Research Spotlight

Posted July 15th 2016

Setting a national agenda for surgical disparities research: Recommendations from the national institutes of health and american college of surgeons summit.

Shahid Shafi M.D.

Shahid Shafi M.D.

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.


Posted July 15th 2016

Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations.

Joanne L. Blum M.D.

Joanne L. Blum M.D.

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.


Posted July 15th 2016

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer.

Thomas Hutson D.O.

Thomas Hutson D.O.

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.


Posted July 15th 2016

2016 comprehensive update of the banff working group on liver allograft pathology: Introduction of antibody-mediated rejection.

Göran Klintmalm M.D.

Göran Klintmalm M.D.

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.


Posted July 15th 2016

Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Yoshida, K., T. Nagasaka, Y. Umeda, T. Tanaka, K. Kimura, F. Taniguchi, T. Fuji, K. Shigeyasu, Y. Mori, H. Yanai, T. Yagi, A. Goel and T. Fujiwara (2016). “Expansion of epigenetic alterations in efemp1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms.” J Cancer Res Clin Oncol 142(7): 1557-1569.

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PURPOSE: Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN. METHODS: A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC). RESULTS: KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p < 0.0001). CONCLUSIONS: Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression.