Kristen Wroblewski

Prognostic value of metabolic tumor burden on 18F-FDG PET in nonsurgical patients with non-small cell lung cancer.

OBJECTIVE To assess the prognostic value of metabolic tumor burden as measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT), independent of current Union Internacional Contra la Cancrum/American Joint Committee on Cancer tumor, node, and metastasis (TNM) stage; in comparison with that of standardized uptake value (SUV) in surgical patients with non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS This study retrospectively reviewed 104 consecutive surgical patients (47 males, 57 females, median age at PET/CT scan of 67.92 years) with diagnosed stage I to IV NSCLC who had baseline (18)F-FDG PET/CT scans. The (18)F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of tumors in the whole body (MTV(WB)), TLG of tumors in the whole body (TLG(WB)), the maximum standardized uptake value of tumors in the whole body (SUV(maxWB)) as well as the mean standardized uptake value of tumor in the whole body (SUV(meanWB)) were measured. The median follow-up among 67 survivors was 42.07 months from the PET/CT (range 2.82-80.95 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics. The interobserver variability of SUV(maxWB), SUV(meanWB), MTV(WB), and TLG(WB) between two observers was analyzed using concordance correlation coefficients (CCCs). RESULTS The interobserver variability of SUV(maxWB), SUV(meanWB), MTV(WB) and TLG(WB) was very low with CCCs greater than 0.882. There was a statistically significant association of stage with overall survival (OS). The hazard ratio (HR) of stage III and stage IV as compared with stage I was 3.60 (P = .001) and 4.00 (P = .013), respectively. The MTV(WB) was significantly associated with OS with a HR for 1-unit increase of ln(MTV(WB)) of 1.40/1.32 (P = .004/.039), before/after adjusting for stage and other prognostic factors including chemoradiation therapy, and surgical procedure, respectively. TLG(WB) had a statistically significant association with OS before and after adjusting for stage and the other prognostic factors. The HR for 1-unit increase in ln(TLG(WB)) was 1.26 (P = .011) and 1.25 (P = .031), before and after the adjustment, respectively. Subjects with conditions that led to pneumonectomy (HR = 2.82, P = .035) or segmental resection (HR = 3.44, P = .044) had significantly worse survival than those needing lobectomy. There was no statistically significant association between OS and age, gender, tumor histology, ln(SUV(maxWB)), and ln(SUV(meanWB)) (all P > .05). There were 37 deaths during follow-up. CONCLUSION Baseline whole-body metabolic tumor burden as measured with MTV(WB) and TLG(WB) on FDG PET is a prognostic measure independent of clinical stage and other prognostic factors including chemoradiation therapy and surgical procedure with low interobserver variability and may be used to further risk stratify surgical patients with NSCLC. This study also suggests that MTV and TLG are better prognostic measures than SUV(max) and SUV(mean). These results will need to be validated in larger cohorts in a prospective study.

Assessing gynecologic and breast cancer survivors' sexual health care needs.

The objective of this study was to identify patterns of interest in receiving care for sexual concerns among women who were survivors of gynecologic and breast cancers.

Identification of a Sporozoite-Specific Antigen from Toxoplasma gondii

Abstract Reduction of risk for human and food animal infection with Toxoplasma gondii is hampered by the lack of epidemiological data documenting the predominant routes of infection (oocyst vs. tissue cyst consumption) in horizontally transmitted toxoplasmosis. Existing serological assays can determine previous exposure to the parasite, but not the route of infection. We have used difference gel electrophoresis, in combination with tandem mass spectroscopy and Western blot, to identify a sporozoite-specific protein (T. gondii embryogenesis-related protein [TgERP]), which elicited antibody and differentiated oocyst- versus tissue cyst–induced infection in pigs and mice. The recombinant protein was selected from a cDNA library constructed from T. gondii sporozoites; this protein was used in Western blots and probed with sera from T. gondii–infected humans. Serum antibody to TgERP was detected in humans within 6–8 mo of initial oocyst-acquired infection. Of 163 individuals in the acute stage of infection (anti–T. gondii IgM detected in sera, or <30 in the IgG avidity test), 103 (63.2%) had detectable antibodies that reacted with TgERP. Of 176 individuals with unknown infection route and in the chronic stage of infection (no anti–T. gondii IgM detected in sera, or >30 in the IgG avidity test), antibody to TgERP was detected in 31 (17.6%). None of the 132 uninfected individuals tested had detectable antibody to TgERP. These data suggest that TgERP may be useful in detecting exposure to sporozoites in early T. gondii infection and implicates oocysts as the agent of infection.

Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981–2009)

BACKGROUND Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types. METHODS ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined. RESULTS Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment. CONCLUSIONS Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment. CLINICAL TRIALS REGISTRATION NCT00004317.

General internists' preferences and knowledge about the care of adult survivors of childhood cancer: a cross-sectional survey.

Context Most adult childhood cancer survivors (CCSs) receive health care from primary care physicians. Contribution This survey of general internists found that about half provided care for adult CCSs but most had never received a treatment summary from a referring cancer center. Internists were somewhat uncomfortable caring for survivors of Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma. In a vignette case, most general internists did not recommend appropriate surveillance for a Hodgkin lymphoma survivor. Implication Although general internists see adult CCSs, many are unfamiliar with recommended surveillance practices and lack coordinated communication processes with oncologists and cancer centers. The Editors More than 350 000 childhood cancer survivors (CCSs) live in the United States, and this population continues to expand (1, 2). In 2002, the Institute of Medicine recognized the substantial health risks facing CCSs, including end-organ dysfunction, second malignant neoplasms, and cognitive impairment (39). The Institute of Medicine recommended lifelong, risk-based health care to mitigate these late effects. Such care includes a systematic plan for periodic surveillance and prevention that is adapted to the specific risks from the individual patients previous cancer, therapy, genetic predisposition, health behaviors, and comorbid conditions (3, 10). In response, various international groups created and disseminated guidelines for the risk-based care of CCSs (1115). In 2003, the North American Childrens Oncology Group (COG) published the Long-Term Follow-Up (LTFU) Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer, which provide surveillance guidelines based on survivors exposure to cancer therapies (11, 15). Yet, more than a decade after the Institute of Medicine report, most CCSs are not engaged in appropriate risk-based health care (1620). Several factors contribute to this lack of engagement. Survivors treated at a young age often have limited knowledge of the therapies they had and their consequences (21). Many adult CCSs have difficulty obtaining adequate health insurance (2126). Finally, transitions from pediatric to adult-care providers and from tertiary care cancer centers to community clinicians contribute to suboptimal care (27, 28). Previous studies of pediatric oncologists suggest that insufficient understanding of late effects and publically available surveillance guidelines contribute to ineffectual transitions (23, 2931). More than 80% of adult CCSs receive health care from a primary care physician (PCP) in their community, yet our understanding of the care delivered by PCPs to this growing and clinically challenging population is limited (16). As more than half of the adult-focused PCPs in the United States are general internists (32), we conducted a nationally representative survey of practicing general internists to assess their attitudes and knowledge about the care of CCSs. Methods Study Population Using methods from previous studies (33, 34), we selected a national probability sample of practicing physicians who listed general internal medicine as their primary specialty from the American Medical Association Physician Masterfile, a database intended to include all physicians in the United States. We selected 2000 physicians from approximately 148 000, giving a sampling percentage of 1.35% (or 1 physician sampled of every 74 physicians in the population). We obtained approval from the University of Chicagos institutional review board before study initiation. Survey Mailings Surveys were mailed to physicians between September 2011 and August 2012, with a prenotification letter and postcard reminder. Up to 4 mailings were sent to increase response rates. A

Unrecognized Ingestion of Toxoplasma gondii Oocysts Leads to Congenital Toxoplasmosis and Causes Epidemics in North America

10 incentive was included in the first mailing. The third mailing included a

Obstructive Sleep Apnea in Young Lean Men: Impact on insulin sensitivity and secretion

5 incentive, and the fourth and final mailing included

Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial

20 on receipt of a completed survey. During the fourth mailing, physicians were called if a phone number was available. We used the Google search engine (Google, Mountainview, California) to identify discrepant addresses from data provided by the American Medical Association Physician Masterfile for nonrespondents. If an alternate address was identified, subsequent mailings were sent to the new address. Internists were excluded from the analytic sample if surveys were returned 2 or more times with incorrect addresses or if participants were identified as deceased, retired, or no longer practicing internal medicine. Survey Instrument The survey was derived from previous surveys about physician attitudes and knowledge about cancer care (29, 35, 36). A CCS was defined as a patient diagnosed with cancer at or before age 21 years, at least 5 years from cancer therapy completion, and who was cancer free. This definition was chosen to capture physician experiences with patients who had survived the period in which relapse is the predominant health threat and is consistent with terminology used by several groups that research the long-term effects of pediatric cancer (for example, the North American Childhood Cancer Survivor Study and the British Childhood Cancer Survivor Study) (8, 37). The 18-item survey assessed respondents demographics, medical education, and practice structure. We asked internists about the number of CCSs they had cared for in the past 5 years and how frequently they had received a cancer treatment summary (documenting the survivors diagnosis, cancer therapy, and follow-up plan) from a referring cancer center. We assessed comfort level with caring for survivors of acute lymphoblastic leukemia, Hodgkin lymphoma, and osteosarcoma with a 7-point Likert scale, with scores ranging from 1 (very uncomfortable) to 7 (very comfortable). A similar Likert scale assessed familiarity with the available monitoring guidelines for childhood, adolescent, and young adult cancer survivors (scores ranging from 1 [very unfamiliar] to 7 [very familiar]). We asked internists whether they prefer to care for survivors independently, in consultation with a cancer centerbased physician or LTFU clinic, or by referral to a cancer centerbased physician or another PCP. The survey included a hypothetical vignette describing a 29-year-old female survivor of Hodgkin lymphoma whose therapy included mantle radiation and anthracycline chemotherapy (cumulative dose, 150 mg/m2) at age 16 years. Using a set of preselected responses, we asked internists about their approach to breast cancer and cardiac and thyroid surveillance for this patient. We compared responses with the COG LTFU guidelines (15). Finally, we asked internists to rate the usefulness of 11 tools that might assist them in independently caring for such a survivor using a scale ranging from 1 (not at all useful) to 4 (very useful). Statistical Analysis Descriptive statistics included frequency counts and percentages, means with SDs, and medians with ranges. Chi-square tests or 2-sample t tests were conducted for comparisons between groups. We calculated Spearman rank correlation coefficients when determining associations between 2 continuous or ordinal variables. We fit multivariate linear and logistic regression models to examine internists comfort with caring for CCSs and knowledge of surveillance guidelines, respectively. Covariates, chosen a priori, were sex, years of practice, number of patients seen per week, having seen at least 1 CCS in the past 5 years, and practice environment. Age was highly correlated with years of practice (r = 0.92) and was not included in the multivariate models. All analyses were conducted by using Stata software, version 12 (StataCorp, College Station, Texas). Role of the Funding Source The National Cancer Institute provided financial support for this work through a grant to Dr. Henderson. The funding source played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Results We received 1110 completed questionnaires out of 1801 potential respondents (response rate, 61.6%) (Appendix Figure). Characteristics of the participating internists are detailed in Table 1. We found no statistically significant differences in sex, age, or geographic location of practice between respondents and nonrespondents. Appendix Figure. Study flow diagram. AMA = American Medical Association. Table 1. Demographic and Practice Characteristics of Respondents and Nonrespondents Fifty-one percent of respondents reported having cared for at least 1 adult CCS in the 5 years preceding the survey (Table 1). Among this subset, 72.0% reported never having received a treatment summary. Only 61 internists (5.5%) preferred to care for CCSs independently. Most (84.0%) preferred to work in collaboration with a cancer centerbased physician or LTFU clinic, and 10.5% indicated that they would refer CCSs to a cancer centerbased physician, LTFU program, or another PCP. On average, internists reported being somewhat uncomfortable caring for CCSs. Only 36.9%, 27.0%, and 25.0% of respondents indicated that they were somewhat comfortable or comfortable (Likert score 5) caring for Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma survivors, respectively. In multivariate analyses, comfort levels were higher among internists with a larger patient volume, those who had seen at least 1 CCS in the preceding 5 years, and men (Appendix Table 1). Appendix Table 1. Multivariate Linear Regression on Comfort Levels* With CCSs General Internists Familiarity and Knowledge of Published LTFU Guidelines Internists reported being generally unfamiliar with available surveillance guidelines for CCSs. Only 12.0% stated that they felt at least somewhat familiar with available guidelines (Likert score 5). Knowledge of available surveillance guidelines for breast cancer and cardiac and thyroid function was assessed by using the

Sleep Disturbances and Their Relationship to Glucose Tolerance in Pregnancy

BACKGROUND Congenital toxoplasmosis presents as severe, life-altering disease in North America. If mothers of infants with congenital toxoplasmosis could be identified by risks, it would provide strong support for educating pregnant women about risks, to eliminate this disease. Conversely, if not all risks are identifiable, undetectable risks are suggested. A new test detecting antibodies to sporozoites demonstrated that oocysts were the predominant source of Toxoplasma gondii infection in 4 North American epidemics and in mothers of children in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS). This novel test offered the opportunity to determine whether risk factors or demographic characteristics could identify mothers infected with oocysts. METHODS Acutely infected mothers and their congenitally infected infants were evaluated, including in-person interviews concerning risks and evaluation of perinatal maternal serum samples. RESULTS Fifty-nine (78%) of 76 mothers of congenitally infected infants in NCCCTS had primary infection with oocysts. Only 49% of these mothers identified significant risk factors for sporozoite acquisition. Socioeconomic status, hometown size, maternal clinical presentations, and ethnicity were not reliable predictors. CONCLUSIONS Undetected contamination of food and water by oocysts frequently causes human infections in North America. Risks are often unrecognized by those infected. Demographic characteristics did not identify oocyst infections. Thus, although education programs describing hygienic measures may be beneficial, they will not suffice to prevent the suffering and economic consequences associated with congenital toxoplasmosis. Only a vaccine or implementation of systematic serologic testing of pregnant women and newborns, followed by treatment, will prevent most congenital toxoplasmosis in North America.

Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults

OBJECTIVE To assess whether the presence of obstructive sleep apnea (OSA) affects glucose metabolism in young, lean individuals who are healthy and free of cardiometabolic disease. RESEARCH DESIGN AND METHODS In a prospective design, 52 healthy men (age 18–30 years; BMI 18–25 kg/m2) underwent laboratory polysomnogram followed by a morning oral glucose tolerance test (OGTT). We stratified all subjects according to the presence or absence of ethnicity-based diabetes risk and family history of diabetes. We then used a frequency-matching approach and randomly selected individuals without OSA, yielding a total of 20 control men without OSA and 12 men with OSA. Indices of glucose tolerance, insulin sensitivity, and insulin secretion (early phase and total) were compared between men with OSA and control subjects. The incremental areas under the glucose (incAUCglu) and insulin (incAUCins) curves were calculated using the trapezoidal method from 0 to 120 min during the OGTT. RESULTS Men with OSA and control subjects were similar in terms of age, BMI, ethnicity-based diabetes risk, family history of diabetes, and level of exercise. Both groups had normal systolic and diastolic blood pressure and fasting lipid levels. After ingestion of a glucose load, men with OSA had 27% lower insulin sensitivity (estimated by Matsuda index) and 37% higher total insulin secretion (incAUCins) than the control subjects, despite comparable glucose levels (incAUCglu). CONCLUSIONS In young, lean, and healthy men who are free of cardiometabolic disease, the presence of OSA is associated with insulin resistance and a compensatory rise in insulin secretion to maintain normal glucose tolerance. Thus, OSA may increase the risk of type 2 diabetes independently of traditional cardiometabolic risk factors.