Citations

Health care reform focuses on primary care and development of Health Care Homes to improve patient-centered chronic illness care. This pilot study evaluated a community care team intervention that linked chronically ill older patients, support persons, and nurse care coordinators from a Health Care Home with community resources using an adaptation of the Wraparound process. A pragmatic clinical trial design was used. Patient-centered chronic illness care; physical, mental, and social health; service use; and study feasibility were evaluated. Differences between groups were compared using two-sample t, Wilcoxon rank sum, chi-square, or Fisher’s exact tests. At 3 months, the intervention group reported higher patient-centered chronic illness care (mean total Patient Assessment of Chronic Illness Care change scores were 0.39 for the intervention group and −0.11 for the control group, p = .03). Results indicate that the integrated community care team intervention is a promising strategy to support patient-centered chronic illness care.

Abstract Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer. Mol Cancer Ther; 12(6); 1002–15. ©2013 AACR.

Background— The risks of sports participation for implantable cardioverter-defibrillator (ICD) patients are unknown. Methods and Results— Athletes with ICDs (age, 10–60 years) participating in organized (n=328) or high-risk (n=44) sports were recruited. Sports-related and clinical data were obtained by phone interview and medical records. Follow-up occurred every 6 months. ICD shock data and clinical outcomes were adjudicated by 2 electrophysiologists. Median age was 33 years (89 subjects <20 years of age); 33% were female. Sixty were competitive athletes (varsity/junior varsity/traveling team). A pre-ICD history of ventricular arrhythmia was present in 42%. Running, basketball, and soccer were the most common sports. Over a median 31-month (interquartile range, 21–46 months) follow-up, there were no occurrences of either primary end point—death or resuscitated arrest or arrhythmia- or shock-related injury—during sports. There were 49 shocks in 37 participants (10% of study population) during competition/practice, 39 shocks in 29 participants (8%) during other physical activity, and 33 shocks in 24 participants (6%) at rest. In 8 ventricular arrhythmia episodes (device defined), multiple shocks were received: 1 at rest, 4 during competition/practice, and 3 during other physical activity. Ultimately, the ICD terminated all episodes. Freedom from lead malfunction was 97% at 5 years (from implantation) and 90% at 10 years. Conclusions— Many athletes with ICDs can engage in vigorous and competitive sports without physical injury or failure to terminate the arrhythmia despite the occurrence of both inappropriate and appropriate shocks. These data provide a basis for more informed physician and patient decision making in terms of sports participation for athletes with ICDs.

Abstract Introduction: Multivariable models that predict biochemical recurrence (BCR) can indicate patients at higher risk for developing clinical progression after prostatectomy. However, most patients that experience BCR do not metastasize or die from prostate cancer, making BCR an unreliable surrogate endpoint. In this study we compared the clinical and genomic characteristics of prostatectomy patients in order to better delineate the relationship between BCR and aggressive prostate cancer. Methods: Postoperative patients were retrospectively classified into three outcome groups: NED (no evidence of disease recurrence); BCR-only (patients that experienced BCR but didn't have progressive disease as evidenced by bone or CT scans); and CP (clinical progression with BCR plus positive CT or bone scans). Patient specimens were from the Mayo Clinic Radical Prostatectomy Registry, selected using a nested case-control design with 14 years median follow-up. RNA expression levels from FFPE tumor specimens were measured with 1.4 million feature whole-transcriptome oligonucleotide microarrays on 106 matching patients from each outcome group (total 318 patients). We analyzed the clinical covariates of the outcome groups in a pairwise manner (NED vs. BCR-only; NED vs. CP; CP vs. BCR-only), using a conditional logistic model in univariable and multivariable analyses. We performed feature reduction for the genomic data set using Kruskal-Wallis tests and regularized logistic regression. Principal Component Analysis (PCA) was used to quantify the variance of the genomic data with respect to the patient outcome groups. Results: Our initial hypothesis was that all three outcome groups would have different clinical and genomic characteristics. Univariable analysis of clinical variables failed to show statistically significant differences between NED and BCR-only groups. Multivariable analysis of the clinical variables also failed to show statistically significant differences between NED and BCR-only groups. Among the clinical variables only pathological Gleason score was statistically significant when comparing the BCR-only vs. CP and NED vs. CP groups. Genomic analysis found 363 coding and non-coding features that passed thresholds for differential expression between the three outcome groups. PCA established that the primary source of variance in the genomic data stemmed from the separation of CP from NED and BCR-only patients; whereas only a small amount of variance separates NED and BCR-only groups. The 363 features were further compared in the three outcome groups using Wilcoxon tests, adjusting for false-discovery using Benjamini-Hochberg. At a cutoff of p &lt; 0.001 there were no features differentially expressed between NED and BCR-only, while 52 and 34 statistically significant features were found in the NED vs. CP and CP vs. BCR-only comparisons, respectively. Conclusion: Considering the clinical and genomic results together, we find that: 1) Patients that developed clinical progression were significantly different from those that did not, irrespective of whether they experienced BCR or not; 2) the NED and BCR-only groups were statistically very similar to each other. We therefore conclude that BCR may not be the most appropriate endpoint for predictive models that attempt to stratify patients at risk for progression. This abstract is also presented as Poster B44. Citation Format: Anamaria Crisan, Elai Davicion, R. Jeffery Karnes, Robert B. Jenkins, Mercedeh H. Ghadessi, Christine Buerki, Eric J. Bergstrahl, Nicholas Erho, Ismael A. Vergara, Karla V. Ballman, Peter C. Black, Timothy J. Triche. Biochemical recurrence is not a definitive surrogate endpoint for development of clinically useful predictive models for post-prostatectomy patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr PR4.

Abstract Motivations: Gleason score is the most prognostic variable in prostate cancer pathology. Patients with high Gleason (8+) are the most likely to experience biochemical recurrence (BCR), clinical progression (CP) and prostate-cancer specific mortality (PCSM), whereas patients with Gleason ≤6 are expected to have excellent long-term outcomes. However, the majority of prostate cancer patients are diagnosed with Gleason score 7, a heterogeneous group in terms of patient outcomes. In the absence of adverse pathological factors (APF, such as preoperative PSA, SM+, ECE and SVI) most Gleason 7 patients will have excellent outcomes. In contrast, Gleason 7 patients with APF are considered at high-risk for recurrence and therefore are candidates for adjuvant therapy. In this study, we have investigated whether a classifier based on differentially expressed genomic features could be used to improve prognostication of Gleason 7 patients, independent of APF. Methods: Two whole-transcriptome (1.4 million feature) oligonucleotide microarray expression datasets from radical prostatectomy specimens were analyzed. The first one (GEO accession: GSE21032) consisted of 125 fresh frozen (FF) samples from the MSKCC Oncogenome Project and the second dataset had 545 formalin-fixed-paraffin- embedded (FFPE) samples from the Mayo Clinic tumor registry. For genomic feature selection, differential expression in the FF dataset between Gleason ≤6 (n=40) and ≥8 (n=15) was assessed with false discovery rate adjusted t-tests (p&lt;0.05). Next, a k-nearest neighbor (KNN) classifier was trained and tuned using the selected features to predict clinical progression (i.e., positive bone or CT scans after BCR) in the FFPE dataset, again using samples with Gleason score ≤6 (n=63) and ≥8 (n=211). The KNN classifier was evaluated on Gleason score 7 (n=209) FFPE samples (not used for training) using multivariable logistic regression. Results: The KNN classifier segregated the Gleason 7 samples into high and low risk CP groups. The KNN odds ratios were 2.9 (p&lt;0.005), 2.1 (p&lt;0.05) and 2.8 (p&lt;0.05) for BCR, CP and PCSM end-points, respectively when comparing high and low risk groups. Multivariable analysis revealed that the KNN classifier was independently prognostic. Conclusions: A KNN classifier developed using differentially expressed genomic features significantly stratified Gleason score 7 patients for several clinically relevant endpoints. Future validation studies will address the utility of this classifier in predicting pathological Gleason score from biopsy specimens, which may be particularly useful for evaluation of biopsy Gleason 6 cases. In these patients, deferring prostatectomy in favour of active surveillance is an appealing treatment option unless the ‘true’ Gleason of the index lesion is in fact a Gleason 7 or higher, where immediate surgery is likely a life-saving procedure. Citation Format: Nicholas Erho, Thomas Sierocinski, Elai Davicioni, Robert B. Jenkins, Mercedeh Gadhessi, Christine Buerki, Ismael A. Vergara, Anamaria Crisan, Zaid Haddad, Benedikt Zimmermann, Anirban Mitra, Timothy J. Triche. Identification of biomarkers for stratification of Gleason score 7 patients using whole-transcriptome expression profiling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B46.

Abstract Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen-responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate and correlate with aggressive disease. Moreover, the SRF-AR expression signature is associated more strongly with biochemical recurrence than similarly sized sets of AREdriven AR target genes. Thus, understanding the mechanism(s) by which SRF conveys androgen effects to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we explore the role of the RhoA signaling axis, a well-known activating pathway upstream of SRF, in androgen activation of SRF action. PCa cells were treated with inhibitors of RhoA signaling or transfected with siRNAs targeting RhoA, the critical SRF cofactor MAL or control siRNAs in the presence or absence of the synthetic androgen R1881. Real-time RT-PCR and western blotting was done to assess effects on expression of SRF target genes. Cell fractionation experiments evaluated the cellular localization of AR, MAL and SRF. ChIP was performed to assess recruitment of MAL to SRF target genes. Wild-type, dominant-active and dominant-negative versions of RhoA were overexpressed to determine effects on androgen regulation of SRF target genes. Immunohistochemistry was done to evaluate RhoA expression in clinical PCa samples and a tissue microarray derived from a CWR22 PCa xenograft model that mimics progression from androgen-stimulated (AS) to castration-recurrent (CR) disease. Effects on AS and CR PCa cell biology were assessed using proliferation and migration assays. Here, we show that the small GTPase RhoA mediates androgen responsiveness of more than half of SRF target genes tested. Interference with expression of RhoA, activity of the RhoA effector RhoA-associated kinase (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor MAL, all prevented full androgen-regulation of SRF target genes. Androgen treatment increased the nuclear content of MAL and led to MAL recruitment to the promoter of the SRF target gene FHL2. Moreover, in clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival following radical prostatectomy. Overexpression of RhoA markedly increased the androgen responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. Cell lines and a xenograft model that mimics the transition from AS to CR PCa indicate that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Silencing of RhoA, use of ROCK inhibitors or an inhibitor of SRF-MAL interaction blunted (androgen-regulated) cell viability and attenuated AS and CR PCa cell migration. Taken together, our work demonstrates that the RhoA signaling axis mediates clinically relevant AR action in PCa. In addition, these studies are the first to report on overexpression of RhoA in PCa and its association with aggressive disease and poor outcome. Note: This abstract was not presented at the conference because the presenter was unable to attend. Citation Format: Lucy Schmidt, Thomas Sebo, Donald Tindall, Hannelore Heemers, Kelly Duncan, Neelu Yadav, Kevin Regan, Christine Lohse, Elena Pop, Kristopher Attwood, Gregory Wilding, James Mohler. Androgen regulation of SRF target genes in prostate cancer cells is mediated in part by the small GTPase RhoA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A8.

Abstract Aims The proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart. Methods and results Female domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N + PSI, n = 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N + PSI (106.5 ± 16.4 g vs. 183.1 ± 24.2 g, P &lt; 0.05). The early to late diastolic filling ratio was increased in N + PSI vs. N (3.5 ± 0.6 vs. 1.8 ± 0.1, P &lt; 0.05). The EF tended to be lower (46 ± 12% and 53 ± 9%, respectively) and cardiac output was significantly lower in N + PSI than in N (2.9 ± 1.1 vs. 4.7 ± 1.1 L/min, P &lt; 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N + PSI. Conclusion The current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophic–restrictive cardiomyopathy phenotype.

SummaryDexamethasone ± thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T)PACE] is generally reserved as salvage therapy for aggressive multiple myeloma (MM) or plasma cell leukaemia (PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T)PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona. At time of D(T)PACE, 16 patients had PCL and three patients had leptomeningeal disease. Patients were heavily pretreated (median three prior regimens, range 1–12; prior autologous stem cell transplant [ASCT] 33%). Overall response rate was 49% (very‐good partial response 16%, partial response 33%) with stable disease in an additional 36%. Median progression‐free survival (PFS) was 5·5 months (95% confidence interval [CI]:4·3–9·8); overall survival (OS) 14·0 months (95% CI:8·7–19·3). Thirty‐five patients proceeded to ASCT or clinical trial, with median PFS for this subset of 13·4 months (95% CI:7·7–20·1) and OS 20·5 months (95% CI:14·8–63·8). D(T)PACE is an effective salvage therapy for heavily pretreated MM patients. Although the overall response rate of 49% in this poor prognosis cohort is reasonable, the PFS is short, suggesting the best role for D(T)PACE is in bridging to definitive therapy, such as transplantation.