Research Spotlight

Toiyama, Y., Y. Okugawa, K. Tanaka, T. Araki, K. Uchida, A. Hishida, M. Uchino, H. Ikeuchi, S. Hirota, M. Kusunoki, C. R. Boland and A. Goel (2017). “A panel of methylated microrna biomarkers for identifying high-risk patients with ulcerative colitis-associated colorectal cancer.” Gastroenterology: 2017 Aug [Epub ahead of print].

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BACKGROUND&AIMS: Methylation of specific microRNAs (miRNAs) often occurs in an age-dependent manner, as a field defect in some instances, and may be an early event in colitis-associated carcinogenesis. We aimed to determine whether specific mRNA signature patterns (MIR1, MIR9, MIR124, MIR137, MIR34B/C) could be used to identify patients with ulcerative colitis (UC) patients who are at increased risk for colorectal neoplasia. METHODS: We obtained 387 colorectal tissue specimens, collected from 238 patients with UC (152 without neoplasia, 17 with dysplasia, and 69 with UC-associated colorectal cancer [UC-CRC]), from 2 independent cohorts in Japan from 2005 and 2015. We quantified methylation of miRNAs by bisulfite pyrosequencing analysis. We analyzed clinical data to determine whether miRNA methylation patterns associated with age, location, or segment of the colorectum (cecum, transverse colon, and rectum). Differences in tissue miRNA methylation and expression levels were compared among samples and associated with cancer risk using the Wilcoxon test, Mann-Whitney and Kruskal-Wallis tests as appropriately. We performed a validation study of samples from 90 patients without UC and 61 patients with UC-associated dysplasia or cancer to confirm the association between specific methylation patterns of miRNAs in non-tumor rectal mucosa from patients with UC with risk of UC-CRC. RESULTS: Among patients with UC without neoplasia, rectal tissues had significantly higher levels of methylation levels of MIR1, MIR9, MIR124, and MIR137 than in proximal mucosa; levels of methylation associated with age and duration of UC in rectal mucosa. Methylation of all miRNAs was significantly higher in samples from patients with dysplasia or CRC compared to samples from patients without neoplasia. Receiver operating characteristic analysis revealed that methylation levels of miRNAs in rectal mucosa accurately differentiated patients with CRC from those without. Methylation of MIR137 in rectal mucosa was independent risk factor for UC-CRC. Methylation patterns of a set of miRNAs (panel) could discriminated patients with UC patients with or without dysplasia or CRC in the evaluation cohort (area under the curve, 0.81) and the validation cohort (area under the curve, 0.78). CONCLUSIONS: In evaluation and validation cohorts, we found specific miRNAs to be methylated in rectal mucosal samples from patients with UC with dysplasia or CRC compared with patients without neoplasms. This pattern also associated with patient age and might be used to identify patients with UC at greatest risk for developing UC-CRC. Our findings provide evidence for a field defect in rectal mucosa from patients with UC-CRC.

Pierobon, M., C. Ramos, S. Wong, K. A. Hodge, J. Aldrich, S. Byron, S. P. Anthony, N. J. Robert, D. W. Northfelt, M. Jahanzeb, L. Vocila, J. Wulfkuhle, G. Gambara, R. I. Gallagher, B. Dunetz, N. Hoke, T. Dong, D. W. Craig, M. Cristofanilli, B. Leyland-Jones, L. A. Liotta, J. A. O’Shaughnessy, J. D. Carpten and E. F. Petricoin (2017). “Enrichment of pi3k-akt-mtor pathway activation in hepatic metastases from breast cancer.” Clin Cancer Res 23(16): 4919-4928.

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Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.Experimental Design: Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.Results:PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K-AKT-mTOR signaling network.

Chari, A., A. Suvannasankha, J. W. Fay, B. Arnulf, J. L. Kaufman, J. J. Ifthikharuddin, B. M. Weiss, A. Krishnan, S. Lentzsch, R. Comenzo, J. Wang, K. Nottage, C. Chiu, N. Z. Khokhar, T. Ahmadi and S. Lonial (2017). “Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.” Blood 130(8): 974-981.

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Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with >/=2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received >/=3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade >/=3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients.

Cush, J. J. (2017). “Herpes zoster – fear the infection, value the solution.” Arthritis Rheumatol: 2017 Aug [Epub ahead of print].

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Herpes zoster (HZ) is a blistering rash and painful neuritis that results from reactivation of the varicella zoster virus (VZV). Zoster will affect one-third of adults in the United States during their lifetime (1). In addition to the painful rash and a 20% risk of post-herpetic neuralgia, shingles exacts a substantial cost and quality of life on an aging populace. While the incidence of zoster is increasing, the CDC reports that only 28% of adults > 60 years have received preventative vaccination, despite the widespread availability of an approved, effective vaccine (2, 3). Moreover, certain populations incur even higher risks, especially patients with autoimmune disease (4). Risk is further compounded by therapeutics utilized (e.g., corticosteroids, cytotoxics, biologics, and Jak inhibitors) in such patients. There is a imperative need to know who is at risk, when and how they should be vaccinated and what other risk reduction measures should be considered. At a 2015 vaccine symposium held at the annual meeting of the American College of Rheumatology, Dr. William Schaffner stated, “if you don’t fear the infection, you won’t value the solution (the vaccine)”.

Mack, M. and P. Grayburn (2017). “Guideline-directed medical therapy for secondary mitral regurgitation: More questions than answers!” JACC Heart Fail 5(9): 660-662.

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Secondary (also known as functional) mitral regurgitation (MR) is common in heart failure patients. Secondary MR is not caused by a primary abnormality of the mitral leaflets but rather to dilation/dysfunction of the left ventricle (LV). As a result, there is apical-lateral displacement of the papillary muscles resulting in tethering of the mitral leaflets and subsequent failure of anatomically normal leaflets to coapt (1) . Secondary MR results in further LV volume overload and a resulting vicious cycle of more severe MR leading to further LV dilation and congestive heart failure. This mechanism of MR is termed type IIIb in the Carpentier classification of mitral valve leaflet motion and can be due to both ischemic and nonischemic dilated cardiomyopathies (2) . The mainstay of therapy is guideline-directed medical therapy (GDMT) for heart failure including diuretics, beta blockers, aldosterone antagonists, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocking agents. It is an area of intense interest in the fields of surgery and medical device therapy because of the overall poor prognosis with medical therapy alone. Although it is widely recognized that secondary MR is associated with a worse prognosis in heart failure patients, it remains uncertain whether surgical correction of the MR and breaking the “vicious cycle” changes the dismal course of the disease.