Citations

Background: Percutaneous stellate ganglion blockade (SGB) has been used for drug-refractory electrical storm due to ventricular arrhythmia (VA); however, the effects and long-term outcomes have not been well studied. Methods: This study included 30 consecutive patients who had drug-refractory electrical storm and underwent percutaneous SGB between October 1, 2013, and March 31, 2018. Bupivacaine, alone or combined with lidocaine, was injected into the neck with good local anesthetic spread in the vicinity of the left stellate ganglion (n=15) or both stellate ganglia (n=15). Data were collected for patient clinical characteristics, immediate and long-term outcomes, and procedure-related complications. Results: Clinical characteristics included age, 58±14 years; men, 73.3%; and left ventricular ejection fraction, 34±16%. At 24 hours, 60% of patients were free of VA. Patients whose VA was controlled had a lower hospital mortality rate than patients whose VA continued (5.6% versus 50.0%; P =0.009). Implantable cardioverter-defibrillator interrogation showed a significant 92% reduction in VA episodes from 26±41 to 2±4 in the 72 hours after SGB ( P <0.001). Patients who died during the same hospitalization (n=7) were more likely to have ischemic cardiomyopathy (100% versus 43.5%; P =0.03) and recurrent VA within 24 hours (85.7% versus 26.1%; P =0.009). There were no procedure-related major complications. Conclusions: SGB effectively attenuated electrical storm in more than half of patients without procedure-related complications. Percutaneous SGB may be considered for stabilizing ventricular rhythm in patients for whom other therapies have failed.

AbstractBackgroundVascularized lymph node transfer (VLNT) is an emerging surgical treatment for lymphedema. However, literature‐comparing outcomes of upper limb lymphedema (ULL) and lower limb lymphedema (LLL) is limited. Hence, the aim of this study is to compare the long‐term clinical outcomes on ULL versus LLL in patients treated with VLNT.MethodsA retrospective study retrieving data from patients with International Society of Lymphology (ISL) stages II–III who underwent different VLNTs from July 2010 to July 2016 in our institution was performed. Demographics preoperatively, and clinical data (limb circumference, infectious episodes, lymphoscintigraphic studies) preoperatively and postoperatively were recorded. Clinical outcomes by extremity were also analyzed.ResultsA total of 83 patients with lymphedema (ULL: n = 30, LLL: n = 53) were included. Mean follow‐up time was 32.8 months (range 24–49 months). Mean circumference reduction was higher in patients with ULL compared to with LLL (28.6 ± 8.6 vs. 22.3 ± 10.1, p < .001), and for patients with secondary lymphedema (24.8 ± 9.6, p < .001) than for patients with primary lymphedema (18.9 ± 14, p > .05). Infectious episodes per year preoperative and postoperative showed that LLL patients had higher reduction on infection rate compared with ULL patients (2.4 ± 1.1 vs. 1.9 ± 1.2, p < .001).ConclusionVLNT is a promising surgical treatment option for patients with lymphedema. This study suggests that VLNT may have a more beneficial outcome in patients with ULL and with secondary lymphedema.

Abstract Background Previous studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re‐examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS. Methods Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low‐, intermediate‐ and high‐risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event‐free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross‐validated results. Results The 5‐year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%). Conclusions After metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials.

AbstractBackgroundEnterococcal cardiovascular implantable electronic device (CIED) infections are not well characterized.MethodsData from the Multicenter Electrophysiologic Device Infection Cohort, a prospective study of CIED infections, were used for descriptive analysis of adults with enterococcal CIED infections.ResultsOf 433 patients, 21 (4.8%) had enterococcal CIED infection. Median age was 71 years. Twelve patients (57%) had permanent pacemakers, five (24%) implantable cardioverter defibrillators, and four (19%) biventricular devices. Median time from last procedure to infection was 570 days. CIED‐related bloodstream infections occurred in three patients (14%) and 18 (86%) had infective endocarditis (IE), 14 (78%) of which were definite by the modified Duke criteria. IE cases were classified as follows: valvular IE, four; lead IE, eight; both valve and lead IE, six. Vegetations were demonstrated by transesophageal echocardiography in 17 patients (81%). Blood cultures were positive in 19/19 patients with confirmed results. The most common antimicrobial regimen was penicillin plus an aminoglycoside (33%). Antibiotics were given for a median of 43 days. Only 14 patients (67%) underwent device removal. There was one death during the index hospitalization with four additional deaths within 6 months (overall mortality 24%). There were no relapses.ConclusionsEnterococci caused 4.8% of CIED infections in our cohort. Based on the late onset after device placement or manipulation, most infections were likely hematogenous in origin. IE was the most common infection syndrome. Only 67% of patients underwent device removal. At 6 months follow‐up, no CIED infection relapses had occurred, but overall mortality was 24%.

Abstract Background: Prospective validation of breast cancer risk models integrating classical risk factors and genetic variants is required for risk-stratified prevention and screening strategies. The objective of this study was to validate a breast cancer risk model integrating classical risk factors and a 313-variant polygenic risk score (PRS) in multiple prospective cohort studies, and to project five-year risk of breast cancer in six different countries. Methods: The study population included 7,529 cases and 230,103 controls from 14 prospective cohort studies in Australia, Germany, the Netherlands, Sweden, UK, and USA. We used the Individualized Coherent Absolute Risk Estimator (iCARE) tool for risk model building, validation, and risk projection. Expected five-year risk of invasive or in situ breast cancer was compared to observed risk, overall and within deciles of expected risk using goodness of fit statistics. We evaluated calibration of the relative risk through meta-analysis across cohorts, and of the absolute risk within each cohort. Model discrimination was evaluated using the area under the curve (AUC), and percentages of women crossing risk thresholds. Projections of five-year risk distributions were estimated for women of European ancestry aged 50-70 years in the general populations of these six countries. Results: Analysis showed overall good calibration of the integrated iCARE-based model relative risk for both women younger than 50 years (χ2=14.9, P=0.09) and aged 50 years or older (χ2=14.6, P=0.10), with a small overestimation of risk for women in the highest decile of expected risk (RR = 3.5 expected vs 2.3 (95% CI 1.6 to 3.2) observed for women &lt;50 years; and 2.8 expected vs 2.3 (95% CI 2.0 to 2.7) observed for women 50+ years). The age-adjusted AUCs for the integrated model were 63.1 (95% CI 60.9 to 65.3) and 62.9 (95% CI 61.8 to 64.0), for the two age groups respectively. The calibration of absolute risk showed substantial variation across cohorts, particularly for the older group, but had no systematic bias. Model based projections in the general populations showed that compared to the population average, women in the 1st and 99th percentiles of the integrated risk score had relative risks 0.19 and 3.56 respectively. The proportion of women of European ancestry aged 50-70 years with a five-year risk greater than 3% (threshold for consideration of risk-lowering drugs by U.S. Preventive Services Task Force) ranged from 7.1% in Germany to 18.2% in the US, which corresponds to ~5.5 million women in the US. Conclusions: Five-year risk predictions from a model with classical risk factors and PRS are well calibrated and provide substantial risk stratification across multiple cohorts in six different countries. Further studies are needed to evaluate the clinical utility of the validated model for risk stratified screening and prevention of breast cancer. Citation Format: Parichoy Pal Choudhury, Amber Wilcox, Chi Gao, Brian Carter, Anika Husing, Mark Brook, Mikael Eriksson, Kara Martin, Chris Scott, Min Shi, Thomas Ahearn, Michael Jones, Nick Orr, Minouk Schoemaker, Kamila Czene, Jenny Chang-Claude, Jacques Simard, Doug Easton, Marjanka K. Schmidt, Dale Sandler, Clarice R. Weinberg, Celine Vachon, Roger Milne, Per Hall, Anthony Swerdlow, Rudolph Kaaks, Myrto Barrdahl, Mia Gaudet, Antonis Antoniou, Peter Kraft, Montserrat Garcia-Closas, Nilanjan Chatterjee. Validation of breast cancer risk model incorporating classical risk factors and polygenic risk scores in 14 prospective cohort studies in 6 countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 962.

Abstract Background: Understanding the joint effect on breast cancer risk of rare pathogenic variants in cancer predisposition genes and polygenic risk scores (PRS) from common variants can enable a precision approach to breast cancer management. Previous work found that PRS were associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers recruited from cancer genetics clinics (Kuchenbaecker et al. JNCI 2017). The joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no existing study evaluating the effect of PRS in mutation carriers in genes other than BRCA1/2. Here we evaluate the joint effects of PRS and pathogenic mutations in established cancer predisposition genes in a population-based case-control sample. Method: We analyzed 53,199 European-ancestry individuals (20,730 controls and 21,272 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using dual bar-coded QIAseq. Mutation calling was conducted with Haplotype Caller and Vardict. We sequenced 18 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHECK2, FANCC, MLH1, MSH2, MSH6, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53. The PRS was calculated based on 128 common variants using effect estimates from the largest published breast cancer GWAS. The PRS was standardized to a mean of 0 and standard deviation of 1. Logistic regression was performed to assess the combined effect of identified mutation and common variants (including main and interaction effects for carrier status and PRS). Results: A total of 1,770 pathogenic mutations were observed. About 1% of the study sample had mutations in either BRCA1 (n=209) or BRCA2 gene (n=305), and 2.2% had mutations in other genes (n=1,176). The effect of PRS in BRCA1 carriers was OR= 0.97 (95%CI: 0.62, 1.52); however, this is not statistically significantly different from the PRS in non-carriers [OR=1.23 (95%CI: 1.20, 1.25)] or previous estimates in carriers [OR: 1.14, 95%CI: 1.11-1.17]. The effect of PRS in BRCA2 carriers was OR=1.87 (95%CI: 1.31, 2.78) which was statistically significantly different from that of the non-carriers. Among the mutation carriers in genes other than BRCA, the effect of PRS on breast cancer was OR=1.00 (95%CI: 0.88,1.15). Conclusion: Consistent with previous studies, we did not find evidence that the effect of the PRS among BRCA1 carriers was statistically significantly different than non-carriers. We found some evidence that the PRS effect may be larger among BRCA2 carriers than non-carriers. Our results also suggest that PRS may not have a strong effect on breast cancer risk in mutation carriers of other predisposition genes; further work is needed for verification. Citation Format: Chi Gao, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jenna Lilyquist, Nicholas J. Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Paul Auer, Leslie Bernstein, Mia Gaudet, Hoda Anton-Culver, Amy Trentham-Dietz, Julie R. Palmer, Song Yao, Christopher Haiman, Janet E. Olson, Susan Domchek, Jeffrey Weitzel, David Goldgar, Katherine L. Nathanson, Eric C. Polley, Fergus J. Couch, Peter Kraft. The joint effects of polygenic risk scores and pathogenic variants in cancer predisposition genes on breast cancer risk in the general population: results from the CARRIERS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4177.

Abstract Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. Pathogenic mutations in cancer predisposition genes are associated with established risks of breast cancer and are actively used for risk management of breast cancer for women qualifying for genetic testing because of a family history of breast and/or ovarian cancer or young age of diagnosis. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study was to estimate breast cancer risks associated with mutations in hereditary cancer panel genes. Germline DNA from 32,298 breast cancer patients and 31,869 matched unaffected controls enrolled in cohorts and population-based case-control studies were sequenced to identify pathogenic mutations in 37 cancer predisposition genes.The average age at diagnosis was 61.2 years and the average age of last follow-up was 62.1 years. DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions in 37 predisposition genes. Products from 768 samples were pooled and sequenced in a single lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Vardict.High quality sequence data was obtained for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified in 6.2% 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. In case-control association analyses adjusted for age at diagnosis or last follow up and family history of breast and ovarian cancer, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR)&gt;4.0). Mutations in CHEK2 and BARD1 were associated with moderate risks of breast cancer (OR&gt;2.0), whereas mutations in ATM had lower clinical relevance (OR=1.6). Stratification by ER, PR, and HER2 status of tumors found that BRCA1, BRCA2, PALB2 and TP53 were associated with high risks of studies of triple negative breast cancer (TNBC), and that BARD1, BRIP1, FANCM, and RAD51C were associated with moderate risks of TNBC. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in high-risk families. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform on the use of cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J. Couch, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Jenna Lilyquist, Kun Y. Lee, Chi Gao, Bruce Eckloff, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia Gaudet, Christopher Haiman, Julie Palmer, Amy Tentham-Dietz, Song Yao, Susan Domchek, Jeffrey N. Weitzel, David E. Goldgar, Katherine L. Nathanson, Peter Kraft, Eric C. Polley. Population-based breast cancer risk estimates associated with cancer predisposition gene mutations from 32,298 breast cancer patients and 31,869 matched unaffected controls from the CARRIERS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4169.

IntroductionManagement after total pharyngolaryngectomy with free ileocolon flaps can be challenging. Adequate postoperative surgical guidelines are essential to avoid complications. Factors, such as agitation, hypotension, or prolonged mechanical ventilation, might compromise final outcomes. Herein, we describe our experience in the early postoperative care of patients after total pharyngolaryngectomy with immediate reconstruction using the free ileocolon flap.MethodsThis is a retrospective review of all patients who underwent total pharyngolaryngectomy and immediate reconstruction using the free Ileocolon flap. Demographics, etiology of resection, neoadjuvant therapy, surgical time, method of sedation, postoperative use of vasopressors, length of intensive care unit (ICU) stay, time of discontinuation of mechanical ventilation, and complications were recorded and analyzed.ResultsBetween 2010 and 2015, a total of 34 patients underwent total pharyngolaryngectomy and immediate reconstruction using the free Ileocolon flap. The most common cause of total pharyngolaryngectomy was cancer. Twenty-eight patients had neoadjuvant therapy (radiation). The average surgical time was 11.5 hours (range, 8–14.5 hours), average length of ICU stay was 3 days (range, 2–15 days) with an average time for mechanical ventilation cessation of 3 days (range, 1–20 days). Midazolam and dexmedetomidine were the most common sedatives used during surgery and in the ICU period. Three patients required vasopressors due to hypotension, 2 had unplanned self-extubation from the tracheostomy site, 2 experienced postoperative bleeding, 1 had pneumonia, 4 required unplanned return to the operating room, 2 had partial flap loss, and 1 had complete flap loss.ConclusionsOverall, a majority of patients recovered well postoperatively with minimal complications and low rate of reoperation. Our research provides a foundation to develop a risk-stratified approach to determine the need for an ICU admission or early transfer to floor care.

Background:Iberdomide (IBER) is a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that is being investigated as monotherapy, in combination with dexamethasone (DEX), and in combination with DEX and daratumumab or bortezomib in a phase 1b/2a dose‐escalation study in relapsed/refractory multiple myeloma (RRMM). IBER modulates CRBN, which induces ubiquitination of Aiolos, Ikaros and ZFP91, increases their proteasome‐dependent degradation, and thereby inhibits myeloma cell growth. IBER binds more potently to CRBN and is more efficient at degrading Aiolos and Ikaros than the immunomodulatory agents (IMiDs) lenalidomide (LEN) and pomalidomide (POM) and it can overcome IMiD drug resistance in pre‐clinical models.Aims:To determine if IBER is pharmacodynamically (PD) active in multiple myeloma patients refractory to POM and/or LEN, and to establish pharmacokinetic (PK)/PD and PD/dose relationships.Methods:As of Jan 11, 2019, 83 patients received IBER as monotherapy or in combination with DEX; 61 (74%) were LEN refractory and 47 (57%) were POM refractory. Longitudinal immunohistochemistry (IHC) data on CRBN, Aiolos, Ikaros and ZFP91 expression was obtained from bone marrow samples from 14 patients dosed with 0.3–0.9 mg IBER daily ± DEX. PD analysis of immune activity by TruCulture® (n = 45) and by peripheral blood flow cytometry (n = 60) was completed on a subset of patients dosed up to 1.0 mg IBER ± DEX. A population PK approach was used to estimate exposure (area under the concentration curve over the 24 hr dosing interval [AUCτ]) on 59 patients dosed up to 1.0 mg IBER ± DEX.Results:IBER AUCτ increased in a dose‐proportional manner in RRMM patients over the dose range 0.3–1.0 mg (22.4–65.31 ng∗hr/mL, respectively). In patient biopsies analyzed to date, CRBN expression was observed in all tumors by IHC at baseline and did not significantly change while on‐treatment. Furthermore, no significant decrease in baseline CRBN expression was observed in patients refractory to POM. In MM cells, significant decreases in Aiolos (median 37% decrease, P < 0.001), Ikaros (median 12% decrease, P = 0.006), and ZFP91 (median 47% decrease, P < 0.001) protein expression were observed on‐treatment across all dose levels; these decreases were unrelated to levels of CRBN expression at screening or prior LEN or POM refractoriness. In TruCulture® samples, dose‐dependent increases were observed in IL‐2 and IFN‐γ, with median increases of 78% and 66%, respectively, 5 hours post 0.9 mg dose of IBER. A dose‐ and exposure‐dependent decrease in B‐cells was detected (median 74% decrease at cycle 2 day 15, IBER 0.9 mg). These observations are consistent with the proposed IBER mechanism of action. Immunoprofiling showed significant increases in total and proliferating NK cells in RRMM patients treated with IBER, and a dose‐dependent increase in proliferating, activated, and effector memory T‐cells. These trends were consistent in RRMM patients treated with IBER monotherapy and in combination with DEX.Summary/Conclusion:These translational analyses from IBER treated RRMM patients indicate it is pharmacodynamically active at the lowest dose (0.3 mg) and exhibits dose‐ and exposure‐dependent immunostimulatory activity, supporting further dose‐escalation beyond 1.0 mg, which is currently ongoing. These results also suggest that prior refractoriness to LEN or POM is not associated with significant loss of CRBN or IBER PD activity, supporting continued investigation of IBER in RRMM patients refractory to IMiD drugs.