Citations

Background: Recognition of rates and causes of hard, patient-centered outcomes of death and cerebrovascular events (CVEs) after heart rhythm disorder management (HRDM) procedures is an essential step for the development of quality improvement programs in electrophysiology laboratories. Our primary aim was to assess and characterize death and CVEs (stroke or transient ischemic attack) after HRDM procedures over a 17-year period. Methods: We performed a retrospective cohort study of all patients undergoing HRDM procedures between January 2000 and November 2016 at the Mayo Clinic. Patients from all 3 tertiary academic centers (Rochester, Phoenix, and Jacksonville) were included in the study. All in-hospital deaths and CVEs after HRDM procedures were identified and were further characterized as directly or indirectly related to the HRDM procedure. Subgroup analysis of death and CVE rates was performed for ablation, device implantation, electrophysiology study, lead extraction, and defibrillation threshold testing procedures. Results: A total of 48 913 patients (age, 65.7±6.6 years; 64% male) who underwent a total of 62 065 HRDM procedures were included in the study. The overall mortality and CVE rates in the cohort were 0.36% (95% confidence interval [CI], 0.31–0.42) and 0.12% (95% CI, 0.09–0.16), respectively. Patients undergoing lead extraction had the highest overall mortality rate at 1.9% (95% CI, 1.34–2.61) and CVE rate at 0.62% (95% CI, 0.32–1.07). Among patients undergoing HRDM procedures, 48% of deaths directly related to the HDRM procedure were among patients undergoing device implantation procedures. Overall, cardiac tamponade was the most frequent direct cause of death (40%), and infection was the most common indirect cause of death (29%). The overall 30-day mortality rate was 0.76%, with the highest being in lead extraction procedures (3.08%), followed by device implantation procedures (0.94%). Conclusions: Half of the deaths directly related to an HRDM procedure were among the patients undergoing device implantation procedures, with cardiac tamponade being the most common cause of death. This highlights the importance of the development of protocols for the quick identification and management of cardiac tamponade even in procedures typically believed to be lower risk such as device implantation.

OBJECTIVE Artificial pancreas (AP) systems are best positioned for optimal treatment of type 1 diabetes (T1D) and are currently being tested in outpatient clinical trials. Our consortium developed and tested a novel adaptive AP in an outpatient, single-arm, uncontrolled multicenter clinical trial lasting 12 weeks. RESEARCH DESIGN AND METHODS Thirty adults with T1D completed a continuous glucose monitor (CGM)-augmented 1-week sensor-augmented pump (SAP) period. After the AP was started, basal insulin delivery settings used by the AP for initialization were adapted weekly, and carbohydrate ratios were adapted every 4 weeks by an algorithm running on a cloud-based server, with automatic data upload from devices. Adaptations were reviewed by expert study clinicians and patients. The primary end point was change in hemoglobin A1c (HbA1c). Outcomes are reported adhering to consensus recommendations on reporting of AP trials. RESULTS Twenty-nine patients completed the trial. HbA1c, 7.0 ± 0.8% at the start of AP use, improved to 6.7 ± 0.6% after 12 weeks (−0.3, 95% CI −0.5 to −0.2, P < 0.001). Compared with the SAP run-in, CGM time spent in the hypoglycemic range improved during the day from 5.0 to 1.9% (−3.1, 95% CI −4.1 to −2.1, P < 0.001) and overnight from 4.1 to 1.1% (−3.1, 95% CI −4.2 to −1.9, P < 0.001). Whereas carbohydrate ratios were adapted to a larger extent initially with minimal changes thereafter, basal insulin was adapted throughout. Approximately 10% of adaptation recommendations were manually overridden. There were no protocol-related serious adverse events. CONCLUSIONS Use of our novel adaptive AP yielded significant reductions in HbA1c and hypoglycemia.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta = 2.95, p < 2.0 × 10 −16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10 −16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1‐34 and anti‐sclerostin antibody attenuates radiation‐induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone‐protective effects against radiation damage. MG132 treatment greatly reduced radiation‐induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up‐regulation of Ku70 and DNA‐dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end‐ joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone‐lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation‐induced osteoporosis.—Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.‐J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis. FASEB J. 32, 52‐62 (2018). www.fasebj.org

Abstract Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. FGFR2 translocations are the most common FGFR alterations, which occur in ~13% of pts with intrahepatic CCA and involve a variety of fusion partners/breakpoints. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or surgically unresectable CCA (Table; NCT02924376). Pts will be prescreened centrally for FGF/FGFR status and enrolled in the following cohorts prior to start of treatment: FGFR2 translocations (Cohort A); other FGF/FGFR alterations (Cohort B); no FGF/FGFR alterations (Cohort C; negative control for effects of FGF/FGFR alterations on objective response rate [ORR]). Pts must be aged ≥18 years, with Eastern Cooperative Oncology Group performance status ≤2, disease progression after ≥1 prior systemic therapy, and no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg once-daily on a 21-day cycle (2 weeks on; 1 week off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response per independent radiologic review committee using Response Evaluation Criteria in Solid Tumors v1.1) in pts with FGFR2 translocations (Cohort A). Secondary endpoints will include ORR in pts positive or negative for any FGF/FGFR alterations and duration of response, progression-free survival, overall survival, and safety (all cohorts). The study is currently open for enrollment (estimated primary completion date, April, 2018). Study DesignPrescreen for FGF/FGFR Status• Adults with metastatic/surgically unresectable cholangiocarcinoma with disease progression after ≥1 previous systemic treatment- FGFR2 translocations → cohort A (n~60)- Other FGF/FGFR alterations → cohort B (n~20)- No FGF/FGFR alterations → cohort C (n~20)Screen for eligibility criteria and patient characteristics• Eastern Cooperative Oncology Group performance status ≤2• Adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN; ≤2.5 × ULN for Gilbert syndrome or disease involving liver]; aminotransferases &lt;2.5 × ULN [&lt;5 × ULN with liver metastases])• Adequate renal function (creatinine clearance ≥30 mL/min; serum phosphate &gt;institutional ULN; serum calcium &gt;institutional normal range; potassium &gt;institutional lower limit of normal)• Life expectancy ≥12 weeksEnroll and initiate INCB054828 treatment• Oral once daily dosing: 21-day (2-weeks-on/1-week-off) cycleStart response assessment after cycle 2• Stable disease/partial or complete response → continue treatment with restaging after cycle 4; imaging assessments increase to every 3 cycles after cycle 4• Disease progression → discontinue treatment; safety and survival follow-up Citation Format: Mitesh J. Borad, S. Lindsey Davis, Maeve A. Lowery, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Ghassan K. Abou-Alfa. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT063. doi:10.1158/1538-7445.AM2017-CT063

Abstract Mutant peptides presented in cancer are superior vaccine candidates than self peptides. The efficacy of mutant K-Ras, P53 and EFGR peptides have been tested as cancer vaccines in pancreatic cancer, colorectal cancer, and lung adenocarcinoma. However, the occurrence of these mutations in cancer is limited. Further more, these mutant peptides can only be presented by certain MHC alleles. Neoantigens expressed by passenger mutations which are not involved in common proliferative molecular pathways are potential candidates for personalized vaccine design. Such passenger mutations have drawn attention by the recent clinical data that colorectal cancer with a large number of somatic mutations due to mismatch-repair defects are more susceptible to immune checkpoint blockade by PD1 antibody therapy. In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules. We found 18175 expressed clonal somatic mutations, with an average of 124 per patient. Based on such somatic mutations, we predicted 8731 neo-peptides, among which 3888 strong-binders and 4843 weak-binders to MHC Class I molecules were found by NetMHCPan. For HLA-A*02:01, 778 strong binding and 822 weak binding neo-peptides were found. In average, 11 neo-antigen peptides of mutations were predicted per individual patient with HLA-A*02:01 allele. Smokers expressed 5.73 fold higher mutant neo-antigen peptides than non-smokers. The 20 most commonly mutated genes with predicted neo-antigens are TTN, RYR2, MUC16, KRAS, ZFHX4, TP53, USH2A, NAV3, KEAP1, ANK2, DNAH9, ADAMTS12, CSMD1, CSMD3, SPTA1, FAT3, ZNF804A, PAPPA2, PCLO, EGFR. As a positive control, the frequency of known proliferation-related mutations (KRAS, P53, and EGFR) were determined in 147 patients, which are consistent with previously next generation sequencing studies of lung adenocarcinoma. Mutation hotspots were found in proliferation-related mutations (KRAS), but not in passenger mutations. 6950 neo-peptides, including 259 strong binders and 6691 weak binders were found for HLA DRB1, an MHC Class II molecule. INDEL mutation type of neo-epitopes were found in 119 of 147 patients, with an average of 4.34 INDEL mutations presented by MHC Class I and 0.86 INDEL mutations presented by MHC Class II molecule HLA DRB1 in every patient. Our results support the feasibility of discovering individualized mutant peptides as candidates for immunodiagnosis and immunotherapy of lung adenocarcinoma. Neo-epitopes which can be presented by both MHC Class I and MHC Class II molecules are attractive targets for designing long-peptide vaccines. Note: This abstract was not presented at the meeting. Citation Format: Dapeng Zhou, Weijing Cai, Deng Pan, Tan Wen Ling, Jiaqian Wang, Caichun Zhou, Yanyan Lou. Neoantigens predicted by clonal mutation analysis in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 628. doi:10.1158/1538-7445.AM2017-628

BackgroundReconstruction in a vessel‐depleted neck is challenging. The success rates can be markedly decreased because of unavailability of suitable recipient vessels. In order to obtain a reliable flow, recipient vessels away from the zone of fibrosis, radiation, or infection need to be explored. The aim of this report is to present our experience and clinical outcomes using the retrograde flow coming from the distal transverse cervical artery (TCA) as a source for arterial inflow for complex head and neck reconstruction in patients with a vessel‐depleted neck.MethodsBetween July 2010 and June 2016, nine patients with a vessel‐depleted neck underwent secondary head and neck reconstruction using the retrograde TCA as recipient vessel for microanastomosis. The mean age was 49.6 years (range, 36 to 68 years). All patients had previous bilateral neck dissections and all, except one, had also received radiotherapy. Indications included neck contracture release (n = 3), oral (n = 1), mandibular (n = 3) and pharyngoesophageal (n = 2) reconstruction necessitating free anterolateral thigh (n = 3) and medial sural artery (n = 1) perforator flaps, fibula (n = 3) and ileocolon (n = 2) flaps respectively.ResultsThere was 100% flap survival rate with no re‐exploration or any partial flap loss. One case of intra‐operative arterial vasospasm at the anastomotic suture line was managed intra‐operatively with vein graft interposition. There were no other complications or donor site morbidity during the follow‐up period.ConclusionsIn a vessel‐depleted neck, the reverse flow of the TCA may be a reliable option for complex secondary head and neck reconstruction in selected patients.

AbstractObjectivesWe assessed the effectiveness and safety of cryoballoon ablation (CBA) in the Chinese population with paroxysmal atrial fibrillation (AF) with a 1‐year follow‐up and determined the association of early recurrence of atrial tachyarrhythmias (ERAT) with late recurrence (LR).MethodsA total of 114 patients (age 61 ± 10 years, 78 males) with paroxysmal AF who underwent CBA were consecutively enrolled. After procedures, patients were observed for 3 days with continuous electrocardiogram monitoring in the hospital with routine follow‐up visits at 3 months, 6 months, and 1 year. Documented atrial tachyarrhythmia >30 seconds was defined as recurrence. ERAT was defined as any recurrence during the first 3 months, and LR was recurrence between 3 and 12 months.ResultsWith the first 3 months as blanking period, 76% of patients were free of LR at 12 months. Five patients (4%) experienced complications, including phrenic nerve palsy, stroke, and groin complications. Forty‐five percent of patients had ERAT in the first 3 months and 31% of patients had ERAT in the first 3 days. Patients with ERAT had higher LR rate (LRR) than those without ERAT (43% vs 8%, P < 0.001). The LRR of patients with ERAT only in the first 3 days was lower than those with ERAT both in the first 3 days and in 4–90 days (29% vs 64%, P = 0.036).ConclusionsCBA was an effective and safe treatment option for paroxysmal AF. Patients with ERAT had higher LRR after CBA of AF. The time when ERAT occurred had an impact on LRR.

Abstract Germline and somatic mutations in BRCA1 and BRCA2 (BRCA) confer PARP inhibitor sensitivity. Promoter hypermethylation is an alternate mechanism of gene down-regulation, and BRCA1 promoter methylation is relatively common in sporadic ovarian cancer. The clinical significance of BRCA1 methylation is less clear than for mutations, as the Cancer Genome Atlas (TCGA) and others have failed to show improved survival in ovarian carcinomas with BRCA1 methylation. No one has previously tested whether BRCA1 methylation confers in vivo sensitivity to PARP inhibitors in patients with ovarian cancer. ARIEL2 is a phase 2 study of the PARP inhibitor rucaparib in patients with recurrent platinum sensitive high-grade ovarian, peritoneal or fallopian tube carcinoma. At enrollment, ARIEL2 required pre-treatment tumor biopsies with the goal of developing tissue predictors of PARP inhibitor sensitivity other than BRCA mutations. The number of women with known germline mutations was capped at 15 patients in order to predominantly enroll BRCA wildtype cases. As presented at ASCO 2016, in cases with no BRCA mutations, a high fraction of genomic loss of heterozygosity (LOH) significantly predicted a better progression-free survival (the primary endpoint), longer duration of response, and a higher fraction of responders compared to cases with low LOH. We assessed BRCA1 and RAD51C promoter hypermethylation using methylation-sensitive polymerase chain reaction in paired archival and pre-treatment biopsies from patients on ARIEL2. Of 165 cases for which methylation analyses were completed, 21 (12.7%) were methylated at the BRCA1 promoter and four (2.4%) at the RAD51C promoter. Methylation of BRCA1 and RAD51C was mutually exclusive with mutation in BRCA or other homologous recombination genes. All four cases with RAD51C methylation and 15/19 (78.9%) with BRCA1 methylation were associated with high LOH. In 90 paired samples archival and pre-treatment tissues, RAD51C methylation was 100% concordant and BRCA1 methylation was highly concordant (p&lt;0·001). For 13 cases with BRCA1 methylation in the archival specimen, 4 (30·8%) were unmethylated in the paired pretreatment tumor, but for 77 unmethylated archival specimens, gain of methylation in the pretreatment biopsy was observed just once. Confirmed RECIST responses were seen in 52.4% (11/21) BRCA1 methylated and 75.0% (3/4) RAD51C methylated cases. In conclusion, BRCA1 and RAD51C methylation in ovarian carcinomas correlates with a high response rate to PARP inhibitors. If methylation was to be used as a predictor of PARP inhibitor sensitivity, it would need to be assessed in a pre-treatment (not archival) specimen. The loss of BRCA1 methylation in recurrent ovarian carcinoma, which was common even in these platinum sensitive cases, could explain why BRCA1 methylation is associated with similar survival to methylated cases, despite initial improved therapeutic sensitivity. Citation Format: Elizabeth Swisher, Maria Harrell, Kevin K. Lin, Clare Scott, Sandra Goble, Amit Oza, Robert L. Coleman, Gottfried Konecny, Anna V. Tinker, David M. O'Malley, Rebecca Kristeleit, Ling Ma, James Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Mitch Rapon, Iain McNeish, Scott H. Kaufmann. BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP28.