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Abstract We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

PURPOSE There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. METHODS We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. RESULTS In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. CONCLUSION Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

AbstractObjectivePerforate the expanded polytetrafluoroethylene membrane of the GORE® CARDIOFORM Septal Occluder (GSO) and GORE® CARDIOFORM ASD Occluder (GCA) after implantation.BackgroundPercutaneous transseptal access to the left atrium is necessary for many structural and electrophysiological procedures. The potential need to access the left atrium may influence decision‐making for patent foramen ovale or atrial septal defect closure.MethodsSixteen canines underwent implantation of equal number GSO or GCA devices. A transseptal crossing procedure was performed through the device 85 (±1) days postoccluder implantation. The crossing procedure was performed utilizing commercially available equipment: radiofrequency/SureFlex sheath and standard needle/Mullin's sheath. Progressive dilation of the perforation was performed to allow passage of a 12 French Mullin's sheath into the left atrium.ResultsLeft atrial access was achieved in all cases. Postmortem analysis demonstrated passage through both occluder discs in all radiofrequency/SureFlex sheath cases (4 GSO, 4 GCA) and half of the standard needle/Mullin's sheath cases (3 GSO, 1 GCA). The remaining standard needle/Mullin's sheath cases demonstrated perforation through the right atrial disc but passage around the septal aspect of the left atrial disc, thus not perforating the left atrial disc. No acute embolic complications from the procedure were observed.ConclusionsLeft atrial access may be achieved through the GSO or GCA devices after implantation and endothelialization. The combination of a radiofrequency needle and steerable sheath provides benefit over a standard needle and Mullin's sheath in accomplishing passage through both occluder discs.

Utilization of venoarterial extracorporeal membrane oxygenation (VA-ECMO) is expanding, but dual VA-ECMO circuits to treat cardiogenic shock with refractory hypoxemia is unreported. We describe the case of combined cardiogenic and distributive shock due to necrotizing pulmonary blastomycosis. After initial central VA-ECMO cannulation, acute respiratory distress syndrome (ARDS) with increasing shunt resulted in significant central hypoxemia due to progressive ventilation-perfusion mismatch. An additional circuit provided complete oxygenation of the high circulating volume. After 4 months on support, he underwent successful heart-lung-kidney transplantation. Dual ECMO circuits are technically feasible and may be advantageous in specific circumstances of high pulmonary shunting resulting in excessive hypoxemia unbalanced with appropriate oxygen delivery.

7524 Background: A multicenter study (Z4032) compared sublobar resection (SR) to sublobar resection with brachytherapy (SRB) for stage I NSCLC. Local recurrence (LR) and overall survival (OS) rates at 3-years (3-yr) were similar between arms (see abstract 113613). This analysis combines arms, and evaluates the effect of factors previously reported to impact oncological outcomes after SR. Methods: 213 patients (pts) were evaluable for analysis. LR was defined as recurrence at the staple line (local progression), same lobe away from the staple line, or within hilar nodes. Factors assessed for impact on 3-yr outcomes were: resection type (wedge/segmentectomy), margin size (<1cm /≥1cm), margin:tumor ratio (<1/ ≥1), tumor size (≤2cm/>2cm) and staple line cytology (+/-). Results: LR occurred in 27/213 (12.6%) pts and included local progression in 12/213 (5.6%). OS rate at 3-yr was 152/213 (71.4%). Trends favored the use of segmentectomy, margin:tumor ratio≥1, tumor size ≤2cm and negative staple line cytology; no factor reached statistical significance at 3-yr. The only factor significantly (p=0.02) associated with decreased 3-yr LR was margin size ≥1cm (8.3%) compared to margin<1cm (19.3%). Conclusions: SR is a good option for high-risk pts with NSCLC. The 3-yr OS rate of 71.4% and local progression rate of 5.6% are useful benchmarks to compare to other therapies. A resection margin of at least 1 cm is desirable. Clinical trial information: NCT00107172. [Table: see text]

7502 Background: Prior studies suggest that adjuvant brachytherapy reduces local recurrence (LR) after sublobar resection (SR) for NSCLC. A multicenter randomized study was undertaken in patients (pts) with stage I NSCLC ≤3cm comparing SR to SR with brachytherapy (SRB). Methods: High-risk operable patients with NSCLC were randomized to SR or SRB. Brachytherapy involved placement of I125 seeds incorporated into Vicryl sutures or into Vicryl mesh placed over the staple line. Wedge or segmental resection was allowed. The primary endpoint was time to local recurrence (LR) defined as recurrence within the primary tumor lobe at the staple line (local progression), away from the staple line or within hilar nodes. The trial was designed to have 90% power to detect a hazard ratio (HR) of 0.315 in favor of the SRB arm using a one-sided α of 0.05 with a sample size of 100 eligible pts per arm. Follow-up CT scans were obtained serially for 36 months. Results: 224 pts were randomized; 213 (109 SR,104 SRB) were eligible. Median (range) age was 71 (49-87) yrs; 94 (44%) were male. No differences were found in baseline characteristics. Adverse events, previously reported, were not different between arms. Median (range) follow-up was 4.06 (0.04, 5.0) yrs. There was no difference between arms in time to LR (HR = 0.87; 5% CI: 0.41, 1.86, p=0.72) or to LR or death (LRD) (HR = 0.81, 95% CI: 0.50, 1.32, p=0.40). There was no difference between arms in pattern of LR (table). In subgroups of pts with potentially compromised surgical margin (margin < 1cm; margin:tumor ratio <1; positive staple line cytology) SRB did not reduce LR or LRD at 3-yrs. Overall 3-yr survival was similar for SR (71%) and SRB (72%) (p=0.81). Conclusions: LR remains a concern after sublobar resection. However, local progression at the staple line was low. This trial demonstrated that adjuvant brachytherapy does not impact oncologic outcomes. Clinical trial information: NCT00107172. [Table: see text]

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Despite increasing legalization and use of marijuana, there is no consensus among pediatric heart transplant institutions or providers regarding users' eligibility for cardiac transplant. We sent a survey to pediatric and ACHD transplant providers (physicians, surgeons, transplant coordinators, and pharmacists) assessing their current institution's policies and their personal opinions about marijuana use in patients being considered for heart transplantation. Of the respondents, 84% practice in the United States and Canada. Most providers (80%) care for both pediatric and ACHD patients. Respondents included cardiologists (77%) and surgeons (11%), with the remaining being coordinators and pharmacists. Most providers (73%) reported their institution had no policy regarding marijuana use in heart transplant candidates. Only 20% of respondents' institutions consider mode of consumption, with 87% and 53% approving of oral and transdermal routes, respectively, and only 7% approving of vaporized or smoked routes. While 73% of providers would consider illegal marijuana use an absolute/relative contraindication to heart transplant listing, the number decreases to 57% for legal recreational users and 21% for legal medical users. Most providers personally believe marijuana to be physically and mentally/emotionally harmful to pediatric patients (67% and 72%, respectively). Many institutions lack a policy regarding marijuana use in pediatric and ACHD heart transplant candidates, and there is considerable disagreement among providers on the best practice. With increasing legalization and use of marijuana, each institution will have to address this issue thoughtfully to continue to provide high‐quality, consistent, and equitable care for pediatric and ACHD heart transplant candidates.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.