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Supplementary Data Table 2 from Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis

Supplementary Data Table 3 from Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis

Purpose: Our aim was to discover possible inherited factors associated with glioblastoma age at diagnosis and survival. Although new genotyping technologies allow greatly expanded exploration of such factors, they pose many challenges.Experimental Design: In this pilot study, we (a) genotyped 112 newly diagnosed glioblastoma patients ascertained through a population-based study (group 1) with the ParAllele assay panel of ∼10,000 nonsynonymous coding single-nucleotide polymorphisms (SNP), (b) used several statistical and bioinformatic techniques to identify 17 SNPs potentially related to either glioblastoma age at diagnosis or survival, and (c) genotyped 16 of these SNPs using conventional PCR methods in an independent group of 195 glioblastoma patients (group 2).Results: In group 2, only one of the 16 SNPs, rs8057643 (located on 16p13.2), was significantly associated with glioblastoma age at diagnosis (nominal P = 0.0017; Bonferroni corrected P = 0.054). Median ages at diagnosis for those with 0, 1, or 2 T alleles were 66, 57, and 59 years in group 1 and 64, 57, and 55 years in group 2 (combined P = 0.001). Furthermore, Cox regression analyses of time to death with number of T alleles adjusted for gender and patient group yielded a hazard ratio of 0.82 (95% confidence interval, 0.68-0.98; P = 0.03).Conclusions: Although limited by a relatively small sample size, this pilot study, using well-characterized, unambiguous disease characteristics, illustrates the necessity of independent replication owing to the likelihood of false positives. Several other challenges are discussed, including attempts to incorporate information on the potential functional importance of SNPs in genome-disease association studies.

We and others have reported previously that adults with glioma are 1.5- to 4-fold less likely than controls to report a variety of allergic conditions. The consistent nature of this relationship calls for a biological explanation so that preventative or therapeutic modalities can be explored. We enrolled 403 newly diagnosed adult glioma cases in the San Francisco Bay Area over a 3-year period using a population-based cancer registry and 402 age/gender/ethnicity frequency-matched controls identified via random digit dialing. We assessed total, food-specific, and respiratory-specific IgE in available case (n = 228) and control (n = 289) serum samples. IgE levels were associated with gender, age, smoking status, and ethnicity among cases and/or controls. Among the cases, IgE levels were not associated with aspects of glioma therapy including radiation, chemotherapy, or tumor resection. Total IgE levels were lower in cases than controls: age/gender/ethnicity/education/smoking-adjusted odds ratio (OR) for elevated versus normal total IgE was 0.37 [95% confidence interval (CI), 0.22–0.64]. For the food panel, OR was 0.12 (95% CI, 0.04–0.41). For the respiratory panel, OR was 0.76 (95% CI, 0.52–1.1). Among respiratory allergies, late age of onset (>12 years) but not IgE levels defined a group with strong associations with risk (OR, 0.50; 95% CI, 0.33–0.75). These results corroborate and strengthen our findings of an inverse association between allergic reactions and glioma by showing a relationship with a biomarker for allergy and cancer for the first time. Furthermore, the results indicate a complex relationship between allergic disease and glioma risk that varies by allergen and allergic pathology.

Supplementary Table 1-5 from Reduced Immunoglobulin E and Allergy among Adults with Glioma Compared with Controls

During the COVID-19 pandemic, many health jurisdictions deployed digital informatics systems to support “manual” case investigation and contact tracing (CICT). This case study evaluates the implementation and use of a digital information system through the experiences of CICT workers in the City and County of San Francisco (CCSF). We conducted semi-structured, 90-min interviews with a sample of the CCSF CICT workforce (n = 37). Participants also completed standardized assessments of the digital system using the System Usability Scale (SUS). Qualitative analyses highlighted (1) the importance of digital tools to ensure rapid onboarding and effective data capture in a public health emergency; (2) the use of digital systems to support culturally sensitive care; and (3) the role of digitals tools in building supportive work environments. The mean SUS score was 70/100 (SD = 17), indicating relative ease of use. In summary, the analysis highlights the importance of digital tools to support manual CICT in the COVID-19 response., Lay Summary During the COVID-19 pandemic, many health departments implemented digital systems to collect, store, and share data for case investigation and contact tracing (CICT). In San Francisco, much of the contact tracing workforce was entirely remote and had little to no public health experience. Given this unique situation, we wanted to understand their experience with the digital system to inform future implementation of digital systems for public health responses. This case study describes how CICT workers in San Francisco experienced and used the digital system and how it could be improved. We conducted semi-structured, 90-min interviews and a short survey with a sample of 37 CICT workers and found that, overall, the digital system was easy to learn and improved workers’ experience of data management during the pandemic. The digital system was also important in fostering a supportive and collaborative work environment. We found that the system could be improved to better support culturally sensitive care and highlight the importance of digital systems in ensuring equitable public health responses.

Background: The decrease in trial of labor after cesarean (TOLAC) at institutions that offer this option suggests that patient preference could be a factor in the declining TOLAC rate. However, data regarding how women value the potential processes and outcomes of TOLAC and elective repeat cesarean delivery (ERCD) are limited. We sought to determine how women view the processes and outcomes of TOLAC and ERCD and identify sociodemographic and clinical factors associated with these preferences. Materials and Methods: This is a multicenter cross-sectional study of mode of delivery preferences among TOLAC-eligible women at 26–34 weeks gestation. The time tradeoff metric was used to obtain utilities for the processes and outcomes of TOLAC and ERCD. Multivariable regression analysis was utilized to identify independent predictors of utilities. Results: The 299 study participants constituted a geographically and racially/ethnically diverse group. Although uncomplicated TOLAC resulting in vaginal birth after cesarean and uncomplicated ERCD resulted in high utility values, any alteration in either the process or outcome resulted in substantial utility decrements. In multivariable regression analysis, race/ethnicity, insurance status, and order of scenario presentation emerged as statistically significant predictors. Conclusions: Information regarding both maternal and infant implications is important to women in discussions about approach to delivery. Both the way in which information regarding labor interventions and potential complications is presented and the characteristics of the women contemplating this information affect its impact. These findings underscore the need for evidence-based decision support to help create realistic expectations and incorporate informed patient preferences into decision-making to optimize both clinical outcomes and individual patient experience for women with a prior cesarean delivery.

Kenya introduced universal antiretroviral treatment (ART) for pregnant and breastfeeding women living with HIV (Option B+) in 2014. A retrospective study was conducted to review consecutive records for HIV positive pregnant women presenting for antenatal care (ANC) at five clinics in western Kenya. Known positive women (KP :HIV diagnosis prior to current pregnancy) were compared to newly positive (NP) women regarding virologic suppression and retention in care. Among 165 women included, 71 (43%) NP and 94 (57%) KP, NP were younger (24.5 years (SD 4.6) vs. 28.1 years (SD 5.6) compared to KP (p .001). Almost all NP (97%) were initiated on Option B+ while over half of KP (59%) started ART for clinical/immunological criteria (p .0001). KPs were more likely than NPs to have a VL performed following Kenyan guidelines (64% vs. 31%; p .001). Among those tested, virologic suppression was high in both groups (92% KP vs. 100% NP; p = .31). More KPs (82%) vs. NPs (66%) remained active in care at 15-18 months of follow-up (p = .02). Women newly diagnosed with HIV during pregnancy show poorer uptake of VL testing and worse retention in care than those diagnosed prior to pregnancy.

New HIV infections among adolescents continues to be a large public health burden in sub-Saharan Africa, with few adolescents accessing HIV testing and counseling (HTC) services. We evaluated the effect of a peer referral program among adolescents in Kisumu county, Kenya in accessing HTC. Female adolescents aged 15 to 19years were recruited from three health clinics in Kisumu County. They, in turn, recruited their peers for HTC by handing out referral cards. Referrals would then recruit their peers and this peer-referral repeated for approximately 5months. The 252 female index seeds showed a relatively higher-risk profile for HIV compared to the 792 referral participants. The referral system yielded an increased proportion of first-time adolescent testers from 13.1% among index seeds to 42.7% among the second wave of referrals. However, the peer referral system ultimately did not increase the absolute number of adolescents Queryaccessing HTC. Future strategies should consider these findings to better target those with undiagnosed HIV infection.

To identify predictors of hysterotomy extension in women undergoing cesarean delivery (CD) in the second stage of labor, and whether use of nitroglycerin (NTG) during CD has a protective effect.We conducted a retrospective cohort study of women undergoing CD in the second stage of labor from 2012 to 2015. Some women received NTG at the obstetrician's request. Logistic regression was used to examine the relationship between second stage duration and NTG administration on maternal and neonatal outcomes.Of the 391 women in the sample, 27% had an extension and 12% received NTG. Second stage ≥4 h was associated with a 2.14-fold higher risk of extension (95% CI 1.22-3.75), a 2.00-fold higher risk of hemorrhage (95% CI: 1.20-3.33) and 2.42-fold higher risk of blood transfusion during delivery hospitalization (95% CI: 0.99-5.91). Intravenous (IV) and sublingual-spray (SL-spray) NTG administration were not associated with an increased risk of hemorrhage or extension. SL-NTG was associated with 4.68-fold increased odds of 5-min Apgar 7 (95% CI 1.42-15.41) and 3.36-fold greater odds of NICU admission (95% CI 1.20-9.41).We found no evidence that NTG protects against extension, and SL-NTG use was associated with adverse neonatal outcomes. Clinical trials should be conducted to evaluate risk and benefits of NTG use.

To evaluate the effectiveness of the implementation of the adolescent package of care (APOC) training on adolescent viral suppression at Family AIDS CareEducation Services (FACES)-supported sites.The effect of APOC training was evaluated based on viral load suppression (1000 copies/mL) of 10-19-year-olds in 13 FACES-supported sites in six months before (January 2015-August 2016) and after (November 2015-March 2017) the APOC training for each site.Patient-level data were abstracted from the FACES electronic medical records (OpenMRS) and the National AIDS and STI Control Programme viral load website. Information on adolescent clinic day implementation and utilization of an APOC checklist as a proxy for services provided at each site was collected. Generalized estimating equations with repeated measures clustered by patients were used for bivariate and multivariate modeling to assess factors associated with viral suppression.In the pretraining period, 60% of adolescents received services at clinics offering adolescent clinic days compared to 95% in the post-training period. Among those tested, 65% were virally suppressed during the pretraining period compared to 72% during the post-training period (odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.12, 1.53, P 0.01). In multivariable analysis, there was no statistically significant change in viral load suppression due to APOC training (adjusted OR [aOR] = 0.97, 95% CI: 0.72, 1.30, P = 0.84). However, at clinics offering adolescent-friendly clinic days, adolescents were nearly 2 times more likely to be virally suppressed than at facilities not offering these specialized clinic days (aOR = 1.86, 95% CI: 1.04, 3.32, P = 0.04).This study suggests that adolescent clinic days greatly improve adolescent viral load suppression and should be considered for implementation across HIV programs.

PurposeTo summarize data on computed tomographic (CT) radiation doses collected from consecutive CT examinations performed at 12 facilities that can contribute to the creation of reference levels.Materials and methodsThe study was approved by the institutional review boards of the collaborating institutions and was compliant with HIPAA. Radiation dose metrics were prospectively and electronically collected from 199 656 consecutive CT examinations in 83 181 adults and 3871 consecutive CT examinations in 2609 children at the five University of California medical centers during 2013. The median volume CT dose index (CTDIvol), dose-length product (DLP), and effective dose, along with the interquartile range (IQR), were calculated separately for adults and children and stratified according to anatomic region. Distributions for DLP and effective dose are reported for single-phase examinations, multiphase examinations, and all examinations.ResultsFor adults, the median CTDIvol was 50 mGy (IQR, 37-62 mGy) for the head, 12 mGy (IQR, 7-17 mGy) for the chest, and 12 mGy (IQR, 8-17 mGy) for the abdomen. The median DLPs for single-phase, multiphase, and all examinations, respectively, were as follows: head, 880 mGy · cm (IQR, 640-1120 mGy · cm), 1550 mGy · cm (IQR, 1150-2130 mGy · cm), and 960 mGy · cm (IQR, 690-1300 mGy · cm); chest, 420 mGy · cm (IQR, 260-610 mGy · cm), 880 mGy · cm (IQR, 570-1430 mGy · cm), and 550 mGy · cm (IQR 320-830 mGy · cm); and abdomen, 580 mGy · cm (IQR, 360-860 mGy · cm), 1220 mGy · cm (IQR, 850-1790 mGy · cm), and 960 mGy · cm (IQR, 600-1460 mGy · cm). Median effective doses for single-phase, multiphase, and all examinations, respectively, were as follows: head, 2 mSv (IQR, 1-3 mSv), 4 mSv (IQR, 3-8 mSv), and 2 mSv (IQR, 2-3 mSv); chest, 9 mSv (IQR, 5-13 mSv), 18 mSv (IQR, 12-29 mSv), and 11 mSv (IQR, 6-18 mSv); and abdomen, 10 mSv (IQR, 6-16 mSv), 22 mSv (IQR, 15-32 mSv), and 17 mSv (IQR, 11-26 mSv). In general, values for children were approximately 50% those for adults in the head and 25% those for adults in the chest and abdomen.ConclusionThese summary dose data provide a starting point for institutional evaluation of CT radiation doses.

Background The American College of Physicians strongly recommends against performing pelvic examinations in asymptomatic, nonpregnant women, citing evidence of harm (false-positive testing, unnecessary surgery) and no evidence of benefit. In contrast, the American Congress of Obstetricians and Gynecologists recommends pelvic examinations in asymptomatic women beginning at age 21 years, citing expert opinion. Objective We sought to evaluate if providing women with professional societies’ conflicting statements about pelvic examinations (recommendations and rationales) would influence their desire for a routine examination. Study Design We recruited 452 women ages 21-65 years from 2 women’s clinics to participate in a 50-minute face-to-face interview about cervical cancer screening that included a 2-phase study related to pelvic examinations. In the first phase, 262 women were asked about their desire for the examination without being provided information about professional societies’ recommendations. In the second phase, 190 women were randomized to review summaries of the American College of Physicians or American Congress of Obstetricians and Gynecologists statement followed by an interview. Results First-phase participants served as the referent: 79% (208/262) indicated they would want a routine examination if given a choice. In the second phase, a similar percentage of women randomized to the American Congress of Obstetricians and Gynecologists summary had this desire (82%: 80/97; adjusted odds ratio, 1.37; 95% confidence interval, 0.69–2.70). Women randomized to the American College of Physicians summary, however, were less likely to indicate they would opt for an examination (39%: 36/93; adjusted odds ratio, 0.12; 95% confidence interval, 0.06–0.21). Overall, 94% (179/190) believed the potential benefits and harms should be discussed prior to the examination. Conclusion Providing women with a professional society’s recommendation advising against routine pelvic examinations substantially reduced their desire to have one. Educational materials are needed to ensure women’s informed preferences and values are reflected in decisions about pelvic examinations.

Purpose To determine patient, vendor, and institutional factors that influence computed tomography (CT) radiation dose. Materials and Methods The relevant institutional review boards approved this HIPAA-compliant study, with waiver of informed consent. Volume CT dose index (CTDIvol) and effective dose in 274 124 head, chest, and abdominal CT examinations performed in adult patients at 12 facilities in 2013 were collected prospectively. Patient, vendor, and institutional characteristics that could be used to predict (a) median dose by using linear regression after log transformation of doses and (b) high-dose examinations (top 25% of dose within anatomic strata) by using modified Poisson regression were assessed. Results There was wide variation in dose within and across medical centers. For chest CTDIvol, overall median dose across all institutions was 11 mGy, and institutional median dose was 7-16 mGy. Models including patient, vendor, and institutional factors were good for prediction of median doses (R2 = 0.31-0.61). The specific institution where the examination was performed (reflecting the specific protocols used) accounted for a moderate to large proportion of dose variation. For chest CTDIvol, unadjusted median CTDIvol was 16.5 mGy at one institution and 6.7 mGy at another (adjusted relative median dose, 2.6 mGy [95% confidence interval: 2.5, 2.7]). Several variables were important predictors that a patient would undergo high-dose CT. These included patient size, the specific institution where CT was performed, and the use of multiphase scanning. For example, while 49% of patients (21 411 of 43 696) who underwent multiphase abdominal CT had a high-dose examination, 8% of patients (4977 of 62 212) who underwent single-phase CT had a high-dose examination (adjusted relative risk, 6.20 [95% CI: 6.17, 6.23]). If all patients had been examined with single-phase CT, 69% (18 208 of 26 388) of high-dose examinations would have been eliminated. Patient size, institutional-specific protocols, and multiphase scanning were the most important predictors of dose (change in R2 = 8%-32%), followed by manufacturer and iterative reconstruction (change in R2, 0.2%-15.0%). Conclusion CT doses vary considerably within and across facilities. The primary factors that influenced dose variation were multiphase scanning and institutional protocol choices. It is unknown if the variation in these factors influenced diagnostic accuracy. © RSNA, 2016.

Background The American Congress of Obstetricians and Gynecologists recommends that a pelvic examination be offered to asymptomatic women after an informed discussion with their provider. Although the adverse health outcomes that the examination averts were not delineated, the organization stated that it helps establish open communication between patients and physicians. Recent surveys have focused on obstetrician-gynecologists’ attitudes and beliefs about the examination, but the perspectives of women have not been well-characterized. Objective The purpose of this study was to better understand women’s beliefs about the purpose and value of routine pelvic examinations. Study Design We completed structured interviews with 262 women who were 21–65 years old who agreed to participate in a 50-minute interview about cervical cancer screening. Recruitment took place in outpatient women’s clinics at a public hospital and an academic medical center in San Francisco, CA. Women were shown an illustration of a bimanual pelvic examination and asked a series of closed-ended questions: if they knew why it was performed, if it reassured them of their health, and if they believed it helped establish open communication with their provider. Women were asked an open-ended question about their perception of the examination’s purpose. Multivariable logistic regression analysis was used to identify demographic predictors of responses. Results Approximately one-half of the participants (56%) stated that they knew the examination’s purpose. The most frequently cited reason was assurance of normalcy. Most of participants (82%) believed that the examination reassured them of their health. Approximately two-thirds of the participants (62%) believed that the examination helps establish open communication with their provider. In multivariate analyses, older age (≥45 years) independently predicted a higher likelihood of a belief that they knew the examination’s purpose (odds ratio, 2.9; 95% confidence interval, 1.5–5.6) and a belief that it facilitates open communication (odds ratio, 2.1; 95% confidence interval, 1.1–3.9). Non-white race also was associated with a belief that the examination helps facilitate open communication between patients and providers (odds ratio, 1.9; 95% confidence interval, 1.1–3.1). Conclusion Approximately one-half of the women who participated in our study reported not knowing the purpose of the pelvic examination, yet most of them believed it to be of some value, especially reassurance of health. To achieve shared, informed decision-making, clinicians will need to communicate better to their patients the examination’s purpose.

PurposeIn the emergency department ultrasonography is emerging as an alternative to computerized tomography for diagnosing patients with nephrolithiasis. In this multicenter randomized clinical trial we examined rates of urological referral and intervention to elucidate whether the initial diagnostic imaging modality affected the management of nephrolithiasis.Materials and methodsPatients 18 to 76 years old who presented to the emergency department with renal colic across 15 diverse treatment centers were randomized to receive abdominal ultrasonography by an emergency department physician or a radiologist, or abdominal computerized tomography. We analyzed the 90-day followup for patients diagnosed with nephrolithiasis to assess subsequent urological evaluation, procedure type and time to intervention.ResultsOf 1,666 patients diagnosed with nephrolithiasis in the emergency department 241 (14.5%) had a consultation with urology at initial presentation, 503 (30%) saw a urologist in followup and 192 (12%) underwent at least 1 urological procedure. Median time to outpatient procedure and type of procedure performed did not vary significantly among imaging groups. Most patients (78%) had computerized tomography performed before elective intervention. Patients with ultrasonography performed by an emergency department physician were 2.6 times more likely to undergo computerized tomography before intervention than those who had ultrasonography performed by a radiologist.ConclusionsPatients undergoing a urological intervention who had ultrasonography as initial imaging do not experience a significant delay to intervention or different procedure types, but the majority ultimately undergoes computerized tomography before surgery. Formal ultrasonography by a radiologist may encourage less computerized tomography preoperatively.

Decreasing the use of high-cost tests may reduce health care costs.To compare costs of care for patients presenting to the emergency department (ED) with suspected kidney stones randomized to 1 of 3 initial imaging tests.Patients were randomized to point-of-care ultrasound (POC US, least costly), radiology ultrasound (RAD US), or computed tomography (CT, most costly). Subsequent testing and treatment were the choice of the treating physician.A total of 2759 patients at 15 EDs were randomized to POC US (n=908), RAD US, (n=893), or CT (n=958). Mean age was 40.4 years; 51.8% were male.All medical care documented in the trial database in the 7 days following enrollment was abstracted and coded to estimate costs using national average 2012 Medicare reimbursements. Costs for initial ED care and total 7-day costs were compared using nonparametric bootstrap to account for clustering of patients within medical centers.Initial ED visit costs were modestly lower for patients assigned to RAD US: $423 ($411, $434) compared with patients assigned to CT: $448 ($438, $459) (P0.0001). Total costs were not significantly different between groups: $1014 ($912, $1129) for POC US, $970 ($878, $1078) for RAD US, and $959 ($870, $1044) for CT. Hospital admissions contributed over 50% of total costs, though only 11% of patients were admitted. Mean total costs (and admission rates) varied substantially by site from $749 to $1239.Assignment to a less costly test had no impact on overall health care costs for ED patients. System-level interventions addressing variation in admission rates from the ED might have greater impact on costs.

Previous studies have shown that glioma patients report allergies less frequently than controls, harbor lower atopy-associated IgE levels, and harbor different frequencies of polymorphisms in the IL13 and IL4 pathways than controls. We sought to confirm this latter result and extend the analysis to IgE levels. Glioma patients (n = 456) and controls (n = 541) were genotyped for genetic variants in IL4, IL4R, and IL13 and tested for total IgE levels (n = 248 controls and 289 cases). Among Whites, IL4 and IL4R polymorphisms and haplotypes were neither significantly associated with IgE levels in controls nor associated with glioma status. IL13 R110G and C-1112T were associated with increased IgE levels in controls (P < 0.001 and P = 0.04, respectively), and IL13 C-1112T was inversely associated with case-control status (P = 0.05, test for trend in dose model). An IL4R haplotype was borderline associated with increased risk in case-control analysis [odds ratio (OR), 1.5; 95% confidence interval (95% CI), 1.0-2.3]. In addition, a rare haplotype for IL4 was associated with decreased risk (OR, 0.23; 95% CI, 0.07-0.83), and a common haplotype in IL13 was associated with decreased risk (OR, 0.73; 95% CI, 0.53-1.00). Our data provide evidence for a role of IL13 polymorphisms on IgE levels and a role for IL4, IL4R, and IL13 haplotypes on case-control status. We did not find any evidence that the interleukin (IL) polymorphisms exerted their effect on glioma risk via their effects on IgE levels. Further exploration of immune susceptibility factors, including genetics, in glioma etiology is advisable. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1229–35)

ERCC2 and ERCC1 are important in DNA nucleotide excision repair and lie on chromosome 19q13.3 near a putative glioma suppressor region. We genotyped constitutive variants ERCC1 C8092A and ERCC2 K751Q and R156R in approximately 450 adults with glioma and 500 controls from two independent population-based series, uniformly reviewed patients’ tumors to determine histopathologic category, and determined a variety of tumor markers among astrocytic tumors. Odds ratios (ORs) for glioblastoma for those carrying two ERCC1 A alleles versus none or one were 1.67 in series 1 and 1.64 in series 2, which yielded a combined OR of 1.67 (95% CI, 0.93–3.02; P = 0.09), adjusted for age, gender, ethnicity, and series. Odds ratios for the ERCC2 variants were not consistently elevated or reduced for the two series in all cases versus controls. However, among whites, for those with ERCC2 K751Q genotype QQ versus QK/KK, the OR for nonglioblastoma histologies versus controls was 1.82 (95% CI, 0.97–3.44; P = 0.06). Also, among whites, glioma patients were significantly more likely than controls to be homozygous for variants in both ERCC1 C8092A and ERCC2 K751Q (OR, 3.2; 95% CI, 1.1–9.3). Given the numbers of comparisons made, these findings could be due to chance. However, the results might warrant clarification in additional series in conjunction with the nearby putative glioma suppressor genes (GLTSCR1 and GLTSCR2)

Background: Risk factors for adult glioma in the San Francisco Bay Area include well-known demographic features such as age and race/ethnicity, and our previous studies indicated that these characteristics are associated with the TP53 mutation status of patients' tumors. We enlarged our study to assess the relationships of risk factors with TP53 as well as epidermal growth factor receptor (EGFR) and murine double minute-2 (MDM2) gene amplification and expression and the germ line Leu84Phe polymorphism in the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT). MGMT expression may depend on the TP53 status of cells.Methods: Molecular analyses were carried out on 556 incident astrocytic tumors. MGMT genotype data were collected on germ line DNA from 260 of these cases.Results: The tumor data confirm the inverse relationships between TP53 mutation and MDM2 (P = 0.04) or EGFR (P = 0.004) amplification and that patients whose tumors contain TP53 mutations are younger than those without (P < 0.001). Although there was little difference in age of patient by EGFR amplification or expression among glioblastoma multiforme cases, EGFR gene amplification was associated with much older age of onset of anaplastic astrocytoma; for example, EGFR-amplified anaplastic astrocytoma cases were on average 63 years old compared with 48 years for nonamplified cases (P = 0.005). An increased prevalence of TP53 mutation positive glioblastoma multiforme was noted among nonwhites (African American and Asian) compared with whites (Latino and non-Latino; P = 0.004). Carriers of the MGMT variant 84Phe allele were significantly less likely to have tumors with TP53 overexpression (odds ratio, 0.30; 95% confidence interval, 0.13-0.71) and somewhat less likely to have tumors with any TP53 mutation (odds ratio, 0.47; 95% confidence interval, 0.13-1.69) after adjusting for age, gender, and ethnicity. Interestingly, EGFR gene amplification and EGFR protein overexpression were also inversely associated with the MGMT 84Phe allele.Conclusions: Our results are consistent with ethnic variation in glioma pathogenesis. The data on MGMT show that an inherited factor involving the repair of methylation and other alkylation damage, specifically to the O6 position of guanine, may be associated with the development of tumors that proceed in their development without TP53 mutations or accumulation of TP53 protein and possibly also those that do not involve amplification of the EGFR locus.

Introduction: The multidrug resistance-1 (MDR1) gene encodes a pump that prevents potentially carcinogenic substances from crossing the blood-brain barrier. We compare adult glioma cases and controls for the C3435T polymorphism that has been associated with reduced MDR1 expression. Methods: Adult glioma in the San Francisco Bay area and population-based controls were identified between 1991–1994 and 1997–1999. Genotyped cases (n = 458) and controls (n = 528) were compared using logistic regression controlling for age, gender and ethnicity, with later stratification by ethnicity, gender and histology. Results: With CC as the referent, the TT genotype was nonsignificantly less frequent among cases compared to controls (OR, 0.87; 95% CI: 0.6, 1.2). After stratification, only male glioblastoma was associated with TT genotype (OR, 0.51; 95% CI: 0.3, 1.0). Conclusions: Although the C3435T polymorphism does not appear to be associated with other types of glioma, we cannot rule out that this MDR1 polymorphism may be associated with glioblastoma among men.

We and others have reported previously that adults with glioma are 1.5- to 4-fold less likely than controls to report a variety of allergic conditions. The consistent nature of this relationship calls for a biological explanation so that preventative or therapeutic modalities can be explored. We enrolled 403 newly diagnosed adult glioma cases in the San Francisco Bay Area over a 3-year period using a population-based cancer registry and 402 age/gender/ethnicity frequency-matched controls identified via random digit dialing. We assessed total, food-specific, and respiratory-specific IgE in available case (n = 228) and control (n = 289) serum samples. IgE levels were associated with gender, age, smoking status, and ethnicity among cases and/or controls. Among the cases, IgE levels were not associated with aspects of glioma therapy including radiation, chemotherapy, or tumor resection. Total IgE levels were lower in cases than controls: age/gender/ethnicity/education/smoking-adjusted odds ratio (OR) for elevated versus normal total IgE was 0.37 [95% confidence interval (CI), 0.22–0.64]. For the food panel, OR was 0.12 (95% CI, 0.04–0.41). For the respiratory panel, OR was 0.76 (95% CI, 0.52–1.1). Among respiratory allergies, late age of onset (>12 years) but not IgE levels defined a group with strong associations with risk (OR, 0.50; 95% CI, 0.33–0.75). These results corroborate and strengthen our findings of an inverse association between allergic reactions and glioma by showing a relationship with a biomarker for allergy and cancer for the first time. Furthermore, the results indicate a complex relationship between allergic disease and glioma risk that varies by allergen and allergic pathology.

Evidence from epidemiologic and experimental studies suggests that use of nonsteroidal antiinflammatory drugs (NSAIDs) reduces risk of colon and breast cancer. The association between use of aspirin and other NSAIDs and risk of adult glioblastoma multiforme (GBM) was evaluated among 236 incident GBM cases and 401 population-based controls frequency-matched on age, gender, and ethnicity from the San Francisco Bay Area Adult Glioma Study. Cases (or proxies) and controls were interviewed in person between May 1997 and August 2000. Cases with self-reported GBM reported less use of at least 600 pills of all types of NSAIDs combined during the 10-year prediagnostic period than did controls (odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.3, 0.8). Findings were consistent for aspirin (OR = 0.51, 95% CI: 0.3, 0.8), ibuprofen (OR = 0.41, 95% CI: 0.2, 0.8), and naproxen/other NSAIDs (OR = 0.34, 95% CI: 0.1, 0.8). GBM cases also reported less use of acetaminophen than did controls (OR = 0.51, 95% CI: 0.3, 1.0). Eliminating participants who initiated NSAID use within 2 years of diagnosis yielded similar results. These findings show an inverse association between NSAID use and GBM. Further studies are warranted to determine whether NSAIDs might be effective in the inhibition of GBM development or progression. acetaminophen; anti-inflammatory agents, non-steroidal; case-control studies; glioblastoma Abbreviations: CI, confidence interval; NSAID(s), nonsteroidal antiinflammatory drug(s); OR, odds ratio.

Background This report examines generally recognized breast cancer risk factors and years of residence in Marin County, California, an area with high breast cancer incidence and mortality rates. Methods Eligible women who were residents of Marin County diagnosed with breast cancer in 1997–99 and women without breast cancer obtained through random digit dialing, frequency-matched by cases' age at diagnosis and ethnicity, participated in either full in-person or abbreviated telephone interviews. Results In multivariate analyses, 285 cases were statistically significantly more likely than 286 controls to report being premenopausal, never to have used birth control pills, a lower highest lifetime body mass index, four or more mammograms in 1990–94, beginning drinking after the age of 21, on average drinking two or more drinks per day, the highest quartile of pack-years of cigarette smoking and having been raised in an organized religion. Cases and controls did not significantly differ with regard to having a first-degree relative with breast cancer, a history of benign breast biopsy, previous radiation treatment, age at menarche, parity, use of hormone replacement therapy, age of first living in Marin County, or total years lived in Marin County. Results for several factors differed for women aged under 50 years or 50 years and over. Conclusions Despite similar distributions of several known breast cancer risk factors, case-control differences in alcohol consumption suggest that risk in this high-risk population might be modifiable. Intensive study of this or other areas of similarly high incidence might reveal other important risk factors proximate to diagnosis.

BackgroundThere is a lack of consensus about whether the initial imaging method for patients with suspected nephrolithiasis should be computed tomography (CT) or ultrasonography.MethodsIn this multicenter, pragmatic, comparative effectiveness trial, we randomly assigned patients 18 to 76 years of age who presented to the emergency department with suspected nephrolithiasis to undergo initial diagnostic ultrasonography performed by an emergency physician (point-of-care ultrasonography), ultrasonography performed by a radiologist (radiology ultrasonography), or abdominal CT. Subsequent management, including additional imaging, was at the discretion of the physician. We compared the three groups with respect to the 30-day incidence of high-risk diagnoses with complications that could be related to missed or delayed diagnosis and the 6-month cumulative radiation exposure. Secondary outcomes were serious adverse events, related serious adverse events (deemed attributable to study participation), pain (assessed on an 11-point visual-analogue scale, with higher scores indicating more severe pain), return emergency department visits, hospitalizations, and diagnostic accuracy.ResultsA total of 2759 patients underwent randomization: 908 to point-of-care ultrasonography, 893 to radiology ultrasonography, and 958 to CT. The incidence of high-risk diagnoses with complications in the first 30 days was low (0.4%) and did not vary according to imaging method. The mean 6-month cumulative radiation exposure was significantly lower in the ultrasonography groups than in the CT group (P

Background Urolithiasis (kidney stones) is a common reason for Emergency Department (ED) visits, accounting for nearly 1% of all visits in the United States. Computed tomography (CT) has become the most common imaging test for these patients but there are few comparative effectiveness data to support its use in comparison to ultrasound. This paper describes the rationale and methods of STONE (Study of Tomography Of Nephrolithiasis Evaluation), a pragmatic randomized comparative effectiveness trial comparing different imaging strategies for patients with suspected urolithiasis. Methods STONE is a multi-center, non-blinded pragmatic randomized comparative effectiveness trial of patients between ages 18 and 75 with suspected nephrolithiasis seen in an ED setting. Patients were randomized to one of three initial imaging examinations: point-of-care ultrasound, ultrasound performed by a radiologist or CT. Participants then received diagnosis and treatment per usual care. The primary aim is to compare the rate of severe SAEs (Serious Adverse Events) between the three arms. In addition, a broad range of secondary outcomes was assessed at baseline and regularly for six months post-baseline using phone, email and mail questionnaires. Results Excluding 17 patients who withdrew after randomization, a total of 2759 patients were randomized and completed a baseline questionnaire (n = 908, 893 and 958 in the point-of-care ultrasound, radiology ultrasound and radiology CT arms, respectively). Follow-up is complete, and full or partial outcomes were assessed on over 90% of participants. Conclusions The detailed methodology of STONE will provide a roadmap for comparative effectiveness studies of diagnostic imaging conducted in an ED setting.

Purpose: Our aim was to discover possible inherited factors associated with glioblastoma age at diagnosis and survival. Although new genotyping technologies allow greatly expanded exploration of such factors, they pose many challenges. Experimental Design: In this pilot study, we (a) genotyped 112 newly diagnosed glioblastoma patients ascertained through a population-based study (group 1) with the ParAllele assay panel of ∼10,000 nonsynonymous coding single-nucleotide polymorphisms (SNP), (b) used several statistical and bioinformatic techniques to identify 17 SNPs potentially related to either glioblastoma age at diagnosis or survival, and (c) genotyped 16 of these SNPs using conventional PCR methods in an independent group of 195 glioblastoma patients (group 2). Results: In group 2, only one of the 16 SNPs, rs8057643 (located on 16p13.2), was significantly associated with glioblastoma age at diagnosis (nominal P = 0.0017; Bonferroni corrected P = 0.054). Median ages at diagnosis for those with 0, 1, or 2 T alleles were 66, 57, and 59 years in group 1 and 64, 57, and 55 years in group 2 (combined P = 0.001). Furthermore, Cox regression analyses of time to death with number of T alleles adjusted for gender and patient group yielded a hazard ratio of 0.82 (95% confidence interval, 0.68-0.98; P = 0.03). Conclusions: Although limited by a relatively small sample size, this pilot study, using well-characterized, unambiguous disease characteristics, illustrates the necessity of independent replication owing to the likelihood of false positives. Several other challenges are discussed, including attempts to incorporate information on the potential functional importance of SNPs in genome-disease association studies.

In population-based glioma patients, we examined survival in relation to potentially pertinent constitutive polymorphisms, serologic factors, and tumor genetic and protein alterations in epidermal growth factor receptor (EGFR), MDM2, and TP53. Subjects were newly diagnosed adults residing in the San Francisco Bay Surveillance Epidemiology and End Results Area during 1991 to 1994 and 1997 to 1999 with central neuropathology review (n = 873). Subjects provided blood for serologic studies of IgE and IgG to four herpes viruses and constitutive specimens for genotyping 22 polymorphisms in 13 genes (n = 471). We obtained 595 of 697 astrocytic tumors for marker studies. We determined treatments, vital status, and other factors using registry, interview, medical record, and active follow-up data. Cox regressions for survival were adjusted for age, gender, ethnicity, study series, resection versus biopsy only, radiation, and chemotherapy. Using a stringent P < 0.001, glioma survival was associated with ERCC1 C8092A [hazard ratio (HR), 0.72; 95% confidence limits (95% CL), 0.60-0.86; P = 0.0004] and GSTT1 deletion (HR, 1.64; 95% CL, 1.25-2.16; P = 0.0004); glioblastoma patients with elevated IgE had 9 months longer survival than those with normal or borderline IgE levels (HR, 0.62; 95% CL, 0.47-0.82; P = 0.0007), and EGFR expression in anaplastic astrocytoma was associated with nearly 3-fold poorer survival (HR, 2.97; 95% CL, 1.70-5.19; P = 0.0001). Based on our and others' findings, we recommend further studies to (a) understand relationships of elevated IgE levels and other immunologic factors with improved glioblastoma survival potentially relevant to immunologic therapies and (b) determine which inherited ERCC1 variants or other variants in the 19q13.3 region influence survival. We also suggest that tumor EGFR expression be incorporated into clinical evaluation of anaplastic astrocytoma patients. (Cancer Res 2006; 66(8): 4531-41)

Introduction: Conflicting findings have been reported for associations of primary brain tumors and constitutive polymorphisms in glutathione-S-transferases (GSTs). Methods: We genotyped population-based cases ascertained through rapid case ascertainment and controls identified through random-digit dialing in the San Francisco Bay Area between 1991–1994 (series 1) and 1997–2000 (series 2) for homozygous deletion or presence of GSTM1 (μ) and GSTT1 (𝛉) genes and for two variants in GSTP (π i.e., I105V and A114V). A single neuropathologist for each series determined histological type. Blood or buccal swabs were obtained from about 53.8% of cases and 64.6% of controls. Case-control genotype frequencies were compared overall and by histological type and by age group (≤40, 41–60, and >60), gender, and series. Results: Among whites, 367 cases (179 glioblastoma, 62 other astrocytoma, 94 oligodendroglioma or oligoastrocytoma, and 32 other histologies) and 428 controls were genotyped for all four polymorphisms. Multivariate logistic models including the four GST loci, age, gender (except in gender-specific models), and series showed no significant case-control differences for GST genotypes. Among cases over age 60, prevalence of GSTP I105V Val/Val was 6.4% of 108 cases versus 15% of 176 controls [odds ratio (OR) 0.38; 95% confidence interval (CI) 0.15–0.93; P = 0.03]. GSTT1 deletion was nearly significantly more common among glioblastoma cases with tumor p53 mutation than for those whose tumors did not have p53 mutation (OR 2.8; 95% CI 0.93–8.4; P = 0.07). Conclusions: There is little evidence for associations of GST variants with major glioma histological subtypes, but GST polymorphisms might influence certain molecular subtypes or progression.

Background Past studies have shown that women with abnormal cytology or epithelial cells in nipple aspirate fluid (NAF) have an increased relative risk (RR) of breast cancer when compared to women from whom NAF was attempted but not obtained (non-yielders). This study analyzed NAF results from a group of women seen in a breast clinic between 1970–1991 (N = 2480). Our analysis presented here is an aggregate of two sub-groups: women with questionnaire data (n = 712) and those with NAF visits beginning in 1988 (n = 238), the year in which cancer case information was uniformly collected in California. Methods Cytological classification was determined for a group of 946 women using the most abnormal epithelial cytology observed in fluid specimens. Breast cancer incidence and mortality status was determined through June 2006 using data from the California Cancer Registry, California Vital Statistics and self-report. We estimated odd ratios (ORs) for breast cancer using logistic regression analysis, adjusting for age. We analyzed breast cancer risk related to abnormality of NAF cytology using non-yielders as the referent group and breast cancer risk related to the presence or absence of epithelial cells in NAF, using non-yielders/fluid without epithelial cells as the referent group. Results Overall, 10% (93) of the 946 women developed breast cancer during the follow-up period. Age-adjusted ORs and 95% confidence intervals (C.I.) compared to non-yielders were 1.4 (0.3 to 6.4), 1.7 (0.9 to 3.5), and 2.0 (1.1 to 3.6) for women with fluid without epithelial cells, normal epithelial cells and hyperplasia/atypia, respectively. Comparing the presence or absence of epithelial cells in NAF, women with epithelial cells present in NAF were more likely to develop breast cancer than non-yielders or women with fluid without epithelial cells (RR = 1.9, 1.2 to 3.1). Conclusion These results support previous findings that 1) women with abnormal epithelial cells in NAF have an increased risk of breast cancer when compared to non-yielders or women with normal epithelial cells in NAF and 2) women with epithelial cells present in NAF have an increased risk of breast cancer when compared to non-yielders or women who had NAF without epithelial cells present.

Study objective The STONE score is a clinical decision rule that classifies patients with suspected nephrolithiasis into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone. We evaluate the STONE score in a multi-institutional cohort compared with physician gestalt and hypothesize that it has a sufficiently high specificity to allow clinicians to defer computed tomography (CT) scan in patients with suspected nephrolithiasis. Methods We assessed the STONE score with data from a randomized trial for participants with suspected nephrolithiasis who enrolled at 9 emergency departments between October 2011 and February 2013. In accordance with STONE predictors, we categorized participants into low-, moderate-, or high-score groups. We determined the performance of the STONE score and physician gestalt for ureteral stone. Results Eight hundred forty-five participants were included for analysis; 331 (39%) had a ureteral stone. The global performance of the STONE score was superior to physician gestalt (area under the receiver operating characteristic curve=0.78 [95% confidence interval {CI} 0.74 to 0.81] versus 0.68 [95% CI 0.64 to 0.71]). The prevalence of ureteral stone on CT scan ranged from 14% (95% CI 9% to 19%) to 73% (95% CI 67% to 78%) in the low-, moderate-, and high-score groups. The sensitivity and specificity of a high score were 53% (95% CI 48% to 59%) and 87% (95% CI 84% to 90%), respectively. Conclusion The STONE score can successfully aggregate patients into low-, medium-, and high-risk groups and predicts ureteral stone with a higher specificity than physician gestalt. However, in its present form, the STONE score lacks sufficient accuracy to allow clinicians to defer CT scan for suspected ureteral stone.