Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials.

PURPOSE: Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long-term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. METHODS: We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. RESULTS: Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. CONCLUSION: This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Prevalence of Skin Cancer and Related Skin Tumors in High-Risk Kidney and Liver Transplant Recipients in Queensland, Australia.

The increased skin cancer incidence in organ transplant recipients is well-known, but the skin cancer burden at any one time is unknown. Our objective was to estimate the period prevalence of untreated skin malignancy and actinic keratoses in high-risk kidney and liver transplant recipients and to assess associated factors. Organ transplant recipients underwent full skin examinations by dermatologically trained physicians. The proportion of examined organ transplant recipients with histopathologically confirmed skin cancer in the 3-month baseline period was estimated. Prevalence ratios with 95% confidence intervals indicated significant associations. Of 495 high-risk organ transplant recipients (average age = 54 years, time immunosuppressed = 8.9 years), 135 (27%) had basal cell carcinoma, squamous cell carcinoma or Bowen's disease (intraepidermal carcinoma) present and confirmed in the baseline period, with respective prevalence proportions of 10%, 11%, and 18% in kidney transplant recipients and 10%, 9%, and 13% in liver transplant recipients. Over 80% had actinic keratosis present, with approximately 30% having 5 or more actinic keratoses. Organ transplant recipients with the highest skin cancer burden were Australian born, were fair skinned (prevalence ratio = 1.61, 95% confidence interval = [1.07, 2.43]), reported past skin cancer (prevalence ratio =3.39, 95% confidence interval = [1.93, 5.95]), and were receiving the most frequent skin checks (prevalence ratio = 1.76, 95% confidence interval = [1.15, 2.70]). In conclusion, high-risk organ transplant recipients carry a substantial measurable skin cancer burden at any given time and require frequent review through easily accessible, specialized services.

Racial disparity in adherence to positive airway pressure among US veterans.

PURPOSE: Despite advances in continuous positive airway pressure (CPAP) technology, compliance with CPAP therapy remains suboptimal. Studies conducted since the advent of objective CPAP recording have noted that African Americans (AA) may use CPAP less than Whites. We sought to confirm this finding among a large sample of veterans and examine effect modifiers of the differential usage. METHODS: A retrospective cohort of 233 AA and 1939 White Veterans Administration (VA) patients who had a sleep study between January 2003 and October 2006 and received CPAP therapy by the end of 2007. CPAP compliance was summarized at 2 weeks and 6 months post CPAP receipt. RESULTS: AAs were significantly less adherent than Whites even when controlling for age, gender, marital status, median household income for zip code, BMI, comorbidities, and obstructive sleep apnea (OSA) severity. AAs with severe OSA were 3 times more likely to use CPAP than AAs with mild/moderate OSA (p ≤ 0.001); a much smaller but still statistically significant difference was seen for Whites. CONCLUSIONS: CPAP compliance is considerably lower in AAs than in Whites, though severity of OSA modifies this association. These findings are not readily explained by differences in demographics or comorbidity.

Sun Protection Behavior in Organ Transplant Recipients in Queensland, Australia.

BACKGROUND: Organ transplant recipients (OTRs) have a high risk of skin cancer, and excessive sun exposure is a major contributing factor. OBJECTIVE: To document the prevalence of sun protection and associated factors in OTRs in Queensland, Australia. METHODS: Cross-sectional study of the frequency of wearing hats, long sleeves and using sunscreens among OTRs and factors associated with regular use. Adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression models. RESULTS: Among 446 OTRs, 66, 49 and 39% wore a hat, sunscreen and long sleeves, respectively, mostly when outdoors. 52% regularly practiced multiple sun protection measures while 19% did not. Sunburn-prone skin (PR = 1.43, 95% CI = 1.06-1.93) and frequent whole-body skin examinations (PR = 1.48, 95% CI = 1.19-1.84) were independently associated with regular use of multiple sun protection measures. CONCLUSION: Findings are consistent with sun-conscious OTRs also having more regular skin screening and that having frequent skin examinations promotes sun-protective habits.

Comparison of melanoma incidence and trends among youth under 25 years in Australia and England, 1990-2010.

White populations in Australia and England share many genetic and phenotypic characteristics due to common ancestry, but Australians experience far higher rates of melanoma due to higher ambient ultraviolet radiation (UVR) levels. To gain insight into the role of UVR on melanoma development early in life, we used national cancer registration data and compared recent incidence rates and long-term trends of primary invasive cutaneous melanoma in Australian and English youth aged 0-24 years diagnosed 1990-2010. Incidence rates and standardized rate ratios (SRRs) with 95% confidence intervals (CIs) for 2006-2010 were calculated and incidence trends across the whole period were examined using JoinPoint regression. In Australian youth, overall melanoma incidence was double that in English youth (2.2 and 1.1 per 100,000, respectively). While melanoma rates were similarly rare among children <10 years in both countries, in subsequent 5-year age groups, incidence was significantly higher in Australia compared to England. Melanoma incidence among 15-24 year olds significantly increased by more than 2% per year in both sexes in England. However, after an initial non-significant increase, Australian rates for this older age group significantly decreased by 6.0% (95% CI, -8.2 to -3.8) per year in females from 1997 and decreased by 12.4% (95% CI, -20.3 to -3.8) per year in males from 2004. Long-standing primary prevention strategies targeted at curbing UVR exposure appear to have been effective in mitigating incidence trends in Australian youth, but decreases in incidence in English youth are yet to be observed.

Melanoma incidence trends and survival in adolescents and young adults in Queensland, Australia.

Cutaneous melanoma is a relatively common cancer in adolescents and young adults in Australia, but detailed information about occurrence patterns and prognosis is limited. We evaluated incidence trends from 1982 to 2010 and recent survival rates in those aged 15-24 years in the state of Queensland. In situ and invasive melanoma cases were identified from the Queensland Cancer Registry. Incidence rates were age-standardised to the 2000 World population and trends calculated using joinpoint regression. Five-year relative survival was estimated by the period method and Poisson models were used to produce adjusted mortality hazard ratios. Average annual incidence rates for the 5-year period 2006-2010 were 6.3 per 100,000 [95% confidence interval (CI) 5.4, 7.2] for in situ and 10.1 per 100,000 (95% CI 9.0, 11.3) for invasive melanoma. Since the mid-1990s, incidence rates for in situ melanomas have been stabilizing while invasive melanoma has decreased in both sexes, mainly owing to declining rates of thin tumours (≤1 mm) (-5.4% per year, 95% CI -8.3%, -2.4%). Incidence rates of melanomas >1 mm in thickness have remained relatively unchanged since 1991 however. In the period 2006-2010, relative 5-year survival of 15-24 year olds with invasive melanoma was 95.7% (95% CI 92.9%, 97.5%). The subgroup with tumours >1 mm was nearly six times more likely to die within 5 years than those with thin tumours (adjusted hazard ratio = 5.53, 95% CI 1.72, 17.80). Incidence of thin melanoma in young people in Queensland is declining, suggesting benefits of primary prevention efforts are being realised.

Natural history of cutaneous human papillomavirus (HPV) infection in men: the HIM study.

Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection is associated with non-melanoma skin cancer (NMSC). Little is known about the natural history of cutaneous HPV. A sub-cohort of 209 men with no NMSC history, initially enrolled in the HPV infection in men (HIM) study, were followed for a median of 12.6 months. Epidemiological data were collected through self-administered questionnaires. Cutaneous HPV DNA was measured in normal skin swabs (SS) and eyebrow hairs (EB) for 25 and 16 HPV types in genera ß and γ, respectively. Any ß HPV infection was more prevalent in SS (67.3%) compared to EB (56.5%, p = 0.04). Incidence in SS was higher than 20 per 1,000 person-months for HPV types 4, 5, 23, 38 and 76. Median duration of persistence of ß and γ HPV infection was 8.6 and 6.1 months in EB, respectively, and 11.3 months and 6.3 months, in SS, respectively. Older age (>44 years vs. 18-30 years) was significantly associated with prevalent (SS OR = 3.0, 95% CI = 1.2-7.0) and persistent ß HPV infection (EB OR = 6.1, 95% CI = 2.6-14.1). History of blistering sunburn was associated with prevalent (OR = 2.8, 95% CI = 1.3-5.8) and persistent (OR = 2.3, 95% CI = 1.2-4.6) ß HPV infection in SS. Cutaneous HPV is highly prevalent in men, with age and blistering sunburn being significant risk factors for cutaneous ß HPV infection.

The epidemiology of human papillomaviruses.

Epidemiological studies indicate that most men and women will acquire a sexually transmitted anogenital human papillomavirus (HPV) infection in their lifetimes. In addition, infection with cutaneous HPV types is essentially ubiquitous. Most HPV infections are transient with no clinical symptoms although a minority of infections result in clinical disease such as warts or malignancies. Anogenital warts are the most common clinical manifestation of HPV infection with a prevalence of perhaps 1%. Virtually 100% of cervical cancers, 90-93% of anal canal cancers, 12-63% of oropharyngeal cancers, 36-40% of penile cancers, 40-64% of vaginal cancers and 40-51% of vulvar cancers are attributable to HPV infection. Of the estimated 12.7 million cancers occurring globally in 2008, 610,000 (approx. 5%) were HPV-associated anogenital or oral cancers. Cutaneous HPV types may increase the risk for nonmelanoma skin cancers. Sexual behavior is a primary risk factor associated with anogenital and oral HPV infection among men and women.

Effects of sunscreen on skin cancer and photoaging.

Application of sunscreen to the skin is widely used as an adjunct strategy, along with wearing protective clothing and seeking shade, to protect against skin cancer and photoaging that result from excessive sun exposure. Many epidemiological studies of case-control and cohort study design have studied the effects of sunscreen use on skin cancer, and more recently photoaging, but their findings have been mostly uninformative. This review of results of randomized controlled trials shows that the evidence, though limited, supports beneficial effects of sunscreen application on the occurrence of skin cancers and skin photoaging.

High rate of uncaptured myelodysplastic syndrome cases and an improved method of case ascertainment.

The myelodysplastic syndromes (MDS) are often diagnosed in outpatient clinics and may be under-reported to state cancer registries, which predominantly rely on hospital records and laboratory reports. We used a new method of cancer case capture to determine the rate of missed cases and estimate a more accurate incidence of MDS. Using a unique keyword algorithm, we queried all electronic pathology (E-path) reports sent to the state of Florida cancer registry in 2006 to identify potential MDS cases. A stratified, random sample of E-path reports was then reviewed to confirm diagnosis and assign MDS subtype. Characteristics were compared between captured and uncaptured MDS cases. 7111 E-path reports with MDS keyword hits were identified, of which only 18% linked to a registered MDS case, 47% linked to a different cancer, and 34% did not link with any record. Case review of a stratified, random sampling of 285 individuals led to the discovery that uncaptured cases made up 37.7% of the total true MDS cases in 2006. It is estimated that the true incidence of MDS is 5.3 individuals out of 100,000, compared to previous reports of 3.3 out of 100,000. Uncaptured MDS cases were younger and more likely to have information in the pathology report facilitating MDS subtype assignment. Only two-thirds of true MDS cases are captured in Florida using current case-finding mechanisms. Application of a keyword search strategy to identify cases among E-path reports is a feasible technique to improve MDS case ascertainment.

Case-control study of genus-beta human papillomaviruses in plucked eyebrow hairs and cutaneous squamous cell carcinoma.

Cutaneous human papillomaviruses (HPV) have been reported in cutaneous squamous cell carcinoma (SCC). We conducted a clinic-based case-control study to investigate the association between genus-beta HPV DNA in eyebrow hairs (EBH) and SCC. EBH from 168 SCC cases and 290 controls were genotyped for genus-beta HPV DNA. SCC tumors from a subset of cases (n = 142) were also genotyped. Viral load was determined in a subset of specimens positive for a single HPV type. Associations with SCC were estimated by odds ratios (OR) and 95% confidence intervals (CI) adjusted for age and sex using logistic regression. Statistical tests were two-sided. EBH DNA prevalence was greater in cases (87%) than controls (73%) (p < 0.05), and the association with SCC increased with the number of HPV types present, (≥ 4 types vs. HPV-negative: OR = 2.02, 95% CI = 1.07-3.80; p(trend) = 0.02). Type-specific associations were observed between SCC and DNA in EBH for HPV23 (OR = 1.90, 95% CI = 1.10-3.30) and HPV38 (OR = 1.84, 95% CI = 1.04-3.24). Additionally, when compared with the controls, the DNA prevalence in EBH was significantly higher among cases for 11 of the 25 genus-beta types tested, when accounting for DNA for the same HPV type in the tumor (ORs = 3.44-76.50). Compared to controls, the mean viral DNA load in EBH among the selected cases was greater for HPV5, HPV8 and HPV24, but lower for HPV38. SCC cases were more likely than controls to have HPV DNA+ EBH for single and multiple HPV types, providing additional support for the potential role of genus-beta HPV infections in SCC development.

Towards skin cancer prevention and early detection: evolution of skin cancer awareness campaigns in Australia.

Since the 1980s, Australia's mass-media campaigns promoting skin cancer awareness, namely skin cancer-preventative behaviors and early detection, have targeted the general community as well as high-risk groups, including outdoor workers, schoolchildren and youths. During that time, campaigns have evolved in tone and method of delivery. Their messages are today accompanied by policies, supportive environments such as shade and access to quality sun-protection products governed by national standards. Early detection of skin cancer has been the other aim of these campaigns, and recent downturns in incidence rates, especially in the young, and the shift to mostly thin melanomas at diagnosis in Australia, may partly reflect some campaign success. However, sustained efforts are required for long-lasting skin cancer control.

Correlates of a prescription for Bilevel positive airway pressure for treatment of obstructive sleep apnea among veterans.

INTRODUCTION: The acceptance of portable home-based polysomnography together with auto-titrating CPAP has bypassed the need for a laboratory polysomnography. Since bilevel airway pressure (BPAP) is titrated in the sleep lab, patients diagnosed using portable home-based polysomnography may not have the opportunity to receive BPAP. It is unknown whether the patients who would have ordinarily received a BPAP would benefit from it. We determine correlates of receiving BPAP and of being switched from BPAP to CPAP. We examine whether patients with these correlates have better adherence to BPAP versus CPAP. METHODS: Retrospective Cohort Study (Correlates at baseline) of 2,513 VA patients with a sleep study between January 2003 and October 2006 and receiving continuous or bilevel positive airway pressure (CPAP [N = 2,251]) or BPAP [N = 262]) by the end of 2007. PAP adherence up to 30 months was assessed. RESULTS: Significant correlates of BPAP were older age (p < 0.001), higher BMI and CHF (p < 0.01), COPD (p < 0.001), higher blood CO2 (p < 0.05), higher AHI and OSA severity (p < 0.001), lower nadir SpO2 (p < 0.001), and greater sleepiness (ESS) (p < 0.01). Patients on BPAP were more adherent to PAP therapy (p < 0.01), but the association largely disappeared following adjustment for BPAP correlates. There was preliminary evidence that these correlates predict long-term adherence to PAP therapy regardless of mode. CONCLUSIONS: We identified baseline factors that can help clinicians decide whether to prescribe an auto-BPAP as first-line therapy and that predict good long-term PAP adherence.

Case-control study of cutaneous human papillomavirus infection in Basal cell carcinoma of the skin.

Genus-ß human papillomavirus (HPV) DNA has been detected in basal cell carcinoma (BCC) tumors, but most epidemiologic studies have not observed associations between genus-ß HPV seropositivity and BCC. A clinic-based case-control study was conducted to investigate cutaneous HPV infection in BCC. BCC cases (n=224) were recruited from a dermatology clinic, and controls (n=300) were patients who were screened negative for skin cancer. Antibodies against cutaneous HPV types in genera α, ß, γ, mu, and nu were measured, and tumors from a subset of BCC cases (n=195) were tested for HPV DNA. Overall associations were observed between BCC and seropositivity for HPV types in genus-α (odds ratio (OR)=1.61; 95% confidence interval (CI)=1.11-2.35), γ (OR=1.78; 95% CI=1.22-2.60), and mu (OR=1.56; 95% CI=1.06-2.30). BCC cases with ß-HPV DNA in their tumors were more likely to be ß-HPV seropositive than controls (OR=1.76; 95% CI=1.03-3.01), with type-specific associations observed for HPV8 and HPV23, whereas no association was observed between ß-HPV seropositivity and ß-HPV DNA-negative BCC. No concordance between seropositivity and tumor DNA status was observed for HPV types in genera α and γ. In conclusion, the combined serology and tumor DNA results suggest that ß HPV types may have a role in BCC. Additional studies of BCC that assess HPV types in multiple genera are needed.

Comparison of hybrid capture II, linear array, and a bead-based multiplex genotyping assay for detection of human papillomavirus in women with negative pap test results and atypical squamous cells of undetermined significance.

Many methods with different levels of analytical sensitivity and clinical specificity have been developed to detect the presence of high-risk (HR) types of the human papillomavirus (HPV) in cervical samples. The Hybrid Capture II (HC-II) assay is broadly used for primary screening. In addition, several HPV genotyping assays, based on PCR methods, display higher sensitivity than the HC-II and are also used in screening programs. We evaluated the performance of three HPV DNA tests, namely, the HC-II, the Linear Array (LA) HPV genotyping assay, and an HPV type-specific E7 PCR bead-based multiplex genotyping assay (TS-MPG) that is a laboratory-developed method for the detection of HPV, in 94 women with atypical squamous cells of undetermined significance (ASC-US) and in cytological samples from 86 women with a negative Pap test. The HPV prevalence with the TS-MPG assay was increased compared to the prevalence with the LA and HC-II assays. The HPV DNA prevalence in women with ASC-US was greater with the TS-MPG assay (46.2%) than with the LA (36.3%) and HC-II (29.7%) assays. The HPV DNA prevalence in the control group was greater with the TS-MPG assay (32.1%) than with the LA assay (10.7%). Two women with ASC-US who were HPV DNA negative by the HC-II and positive by the TS-MPG or/and LA assays had lesions that progressed to low-grade squamous intraepithelial and high-grade squamous intraepithelial lesions. This study shows that the TS-MPG assay exhibited higher analytical sensitivity than the LA and HC-II assays for the detection of HPV DNA, which reduces the potential to incorrectly identify a woman's HPV infection status.

Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin--a case-control study.

BACKGROUND: Non-melanoma skin cancer (NMSC), comprised of basal (BCC) and squamous (SCC) cell carcinomas, is the most common cancer in Caucasians. Ultraviolet radiation (UVR) exposure is the most important environmental risk factor for NMSC. However, the precise relationship between UVR and the risk of NMSC is complex, and the relationship may differ by skin cancer type. METHODS: A case-control study was conducted among Florida residents to investigate measures of patterns (intermittent vs. continuous) and timing (childhood vs. adulthood) of sunlight exposure in BCC and SCC. Participants included 218 BCC and 169 SCC cases recruited from a university dermatology clinic and 316 controls with no history of skin or other cancers. RESULTS: A history of blistering sunburn (a measure of intermittent sunlight exposure) was associated with both BCC (OR = 1.96, 95% CI = 1.27-3.03) and SCC (OR = 2.02, 95% CI = 1.22-3.33). Additionally, having a job in the sun for ≥ 3 months for 10 years or longer (a measure of continuous sunlight exposure) was also associated with both BCC and SCC in our study population. With the exception of younger age at first blistering sunburn, measures of younger age at sunlight exposure tended to be associated with SCC, but not BCC risk. CONCLUSIONS: Results from the current study suggest that sunlight exposure is associated with both BCC and SCC risk regardless of the pattern in which the exposure was received (i.e. intermittent vs. continuous). The data also suggest that sunlight exposure at a younger age may be more important for SCC but not BCC, however additional studies are needed to further characterize sunlight exposure-response relationships in different types of NMSC.

Sunlight exposure and cutaneous human papillomavirus seroreactivity in basal cell and squamous cell carcinomas of the skin.

BACKGROUND: Ultraviolet radiation exposure may interact synergistically with cutaneous human papillomavirus (HPV) infection in the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. METHODS: To investigate differences in the risk of sunlight-associated BCC and SCC by cutaneous genus-specific HPV serostatus, a case-control study was conducted among 204 BCC and 156 SCC cases who were recruited from a university dermatology clinic and 297 controls who had no history of cancer and screened negative for current skin cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between measures of sunlight exposure and BCC/SCC, stratified by genus-specific HPV serostatus, with adjustment for age and sex. RESULTS: Sunburn due to cutaneous sensitivity to sunlight exposure (P = .006) and poor tanning ability (P = .003) were associated with a higher seroprevalence for genus beta HPV types. Poor or no tanning ability was more strongly associated with SCC among individuals who were seropositive for antibodies to cutaneous HPV types in genera alpha (OR, 15.60; 95% CI, 5.40-45.1; P = .01 for interaction) and beta (OR, 6.86; 95% CI, 3.68-12.80; P = .001 for interaction), compared with individuals who were seronegative for these HPV types. CONCLUSIONS: Seropositivity for HPV types in genera alpha or beta increased the risk of SCC associated with poor tanning ability.

Case-control study of cutaneous human papillomaviruses in squamous cell carcinoma of the skin.

BACKGROUND: Cutaneous human papillomavirus (HPV) infection may be a risk factor for squamous cell carcinoma (SCC) of the skin. METHODS: To investigate the association between cutaneous HPV and SCC, a case-control study was conducted, including 173 SCC cases from a university dermatology clinic and 300 controls that screened negative for skin cancer. Serum antibodies against cutaneous HPV types in genera alpha, beta, gamma, mu, and nu were measured. Tumor tissue from 159 SCC cases was tested for the presence of DNA for genus-beta HPV types. Using logistic regression ORs and 95% confidence intervals (CI) were estimated for the associations between SCC and cutaneous HPV infection, adjusting for age and sex. The Bonferroni method was used to account for multiple comparisons. RESULTS: SCC was positively associated with seropositivity to any genus-beta HPV type (OR, 1.93; 95% CI, 1.23-3.02), particularly with types in species-1 (OR, 1.86; 95% CI, 1.22-2.85). Type-specific associations with SCC were observed for HPV 8 (OR, 1.80; 95% CI, 1.14-2.84), 17 (OR, 1.59; 95% CI, 1.02-2.49) and HPV 10 from genus-alpha (OR, 2.24; 95% CI, 1.04-4.85). None of the type-specific associations remained statistically significant after correction for multiple comparisons. When DNA-positive SCC cases were compared with controls, strong serologic associations were observed for HPVs 5 (OR, 3.48; 95% CI, 1.27-9.59), 17 (OR, 3.36; 95% CI, 1.29-8.72), and 24 (OR, 3.79; 95% CI, 1.24-11.5). CONCLUSION: Genus-beta HPV infections were associated with SCC in our study population. IMPACT: Identifying the role of cutaneous HPV infection in SCC may lead to improved characterization of high-risk individuals and the development of novel prevention strategies.

Case-control study of smoking and non-melanoma skin cancer.

OBJECTIVE: To investigate the association between cigarette smoking and basal and squamous cell carcinomas (BCC and SCC) of the skin, a clinic-based case-control study was conducted in Tampa, FL. METHODS: Patients with histologically confirmed BCC/SCC were recruited from a university dermatology clinic (n = 215 BCC, 165 SCC). Controls were comprised of individuals with no history of skin cancer who screened negative for skin cancer upon physical examination at the affiliated cancer screening or primary care clinics (n = 315). Information on smoking and other risk factors was obtained from self-administered questionnaires. RESULTS: After adjustment for age, sex, and other skin cancer-risk factors, ever smoking was not associated with BCC (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 0.83-1.92), but was statistically significantly associated with SCC (OR = 1.97, 95% CI = 1.19-3.26), with significant trends observed for SCC associated with increasing cigarettes per day (p = 0.01) and pack-years smoked (p = 0.01). Among men, smoking ≥20 pack-years was associated with non-significant increased risks of BCC (OR = 1.90, 95% CI = 0.88-4.12) and SCC (OR = 1.97, 95% CI = 0.84-4.66), whereas among women, no association was observed with BCC (OR = 0.98, 95% CI = 0.39-2.46) while a statistically significant three-fold risk was observed with SCC (OR = 3.00, 95% CI = 1.02-8.80). CONCLUSION: Cigarette smoking is more strongly associated with SCC than BCC, particularly among women.

Case-control study of Merkel cell polyomavirus infection and cutaneous squamous cell carcinoma.

BACKGROUND: Merkel cell polyomavirus (MCV) DNA has been reported in 0% to 25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. We conducted the first serologic case-control study of MCV and SCC. METHODS: Patients with histologically confirmed cutaneous SCC (n = 173) were recruited from a university dermatology clinic. Controls were individuals who screened negative for and had no history of skin or other cancers (n = 300). Levels of antibodies against capsid antigens for MCV and another polyomavirus, JC virus (JCV), were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases and tested for MCV DNA by multiplexed PCR. Associations between MCV seroreactivity and SCC were estimated by ORs and 95% CIs calculated using logistic regression with adjustment for age and sex. RESULTS: MCV DNA was detected in SCC tumor tissues from 55 (38%) of 145 cases. A statistically significant association was observed between MCV seropositivity and MCV DNA-positive SCC (OR = 2.49, 95% CI = 1.03-6.04), with an almost four-fold association observed when comparing those with MCV antibodies in the fourth versus first quartiles (OR = 3.93, 95% CI = 1.43-10.76, P(trend) = 0.01). No significant associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR = 1.38, 95% CI = 0.76-2.48) or between JCV seropositivity and MCV DNA-positive or DNA-negative SCC. CONCLUSION: Past exposure to MCV may be a risk factor for SCC. IMPACT: Understanding the role of viral infections in the development of nonmelanoma skin cancer could lead to novel prevention strategies.