Epidemiology of minimal breast cancer among women screened in New York City.

A case-control study based on a screened population in New York City examined epidemiologic risk factor differences between minimal breast cancer (in situ and small invasive carcinomas) and all other breast carcinomas, referred to as clinical breast cancer. Histopathologic re-review of the original slides identified 113 minimal and 792 clinical breast cancers among 1,290 eligible cases; 2,173 randomly selected screenees served as controls. Among those who developed cancer, black women were twice as likely to develop minimal, as compared to clinical, breast cancer. Women who were less than 20 years of age at first live birth had more than double the probability of being diagnosed with minimal breast cancer, whereas women with first live birth at age 30 years or greater and nulliparous women were at 1.5 times the risk of clinical breast cancer. The relative proportion of minimal breast cancer increased with increasing number of children breast fed, being twofold among women who nursed 2 children or more. Unlike clinical breast cancer, minimal breast cancer was not associated with either family history of breast cancer or obesity. Meaningful histologic differences were not apparent between the case subgroups. Except possibly for obesity, these results could not be explained by any plausible diagnostic bias.

Reduction of N-methyl-N-nitrosourea-induced colon tumors in the rat by cholesterol.

Patient populations with a propensity to develop colon cancer have increased amounts of fecal cholesterol (and/or cholesterol metabolites). In this study, we report the effect of increased colonic concentrations of cholesterol and its metabolites on colon tumor promotion. The chemical carcinogen N-methyl-N-nitrosourea was instilled intrarectally into rats to initiate colon tumor formation. Following initiation, a cholesterol-supplemented diet was given. Despite a 2-fold elevation of fecal cholesterol, the number of colon tumors found was significantly reduced. These studies suggest that under certain conditions cholesterol may inhibit colon carcinogenesis.

Protective effect of plant sterols against chemically induced colon tumors in rats.

Diets rich in vegetables are associated with a low incidence of colon cancer. Since plant sterols are plentiful in vegetarian diets, we studied the effect of beta-sitosterol on colon tumor formation in rats treated with the carcinogen N-methyl-N-nitrosourea. We demonstrated that beta-sitosterol nullified in part the effect of this direct-acting carcinogen on the colon. We suggest that plant sterols may have a protective dietary action action to retard colon tumor formation. The beneficial effects of vegetarian diets may be enhanced because of the presence of these compounds.

4'Epidoxorubicin (epirubicin): activity in hepatocellular carcinoma.

Doxorubicin provides the most consistent response rate in hepatocellular carcinoma. We therefore initiated a trial with its analog 4'epidoxorubicin. Eighteen patients, all without prior treatment, were given the drug as a single agent every 3 weeks with dose escalation whenever possible. Five patients were treated by six-hour infusion and 13 by intravenous (IV) bolus injection, with the median dose being 90 mg/m2. The patients were of diverse ethnic background and included some with underlying cirrhosis and hepatitis B surface antigenemia. Three patients had partial remissions (6, 12, 48 weeks) for a response rate of 17%. Four patients also had prolonged stable disease (14, 26, 27, 38 weeks). Toxicity was mild, although cardiac toxicity developed in three patients at 685, 825, and 1,460 mg/m2 cumulative dose. The response to 4'epidoxorubicin in this study appears to be equivalent to the reported response rates for doxorubicin, with decreased toxicity.

Experience with selegiline and levodopa in advanced Parkinson's disease.

We compared the results of treatment with selegiline (deprenyl, Eldepryl) in 17 patients with advanced Stage 4 Parkinson Disease (PD) who were on levodopa (as Sinemet) with 65 Stage 2 or 3 patients with early PD who were also on levodopa. The first group consisted of 17 patients with advanced Stage 4 PD without response fluctuations ("wearing off" or "on off" phenomena). Their mean age was 72.1 +/- 7.5 years, their mean duration of PD was 7.4 +/- 3.2 years. The second group consisted of 65 patients with Stage 2 or 3 PD who had recently been started on levodopa. Their mean age was 63 +/- 12.1 years, their mean duration of PD was 7.4 +/- 3.2 years. The mean dose of selegiline was 10.0 +/- 1.8 mg per day (range 5-20 mg). The mean duration of treatment was 1.5 +/- 0.8 years. During the four years of observation 55.3 +/- 8.0% of the Stage 2 or 3 patients improved while only 14.3 +/- 13.5% of the Stage 4 patients improved. This difference was significant (p less than 0.05). During this time 22.0 +/- 6.7% of the Stage 2 or 3 patients worsened and 60.7 +/- of the Stage 4 patients worsened. This degree of worsening was significant (p less than 0.05). Adverse effects were minor and reversible. Our observations suggest that selegiline is more effective (higher percent of patients improving, lower percent of patients worsening) when it is added earlier with patients on levodopa than when it is added later.

Stereotaxic implantation of autologous adrenal medulla into caudate nucleus in four patients with parkinsonism. One-year follow-up.

Four patients with levodopa-responsive parkinsonism (aged 26, 35, 45, and 49 years) received autologous adrenal medullary implants into or near the left caudate nucleus by stereotaxic implantation after flank adrenalectomy. All patients had an immediate response to implantation lasting several days, during which parkinsonian signs and symptoms decreased. This period was followed by a gradual reappearance of symptoms in all but one patient. This patient had had a dramatic increase in "on" time without dyskinesias and a decrease in the severity and duration of "off" time. He died of multifocal glioblastoma 1 year after transplantation. Autopsy revealed no surviving adrenal cells. In one case, the stereotaxic implantation missed the basal ganglia, resulting in the placement of the adrenal medullary tissue into the medial thalamus and near the third ventricle; the patient did not improve. In the other two cases, a modest but definite increase in "on" time without dyskinesia and a reduction in the severity and duration of "off" time has been observed. The role of autologous adrenal medullary transplantation in patients with parkinsonism remains to be determined. Patients with a family history of cerebral malignancy may be at increased risk for the development of transplant-induced malignancy.

Stereotactic pallidotomy for Parkinson's disease: a long-term follow-up of unilateral pallidotomy.

Eleven patients suffering from Parkinson's disease were followed for up to 4 years after unilateral pallidotomy. We observed persistent contralateral improvement and unexpected ipsilateral improvement of motor symptoms. In addition, there was a protracted relief of contralateral dyskinesias and maintenance of relatively stable levodopa dosage.

Stereotactic ventral pallidotomy for Parkinson's disease.

Eighteen patients with medically intractable Parkinson's disease that was characterized by bradykinesia, rigidity, and marked "on-off" fluctuations underwent stereotactic ventral pallidotomy under local anesthesia. Targeting was aided by anatomic coordinates derived from the MRI, intraoperative cell recordings, and electrical stimulation prior to lesioning. A nonsurgically treated group of seven similarly affected individuals was also followed. Assessment of motor function was made at baseline and at 3-month intervals for 1 year. Following the lesioning, patients improved in bradykinesia, rigidity, resting tremor, and balance with resolution of medication-induced contralateral dyskinesia. When compared with preoperative baseline, all quantifiable test scores after surgery improved significantly with the patients off medications for 12 hours: UPDRS by 65%, and CAPIT subtest scores on the contralateral limb by 38.2% and the ipsilateral limb by 24.2%. Walk scores improved by 45%. Medication requirements were unchanged, but the patients who had had surgery were able to tolerate larger doses because of reduced dyskinesia. Ventral pallidotomy produces statistically significant reduction in parkinsonism and contralateral "on" dyskinesia without morbidity or mortality and with a short hospitalization in Parkinson's disease patients for whom medical therapy has failed.

Dominantly inherited, early-onset parkinsonism: neuropathology of a new form.

We report postmortem findings in a 46-year-old man with dominantly inherited parkinsonism whose symptoms started at age 28. At least 13 other family members in three generations have been affected, some from early childhood. Dystonia is a prominent feature in several of the youngest patients, but was not present in this patient. After several years of successful treatment with medication, he developed severe on-off fluctuations and dyskinesias. At age 45, the patient underwent stereotaxic implantation of autologous adrenal medullary tissue into the left corpus striatum and lateral ventricle. He improved considerably over the following 6 months, but then developed glioblastoma multiforme and died 1 year after transplantation. There was severe neuronal loss in the pars compacta and pars reticulata of the substantia nigra, with prominent gliosis in the pars reticulata. The nigral neurons remaining in the pars compacta were poorly pigmented. Neither Lewy bodies nor neurofibrillary tangles were present, and we identified no other degenerative neuropathologic changes. This combination of pathologic and clinical features differs from any previously reported case.

Central motor loop oscillations in parkinsonian resting tremor revealed by magnetoencephalography.

A variety of clinical and experimental findings suggest that parkinsonian resting tremor results from the involuntary activation of a central mechanism normally used for the production of rapid voluntary alternating movements. However, such central motor loop oscillations have never been directly demonstrated in parkinsonian patients. Using magnetoencephalography, we recorded synchronized and tremor-related neuromagnetic activity over wide areas of the frontal and parietal cortex. The spatial and temporal organization of this activity was studied in seven patients suffering from early-stage idiopathic Parkinson's disease (PD). Single equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions (magnetic field tomography, MFT) were used in this analysis. ECD and MFT solutions were superimposed on high-resolution MRI. The findings indicate that 3 to 6 Hz tremor in PD is accompanied by rhythmic subsequent electrical activation at the diencephalic level and in lateral premotor, somatomotor, and somatosensory cortex. Tremor-evoked magnetic activity can be attributed to source generators that were previously described for voluntary movements. The interference of such slow central motor loop oscillations with voluntary motor activity may therefore constitute a pathophysiologic link between tremor and bradykinesia in PD.

Preoperative indicators of clinical outcome following stereotaxic pallidotomy.

We assessed the utility of preoperative clinical assessment and functional brain imaging with 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) in predicting the clinical outcome of stereotaxic pallidotomy for the treatment of advanced Parkinson's disease (PD). Twenty-two PD patients undergoing posteroventral pallidotomy were assessed preoperatively with the Core Assessment Program for Intracerebral Transplantation (CAPIT) ratings measured on and off levodopa; quantitative FDG/PET was also performed before surgery. Preoperative clinical and metabolic measurements were correlated with changes in off-state CAPIT ratings determined 3 months after surgery. Clinical outcome following pallidotomy was also correlated with intraoperative measures of spontaneous pallidal single-unit activity as well as postoperative MRI measurements of lesion volume and location. We found that unilateral pallidotomy resulted in variable clinical improvement in off-state CAPIT scores for the contralateral limbs (mean change 30.9 +/- 15.5%). Postoperative MRI revealed that pallidotomy lesions were comparable in location and volume across the patients. Clinical outcome following surgery correlated significantly with preoperative measures of CAPIT score change with levodopa administration (r = 0.60, p < 0.005) and with preoperative FDG/PET measurements of lentiform glucose metabolism (r = 0.71, p < 0.0005). Operative outcome did not correlate with intraoperative measures of spontaneous pallidal neuronal firing rate. We conclude that preoperative measurements of lentiform glucose metabolism and levodopa responsiveness may be useful indicators of motor improvement following pallidotomy. Both preoperative quantitative measures, either singly or in combination, may be helpful in selecting optimal candidates for surgery.

Hermansky-Pudlak syndrome. Pulmonary manifestations of a ceroid storage disorder.

The Hermansky-Pudlak syndrome is a form of oculocutaneous albinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Hermansky-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients.

Hermansky-Pudlak syndrome: a clinicopathologic study.

The Hermansky-Pudlak syndrome is a rare disease characterized by multisystemic involvement. Seven families with the disorder were identified in the Puerto Rican population of one municipal hospital, suggesting that the incidence in the Puerto Rican community is sufficient to warrant both dissemination of information about the disease and further investigation. The present study was an attempt to achieve both of these goals.

Pulmonary manifestations of Kaposi's sarcoma.

Pulmonary Kaposi's sarcoma is an unusual pre-mortem diagnosis in AIDS patients. During a four-year period, 318 patients with AIDS-associated Kaposi's sarcoma presented to New York University Medical Center; 19 patients were found to have pulmonary involvement. All 19 patients were homosexual men; 18 of these patients presented with cutaneous and/or visceral Kaposi's sarcoma. Seventy-nine percent of patients had previous or concurrent pulmonary opportunistic infections. Clinical presentation of pulmonary Kaposi's sarcoma was indistinguishable from opportunistic pneumonia with respect to symptoms, physical examination results, and laboratory findings. Chest roentgenograms revealed a typical nodular pattern in only five patients. In contrast to AIDS-associated opportunistic pneumonia, the yield from fiberoptic bronchoscopy (24 percent) and open lung biopsy (56 percent) was low. Pathologically, Kaposi's sarcoma of the lung is less cellular than the cutaneous lesion. It is focal and scattered throughout the pulmonary interstitium, which may explain the difficulty in pre-mortem diagnosis.

GM1 gangliosides alter acute MPTP-induced behavioral and neurochemical toxicity in mice.

We investigated the effect of GM1 gangliosides on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson disease. Five groups of mice (saline, GM1 (30 mg/kg), MPTP, MPTP + GM1 (15 mg/kg), MPTP + GM1 (30 mg/kg] were compared. GM1 was given daily via intraperitoneal injection before and during 13 daily doses of MPTP (30 mg/kg). Mice were tested for locomotion (1) within 2 h of an MPTP dose (to measure reduced motor activity), and (2) within 24 h of an MPTP dose (after animals had recovered and exhibited hyperactivity). We found that mice given GM1 gangliosides exhibited significantly less MPTP-induced behavior. This effect was most evident with the 15 mg/kg GM1 dose. GM1 also appeared to attenuate MPTP-induced neurochemical changes. GM1 effects indicating enhancement of DA turnover and preservation of DA, DOPAC and HVA concentrations in the striatum were found after the 8th MPTP dose. These latter neurochemical changes, however, were transient and not present after the 13th MPTP dose. Our data would suggest that gangliosides may reduce acute MPTP-induced neurotoxicity in mice either through an increase in DA neuron survival and/or the augmentation of striatal DA activity.

Giant lymph node hyperplasia. An immunopathologic and ultrastructural study of a case of the multicentric plasma cell variant.

A case of the multicentric plasma cell variant of giant lymph node hyperplasia (Castleman's disease) was studied. The left supraclavicular and axillary lymph nodes were affected. The parafollicular region of the lymph nodes was greatly expanded by sheets of mature plasma cells and by regionally concentrated as well as singly occurring immunoblasts. Both plasma cells and immunoblasts were polyclonal, as judged by the heterogeneity of immunoglobulin light-and heavy-chain components documented by immunofluorescence microscopy and immunohistochemistry. Ultrastructurally, free ribosomes and polyribosomes were the predominant cytoplasm organelles seen in immunoblasts. In plasma cells, rough endoplasmic reticulum was typically abundant and often contained electron-dense secretory product.

Selection criteria for unilateral posteroventral pallidotomy.

In an attempt to refine the indications for posteroventral pallidotomy (PVP) the authors instituted strict selection criteria which are based on the experience gained from the first 60 pallidotomy patients treated at their institution. In addition to clinical evaluation, all pallidotomy candidates undergo neuropsychological testing and 18F-fluoro-deoxyglucose utilization positron emission tomography (FDG/PET). The data from which these criteria were developed are presented as are early clinical results. The authors demonstrate that these criteria enhance the efficacy of the procedure by assuring therapeutic response and reducing the incidence of post-operative dementia. Their indications and contraindications for pallidotomy are discussed.

Anatomic and physiological considerations in pallidotomy for Parkinson's disease.

Our ongoing study of ventral pallidotomy for the control of Parkinson's disease in selected patients has provided the opportunity to explore the topographical and somatotopic organization of the human globus pallidus. Utilizing microelectrode techniques we have obtained recordings which were correlated with data from MPTP-parkinsonian primates. In addition, we performed pre- and post-operative FDG/PET scans in these patients. Our studies reveal similarities between the MPTP-parkinsonian primate model and human Parkinson's disease in terms of physiologic recordings and responses. However, we have encountered significant differences between dominant and non-dominant hemisphere representations, particularly for the hand, in the human. In addition, our PET studies confirmed, as in previous parkinsonian primate models, glucose hypermetabolism in the lenticular area of Parkinson's disease patients. This hypermetabolism is dramatically altered by creation of a lesion in the globus pallidus medialis. This is demonstrated by follow-up PET scans which reveal not only a decrease in metabolism of the operated lenticular region, but also in the frontal cortical projections. These combined observations of the cellular activity in the globus pallidus and the observed changes in PET metabolism support the selection of the pallidum for lesioning and control of Parkinson's disease, and offer insight into the underlying physiology of this disorder. The above physiological and PET data will be clinically correlated with our ongoing series of 35+ patients.

Efficacy of bilateral pallidotomy.

Unilateral pallidotomy is a safe and effective treatment for medically refractory bradykinetic Parkinson's disease, especially in those patients with levodopa-induced dyskinesia and severe on-off fluctuations. The efficacy of bilateral pallidotomy is less certain. The authors completed 11 of 12 attempted bilateral pallidotomies among 150 patients undergoing pallidotomy at New York University. In all but one patient, the pallidotomies were separated by at least 9 months. Patients were selected for bilateral pallidotomy if they exhibited bilateral rigidity, bradykinesia, or levodopa-induced dyskinesia prior to treatment or if they exhibited disease progression contralateral to their previously treated side. The Unified Parkinson's Disease Rating Scale (UPDRS) and timed upper-extremity tasks of the Core Assessment Protocol for Intracerebral Transplantation (CAPIT) were administered to all 12 patients in the "off" state (12 hours without receiving medications) preoperatively and again at 6 and 12 months after each procedure. The median UPDRS and contralateral CAPIT scores improved 60% following the initial procedure (p = 0.008, Wilcoxon rank sums test). The second pallidotomy generated only an additional 10% improvement in the UPDRS and CAPIT scores ipsilateral to the original procedure (p = 0.05). Worsened speech was observed in two cases. In the 12th case, total speech arrest was noted during test stimulation. Speech returned within minutes after stimulation was halted. Lesioning was not performed. These results indicate that bilateral pallidotomy has a narrow therapeutic window. Motor improvement ipsilateral to the first lesion leaves little room for further improvement from the second lesion and the risk of speech deficit is greatly enhanced. Chronic pallidal stimulation contralateral to a previously successful pallidotomy may prove to be a safer alternative for the subset of patients who require bilateral procedures.

Percutaneous fine-needle aspiration biopsy in malignant lymphoma: a case report of an unusual cytologic presentation.

A case of an elderly Hispanic male who presented with clinical findings suspicious for lymphoma and cytologic evidence suggestive of carcinoma is presented and discussed. Percutaneous fine-needle aspiration biopsy of a group of mesenteric lymph nodes and a pleural fluid specimen showed clusters of tumor cells suggestive of carcinoma. Electron microscopic analysis of the pleural fluid showed comparable clusters of tumor cells, which proved to be lymphoma cells enveloped by macrophages. Histologic, electron microscopic, and histocytochemical examination of an enlarged inguinal lymph node confirmed the diagnosis of lymphoma with several alpha-naphthyl acetate esterase-positive macrophages interspersed among the tumor cells. To date, the phenomenon of macrophages enveloping lymphoma cells, so as to simulate tumor cell clustering, has not been reported. It is, however, an important possibility to keep in mind with cytologically distinguishing a lymphoma from a carcinoma.