Spatially-explicit survival modeling with discrete grouping of cancer predictors.

In this paper, the spatially explicit survival model is extended by allowing the relation with the explanatory covariates to be spatially adaptive using a threshold conditional autoregressive (CAR) model, further extended to allow the inclusion of multiple threshold levels. The model is applied to prostate cancer survival based on Louisiana SEER registry, which holds individual records linked to vital outcomes and is geocoded at the parish level.

Prosocial Emotion, Adolescence, and Warfare : DNA Methylation Associates with Culturally Salient Combat Variables.

Examining the costs and motivations of warfare is key to conundrums concerning the relevance of this troubling phenomenon to the evolution of social attachment and cooperation, particularly during adolescence and young adulthood-the developmental time period during which many participants are first recruited for warfare. The study focuses on Samburu, a pastoralist society of approximately 200,000 people occupying northern Kenya's semi-arid and arid lands, asking what role the emotionally sensitized, peer-driven adolescent life stage may have played in the cultural and genetic coevolution of coalitional lethal aggression. Research in small-scale societies provides unparalleled opportunities for sharply defined variables, particularly in age generation societies in which all young men are initiated into "warriorhood." Proposing an epigenetic and component behavior approach, we examine whether raiding activities such as number of raids, killing, and sparing enemy lives associate with DNA methylation in two candidate genes: MAOA, linked to mood and arousal, and NR3C1, linked to stress and immune response. We report statistically significant associations between the epigenetic variables and the combat (exposure) variables of overall raiding activity and reportedly showing mercy to enemies. In contrast, epigenetic variables did not associate with post-traumatic stress disorder (PTSD) symptom scores (a potential outcome measure), and the only combat variable associated with PTSD (but not DNA methylation) was losing one's own livestock in a raid. These findings raise important questions concerning the mechanisms driving warfare's paradoxical mix of violent and altruistic behaviors.

Bayesian cure-rate survival model with spatially structured censoring.

We propose a Bayesian spatial model for time-to-event data in which we allow the censoring mechanism to depend on covariates and have a spatial structure. The survival model incorporates a cure rate fraction and assumes that the time-to-event follows a Weibull distribution, with covariates such as race, stage, grade, marital status and age at diagnosis being linked to its scale parameter. With right censoring being a primary concern, we consider a joint logistic regression model for the death versus censoring indicator, allowing dependence on covariates and including a spatial structure via the use of random effects. We apply the models to examine prostate cancer data from the Surveillance, Epidemiology, and End Results (SEER) registry, which displays marked spatial variation.

Bayesian accelerated failure time model for space-time dependency in a geographically augmented survival model.

In this paper, we extend the spatially explicit survival model for small area cancer data by allowing dependency between space and time and using accelerated failure time models. Spatial dependency is modeled directly in the definition of the survival, density, and hazard functions. The models are developed in the context of county level aggregated data. Two cases are considered: the first assumes that the spatial and temporal distributions are independent; the second allows for dependency between the spatial and temporal components. We apply the models to prostate cancer data from the Louisiana SEER cancer registry.

Bayesian importance parameter modeling of misaligned predictors: soil metal measures related to residential history and intellectual disability in children.

In this paper, we propose a novel spatial importance parameter hierarchical logistic regression modeling approach that includes measurement error from misalignment. We apply this model to study the relationship between the estimated concentration of soil metals at the residence of mothers and the development of intellectual disability (ID) in their children. The data consist of monthly computerized claims data about the prenatal experience of pregnant women living in nine areas within South Carolina and insured by Medicaid during January 1, 1996 and December 31, 2001 and the outcome of ID in their children during early childhood. We excluded mother-child pairs if the mother moved to an unknown location during pregnancy. We identified an association of the ID outcome with arsenic (As) and mercury (Hg) concentration in soil during pregnancy, controlling for infant sex, maternal race, mother's age, and gestational weeks at delivery. There is some indication that Hg has a slightly higher importance in the third and fourth months of pregnancy, while As has a more uniform effect over all the months with a suggestion of a slight increase in risk in later months.

A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice.

Recent advancements in T cell immunotherapy suggest that T cells engineered with high-affinity TCR can offer better tumor regression. However, whether a high-affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope-reactive, CD8-independent, high-affinity TCR isolated from MHC class I-restricted CD4(+) T cells obtained from tumor-infiltrating lymphocytes (TIL) of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2-restricted TCR was positively selected on both CD4(+) and CD8(+) single-positive cells. However, when the TCR transgenic mouse was developed with a HLA-A2 background, the transgenic TCR was primarily expressed by CD3(+)CD4(-)CD8(-) double-negative T cells. TIL 1383I TCR transgenic CD4(+), CD8(+), and CD4(-)CD8(-) T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2(+)/human tyrosinase TCR double-transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high-affinity TIL 1383I TCR alone in CD3(+) T cells is sufficient to control the growth of murine and human melanoma, and the presence or absence of CD4 and CD8 coreceptors had little effect on its functional capacity.

Histone deacetylase inhibitors restore cell surface expression of the coxsackie adenovirus receptor and enhance CMV promoter activity in castration-resistant prostate cancer cells.

Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.

The comparative effectiveness of a team-based versus group-based physical activity intervention for cancer survivors.

PURPOSE: Physical activity benefits cancer survivors, but the comparative effectiveness of a team-based delivery approach remains unexplored. The hypothesis tested was that a team-based physical activity intervention delivery approach has added physical and psychological benefits compared to a group-based approach. A team-based sport accessible to survivors is dragon boating, which requires no previous experience and allows for diverse skill levels. METHODS: In a non-randomized trial, cancer survivors chose between two similarly structured 8-week programs, a dragon boat paddling team (n = 68) or group-based walking program (n = 52). Three separate intervention rounds were carried out in 2007-2008. Pre-post testing measured physical and psychosocial outcomes. RESULTS: Compared to walkers, paddlers had significantly greater (all p < 0.01) team cohesion, program adherence/attendance, and increased upper-body strength. For quality-of-life outcomes, both interventions were associated with pre-post improvements, but with no clear-cut pattern of between-intervention differences. CONCLUSIONS: These hypothesis-generating findings suggest that a short-term, team-based physical activity program (dragon boat paddling) was associated with increased cohesion and adherence/attendance. Improvements in physical fitness and psychosocial benefits were comparable to a traditional, group-based walking program. Compared to a group-based intervention delivery format, the team-based intervention delivery format holds promise for promoting physical activity program adherence/attendance in cancer survivors.

Secondhand smoke exposure in young people and parental rules against smoking at home and in the car.

OBJECTIVES: Secondhand smoke (SHS) exposure is an important cause of morbidity in children. We assessed the impact of family rules about smoking in the home and car on SHS exposure prevalence in students in grades six to 12. METHODS: We studied never-smoking young people (n = 1,698) in the random sample cross-sectional South Carolina Youth Tobacco Survey, a 2006 survey of middle and high school students in South Carolina. RESULTS: Overall, 40% of the students reported SHS exposure in either the home or car in the past week; among these, 85% reported exposure in cars. Subsequent analyses focused on students who lived with a smoker (n = 602). Compared with those whose families prohibited smoking in the home or car, SHS exposure prevalence was 30% (p < 0.0001) higher for households with smoke-free rules for only one place (home or car) and 36% (p < 0.0001) higher for households with no rules. Compared with students from households with strict rules, SHS exposure prevalence was 48% greater (p < 0.0001) among those with only partial rules against smoking in the home or car, and 55% (p < 0.0001) greater among those from households with no rules. Similarly, compared with students with strict family rules for home and car that were adhered to, SHS exposure prevalence was significantly higher (p < 0.0001) among students when only one or no rules were followed. CONCLUSIONS: Young people from families that made and enforced strong rules against smoking in homes and cars were much less likely to report SHS exposure. Parents would be wise to endorse and enforce strong smoke-free policies for both homes and cars.

A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells.

We recently demonstrated that human BM cells can be treated in vitro with defined growth factors to induce the rapid generation of myeloid-derived suppressor cells (MDSCs), hereafter defined as BM-MDSCs. Indeed, combination of G-CSF + GM-CSF led to the development of a heterogeneous mixture of immature myeloid cells ranging from myeloblasts to band cells that were able to suppress alloantigen- and mitogen-stimulated T lymphocytes. Here, we further investigate the mechanism of suppression and define the cell subset that is fully responsible for BM-MDSC-mediated immune suppression. This population, which displays the structure and markers of promyelocytes, is however distinct from physiologic promyelocytes that, instead, are devoid of immuosuppressive function. In addition, we demonstrate that promyelocyte-like cells proliferate in the presence of activated lymphocytes and that, when these cells exert suppressive activity, they do not differentiate but rather maintain their immature phenotype. Finally, we show that promyelocyte-like BM-MDSCs are equivalent to MDSCs present in the blood of patients with breast cancer and patients with colorectal cancer and that increased circulating levels of these immunosuppressive myeloid cells correlate with worse prognosis and radiographic progression.

Using endobronchial ultrasound features to predict lymph node metastasis in patients with lung cancer.

PURPOSES: Reliable staging of the mediastinum determines TNM classification and directs therapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate predictors of mediastinal lymph node metastasis in patients undergoing endobronchial ultrasound (EBUS). METHODS: Patients with known or suspected lung cancer undergoing EBUS for staging were included. Lymph node radiographic characteristics on chest CT/PET scan and ultrasound characteristics of size, shape, border, echogenicity, and number were correlated with rapid on-site evaluation (ROSE) and final pathology. Logistic regression (estimated with generalized estimating equations to account for correlation across nodes within patients) was used with cancer (vs normal pathology) as the outcome. ORs compare risks across groups, and testing was performed with two-sided α of 0.05. RESULTS: Two hundred twenty-seven distinct lymph nodes (22.5% positive for malignancy) were evaluated in 100 patients. Lymph node size, by CT scan and EBUS measurements, and round and oval shape were predictive of mediastinal metastasis. Increasing size of lymph nodes on EBUS was associated with increasing malignancy risk (P = .0002). When adjusted for CT scan size, hypermetabolic lymph nodes on PET scan did not predict malignancy. Echogenicity and border contour on EBUS and site of biopsy were not significantly associated with cancer. In 94.8% of lymph nodes with a clear diagnosis, the ROSE of the first pass correlated with subsequent passes. CONCLUSIONS: Lymph node size on CT scan and EBUS and round or oval shape by EBUS are predictors of malignancy, but no single characteristic can exclude a visualized lymph node from biopsy. Further, increasing the number of samples taken is unlikely to significantly improve sensitivity.

Preliminary development and evaluation of online tobacco and alcohol modules for dental students.

Tobacco use and heavy alcohol consumption are major risk factors for the development of oral and pharyngeal cancer (OPC). Detection and modification of these risks by dentists are keys in preventing OPC. While dentists are encouraged to screen patients for tobacco and alcohol use and educate them about the oral health risks they pose, dental students receive little formalized training in this area. This pilot project was designed to develop and evaluate two online training modules for dental students: one on tobacco and oral health risk factors, and one on methods of alcohol screening. Results indicated that online tobacco/alcohol education for dental students is feasible. The modules resulted in meaningful improvement in dental students' knowledge of tobacco and alcohol use as well as alcohol screening methods. The alcohol module resulted in statistically significant increases in intention to screen patients for alcohol use and in comfort level in performing alcohol screening.

Comparison of intraoperatively built custom linked seeds versus loose seed gun applicator technique using real-time intraoperative planning for permanent prostate brachytherapy.

PURPOSE: To report our dosimetric results using a novel push-button seed delivery system that constructs custom links of seeds intraoperatively. METHODS AND MATERIALS: From 2005 to 2007, 43 patients underwent implantation using a gun applicator (GA), and from 2007 to 2008, 48 patients underwent implantation with a novel technique allowing creation of intraoperatively built custom links of seeds (IBCL). Specific endpoint analyses were prostate D90% (pD90%), rV100% > 1.3 cc, and overall time under anesthesia. RESULTS: Final analyses included 91 patients, 43 GA and 48 IBCL. Absolute change in pD90% (ΔpD90%) between intraoperative and postoperative plans was evaluated. Using GA method, the ΔpD90% was -8.1 Gy and -12.8 Gy for I-125 and Pd-103 implants, respectively. Similarly, the IBCL technique resulted in a ΔpD90% of -8.7 Gy and -9.8 Gy for I-125 and Pd-103 implants, respectively. No statistically significant difference in ΔpD90% was found comparing methods. The GA method had two intraoperative and 10 postoperative rV100% >1.3 cc. For IBCL, five intraoperative and eight postoperative plans had rV100% >1.3 cc. For GA, the mean time under anesthesia was 75 min and 87 min for Pd-103 and I-125 implants, respectively. For IBCL, the mean time was 86 and 98 min for Pd-103 and I-125. There was a statistical difference between the methods when comparing mean time under anesthesia. CONCLUSIONS: Dosimetrically relevant endpoints were equivalent between the two methods. Currently, time under anesthesia is longer using the IBCL technique but has decreased over time. IBCL is a straightforward brachytherapy technique that can be implemented into clinical practice as an alternative to gun applicators.

Foot and mouth disease revisited: re-analysis using Bayesian spatial susceptible-infectious-removed models.

The foot and mouth disease (FMD) outbreak in the United Kingdom in 2001 was modeled via the use of Bayesian spatial susceptible-infected-removed (SIR) models. In these models the underlying mean of the incident cases was modeled spatially and in time. Dependence structures at the parish level between previous and current cases were modeled either with individual dependence or with neighborhood dependencies. Additional confounding was modeled via random effects that can have either uncorrelated or spatially correlated prior distributions. The best models found relied on lagged population and infection count within the same parish but neighborhood lagged dependencies overall did not provide a good fit. Models with only a space-time interaction effect were preferred over more complex models. The estimation of 'decline' markers for different areas was considered via difference operators as posterior functionals. These proved to be useful in giving an early indication of the waning phase of the epidemic locally.

Normothermia to prevent surgical site infections after gastrointestinal surgery: holy grail or false idol?

OBJECTIVE: To analyze the association between perioperative normothermia (temperature ≥36°C) and surgical site infections (SSIs) after gastrointestinal (GI) surgery. SUMMARY OF BACKGROUND DATA: Although active warming during colorectal surgery reduces SSIs, there is limited evidence that perioperative normothermia is associated with lower rates of SSI. Nonetheless, hospitals participating in the Surgical Care Improvement Project must report normothermia rates during major surgery. METHODS: We conducted a nested, matched, case-control study; cases consisted of GI surgery patients enrolled in our National Surgical Quality Improvement Program database between March 2006 and March 2009 who developed SSIs. Patient/surgery risk factors for SSI were obtained from the National Surgical Quality Improvement Program database. Perioperative temperature/antibiotic/glucose data were obtained from medical records. Cases/controls were compared using univariate/random effects/logistic regression models. Independent risk factors for SSIs were identified using multivariate/random effects/logistic regression models. RESULTS: A total of 146 cases and 323 matched controls were identified; 82% of patients underwent noncolorectal surgery. Cases were more likely to have final intraoperative normothermia compared with controls (87.6% vs. 77.8%, P = 0.015); rates of immediate postoperative normothermia were similar (70.6% vs. 65.3%, respectively, P = 0.19). Emergent surgery/higher wound class were associated with higher rates of intraoperative normothermia. Independent risk factors for SSI were diabetes, surgical complexity, small bowel surgery, and nonlaparoscopic surgery. There was no independent association between perioperative normothermia and SSI (adjusted odds ratio, 1.05; 95% confidence interval, 0.48-2.33; P = 0.90). CONCLUSIONS: Pay-for-reporting measures focusing on perioperative normothermia may be of limited value in preventing SSI after GI surgery. Studies to define the benefit of active warming after noncolorectal GI surgery are warranted.

Factors associated with cancer survivors' selection between two group physical activity programs.

INTRODUCTION: Physical activity programs have health benefits for cancer survivors, but little is known about factors that influence cancer survivors' actual choices between different physical activity programs. To address this knowledge gap, we examined factors associated with selecting between two group physical activity programs. METHODS: The present study is nested in a non-randomized trial. After attending an orientation to learn about the programs offered, cancer survivors (n=133) selected between a dragon boat paddling team and group walking program. We measured the association between physical activity program chosen and demographic, clinical, physical and psychosocial characteristics. RESULTS: Roughly equal proportions chose to participate in dragon boat paddling or walking (55% versus 45%). Of the many variables studied, few were associated with program selection. Compared to those who chose the walking program, those who chose the dragon boat paddling team were more likely to be Caucasians (p= .015) and younger (p= .027), and marginally significantly more like to have cancers other than breast cancer (p= .056) and have greater lower-body strength (.062). DISCUSSIONS/CONCLUSIONS: Among a cohort of cancer survivors who were interested in physical activity programs who chose between two markedly different group physical activity programs, the two programs attracted groups of approximately the same size and with remarkably similar characteristics overall. The two most notable associations were that Caucasians and younger adults were significantly more likely to choose the dragon boat paddling program. IMPLICATIONS FOR CANCER SURVIVORS: To meet the needs of cancer survivors, a menu of physical activity program options may be optimal.

Joint disease mapping of cervical and male oropharyngeal cancer incidence in blacks and whites in South Carolina.

Human papillomavirus (HPV) infection is an established causal agent for cervical cancer and a subset of oropharyngeal cancers. It is hypothesized that orogenital transmission results in oral cavity infection. In this paper we explore the geographical association between cervical and male oropharyngeal cancer incidence in blacks and whites in South Carolina using Bayesian joint disease mapping models fit to publicly available data. Our results suggest weak evidence for county-level association between the diseases, and different patterns of joint disease behavior for blacks and whites.

Capromab pendetide scanning has a potential role in optimizing patient selection for salvage cryosurgical ablation of the prostate.

OBJECTIVES: To evaluate an algorithm using Capromab pendetide scanning (CPS) and prostate biopsy to select appropriate patients with biochemical recurrence (BCR) after radiation therapy (RT) for salvage cryosurgical ablation of the prostate (CSAP) and to avoid premature androgen deprivation therapy (ADT); and to estimate the local salvage success rate for patients with high-risk clinical features. METHODS: Sixty-nine patients underwent a history, physical, CPS, and prostate biopsy. Patients with a negative or prostate-only positive signal and a positive biopsy were offered CSAP. Success was defined as a postsalvage nadir PSA of ≤ 0.4 ng/mL. Patients who failed were followed to establish when they required ADT. The results were compared with the putative results of applying clinical parameters alone. Patients were considered high-risk if they had any of the following characteristics: stage T3B-T4, Gleason ≥ 4 + 3, PSADT ≤ 10 months or presalvage PSA > 10 ng/mL. RESULTS: Twelve patients (6 with metastatic signal and 6 with negative biopsy) were excluded. Fifty-seven patients underwent CSAP. Overall 67% were successfully treated. Pre-salvage PSA was significantly associated with success (P = .013). Using clinical risk alone, only 14 patients achieved success compared with 38 using our algorithm. Most of the patients (75%) avoided ADT over a period of 21 months. CONCLUSIONS: Using our algorithm with CPS and prostate biopsy enabled us to spare some low-risk patients the undue morbidity of local salvage procedures that are likely to fail, while offering selected high-risk patients the opportunity for cure, avoiding premature ADT. Low presalvage PSA seems to be correlated with successful outcomes.

A survey of oral health education provided by certified diabetes educators.

The purpose of this study was to investigate certified diabetes educators' (CDEs) perceptions of the adequacy of their diabetes education curricula in providing oral health information. A questionnaire was mailed to all CDEs with a mailing address in South Carolina (SC), United States (US). Of the 130 respondents, between 50%-60% indicated that they adequately addressed frequent dental visits, daily brushing and flossing, and importance of good oral hygiene. Almost all (93.8%) reported that their curricula did not include an oral health module; the two predominant reasons were: not having enough time (61.0%), and not knowing enough about oral health and its relationship to diabetes (37.0%). Respondents who expressed that they did not know enough about oral health and its relationship to diabetes were less likely to provide adequate 'oral-health-related information' (p=0.008), especially information about the effect of periodontal disease on diabetes (p=0.016). This study indicates that SC CDEs do not routinely provide comprehensive oral health education to people with diabetes primarily due to lack of time and knowledge related to oral health. To better serve their patients, CDEs should integrate oral health education in the diabetes education curriculum.

Estimating the risks and benefits of nicotine replacement therapy for smoking cessation in the United States.

OBJECTIVES: To compare potential population-wide benefits and risks, we examined the potential impact of increased nicotine replacement therapy (NRT) use for smoking cessation on future US mortality. METHODS: We developed a simulation model incorporating a Monte Carlo uncertainty analysis, with data from the 2005 National Health Interview Survey and Cancer Prevention Study II. We estimated the number of avoided premature deaths from smoking attributable to increased NRT use, before and after incorporating assumptions about NRT harm. RESULTS: We estimate that a gradual increase in the proportion of NRT-aided quit attempts to 100% by 2025 would lead to 40,000 (95% credible interval=31,000, 50,000) premature deaths avoided over a 20-year period. Most avoided deaths would be attributable to lung cancer and cardiovascular disease. After we incorporated assumptions about potential risk from long-term NRT, the estimate of avoided premature deaths from all causes declined to 32 000. CONCLUSIONS: Even after we assumed some harm from long-term NRT use, the benefits from increased cessation success far outweigh the risks. However, the projected reduction in premature mortality still reflects a small portion of the tobacco-related deaths expected over a 20-year period.