Research Spotlight

Dickler, M. N., S. M. Tolaney, H. S. Rugo, J. Cortes, V. Dieras, D. Patt, H. Wildiers, C. A. Hudis, J. O’Shaughnessy, E. Zamora, D. A. Yardley, M. Frenzel, A. Koustenis and J. Baselga (2017). “Monarch 1, a phase ii study of abemaciclib, a cdk4 and cdk6 inhibitor, as a single agent, in patients with refractory hr+/her2- metastatic breast cancer.” Clin Cancer Res 23(17): 5218-5224.

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Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor-positive (HR+), HER2- metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).Results: Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had >/=3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3-27.5; 15% not excluded); clinical benefit rate (CR+PR+SD>/=6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity.

Gupta, N., V. Konda and U. Siddiqui (2017). “Gastric cardia lesion with abnormal volumetric laser endomicroscopy imaging.” Gastrointest Endosc: 2017 Aug [Epub ahead of print].

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A 71-year-old male with a history of epigastric pain and dyspepsia had previously been found to have Barrett’s esophagus (BE) with low-grade dysplasia. He presented to our institution for repeat EGD to thoroughly assess the Barrett’s segment. EGD showed short-segment BE with a 2-cm area of nodular, polypoid-appearing mucosa on the gastric cardia side of the gastroesophageal junction (A). The area was examined by high-definition white-light endoscopy (WLE) and narrow-band imaging (NBI) with near focus (A). Volumetric laser endomicroscopy (VLE) was also used (NVisionVLE, NinePoint Medical) and showed suspicious features including irregular surface (blue arrow) and atypical glands (red circle) in the area corresponding to the nodular mucosa (B).

Goldberg, R. J. and H. L. Nguyen (2017). “Unlocking the keys to site activation and recruitment success in a randomized controlled trial.” Stroke 48(9): 2339-2340.

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Two of the most crucial requirements for successfully carrying out and completing an RCT are the initial construction of different hypothetical scenarios to determine how many healthy individuals or patients with a specific disease or condition are needed to be enrolled in the trial and eventually followed on either a short- or long-term basis to find clinically meaningful differences in one’s principal study outcomes and, subsequently, to go out into the field, find, and recruit a sufficient number of patients to the proposed trial to satisfy one’s predetermined sample size requirements. Moreover, the logistical operations of an RCT need to be performed within the confines of a manageable budget and typically tight timeline for patient enrollment and follow-up in which all too often projected estimates of the number of patients to be enrolled and successfully retained in the trial greatly exceed reality.

Izumi, D., T. Ishimoto, K. Miyake, T. Eto, K. Arima, Y. Kiyozumi, T. Uchihara, J. Kurashige, M. Iwatsuki, Y. Baba, Y. Sakamoto, Y. Miyamoto, N. Yoshida, M. Watanabe, A. Goel, P. Tan and H. Baba (2017). “Colorectal cancer stem cells acquire chemoresistance through the upregulation of f-box/wd repeat-containing protein 7 and the consequent degradation of c-myc.” Stem Cells 35(9): 2027-2036.

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The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5+ human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs.

Klintmalm, G. B. and B. Kaplan (2017). “The kidney allocation system claims equity;it is time to review utility and fairness.” Am J Transplant: 2017 Aug [Epub ahead of print].

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The current kidney allocation system (KAS) implemented by the United Network for Organ Sharing in December 2014 was intended to balance inequities in kidney allocation while increasing utility by transplanting kidneys expected to last the longest in patients expected to live the longest. In its first iteration, termed Life Years from Transplant (LYFT), a fairly simple system of allocation was proposed to allocate kidneys based on this principle. LYFT, as opposed to our current process, also addressed the need to have a codified system to allocate kidneys unsuitable for younger patients to older recipients, such that utility could be maximized across the spectrum of potential recipients. Due to political pressures, LYFT was not instituted and our current KAS was implemented as a compromise solution (1).