Citations

AbstractCarney complex is an autosomal dominant neoplasia syndrome characterized by spotty skin pigmentation, myxomatosis, endocrine tumors, and schwannomas. This condition may be caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A. To better understand the mechanism by which PRKAR1A mutations cause disease, we have developed conventional and conditional null alleles for Prkar1a in the mouse. Prkar1a+/− mice developed nonpigmented schwannomas and fibro-osseous bone lesions beginning at ∼6 months of age. Although genotype-specific cardiac and adrenal lesions were not seen, benign and malignant thyroid neoplasias were observed in older mice. This spectrum of tumors overlaps that seen in Carney complex patients, confirming the validity of this mouse model. Genetic analysis indicated that allelic loss occurred in a subset of tumor cells, suggesting that complete loss of Prkar1a plays a key role in tumorigenesis. Similarly, tissue-specific ablation of Prkar1a from a subset of facial neural crest cells caused the formation of schwannomas with divergent differentiation. These observations confirm the identity of PRKAR1A as a tumor suppressor gene with specific importance to cyclic AMP–responsive tissues and suggest that these mice may be valuable tools not only for understanding endocrine tumorigenesis but also for understanding inherited predispositions for schwannoma formation.

Background. Although glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is prevalent in African Americans, their risk of associated neonatal hyperbilirubinemia has not been prospectively studied.Objective. To compare hemolysis and the risk of hyperbilirubinemia among African American, G-6-PD-deficient neonates (study group) and G-6-PD-normal control subjects.Methods. Consecutive, healthy, term and near-term, male neonates born to African American mothers comprised the patient cohort. G-6-PD testing was performed with umbilical cord blood samples. Routine management included measurement of the end tidal carbon monoxide level corrected for ambient carbon monoxide level (ETCOc) within 4 hours after delivery (assessment of hemolysis), ≥1 predischarge bilirubin determination, and additional bilirubin testing as clinically indicated. Indications for phototherapy were identical for study patients and control subjects. Neonates were monitored for the first 1 week of life. ETCOc results, the incidence of hyperbilirubinemia (defined as a transcutaneous or plasma total bilirubin concentration of ≥95th percentile for the hour of life), and the need for phototherapy were compared between the G-6-PD-deficient and G-6-PD-normal groups.Results. Five hundred male patients were enrolled, of whom 64 (12.8%) were G-6-PD-deficient. ETCOc values (median and interquartile range) were higher among G-6-PD-deficient neonates than among control neonates (2.4 ppm [2.0–2.9 ppm] vs 2.1 ppm [1.7–2.5 ppm]). More G-6-PD-deficient neonates developed hyperbilirubinemia than did control subjects (14 of 64, 21.9%, vs 29 of 436, 6.7%; relative risk: 3.27; 95% confidence interval: 1.83-5.86), whereas 13 (20.3%) met the criteria for phototherapy, compared with 25 control subjects (5.7%) (relative risk: 3.53; 95% confidence interval: 1.91-6.56). No cases of kernicterus were observed.Conclusions. Within the African American neonatal population, there is a subgroup of G-6-PD-deficient infants with elevated rates of hemolysis, a higher incidence of hyperbilirubinemia, and a greater requirement for phototherapy, compared with G-6-PD-normal control subjects. These newborns should be monitored vigilantly for the development of hyperbilirubinemia.

Purpose Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. Patients and Methods Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). Results Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P < .05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P < .01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. Conclusion This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.