William J. Fulp

Age-Specific Seroprevalence of Merkel Cell Polyomavirus, BK Virus, and JC Virus

ABSTRACT We produced capsids of Merkel cell polyomavirus (MCPyV) in a baculovirus expression system and developed a virus-like particle (VLP) enzyme-linked immunosorbent assay (ELISA). To determine age-specific seroprevalence, serum samples were collected from 947 individuals attending hospital outpatient clinics and ranging in age from 1 to 93 years. To evaluate the association between exposure to MCPyV and Merkel cell cancer (MCC), plasma samples were obtained from 33 MCC patients and 37 controls. MCPyV seroprevalence was 45% in children under 10 years of age, increased to 60% in the next decade of life, and peaked at 81% among those 60 to 69 years of age. Levels of MCPyV capsid antibodies were positively correlated with age (P = 0.007). Virus specificity of MCPyV seroreactivity was supported by competitive inhibition of reactivity by MCPyV VLPs and not by BK polyomavirus (BKPyV) VLPs. MCPyV seroprevalence was greater among MCC patients (91%) than controls (68%; age-adjusted P value, 0.32); the mean level of MCPyV antibodies was also greater (P = 0.04). The age-specific seroprevalence of MCPyV shares with previously known polyomaviruses, BKPyV and JC polyomavirus (JCPyV), evidence of widespread exposure in human populations beginning early in life. MCPyV age-specific seroprevalence also has unique features. Seroprevalence among children is higher than that of JCPyV but lower than that of BKPyV. Among older adults, MCPyV seroprevalence remains high, while that of BKPyV declines and that of JCPyV continues to rise. In agreement with results from other studies, we found an association between MCPyV seropositivity and MCC, and higher levels of serum MCPyV capsid antibodies in MCC patients than in controls.

Lung tumor NF-κB signaling promotes T cell–mediated immune surveillance

NF-κB is constitutively activated in many cancer types and is a potential key mediator of tumor-associated inflammation, tumor growth, and metastasis. We investigated the role of cancer cell NF-κB activity in T cell-mediated antitumor responses. In tumors rendered immunogenic by model antigen expression or following administration of antitumor vaccines, we found that high NF-κB activity leads to tumor rejection and/or growth suppression in mice. Using a global RNA expression microarray, we demonstrated that NF-κB enhanced expression of several T cell chemokines, including Ccl2, and decreased CCL2 expression was associated with enhanced tumor growth in a mouse lung cancer model. To investigate NF-κB function in human lung tumors, we identified a gene expression signature in human lung adenocarcinoma cell lines that was associated with NF-κB activity level. In patient tumor samples, overall lung tumor NF-κB activity was strongly associated with T cell infiltration but not with cancer cell proliferation. These results therefore indicate that NF-κB activity mediates immune surveillance and promotes antitumor T cell responses in both murine and human lung cancer.

If You Did Not Document It, It Did Not Happen: Rates of Documentation of Discussion of Infertility Risk in Adolescent and Young Adult Oncology Patients' Medical Records

PURPOSEnThe adolescent and young adult (AYA) population is underserved because of unique late-effect issues, particularly future fertility. This study sought to establish rates of documentation of discussion of risk of infertility, fertility preservation (FP) options, and referrals to fertility specialists in AYA patients medical records at four cancer centers.nnnMETHODSnAll centers reviewed randomized records within the top four AYA disease sites (breast, leukemia/lymphoma, sarcoma, and testicular). Eligible records included those of patients: diagnosed in 2011, with no prior receipt of gonadotoxic therapy; age 18 to 45 years; with no multiple primary cancers; and for whom record was not second opinion. Quality Oncology Practice Initiative methods were used to evaluate documentation of discussion of risk of infertility, discussion of FP options, and referral to a fertility specialist.nnnRESULTSnOf 231 records, 26% documented infertility risk discussion, 24% documented FP option discussion, and 13% documented referral to a fertility specialist. Records were less likely to contain evidence of infertility risk and FP option discussions for female patients (P = .030 and .004, respectively) and those with breast cancer (P = .021 and < .001, respectively). Records for Hispanic/Latino patients were less likely to contain evidence of infertility risk discussion (P = .037). Records were less likely to document infertility risk discussion, FP option discussion, and fertility specialist referral for patients age ≥ 40 years (P < .001, < .001, and .002, respectively) and those who already had children (all P < .001).nnnCONCLUSIONnThe overall rate of documentation of discussion of FP is low, and results show disparities among specific groups. Although greater numbers of discussions may be occurring, there is a need to create interventions to improve documentation.

Cutaneous Angiosarcoma: A Single-Institution Experience

BackgroundCutaneous angiosarcoma (CAS) is a rare, aggressive vascular sarcoma with a poor prognosis, historically associated with 5-year overall survival (OS) rates between 10 and 30xa0%.MethodsThis is a single-institution retrospective review of patients treated for CAS from 1999–2011. Demographics, primary tumor characteristics, treatment, and outcomes were analyzed.ResultsA total of 88 patients were identified (median age 70xa0years and 57xa0% female). Median tumor size was 3xa0cm. Median follow-up was 22xa0months. The 5-year OS and recurrence-free survival (RFS) were 35.2 and 32.3xa0%, respectively; median was 22.1xa0months. Also, 36 patients (41xa0%) received surgery alone, 7 (8xa0%) received XRT alone, and 41 (47xa0%) received surgery and XRT. Of the 67 of 88 patients who were disease-free after treatment, 33 (50xa0%) recurred (median of 12.3xa0months). Surgery alone had the highest 5-year OS (46.9xa0%) and RFS (39.9xa0%) (pxa0=xa0ns). Four presentation groups were identified: (1) XRT-induced, nxa0=xa030 (34xa0%), 26 of 30 occurred in females with a prior breast cancer, (2) sporadic CAS on head and neck (H/N), nxa0=xa038, (3) sporadic CAS on trunk/extremities, nxa0=xa013, and (4) Stewart–Treves nxa0=xa07. Those with trunk/extremity CAS had the highest 5-year OS (64.8xa0%), with H/N CAS having the worst 5-year OS (21.5xa0%). On MV analysis, only tumor size <5xa0cm correlated with improved OS (pxa0=xa00.014).DiscussionIn this large series, there appears to be a better overall prognosis than historically reported, especially in Stewart–Treves and CAS on trunk or extremities. While surgery alone was associated with better OS and RFS compared with other treatment modalities, this was not statistically significant. Tumor size was a significant prognostic factor for OS.

Analysis of overdispersed count data: application to the Human Papillomavirus Infection in Men (HIM) Study

The Poisson model can be applied to the count of events occurring within a specific time period. The main feature of the Poisson model is the assumption that the mean and variance of the count data are equal. However, this equal mean-variance relationship rarely occurs in observational data. In most cases, the observed variance is larger than the assumed variance, which is called overdispersion. Further, when the observed data involve excessive zero counts, the problem of overdispersion results in underestimating the variance of the estimated parameter, and thus produces a misleading conclusion. We illustrated the use of four models for overdispersed count data that may be attributed to excessive zeros. These are Poisson, negative binomial, zero-inflated Poisson and zero-inflated negative binomial models. The example data in this article deal with the number of incidents involving human papillomavirus infection. The four models resulted in differing statistical inferences. The Poisson model, which is widely used in epidemiology research, underestimated the standard errors and overstated the significance of some covariates.

Prospective study of JC virus seroreactivity and the development of colorectal cancers and adenomas

Background: Infection with JC virus has been proposed as a risk factor for colorectal cancer. A nested case-control study was conducted to evaluate the association between prediagnostic JC virus antibodies and the risk of incident colorectal cancer and adenomas. Methods: Two research serum banks were established in Washington County, MD in 1974 and 1989, with the collection of blood samples from >45,000 volunteers. Incident colorectal cancer cases diagnosed through 2006 (n = 611) were identified among participants by linkage to population-based cancer registries, contributing 729 pairs of observations. Cases of adenomatous polyps (n = 123) were identified from participants of the 1989 cohort who reported having a colonoscopy-detected adenoma at follow-up through 2000 with histology confirmed through medical record review. One control was matched to each case on age, sex, race, and date of blood draw, and, for adenoma controls, date of endoscopy. IgG antibodies to JC virus were measured using virus-like particle ELISA. Associations between JC virus seropositivity and colorectal cancer and adenomas were estimated using conditional logistic regression. Results: Overall, there was no association between antibodies to JC virus and colorectal cancer [odds ratio (OR), 0.91; 95% confidence interval (95% CI), 0.71-1.17]. However, a statistically significant positive association between JC virus seropositivity and subsequent adenoma diagnosis was observed among males (OR, 2.31; 95% CI, 1.20-4.46), whereas a statistically significant inverse association was observed among females (OR, 0.31; 95% CI, 0.14-0.67; P for interaction = 0.01), after adjustment for baseline smoking and body mass index. Conclusions: Overall, JC virus seropositivity was not associated with colorectal cancer development up to 31 years later. Future studies are needed to confirm the adenoma findings. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1515–23)

Carboplatin and paclitaxel treatment is effective in advanced anal cancer.

Background: The development of distant metastases of squamous cell carcinoma of the anal canal (SCCA) is rare but has a poor prognosis. A combination of carboplatin and paclitaxel is commonly used for treating squamous cell cancer in different organs, but its efficacy in advanced SCCA is unclear. The objective of this study is to determine the tolerability and outcome of patients with advanced SCCA on carboplatin plus paclitaxel treatment at the Moffitt Cancer Center. Methods: Retrospective analysis was conducted by looking at records from the Moffitt Cancer Center Tumor Registry from January 2007 to January 2012. Eligible patients had to have a diagnosis of SCCA and have received carboplatin plus paclitaxel every 3 weeks as part of the treatment plan. Results: Eighteen patients fulfilled the criteria; 14 were initially diagnosed with early-stage disease and received concurrent chemoradiation, but then relapsed. Median age was 56 years. Upon diagnosis of metastatic disease, 12 patients received carboplatin plus paclitaxel as a first-line treatment. Five patients had received prior systemic chemotherapy regimens and 1 had received prior local regional therapy. The response rate was high at 53% including 3 patients who achieved a complete response. Median overall survival was 12.19 months. Conclusions: Carboplatin and paclitaxel treatment shows encouraging activity in advanced SCCA.

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.

A Predictive Risk Probability Approach for Microarray Data with Survival as an Endpoint

Gene expression profiling has played an important role in cancer risk classification and has shown promising results. Since gene expression profiling often involves determination of a set of top rank genes for analysis, it is important to evaluate how modeling performance varies with the number of selected top ranked genes incorporated in the model. We used a colon data set collected at Moffitt Cancer Center as an example of the study, and ranked genes based on the univariate Cox proportional hazards model. A set of top ranked genes was selected for evaluation. The selection was done by choosing the top k ranked genes for k = 1 to 12,500. An analysis indicated a considerable variation of classification outcomes when the number of top ranked genes was changed. We developed a predictive risk probability approach to accommodate this variation by identifying a range number of top ranked genes. For each number of top ranked genes, the procedure classifies each patient as having high risk (score = 1) or low risk (score = 0). The categorizations are then averaged, giving a risk score between 0 and 1, thus providing a ranking for the patients need for further treatment. This approach was applied to the colon data set and demonstrated the strength of this approach by three criteria: First, a univariate Cox proportional hazards model showed a highly statistically significant level (log-rank χ 2 statistics = 110 with p -value <10 −16) for the predictive risk probability classification. Second, the survival tree model used the risk probability to partition patients into five risk groups showing a good separation of survival curves (log-rank χ 2 statistics = 215). In addition, utilization of the risk group status identified a small set of risk genes that may be practical for biological validation. Third, analysis of resampling the risk probability suggested the variation pattern of the log-rank χ 2 in the colon cancer data set was unlikely caused by chance.