Variants in Hormone Biosynthesis Genes and Risk of Endometrial Cancer.

We investigated the risk associated with variants in three genes involved in estrogen biosynthesis, CYP11A1, CYP17A1, and CYP19A1, in the population-based case-control study of Estrogen, Diet, Genetics, and Endometrial Cancer. This study was conducted in New Jersey in 2001-2006 with 417 cases and 402 controls. For CYP11A1, there was no association between the number of [TTTTA]( n ) repeats (D15S520) and risk. For CYP17A1, risk was somewhat lower among women with the C/C genotype at T-34C (rs743572) (adjusted OR = 0.65, 95% CI 0.41-1.02). For CYP19A1, risk was lower among women homozygous for the 3-bp deletion (rs11575899) in exon 4 (adjusted OR = 0.44, 95% CI 0.26-0.76), while the number of [TTTA]( n ) repeats was not significantly related to risk: the adjusted OR for n = 7/7 repeats versus n \u3e 7/\u3e7 repeats was 0.81 (95% CI 0.54-1.23). In stratified analyses, results for CYP19A1 were stronger among women with higher (\u3e or =27.4) body mass index: for the homozygous deletion, OR = 0.30 (95% CI 0.15-0.62); for the n = 7/7 genotype, OR = 0.49 (95% CI 0.26-0.93). The interaction between the n = 7/7 genotype and BMI was statistically significant (p = 0.01). The insertion/deletion variant in CYP19A1 appears to be related to risk of endometrial cancer; risk associated with variants in this gene may vary according to BMI

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients with COVID-19 Pneumonia: A Randomized Clinical Trial

Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. Design, Setting, and Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible. Interventions: Patients in the experimental group received intravenous high-titer CP (≥1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. Main Outcomes and Measures: The primary outcome was a composite of worsening respiratory failure (Pao2/Fio2ratio <150 mm Hg) or death within 30 days from randomization. Results: Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P =.54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P =.04). Conclusions and Relevance: In patients with moderate to severe COVID-19 pneumonia, high-titer anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04716556

Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway

Neuroendocrine tumors (NETs) comprise a group of rare tumors derived from the diffuse neuroendocrine system or islet endocrine cells of the pancreas. The molecular mechanisms underlying NETs are largely unknown. The tumor suppressor p53 plays a critical role in maintaining genomic stability and tumor prevention. The p53 pathway is tightly regulated by a number of proteins, among which MDM2, MDM4, and WIP1 are key negative regulators of p53 protein levels or activity. Aberrant activation of these negative regulators can attenuate the p53 function that serves as an important mechanism of tumorigenesis. In this study, several genetic alterations in pancreatic NETs were studied. These tumors exhibit various chromosomal aberrations throughout the whole genome as examined by array-based comparative genomic hybridization. Although p53 mutations are rare in NETs (<3%), this study presents evidence that the p53 pathway is altered in pancreatic NETs through aberrant activation of its negative regulators. A high percentage of pancreatic NETs contain extra gene copies of MDM2 (22%), MDM4 (30%), and WIP1 (51%), which are correlated with expression of corresponding mRNAs and proteins. In addition, there is a higher frequency (23% v. 15% in the control population) of the G/G genotype of MDM2 SNP309, a functional single-nucleotide polymorphism in the MDM2 gene that attenuates the function of the p53 protein. Overall, approximately 70% of pancreatic NETs have one or more of these genetic changes. These findings suggest that the negative regulation of p53 function could be an important mechanism for the initiation and/or progression of pancreatic NETs, and reactivation of p53 could be a potential therapeutic strategy for patients with this disease

WPOI-5: Accurately Identified at Intraoperative Consultation and Predictive of Occult Cervical Metastases

BACKGROUND: Frozen section analysis of oral cancer specimens is ideal for assessing margin distances and depth of invasion (DOI); the latter impacts intraoperative decisions regarding elective neck dissection (END). Here, we show that intraoperative determination of worst pattern of invasion (WPOI), specifically WPOI-5, has a high level of accuracy. This relates to our demonstration herein that WPOI-5 predicts occult cervical metastases (OCM) for pT1 oral squamous carcinoma (OSC). METHODS: The presence of OCM was correlated with WPOI in 228 patients with primary T1/T2/cN0 OSC undergoing resection and END. Concordance between intraoperative and final pathology WPOI determination was assessed on 51 cases of OSC. RESULTS: WPOI-5 predicts OCM in pT1 patients, compared with WPOI-4/WPOI-3 (p \u3c 0.0001). Most pT1 WPOI-5 tumors had DOI of 4-5 mm (24/59 or 40.7%). Only two pT1 WPOI-5 tumors had DOI \u3c 4 mm (3.0 and 3.5 mm). If END were performed in this pT1 cohort for all WPOI-5 OSC patients regardless of DOI, OR all OSC patients with DOI ≥ 4 mm regardless of WPOI, then no OCM would be missed (p = 0.017, 100% sensitivity, 29% specificity, 77% positive predictive value, 23% negative predictive value). With respect to intraoperative WPOI-5 determination, the accuracy, sensitivity, and specificity was 92.16, 73.33, and 100.0%, respectively. CONCLUSIONS: DOI ≥ 4 mm is the dominant predictor of OCM. For the rare WPOI-5 OSC with DOI \u3c 4 mm, it is reasonable to suggest that surgeons perform END. WPOI-5 may be accurately determined intraoperatively. As microscopic instruction is needed to accurately assess WPOI-5, a teaching link is included in this manuscript