Detecting anal human papillomavirus infection in men who have sex with men living with HIV: implications of assay variability.

BACKGROUND: Incidence of anal cancer (AC) caused by persistent human papillomavirus (HPV) infection has risen in the last years in men who have sex with men (MSM) living with HIV. There is consensus that this population should be screened for anal precancerous lesions, but the role of HPV DNA testing in AC screening programmes is still under debate. OBJECTIVES: This study employed two molecular test to detect anal HPV DNA and compared assay performance and prognostic value for the diagnosis of histology proven high-grade intraepithelial anal lesions. METHODS: MSM living with HIV attended their regular check-up visits consisting of detection of anal HPV infection, anal cytology, digital anorectal examination and high resolution anoscopy. HPV DNA was detected using Hybrid Capture 2 High-Risk test (HC2, total assay) and LINEAR ARRAY HPV Genotyping Test (LA, type-specific assay) RESULTS: Among 274 participant, prevalence of HPV DNA was 48.5% by HC2 and 89.4% by LA. HPV16 (30.6%) and HPV6 (19.6%) were the most common genotypes identified. Prevalence of multiple HPV infections was 56.2%. Agreement between HPV DNA assays was 75.2% (κ=0.51; 95% CI 0.42 to 0.60). Total HPV detection demonstrated high sensitivity (90%; 95% CI 68.3 to 98.8) and moderate specificity (58.4%; 95% CI 50.2 to 66.3), while type-specific HPV16/18 genotyping provided an increase in specificity and showed the highest area under the curve (0.81; 95% CI 0.74 to 0.89) and Youden's index (0.63). CONCLUSIONS: Both methodologies identified a high prevalence of anal HPV infection and multiple HPV infections in MSM living with HIV, showing a moderate overall agreement between them. Either total HPV detection or type-specific HPV16/18 detection together with a threshold ≥atypical squamous cells of undetermined significance for abnormal cytology showed an acceptable diagnostic accuracy.

Comparison of two sample collection devices for anal cytology in HIV-positive men who have sex with men: Cytology brush and Dacron swab.

OBJECTIVE: HIV-positive men who have sex with men (MSM) are a vulnerable group for anal cancer (AC), a cancer with a well-described precursor lesion, which can be detected early in screening programs using anal liquid-based cytology (aLBC). We aim to compare two aLBC sample collection devices: cytology brush (CB) and Dacron swab (DS). METHODS: Retrospective analysis of two consecutive study periods, the first using CB and the second DS. Participants underwent an aLBC, a human papillomavirus (HPV) DNA test and a high-resolution anoscopy (HRA), and a biopsy was performed for suspicious lesions. The sensitivity and specificity of aLBC, area under the receiver operating characteristic (ROC) curve (AUC), and concordance between cytology and HRA were assessed using Cohen's kappa coefficient. RESULTS: A total of 239 participants were enrolled (CB group, 120; DS group, 119). aLBC was benign in 46% of samples, and high-grade squamous intraepithelial lesion (HSIL) was detected in 11.7%. Prevalence of biopsy-proven HSIL was 15.3%. No differences in cytological and histological results were observed between the groups. aLBC-HRA concordance was weak for benign results (CB group, k = 0.309; DS group, k = 0.350) as well as for HSIL (k = 0.321 and 0.387, respectively). Sensitivity and specificity were 100% and 51.4%, respectively, in the CB group and 88% and 54.3% in the DS group (AUC = 0.711 and 0.759, respectively, P-value = .514). Representation of the transformation zone (TZ) was adequate in 83.3% of samples in the CB group and 50.4% in the DS group (P-value <.001). CONCLUSION: Our data suggest that both devices had similar accuracy to detect anal HSIL, although samples collected with CB are more likely to have an adequate TZ representation, the presence of which could be an indicator of sample quality.

Developing indicators for quality assurance in cytopathology. Catalan Society of Cytopathology.

BACKGROUND: Quality control in cytology must be established through reliable and easily measurable indicators. METHODS: From the Catalan Society of Cytopathology a group of experts has been established to write a document with 13 indicators that cover the entire cytological process, based on its Cytopathology Quality Guide. It has been elaborated through guides and documents with scientific evidence and DELPHI methodology in order to reach a structured consensus on the opinions of a group of experts. RESULTS: Thirteen indicators, covering all the cytologic process are expressed in worksheets specifying all their characteristics. CONCLUSION: This document allows the control of all stages of the cytological process.

Can we avoid axillary lymph node dissection in N2 breast cancer patients with chemo-sensitive tumours such as HER2 and TNBC?

PURPOSE: To find a group of cN2 patients or patients with high axillary burden who become ypN0 after neoadjuvant chemotherapy (NACT) and who may benefit from avoiding a lymphadenectomy. METHODS: A retrospective observational cohort study was conducted with 221 clinically staged N2 patients or patients with at least 3 suspicious lymph nodes found by ultrasound at diagnosis. The predictive factors for ypN0 analysed were age, MRI-determined tumour size, histological subtype, the Nottingham histologic grade, surrogate molecular subtype, ki-67 and vascular invasion when present. Clinical and radiological responses after NACT were also evaluated. Univariate and multivariate analyses by logistic regression were performed. Distant disease-free survival (DDFS) was calculated in relation to the status of the axillary lymph nodes after NACT. RESULTS: After NACT, 89 patients (40.3%) had axillary pathologic complete response (pCR) (ypN0) and 132 (59.7%) had residual axillary disease (ypN+). Molecular surrogate subtype, Ki-67 expression, and the clinical and radiological responses to NACT were the only independent factors associated with ypN0. Axillary pCR was observed more often in HER2-positive and triple-negative tumours than in luminal ones (OR 7.5 and 3.6, respectively). DDFS was 88.7% (95% CI 80.7-96.7%) for ypN0 and 56.2% (95% CI 32.1-80.3%) for ypN+ (p = 0.09). CONCLUSIONS: In HER2-positive and triple-negative breast cancer patients staged as cN2 or with high axillary burden before NACT, a sentinel lymph node biopsy after NACT could be recommended if there is a clinical and radiological response.

Long-term protection of HPV test in women at risk of cervical cancer.

OBJECTIVE: To evaluate the 9-year incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cumulative adherence to perform a next test in a cohort of women aged 40+ years with no cervical screening cytology within a window of 5 years (underscreened women), after baseline cervical cytology and HPV tests. METHODS: In Catalonia, Spain, co-testing with cytology and HPV test has been recommended in the Public Health system since 2006 for underscreened women. In 2007, 1,594 women with underscreened criteria were identified and followed through medical records form Pathological Department. 9-year cumulative incidence of histologically confirmed CIN2+ and cumulative adherence to perform a next test were estimated using Kaplan-Meier statistics. RESULTS: Follow-up was available for 1,009 women (63.3%) resulting in 23 women with. CIN2+ (2.3%). Of them, 4 women (17%) had both tests negative at baseline (3CIN2 and 1CIN3) with cumulative incidence of CIN2+ of 0.4% (95% CI: 0.1-1.4) at 5-years and 1.3% (95% CI: 0.4-3.7) at 9-years. During the first year, the prevalence among women with both tests positive was 27.0% (95% CI: 13.0-50.6) for CIN2+. Lost to follow-up was higher among women with both tests negative compared to those with both positive tests (38.7% vs 4.2%, p-value <0.001). 40.5% of the women HPV-/cyto- had a re-screening test during the 4 years following the baseline, increasing until 53.5% during the 6 years of follow-up. CONCLUSIONS: HPV detection shows a high longitudinal predictive value at 9-year to identify women at risk to develop CIN2+. The data validate a safe extension of the 3-year screening intervals (current screening interval) to 5-year intervals in underscreened women that had negative HPV result at baseline. It is necessary to establish mechanisms to ensure screening participation and adequate follow-up for these women.

Adrenal metastasis of hepatocellular carcinoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration of the right adrenal gland.

Recent studies have shown that the adrenal gland is the fourth most common site of HCC extrahepatic metastasis; despite this, the incidence of right adrenal metastasis of HCC is unclear. EUS-guided FNA of the right adrenal gland is technically possible and safe, and should be considered in cases of right adrenal tumors with no diagnostic criteria by imaging test.

Adrenal metastasis of hepatocellular carcinoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration of the right adrenal gland

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Visceral leishmaniasis with mediastinal lymphadenopathy diagnosed with endoscopic ultrasound-guided fine needle aspiration.

A 44-year-old man with a HIV infection and levels of CD4 < 100/mm3, under antiretroviral therapy and with a previous medical history of visceral leishmaniasis (VL), was admitted to hospital with progressive muscular weakness and paraesthesia in both legs for three months. Imaging procedures were performed, showing a leptomeningeal thickening and enlargement of hilar and mediastinal lymph nodes.

Visceral leishmaniasis with mediastinal lymphadenopathy diagnosed by endoscopic ultrasound-guided fine needle aspiration

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Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

A quick diagnosis unit as an alternative to conventional hospitalization in a tertiary public hospital: a descriptive study.

INTRODUCTION:  Reports indicate that a significant number of patients admitted to internal medicine units could be studied on an outpatient basis. OBJECTIVES:  This article assesses a quick diagnosis unit (QDU) as an alternative to acute hospitalization for the diagnostic study of patients with potentially serious diseases and suspected malignancy.  PATIENTS AND METHODS:  Between March 2008 and June 2012, 1226 patients were attended by the QDU. Patients were referred from the emergency department, primary health care centers, and outpatient clinics according to well­defined criteria. Clinical information was prospectively registered in a database.  RESULTS:  There were 634 men (51.7%), with a mean age of 60.5 ±17.5 years. The mean time to the first visit was 3.5 ±5.3 days. Most patients (65.7%) required only 2 visits. The mean interval to diagnosis was 12.2 ±14.7 days. A total of 324 patients (26.4%) had cancer. The diagnosis was  solid tumor in 81.5% of the cases, lymphoma in 19.8%, and various hematologic malignancies in 4.3%. The second most common diagnosis was anemia not associated with cancer (8.6% of the cases). Admission to the QDU allowed to avoid conventional hospitalization for diagnostic studies in 71.5% of the patients, representing a mean freeing­up rate of 7 internal medicine beds per day. In a satisfaction survey, 97% of the patients were completely or very satisfied and 96% preferred the QDU to conventional hospitalization.  CONCLUSIONS:  A QDU may be a feasible alternative to conventional hospitalization for the diagnosis of otherwise healthy patients with suspected severe disease. Appropriately managed and supported, QDUs can lighten the burden of emergency departments and reduce the need for hospitals beds.

Single-session endosonography and endoscopic retrograde cholangiopancreatography for biliopancreatic diseases is feasible, effective and cost beneficial.

BACKGROUND: Endoscopic ultrasonography (EUS) and Endoscopic Retrograde Cholangiopancreatography (ERCP) are often required in patients with pancreaticobiliary disorders. AIMS: To assess the clinical impact and costs savings of a single session EUS-ERCP. METHODS: Patient and intervention data from April 2009 to March 2012 were prospectively recruited and retrospectively analyzed from a database at a tertiary hospital. Indications, diagnostic yield, procedure details, complications and costs were evaluated. RESULTS: Fifty-five scheduled combined procedures were done in 53 patients. The accuracy of EUS-fine needle aspiration for malignancy was 90%. The main clinical indication was a malignant obstructing lesion (66%). The ERCP cannulation was successful in 67%, and in 11/15 failed ERCP (73%), drainage was completed thanks to an EUS-guided biliary drainage: 6 transmurals, 5 rendezvous. Eight patients (14%) had related complications: bacteremia (n = 3), pancreatitis (n = 2), bleeding (n = 2) and perforation (n = 1). The mean duration was 65 ± 22.2 min. The mean estimated cost for a single session was €3437, and €4095 for two separate sessions. The estimated cost savings using a single-session strategy was €658 per patient, representing a total savings of €36,189. CONCLUSION: Combined EUS and ERCP is safe, technically feasible and cost beneficial. Furthermore, in failed ERCP cases, the endoscopic biliary drainage can be completed with EUS-guided biliary access in the same procedure.

Prediction of cervical intraepithelial neoplasia grade 2+ (CIN2+) using HPV DNA testing after a diagnosis of atypical squamous cell of undetermined significance (ASC-US) in Catalonia, Spain.

BACKGROUND: A protocol for cervical cancer screening among sexually active women 25 to 65 years of age was introduced in 2006 in Catalonia, Spain to increase coverage and to recommend a 3-year-interval between screening cytology. In addition, Human Papillomavirus (HPV) was offered as a triage test for women with a diagnosis of atypical squamous cells of undetermined significance (ASC-US). HPV testing was recommended within 3 months of ASC-US diagnosis. According to protocol, HPV negative women were referred to regular screening including a cytological exam every 3 years while HPV positive women were referred to colposcopy and closer follow-up. We evaluated the implementation of the protocol and the prediction of HPV testing as a triage tool for cervical intraepithelial lesions grade two or worse (CIN2+) in women with a cytological diagnosis of ASC-US. METHODS: During 2007-08 a total of 611 women from five reference laboratories in Catalonia with a novel diagnosis of ASC-US were referred for high risk HPV (hrHPV) triage using high risk Hybrid Capture version 2. Using routine record linkage data, women were followed for 3 years to evaluate hrHPV testing efficacy for predicting CIN2+ cases. Logistic regression analysis was used to estimate the odds ratio for CIN2 +. RESULTS: Among the 611 women diagnosed with ASC-US, 493 (80.7%) had at least one follow-up visit during the study period. hrHPV was detected in 48.3% of the women at study entry (mean age 35.2 years). hrHPV positivity decreased with increasing age from 72.6% among women younger than 25 years to 31.6% in women older than 54 years (p < 0.01). At the end of the 3 years follow-up period, 37 women with a diagnosis of CIN2+ (18 CIN2, 16 CIN3, 2 cancers, and 1 with high squamous intraepithelial lesions--HSIL) were identified and all but one had a hrHPV positive test at study entry. Sensitivity to detect CIN2+ of hrHPV was 97.2% (95%confidence interval (CI) = 85.5-99.9) and specificity was 68.3% (95%CI = 63.1-73.2). The odds ratio for CIN2+ was 45.3 (95% CI: 6.2-333.0), when among ASC-US hrHPV positive women were compared to ASC-US hrHPV negative women. CONCLUSIONS: Triage of ASC-US with hrHPV testing showed a high sensitivity for the detection of CIN2+ and a high negative predictive value after 3 years of follow-up. The results of this study are in line with the current guidelines for triage of women with ASC-US in the target age range of 25-65. Non adherence to guidelines will lead to unnecessary medical interventions. Further investigation is needed to improve specificity of ASC-US triage.

Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Diagnóstico definitivo de los tumores neuroendocrinos (TNE) mediante PAAF ecodirigida por ultrasonografía endoscópica (USE) / No disponible

Introducción: la localización y diagnóstico de los tumores neuroendocrinos (TNE) es difícil. La ultrasonografía endoscópica (USE) tiene un papel significativo en la detección de TNE sospechados por la clínica u otras técnicas de imagen, así como en la localización exacta y confirmación citológica mediante USEPAAF. Objetivo: valorar la utilidad y precisión de la PAAF-USE en el diagnóstico diferencial y de confirmación de los TNE, en una revisión retrospectiva de la experiencia de nuestro grupo. Pacientes y métodos: de un total de 55 enfermos con sospecha de TNE a los que se le practicó USE radial o sectorial, se detectaron 42 tumores en 40 casos. En 16 casos con sospecha de TNE funcionantes (trastornos hormonales: 6 casos) y no funcionantes (10 casos), se les practicó USE-PAAF con 22 G. En todos se efectuó Ki 67 o inmunocitoquímica (ICQ). Hubo confirmación quirúrgica en 9 casos (5 M y 4 V), con una media de edad de 51 años (rango: 41-81 años). Los tumores se localizaban todos en el páncreas, excepto uno en el mediastino y uno en el recto, con un tamaño medio de 19 mm (rango: 10-40 mm). Resultados: no hubo complicaciones atribuibles a la PAAF. La sensibilidad fue del 100% (8/8), y la precisión y el VPP fue del 89% (8/9), ya que hubo un falso positivo que en el estudio cito - lógico sugirió el diagnóstico de TNE pero que su resección quirúrgica confirmó el diagnóstico de tumor sólido seudopapilar del páncreas. Conclusiones: la USE-PAAF con 22 G de los TNE posee una alta sensibilidad y VPP en la confirmación citológica de estos pacientes, con muy escasas complicaciones(AU)

Background: the detection and diagnosis of neuroendocrine tumors (NETs) is challenging. Endoscopic ultrasonography (EUS) has a significant role in the detection of NETs suspected from clinical manifestations or imaging techniques, as well as in their precise localization and cytological confirmation using EUS-Fine-needle aspiration-puncture (FNA). Objective: to assess the usefulness and precision of EUSFNAP in the differential diagnosis and confirmation of NETs, in a retrospective review of our experience. Patients and methods: in a total of 55 patients with suspected NETs who underwent radial or sectorial EUS, 42 tumors were detected in 40 cases. EUS-FNA using a 22G needle was performed for 16 cases with suspected functional (hormonal disorders: 6 cases) and non-functional NETs (10 cases). Ki 67 or immunocytochemistry (ICC) testing was performed for all. There was confirmation in 9 cases (5 female and 4 male) with a mean age of 51 years (range: 41-81 years). All tumors were located in the pancreas except for one in the mediastinum and one in the rectum, with a mean size of 19 mm (range: 10-40 mm). Results: there were no complications attributable to FNA. Sensitivity was 100% and both precision and PPV were 89%, as a false positive result suggested a diagnosis with NET during cytology that surgery finally revealed to be a pancreatic pseudopapillary solid tumor. Conclusions: EUS-FNA with a 22G needle for NETs has high sensitivity and PPV at cytological confirmation with few complications(AU)

Metástasis muscular de una neoplasia de pulmón / Muscle metastasis of lung cancer

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