Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study.

BACKGROUND: Approximately 1 in 10 adult survivors of childhood cancer is underweight. Although the consequences of being overweight or obese have been well described, outcomes among childhood cancer survivors who are underweight are unknown. OBJECTIVE: To determine whether underweight status increases the risk of mortality. PROCEDURE: Cohort study: Marginal models with generalized estimating equations to evaluate the associations between body mass index (BMI), serious or life-threatening chronic conditions, and death in the setting of long-term follow-up questionnaires and National Death Index search. PARTICIPANTS: Childhood cancer five-year survivors diagnosed during 1970-1986 in the Childhood Cancer Survivor Study Exposure: Underweight status, defined as body mass index (BMI) < 18.5 kg/m2 compared with ideal body weight. Based on available literature on body weight and mortality from the general population, ideal body weight was defined as BMI 22.0-24.9 kg/m2. MAIN OUTCOMES: Overall mortality and cancer-specific mortality. RESULTS: Of 9454 survivors (median age 35 years old (range, 17-58), an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline or follow-up questionnaire. Of 184 deaths, 29 were among underweight survivors. Underweight status was more common among females (9.1% vs. 4.5%, p < .01) and participants with younger age at diagnosis (8.2% for < 5 years vs. 6.1% for ≥5 years, p < .01), lower household income (8.9% for < $20,000 vs. 6.0% for ≥ $20,000, p < .01), or a history of serious chronic condition (p = .05). After adjustment for these factors, in addition to prior smoking and a history of radiation therapy, the risk of all-cause mortality within two years of BMI report was increased (OR 2.85; 95% CI: 1.63-4.97; p < .01) for underweight survivors, compared with ideal-weight survivors. CONCLUSIONS: Childhood cancer survivors who are underweight are at increased risk for late mortality that appears unrelated to smoking status, recognized chronic disease, or subsequent malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.

Ovarian function in female survivors of high-risk neuroblastoma.

INTRODUCTION: Data on ovarian function in neuroblastoma survivors are limited. We sought to determine the prevalence of ovarian dysfunction in a cohort of high-risk neuroblastoma survivors and compare outcomes among survivors treated with and without autologous stem cell rescue (ASCR) preceded by myeloablative chemotherapy. METHODS: Retrospective review of female survivors of high-risk neuroblastoma ≥5 years from diagnosis, diagnosed between 1982 and 2014, and followed in a tertiary cancer center. Participants were divided into two groups: individuals treated with conventional chemotherapy ± radiation ("non-ASCR") (n = 32) or with chemotherapy ± radiation followed by myeloablative chemotherapy with ASCR ("ASCR") (n = 51). Ovarian dysfunction was defined as follicle-stimulating hormone ≥15 mU/mL, while premature ovarian insufficiency (POI) was defined as persistent ovarian dysfunction requiring hormone replacement therapy. Poisson models were used to determine prevalence ratios of ovarian dysfunction and POI. RESULTS: Among 83 females (median attained age: 19 years [range, 10-36]; median follow-up: 15 years [range, 7-36]), 49 (59%) had ovarian dysfunction, and 34 (41%) developed POI. Survivors treated with ASCR were 3.2-fold more likely to develop ovarian dysfunction (95% CI: 1.8-6.0; p < 0.001) and 4.5-fold more likely to develop POI (95% CI: 1.7-11.7; p = 0.002) when compared with those treated with conventional chemotherapy, after adjusting for attained age. Two participants in the non-ASCR group and six in the ASCR group achieved at least one spontaneous pregnancy. DISCUSSION: Ovarian dysfunction is prevalent in female high-risk neuroblastoma survivors, especially after ASCR. Longitudinal follow-up of larger cohorts is needed to inform counseling about the risk of impaired ovarian function after neuroblastoma therapy.

Timing of exercise therapy when initiating adjuvant chemotherapy for breast cancer: a randomized trial.

AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

Prospective Evaluation of Immune Activation Associated with Response to Radioembolization Assessed with PET/CT in Women with Breast Cancer Liver Metastasis.

Background The impact of transarterial radioembolization (TARE) of breast cancer liver metastasis (BCLM) on antitumor immunity is unknown, which hinders the optimal selection of candidates for TARE. Purpose To determine whether response to TARE at PET/CT in participants with BCLM is associated with specific immune markers (cytokines and immune cell populations). Materials and Methods This prospective pilot study enrolled 23 women with BCLM who planned to undergo TARE (June 2018 to February 2020). Peripheral blood and liver tumor biopsies were collected at baseline and 1-2 months after TARE. Monocyte, myeloid-derived suppressor cell (MDSC), interleukin (IL), and tumor-infiltrating lymphocyte (TIL) levels were assessed with use of gene expression studies and flow cytometry, and immune checkpoint and cell surface marker levels with immunohistochemistry. Modified PET Response Criteria in Solid Tumors was used to determine complete response (CR) in treated tissue. After log-transformation, immune marker levels before and after TARE were compared using paired t tests. Association with CR was assessed with Wilcoxon rank-sum or unpaired t tests. Results Twenty women were included. After TARE, peripheral IL-6 (geometric mean, 1.0 vs 1.6 pg/mL; P = .02), IL-10 (0.2 vs 0.4 pg/mL; P = .001), and IL-15 (1.9 vs 2.4 pg/mL; P = .01) increased. In biopsy tissue, lymphocyte activation gene 3-positive CD4+ TILs (15% vs 31%; P < .001) increased. Eight of 20 participants (40% [exact 95% CI: 19, 64]) achieved CR. Participants with CR had lower baseline peripheral monocytes (10% vs 29%; P < .001) and MDSCs (1% vs 5%; P < .001) and higher programmed cell death protein (PD) 1-positive CD4+ TILs (59% vs 26%; P = .006) at flow cytometry and higher PD-1+ staining in tumor (2% vs 1%; P = .046). Conclusion Complete response to transarterial radioembolization was associated with lower baseline cytokine, monocyte, and myeloid-derived suppressor cell levels and higher programmed cell death protein 1-positive tumor-infiltrating lymphocyte levels. © RSNA, 2022 Online supplemental material is available for this article.

Ethnic diversity in treatment response for colorectal cancer: proof of concept for radiomics-driven enrichment trials.

BACKGROUND: Several barriers hamper recruitment of diverse patient populations in multicenter clinical trials which determine efficacy of new systemic cancer therapies. PURPOSE: We assessed if quantitative analysis of computed tomography (CT) scans of metastatic colorectal cancer (mCRC) patients using imaging features that predict overall survival (OS) can unravel the association between ethnicity and efficacy. METHODS: We retrospectively analyzed CT images from 1584 mCRC patients in two phase III trials evaluating FOLFOX ± panitumumab (n = 331, 350) and FOLFIRI ± aflibercept (n = 437, 466) collected from August 2006 to March 2013. Primary and secondary endpoints compared RECIST1.1 response at month-2 and delta tumor volume at month-2, respectively. An ancillary study compared imaging phenotype using a peer-reviewed radiomics-signature combining 3 imaging features to predict OS landmarked from month-2. Analysis was stratified by ethnicity. RESULTS: In total, 1584 patients were included (mean age, 60.25 ± 10.57 years; 969 men). Ethnicity was as follows: African (n = 50, 3.2%), Asian (n = 66, 4.2%), Caucasian (n = 1413, 89.2%), Latino (n = 27, 1.7%), Other (n = 28, 1.8%). Overall baseline tumor volume demonstrated Africans and Caucasians had more advanced disease (p < 0.001). Ethnicity was associated with treatment response. Response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. Overall delta tumor volume at month-2 demonstrated that Latino patients more likely experienced response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023). CONCLUSION: This study highlights how clinical trials that inadequately represent minority groups may impact associated translational work. In appropriately powered studies, radiomics features may allow us to unravel associations between ethnicity and treatment efficacy, better elucidate mechanisms of resistance, and promote diversity in trials through predictive enrichment. CLINICAL RELEVANCE STATEMENT: Radiomics could promote clinical trial diversity through predictive enrichment, hence benefit to historically underrepresented racial/ethnic groups that may respond variably to treatment due to socioeconomic factors and built environment, collectively referred to as social determinants of health. KEY POINTS: •Findings indicate ethnicity was associated with treatment response across all 3 endpoints. First, response per RECIST1.1 at month-2 was distinct between ethnicities (p = 0.048) with higher response rate (55.6%) in Latinos. •Second, the overall delta tumor volume at month-2 demonstrated that Latino patients were more likely to experience response to treatment (p = 0.021). Radiomics phenotype was also distinct in terms of tumor radiomics heterogeneity (p = 0.023).

Radiomic Analysis: Study Design, Statistical Analysis, and Other Bias Mitigation Strategies.

Rapid advances in automated methods for extracting large numbers of quantitative features from medical images have led to tremendous growth of publications reporting on radiomic analyses. Translation of these research studies into clinical practice can be hindered by biases introduced during the design, analysis, or reporting of the studies. Herein, the authors review biases, sources of variability, and pitfalls that frequently arise in radiomic research, with an emphasis on study design and statistical analysis considerations. Drawing on existing work in the statistical, radiologic, and machine learning literature, approaches for avoiding these pitfalls are described.

Implementing a mHealth intervention to increase colorectal cancer screening among high-risk cancer survivors treated with radiotherapy in the Childhood Cancer Survivor Study (CCSS).

BACKGROUND: Cancer survivors treated with any dose of radiation to the abdomen, pelvis, spine, or total body irradiation (TBI) are at increased risk for developing colorectal cancer (CRC) compared to the general population. Since earlier detection of CRC is strongly associated with improved survival, the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines recommend that these high-risk cancer survivors begin CRC screening via a colonoscopy or a multitarget stool DNA test at the age of 30 years or 5 years following the radiation treatment (whichever occurs last). However, only 37% (95% CI 34.1-39.9%) of high-risk survivors adhere to CRC surveillance. The Activating cancer Survivors and their Primary care providers (PCP) to Increase colorectal cancer Screening (ASPIRES) study is designed to assess the efficacy of an intervention to increase the rate of CRC screening among high-risk cancer survivors through interactive, educational text-messages and resources provided to participants, and CRC screening resources provided to their PCPs. METHODS: ASPIRES is a three-arm, hybrid type II effectiveness and implementation study designed to simultaneously evaluate the efficacy of an intervention and assess the implementation process among participants in the Childhood Cancer Survivor Study (CCSS), a North American longitudinal cohort of childhood cancer survivors. The Control (C) arm participants receive electronic resources, participants in Treatment arm 1 receive electronic resources as well as interactive text messages, and participants in Treatment arm 2 receive electronic educational resources, interactive text messages, and their PCP's receive faxed materials. We describe our plan to collect quantitative (questionnaires, medical records, study logs, CCSS data) and qualitative (semi-structured interviews) intervention outcome data as well as quantitative (questionnaires) and qualitative (interviews) data on the implementation process. DISCUSSION: There is a critical need to increase the rate of CRC screening among high-risk cancer survivors. This hybrid effectiveness-implementation study will evaluate the effectiveness and implementation of an mHealth intervention consisting of interactive text-messages, electronic tools, and primary care provider resources. Findings from this research will advance CRC prevention efforts by enhancing understanding of the effectiveness of an mHealth intervention and highlighting factors that determine the successful implementation of this intervention within the high-risk cancer survivor population. TRIAL REGISTRATION: This protocol was registered at clinicaltrials.gov (identifier NCT05084833 ) on October 20, 2021.

Bronchial or Pulmonary Artery Chemoembolization for Unresectable and Unablatable Lung Metastases: A Phase I Clinical Trial.

Background Lung chemoembolization is an emerging treatment option for lung tumors, but the optimal embolic, drug, and technique are unknown. Purpose To determine the technical success rate and safety of bronchial or pulmonary artery chemoembolization of lung metastases using ethiodized oil, mitomycin, and microspheres. Materials and Methods Patients with unresectable and unablatable lung, endobronchial, or mediastinal metastases, who failed systemic chemotherapy, were enrolled in this prospective, single-center, single-arm, phase I clinical trial (December 2019-September 2020). Pulmonary and bronchial angiography was performed to determine the blood supply to the lung metastases. Based on the angiographic findings, bronchial or pulmonary artery chemoembolization was performed using an ethiodized oil and mitomycin emulsion, followed by microspheres. The primary objectives were technical success rate and safety, according to the National Cancer Institute Common Terminology Criteria for Adverse Events. CIs of proportions were estimated with the equal-tailed Jeffreys prior interval, and correlations were evaluated with the Spearman test. Results Ten participants (median age, 60 years; interquartile range, 52-70 years; six women) were evaluated. Nine of the 10 participants (90%) had lung metastases supplied by the bronchial artery, and one of the 10 participants (10%) had lung metastases supplied by the pulmonary artery. The technical success rate of intratumoral drug delivery was 10 of 10 (100%) (95% CI: 78, 100). There were no severe adverse events (95% CI: 0, 22). The response rate of treated tumors was one of 10 (10%) according to the Response Evaluation Criteria in Solid Tumors and four of 10 (40%) according to the PET Response Criteria in Solid Tumors. Ethiodized oil retention at 4-6 weeks was correlated with reduced tumor size (ρ = -0.83, P = .003) and metabolic activity (ρ = -0.71, P = .03). Pharmacokinetics showed that 45% of the mitomycin dose underwent burst release in 2 minutes, and 55% of the dose was retained intratumorally with a half-life of more than 5 hours. The initial tumor-to-plasma ratio of mitomycin concentration was 380. Conclusion Lung chemoembolization was technically successful for the treatment of lung, mediastinal, and endobronchial metastases, with no severe adverse events. Clinical trial registration no. NCT04200417 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Georgiades et al in this issue.

Clinical Benefits, Harms, and Cost-Effectiveness of Breast Cancer Screening for Survivors of Childhood Cancer Treated With Chest Radiation : A Comparative Modeling Study.

BACKGROUND: Surveillance with annual mammography and breast magnetic resonance imaging (MRI) is recommended for female survivors of childhood cancer treated with chest radiation, yet benefits, harms, and costs are uncertain. OBJECTIVE: To compare the benefits, harms, and cost-effectiveness of breast cancer screening strategies in childhood cancer survivors. DESIGN: Collaborative simulation modeling using 2 Cancer Intervention and Surveillance Modeling Network breast cancer models. DATA SOURCES: Childhood Cancer Survivor Study and published data. TARGET POPULATION: Women aged 20 years with a history of chest radiotherapy. TIME HORIZON: Lifetime. PERSPECTIVE: Payer. INTERVENTION: Annual MRI with or without mammography, starting at age 25, 30, or 35 years. OUTCOME MEASURES: Breast cancer deaths averted, false-positive screening results, benign biopsy results, and incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: Lifetime breast cancer mortality risk without screening was 10% to 11% across models. Compared with no screening, starting at age 25 years, annual mammography with MRI averted the most deaths (56% to 71%) and annual MRI (without mammography) averted 56% to 62%. Both strategies had the most screening tests, false-positive screening results, and benign biopsy results. For an ICER threshold of less than $100 000 per quality-adjusted life-year gained, screening beginning at age 30 years was preferred. RESULTS OF SENSITIVITY ANALYSIS: Assuming lower screening performance, the benefit of adding mammography to MRI increased in both models, although the conclusions about preferred starting age remained unchanged. LIMITATION: Elevated breast cancer risk was based on survivors diagnosed with childhood cancer between 1970 and 1986. CONCLUSION: Early initiation (at ages 25 to 30 years) of annual breast cancer screening with MRI, with or without mammography, might reduce breast cancer mortality by half or more in survivors of childhood cancer. PRIMARY FUNDING SOURCE: American Cancer Society and National Institutes of Health.

Ablation Zone Involution of Liver Tumors Is Faster in Patients Treated with Irreversible Electroporation Than Microwave Ablation.

Background and Objectives: To compare ablation zone involution following microwave ablation (MWA) or irreversible electroporation (IRE) of liver tumors. Materials and Methods: MWA or IRE performed for colorectal cancer liver metastasis (CRLM) or hepatocellular carcinoma (HCC) during January 2011 to December 2015 were analyzed. Patients with a tumoral response on 1-year follow-up computed tomography (CT) were included. Generalized estimating equations were used to evaluate the differences between the two modalities on ablation zone involution observed on CT at 6 (M6) and 12 months (M12), and on laboratory values (total bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase, albumin, and platelets count). The likelihood ratio test was used to assess whether the association between ablation modalities and these outcomes differed over time. Results: Seventeen (17/44, 39%) women and 27 (27/44, 61%) men were included, with 25 HCC (25/44, 57%) and 19 CRLM (19/44, 43%) patients. IRE was used in 9 (9/19, 47%) CRLM and 5 (5/25, 20%) HCC patients, respectively. All other patients had MWA. Ablation zone size and involution between IRE and MWA differed significantly over time (interaction p < 0.01), with a mean of 241.04 vs. 771.08 mm2 (ratio 0.313; 95% CI, 0.165-0.592; p < 0.01) at M6 and 60.47 vs. 589.43 mm2 (ratio 0.103; 95% CI, 0.029-0.365; p < 0.01) at M12. Changes in liver enzymes did not differ significantly between IRE and MWA at both timepoints. Conclusions: Liver tumors treated with IRE underwent faster involution when compared to tumors treated with MWA, but liver enzymes levels were comparable.

Barriers and facilitators of risk-based health care for adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Optimal risk-based survivor health care includes surveillance for late effects and education targeted at reducing or preventing risky health behaviors. Understanding the reasons for a lack of risk-based follow-up care is essential. METHODS: Adult participants from the Childhood Cancer Survivor Study were surveyed about having a cancer-related visit in the past 2 years and the likelihood of having a cancer-related visit in the future. Additional factors thought to be related to the primary outcomes were also assessed. RESULTS: Nine hundred seventy-five survivors completed the survey. Twenty-seven percent (95% confidence interval [CI], 24%-30%) had a cancer-related medical visit in the previous 2 years, and 41% (95% CI, 38%-44%) planned to have such a visit within the next 2 years. The likelihood of having had a cancer-related visit within the last 2 years was higher among survivors assigning greater importance to these visits (relative risk [RR], 1.2; 95% CI, 1.1-1.3), perceiving greater susceptibility to health problems (RR, 1.2; 95% CI, 1.1-1.3), having a moderate to life-threatening chronic health problem related to their cancer (RR, 2.1; 95% CI, 1.7-2.7), seeing a primary care provider for a cancer-related problem (RR, 1.3; 95% CI, 1.0-1.6), having a cancer treatment summary (RR, 1.3; 95% CI, 1.0-1.6), and endorsing greater confidence in physicians' abilities to address questions and concerns (RR, 1.2; 95% CI, 1.0-1.3). CONCLUSIONS: Educational interventions improving awareness of treatment history and susceptibility to cancer-related late effects and corresponding risk-based care are likely to be beneficial for survivors of childhood cancers.

Temporary Organ Displacement to Escalate Radiation Dose to Retroperitoneal Tumors and Decrease Toxicity to Organs at Risk.

PURPOSE: To demonstrate that temporary organ displacement (TOD) by drainage catheter placement and hydrodissection is feasible and reproducible for simulation (SIM) and stereotactic body radiation treatment (SBRT). MATERIALS AND METHODS: Between February 2010 and December 2018, 31 consecutive patients (20 men and 11 women; median age, 59 years; range 20-80 years) received both SIM and SBRT with TOD. The minimum required displacement was 10 mm between the gross tumor volume (GTV) and the organ at risk (OAR). Complete displacement was defined as the ability to displace the OAR from the GTV a minimum of 10 mm across the entire boundary. SIM was performed with hydrodissection on the same day. On the day of SBRT, displacement was reproduced by hydrodissection. Displacement was measured on computed tomography images of TOD, SIM, and SBRT. The drain was removed after SBRT. RESULTS: TOD (hydrodissection) was significantly associated with successful displacement of the OAR from a GTV greater than 10 mm (median, 20 mm vs 4.1 mm, P < .001) and maintained displacement at SIM and SBRT (SIM: 29.4 mm vs 4.1 mm, P < .001; SBRT: 32.4 mm vs 4.1 mm, P < .001). The OAR-GTV boundary showed a median reduction of 35 mm (95% confidence interval, 27.5-37.5 mm) after TOD. TOD achieved complete displacement in 22 of 31 (71%) patients, and 25 of 31 (81%) patients were able to undergo single-fraction ablative SBRT. No patients developed procedure-related complications within 30 days. SIM and SBRT were successful without OAR toxicities within a median of 33 months (range, 3-92 months). CONCLUSIONS: TOD with placement of drain and hydrodissection is technically feasible and safe and maintains displacement for SIM and SBRT.

Whole-body magnetic resonance imaging as surveillance for subsequent malignancies in preadolescent, adolescent, and young adult survivors of germline retinoblastoma: An update.

BACKGROUND: Germline retinoblastoma (Rb) survivors are at lifelong risk for developing subsequent malignancies (SMNs). Optimal surveillance modalities are needed to detect SMN at an early stage in this high-risk cohort. We investigated the use of rapid whole-body magnetic resonance imaging (WB-MRI) as a noninvasive screening modality in this cohort. PROCEDURE: WB-MRI was performed in asymptomatic preadolescent, adolescent, or young adult survivors of germline Rb from February 1, 2008 to December 31, 2018 at a tertiary cancer center. We calculated sensitivity and specificity of WB-MRI and rate of false-positive findings requiring additional evaluation. RESULTS: Overall, 110 WB-MRI were performed in 47 germline Rb survivors (51% female; median age at initial WB-MRI: 15.5 years [range 8-25.3]). Patients received 1-10 annual WB-MRI examinations (median: two). Thirteen patients had an abnormal WB-MRI; three findings were deemed to be likely benign and were not evaluated further. Ten patients required dedicated imaging and three required biopsy; two patients were diagnosed with localized high-grade osteosarcoma, while the other eight had benign findings. One patient was diagnosed with secondary osteosarcoma 3 months after normal WB-MRI. In total, there were 96 true negatives, 11 false positives, two true positives, and one false negative. The sensitivity of WB-MRI in this cohort was 66.7% (95% confidence interval [CI], 14.2-96.0) and the specificity was 89.7% (95% CI, 83.6-93.7). CONCLUSIONS: Based on our 10-year experience, surveillance WB-MRI appears to have limited utility as a surveillance modality for SMN in germline Rb survivors. Alternate screening modalities should be investigated.

Performance of Dual-Energy Contrast-enhanced Digital Mammography for Screening Women at Increased Risk of Breast Cancer.

BackgroundContrast agent-enhanced digital mammography (CEDM) has been shown to be more sensitive and specific than two-dimensional full-field digital mammography in the diagnostic setting. Few studies have reported on its performance in the screening setting.PurposeTo evaluate the performance of CEDM for breast cancer screening.Materials and MethodsThis retrospective study included women who underwent dual-energy CEDM for breast cancer screening from December 2012 through April 2016. Medical records were reviewed for age, risk factors, short-interval follow-up and biopsies recommended, and cancers detected. Sensitivity, specificity, positive predictive value of abnormal findings at screening (PPV1), positive predictive value of biopsy performed (PPV3), and negative predictive value were determined.ResultsIn the study period 904 baseline CEDMs were performed. Mean age was 51.8 years ± 9.4 (standard deviation). Of 904 patients, 700 (77.4%) had dense breasts, 247 (27.3%) had a family history of breast cancer in a first-degree relative age 50 years or younger, and 363 (40.2%) a personal history of breast cancer. The final Breast Imaging Reporting and Data System score was 1 or 2 in 832 of 904 (92.0%) patients, score of 3 in 25 of 904 (2.8%) patients, and score of 4 or 5 in 47 of 904 (5.2%) patients. By using CEDM, 15 cancers were diagnosed in 14 of 904 women (cancer detection rate, 15.5 of 1000). PPV3 was 29.4% (15 of 51). At least 1-year follow up was available in 858 women. There were two interval cancers. Sensitivity was 50.0% (eight of 16; 95% confidence interval [CI]: 24.7%, 75.3%) on the low-energy images compared with 87.5% (14 of 16; 95% CI: 61.7%, 98.4%) for the entire study (low-energy and iodine images; P = .03). Specificity was 93.7% (789 of 842; 95% CI: 91.8%, 95.2%); PPV1 was 20.9% (14 of 67; 95% CI: 11.9%, 32.6%), and negative predictive value was 99.7% (789 of 791; 95% CI: 99.09%, 99.97%).ConclusionContrast-enhanced digital mammography is a promising technique for screening women with higher-than-average risk for breast cancer.© RSNA, 2019.

Autologous Blood Patch Injection versus Hydrogel Plug in CT-guided Lung Biopsy: A Prospective Randomized Trial.

Purpose To compare the effect of autologous blood patch injection (ABPI) with that of a hydrogel plug on the rate of pneumothorax at CT-guided percutaneous lung biopsy. Materials and Methods In this prospective randomized controlled trial ( https://ClinicalTrials.gov , NCT02224924), a noninferiority design was used for ABPI, with a 10% noninferiority margin when compared with the hydrogel plug, with the primary outcome of pneumothorax rate within 2 hours of biopsy. A type I error rate of 0.05 and 90% power were specified with a target study population of 552 participants (276 in each arm). From October 2014 to February 2017, all potential study participants referred for CT-guided lung biopsy (n = 2052) were assessed for enrollment. Results The data safety monitoring board recommended the trial be closed to accrual after an interim analysis met prespecified criteria for early stopping based on noninferiority. The final study group consisted of 453 participants who were randomly assigned to the ABPI (n = 226) or hydrogel plug (n = 227) arms. Of these, 407 underwent lung biopsy. Pneumothorax rates within 2 hours of biopsy were 21% (42 of 199) and 29% (60 of 208); chest tube rates were 9% (18 of 199) and 13% (27 of 208); and delayed pneumothorax rates within 2 weeks after biopsy were 1.4% (three of 199) and 1.5% (three of 208) in the ABPI and hydrogel plug arms, respectively. Conclusion Autologous blood patch injection is noninferior to a hydrogel plug regarding the rate of pneumothorax after CT-guided percutaneous lung biopsy. © RSNA, 2018 Online supplemental material is available for this article.

Automated Breast Density Measurements From Chest Computed Tomography Scans.

To develop an automated method for quantifying percent breast density from chest computed tomography (CT) scans. A naïve Bayesian classifier based on gray-level intensities and spatial relationships was developed on CT scans from 10 patients diagnosed with Hodgkin lymphoma (HL) and imaged as part of routine clinical care. The algorithm was validated on CT scans from 75 additional HL patients. The classifier was developed and validated using a reference dataset with consensus manual segmentation of fibroglandular tissue. Accuracy was evaluated at the pixel-level to examine how well the algorithm identified pixels with fibroglandular tissue using true and false positive fractions (TPF and FPF, respectively). Quantitative estimates of the patient-level CT percent density were contrasted to each other using the concordance correlation coefficient, ρc, and to subjective ACR BI-RADS density assessments using Kendall's τb. The pixel-level TPF for identifying pixels with fibroglandular tissue was 82.7% (interquartile range of patient-specific TPFs 65.5%-89.6%). The pixel-level FPF was 9.2% (interquartile range of patient-specific FPFs 2.5%-45.3%). Patient-level agreement of the algorithm's automated density estimate with that obtained from the reference dataset was high, ρc = 0.93 (95% CI 0.90-0.96) as was agreement with a radiologist's subjective ACR-BI-RADS assessments, τb = 0.77. It is possible to obtain automated measurements of percent density from clinical CT scans.

Inference for the difference in the area under the ROC curve derived from nested binary regression models.

The area under the curve (AUC) statistic is a common measure of model performance in a binary regression model. Nested models are used to ascertain whether the AUC statistic increases when new factors enter the model. The regression coefficient estimates used in the AUC statistics are computed using the maximum rank correlation methodology. Typically, inference for the difference in AUC statistics from nested models is derived under asymptotic normality. In this work, it is demonstrated that the asymptotic normality is true only when at least one of the new factors is associated with the binary outcome. When none of the new factors are associated with the binary outcome, the asymptotic distribution for the difference in AUC statistics is a linear combination of chi-square random variables. Further, when at least one new factor is associated with the outcome and the population difference is small, a variance stabilizing reparameterization improves the asymptotic normality of the AUC difference statistic. A confidence interval using this reparameterization is developed and simulations are generated to determine their coverage properties. The derived confidence interval provides information on the magnitude of the added value of new factors and enables investigators to weigh the size of the improvement against potential costs associated with the new factors. A pancreatic cancer data example is used to illustrate this approach.

Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study.

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for both insulin-dependent and non-insulin-dependent diabetes. We sought to clarify the pathophysiology of diabetes after abdRT by performing dynamic studies of insulin and glucose and testing for type 1 diabetes-associated autoantibodies. PROCEDURE: Cross-sectional analysis of 2-year childhood cancer survivors treated with abdRT at age ≤21 years who underwent oral glucose tolerance testing and assessment of diabetes-related autoantibodies from December 2014 to September 2016. Prevalence of insulin/glucose derangements, indices of insulin sensitivity/secretion (homeostatic model assessment of insulin resistance [HOMA-IR], whole-body insulin sensitivity, insulinogenic index), autoantibody positivity, and treatment/demographic factors associated with adverse metabolic outcomes were assessed. RESULTS: Among 40 participants previously exposed to abdRT (57.5% male; median age at cancer diagnosis, 3.3 years [range, 0.5-20.1]; median age at study 14.3 years [range, 8.3-49.8]; none with obesity), 9 (22.5%) had glucose derangements (n = 4 with impaired fasting glucose [≥100 mg/dL]; n = 4 with impaired glucose tolerance [2-hour glucose 140-199 mg/dL]; n = 1 with previously unrecognized diabetes [2-hour glucose ≥200 mg/dL]). Three of the four individuals with impaired fasting glucose also had insulin resistance, as measured by HOMA-IR; an additional four subjects with normal glucose tolerance were insulin resistant. The subject with diabetes had normal HOMA-IR. No participant had absolute insulinopenia or >1 positive diabetes-related autoantibody. CONCLUSIONS: This study suggests that radiation-induced damage to the insulin-producing ß-cells is an unlikely explanation for the early derangements in glucose metabolism observed after abdRT. Research into alternative pathways leading to diabetes after abdRT is needed.

Cardiovascular Risk Factors in Survivors of Childhood Hematopoietic Cell Transplantation Treated with Total Body Irradiation: A Longitudinal Analysis.

Hematopoietic cell transplantation (HCT) survivors treated with total body irradiation (TBI) are known to be at increased risk for the development of cardiovascular risk factors (CVRFs). We sought to characterize the incidence of CVRFs in a TBI-exposed survivor cohort and to describe prognostic indicators of their development through a retrospective analysis of CVRFs in 1-year survivors of leukemia or lymphoma treated with TBI at Memorial Sloan Kettering between April 1987 and May 2011. Eligible participants were age ≤21 years at the time of TBI and were not receiving glucocorticoid therapy at the time of entry to long-term follow-up. Survivors were assessed for obesity (body mass index ≥95th percentile for age ≤ 20 years and ≥30 kg/m2 for age >20 years), elevated blood pressure, dyslipidemia (elevated triglycerides [TG], low high-density lipoprotein [HDL]), and glucose intolerance (fasting glucose ≥100 mg/dL); those with ≥3 risk factors were deemed to have a CVRF cluster, a surrogate for metabolic syndrome. Cox regression models were used to estimate hazard ratios (HRs) for factors associated with each CVRF. To compare the prevalence of CVRFs in HCT survivors and the general population, survivors were compared with age-, sex-, and race-matched controls from the National Health and Nutrition Examination Survey. A total of 123 survivors were evaluated (62.6% males). The median age at TBI was 11.8 years (range, 1.6 to 21.9 years). The median duration of follow-up was 8.0 years (range, 1.01 to 24.6 years), and the median age at last follow-up was 20.1 years (range, 4.0 to 41.3 years). The 5-year cumulative incidence was 14.7% for elevated blood pressure, 10.5% for elevated glucose, 26.8% for low HDL, 39.2% for hypertriglyceridemia, and 16.0% for obesity, and corresponding 10-year cumulative incidences of 28.8%, 33.1%, 52.0%, 65.0%, and 18.6%. The median cumulative incidence of a CVRF cluster rose from 10.6% (range, 5.6% to 17.5%) at 5 years to 28.4% (range, 18.8% to 38.7%) at 10 years. In multivariate analysis, growth hormone (GH) deficiency (hazard ratio [HR], 8.6; 95% confidence interval [CI], 2.1 to 34.4; P = .002), history of cranial radiation (HR, 4.0; 95% CI, 1.7 to 9.6; P = .002), and grade II-IV acute graft-versus-host disease GVHD (HR, 4.2; 95% CI, 1.5 to 12.2; P = .008) were associated with the risk of developing a CVRF cluster. Compared with a random sample of matched population controls, HCT survivors had an increased prevalence of hypertriglyceridemia and low HDL, but not of glucose intolerance, elevated blood pressure, or CVRF cluster. Given the young age of this HCT survivor cohort, these data highlight the importance of routine screening for CVRF starting in childhood in individuals exposed to TBI.

Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain. METHODS: Participants included 1108 females from the Childhood Cancer Survivor Study who were diagnosed with childhood cancer 1970-1986, treated with chest radiotherapy, and survived to ages ⩾20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk. RESULTS: Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ⩾10 years of ovarian function after chest radiotherapy vs <10 years (HR=2.89, CI 1.56-5.53) and for radiotherapy given within 1 year of menarche vs >1 year from menarche (HR=1.80, CI 1.19-2.72). Risk decreased with decreasing age at menopause (Ptrend=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause <20 years treated with hormone therapy had a lower breast cancer risk than premenopausal survivors (HR=0.47, CI 0.23-0.94). CONCLUSIONS: Endogenous hormones are key contributors to breast cancer observed among childhood cancer survivors. Hormone therapy given for premature ovarian insufficiency does not fully replace the function that endogenous hormones have in breast cancer development.