bluuebunny/crossref_metadata_2025 huggingface dataset:
Satisfaction with a Quitline-based Smoking Cessation Intervention among Cancer Survivors
Authors: Weaver KE , Kaplan S , Griffin L , Urbanic J , Zbikowski S , Danhauer SC
Published: April 2015

Continued smoking after diagnosis jeopardizes cancer survivors' health and well-being. Quitline-based smoking cessation treatment is convenient, widely available and free, yet the appropriateness of this treatment approach for survivors is not known. We assessed satisfaction among participants in an enhanced quitline intervention as part of a randomized clinical trial assessing feasibility. Methods: We recruited cancer survivors through the NCI Community Clinical Oncology Program (CCOP) network within 6 months of treatment who smoked within the last 7 days and randomized them 2:1 to an enhanced quitline- based intervention (brief in-person motivational interviewing counseling session, quitline telephone counseling, 6 weeks of nicotine replacement patches) or usual care. We collected treatment satisfaction data and self-reported smoking status at 12 weeks and confirmed smoking status for reported non-smokers using a semi-quantitative urinary cotinine assessment. Results: We enrolled 146 survivors (75% female, 79% non-Hispanic white, mean age = 58 years). At entry, survivors reported smoking an average of 15 cigarettes per day; 77% reported smoking within 30 minutes of awakening. Assessments were completed by 63% of the quitline group and 75% of the usual care group at 12 weeks (P > 0.05). 83% of participants in the intervention arm (n = 98) completed at least one quitline call, and 18% completed ≥3 calls. Use of nicotine patches was 61% in the quitline group and 42% in usual care. Quitline participants were generally satisfied with both the in-person counseling (mean satisfaction score = 4.2 (SD = 1.0), on 1–5 scale) and the quitline telephone counseling (mean satisfaction score = 3.4 (SD = 1.3)). 87% would recommend the quitline program to others. Self-reported 7-day point prevalence cessation was 26% in the quitline group and 17% in the usual care arm (P = 0.33). Conclusions: An enhanced quitline smoking cessation intervention appears to be acceptable to cancer survivors and to result in a trend towards slightly higher cessation at 12 weeks. Increased efforts to retain survivors in treatment and encourage the use of nicotine replacement may be necessary to increase the impact of this intervention approach.
Weight Lifting and Physical Function among Breast Cancer Survivors: A Post Hoc Analysis of a Randomized Controlled Trial
Authors: Brown JC , Schmitz KH
Published: April 2015

Breast cancer survivors may experience deterioration of physical function. This is important because poor physical function may be associated with premature mortality, injurious falls, bone fracture, and disability. We conducted a post hoc analysis to explore the potential efficacy of slowly-progressive weight lifting to reduce the incidence of physical function deterioration among breast cancer survivors. Methods: Between October 2005 and August 2008, we conducted a single-blind, 12-month, randomized controlled trial of twice-weekly slowly-progressive weight lifting or standard care among 295 non-metastatic breast cancer survivors. In this post hoc analysis of data from the Physical Activity and Lymphedema Trial, we examined incident deterioration of physical function after 12-months, defined as a ≥10-point decline in the physical function subscale of the Medical Outcomes Short-Form 36-item (SF-36) questionnaire. We calculated the relative risk (RR) and 95% confidence interval (95% CI) using an unadjusted generalized linear model. Results: Study participants were 56 ± 9 years old (range 36–80). Median adherence to the weight lifting protocol was 81% over 12-months. As compared with the control group, the weight lifting group had greater improvements in upper- and lower-body strength at 12-months (both comparisons P < 0.001). The proportion of participants who experienced incident physical function deterioration after 12-months was 16.3% (24/147) in the control group and 8.1% (12/148) in the weight lifting group [RR: 0.49 (95% CI, 0.25–0.96); P = 0.04]. No serious or unexpected adverse events occurred that were related to weight lifting. Conclusion: Slowly-progressive weight lifting compared to standard care reduced the incidence of physical function deterioration among breast cancer survivors. These data are hypothesis generating. Future studies should directly compare the efficacy of weight lifting to other modalities of exercise, such as brisk walking, to appropriately inform the development of a confirmatory study designed to preserve physical function among breast cancer survivors.
Prediagnostic Body-mass Index, Smoking and Prostate Cancer Survival: A Cohort Consortium Study of Over 10,000 White Men with Prostate Cancer
Authors: Yuan C , Cao Y , Chavarro J , Lindstrom S , Qiu W , Willett W , Hsing A , Kibel A , Rosner B , Stampfer M , Kra P , Ma J
Published: April 2015

Few prospective studies have investigated the relationship between pre-diagnostic obesity, smoking and prostate cancer (PCa) survival by timing of measurement, by age at diagnosis, and evaluated the interaction between obesity and smoking. METHODS: We conducted a multinational survival analysis among 10,106 PCa cases (1,007 PCa deaths and 2,893 total deaths) from eight cohorts with an average of 8.2 years of follow up. Hazard ratio (HR) of PCa death was estimated using Cox proportional hazard model, adjusting for age, alcohol intake, diabetes status, cohort and duration between baseline and diagnosis and subsequently adjusted for tumor stage and grade. RESULTS: Higher prediagnostic BMI was related to higher risk of PCa death. With each 5 kg/m2 increase in BMI, the multivariate HR for PCa death was 1.08 (95% CI, 1.02–1.14) among overall participants (p-trend = 0.01) and 1.33 (95% CI, 1.18–1.51) among never or former smokers (p-trend < 0.001). This positive trend for PCa mortality was mainly observed among men with BMI measured more than 5 years before diagnosis, and among those age >65 years old at diagnosis. Compared with never smokers, current smokers had significantly elevated risk of PCa death, with a HR of 1.92 (95% CI, 1.52–2.43) regardless of the time of measurement, age at diagnosis and BMI. After further adjusting for tumor stage and grade, the association between BMI, smoking and PCa death was attenuated but remained statistical significant. CONCLUSIONS: In this consortium study of eight large cohorts, smoking and overweight/obesity before diagnosis were significant predictors for subsequent PCa-specific mortality. Smoking significantly modifies the association of BMI and PCa-specific mortality.
Decision Making about Contralateral Prophylactic Mastectomy Among BRCA1/2 Noncarriers with Newly-diagnosed Breast Cancer: Examining Cognitive, Emotional, and Sociodemographic Influences
Authors: Hamilton JG , Salerno M , Amoroso K , Sheehan M , Harlan Fleischut M , Glogowski E , Siegel B , Arnold AG , Salo-Mullen EE , Hay J , Offit K , Robson ME
Published: April 2015

Pre-surgical BRCA1/2 genetic testing provides valuable risk information to guide a newly-diagnosed breast cancer patient's decision about whether to have a contralateral prophylactic mastectomy (CPM) to reduce her future risk of cancer in her unaffected breast. Although BRCA1/2 mutation noncarriers face a much lower objective ten-year risk of developing contralateral disease (approximately 3–10%) as compared to the risk of BRCA1/2 mutation carriers (27–37%), some noncarriers still choose to undergo a CPM. The psychosocial factors that motivate this decision are not well understood and warrant investigation. Thus, as part of a prospective study of pre-surgical BRCA1/2 testing, we examined the frequency and psychosocial correlates of the decision to undergo a CPM among newly-diagnosed breast cancer patients who were identified as BRCA1/2 mutation noncarriers. Self-report questionnaire data from 90 BRCA1/2 noncarriers (median age = 43 years, range = 29–59) were analyzed. A sizeable minority of the BRCA1/2 noncarriers (24.4%) chose to undergo a CPM after learning their mutation status (compared to 88% of the 8 BRCA1/2 carriers in the sample). Both bivariate and multivariable analyses indicated that perceiving that one's physician had recommended CPM (OR = 11.17, P = 0.007), perceiving greater risk for contralateral breast cancer (OR = 6.46, P = 0.02), and perceiving greater pros of CPM (OR = 1.37, P = 0.004) were all significantly associated with noncarriers' decision to undergo CPM. However, factors including age, Ashkenazi Jewish ethnicity, breast cancer-related distress, perceived cons of CPM, and decisional conflict regarding CPM were not related to the CPM decision (all ps > 0.05). Results demonstrate that although noncarriers' decision making regarding CPM was unrelated to sociodemographic and emotional factors, their cognitive perceptions of contralateral disease risk, surgical benefits, and physician recommendations were particularly important. Future studies should examine the content of patient-physician communication regarding CPM and hereditary risk in greater detail, and explore how these conversations shape and interact with women's past experiences, emotions, and beliefs to influence their cancer prevention decisions.
E-cigarette and Traditional Cigarette Use Among Smokers During Hospitalization and 6 Months Later
Authors: Harrington KF , Cheong J , Hendricks S , Kohler C , Bailey WC
Published: April 2015

Use of electronic nicotine delivery systems, most commonly called e-cigarettes (e-cigs,) has been rising over the past few years, with the greatest use among traditional cigarette smokers. The utility and harm of this group of emerging tobacco products are under debate. While some propose them as novel tobacco cessation tools, others decry their potential for sustained addiction and negative health effects. We examined smokers' e-cig use and smoking behaviors at hospitalization and 6 months later. Methods: 979 smokers hospitalized at a tertiary care medical center were recruited to a longitudinal observational study and provided baseline data during hospitalization and 6-months later. Past 30-day (current) e-cig use and smoking rates at both baseline and 6-month follow-up were examined with t-tests. Chi square test examined baseline e-cig use and 6-month smoking status. Results: 823 (84.1%) participants provided data at both time points: mean age was 46 years; 53.6% were White, 44.0% were Black, and 2.5% other; 22.5% had less than a high school degree, 38.8% had a high school diploma/GED, and 38.7% had some college or more; 30.8% were married/domestic partner and 53.6% were male. Current e-cig use was reported by 171 (20.7%) at baseline and 246 (29.9%) at 6-month follow- up, with 98 (11.9%) reporting current e-cig use at both time points. At 6-months follow- up, 12.2% of baseline current e-cig users vs. 13.4% of baseline non-users reported quitting smoking (P = 0.80), with 22% of baseline e-cig users who quit still using e-cigs at 6–months follow-up. Baseline current e-cig users reported higher daily cigarette consumption (14.1 vs. 11.9; P = 0.010) at baseline but not 6-months later (10.3 vs. 9.8; P = 0.619); whereas, continuing smokers with current e-cig use at 6 months follow-up reported fewer cigarettes per day (8.4 vs. 10.5; P = 0.008). Conclusions: Among adult smokers, current e-cig use at hospitalization was associated with higher cigarette consumption at baseline but was not predictive of quitting or consumption (among continuing smokers) at 6-months follow-up. Further, current e-cig use at 6 months was associated with a greater reduction in cigarettes smoked per day among continuing smokers at 6-months after hospitalization.
Statewide Vaccine Registry Data Indicate High Number of Missed Opportunities for the HPV Vaccine Among Eligible Girls
Authors: Kepka D , Balch A , Warner E , Spigarelli M
Published: April 2015

This study investigates the rate of missed opportunities for the HPV vaccine among eligible girls using statewide vaccine registry data. Methods: Using data from the Utah Statewide Immunization Information System (USIIS) from 2008–2012 for approximately 55,000 girls ages 11–18, we assessed the frequency of missed opportunities (receipt of other recommended vaccinations such as TDap, MCV4, and/or flu and not the HPV vaccine) among eligible female patients for the HPV vaccine. USIIS is a free, confidential, web-based information system that contains immunization histories for Utah residents of all ages. Records of all persons born in Utah since 1998 are in USIIS. USIIS is designed to help enrolled healthcare providers track immunization records for patient care by consolidating immunizations from enrolled providers into one centralized record. Vaccine administration from 86% of healthcare providers in Utah is reported to USIIS. USIIS data used for the study include date of birth, age, gender, ethnicity and race, zip code, and date and type of vaccine received. Descriptive statistics and chi- square tests were used to assess rate of missed opportunities for the HPV vaccine and associated demographic factors. Results: Approximately 65% of preteens (ages 11–12; N = 2,593) and 32% of female teens (ages 13–18; N = 4,937) had a missed opportunity for the HPV vaccine between years 2008–2012 in Utah (P < 0.001). Race and ethnicity related to rates of missed opportunities for the HPV vaccine among all girls ages 11–18 (Whites = 36%, N = 2,454; Hispanics = 21%, N = 254) (P < 0.001). Rural and urban locations were also associated with rates of missed opportunities for the HPV vaccine (urban = 31%, N = 4,448; large rural town = 42%, N = 202) (P < 0.001). Conclusions: For more than eight years, a vaccine to prevent cervical and other HPV-related cancers has been available, yet receipt of the 3-dose HPV vaccine in the United States is far below national goals for girls (33% vs. 80%; actual vs. target). Using statewide vaccine registry data, our study demonstrates that administering the HPV vaccine when providing other recommended adolescent vaccinations may dramatically improve rates of HPV vaccination among girls in a state with low HPV vaccine uptake. In addition, targeting rural communities and non-Hispanic White patients may further reduce missed opportunities.
Charitable Food Distribution Sites Offer Novel Opportunities for Cancer Prevention Research and Intervention Among Vulnerable, Hard-to-reach, and Underserved Populations
Authors: Higashi RT , Craddock Lee SJC , Leonard T , Cuate E , Pruitt SL
Published: April 2015

People who live in food-insecure households face significant unmet health needs. At the same time, this population may be under-represented in clinical research studies because of the population's limited and intermittent engagement with the health care system. We describe preliminary results of a research partnership between UT Southwestern Medical Center (UTSW) and Crossroads Community Services (CCS), the largest charitable food distributor of the North Texas Food Bank. The goal of the study is to improve understanding of this population's health- and mammography-related needs, knowledge and service utilization. Eight structured focus groups were conducted in English (n = 4) and Spanish (n = 4) at CCS. Discussions focused on 13 open-ended questions designed to solicit group communication about members' health status, healthcare access, mammography awareness and utilization, and attitudes toward participation in future health research. Participants included 42 CCS clients, about 90% of whom were Hispanic or African-American women. Key findings include: (1) Participants reported multiple co-morbid conditions among themselves and household members, yet utilization of health services was cost-dependent and often limited to emergency triage. (2) Many participants did not know what a mammogram was and utilization was closely linked to having health insurance, which most did not. (3) Despite reporting numerous daily life challenges, the majority were interested in participating in future research-related focus groups as a means of communicating their health needs and obtaining information and emotional support from peers. Recruitment from charitable food distribution sites will target a high-need, underserved population. The community-academic partnership between CCS and UTSW has created a robust foundation for cancer prevention research that has already produced important insights about the population's needs and willingness to participate in research. Ongoing research is focused on implementing longitudinal health assessments of CCS clients. These data will be used to guide future interventions to increase awareness and utilization of cancer prevention services, e.g. mammography, in a population facing multiple barriers to care.
Associations of Obesity with Prostate Cancer Risk Differ Between U.S. African-American and Non-Hispanic White Men: Results from the Selenium and Vitamin E Cancer Prevention Trial
Authors: Barrington WE , Schenk JM , Etzioni R , Arnold KB , Neuhouser ML , Thompson IM , Lucia MS , Kristal AR
Published: April 2015

African-American (AA) men have the highest rates of prostate cancer incidence and mortality in the US. Understanding underlying reasons for this disparity could identify preventive interventions important to AA men. PURPOSE: To determine whether the association of obesity with prostate cancer risk differs between AA and non-Hispanic white (NHW) men and whether obesity modifies the excess risk associated with AA race. METHODS: This is a prospective study among 3398 AA and 22673 NHW men who participated in the Selenium and Vitamin E Cancer Prevention Trial (2001–2011). Using Cox regression, we estimated hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) associated with AA and NHW race and body mass index (BMI) [kg/m2] on total, low- (Gleason score <7), and high-grade (Gleason score ≥7) prostate cancer incidence while adjusting for relevant covariates. RESULTS: There were 270, 148, and 88 cases of total, low-, and high-grade prostate cancers among AA men and a corresponding 1453, 898, and 441 cases in NHW men (median follow-up of 5.6 years). BMI was not associated with risk of total cancer among NHW men, but was positively associated with risk among AA men (BMI < 25 kg/m2 vs. ≥35 kg/m2, HR = 1.49; 95% CI, 0.95–2.34; Ptrend = 0.03). Consequently, the risk associated with AA race increased from 28% (HR = 1.28; 95% CI, 0.91–1.80) among men with BMI < 25 kg/m2 to 103% (HR = 2.03; 95% CI, 1.38–2.98) among AA men with BMI≥35 kg/m2 (Ptrend = 0.03). BMI was inversely associated with low-grade prostate cancer risk among NHW men (BMI < 25 kg/m2 vs. ≥35 kg/m2, HR = 0.80; 95% CI, 0.58–1.09; Ptrend = 0.02), but positively associated with risk among AA men (BMI < 25 kg/m2 vs. ≥35 kg/m2, HR = 1.77; 95% CI, 1.14–2.76; Ptrend = 0.05). BMI was positively associated with risk of high-grade prostate cancer in both NHW (BMI < 25 kg/m2 vs. ≥35 kg/m2, HR = 1.33; 95% CI, 0.90–1.97; Ptrend = 0.01) and AA men (BMI < 25 kg/m2 vs. ≥35 kg/m2, HR = 1.81; 95% CI, 0.79–4.11; Ptrend = 0.02), but associations were not significantly different. CONCLUSION: Obesity is more strongly associated with increased prostate cancer risk among AA than NHW men and reducing obesity among AA men could reduce the racial disparity in cancer incidence. Research is needed to test mechanisms underpinning these associations.
Prevalence of Major Risk Factors and Use of Screening Tests for Cancer in the United States
Authors: Fedewa Stacey A. , Sauer Ann Goding , Siegel Rebecca L. , Jemal Ahmedin
Published: April 2015

Much of the suffering and death from cancer could be prevented by more systematic efforts to reduce tobacco use, improve diet, increase physical activity, reduce obesity, and expand the use of established screening tests. Monitoring the prevalence of cancer risk factors and screening is important to measure progress and strengthen cancer prevention and early detection efforts. In this review article, we provide recent prevalence estimates for several cancer risk factors, including tobacco, obesity, physical activity, nutrition, ultraviolet radiation exposure as well as human papillomavirus and hepatitis B vaccination coverage and cancer screening prevalence in the United States. In 2013, cigarette smoking prevalence was 17.8% among adults nationally, but ranged from 10.3% in Utah to 27.3% in West Virginia. In addition, 15.7% of U.S. high school students were current smokers. In 2011–2012, obesity prevalence was high among both adults (34.9%) and adolescents (20.5%), but has leveled off since 2002. About 20.2% of high school girls were users of indoor tanning devices, compared with 5.3% of boys. In 2013, cancer screening prevalence ranged from 58.6% for colorectal cancer to 80.8% for cervical cancer and remains low among the uninsured, particularly for colorectal cancer screening where only 21.9% of eligible adults received recommended colorectal cancer screening. Cancer Epidemiol Biomarkers Prev; 24(4); 637–52. ©2015 AACR.
Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate–Treated Castration-Resistant Prostate Cancer Patients
Authors: Xu Xu S. , Ryan Charles J. , Stuyckens Kim , Smith Matthew R. , Saad Fred , Griffin Thomas W. , Park Youn C. , Yu Margaret K. , Vermeulen An , Poggesi Italo , Nandy Partha
Published: April 2015

Purpose: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA).

Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model.

Results: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival.

Conclusions: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. Clin Cancer Res; 21(14); 3170–7. ©2015 AACR.
CCR 20th Anniversary Commentary: In Search of Cetuximab's First Indication—Combination Therapy with Irinotecan in Colorectal Cancer
Authors: Hicklin Daniel J.
Published: April 2015

The research article by Prewett and colleagues, published in the May 1, 2002, issue of Clinical Cancer Research, provided important translational data that extended earlier preclinical and clinical studies with the human–murine chimeric anti-EGFR monoclonal antibody C225. Subsequent clinical trials with C225 led to the demonstration of its efficacy in combination with irinotecan and regulatory approval for the treatment of metastatic colorectal cancer. Clin Cancer Res; 21(7); 1505–7. ©2015 AACR.

See related article by Prewett et al., Clin Cancer Res 2002;8(5) May 2002;994–1003
Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy
Authors: Mok Tony , Wu Yi-Long , Lee Jin Soo , Yu Chong-Jen , Sriuranpong Virote , Sandoval-Tan Jennifer , Ladrera Guia , Thongprasert Sumitra , Srimuninnimit Vichien , Liao Meilin , Zhu Yunzhong , Zhou Caicun , Fuerte Fatima , Margono Benjamin , Wen Wei , Tsai Julie , Truman Matt , Klughammer Barbara , Shames David S. , Wu Lin
Published: April 2015

Purpose: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study.

Experimental Design: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS).

Results: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut+ cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14–0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut− cfDNA subgroup (HR, 0.83; 95% CI, 0.65–1.04, P = 0.1076). For patients with EGFR mut+ cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut+ cfDNA versus cycle 3 EGFR mut− patients, respectively (HR, 0.32; 95% CI, 0.21–0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31–0.84, P = 0.0066).

Conclusions: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes. Clin Cancer Res; 21(14); 3196–203. ©2015 AACR.
A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment
Authors: Hagleitner Melanie M. , Coenen Marieke J.H. , Gelderblom Hans , Makkinje Remco R. , Vos Hanneke I. , de Bont Eveline S.J.M. , van der Graaf Winette T.A. , Schreuder H.W. Bart , Flucke Uta , van Leeuwen Frank N. , Hoogerbrugge Peter M. , Guchelaar Henk-Jan , te Loo Dunja M.W.M
Published: April 2015

Purpose: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.

Experimental Design: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r2 = 0.8)–based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma.

Results: We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001).

Conclusions: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome. Clin Cancer Res; 21(15); 3436–41. ©2015 AACR.
Multimerin-1 (MMRN1) as Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group
Authors: Laszlo George S. , Alonzo Todd A. , Gudgeon Chelsea J. , Harrington Kimberly H. , Gerbing Robert B. , Wang Yi-Cheng , Ries Rhonda E. , Raimondi Susana C. , Hirsch Betsy A. , Gamis Alan S. , Meshinchi Soheil , Walter Roland B.
Published: April 2015

Purpose: Exploratory gene expression array analyses suggested multimerin-1 (MMRN1) to be a predictive biomarker in acute myelogenous leukemia (AML). Following up on these studies, we evaluated the role of MMRN1 expression as outcome predictor in two recent Children's Oncology Group trials.

Experimental Design: We retrospectively quantified MMRN1 expression in 183 participants of AAML03P1 and 750 participants of AAML0531 by reverse-transcriptase PCR and correlated expression levels with disease characteristics and clinical outcome.

Results: In AAML03P1, the highest quartile of MMRN1 expression (expression ≥0.5 relative to β-glucuronidase; n = 45) was associated with inferior event-free survival (EFS; P < 0.002) and higher relapse risk (P < 0.004). In AAML0531, in which we quantified MMRN1 mRNA for validation, patients with relative MMRN1 expression ≥0.5 (n = 160) less likely achieved remission (67% vs. 77%, P = 0.006), and more frequently had minimal residual disease (43% vs. 24%, P = 0.001) after one induction course. They had inferior overall survival (OS; 44% ± 9% vs. 69% ± 4% at 5 years; P < 0.001) and EFS (32% ± 8% vs. 54% ± 4% at 5 years; P < 0.001) and higher relapse risk (57% ± 10% vs. 35% ± 5% at 5 years; P < 0.001). These differences were partly attributable to the fact that patients with high MMRN1 expression less likely had cytogenetic/molecular low-risk disease (P < 0.001) than those with low MMRN1 expression. Nevertheless, after multivariable adjustment, high MMRN1 expression remained statistically significantly associated with shorter OS (HR, 1.57; 95% confidence interval, 1.17–2.12; P = 0.003) and EFS (HR, 1.34; 1.04–1.73; P = 0.025), and higher relapse risk (HR, 1.40; 1.01–1.94; P = 0.044).

Conclusions: Together, our studies identify MMRN1 expression as a novel biomarker that may refine AML risk stratification. Clin Cancer Res; 21(14); 3187–95. ©2015 AACR.
The Impact of Macrophage- and Microglia-Secreted TNFα on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment
Authors: Meisen W. Hans , Wohleb Eric S. , Jaime-Ramirez Alena Cristina , Bolyard Chelsea , Yoo Ji Young , Russell Luke , Hardcastle Jayson , Dubin Samuel , Muili Kamaldeen , Yu Jianhua , Caligiuri Michael , Godbout Jonathan , Kaur Balveen
Published: April 2015

Purpose: Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM.

Experimental Design: Quantitative flow cytometry of mice with intracranial gliomas (±oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNFα-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFα on virus replication. TNFα blocking antibodies were used to evaluate the impact of TNFα on oHSV therapy in vivo.

Results: Flow-cytometry analysis revealed a 7.9-fold increase in macrophage infiltration after virus treatment. Tumor-infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFα in response to infected glioma cells in vitro and in vivo. Using TNFα-blocking antibodies and macrophages derived from TNFα-knockout mice, we discovered TNFα-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors.

Conclusions: The results of these studies suggest that FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy. Clin Cancer Res; 21(14); 3274–85. ©2015 AACR.
1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling
Authors: Chen Ping-Tsung , Hsieh Ching-Chuan , Wu Chun-Te , Yen Tzu-Chen , Lin Paul-Yang , Chen Wen-Cheng , Chen Miao-Fen
Published: April 2015

The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)–induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial–mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO–induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO–induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC. Mol Cancer Ther; 14(6); 1365–75. ©2015 AACR.
Clinical Features and Survival of Asian Pediatric Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from a Single Center in China
Authors: Ge Meili , Shi Jun , Li Xingxin , Shao Yingqi , Huang Jinbo , Huang Zhendong , Zhang Jing , Nie Neng , Zheng Yizhou
Published: April 2015

Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children. To characterize the clinical presentations and survival, we performed a retrospective analysis of pediatric patients. Methods: We reviewed 55 pediatric patients with PNH referred to our hospital from January 1990 through June 2012 to assess clinical presentations, survival, and differences among subcategories. Results: The overall survival 10 years after diagnosis estimated via the Kaplan-Meier method was 77.6%. The cohort of patients was divided into subcategories of classic PNH, PNH/aplastic anemia (AA), and subclinical PNH (PNH-sc)/AA based on the recently proposed PNH working clinical classification. We found that patients with classic PNH and PNH/AA had larger PNH clones and many more parameters of hemolysis, but patients with PNH-sc/AA had smaller PNH clones, fewer parameters of hemolysis, and a higher rate of bone marrow failure. Our results revealed a high rate of bone marrow failure and a low rate of hemoglobinuria at presentation. Furthermore, thrombotic events were not observed in our patients, which is significantly different from the rate seen in Caucasian patients. Additionally, pediatric patients with PNH may develop bone marrow cytogenetic abnormalities. Conclusion: This study provides insight into Chinese pediatric PNH patients and may aid in setting up individualized therapeutic regimens.
Clinical Relevance of As-Needed Treatment with Nalmefene in Alcohol-Dependent Patients
Authors: Aubin Henri-Jean , Reimer Jens , Nutt David J. , Bladström Anna , Torup Lars , François Clément , Chick Jonathan
Published: April 2015

Nalmefene is the first drug approved for reduction of alcohol consumption. The aim of this study was to evaluate the clinical relevance of treatment with nalmefene in alcohol-dependent patients with a high drinking risk level from two randomised placebo-controlled 6-month studies (NCT00811720 and NCT00812461). Response criteria were based on alcohol consumption, Clinical Global Impression, and Short Form Health Survey mental component summary scores at month 6, analysed using logistic regression. The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios significantly in favour of nalmefene for all responder criteria; numbers-needed-to-treat ranged from 6 to 10. Significant differences from placebo in clinician-rated and patient-reported outcomes, and liver enzymes further supported the clinical relevance of the treatment effect. In conclusion, this study supports the clinical relevance of nalmefene treatment in patients with alcohol dependence. Nalmefene may help to reduce the alcohol-related burden and the large treatment gap, with currently less than 10% of alcohol-dependent patients in Europe receiving treatment.
Is the Proportion of Patients Diagnosed with Synchronous Stage IV Breast Cancer Who Survive More than Two Years Increasing over Time?
Authors: Dawood Shaheenah , Haaland Benjamin , Albaracin Constance , Gupta Sudeep , Cortes Javier , Sim Yap Yoon , Dent Rebecca A.
Published: April 2015

Background: Studies have shown a moderate increase in survival over time among patients with stage IV breast cancer. Median survival is approximately 2 years. The aim of this study was to evaluate trends over time in survival of >2 years of patients with synchronous stage IV disease. Methods: Using the SEER (Surveillance, Epidemiology and End Results) registry, we identified patients with synchronous stage IV breast cancer diagnosed between 1990 and 2007. Patients were divided into 3 groups according to the year of diagnosis (1990-1995, 1996-2000, and 2001-2007). The probability of survival of >2 years was computed within each group of diagnosis years. A multivariate logistic regression model was then fit to determine the association between year of diagnosis and probability of surviving >2 years after adjusting for important prognostic factors. Results: 22,601 patients were identified, of whom 9,435 (41.7%) had an overall survival of >2 years. The probability of breast cancer-specific survival (BCSS) of >2 years was 40.1, 44, and 48.1% among patients diagnosed in the periods 1990-1995, 1996-2000, and 2001-2007, respectively (p < 0.001). In the multivariate model, the probability of BCSS of >2 years increased with the more recent year of diagnosis (OR 1.058, 95% CI 1.046-1.069, p < 0.001). Other factors significantly associated with an increased probability of surviving >2 years included surgery of the primary tumor, lower grade, younger age, hormone receptor-positive disease, and noninflammatory disease. Conclusion: Our results indicate that among the patients with synchronous stage IV breast cancer, the probability of BCSS of >2 years in the US has increased over time. Attributable factors may be the increasing number of efficacious agents and improved palliative care services over time.
Multimodal Imaging of Spontaneously Shifting Primary Vitreoretinal Lymphoma
Authors: Mantopoulos Dimosthenis , Cebulla Colleen M.
Published: April 2015

Purpose: To correlate spectral domain optical coherence tomography (SD-OCT) and photographic imaging before and after spontaneous regression of primary vitreoretinal lymphoma (PVRL) lesions. Procedures: We report the case of a 60-year-old female. Results: The patient presented with bilateral creamy deposits under the retina and retinal pigment epithelium (RPE), and lesions were visible along Bruch's membrane with SD-OCT and suspicious for PVRL. Systemic workup revealed nonspecific areas of enhancement on neuroimaging. The patient was largely asymptomatic and the decision was made to observe her. Three months later, a new lesion pattern had developed. The color fundus photographs and SD-OCT demonstrated spontaneous regression of the largest sub-RPE lesion, leaving areas of RPE atrophy, while a new larger sub-RPE lesion had formed in the other eye. Vitreous biopsy showed lymphocytes and no malignant cells, while sub-RPE biopsy of the newly formed lesion revealed highly atypical cells positive for CD19 and CD20. Conclusions: Multimodal imaging documents that PVRL lesion regression and early RPE changes can develop within a 3-month period. Immune control is an important factor in lesion regression in the eye.
Full-Dose Gemcitabine Is a More Effective Chemotherapeutic Agent Than 5-Fluorouracil for Concurrent Chemoradiotherapy as First-Line Treatment in Locally Advanced Pancreatic Cancer
Authors: Kang Huapyong , Chang Jee Suk , Oh Tak Geun , Chung Moon Jae , Park Jeong Youp , Park Seung Woo , Seong Jinsil , Song Si Young , Chung Jae Bok , Bang Seungmin
Published: April 2015

Objectives: To compare the efficacy of full-dose gemcitabine-based concurrent chemoradiotherapy (FG-CCRT) and conventional 5-fluorouracil CCRT (5FU-CCRT) for locally advanced pancreatic cancer (LAPC). Methods: 109 LAPC cases treated with FG-CCRT (n = 89) or 5FU-CCRT (n = 20) were reviewed retrospectively. The FG-CCRT group was composed of a full-dose gemcitabine monotherapy (1,000 mg/m2) arm and a combination therapy with cisplatin (70 mg/m2) arm. The 5FU-CCRT group used a radiosensitizing dose of 5-FU (500 mg/m2) plus leucovorin (20 mg/m2). Concurrent radiotherapy was targeted at the tumor with a 5-mm margin without lymph node irradiation. Results: Objective response rate (ORR) and disease control rate (DCR) was significantly higher in the FG-CCRT group (ORR: 32.6 vs. 5%, p = 0.013; DCR: 79.8 vs. 50.0%, p = 0.006). FG-CCRT showed remarkable superiority to 5FU-CCRT for suppressing distant metastasis (18.0 vs. 45.0%, p = 0.017). Neutropenia (34.8 vs. 10%, p = 0.032) and thrombocytopenia (21.3 vs. 0.0%, p = 0.021) were more frequent in the FG-CCRT group as originally expected. When dividing the FG-CCRT group to gemcitabine monotherapy (GEM) and gemcitabine plus cisplatin, toxicities of the GEM subgroup were not different than those of the 5FU-CCRT group. Conclusion: FG-CCRT, especially full-dose gemcitabine monotherapy-based CCRT was more effective for the initial control of LAPC than 5FU-CCRT, and also relatively safe.
Increased Cerebral Cannabinoid-1 Receptor Availability Is a Stable Feature of Functional Dyspepsia: A [18F]MK-9470 PET Study
Authors: Ly Huynh Giao , Ceccarini Jenny , Weltens Nathalie , Bormans Guy , Van Laere Koen , Tack Jan , Van Oudenhove Lukas
Published: April 2015

Background: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). Methods: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [18F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months). Results: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months. Conclusions: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs.
The Diagnosis of Polycystic Ovary Syndrome during Adolescence
Authors: Witchel Selma F. , Oberfield Sharon , Rosenfield Robert L. , Codner Ethel , Bonny Andrea , Ibáñez Lourdes , Pena Alexia , Horikawa Reiko , Gomez-Lobo Veronica , Joel Dipesalema , Tfayli Hala , Arslanian Silva , Dabadghao Preeti , Garcia Rudaz Cecilia , Lee Peter A.
Published: April 2015

Background/Aims: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. Methods: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. Results and Conclusion: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls.