Research Spotlight

Patel, A. N., T. D. Henry, A. A. Quyyumi, G. L. Schaer, R. D. Anderson, C. Toma, C. East, A. E. Remmers, J. Goodrich, A. S. Desai, D. Recker and A. DeMaria (2016). “Ixmyelocel-t for patients with ischaemic heart failure: A prospective randomised double-blind trial.” Lancet 387(10036): 2412-2421.

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BACKGROUND: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient’s own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. METHODS: In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. FINDINGS: Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0.63 [95% CI 0.42-0.97]; p=0.0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0.0197). INTERPRETATION: To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes.

Haider, A. H., I. Dankwa-Mullan, A. C. Maragh-Bass, M. Torain, C. K. Zogg, E. J. Lilley, L. M. Kodadek, N. R. Changoor, P. Najjar, J. A. Rose, Jr., H. R. Ford, A. Salim, S. C. Stain, S. Shafi, B. Sutton, D. Hoyt, Y. T. Maddox and L. D. Britt (2016). “Setting a national agenda for surgical disparities research: Recommendations from the national institutes of health and american college of surgeons summit.” JAMA Surg 151(6): 554-563.

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Health care disparities (differential access, care, and outcomes owing to factors such as race/ethnicity) are widely established. Compared with other groups, African American individuals have an increased mortality risk across multiple surgical procedures. Gender, sexual orientation, age, and geographic disparities are also well documented. Further research is needed to mitigate these inequities. To do so, the American College of Surgeons and the National Institutes of Health-National Institute of Minority Health and Disparities convened a research summit to develop a national surgical disparities research agenda and funding priorities. Sixty leading researchers and clinicians gathered in May 2015 for a 2-day summit. First, literature on surgical disparities was presented within 5 themes: (1) clinician, (2) patient, (3) systemic/access, (4) clinical quality, and (5) postoperative care and rehabilitation-related factors. These themes were identified via an exhaustive preconference literature review and guided the summit and its interactive consensus-building exercises. After individual thematic presentations, attendees contributed research priorities for each theme. Suggestions were collated, refined, and prioritized during the latter half of the summit. Breakout sessions yielded 3 to 5 top research priorities by theme. Overall priorities, regardless of theme, included improving patient-clinician communication, fostering engagement and community outreach by using technology, improving care at facilities with a higher proportion of minority patients, evaluating the longer-term effect of acute intervention and rehabilitation support, and improving patient centeredness by identifying expectations for recovery. The National Institutes of Health and American College of Surgeons Summit on Surgical Disparities Research succeeded in identifying a comprehensive research agenda. Future research and funding priorities should prioritize patients’ care perspectives, workforce diversification and training, and systematic evaluation of health technologies to reduce surgical disparities.

Shu, C. A., M. C. Pike, A. R. Jotwani, T. M. Friebel, R. A. Soslow, D. A. Levine, K. L. Nathanson, J. A. Konner, A. G. Arnold, F. Bogomolniy, F. Dao, N. Olvera, E. K. Bancroft, D. J. Goldfrank, Z. K. Stadler, M. E. Robson, C. L. Brown, M. M. Leitao, Jr., N. R. Abu-Rustum, C. A. Aghajanian, J. L. Blum, S. L. Neuhausen, J. E. Garber, M. B. Daly, C. Isaacs, R. A. Eeles, P. A. Ganz, R. R. Barakat, K. Offit, S. M. Domchek, T. R. Rebbeck and N. D. Kauff (2016). “Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with brca mutations.” JAMA Oncol: 2016 June [Epub ahead of print].

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Importance: The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial. Objective: To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy. Design, Setting, and Participants: This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression. Main Outcomes and Measures: Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database. Results: Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 – 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors. Conclusions and Relevance: Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.

Sternberg, C., A. Armstrong, R. Pili, S. Ng, R. Huddart, N. Agarwal, D. Khvorostenko, O. Lyulko, A. Brize, N. Vogelzang, R. Delva, M. Harza, A. Thanos, N. James, P. Werbrouck, M. Bogemann, T. Hutson, P. Milecki, S. Chowdhury, E. Gallardo, G. Schwartsmann, J. C. Pouget, F. Baton, T. Nederman, H. Tuvesson and M. Carducci (2016). “Randomized, double-blind, placebo-controlled phase iii study of tasquinimod in men with metastatic castration-resistant prostate cancer.” J Clin Oncol: 2016 June [Epub ahead of print].

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PURPOSE: Tasquinimod, a novel oral therapy targeting the tumor microenvironment, significantly improved progression-free survival (PFS) in a randomized, placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). This phase III study was conducted to confirm the phase II results and to detect an overall survival (OS) benefit. PATIENTS AND METHODS: Men with chemotherapy-naive mCRPC and evidence of bone metastases were assigned (2:1) to receive tasquinimod once per day or placebo until progression or toxicity. The primary end point was radiographic PFS (rPFS; time from random assignment to radiologic progression or death) per Prostate Cancer Working Group 2 criteria and RECIST 1.1. The study had 99.9% power to detect an rPFS hazard ratio (HR) of 0.6 with a two-sided alpha error of .05 and 80% power to detect a target HR of 0.8 for OS, the key secondary end point. RESULTS: In all, 1,245 patients were randomly assigned to either tasquinimod (n = 832) or placebo (n = 413) between March 2011 and December 2012 at 241 sites in 37 countries. Baseline characteristics were balanced between groups: median age, 71 years; Karnofsky performance status >/= 90%, 77.3%; and visceral metastases, 21.1%. Estimated median rPFS by central review was 7.0 months (95% CI, 5.8 to 8.2 months) with tasquinimod and 4.4 months (95% CI, 3.5 to 5.5 months) with placebo (HR, 0.64; 95% CI, 0.54 to 0.75; P < .001). Median OS was 21.3 months (95% CI, 19.5 to 23.0 months) with tasquinimod and 24.0 months (95% CI, 21.4 to 26.9 months) with placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). Grade >/= 3 adverse events were more frequent with tasquinimod (42.8% v 33.6%), the most common being anemia, fatigue, and cancer pain. CONCLUSION: In chemotherapy-naive men with mCRPC, tasquinimod significantly improved rPFS compared with placebo. However, no OS benefit was observed.

Demetris, A. J., C. Bellamy, S. G. Hubscher, J. O’Leary, P. S. Randhawa, S. Feng, D. Neil, R. B. Colvin, G. McCaughan, J. J. Fung, A. Del Bello, F. P. Reinholt, H. Haga, O. Adeyi, A. J. Czaja, T. Schiano, M. I. Fiel, M. L. Smith, M. Sebagh, R. Y. Tanigawa, F. Yilmaz, G. Alexander, L. Baiocchi, M. Balasubramanian, I. Batal, A. K. Bhan, J. Bucuvalas, C. T. Cerski, F. Charlotte, M. E. de Vera, M. ElMonayeri, P. Fontes, E. E. Furth, A. S. Gouw, S. Hafezi-Bakhtiari, J. Hart, E. Honsova, W. Ismail, T. Itoh, N. C. Jhala, U. Khettry, G. B. Klintmalm, S. Knechtle, T. Koshiba, T. Kozlowski, C. R. Lassman, J. Lerut, J. Levitsky, L. Licini, R. Liotta, G. Mazariegos, M. I. Minervini, J. Misdraji, T. Mohanakumar, J. Molne, I. Nasser, J. Neuberger, M. O’Neil, O. Pappo, L. Petrovic, P. Ruiz, O. Sagol, A. Sanchez Fueyo, E. Sasatomi, A. Shaked, M. Shiller, T. Shimizu, B. Sis, A. Sonzogni, H. L. Stevenson, S. N. Thung, G. Tisone, A. C. Tsamandas, A. Wernerson, T. Wu, A. Zeevi and Y. Zen (2016). “2016 comprehensive update of the banff working group on liver allograft pathology: Introduction of antibody-mediated rejection.” Am J Transplant: 2016 Jun [Epub ahead of print].

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The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding liver allograft antibody-mediated at the 11th (Paris, France, June 5 to 10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013) and 13th (Vancouver, British Columbia Dates: 05 – 10 Oct, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued on line. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for C4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.