Kelley M. Kidwell

Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality: Analysis of the extracorporeal life support organization registry

RATIONALE Recent pediatric studies suggest a survival benefit exists for higher-volume extracorporeal membrane oxygenation (ECMO) centers. OBJECTIVES To determine if higher annual ECMO patient volume is associated with lower case-mix-adjusted hospital mortality rate. METHODS We retrospectively analyzed an international registry of ECMO support from 1989 to 2013. Patients were separated into three age groups: neonatal (0-28 d), pediatric (29 d to <18 yr), and adult (≥18 yr). The measure of hospital ECMO volume was age group-specific and adjusted for patient-level case-mix and hospital-level variance using multivariable hierarchical logistic regression modeling. The primary outcome was death before hospital discharge. A subgroup analysis was conducted for 2008-2013. MEASUREMENTS AND MAIN RESULTS From 1989 to 2013, a total of 290 centers provided ECMO support to 56,222 patients (30,909 neonates, 14,725 children, and 10,588 adults). Annual ECMO mortality rates varied widely across ECMO centers: the interquartile range was 18-50% for neonates, 25-66% for pediatrics, and 33-92% for adults. For 1989-2013, higher age group-specific ECMO volume was associated with lower odds of ECMO mortality for neonates and adults but not for pediatric cases. In 2008-2013, the volume-outcome association remained statistically significant only among adults. Patients receiving ECMO at hospitals with more than 30 adult annual ECMO cases had significantly lower odds of mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.46-0.80) compared with adults receiving ECMO at hospitals with less than six annual cases. CONCLUSIONS In this international, case-mix-adjusted analysis, higher annual hospital ECMO volume was associated with lower mortality in 1989-2013 for neonates and adults; the association among adults persisted in 2008-2013.

Survival Outcome After Stereotactic Body Radiation Therapy and Surgery for Stage I Non-Small Cell Lung Cancer: A Meta-Analysis

PURPOSE This study compared treatment outcomes of stereotactic body radiation therapy (SBRT) with those of surgery in stage I non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Eligible studies of SBRT and surgery were retrieved through extensive searches of the PubMed, Medline, Embase, and Cochrane library databases from 2000 to 2012. Original English publications of stage I NSCLC with adequate sample sizes and adequate SBRT doses were included. A multivariate random effects model was used to perform a meta-analysis to compare survival between treatments while adjusting for differences in patient characteristics. RESULTS Forty SBRT studies (4850 patients) and 23 surgery studies (7071 patients) published in the same period were eligible. The median age and follow-up duration were 74 years and 28.0 months for SBRT patients and 66 years and 37 months for surgery patients, respectively. The mean unadjusted overall survival rates at 1, 3, and 5 years with SBRT were 83.4%, 56.6%, and 41.2% compared to 92.5%, 77.9%, and 66.1% with lobectomy and 93.2%, 80.7%, and 71.7% with limited lung resections. In SBRT studies, overall survival improved with increasing proportion of operable patients. After we adjusted for proportion of operable patients and age, SBRT and surgery had similar estimated overall and disease-free survival. CONCLUSIONS Patients treated with SBRT differ substantially from patients treated with surgery in age and operability. After adjustment for these differences, OS and DFS do not differ significantly between SBRT and surgery in patients with operable stage I NSCLC. A randomized prospective trial is warranted to compare the efficacy of SBRT and surgery.

EZH2 expands breast stem cells through activation of NOTCH1 signaling

Significance Triple-negative breast cancers comprise 10% of invasive breast carcinomas but are responsible for a disproportionate number of deaths and remain poorly understood. Unfortunately, current therapies are only weakly effective, and the median disease-free survival is 4 y among young women. Clinical studies support the relevance of Enhancer of Zeste Homolog 2 (EZH2) overexpression to the progression of triple-negative breast carcinomas. Our study shows that EZH2 acts as an activator of the NOTCH1 promoter and signaling to expand the stem cell pool, leading to accelerated breast cancer initiation and growth. We discovered that this function is independent of EZH2 histone methyltransferase activity and of its Polycomb Repressive Complex 2-binding partners, paving the way for novel therapeutic strategies. Breast cancer is the second-leading cause of cancer-related deaths in women, but the details of how it begins remain elusive. Increasing evidence supports the association of aggressive triple-negative (TN) breast cancer with heightened expression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) and increased tumor-initiating cells (TICs). However, mechanistic links between EZH2 and TICs are unclear, and direct demonstration of a tumorigenic function of EZH2 in vivo is lacking. Here, we identify an unrecognized EZH2/NOTCH1 axis that controls breast TICs in TN breast carcinomas. EZH2 overexpression increases NOTCH1 expression and signaling, and inhibition of NOTCH1 activity prevents EZH2-mediated stem cell expansion in nontumorigenic breast cells. We uncover a unique role of EZH2 in activating, rather than repressing, NOTCH1 signaling through binding to the NOTCH1 promoter in TN breast cancer cells. EZH2 binding is independent of its catalytic histone H3 lysine 27 methyltransferase activity and of the Polycomb Repressive Complex 2 but corresponds instead to transcriptional activation marks. In vivo, EZH2 knockdown decreases the onset and volume of xenografts derived from TN breast TICs. Conversely, transgenic EZH2 overexpression accelerates mammary tumor initiation and increases NOTCH1 activation in mouse mammary tumor virus-neu mice. Consonant with these findings, in clinical samples, high levels of EZH2 are significantly associated with activated NOTCH1 protein and increased TICs in TN invasive carcinomas. These data reveal a functional and mechanistic link between EZH2 levels, NOTCH1 signaling activation, and TICs, and provide previously unidentified evidence that EZH2 enhances breast cancer initiation.

Development of Circulating Tumor Cell-Endocrine Therapy Index in Patients with Hormone Receptor Positive Breast Cancer

Background: Endocrine therapy (ET) fails to induce a response in one half of patients with hormone receptor (HR)–positive metastatic breast cancer (MBC), and almost all will eventually become refractory to ET. Circulating tumor cells (CTC) are associated with worse prognosis in patients with MBC, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multiparameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR-positive MBC. Methods: The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC. Results: The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in patients with MBC. CTC-ETI was successfully determined in 44 of 50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Interobserver concordance of CTC-ETI determination was from 94% to 95% (Kappa statistic, 0.90–0.91). Inter- and cell-to-cell intrapatient heterogeneity of expression of each of the CTC markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissues. Conclusions: CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC biomarker expression, are being evaluated in an ongoing prospective trial. Clin Cancer Res; 21(11); 2487–98. ©2014 AACR. See related commentary by Mathew et al., p. 2421

Akt Phosphorylation at Ser473 Predicts Benefit of Paclitaxel Chemotherapy in Node-Positive Breast Cancer

PURPOSE We tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. PATIENTS AND METHODS Primary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status. RESULTS With a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17). CONCLUSION pAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel.

Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy.

Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor‐positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment‐related toxicities like musculoskeletal pain. Although pain‐related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation.

Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy

Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor‐positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment‐related toxicities like musculoskeletal pain. Although pain‐related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation.

Patient‐Reported Outcomes and Early Discontinuation in Aromatase Inhibitor‐Treated Postmenopausal Women With Early Stage Breast Cancer

In the prospective Exemestane and Letrozole Pharmacogenetics trial of adjuvant aromatase inhibitor (AI) therapy for early-stage breast cancer, worsening of multiple treatment-related symptoms during AI therapy predicted AI early discontinuation. If these findings are confirmed in independent trials, early detection of changes in PRO measures could be used clinically to target interventions in patients at high risk for early discontinuation.

Use of Acellular Dermal Matrix in Postmastectomy Breast Reconstruction: Are All Acellular Dermal Matrices Created Equal?

Background: AlloDerm and FlexHD are two types of acellular dermal matrices commonly used in implant-based reconstruction. Although the use of acellular dermal matrix has revolutionized immediate breast reconstruction in the setting of breast cancer, it remains unclear which type of acellular dermal matrix is best. The purpose of this retrospective cohort study was to compare postoperative complication rates between these two types of acellular dermal matrix. Methods: The authors reviewed the records of all patients who underwent implant-based breast reconstruction at their institution between 1998 and 2013. Dependent variables of seroma, hematoma, infection, delayed wound healing, implant exposure, and return to the operating room for management of complications were recorded. Results: A total of 309 consecutive patients were identified. Of these, AlloDerm was used in 123 patients (39.8 percent) and FlexHD was used in 186 patients (60.2 percent). Most patients in the authors’ cohort underwent immediate reconstruction [n = 288 (93.2 percent)], with a mean follow-up of 20.0 months. Patients receiving AlloDerm were half as likely to have major infections compared with patients receiving FlexHD (OR, 0.50; 95 percent CI, 0.16 to 1.00; p < 0.05). The rates of other complications were similar between the two groups. Conclusion: There are significantly increased odds of a major infection in patients who undergo implant-based breast reconstruction using FlexHD compared with AlloDerm. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

A five‐year retrospective analysis of adherence in cystic fibrosis

We conducted a retrospective analysis of medication adherence and health outcomes over a 5‐year period in children with cystic fibrosis (CF).