Salaheddin M. Mahmud

Human Papillomavirus Infections with Multiple Types and Risk of Cervical Neoplasia

Background: Besides an established role for certain human papillomavirus (HPV) genotypes in the etiology of cervical cancer, little is known about the influence of multiple-type HPV infections on cervical lesion risk. We studied the association between multiple HPV types and cervical lesions among 2,462 Brazilian women participating in the Ludwig-McGill study group investigation of the natural history of HPVs and cervical neoplasia. Methods: Cervical specimens were typed by a PCR protocol. The cohorts repeated-measurement design permitted the assessment of the relation between the cumulative and concurrent number of HPV types and any-grade squamous intraepithelial lesions (SIL) and high-grade SIL (HSIL). Result: At individual visits, 1.9% to 3.2% of the women were infected with multiple HPVs. Cumulatively during the first year and the first 4 years of follow-up, 12.3% and 22.3% were infected with multiple types, respectively. HSIL risk markedly increased with the number of types [odds ratio (OR), 41.5; 95% confidence interval (95% CI), 5.3-323.2 for single-type infections; OR, 91.7; 95% CI, 11.6-728.1 for two to three types; and OR, 424.0; 95% CI, 31.8-5651.8 for four to six types, relative to women consistently HPV-negative during the first year of follow-up]. The excess risks for multiple-type infections remained after exclusion of women infected with HPV-16, with high-risk HPV types, or persistent infections, particularly for any-grade SIL. Coinfections involving HPV-16 and HPV-58 seemed particularly prone to increase risk. Conclusion: Infections with multiple HPV types seem to act synergistically in cervical carcinogenesis. These findings have implications for the management of cervical lesions and prediction of the outcome of HPV infections. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1274–80)

Low 2012–13 Influenza Vaccine Effectiveness Associated with Mutation in the Egg-Adapted H3N2 Vaccine Strain Not Antigenic Drift in Circulating Viruses

Background Influenza vaccine effectiveness (VE) is generally interpreted in the context of vaccine match/mismatch to circulating strains with evolutionary drift in the latter invoked to explain reduced protection. During the 2012–13 season, however, detailed genotypic and phenotypic characterization shows that low VE was instead related to mutations in the egg-adapted H3N2 vaccine strain rather than antigenic drift in circulating viruses. Methods/Findings Component-specific VE against medically-attended, PCR-confirmed influenza was estimated in Canada by test-negative case-control design. Influenza A viruses were characterized genotypically by amino acid (AA) sequencing of established haemagglutinin (HA) antigenic sites and phenotypically through haemagglutination inhibition (HI) assay. H3N2 viruses were characterized in relation to the WHO-recommended, cell-passaged vaccine prototype (A/Victoria/361/2011) as well as the egg-adapted strain as per actually used in vaccine production. Among the total of 1501 participants, influenza virus was detected in 652 (43%). Nearly two-thirds of viruses typed/subtyped were A(H3N2) (394/626; 63%); the remainder were A(H1N1)pdm09 (79/626; 13%), B/Yamagata (98/626; 16%) or B/Victoria (54/626; 9%). Suboptimal VE of 50% (95%CI: 33–63%) overall was driven by predominant H3N2 activity for which VE was 41% (95%CI: 17–59%). All H3N2 field isolates were HI-characterized as well-matched to the WHO-recommended A/Victoria/361/2011 prototype whereas all but one were antigenically distinct from the egg-adapted strain as per actually used in vaccine production. The egg-adapted strain was itself antigenically distinct from the WHO-recommended prototype, and bore three AA mutations at antigenic sites B [H156Q, G186V] and D [S219Y]. Conversely, circulating viruses were identical to the WHO-recommended prototype at these positions with other genetic variation that did not affect antigenicity. VE was 59% (95%CI:16–80%) against A(H1N1)pdm09, 67% (95%CI: 30–85%) against B/Yamagata (vaccine-lineage) and 75% (95%CI: 29–91%) against B/Victoria (non-vaccine-lineage) viruses. Conclusions These findings underscore the need to monitor vaccine viruses as well as circulating strains to explain vaccine performance. Evolutionary drift in circulating viruses cannot be regulated, but influential mutations introduced as part of egg-based vaccine production may be amenable to improvements.

Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis

Animal and laboratory studies suggest that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. To assess this association, we conducted a systematic review and meta-analysis of observational studies published before January 2003. We derived summary odds ratios (ORs) using both fixed and random effects models and performed subgroup analyses to explore the possible sources of heterogeneity between combined studies. We identified 12 reports (five retrospective and seven prospective studies). Most studies of aspirin use reported inverse associations, but only two were statistically significant. The summary OR for the association between aspirin use and prostate cancer was 0.9 (95% confidence interval: 0.82–0.99; test of homogeneity P=0.32), and varied from 1.0 for retrospective studies to 0.85 for prospective studies. Studies that measured exposure to a mixture of NSAIDs were less consistent. These results indicate an inverse association between aspirin use and prostate cancer risk. The current epidemiological evidence and, in particular, the strong and consistent laboratory evidence underline the need for additional epidemiological studies to confirm the direction and magnitude of the association.

Predictors of colorectal cancer after negative colonoscopy: a population-based study.

OBJECTIVES:A higher proportion of colorectal neoplasia among women occurs in the proximal colon, which might be more frequently missed by colonoscopy. There are no data on predictors of developing colorectal cancer (CRC) after a negative colonoscopy in usual clinical practice. We evaluated gender differences and predictors of CRC occurring after a negative colonoscopy.METHODS:All individuals 40 years or older with negative colonoscopy were identified from Manitobas provincial physicians’ billing claims database. Individuals with less than 5 years of coverage by the provincial health plan, earlier CRC, inflammatory bowel disease, resective colorectal surgery, or lower gastrointestinal endoscopy were excluded. CRC risk after negative colonoscopy was compared to that in the general population by standardized incidence ratios. Cox regression analysis was performed to determine the independent predictors of CRC occurring after negative colonoscopy.RESULTS:A total of 45,985 individuals (18,606 men; 27,379 women) were followed up for 229,090 person-years. After a negative colonoscopy, men had a 40–50% lower risk of CRC diagnosis through most of the follow-up time. Risk among women was similar to that of women in the general population in the first 3 years and then was 40–50% lower. Older subject age and performance of index colonoscopy by non-gastroenterologists were independent predictors for early/missed CRC (cancers occurring within 3 years of negative colonoscopy).CONCLUSIONS:Women may have a higher rate of missed/early CRCs after negative colonoscopy. Predictors of missed/early CRCs after negative colonoscopy include older age and performance of index colonoscopy by a non-gastroenterologist.

Type-Specific Duration of Human Papillomavirus Infection: Implications for Human Papillomavirus Screening and Vaccination

BACKGROUND Understanding the duration of human papillomavirus (HPV) infection may help find suitable end points for vaccine trials and testing intervals in screening studies. We studied genotype-specific infection duration among 2462 women enrolled in the Ludwig-McGill cohort study. METHODS Cervical specimens collected every 4-6 months were tested by a polymerase chain reaction protocol. Actuarial techniques were used to estimate the duration of HPV infection and to investigate the influence of age, number of sexual partners, and coinfection with multiple HPV types. RESULTS At enrollment, the prevalence of infection with high-risk HPV types was 10.6%, and the prevalence of infection with low-risk HPV types was 6.1%; incidence rates were 6.1 and 5.0 infections per 1000 women-months, respectively. Prevalent infections took longer to clear than incident infections (mean time to clearance, 18.6 months vs. 13.5 months). The mean duration of incident infection with high- and low-risk HPV varied according to the analytic approach used to measure this variable and showed considerable variation by HPV type (range, 5.1-15.4 months). Age and number of partners did not influence infection duration, whereas coinfection was associated with increased infection duration. The mean duration of HPV-16 monoinfection was 11.0 months, and the mean duration of HPV-16 coinfection was 15.4 months. CONCLUSION There was considerable variation among HPV types with regard to the duration of infection. Coinfection with multiple types contributed to an increased infection duration.

Quality of life and survival prediction in terminal cancer patients: a multicenter study.

It remains unclear whether health‐related quality of life (HRQoL) measurements from patients and staff can be combined with medical data to predict survival in patients with terminal cancer.

Risk of Cervical Abnormalities in Women With Inflammatory Bowel Disease: A Population-Based Nested Case-Control Study

BACKGROUND & AIMS We evaluated the risk of cervical abnormalities in women with inflammatory bowel disease (IBD) in a population-based, nested, case-control study. METHODS Cases with abnormal Papanicolaou (Pap) smears or cervical biopsies were matched with up to 3 controls (normal Pap smears) by year of birth, year of first health care coverage, and number of Pap smears in the preceding 5 years. A diagnosis of IBD before the index date was identified from the University of Manitoba IBD Epidemiology Database. Exposures to immunosuppressant drugs and corticosteroids were determined from the provincial drug prescription database. Analyses were adjusted for socioeconomic status and exposure to oral contraceptives and nonsteroidal anti-inflammatory drugs. RESULTS 19,692 women with cervical cytologic and/or histologic abnormalities were matched with 57,898 controls with normal Pap smears. There was no association between cervical abnormalities and ulcerative colitis (odds ratio [OR], 1.03; 95% confidence interval [CI], 0.77-1.38). The increase in risk in women with Crohns disease was limited to those exposed to 10 or more prescriptions of oral contraceptives (OR, 1.66; 95% CI, 1.08-2.54). The combined exposure to corticosteroids and immunosuppressants was associated with increased risk of cervical abnormalities (OR, 1.41; 95% CI, 1.09-1.81). There was no interaction between the effect of IBD and corticosteroids and/or immunosuppressants. CONCLUSIONS These findings do not support an association between IBD itself and the risk of developing cervical abnormalities. An increased risk in patients given a combination of corticosteroids and immunosuppressants should be considered in managing women with IBD.

Visual inspection as a cervical cancer screening method in a primary health care setting in Africa

We evaluated the feasibility and performance of visual inspection with acetic acid (VIA) and Lugols iodine (VILI) for cervical cancer screening in a primary health‐care setting in Kinshasa, Congo. Women (1,528) aged ≥30 years were screened independently by nurses and physicians by VIA and VILI and Pap cytology. Biopsy samples were obtained from women with abnormal colposcopies and from 290 randomly chosen women with normal colposcopy. Cytological and histological examinations were performed in Lyon and Montreal, respectively. The prevalence of cervical intraepithelial neoplasia (CIN) of grades 1, 2 and 3 was 4.5, 1.3 and 4%, respectively. Using biopsy as the reference, the sensitivity, specificity and negative predictive value (NPV) for ≥CIN 2 for VIA‐nurse were 55.5% (95% CI: 34.7–76.2), 64.6% (95% CI: 62.0–67.1) and 96.8% (95% CI: 93.5–98.7), respectively. The corresponding values for VILI‐nurse were 44.0% (95% CI: 24.2–63.8), 74.6% (95% CI: 72.3–76.9) and 96.7% (95% CI: 93.7–98.6). The equivalent parameters for physicians were 71.1% (95% CI: 46.7–95.5), 71.3% (95% CI: 68.9–73.6) and 98.6% (95% CI: 96.0–99.7) for VIA and 68.3% (95% CI: 42.5–94.0), 76.2% (95% CI: 74.0–78.4) and 97.2% (95% CI: 95.3–98.5) for VILI. The sensitivity of cytology ranged between 31 and 72%, depending on the abnormality threshold used to define positivity, with a corresponding specificity range of 94–99% and a NPV range of 97–99%. Our results show that VIA and VILI performed by nurses and physicians are slightly more sensitive but less specific than Pap cytology across multiple combinations of test and lesion thresholds. Given their lower cost and easy deployment, visual inspection methods merit further assessment as cervical cancer screening methods for low‐resource countries.

Effect of Preoperative Delay on Survival in Patients With Bladder Cancer Undergoing Cystectomy in Quebec: A Population Based Study

PURPOSE In Canada there is growing concern that waiting time for cancer surgery has been increasing. We used population based data to estimate the average PD for RC in Quebec and assess whether delayed surgery has a negative impact on long-term survival. MATERIALS AND METHODS We used the provincial billing database of the maladie du Quebec to identify all patients with bladder cancer 18 years or older who underwent RAMQ from 1990 to 2002. PD was calculated as the time elapsed between the most recent transurethral resection and the date of RC. Patients were categorized according to PD tertiles into 3 groups, namely 1) 20 or less, 2) 21 to 47 and (C) 48 days or greater. Cox proportional hazards models were used to assess the effect of PD on overall survival, while adjusting for patient and provider factors. RESULTS During the study period 1,592 radical cystectomies were performed. Overall median PD was 33 days (95% CI 30 to 35). Median PD increased from 23 days in 1990 to 50 in 2002. After adjusting for calendar year, and patient and provider variables there were no significant differences in survival among the 3 delay categories. However, patients subject to greater than 12 weeks of delay were at 20% greater risk for dying (95% CI 1.0 to 1.5, p = 0.051). CONCLUSIONS In line with previous reports PD greater than 12 weeks seems to be associated with a worse long-term prognosis.

Use of nonsteroidal anti-inflammatory drugs and prostate cancer risk: a meta-analysis

The association between use of aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) and the risk of prostate cancer remains controversial despite many observational epidemiological studies. We conducted a systematic meta‐analysis of these studies to examine both the strength and the consistency of the association, and to explore sources of variability between studies. We searched 12 computerized literature databases for reports published before June 2008 and included any epidemiologic studies where the outcome was prostate cancer incidence or mortality, and the exposure was use of NSAIDs. Studies that met the inclusion criteria comprised 10 case–control and 14 cohort studies with a total of 24,230 prostate cancer cases. Studies that assessed the effect of aspirin use on total prostate cancer had a pooled odds ratio (POR) of 0.83 (95%CI: 0.77–0.89), whereas those that assessed the effect of aspirin on advanced prostate cancer had a POR of 0.81 (0.72–0.92). Studies that examined the effects of non‐aspirin NSAIDs or all NSAIDs were less consistent but still suggestive of reduced risks. However, most reviewed studies were limited by exposure and disease misclassification, by inadequate information on dose and duration of use and by the possibility of screening and other biases. In conclusion, the epidemiologic evidence for a protective effect of aspirin and other NSAID use against prostate cancer is suggestive but not conclusive. There is a need for well‐designed observational studies with adequate exposure measurements, accurate case definition, attention to latency effects, and careful adjustment for screening and other biases.