Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention.

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.

Quantification of pulmonary/systemic shunt ratio by single-acquisition phase-contrast cardiovascular magnetic resonance.

PURPOSE: Phase-contrast cardiovascular magnetic resonance (PC-CMR) quantification of intracardiac shunt (measuring the pulmonary to systemic flow ratio, Qp/Qs) is typically determined by measuring flow through planes perpendicular the pulmonary trunk (PA) and ascending aorta (Ao). This method is subject to error from presence of background velocity offsets and requires two scan acquisitions. We evaluated an alternate PC-CMR technique for quantifying Qp/Qs using a single modified plane that encompasses both the PA and Ao. MATERIAL AND METHODS: In 53 patients evaluated for intracardiac shunting, PC-CMR measurement in the individual Ao and PA planes and also in a single-acquisition plane was obtained and Qp/Qs calculated by each method. Bland-Altman analysis was performed to evaluate the agreement between the two methods. RESULTS: The 95% confidence limits of agreement ranged from -0.52 to +0.34 indicating good agreement between the two methods. There was excellent agreement on the clinically relevant threshold value of Qp/Qs ratio of 1.5 (representing criteria for surgical correction of shunt). CONCLUSIONS: Qp/Qs determined from the single-acquisition approach agrees well with that of the individual PA and Ao method and offers potential improved accuracy (due to background velocity offset).

An Uncommon Cause of Dysphagia in a 35 Year Old Male.

Typical causes of intermittent esophageal dysphagia in a young person include eosinophilic esophagitis, esophageal dysmotility and esophageal rings. We report a 35-year-old male with a one year history of intermittent dysphagia to solid foods. After the endoscopic removal of a food bolus, a barium swallow revealed extrinsic compression of the proximal esophagus. Computed tomography angiogram revealed an aberrant right subclavian artery (ARSA) coursing behind the esophagus, suggesting the diagnosis of dysphagia lusoria. Although rare, dysphagia lusoria represents an important consideration in the differential diagnosis of intermittent esophageal dysphagia in a young adult.

Comparison of molecular methods for detection of HPV in oral and oropharyngeal squamous cell carcinoma.

Substantial molecular evidence exists to implicate human papillomavirus (HPV) in the pathogenesis of a subset of oral and oropharyngeal squamous cell carcinomas. Several studies have shown that HPV-associated oral/oropharyngeal tumors differ etiologically, biologically, and clinically from those that lack the virus. HPV infection confers a significant survival benefit; therefore, HPV detection in tumors could be used to risk-stratify patients and drive optimum treatment strategies. We explored the clinical utility of 6 polymerase chain reaction (PCR)-based or signal amplification-based methods in the detection of HPV in 68 invasive oral/oropharyngeal SSCs and 10 reactive tonsil specimens. Agreement for HPV16 results among the 5 different assays capable of detecting this genotype was substantial (multirater κ=0.72). Only moderate agreement was noted for the 3 assays capable of detecting HPV18 (multirater κ=0.43). HPV results for each assay were evaluated relative to a "majority" HPV result derived from the results of all the detection methods. An HPV16 E6 PCR assay showed the highest concordance with adjudicated consensus HPV16 results (98.7%; κ=0.97), followed by the TaqMan (93.4%; κ=0.87), Linear Array (92.1%; κ=0.84), and E7 PCR (92.1%; κ=0.84) assays, all of which had agreements exceeding 90%, whereas the HPV16/18 Invader assay was lower (85.5%; κ=0.71). The presence of high-risk HPV in a minority of "normal" tonsillar tissues may confound assessment of the virus in oral/oropharyngeal squamous cell carcinoma biopsies using in vitro amplification methods.

Multiple human papillomavirus genotype infections in cervical cancer progression in the study to understand cervical cancer early endpoints and determinants.

Determining the causal attribution of human papillomavirus (HPV) genotypes to cervical disease is important to estimate the effect of HPV vaccination and to establish a type spectrum for HPV-based screening. We analyzed the prevalence of HPV infections and their attribution to cervical disease in a population of 1,670 women referred to colposcopy for abnormal cytology at the University of Oklahoma. HPV genotyping was performed from cytology specimens using the Linear Array assay that detects 37 HPV genotypes. We used different methods of type attribution to revised cervical disease categories. We found very high prevalence of multiple HPV infections with up to 14 genotypes detected in single specimens. In all disease categories except for cancers, there was a significant trend of having more infections at a younger age. We did not see type interactions in multiple genotype infections. HPV16 was the most frequent genotype at all disease categories. Based on different attribution strategies, the attribution of vaccine genotypes (6, 11, 16, 18) ranged from 50.5 to 67.3% in cancers (n = 107), from 25.6 to 74.8% in CIN3 (n = 305), from 15.2 to 52.2% in CIN2 (n = 427), and from 6.6 to 26.0% in

HFE mutations in heart disease.

Given the reported association of cardiac complications with hereditary hemochromatosis and the high carrier frequency of HFE gene mutations in the natural population, it seems reasonable that such mutations might appear more frequently than expected among symptomatic cardiac patients. Thus, H63D, C282Y, and S65C mutations and their possible associations were examined in 477 Caucasian males undergoing coronary angiography. Genotypes were analyzed for differences between ferritin and transferrin levels, coronary artery disease (CAD), cardiomyopathy (CM), and cardiovascular disease (CVD) mortality. No significant differences were found in ferritin levels between those with or without HFE mutations (C282Y P = 0.632, H63D P = 0.765, S65C P = 0.568, and HFE mutation P = 0.568); however, there was a significant difference (P = 0.005) in mean transferrin levels between those with (252 microg/l) and without (275 microg/l) C282Y. No relationship between HFE mutations and CAD (C282Y, P = 0.402; H63D, P = 0.112; S65C, P = 0.170) or CVD death (C282Y, P = 0.560; H63D, P = 0.682; S65C, P = 0.664) was demonstrated using logistic regression. However, an association between S65C and CM was found (odds ratio 4.4; 95% confidence interval 1.3-13.3, P = 0.018). This suggests that the S65C allele may contribute to the development of CM, but that these three HFE mutations do not appear to play a significant role in development of ischemic heart disease.

Cytogenetic changes associated with myelodysplastic syndrome affecting bone marrow engraftment analysis.

In vitro amplification of polymorphic genetic markers, especially short tandem repeats (STRs), has become standard laboratory practice in the monitoring of allogeneic bone marrow transplant patients. After initial analysis of donor and recipient samples at multiple loci before transplantation, one or more loci are used to follow engraftment status in subsequent specimens. We describe an unusual pattern of STRs in a transplanted patient with a prior history of refractory acute myelogenous leukemia. DNA chimerism studies showed a lack of engraftment at 1 and 2 months after transplantation. Atypical minor peaks occurred at each of three STR loci in the pre-transplant and 2-month post-transplant recipient samples. However, these peaks were of equal amplitude as the major corresponding allele in the 1-month post-transplant sample. A history of myelodysplasia with specific chromosomal deletions before the patient's acute myelogenous leukemia diagnosis appears to explain the spurious peaks. STR analysis of blood and archival paraffin-embedded tissues collected from the patient at various time points before transplantation reflected the evolution, progression, and response to therapy of the myelodysplasia. The case illustrates the need for comprehensive evaluation of pertinent clinical and laboratory data during engraftment monitoring to identify potential sources for error in interpretation of STR analysis.