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Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation (BRCA1meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 (BRCAmut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1meth and BRCAmut states, BRCA1meth uniformly associates with poor outcomes. Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCAmut cancers, where BRCA loss is a genetically "fixed" deficiency state, BRCA1meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa. Breaking down BRCA heterogeneity: Loss of BRCA1 or BRCA2 (BRCA) activity is common in triple-negative breast cancer (TNBC) and ovarian cancer (OvCa); however, the type of alteration can result in different treatment responses. Here, Menghi et al. examined the differences in response to platinum therapy of patients with TNBC and OvCa who had BRCA loss or genetic alterations as compared to promotor methylation of BRCA. They saw that both patients and mice with promotor methylation were able to adaptively lose methylation, gain BRCA1 expression, and acquire resistance to platinum therapy. These findings have broad implications in using BRCA alteration status to better predict patient. [ABSTRACT FROM AUTHOR]

We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis. [ABSTRACT FROM AUTHOR]

Determines the etiology of esophageal symptoms in human immunodeficiency virus (HIV)-infected patients failing antifungal treatment. Common occurrence of esophageal disorders in HIV patients; Absence of endoscopic abnormalities in some patients; Most common cause of esophageal symptoms in HIV patients; Test of choice for the nonresponders.

Evaluates the cytomegalovirus (CMV) esophagitis' response to ganciclovir therapy. Relapse rate without maintenance therapy; Cause of morbidity in patients with AIDS; Calculation of confidence intervals for response and relapse.

Objective: To determine prospectively the causes of upper GI hemorrhage (UGIH) in alcoholics, focusing on the prevalence of alcoholic gastropathy, and to compare the etiology of bleeding in patients who drink alcohol to that of nondrinkers. Methods: From August 1, 1990 through September 9, 1994, all patients evaluated by the gastroenterology consultative service at a large inner-city hospital presenting with UGIH were prospectively identified. Patients had to have a subnormal hematocrit on or within 12 h of admission or a fall of at least 5 points from a previous baseline determination to be included. Upper GI endoscopy was performed in all patients within 48 h of admission. Alcohol use was quantitated as chronic (80 g or more per day for at least 1 month), binge, occasional, or none. Results: Over the 4-yr study period, 727 patients met the inclusion criteria, and of these, 212 (29%) were classified as chronic alcohol users. Overall, peptic ulcer disease was the most common cause of bleeding (60%). Gastropathy (diffuse subepithelial hemorrhage) was considered etiological in only 32 patients (4%). The most common causes of gastropathy were portal hypertension in 22 patients and nonsteroidal anti-inflammatory drug use in five. Only three patients were identified in whom alcoholic gastropathy was considered etiological; in these patients, bleeding was mild and self-limited. When the causes of bleeding were compared between drinkers and nondrinkers, drinkers were more likely to bleed from varices (p = 0.024) or other portal hypertension-related causes (p < 0.01), whereas peptic ulcer was more common in nondrinkers compared with chronic users (67 vs 53%; p < 0.01). Esophagitis (p = 0.95) and Mallory-Weiss tear (p = 0.15) prevalences were not significantly different between the two groups. Conclusion: In the actively drinking patient, the most common causes of UGIH are peptic ulcer and disorders related to portal... [ABSTRACT FROM AUTHOR]

Objective: Although the presence of oropharyngeal (OP) candidiasis plays an important role in the evaluation of human immunodeficiency virus (HIV)-infected patients with esophageal symptoms, there is little information on the utility of OP findings in patients with esophageal ulceration. Methods: Over a 54-month period, all HIV-infected patients with esophageal ulceration had careful inspection of the oropharynx at the time of presentation with esophageal complaints and at endoscopy. HIV-infected patients without esophageal ulceration undergoing endoscopy during the last 30 months had OP findings similarly documented. OP ulceration was not routinely biopsied. The cause of esophageal ulceration was determined based on clinical, endoscopic, and histopathological findings. Results: Of the 124 patients identified with esophageal ulcer, 14 (11%) had coexistent OP ulceration: herpes simplex virus, four; idiopathic esophageal ulcer, four; cytomegalovirus, three; herpes simplex virus and cytomegalovirus, two; idiopathic and cytomegalovirus, one. Four patients had OP ulcer without esophageal ulcer; only one of these patients had esophageal symptoms. All OP lesions healed with therapy for the esophageal ulcer. Twenty-eight patients with esophageal ulcer had OP candidiasis (23%); 21 of these patients (75 %) also had Candida esophagitis. The sensitivity and specificity of OP ulcer for esophageal ulcer were 11% and 97%, respectively. The positive and negative predictive values of OP candidiasis for esophageal candidiasis were 90% and 82%, respectively. Conclusions: OP ulceration is uncommon in patients with esophageal ulceration, with the exception of herpes simplex virus esophagitis. OP candidiasis is common in patients with underlying esophageal ulcer, potentially resulting in diagnostic confusion. OP candidiasis appears to be a moderately useful diagnostic marker for Candida esophagitis. [ABSTRACT FROM AUTHOR]

Vascular tumors are among the most common neoplasms in infants and children; 5%–10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS , KRAS , NRAS , GNAQ , and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective: To assess two zona drilling methods in terms of blastocyst development rates using sister embryos. Design: Prospective, randomized study. Sister embryos of 14 patients were randomly assigned on day 3 to acidified Tyrode’s zona drilling or to laser zona drilling. After biopsy, subsequent embryo culture until the blastocyst stage (day 5) was performed. Setting: Private fertility center. Patient(s): Patients undergoing IVF–preimplantation genetic diagnosis. Intervention(s): Embryo biopsy using either laser-assisted hatching or acidified Tyrode’s hatching on sibling embryos and subsequent blastocyst development evaluation. Main Outcome Measure(s): Evaluation of blastocyst development in terms of degree of expansion and cell number in the inner cell mass and trophectoderm. Result(s): Blastocyst development rates (and blastocyst quality) were similarly high in both the acidified Tyrode’s hatching group and the laser-assisted hatching group. Conclusion(s): Laser hatching does not impair embryonic development to the blastocyst stage, demonstrating that laser-assisted hatching is a suitable alternative to the use of acidified Tyrode’s solution for zona drilling. [Copyright &y& Elsevier]

The objective of the present study was to compare a traditionally used bovine-derived hyaluronidase (Hyase) with the newly developed recombinant human-derived enzyme product (Cumulase) in intracytoplasmic sperm injection (ICSI) procedures using a sibling oocyte model in a prospective randomized design. The results of the study demonstrate that Cumulase is safe and effective in an ICSI treatment program and can provide comparable if not improved parameters, including fertilization and embryo developmental rates. [Copyright &y& Elsevier]