-ras(Ha) gene. Introduction of a recombinant RARalpha expression vector into benign keratinocyte tumor cells reduced the S-phase population and inhibited [3H]thymidine incorporation in response to retinoic acid. Furthermore, transactivation of B-RARE-tk-LUC by retinoic acid was markedly decreased in keratinocytes transduced with the v-ras(Ha) oncogene (v-ras(Ha)-keratinocytes). Blocking protein kinase C function in v-ras(Ha)-keratinocytes with bryostatin restored RARalpha protein to near normal levels, reflecting the involvement of protein kinase C in RARalpha regulation. Both RARalpha and RARgamma are down-regulated in cultured keratinocytes by 12-O-tetradecanoylphorbol-13-acetate, further implicating PKC in the regulation of retinoid receptors. Our data suggest that modulation of RARs could contribute to the neoplastic phenotype in mouse skin carcinogenesis and may be involved in the differential promoting activity of mezerein and 12-O-tetradecanoylphorbol-13-acetate, particularly for selecting tumors at high risk for malignant conversion.

Myelofibrosis associated with multiple myeloma.

Two patients had both multiple myeloma and myelofibrosis. One, who had both conditions, had autopsy confirmation of diagnosis three months later. The typical picture of agnogenic myeloid metasplasia with myelofibrosis developed in the second patient almost four years after the onset of k light chain myeloma. At this time all evidence of multiple myeloma had disappeared perhaps related to cyclophosphamide therapy. We were able to find two similar cases described in the English language literature. The two conditions may be related.

Hypercalcemia in prostatic carcinoma. Report of eight cases.

Hypercalcemia is a rare complication of disseminated carcinoma of the prostate. To our knowledge, only three such patients have had their cases previously reported in the English language literature. Eight patients with prostatic cancer and hypercalcemia were seen at Montefiore Hospital and Medical Center, Bronx, NY, within the last six years. In six of the patients, the prostatic carcinoma exhibited unusual histologic patterns.

Unusual cardiac reaction to chemotherapy following mediastinal irradiation in a patient with Hodgkin's disease.

A 27 year old man with Hodgkin's disease experienced three separate episodes of chest pain, each occurring on the sixth day of a cycle of mustargen, oncovin, procarbazine, prednisone (MOPP) combination chermotherapy. The first episode appeared to represent a myocardial infarction, whereas the next two were less serious. Numerous studies were performed including coronary angiography, cardiac catheterization and open pericardial biopsy. It is suggested that the patient represents an example of a previously undescribed syndrome due to chemotherapy administered after cardiac irradiation.

Scintillation-proximity assay of antigen-antibody binding kinetics: concise communication.

Tritiated latex particles and scintillant latex particles have been covalently coated with an antigen (human albumin) and both types of particles are than combined in dilute aqueous suspensions. The formation of antibody-induced dimer and higher-order aggregation resulted in scintillations that could be measured in a standard liquid-scintillation counter, energy-gated for H-3. Rabbit anti-human antiserum was easily detected at a titer of 1:10(6). Human albumin, in the inhibition mode, was also easily detected at 0.1 ng/ml. Since the samples are nondestructively assased, it was possible to examine the kinetics of aggregation under a variety of conditions.

Psychiatric complications during flooding therapy for posttraumatic stress disorder.

The authors use six case vignettes to illustrate underrecognized complications occurring during flooding therapy for posttraumatic stress disorder (PTSD), including exacerbation of depression, relapse of alcoholism, and precipitation of panic disorder. A common denominator to the majority of these cases appears to be the mobilization of negative posttrauma appraisal, accompanied by shame, guilt, and anger. The authors suggest that flooding may not be helpful for these negative emotions in the manner that it is for anxiety. Suggestions for preventing and treating complications of flooding therapy for PTSD include employing more cognitive forms of therapy in cases at risk; supporting abstinence from alcohol and other substances; providing adjunctive pharmacologic treatment as indicated, e.g., tricyclics for depression or panic; and providing long-term follow-up.

Basal cell carcinoma of the vulva.

A clinical and histopathologic study of material from a series of 17 patients with basal cell carcinoma of the vulva are reviewed. The tumors occurred primarily in elderly patients (average age, 59 years), the majority of whom were Causasian. Presenting symptomatology consisted primarily of pruritus vulvae and/or the presence of a vulvar mass (79%) of long duration (average, 6 years, 7 months). The lesions were described grossly as ulcerations or masses located on the anterior labium majus. Etiologies were indeterminate although 2 patients had previously received vulvar irradiation. Therapy consisted primarily of wide local excision and was effective in that follow-up studies in 16 patients revealed no deaths attributable to basal cell carcinoma. These data indicate that basal cell carcinoma is a locally invasive nonmetastasizing tumor best treated by wide local excision providing the tumor edge does not extend to the margin of excision.

Myositis ossificans progressiva and pregnancy.

Myositis ossificans progressiva is a rare inherited ossifying condition of the striated muscle tissue. In the English language literature there is no reported association of this disease with an advanced state of pregnancy, nor is there any well-documented scientific data about the effect of pregnancy on this disease or of this disease on pregnancy. This report is about a patient with myositis ossificans progressiva carrying to 30 weeks' gestation and successfully delivering a viable female infant. The antenatal care and management problems of this case are discussed.

Combination chemotherapy of advanced ovarian cancer with hexamethylmelamine, cis-Platinum, and doxorubicin after failure of prior therapy.

Forty-nine women received a combination of cis-platinum and hexamethylmelamine (36 also received doxorubicin) for advanced ovarian cancer progressing after therapy that included an alkylating agent or extended field radiation. Twenty-six (53%) had an objective remission that lasted a median of 6 months from start of treatment. Response rate was independent of age, extent of prior therapy, and performance status. A long interval from initial diagnosis to entry, response to therapy, and ambulatory performance predicted improved survival from entry. No patient is surviving free of disease. Myelosuppression and vomiting were moderately severe but tolerable. Azotemia and peripheral neuropathy were infrequent and milk. These drugs have major activity in this poor-risk group and should be studied as part of initial therapy when enhanced efficacy and reduced toxicity are to be expected.

Phase II trial of echinomycin in patients with advanced or recurrent colorectal cancer.

Echinomycin is a novel bifunctional intercalating agent derived from Streptomyces echinatus. A phase II clinical trial of echinomycin in patients with advanced, measurable colorectal cancer was initiated to determine the efficacy and toxicities of this agent. Echinomycin, 1.5 mg/m2, was given initially as a 30- to 60-min infusion every 4 weeks. After 4 episodes of anaphylaxis had occurred among the first 14 patients, the schedule was changed to a 24-h infusion, and an additional 16 patients were treated on this schedule. Treatment was given every 3 weeks. A total of 30 patients were eligible and evaluable; there were 3 (10%; 90% confidence interval, 3%-23%) clinical responses lasting 3, 3+, and 12 months, respectively. The most serious toxicity encountered was anaphylaxis, which occurred in 5 patients, although with no serious sequelae. A premedication regimen with dexamethasone, diphenhydramine, and cimetidine and a change of the duration of the infusion to 24 h reduced the incidence of this complication. Grade 2-3 vomiting occurred among earlier patients treated; however, with the 24-h schedule this toxicity was substantially reduced. The sole important case of hematologic toxicity was a single patient with grade 3 thrombocytopenia. Echinomycin employed in this dose and schedule had modest activity against colorectal cancer, comparable with that observed with 5-fluorouracil. Further studies in patients with gastrointestinal malignancies using a 24-h infusion with a dexamethasone premedication regimen similar to that employed prior to administration of taxol may be warranted.

Dopamine D1 agonist R-[11C]SKF 82957: synthesis and in vivo characterization in rats.

The active enantiomer R-SKF 82957 was labeled with 11C by N-[11C]methylation of the full dopamine (D1) agonist R-SKF 81297, using [11C]methyl iodide in the presence of N-ethyldiisopropylamine, in high specific activity, radiochemical purity and yields. Compared with the D1 agonist R/S-[11C]SKF 82957, R-[11C]SKF 82957 showed higher binding in the D1 rich regions, such as striatum and olfactory tubercles (approximately 1.7 times), thereby improving the tissue contrast. R-[11C]SKF 82957 exhibited high in vivo binding selectivity for D1 receptors in rats, because only high doses of D1 competitors, but not D2 or serotonin (5-HT2) blockers, significantly reduced the radioactivity levels in all brain areas. No labeled metabolites were detected in rat brain. These results indicate that R-[11C]SKF 82957 will provide more sensitive measurements of D1 receptors in in vivo studies than the racemic mixture.

Effect of tamoxifen treatment on estrogen metabolism in postmenopausal women with advanced breast cancer.

The effect of tamoxifen therapy on plasma estrone and estradiol concentration, urinary excretion of estrone, estradiol, and estriol glucuronides, and metabolism of a tracer of 3H-estradiol was studied in 12 postmenopausal women with metastatic breast cancer. The most striking change observed was consistent increase in the 72-hour urinary recovery of total radioactivity after the tracer, from a mean of 47% to a mean of 61% of the dose. This increase was accounted for by a corresponding increase in the recovery of total glucuronide radioactivity, from a mean of 32% to a mean of 44% of the dose; there was no change in the proportions of estrone, estradiol, estriol, or 2-hydroxyestrone in the glucuronide fraction. The most likely explanation for this finding is that the estrogen-receptor-blocking effect of tamoxifen decreases estrogen uptake by various tissues and permits the estrogen to be excreted in the urine instead. There was also a small but consistent and significant decrease in plasma estrone (from 47 to 36 pg/ml) and estradiol (from 15 to 13 pg/ml), with no change in urinary excretion of estrogen glucuronides. The drop in plasma estrogen levels without a decrease in estrogen production suggests that tamoxifen may increase the metabolic and/or renal clearance of estrogen metabolites. There was no correlation between the observed effects of tamoxifen and the pretreatment estrogen-receptor status of the patient or her response to tamoxifen therapy.

High-dose megestrol acetate in the treatment of patients with ovarian cancer who have undergone previous treatment: Eastern Cooperative Oncology Group Study PD884.

High-dose megestrol acetate has been reported to be effective salvage therapy for women with ovarian carcinoma. The Eastern Cooperative Oncology Group performed this phase II study of oral megestrol acetate, 200 mg four times daily until disease progression, in 33 patients either with stage III or IV histologically confirmed ovarian carcinoma or with unresectable tumor in the pelvis with measurable or evaluable disease who progressed after treatment with one prior chemotherapy regimen. Thirty and 31 patients were evaluable for response and toxicity, respectively. No patient had an objective response and none had subjective improvement after a median treatment period of 1.4 months. Nausea or vomiting occurred in most patients, usually grade 1-2. Megestrol acetate is ineffective salvage therapy for patients with inoperable, previously treated ovarian carcinoma.

Paying doctors more: use of musculoskeletal specialists and increased physician pay to decrease workers' compensation costs.

Previous studies evaluating workers' compensation care systems used retrospective controls. We performed a concurrent effectiveness study comparing a WC system that used visiting musculoskeletal specialists to assist primary care physicians with a typical discounted-fee, WC, managed-care system. In the new specialist-direct system, physicians could not profit from self-referral, but were paid 35% to 69% more per patient visit than doctors in the discounted-fee clinics. All claims filed by all employees of two hotels for 2 years were examined. Patients had self-selected either a specialist-direct or a discounted-fee clinic, and the entire cost of the claim was assigned to either system of care. Claim costs were 63% lower in the specialist-direct system (P < 0.001). Medical costs were 45% less (P < 0.014), and indemnity 85% less (P < 0.001), in this system. Claims were closed nearly 6 months faster in the specialist-direct system (P < 0.0001). Indemnity claims were more common in the discounted-fee system (P < 0.0001). Claimant and injury characteristics were not significantly different between the systems. This new care model is a cost-effective alternative to discounted WC managed care. Discounting the services of the primary treating physician may result only in cost-shifting, not cost-saving.

Adjuvant radiotherapy for breast cancer as a risk factor for the development of lung cancer.

Women diagnosed with primary breast or lung cancer and recorded between 1972 and 1989 in our tumor registry were identified. Of 4,123 lung cancer patients and 3,537 breast cancer patients, 42 patients with both diagnoses were identified. The two malignancies were diagnosed simultaneously in five patients, lung cancer was diagnosed first in six patients and breast cancer was diagnosed first in 31 (p < 0.001). Nineteen of those 31 patients received adjuvant radiotherapy for breast cancer and developed lung cancer a median of 17 years later. Of the 19 irradiated patients who subsequently developed lung cancer, 15 did so in the ipsilateral lung and only four had lung cancer contralateral to the previously irradiated site (p < 0.001). Adjuvant radiotherapy for breast cancer as delivered decades ago may be an etiologic factor for lung cancer.

A retrospective study of long-term methods of coping with having been sexually abused during childhood.

Methods of coping with childhood sexual abuse were retrospectively studied in a community sample of 54 adult women who had been sexually abused in childhood. From the time the abuse ended until the present, "denial" and "emotional suppression" were the coping methods most commonly employed of the nine methods measured. One purpose of this study was to determine if the methods used to cope with the aftermath of being sexually abused during childhood were associated with current psychological adjustment beyond what could be predicted by the characteristics of the abusive experience per se. A partial correlation analysis and a multiple regression analysis suggested that avoidant/emotion suppressing coping strategies although frequently used and rated by subjects as helpful, were in fact associated with poorer adult psychological adjustment.

Childhood sexual abuse: long-term effects on psychological and sexual functioning in a nonclinical and nonstudent sample of adult women.

The purpose of this study was to explore how the experience of childhood sexual abuse is related to long-term psychological and sexual functioning in a nonclinical and nonstudent community sample of women. Questionnaires were distributed to 1,500 nurses and returned anonymously. Fifty-four women who had been sexually abused as children (age 15 or younger) responded. These subjects were then matched with 54 nonabused control subjects. Although there was no difference on a measure of self-esteem, the abused group reported more symptoms of distress on the Global Severity Index and on seven out of nine subscales of the Derogatis Brief Symptom Inventory. They also reported more disturbance on a scale which examined psychological symptoms that have been commonly reported in the literature to be particularly associated with sexual abuse. These differences between the abused and nonabused groups were evident even after controlling for differences in subjects' perceptions of parental emotional support. Unlike the results for psychological adjustment, however, the abused subjects did not differ from the control subjects on self-reported levels of sexual satisfaction or sexual dysfunction.

A VLSI Neural Monitoring System With Ultra-Wideband Telemetry for Awake Behaving Subjects.

Long-term monitoring of neuronal activity in awake behaving subjects can provide fundamental information about brain dynamics for neuroscience and neuroengineering applications. Here, we present a miniature, lightweight, and low-power recording system for monitoring neural activity in awake behaving animals. The system integrates two custom designed very-large-scale integrated chips, a neural interface module fabricated in 0.5 µm complementary metal-oxide semiconductor technology and an ultra-wideband transmitter module fabricated in a 0.5 µm silicon-on-sapphire (SOS) technology. The system amplifies, filters, digitizes, and transmits 16 channels of neural data at a rate of 1 Mb/s. The entire system, which includes the VLSI circuits, a digital interface board, a battery, and a custom housing, is small and lightweight (24 g) and, thus, can be chronically mounted on small animals. The system consumes 4.8 mA and records continuously for up to 40 h powered by a 3.7-V, 200-mAh rechargeable lithium-ion battery. Experimental benchtop characterizations as well as in vivo multichannel neural recordings from awake behaving rats are presented here.