Citations

AbstractIntroductionAutonomic modulation has been used as a therapy to control recurrent ventricular arrhythmia (VA). This study was to explore stellate ganglion block (SGB) effect on cardiac electrophysiologic properties and evaluate the long‐term outcome of cardiac sympathetic denervation (CSD) for patients with recurrent VA and structural heart disease (SHD).Materials and MethodsPatients who had recurrent VA due to SHD were enrolled prospectively. Electrophysiologic study and ventricular tachycardia (VT) induction were performed before and after left and right SGB. VA burden and long‐term outcomes were assessed for a separate patient group who underwent left or bilateral CSD for drug‐refractory VA due to SHD.ResultsElectrophysiologic study of nine patients showed that baseline mean (SD) corrected sinus node recovery time (cSNRT) increased from 320.4 (73.3) ms to 402.9 (114.2) ms after left and 482.4 (95.7) ms after bilateral SGB (P = .03). SGB did not significantly change P‐R, QRS, and Q‐T intervals and ventricular effective refractory period, nor did the inducibility of VA. Nineteen patients underwent left (n = 14) or bilateral (n = 5) CSD. CSD reduced VA burden and appropriate ICD therapies from a median (interquartile range) of 2.5 (0.4‐11.6) episodes weekly to 0.1 (0.0‐2.4) episodes weekly at 6‐month follow‐up (P = .002). Three‐year freedom from orthotopic heart transplant (OHT) and death was 52.6%. New York Heart Association functional class III/IV and VT rate less than 160 beats per minute were predictors of recurrent VA, OHT, and death.ConclusionSGB increased cSNRT without changing heart rate. CSD was more beneficial for patients with mild‐to‐moderate heart failure and faster VA.

Background The objective of this study was to evaluate local control for patients with intermediate‐risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. Methods This study analyzed 424 patients with intermediate‐risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate‐risk study, D9803. Results For patients with group I/II alveolar RMS (n = 55), the 5‐year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% ( P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 ( P = .02). After adjustments for clinical prognostic factors, event‐free survival and overall survival were worse on ARST0531 ( P = .004 and P = .05, respectively). Conclusions Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.

104 Background: The identification of pathogenic mutations in breast cancer susceptibility genes through clinical genetic testing leads to focused screening and prevention strategies for women at increased risk of cancer. However, the frequency of mutations and the risks of cancer associated with breast cancer predisposition genes has not been established for the African American population. Methods: Germline DNA samples from African American women (5,054 breast cancer cases and 4,993 age-matched unaffected controls) from 10 U.S. studies were tested for mutations in 20 established breast cancer predisposition genes using a QIAseq multiplex amplicon panel as part of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study. The frequency of mutations in each gene and associations between mutations and breast cancer risk, adjusted for study design, age, and first-degree family history of breast cancer, were evaluated. Results: The mean age at diagnosis of breast cancer cases was 54.4 years and the mean age of controls was 55.2 years. 18.2% of cases and 10.8% of controls reported a first-degree family history of breast cancer. Pathogenic mutations in any of the 20 breast cancer predisposition genes were identified in 7.6% of breast cancer cases and 2.4% of controls. In multivariable analyses, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR) > 5.0). Mutations in CHEK2 were associated with moderate risks of breast cancer (OR > 2.0), whereas mutations in ATM had lower clinical relevance (OR = 1.8). Mutations in BRCA1, BRCA2, PALB2, and RAD51D, but not CHEK2 or ATM, were associated with increased risks of estrogen receptor negative breast cancer. Conclusions: Cancer predisposition genes confer similar risks of breast cancer in the African American population as in non-Hispanic Whites. These studies provide important insights into the risks of breast cancer associated with predisposition gene mutations in the African American population.

Abstract Lymphedema refers to the accumulation of protein-rich fluid in the interstitial spaces. This can occur secondary to congenital malformation of the lymphatic channels or nodes or as a result of an insult that damages appropriately formed channels and nodes. Stagnant, protein-rich lymph initiates an inflammatory response that leads to adipocyte proliferation, fibrous tissue deposition, and increased susceptibility to infections. The end result is permanent disfigurement and dermal changes. Early and accurate diagnosis is essential, since lymphedema is a chronic and progressive problem. When lymphedema affects the lower extremity, it is important to manage it in a way that preserves function and mobility. Early diagnosis also allows for a proactive rather than reactive approach to treatment and utilization of novel physiologic procedures, such as lymphovenous anastomosis and vascularized lymph node transfer. Such interventions slow down disease progression and reduce morbidity by allowing the surgeon to salvage the remaining functional lymphatic channels. When physiologic procedures fail or when faced with a delayed presentation, the addition of excisional procedures can provide a more comprehensive treatment of this debilitating disease. The aim of this article is to review the most current concepts in the surgical management of lower extremity lymphedema.

Abstract Background: Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. The identification of pathogenic mutations in established high and moderate predisposition genes may result in improved risk management of breast cancer for tested patients and their family members through tailored screening, prophylactic surgeries, or chemoprevention. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population because previous studies have focused on individuals with a family history of breast and/or ovarian cancer, early onset disease, or triple negative breast cancer. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study is to estimate breast cancer risks associated with mutations in hereditary cancer panel genes in the general population. Methods: Germline DNA samples from blood or saliva were obtained from 39,439 breast cancer patients and matched unaffected controls from six US-based cohorts (BWHS, CPSII, CTS, MEC, NHS1, NHS2, WHI). DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions covering all coding regions of 37 cancer predisposition genes and sequenced. Mutation calling was conducted with Haplotype Caller and Vardict. Results: High quality sequence data was obtained for 38,990 of 39,439 samples (98.9%) and for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified 4.5% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. Differences in mutation frequencies were observed by age with mutations in 7.8% of cases diagnosed £50 years of age and 4.0% of cases diagnosed over age 50. Mutations in ATM, BRCA1, BRCA2, and PALB2 were enriched 2 to 3-fold in cases diagnosed under age 50 relative to older cases. No change in frequency of CHEK2 mutations by age was observed. In case-control analyses mutations in BRCA1, BRCA2 and PALB2 were significantly associated with a high risk of breast cancer (odds ratio (OR)>4.0). Of these, BRCA1 and BRCA2 displayed ORs of 13.5 and 16.6 in the £50 age group, but only 5.7 and 3.2 in the >50 age group. Only minor age-specific effects were observed for PALB2. Mutations in ATM and CHEK2 were associated with moderate risks of breast cancer (OR=2.0 to 4.0) in the younger age group, but not in the older age group. Conclusions: Results from the CARRIERS cohort-based study establish that mutations in known breast cancer predisposition genes are associated with only moderate risks of breast cancer in the general population. However, risks are substantially increased for BRCA1 and BRCA2 but not ATM, CHEK2 or PALB2 mutations in those £50 years of age. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform selection of individuals in the general population who may benefit from genetic testing and associated risk management strategies. Citation Format: Couch FJ, Hu C, Hart SN, Gnanaolivu RD, Lilyquist J, Lee KY, Gao C, Eckloff B, Samara R, Klebba J, Auer P, Bernstein L, Gaudet M, Haiman C, Palmer JR, Yao S, Domchek SM, Weitzel JN, Goldgar DE, Nathanson KL, Kraft P, Polley EC. Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-01.

We provide a case report of reconstruction of a massive chest wall defect after recurrent phyllodes tumour resections. The reconstruction used a bipedicled groin and latissimus dorsi flap, with composite rib autologous reconstruction. The patient successfully recovered from the operation. Our case illustrates the applicability of this flap in the armamentarium of anterior chest wall reconstructive options.

During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF‐β). The result is an epigenetically regulated transcriptional program leading to a pro‐fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF‐β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF‐β. Ingenuity pathway analysis identified “HSC Activation” as the highly up‐regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF‐β response. EZH2 overexpression suppressed TGF‐β‐induced FN protein in vitro, suggesting FN as a direct target of EZH2‐based repression. Chromatin immunoprecipitation assays identified an FN promoter element in which EZH2‐mediated tri‐methylation of lysine 27 on histone 3 is diminished by TGF‐β. TGF‐β also caused a 50% reduction in EZH2 protein levels. Proteasome inhibition rescued EZH2 protein and led to reduced FN production. Immunoprecipitation followed by mass spectrometry identified ubiquitin protein ligase E3 component N‐recognin 4 in complex with EZH2, which was validated by western blotting in vitro. Ubiquitin mutation studies suggested K63‐based ubiquitin linkage and chain elongation on EZH2 in response to TGF‐β. A deletion mutant of EZH2, lacking its N‐terminal domain, abrogates both TGF‐β‐stimulated EZH2 degradation and FN release. In vivo, cholangiocyte‐selective knockout of EZH2 exacerbates bile duct ligation–induced fibrosis whereas MDR2‐/‐ mice are protected from fibrosis by the proteasome inhibitor bortezomib. Conclusion: TGF‐β regulates proteasomal degradation of EZH2 through N‐terminal, K63‐linked ubiquitination in cholangiocytes and activates transcription of a fibrogenic gene program that supports biliary fibrosis.

Interstitial lung disease (ILD) is an inflammatory condition encompassing greater than 200 different chronic disorders that often lead to pulmonary fibrosis and the attendant morbidity and mortality. Distinguishing one ILD from another can be challenging even for experts given similar clinical manifestations. However, firm diagnosis is important for management, counseling, and surveillance. Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER, Mayo Clinic, Rochester, MN, USA), a machine learned image analysis tool for characterizing and quantifying diffused lung diseases on CT, has been shown to correlate with ILD mortality such as for idiopathic pulmonary fibrosis. The CALIPER assessment of ILD is not influenced by confounding conditions such as emphysema or pulmonary hypertension that may affect pulmonary function measurements. Moreover, CALIPER can provide more reproducible results with less inter- and intraobserver variability compared to the conventional subjective visual assessment of CT scans by radiologists. Herein, we aim to provide an overview of ILD and discuss CALIPER evaluation of ILD.

Purpose: The purpose of this study was to characterize reductions in intraocular pressure (IOP) and the need for IOP-lowering medications following phacoemulsification combined with Kahook Dual Blade-assisted goniosynechialysis and excisional goniotomy in eyes with angle-closure glaucoma and cataract. Methods: In this retrospective, interventional case series, preoperative, operative, and postoperative data were collected through 6 months of follow-up from 42 eyes of 24 subjects. Outcomes included mean IOP reduction, reduction in IOP-lowering medications, and the proportion of patients achieving IOP reduction ≥20%, IOP≤18 mm Hg, and reduction of ≥1 medication. Results: Preoperatively, mean (SE) IOP was 25.5 (0.7) mm Hg and the mean number of IOP-lowering medications used was 2.3 (0.1) per eye. Through 6 months of follow-up, mean IOP reductions of 10.1 to 12.8 mm Hg (38.4% to 49.5%; P <0.0001) and mean IOP medication reductions of −2.2 to −2.3 (91.7% to 98.4%; P <0.0001) were seen. At month 6, 92.9% of eyes (39/42) achieved IOP≤18 mm Hg, 100% (42/42) achieved IOP reduction of ≥20%, 100% (42/42) required ≥1 fewer medications for IOP control, and 85.7% (36/42) were medication free. Conclusions: Phacoemulsification combined with Kahook Dual Blade-assisted goniosynechialysis and excisional goniotomy safely provides statistically and clinically meaningful reductions in both IOP and the need for IOP-lowering medications in eyes with angle-closure glaucoma.