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CONTEXT: Persistent high-risk human papillomavirus (hrHPV) infection is essential for the development of cervical cancer and its precursor lesions. High-risk HPV testing has a higher sensitivity than cytology does for detecting cervical epithelial lesions. However, a large study from a single institution showed 31% of patients with invasive cervical cancer had negative baseline hrHPV testing within 5 years preceding the diagnosis. OBJECTIVE: To investigate the limitation of hrHPV testing in detecting invasive cervical cancer. DESIGN: Cases from 2012 with a histologic diagnosis of invasive cervical carcinoma were retrieved from multiple institutions. From those records, prior hrHPV testing and Papanicolaou test results in the 5 years before the cancer diagnosis were recorded. RESULTS: Seventy patients with cervical carcinoma were included in the study. Negative HPV test result rates were 9% (5 of 53), 23% (6 of 26), and 25% (2 of 8) during the periods of less than 1 year, 1 to 3 years, and 3 to 5 years before the histologic diagnoses, respectively. Negative Papanicolaou testing results in the same time intervals were 3.4% (2 of 59), 33% (10 of 30), and 40% (6 of 15). Although the HPV(-) rate seemed to be different among different HPV test methods, no statistical significance was detected because of small sample size. Negative hrHPV rates in patients with adenocarcinoma were similar to those in patients with squamous cell carcinoma. CONCLUSIONS: These data expose limitations for the potential use of primary HPV testing. In addition, current screening guidelines recommending cotesting at 5-year intervals should be evaluated further with additional historic data collection because there are women with negative results for both Papanicolaou tests and hrHPV testing within the period of 3 to 5 years before an invasive carcinoma diagnosis.

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CONTEXT: Anal cytology is being used more frequently for anal cancer screening, yet many cytologists are unfamiliar with it. OBJECTIVE: To describe the performance of anal cytology in the College of American Pathologists' Interlaboratory Comparison Program in Non-Gynecologic Cytology (CAP NGC) educational slide program during a 6-year time span, from 2006 to 2011, using participant responses (pathologist, cytotechnologist, and laboratory). DESIGN: Concordance rates for the target diagnosis and general category for each slide challenge were analyzed. Four main factors were included in the analysis: (1) general category or specific responses, (2) program year from 2006 to 2011, (3) participant type (pathologist, cytotechnologist, or overall laboratory), and (4) preparation type (liquid-based or conventional). RESULTS: Participants most frequently correctly classified negative for intraepithelial lesion or malignancy, low-grade squamous intraepithelial lesion, and herpes simplex virus infection, with concordance rates of 78.8%, 85%, and 80.2%, respectively. Performance on challenges with target diagnoses of high-grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, and ameba was poor, with concordance rates of 57.1%, 56.2%, and 41.5%, respectively. Significant improvement during the 6 years was seen in the concordance rates of participants' responses for low-grade squamous intraepithelial lesion challenges but not for HSIL. There was no significant difference in performance by slide preparation type. CONCLUSIONS: The poor performance on anal cytology in the CAP NGC program, especially with regard to correct identification of HSIL and squamous cell carcinoma, indicates that there is a need for continued education about anal cytology.

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CONTEXT: The College of American Pathologists (CAP) Human Papillomavirus (High-Risk) Survey for Cytopathology and Other Laboratories (CHPV) meets the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) requirements for 5 proficiency testing challenges analyzed 3 times per year. This study reports laboratory performance for CHPV from 2008 through 2010. OBJECTIVE: To identify trends in proficiency testing performance for subscribers to the CAP CHPV. DESIGN: CHPV responses were evaluated by using a nonlinear mixed model (significance level of .05) with a 2-factor interaction term and repeated measures component, comparing year, media, method, and intended response. Media types included Digene transport, SurePath, ThinPrep media, or a mixture of media types. Proficiency testing challenges validated at 80% consensus. RESULTS: All challenges validated; 476 laboratories submitted 14 911 responses with 14 620 correct responses (98%). There were no differences between positive or negative challenges, or rate of correct responses; significant differences existed between media types by year and methods. Digene and ThinPrep media performed better than SurePath (P < .001; P = .03). There was a statistically significant difference between methods (P < .001); "other commercial kits," "other (noncommercial)" tests, and Third Wave performed more poorly than others. CONCLUSIONS: Laboratories performed well when testing for human papillomavirus in CHPV during a period of 3 years. All challenges performed to the 80% threshold. Significant differences were found between methods and media. The CAP CHPV survey provides useful information for laboratories choosing human papillomavirus testing methods.

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CONTEXT: Implementation of proficiency testing for gynecologic cytology was delayed 20 years because of challenges addressing the subjective nature of cytologic interpretation and replicating normal working conditions. Concern remains regarding test scoring, slide validation, test environment, and other issues. How these test results are, or should be, used in quality management has never been explored. OBJECTIVE: To provide information on good laboratory practices for gynecologic cytology proficiency testing based on findings from the College of American Pathologists' survey-based project funded by the Centers for Disease Control and Prevention. DATA SOURCES: An expert working group evaluated results from a Web-based, national laboratory survey plus responses from follow-up questions and findings from the literature. The group created statements on good laboratory practices pertinent to proficiency testing and its role in quality management, which were discussed and voted on at a consensus conference. CONCLUSIONS: Two-thirds of laboratories report having an individual with an unsuccessful proficiency testing score. More than 90% did not initiate any remedial action for 1 or 2 unsuccessful tests; 84% of laboratories reported they actively monitored results from proficiency testing, but most laboratories did not initiate any remedial action for cytotechnologists (81.4%; 376 of 462) or pathologists (87.7%; 405 of 462) who passed a proficiency test but who did not score 100%. Proficiency testing pass-fail rates should be monitored globally for the laboratory and for each individual. Proficiency testing slides should be prescreened by cytotechnologists for pathologists who are not primary screeners. Remedial action should not be required for a passed, but imperfect, test. No remedial action is required for an unsuccessful, first proficiency test result before retesting.

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CONTEXT: There are many long-standing quality monitors for cytopathology laboratories and their cytotechnologists and pathologists. Many of these monitors are based on tradition and empirical good intentions. There is no established standard as to how results of these monitors should be used in a quality assurance program. OBJECTIVE: To review practices that are typically part of a general quality program in cytopathology laboratories and to provide statements regarding good laboratory practices that laboratories may find useful in a quality assurance program in their own setting. DATA SOURCES: An expert working group evaluated results from a national laboratory survey, responses from follow-up questions posted on a Web site, and findings from the literature. The group created statements on good laboratory practices related to general quality practices and quality assurance in gynecologic cytopathology. These were discussed and voted on at a consensus conference. CONCLUSIONS: Laboratories follow many metrics. Most laboratories facilitate comparison of individual metrics against the laboratory's metrics: 81.1% for cytotechnologists and 59.6% for pathologists. The majority of laboratories facilitate comparison of individual cytotechnologist metrics with other cytotechnologists, but less frequently metrics from pathologists with other individuals. The most common methods to recognize variance in performance in individuals were by identifying outliers from the data or by user-defined action limits. The most common method to address variance was an attempt to identify the cause of the variance and conduct a focused review. Quality metrics should be monitored for the laboratory as a whole and in selected cases for both individual pathologists and cytotechnologists. Results should be shared with individuals, and newly hired primary screeners should be monitored. Reviewing selected cases is a useful quality tool. Low-volume methodologies, such as conventional Papanicolaou tests, should have additional oversight.

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Anorectal cytology (ARC) is increasingly accepted as a valid screening tool for the diagnosis of squamous intraepithelial lesions in populations at increased risk for anal cancer. As with cervical cancer screening protocols, proper patient preparation, specimen collection and specimen processing are essential for obtaining an optimal cytological sample. With attention and experience, the clinician can collect the best possible ARC specimen for laboratory evaluation. The incorporation of repeated interval anal cytology into standard surveillance practices for high-risk individuals is a valuable tool for the early detection of human papillomavirus-related anal squamous epithelial lesions and the prevention of anal squamous cell carcinomas.

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Cervical cancer and anal cancer share many similarities including causation by oncogenic human papillomaviruses; however, significant differences exist in their epidemiology, risk factors, biologic behavior, management, and treatment. Although rare, the incidence of anal cancer is alarmingly high and continues to increase in high-risk populations, particularly men who have sex with men regardless of their human immunodeficiency virus (HIV) status. There are no national screening guidelines for anal cancer. Using the success of cervical cancer screening as a model, anal cancer screening approaches apply anal cytology, high-resolution anoscopy, and directed biopsy to guide treatment and management strategies. Although much has been learned about the natural history and epidemiology of anal intraepithelial neoplasia (AIN), the rate of progression of high-grade anal intraepithelial neoplasia (HGAIN) to invasive squamous cell carcinomas is not known. The impact of screening and treatment of HGAIN on morbidity and mortality from anal cancer are also unknown. Because the incidence of HGAIN and anal squamous cell carcinoma continue to increase, it is imperative to find pathways for effective screening, early detection, and therapeutic intervention. This article provides an overview of anal cancer screening while highlighting its differences from cervical cancer screening and the remaining obstacles and controversies to implementation of a successful anal cancer screening program.

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Detection of anti-drug antibodies (ADA) can be difficult, if not impossible, in the presence of drug in the sample. This is a particular concern with therapeutic monoclonal antibodies (mAbs), which have typically longer half-lives than other proteins. For detection of ADA in presence of high drug concentrations, assay choice is limited to ELISA-like methods, capable of incorporating acid dissociation procedures to separate drug-ADA immune complexes. To our knowledge, Biacore assays have not been shown to be directly compatible with acid dissociation procedures, until now. As a consequence, steps to ensure adequate clearance of the drug are prerequisite to enable sensitive detection of ADA. Here we describe the development of a novel, rapid and highly drug tolerant Biacore method that uses an acid dissociation step to detect ADA in the presence of excess drug in human serum. Removal of drug after acid treatment is not required.

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BACKGROUND: Anal carcinoma incidence is increasing, and is highest among men with human immunodeficiency virus (HIV) infection who have sex with men. Anal carcinoma and anal intraepithelial neoplasia (AIN) are ascertained on tissue histology, but requires invasive procedures. Screening for AIN using anal cytology was suggested. The authors evaluated agreement on cytologic and biopsy specimens from HIV-positive men undergoing anal carcinoma screening. METHODS: One hundred twenty-nine HIV-positive men with a history of anal-receptive intercourse underwent anal cytology, anoscopy, and biopsy. Four pathologists independently assessed cytology and biopsy specimens and reached consensus for discordant cases. RESULTS: Each pathologist evaluated 120 cytology and 155 biopsy specimens. The weighted kappa value for overall agreement was 0.54 (95% confidence interval [CI], 0.49-0.59) for cytology specimens and 0.59 (95%CI, 0.55-0.63) for biopsy specimens. The median kappa values for pairwise agreement among pathologists and for agreement with consensus were, respectively, 0.69 and 0.77 for cytology and 0.66 and 0.75 for biopsy. At least 3 pathologists were in agreement for 92 (76.7%) cytology and 134 (86.5%) biopsy specimens. Reliability for the Bethesda classification system was at least moderate, except for the cytologic category of atypical squamous cells of undetermined significance (kappa = 0.12). Fourteen of 29 (48.3%) cytology specimens and 36 of 47 (76.6%) biopsy specimens with consensus interpretation of high-grade squamous intraepithelial lesions (HSIL) were interpreted originally as HSIL by > or = 3 pathologists. The kappa value for agreement with consensus distinguishing HSIL from non-HSIL ranged from 0.55 to 0.88 for cytology specimens and from 0.76 to 0.94 for biopsy specimens. CONCLUSIONS: Agreement for cytologic and biopsy interpretations was generally at least moderate. Nevertheless, these results supported the need for disease indicators with greater reliability.

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