Kevin A. Pearlstein

Population Genetic Inference from Personal Genome Data: Impact of Ancestry and Admixture on Human Genomic Variation

Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in todays African Americans dates back to European gene flow happening only 7-8 generations ago.

Infrared imaging of trauma patients for detection of acute compartment syndrome of the leg

Objective:Early compartment syndrome is difficult to diagnose, and a delay in the diagnosis can result in amputation or death. Our objective was to explore the potential of infrared imaging, a portable and noninvasive technology, for detecting compartment syndrome in the legs of patients with multiple trauma. We hypothesized that development of compartment syndrome is associated with a reduction in surface temperature in the involved leg and that the temperature reduction can be detected by infrared imaging. Design:Observational clinical study. Setting:Level I trauma center between July 2006 and July 2007. Patients:Trauma patients presenting to the emergency department. Interventions:Average temperature of the anterior surface of the proximal and distal region of each leg was measured in the emergency department with a radiometrically calibrated, 320 × 240, uncooled microbolometer infrared camera. Measurements and Main Results:The difference in surface temperature between the thigh and foot regions (thigh-foot index) of the legs in trauma patients was determined by investigators blinded to injury pattern using thermographic image analysis software. The diagnosis of compartment syndrome was made intraoperatively. Thermographic images from 164 patients were analyzed. Eleven patients developed compartment syndrome, and four of those patients had bilateral compartment syndrome. Legs that developed compartment syndrome had a greater difference in proximal vs. distal surface temperature (8.80 ± 2.05°C) vs. legs without compartment syndrome (1.22 ± 0.88°C) (analysis of variance p < .01). Patients who developed unilateral compartment syndrome had a greater proximal vs. distal temperature difference in the leg with (8.57 ± 2.37°C) vs. the contralateral leg without (1.80 ± 1.60°C) development of compartment syndrome (analysis of variance p < .01). Conclusions:Infrared imaging detected a difference in surface temperature between the proximal and distal leg of patients who developed compartment syndrome. This technology holds promise as a supportive tool for the early detection of acute compartment syndrome in trauma patients.

Comparing Dosimetric, Morbidity, Quality of Life, and Cancer Control Outcomes After 3D Conformal, Intensity-Modulated, and Proton Radiation Therapy for Prostate Cancer

New radiation technologies have been developed and adopted for clinical use in prostate cancer treatment in response to a need to deliver dose-escalated radiation therapy while minimizing treatment-related morbidity. The goal of this article is to examine the currently available evidence comparing dosimetric and patient outcomes of newer versus older radiation technologies in prostate cancer. Overall, although a body of dosimetry studies have demonstrated the ability of newer versus older technologies (intensity-modulated radiation therapy vs 3-dimensional conformal radiation therapy; proton vs intensity-modulated radiation therapy) to reduce radiation doses delivered to the rectum and bladder, more studies are needed to demonstrate that these dosimetric benefits translate into improved patient outcomes.

Comparison of Patient Report and Medical Records of Comorbidities: Results From a Population-Based Cohort of Patients With Prostate Cancer

Importance The comorbid conditions of patients with cancer affect treatment decisions, which in turn affect survival and health-related quality-of-life outcomes. Comparative effectiveness research studies must account for these conditions via medical record abstraction or patient report. Objective To examine the agreement between medical records and patient reports in assessing comorbidities. Design, Setting, and Participants Patient-reported information and medical records were prospectively collected as part of the North Carolina Prostate Cancer Comparative Effectiveness & Survivorship Study, a population-based cohort of 881 patients with newly diagnosed localized prostate cancer enrolled in the North Carolina Central Cancer Registry from January 1, 2011, through June 30, 2013. The presence or absence of 20 medical conditions was compared based on patient report vs abstraction of medical records. Main Outcomes and Measures Agreement between patient reports and medical records for each condition was assessed using the &kgr; statistic. Subgroup analyses examined differences in &kgr; statistics based on age, race, marital status, educational level, and income. Logistic regression models for each condition examined factors associated with higher agreement. Results A total of 881 patients participated in the study (median age, 65 years; age range, 41-80 years; 633 white [71.9%]). In 16 of 20 conditions, there was agreement between patient reports and medical records for more than 90% of patients; agreement was lowest for hyperlipidemia (68%; &kgr; = 0.36) and arthritis (66%; &kgr; = 0.14). On multivariable analysis, older age (≥70 years old) was significantly associated with lower agreement for myocardial infarction (odds ratio [OR], 0.31; 95% CI, 0.12-0.80), cerebrovascular disease (OR, 0.10; 95% CI, 0.01-0.78), coronary artery disease (OR, 0.37; 95% CI, 0.20-0.67), arrhythmia (OR, 0.44; 95% CI, 0.25-0.79), and kidney disease (OR, 0.18; 95% CI, 0.06-0.52). Race and educational level were not significantly associated with &kgr; in 18 of 19 modeled conditions. Conclusions and Relevance Overall, patient reporting provides information similar to medical record abstraction without significant differences by patient race or educational level. Use of patient reports, which are less costly than medical record audits, is a reasonable approach for observational comparative effectiveness research.

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer

BACKGROUND AND PURPOSE To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. MATERIAL AND METHODS Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. RESULTS 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. CONCLUSIONS Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity.

Patient-reported quality of life during definitive and postprostatectomy image-guided radiation therapy for prostate cancer

PURPOSE The importance of patient-reported outcomes is well-recognized. Long-term patient-reported symptoms have been described for individuals who completed radiation therapy (RT) for prostate cancer. However, the trajectory of symptom development during the course of treatment has not been well-described in patients receiving modern, image-guided RT. METHODS AND MATERIALS Quality-of-life data were prospectively collected for 111 prostate cancer patients undergoing RT using the validated Prostate Cancer Symptom Indices, which assessed 5 urinary obstructive/irritative and 6 bowel symptoms. Patients who received definitive RT (N = 73) and postprostatectomy RT (N = 38) were analyzed separately. The frequency and severity of symptoms over multiple time points are reported. RESULTS An increasing number of patients had clinically meaningful urinary and bowel symptoms over the course of RT. A greater proportion of patients undergoing definitive RT reported clinically meaningful urinary symptoms at the end of RT compared with baseline in terms of flow (33% vs 19%) and frequency (39% vs 18%). Individuals receiving postprostatectomy radiation also reported an increase in symptoms including frequency (29% vs 3%) and nocturia (50% vs 21%). Clinically meaningful bowel symptoms were less commonly reported. Patients receiving definitive RT reported an increase in diarrhea (9% vs 4%) and urgency (12% vs 6%) at the completion of RT compared with baseline. Both bowel and urinary symptoms approached their baseline levels by the time of first follow-up after treatment completion. The majority of patients who had clinically meaningful urinary or bowel symptoms during RT did not have them at 2 years or beyond, and development of new symptoms in the long term was uncommon. CONCLUSIONS There is a modest increase in urinary and bowel symptoms over the course of treatment for individuals receiving definitive and postprostatectomy image-guided RT. These data can help inform both providers and patients regarding the trajectory of symptoms and allow for reasonable expectations regarding toxicity under treatment.

Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy

BackgroundTo estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptoms during post-prostatectomy radiotherapy (RT). To evaluate the goodness-of-fit and the correlation of those models with those symptoms.MethodsNinety-three consecutive patients treated from 2010 to 2015 with post-prostatectomy image-guided intensity modulated radiotherapy (IMRT) were included in this study. Patient-reported urinary symptoms were collected pre-RT and weekly during treatment using the validated Prostate Cancer Symptom Indices (PCSI). The assessed symptoms were flow, dysuria, urgency, incontinence, frequency and nocturia using a Likert scale of 1 to 4 or 5. For this analysis, an increase by ≥2 levels in a symptom at any time during treatment compared to baseline was considered clinically significant. The dose volume histograms of the bladder were calculated. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS) and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC) and Odds Ratio methods.ResultsFor the symptoms of urinary urgency, leakage, frequency and nocturia, the derived LKB model parameters were: 1) D50 = 64.2Gy, m = 0.50, n = 1.0; 2) D50 = 95.0Gy, m = 0.45, n = 0.50; 3) D50 = 83.1Gy, m = 0.56, n = 1.00; and 4) D50 = 85.4Gy, m = 0.60, n = 1.00, respectively. The AUC values for those symptoms were 0.66, 0.58, 0.64 and 0.64, respectively. The differences in AIC between the different models were less than 2 and ranged within 0.1 and 1.3.ConclusionsDifferent dose metrics were correlated with the symptoms of urgency, incontinence, frequency and nocturia. The symptoms of urinary flow and dysuria were poorly associated with dose. The values of the parameters of three NTCP models were determined for bladder regarding four acute urinary symptoms. All the models could fit the clinical data equally well. The NTCP predictions of urgency showed the best correlation with the patient reported outcomes.

Paraneoplastic psoriasis in a patient with prostate cancer

CASE REPORT A 69-year-old gentlemanwas referred to our clinic for a new diffuse erythematous pruritic rash that initially developed on his left chest and rapidly spread to his face, dorsal hands, and lower legs over the course of 2 weeks. His medical history was significant for type II diabetes mellitus, hypertension, and nonmelanoma skin cancer. The initial biopsy showed mildly elongate rete with blunted tips and diffuse parakeratosis with loss of the granular cell layer. There was minimal spongiosis; no basement membrane zone changes or dyskeratotic cells were seen. Only a mild, superficial, dermal, perivascular lymphocytic infiltrate was present. No eosinophils were seen. These findings were consistent with psoriasiform dermatitis. The patient was subsequently started on clobetasol 0.05% ointment, prednisone, and methotrexate, given the extent of the disease and concern for drug eruption. At his subsequent visit, he was markedly worse, demonstrating an exfoliative erythroderma and severe pruritus (Fig 1). He required admission to the hospital for treatment with topical steroid wet wraps. Repeat biopsies showed changes similar to the first. In addition, a focus with dilated dermal papillae, thinning of the suprapapillary plates, and a few neutrophils in the parakeratotic stratum corneum were found (Fig 2). These findings were diagnostic of psoriasis. Despite 5 days of inpatient treatment, he showed minimal improvement. He was subsequently given cyclosporine and acitretin and ultimately transitioned to adalimumab, which resulted in only marginal improvement of his symptoms.

Treatment patterns for patients with localized (T1-T2) penile squamous cell carcinoma in the United States.

332 Background: The standard treatment for patients with localized penile squamous cell carcinoma is penectomy, which is associated with high psychosocial morbidity. Organ preservation using radiation therapy is an alternative. To our knowledge, this is the first population-based patterns of care study in this disease for a modern cohort of men. METHODS Caucasian (CA, N=1,270) and African American (AA, N=139) patients diagnosed with localized cancer from 2000-2009 were included from the Surveillance, Epidemiology and End Results (SEER) database. Treatments were categorized into ablative therapies (e.g. laser, electrocautery), surgical resection, or radiation therapy (including external beam and brachytherapy). Multivariate logistic regression assessed factors associated with receipt of radiation therapy as primary treatment. RESULTS 57% of patients were married. The vast majority of patients receive surgical resection, with about 1% receiving primary radiation therapy (Table). Patterns of care were not significantly different among AA and CA patients (p=.95). Multivariable analysis including diagnosis year, marital status, age, race and SEER region did not show any covariate significantly associated with receipt of primary radiation treatment. CONCLUSIONS Surgical resection is the predominant treatment for patients with localized penile cancer in the United States, with very few patients receiving primary radiation therapy. [Table: see text].

Prevalence of cardiovascular disease (CVD) risk factors and receipt of preventive care among prostate cancer (CaP) survivors in the United States.

185 Background: CVD is a major cause of mortality in CaP survivors. Prior claims-based studies have reported underutilization of preventive care in cancer survivors, but most CVD preventive care items are not available in claims data. We directly examined the prevalence of CVD risk factors and receipt of care in patients with these risk factors in two population-based data sources: National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS) - both commonly used to examine patterns of care in the US. METHODS 2,938 (NHANES) and 452 (NHIS) men with CaP diagnosed from 1999 to 2011 were included. Statistical analysis accounted for sampling weight, and was stratifiedby Caucasian (CA) vs. non-CA. RESULTS CVD risk factors are highly prevalent (Table), and appear more so in non-Caucasian survivors. Further, 32% of survivors reported history of actual CVD (prior stroke, myocardial infarction, angina, or coronary heart disease). Overall, the majority of survivors receive preventive care. 89%of CA and non-CA survivors visited a primary care physician in the past 1 year. Among survivors with hypertension or hyperlipidemia, >80% received blood pressure or cholesterol checks within past 1 year. Rates of tobacco cessation and exercise were lower. CONCLUSIONS CVD and associated risk factors are prevalent in CaP survivors. However, the majority of these survivors visit a primary care physician and receive CVD preventive care. [Table: see text].