Search

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.

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.

SUMMARY 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.

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

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.

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. What's new? Although some of the highest known incidence rates ofcutaneous melanoma are found in Queensland, Australia, few studies have examined incidence specifically among 15- to 24-year-olds in the state. This evaluation shows that the incidence of invasive melanoma is relatively high for the 15- to 24-year-old age group. However, incidence rates were found to have declined generally among Queensland's adolescents and young adults since the mid- to late 1990s. The decline may be a reflection of successful primary prevention efforts in young people in recent decades.

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.

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.

Genus-β human papillomavirus (HPV) DNA has been detected in basal cell carcinoma (BCC) tumors, but most epidemiologic studies have not observed associations between genus-β 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, β, 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 β-HPV DNA in their tumors were more likely to be β-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 β-HPV seropositivity and β-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 β HPV types may have a role in BCC. Additional studies of BCC that assess HPV types in multiple genera are needed.

Background: Factors that favour a small proportion of HPV16 infections to progress to cancer are still poorly understood, but several studies have implicated a role of HPV16 genetic variation. Methods: To evaluate the association between HPV16 genetic variants and cervical cancer risk, we designed a multicentre case–control study based on HPV16-positive cervical samples (1121 cervical cancer cases and 400 controls) from the International Agency for Research on Cancer biobank. By sequencing the E6 gene, HPV16 isolates were classified into variant lineages and the European (EUR)-lineage isolates were subclassified by the common polymorphism T350G. Results: Incidence of variant lineages differed between cases and controls in Europe/Central Asia (P=0.006, driven by an underrepresentation of African lineages in cases), and South/Central America (P=0.056, driven by an overrepresentation of Asian American/North American lineages in cases). EUR-350G isolates were significantly underrepresented in cervical cancer in East Asia (odds ratio (OR)=0.02 vs EUR-350T; 95% confidence interval (CI)=0.00–0.37) and Europe/Central Asia (OR=0.42; 95% CI=0.27–0.64), whereas the opposite was true in South/Central America (OR=4.69; 95% CI=2.07–10.66). Conclusion: We observed that the distribution of HPV16 variants worldwide, and their relative risks for cervical cancer appear to be population-dependent.

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. Cancer Epidemiol Biomarkers Prev; 21(8); 1303–13. ©2012 AACR.

Background. Little is known about the risk factors for cutaneous human papillomavirus (HPV) infection. Methods. To investigate factors associated with cutaneous HPV seropositivity, we conducted a cross-sectional study of 411 patients undergoing routine skin cancer screening examinations. Serum antibodies were measured and evaluated for 36 cutaneous HPV types in the genera alpha, beta, gamma, mu, and nu. Associations of demographic and lifestyle factors with cutaneous HPV seropositivity were estimated using odds ratios and 95% confidence intervals calculated using logistic regression. Results. The seroprevalence of ≥1 cutaneous HPV type was 96% and 90% for men and women, respectively. Seroprevalence was highest for HPV types 4 (46%), 1 (37%), and 8 (31%) in men and for types 4 (47%), 63 (34%), and 1 (33%) in women. Independent associations of demographic and skin cancer risk factors with genus-specific HPV seropositivity differed by sex. For example, white skin, inability to tan, and lifetime residency in Florida were factors associated with genus-specific HPV seropositivity in men. Heavy smoking, sunscreen use, and green eye color were associated with genus-specific HPV seropositivity in women. Conclusions. Seroreactivity to cutaneous HPV types was highly prevalent in our study population. Different risk factors were independently associated with genus-specific cutaneous HPV seropositivity in men and women.

Cutaneous human papillomavirus (HPV) may be associated with the development of nonmelanoma skin cancer (NMSC), as suggested by reports of HPV DNA in NMSC tumors. HPV has also been investigated as an NMSC risk factor in epidemiologic studies, although findings vary across studies that used different biomarkers of HPV infection in normal tissues. To identify appropriate biomarkers for use in future epidemiologic studies, we conducted a sampling validation study. NMSC tumor tissue was obtained from 20 patients with pathology-confirmed basal or squamous cell carcinoma of the skin, in addition to several normal tissues, including eyebrow hairs, normal skin swabs obtained using multiple techniques, normal skin punch and shave biopsies, and serum for antibody measurement. Presence of cutaneous HPV DNA in tissues was measured with multiplex PCR using HPV type-specific primers and array primer extension (APEX) for HPV typing. Antibody detection was based on glutathione-Stransferase capture ELISA in combination with fluorescent bead technology. Using HPV DNA in tumor tissues as a gold standard, sensitivity and specificity were calculated for each measure of HPV infection in normal tissues. b-Papillomavirus DNA was observed in tumor tissues in 60% of patients. The normal skin punch biopsy demonstrated optimal sensitivity (75%) and specificity (75%). Biomarkers obtained using less-invasive techniques demonstrated poor specificity when considered individually, although specificity improved when biomarkers were combined. Based on the current case series, the combinations of antibodies1eyebrow hairs or antibodies1eyebrow hairs1Dacron swabs are the optimal, minimally invasive markers of cutaneous HPV infection for use in epidemiologic studies. ' 2008 Wiley-Liss, Inc.

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. 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. 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. 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.

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 children10 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.

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.

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.

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.

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 genusspecific 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.

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.

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, Ptrend = 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. Cancer Epidemiol Biomarkers Prev; 21(1); 74–81. ©2011 AACR.

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.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.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).Cigarette smoking is more strongly associated with SCC than BCC, particularly among women.

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 β and γ, respectively. Any β 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 β 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 β 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) β HPV infection in SS. Cutaneous HPV is highly prevalent in men, with age and blistering sunburn being significant risk factors for cutaneous β HPV infection.

Objective: Cutaneous human papillomavirus (HPV) antibodies and/or DNA in eyebrow hairs have been associated with cutaneous squamous cell carcinoma (SCC) in several case-control studies, including one from New Hampshire and ours from Florida. In the New Hampshire study, a single nucleotide polyomorphism (SNP) in the EVER2 gene (rs72080422) was associated with both SCC and cutaneous HPV seropositivity among controls (Patel et al Int J Cancer, 2008). Additional genetic variants in the EVER1/2 region of chromosome 17q25 have since been identified and shown to be associated with cervical cancer susceptibility (Castro et al Int J Cancer, 2011). We investigated the identical EVER1/2 variants in association with multiple markers of cutaneous HPV infection, including HPV seropositivity, and HPV DNA in eyebrow hairs and SCC tumor tissues. Methods: Patients with histologically-confirmed cutaneous SCC (n=142) were recruited from a university dermatology clinic in Tampa, FL. Controls were patients undergoing skin cancer screening exams who screened negative for skin cancer and reported no history of any type of cancer (n=265). Levels of antibodies against capsid antigens for 15 cutaneous HPV types in genus beta were determined by fluorescent bead-based multiplex serology. DNA for 25 beta-HPV types was measured in eyebrow hairs from cases and controls, and in fresh-frozen tumor tissues from 119 SCC cases using multiplex PCR. Twenty-one SNPs in in the EVER1/2 region of chromosome 17q25 were measured from eyebrow hair DNA, including rs7208422. Associations between EVER1/2 SNPs and SCC, and between EVER1/2 SNPs and HPV serostatus or DNA status, were estimated by odds ratios (OR) and 95% confidence intervals (CI) calculated using logistic regression with adjustment for age and sex. Results: None of the 21 SNPs in the EVER1/2 region were associated with SCC, including rs7208422 in EVER2, for which the TT genotype was observed in 23% of cases and 22% of controls (vs. AA: OR=0.99, 95% CI=0.52-1.90). Seropositivity for any beta-HPV type was not associated with any of the EVER1/2 SNPs among the cases or the controls, nor with seropositivity for HPV types 5 and/or 8 specifically. Beta-HPV DNA in eyebrow hairs was associated with two SNPs among the controls only (rs2290907, AG vs. AA: OR= 2.96, 95% CI=1.37-6.40; rs16970829, AG vs. AA: OR=12.8, 95% CI=1.71-95.90). Among the cases, beta-HPV DNA in tumor tissue was associated with rs7217374 (AG vs AG: OR=3.65, 95% CI=1.42-9.36; AA vs GG: OR=2.02, 95% CI=0.71-5.79), but not with any of the other 20 SNPs. Conclusion: In this small case-control study, genetic variation in the EVER1/2 region was not associated with SCC, and none of the 21 SNPs measured were consistently associated with different biomarkers of beta-HPV infection among cases or controls. Citation Format: Dana E. Rollison, Michelle R. Iannacone, Jane L. Messina, Neil A. Fenske, Basil S. Cherpelis, Vernon K. Sondak, Richard G. Roetzheim, Tarik Gheit, Massimo Tommasino, Markus Schmitt, Michael Pawlita. Genetic variation in EVER1/EVER2 and beta human papillomavirus infection in cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4835. doi:10.1158/1538-7445.AM2013-4835

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.

Background: Ultraviolet radiation (UVR) exposure is the most important environmental risk factor for non-melanoma skin cancer (NMSC), comprised of basal (BCC) and squamous (SCC) cell carcinomas. However, the precise relationship between UVR exposure and skin cancer may differ by NMSC type. A case-control study was conducted to evaluate the relationship between patterns and timing of sun exposure and BCC/SCC. Methods: Study participants included histologically confirmed BCC (n=218) and SCC (n=169) cases recruited from a university dermatology clinic and control subjects who underwent a skin cancer screening exam and screened negative for and had no history of cancer (n=316). Information on patterns (intermittent vs. continuous) and timing (childhood vs. adulthood) of sun exposure was obtained from self-administered questionnaires. Associations with BCC/SCC were estimated by odds ratios (OR) and 95% confidence intervals (CI) calculated using logistic regression. Backward stepwise elimination was used to obtain the most parsimonious models that best fit the data. Final main effect models were adjusted for the following factors: age, sex, ethnicity, education, eye and hair color, smoking status, skin sensitivity to sun exposure, sun exposure protection behaviors, and history of dysplastic nevi and actinic keratosis. Results: History of blistering sunburn, a marker of intermittent sun exposure, was significantly positively associated with BCC (OR=2.08, 95% CI=1.19-3.64), but no association was observed with SCC (OR-1.37, 95% CI=0.69-2.69). Compared to reporting no moles on one's forearm, reporting ≥ 10 moles, a marker of increased childhood sun exposure, was positively associated with SCC (OR=5.37, 95% CI=1.11-26.0) but not BCC (OR=0.43, 95% CI=0.07-2.59). High levels of continuous sun exposure (5-6 hours versus Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1881. doi:10.1158/1538-7445.AM2011-1881

Objective: Merkel cell polyomavirus (MCV) DNA has been reported previously in 0-25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. No studies have investigated MCV seroreactivity in individuals with SCC. We conducted a clinic-based case-control study to investigate the association between MCV seroreactivity and SCC, overall and stratified by MCV DNA status of the SCC tumor tissue. Methods: Patients with histologically-confirmed cutaneous SCC (n=173) were recruited from a university dermatology clinic. Controls were patients undergoing skin cancer screening exams who screened negative for and had no history of skin or other cancers (n=300). Levels of antibodies against capsid antigens for MCV and other polyomavirus controls (JC virus (JCV) and KI virus (KIV)) were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases, and DNA from six polyomaviruses (MCV, JCV, KIV, WU virus (WUV), BK virus (BKV) and simian virus 40 (SV40)) was measured using multiplexed PCR. Polyomavirus seropositivity, based on binary cutpoints, and quartiles of seroreactivity, based on the control distribution, were compared between SCC cases and controls, overall and stratified by the presence or absence of MCV DNA in SCC tumor tissues. Associations were estimated by calculating odds ratios (OR) and 95% confidence intervals (CI) using logistic regression to adjust for age, sex, and skin reaction to the sun. Results: MCV seropositivity was associated with a statistically significant increased risk of SCC (OR=1.80, 95% CI=1.03-3.12), whereas no association was observed for JCV (OR=1.17, 95% CI=0.72-1.92) or KIV (OR=0.88, 95% CI=0.37-2.09) seropositivity. MCV DNA was detected in 55 (38%) of SCC tumor tissues, whereas all tissues were negative for DNA from the other five polyomaviruses. Using controls as the reference group, MCV DNA-positive SCC cases were three times as likely to be MCV seropositive (OR=3.15, 95% CI=1.11-8.92) and almost six times as likely to have MCV antibody levels in the fourth versus first quartile (OR=5.94, 95% CI=1.79-19.74, ptrend=0.001). No associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR=1.40, 95% CI=0.78-2.77) or between JCV or KIV seropositivity and MCV DNA-negative or DNA-positive SCC. Conclusion: SCC patients were significantly more likely than controls to exhibit MCV seroreactivity, particularly if they had MCV DNA in their SCC tumor tissue. This association was specific to MCV, with no associations observed for the other polyomaviruses studied. These results suggest that past exposure to MCV may be a risk factor for SCC in immunocompetent individuals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 950. doi:10.1158/1538-7445.AM2011-950

Abstract 1890 The myelodysplastic syndromes (MDS) became reportable malignancies to U.S. population-based cancer registries including the Surveillance, Epidemiology and End Results (SEER) Program in 2001. Registries capture information on MDS cases through reports sent by hospitals and physicians’ offices. Electronic pathology (E-path) reports generated by private pathology laboratories are another potential source for finding cases; however, the sheer volume of E-path reports generated and the limited resources of cancer registries preclude the review of all E-path reports. Therefore, some registries rely on probability scoring based on keyword hits to identify reports most likely consistent with a diagnosis of cancer. Given the diverse morphologic features of MDS pathology and our earlier observation that MDS is often diagnosed and managed in the outpatient setting (Rollison, et al. Blood 2008), we hypothesized that MDS is often not captured by state cancer registries. To estimate the proportion of uncaptured MDS cases in Florida, all E-Path reports sent to Florida Cancer Data System (FCDS), the state cancer registry, in 2006 were queried using a unique keyword search strategy based on an algorithm of identifying bone marrow biopsy reports that met the inclusion and exclusion diagnostic terminology for MDS. Of 7,111 E-path reports identified, only 18% corresponded to individuals registered in FCDS as having been diagnosed with MDS. To estimate the percentage of uncaptured MDS cases in the remaining 82% of E-Path reports, a stratified random sample of E-path reports were reviewed by a single hematologist/oncologist to determine whether the E-path reports were consistent with MDS and to assign an MDS subtype. The strata for random sampling included: 1) reports that linked individuals registered as having been diagnosed with cancers other than MDS in FCDS (48%) versus those that did not link to FCDS (34%) and 2) four categories based on number of keyword hits. Overall, E-path reports corresponding to 285 individuals were reviewed, of which 71 were determined to have MDS. The percentage of uncaptured cases seemed to be lower for those individuals that were registered in FCDS as having a previous cancer (17%) than that for those who did not link to FCDS (28%) and increased with number of keyword hits. Based on the percentages of uncaptured cases estimated within each of the eight strata, and the distribution of those stratified factors in the total sampling frame, we estimated that 641 MDS cases were likely uncaptured, representing approximately 45% of the captured and uncaptured cases combined. Thus, current case finding mechanisms by population-based cancer registries capture approximately half of the true MDS cases. Compared to MDS cases captured by FCDS, uncaptured MDS cases were younger (< 65) (p=0.01), less likely to have Refractory Anemia (RA) and more likely to have Refractory Cytopenia with Multilineage Dysplasia (RCMD) (p=0.002). Gender and race seemed to be similar between the groups. Together, these data indicate that current population-based case finding methods are not capturing a large percentage of MDS cases. Application of a keyword search strategy to identify cases among E-Path reports is a feasible technique to improve MDS case ascertainment in population-based cancer registries until greater resources are committed. Disclosures: No relevant conflicts of interest to declare.