Elevations of DNA topoisomerase I in transitional cell carcinoma of the urinary bladder: correlation with DNA topoisomerase II-alpha and p53 expression

DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of antitumor drugs. Laboratory studies have indicated that cells sensitive to these drugs contain elevated levels of topo I. In this study, we immunostained 49 cases of transitional cell carcinoma from the urinary bladder with a monoclonal antibody directed against human topo I. We found elevated expression of the enzyme in 77% (38 of 49). This included three of six grade I tumors (50%), 9 of 15 grade II tumors (60%), 14 of 15 grade III tumors (93%) and 12 of 13 grade IV tumors (92%). Because the number of cycling cells in a tumor also may be an important determinant of topo I drug response, a proliferation index (topo II-alpha) also was performed for each case. The average topo II-alpha index of grade I tumors was 7.5 x 3.8; for grade II tumors, 20.1+/-10.5; for grade III tumors, 40.3 x 8.2; and for grade IV tumors, 50.5+/-13.0. Because a functional p53 tumor suppressor gene may be necessary for anticancer drug response, we also evaluated our cases for alteration in p53 function. Mutations in the p53 tumor suppressor gene, estimated by immunohistochemical staining, were common, occurring in 23 of 49 cases (47%). The number of cases with elevated topo I, a large growth fraction, and a functional p53 tumor suppressor gene was 4 of 49 (8%). Our results suggest that a small population of patients with transitional cell carcinoma of the urinary bladder may have tumors with molecular features suggesting responsiveness to the new anticancer drugs targeting topo I.     

Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.

OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.     

Mandibular Limitation Due to Bilateral Coronoid Enlargement: Management by Surgery and Physical Therapy

Limitation of mandibular opening may be a presenting sign in many disorders, and the differential diagnosis of its cause must include consideration of both intra- and extra-articular factors. One possible etiological factor is coronoid enlargement, which can be neoplastic, hyperplastic, or developmental. When coronoid enlargement is present, vigorous management is required to gain and maintain a useful, functional opening excursion. In the case presented here, the opening impedance was removed surgically, but relatively prolonged and concentrated physical therapy was required to effect a cure.     

Characterization of edible marijuana product exposures reported to United States poison centers

Context: Edible marijuana products are sold as brownies, cookies, and candies, which may be indistinguishable from counterparts without marijuana and are palatable to children and adults. The consumption of an entire product containing multiple dose-units may result in overdose.

Objective: To characterize edible marijuana exposures reported to US poison centers with subgroup analysis by age.

Methods: We analyzed single substance, human exposure calls coded to marijuana brownies, candies, cookies, beverages, or other foods reported to the National Poison Data System from January 2013 to December 2015. Calls were analyzed by state, age, gender, exposure route, clinical effect, therapies, and level of healthcare facility utilization.

Results: Four-hundred and thirty calls were reported: Colorado (N?=?166, 1.05/100,000 population/year) and Washington (96, 0.46) yielded the highest number of exposures. Three hundred and eighty-one (91%) calls occurred in states with decriminalized medical/recreational marijuana. The number of calls increased every year of the study. The most common age groups were: ≤5 years (N?=?109, 0.15/100,000 population/year) and 13–19 (78, 0.09). The most frequent clinical effects were drowsiness/lethargy (N?=?118, percentage?=?43%), tachycardia (84, 31%), agitated/irritable (37, 14%), and confusion (37, 14%). Children ≤5 years have more drowsiness/lethargy, ataxia, and red eye/conjunctivitis. No deaths were reported. The most common therapies administered were intravenous fluids (85, 20%), dilute/irrigate/wash (48, 11 %), and benzodiazepines (47, 11%). Three patients (ages 4, 10, and 57 years) received intubation. 97 (23%), 217 (50%), and 12 (3%) calls were managed at home, treated/released, admitted to a critical care unit, respectively.

Discussion: Although most clinical effects are minor, ventilatory support may be necessary for children and adults. We speculate the increasing exposures may be related to a combination of delayed absorption kinetics of Δ9-tetrahydrocannablnol, lagging packaging regulations, increased accessibility in decriminalized states, and increased familiarity of poison center specialists with edible product codes.

Conclusions: Edible marijuana exposures are increasing and may lead to severe respiratory depression.     

Rare sellar lesions.

Sellar masses are associated most commonly with pituitary adenomas. Many other neoplastic, inflammatory, infectious, and vascular lesions, however, may affect the sellar region and mimic pituitary tumors. These lesions must be considered in a differential diagnosis. This article describes the characteristics of rare sellar masses that provide clues to their differential diagnosis.     

A Brazilian multicentre study evaluating pregnancies induced by cabergoline in patients harboring prolactinomas

Pituitary - To evaluate the maternal–fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large cohort. The prevalence of tumor growth, miscarriage, preterm, low birth...     

Cirrhotic cardiomyopathy: a specific entity

Cirrhosis is a frequent and severe condition, which is the late stage of numerous chronic liver diseases. It is associated with major hemodynamic alterations characteristic of hyperdynamic circulation and with a series of structural, functional, electrophysiological and biological heart abnormalities termed cirrhotic cardiomyopathy. The pathogenesis of this syndrome is multifactorial. It is usually clinically latent or mild, likely because the peripheral vasodilatation significantly reduces the left ventricle afterload. However, sudden changes of hemodynamic state (vascular filling, surgical or transjugular intrahepatic porto-systemic shunts, peritoneo-venous shunts and orthotopic liver transplantation) or myocardial contractility (introduction of beta-blocker therapy) can unmask its presence, and sometimes convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. This entity has been described recently, and its diagnostic criteria are still under debate. To date, current management recommendations are empirical, nonspecific measures. Recognition of cirrhotic cardiomyopathy depends on a high level of awareness for the presence of this syndrome, particularly in patients with advanced cirrhosis who undergo significant surgical, pharmacological or physiological stresses.