Research Spotlight

Kandimalla, R., H. Tomihara, J. K. Banwait, K. Yamamura, G. Singh, H. Baba and A. Goel (2020). “A 15-gene immune, stromal and proliferation gene signature that significantly associates with poor survival in patients with pancreatic ductal adenocarcinoma.” Clin Cancer Res Mar 31. pii: clincanres.4044.2019. [Epub ahead of print].

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PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC. EXPERIMENTAL DESIGN: The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n=163) transcriptomic data. This was followed by independent validation of the gene signature in The International Cancer Genome Consortium (ICGC, n=95), E-MTAB-6134 (n=288), and GSE71729 (n=123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate cox regression analysis. RESULTS: Our biomarker discovery effort identified a 15-gene immune, stromal and proliferation (ISP) gene signature that significantly associated with poor OS (HR: 3.90, 95% CI, 2.36-6.41, p<0.0001). This signature also robustly predicted survival in 3 independent validation cohorts ICGC (HR:2.63 [1.56-4.41], p<0.0001), E-MTAB-6134 (HR:1.53 [1.14-2.04], p=0.004), and GSE71729 (HR:2.33 [1.49-3.63], p<0.0001). Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all 4 cohorts; TCGA (AUC=0.94), ICGC (AUC=0.91), E-MTAB-6134 (AUC=0.80), and GSE71729 (AUC=0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort (n=119; HR:2.62 [1.50-4.56], p=0.0004). A nomogram was established which included the ISP, CA19-9, T and N-stage for eventual clinical translation. CONCLUSIONS: We report a novel gene signature for risk-stratification and robust identification of PDAC patients with poor molecular subtypes.

Jaramillo-Jimenez, E., M. Gupta, G. Snipes, B. S. Cheek, C. B. Michael, A. M. Navarro-Montoya, T. Gomez-Escobar, J. Jimenez-Villegas, I. Rodriguez-Marquez and I. Melguizo-Gavilanes (2020). “Textiloma Mimicking a Recurrent High-Grade Astrocytoma: A Case Report.” J Neurol Surg Rep 81(1): e7-e9.

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Introduction Textiloma (Txm) is a nonmedical term that has been given to foreign body-related inflammatory pseudotumor arising from retained nonabsorbable cotton matrix that is either inadvertently or deliberately left behind during surgery, which may trigger an inflammatory reaction. This report describes a case of Txm mimicking a recurrent high-grade astrocytoma. Case Report We, here, present the case of a 69-year-old female with a 6-month history of progressive left-sided weakness. Neuroimaging studies revealed a large nonenhancing mass in the right frontoparietal lobe. Pathology reported a World Health Organization tumor classification grade II, diffuse astrocytoma. After surgical intervention, external beam radiation was given to the remaining areas of residual tumor. Routine magnetic resonance imaging (MRI) revealed a nodular area of contrast enhancement in the dorsal and inferior margin of the biopsy tract, growing between interval scans, and perfusion-weighted imaging parameters were elevated being clinically asymptomatic. She underwent a complete resection of this area of interest and pathology returned as a Txm with Surgicel fibers. Conclusion After treatment of a neoplasm, if unexpected clinical or imaging evidence of recurrence is present, a foreign body reaction to hemostatic material used during the initial surgery should be included in the differential diagnosis

Hong, D. S., Y. K. Kang, M. Borad, J. Sachdev, S. Ejadi, H. Y. Lim, A. J. Brenner, K. Park, J. L. Lee, T. Y. Kim, S. Shin, C. R. Becerra, G. Falchook, J. Stoudemire, D. Martin, K. Kelnar, H. Peltier, V. Bonato, A. G. Bader, S. Smith, S. Kim, V. O’Neill and M. S. Beg (2020). “Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.” Br J Cancer Apr 2. [Epub ahead of print].

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BACKGROUND: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. METHODS: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. RESULTS: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m(2) for hepatocellular carcinoma (HCC) and 93 mg/m(2) for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting >/=4 cycles (median, 19 weeks, range, 11-55). CONCLUSION: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. CLINICAL TRIAL REGISTRATION: NCT01829971.

Harhay, M. N., M. K. Rao, K. J. Woodside, K. L. Johansen, K. L. Lentine, S. G. Tullius, R. F. Parsons, T. Alhamad, J. Berger, X. S. Cheng, J. Lappin, R. Lynch, S. Parajuli, J. C. Tan, D. L. Segev, B. Kaplan, J. Kobashigawa, D. M. Dadhania and M. A. McAdams-DeMarco (2020). “An overview of frailty in kidney transplantation: measurement, management and future considerations.” Nephrol Dial Transplant Mar 19. [Epub ahead of print].

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The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

Guerrero, M., S. Vemulapalli, Q. Xiang, D. D. Wang, M. Eleid, A. K. Cabalka, G. Sandhu, M. Salinger, H. Russell, A. Greenbaum, S. Kodali, I. George, D. Dvir, B. Whisenant, M. J. Russo, A. Pershad, K. Fang, M. Coylewright, P. Shah, V. Babaliaros, J. M. Khan, C. Tommaso, J. Saucedo, S. Kar, R. Makkar, M. Mack, D. Holmes, M. Leon, V. Bapat, V. H. Thourani, C. Rihal, W. O’Neill and T. Feldman (2020). “Thirty-Day Outcomes of Transcatheter Mitral Valve Replacement for Degenerated Mitral Bioprostheses (Valve-in-Valve), Failed Surgical Rings (Valve-in-Ring), and Native Valve With Severe Mitral Annular Calcification (Valve-in-Mitral Annular Calcification) in the United States: Data From the Society of Thoracic Surgeons/American College of Cardiology/Transcatheter Valve Therapy Registry.” Circ Cardiovasc Interv 13(3): e008425.

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BACKGROUND: Transcatheter mitral valve replacement using aortic transcatheter heart valves has recently become an alternative for patients with degenerated mitral bioprostheses, failed surgical repairs with annuloplasty rings or severe mitral annular calcification who are poor surgical candidates. Outcomes of these procedures are collected in the Society of Thoracic Surgeons/American College of Cardiology/Transcatheter Valve Therapy Registry. A comprehensive analysis of mitral valve-in-valve (MViV), mitral valve-in-ring (MViR), and valve-in-mitral annular calcification (ViMAC) outcomes has not been performed. We sought to evaluate short-term outcomes of early experience with MViV, MViR, and ViMAC in the United States. METHODS: Retrospective analysis of data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. RESULTS: Nine hundred three high-risk patients (median Society of Thoracic Surgeons score 10%) underwent MViV (n=680), MViR (n=123), or ViMAC (n=100) between March 2013 and June 2017 at 172 hospitals. Median age was 75 years, 59.2% female. Technical and procedural success were higher in MViV. Left ventricular outflow tract obstruction occurred more frequently with ViMAC (ViMAC=10%, MViR=4.9%, MViV=0.7%; P<0.001). In-hospital mortality (MViV=6.3%, MViR=9%, ViMAC=18%; P=0.004) and 30-day mortality (MViV=8.1%, MViR=11.5%, ViMAC=21.8%; P=0.003) were higher in ViMAC. At 30-day follow-up, median mean mitral valve gradient was 7 mm Hg, most patients (96.7%) had mitral regurgitation grade