Citations

Background— Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non–long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting. Methods and Results— In this institutional review board–approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and β-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event. Conclusions— LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.

Abstract Background: In order to understand the genetic events associated with disease progression and the development of drug resistance in multiple myeloma, we studied four longitudinally collected samples from a single, high risk, t(4;14) multiple myeloma patient. Samples over a four-year period were available from diagnosis, at time of first progression on lenalidomide, second progression while on bortezomib, at time of relapsed refractory disease and with end stage plasma cell leukemia. To better understand these genetic events, we utilized DNA extracted from germline tissue and CD138 purified bone marrow tumor cells to conduct whole genome sequencing (WGS) utilizing the Life Technologies SOLiD™ platform. Results: We have sequenced over 100 billion bases per sample with whole genome fragment library sequencing providing an average of 30X aligned coverage at all four time points studied. Each sample was aligned to the reference genome (NCBI36/hg18) with BFAST and post-alignment removal of duplicates and recalibration performed with Picard and Genome Analysis Toolkit (GATK) respectively. We then called point mutations with SolSNP and compared the germline sample to each tumor sample utilizing the Paired Mutation Walker. To date, we have identified 224 nonsynonymous point mutations within 217 genes. We then utilized the Sorting Intolerant from Tolerant (SIFT) algorithm and identified 109 potentially damaging point mutations which include 108 novel mutations in coding exons. Of the 224 somatic mutations observed, only 20 of these mutations are common to all tumor time points. Interestingly, the diagnostic and bortezomib refractory (second progression) samples had 11 mutations in common while the lenalidomide refractory (first progression) sample shared only 4 mutations in common with the bortezomib refractory sample. This suggests the presence of multiple clones at diagnosis that, due to treatment selection pressure, may emerge or regress as the dominant clone. Preliminary pathway analysis reveals the presence of mutations in genes regulating NFKB and Akt, whose pathways are often dysregulated in cancer. Conclusions: Whole genome sequencing has revealed evidence of mutational differences in exons between tumor and germline DNA indicative of the presence of multiple clones at diagnosis and evolution of these clones over time. This data supports the use of multiple drug therapies that target multiple clones and challenges the long held assumption that a patient who becomes refractory to a particular treatment will always be refractory to that treatment. Additional evaluation in a larger population is needed to confirm these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4838. doi:10.1158/1538-7445.AM2011-4838

Abstract We performed a multi-stage genome-wide association study (GWAS) for drug response in ovarian cancer. We selected 313 chemotherapy treated patients from the Australian Ovarian Cancer Study (AOCS). Patients were treated with paclitaxel/carboplatin and the trait of interest was Progression Free Survival (PFS). We maximized power for a fixed genotyping budget by genotyping individuals from the tails of the distribution: 94 with good survival and 94 with poor survival, taking into account extent of residual disease following surgery. Patients were genotyped on Illumina HumanOmni1-Quad arrays (1140419 loci).Two further cohorts with measures of PFS and whole genome data available; 134 ovarian patients from the Mayo clinic (genotyped on Illumina HumanHap 610 arrays, 620901 loci) and 68 patients from The Cancer Genome Atlas ovarian cancer set (genotyped on Illumina Human1M arrays, 1199187 loci) were meta-analyzed with the AOCS set (stage 1). We have imputed all the stage 1 samples with reference of the 1000 Genome data to allow more direct comparison of SNPs not common to all of the arrays used (up to 6 million SNPs with good imputation quality). Based on the chemotherapy treatment received by each patient, we assigned the patients into primary and secondary analysis, with primary analysis using a more strictly defined treatment subgroup. We followed up the stage 1 findings by genotyping 26 SNPs in more than 3,000 samples collected from 8 study sites of Ovarian Cancer Association Consortium (OCAC). These 26 SNPs were mainly genotyped SNPs, chosen from 23 distinct regions showing the strongest association with chemotherapy response from either primary or secondary analysis. 2 SNPs showed nominal significance in the replication sample (chr 12: rs1861932, chr 22: rs708444). We are currently genotyping more regions to seek replication of the initial findings. In summary, we sought to identify genes that underlie individual differences in chemoresistance. In the future, typing variations in these genes will be important for personalizing drug regimes for patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2011-4679

Abstract Multiple Myeloma (MM) is an incurable plasma-cell disorder progressing from indolent monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to relapse MM and finally plasma cell leukemia (PCL). Alterations affecting TP53 are among the principal genetic progression events associated with disease progression. We analyzed results from gene expression profiling (GEP), array-based comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH) and mutational data on the largest cohort published to date of 806 patients from all MM stages and 48 human myeloma cell lines (HMCLs). The prevalence of monoallelic TP53 deletions by aCGH is 1.4%, 3.7%, 8.9% and 25%, in MGUS, SMM, newly diagnosed and relapsed MM respectively. It reaches 53% in HMCLs and 75% in secondary PCL. No biallelic TP53 deletion were observed in patients and only 8% in HMCLs. In relapsed MM, the prevalence of TP53 deletions increases from 12/75 patients (16%) at first, to 9/31 patients (29%) in second and 5/7 patients (71%) in third relapse or more. We studied by FISH the status of TP53 in 113 patients from early stages progressing to relapse. Overall 15/113 patients had TP53 deletion, we confirmed that 10/15 patients acquired TP53 deletion at late stages. Next, we investigated the mutational status of TP53 in 59 relapsed MM patients, 5/59 samples (8.5%) had TP53 mutations, 4/5 mutations were located in the DNA binding domain. Presence of TP53 deletion conferred poor overall survival in relapsed MM patients (4.2 vs. 37.8 months, p = 0.015). A cohort of 239 patients had GEP-aCGH paired analysis we used a validated 70-gene model to stratify patients based on calculations obtained by GEP. The cohort was divided into quartiles and we observed the prevalence of TP53 in the low and high-risk groups. TP53 deletion was observed in 33/239 patients (14%) by aCGH, 2/33 (6%) had GEP values in the low-risk and 13/33 (39%) in the high-risk group. Next, we used a previously proposed cut-off value predicting TP53 deletion when GEP values are less than 733. We tried to validate this value as a surrogate for direct detection of TP53 deletion, and used the positive predictive value (PPV) of such level as a potential clinically useful marker. The fact that aCGH is the gold standard approach to define copy-number alterations, the proposed cut-off value failed to predict TP53 deletion as the PPV was low at 18% and the sensitivity of 69%. Finally, we studied by aCGH the status of MDM2 and CDKN2A, two key regulators of TP53. MDM2 gain and CDKN2A loss were infrequent events in patients even in advanced disease. In 48 HMCLs, only one had MDM2 copy gain (2%) while 14 cell lines had CDKN2A loss (29%). In MM, emergence of TP53 deletion/mutations in MM and its increase in aggressive stages of disease remain the overriding genetic factor for poor prognosis determination and a marker of progressive genetic events. Based on GEP, the 733 cut-off value did not accurately predict TP53 deletion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 219. doi:10.1158/1538-7445.AM2011-219

Abstract Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: <25% change). Metabolic response at Wk 1 was compared to Wk 8 as well as to clinical outcome, including objective response, clinical benefit, and progression-free survival (PFS). Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.

Pelvic lymph node dissection is the gold standard for assessing nodal disease in prostate or bladder cancer and is superior to CT, MRI and PET staging. Endoscopic ultrasound (EUS) provides an alternative, less invasive method of cytohistologic material acquisition, but its performance in pelvic urologic malignancy is unknown. Therefore, our aim was to evaluate the diagnostic accuracy of EUS guided tissue sampling for these malignancies when compared to a composite cytohistologic and surgical gold standard. A median of 3 FNA passes were performed (n=19 patients) revealing a sensitivity, specificity, PPV and NPV of 94.4% (72–99), 100% (2–100), 100% (80–100) and 50% (1–98) respectively. The perirectal space was the most frequently sampled location irrespective of the primary urological cancer origin. Final diagnosis established by EUS tissue sampling included bladder cancer (n=1), bladder cancer local recurrence (n=8), bladder cancer extra pelvic metastases (n=1), prostate cancer (n=2), prostate cancer local recurrence (n=4), prostate cancer extra pelvic metastases (n=1), testicular cancer extra pelvic metastases (n=1) and a benign seminal vesicle (n=1). EUS guided sampling of the gut wall, lymph nodes, or perirectal space yields suitable diagnostic material to establish the presence of primary, local recurrence or extra pelvic metastases of pelvic urologic malignancy.

Background —Data are limited regarding the classification and prognosis of patients with congestive heart failure (CHF) in the community. Methods and Results —Using the resources of the Rochester Epidemiology Project, we evaluated all patients receiving a first diagnosis of CHF in Olmsted County, Minnesota, in 1991 (n=216). Among these patients, 88% were ≥65 years and 49% were ≥80 years of age. The prognosis of patients with a new diagnosis of CHF was poor; survival was 86±2% at 3 months, 76±3% at 1 year, and 35±3% at 5 years. Of the 216 patients, 137 (63%) had an assessment of ejection fraction. In these patients, systolic function was preserved (ejection fraction ≥50%) in 59 (43%) and reduced (ejection fraction <50%) in 78 (57%). Survival adjusted for age, sex, NYHA class, and coronary artery disease was not significantly different between patients with preserved and those with reduced systolic function (relative risk, 0.80; P =0.369). ACE inhibitors were used in only 44% of the total population with CHF. Conclusions —The present study reports the clinical characteristics and natural history of CHF as it presents in the community in the vasodilator era. CHF is a disease of the “very elderly,” frequently occurs in the setting of normal ejection fraction, and has a poor prognosis, regardless of the level of systolic function. Diagnostic and therapeutic methods are underused in the community.

SummaryBackgroundThe extent to which potentially curative therapies are used in patients with hepatocellular cancer (HCC) and their related outcomes are unknown in the US.AimTo determine the rate and outcomes of potentially curative treatment in patients with HCC.MethodsEleven US centers followed patients with HCC between 2001 and 2007. We determined rates of liver transplantation, surgical resection, or tumour ablation during follow‐up, examined differences in adjusted survival of patients receiving these treatments, and determined the factors associated with receipt of potentially curative treatment.ResultsOf the 267 patients, 76 (28%) patients had early HCC, defined as Child A or B cirrhosis, with a solitary HCC or ≤3 nodules, each ≤3 cm. Of these, 53 (69.7%) received curative treatment. Thirty six percent of patients with non‐early HCC received curative treatment. Compared to patients with non‐early HCC who did not receive curative treatment, patients with early HCC and curative treatment had the best survival [hazard ratio, HR = 0.19 (95% CI, 0.08–0.42)] followed by patients with advanced HCC who received curative treatment [HR = 0.37 (95% CI, 0.22–0.64)]. Baseline performance status was significantly associated with receipt of curative treatment as well as survival after adjusting for demographics, clinical characteristics, and HCC stage.ConclusionsIn this multicenter database, most of the patients with early HCC received potentially curative treatment. However, only 28% of patients had early HCC. One‐third of patients with non‐early HCC also underwent curative therapy. Potentially curative treatment improved survival and this effect was seen in patients with early as well as non‐early HCC.