Research Spotlight

O’Shaughnessy, J., A. DeMichele, C. X. Ma, P. Richards, D. A. Yardley, G. S. Wright, K. Kalinsky, R. Steis, S. Diab, G. Kennealey, R. Geschwindt, W. Jiang and H. S. Rugo (2018). “A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation.” Breast Cancer Res Treat. Apr 19. [Epub ahead of print].

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PURPOSE: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] >/= 1). METHODS: Patients with 2 or fewer prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS). RESULTS: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine. CONCLUSIONS: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.

O’Brien, S. M., L. Feng, X. He, Y. Xian, J. P. Jacobs, V. Badhwar, P. A. Kurlansky, A. P. Furnary, J. C. Cleveland, Jr., K. W. Lobdell, C. Vassileva, M. C. Wyler von Ballmoos, V. H. Thourani, J. S. Rankin, J. R. Edgerton, R. S. D’Agostino, N. D. Desai, F. H. Edwards and D. M. Shahian (2018). “The Society of Thoracic Surgeons 2018 Adult Cardiac Surgery Risk Models: Part 2-Statistical Methods and Results.” Ann Thorac Surg 105(5): 1419-1428.

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BACKGROUND: The Society of Thoracic Surgeons (STS) uses statistical models to create risk-adjusted performance metrics for Adult Cardiac Surgery Database (ACSD) participants. Because of temporal changes in patient characteristics and outcomes, evolution of surgical practice, and additional risk factors available in recent ACSD versions, completely new risk models have been developed. METHODS: Using July 2011 to June 2014 ACSD data, risk models were developed for operative mortality, stroke, renal failure, prolonged ventilation, mediastinitis/deep sternal wound infection, reoperation, major morbidity or mortality composite, prolonged postoperative length of stay, and short postoperative length of stay among patients who underwent isolated coronary artery bypass grafting surgery (n = 439,092), aortic or mitral valve surgery (n = 150,150), or combined valve plus coronary artery bypass grafting surgery (n = 81,588). Separate models were developed for each procedure and endpoint except mediastinitis/deep sternal wound infection, which was analyzed in a combined model because of its infrequency. A surgeon panel selected predictors by assessing model performance and clinical face validity of full and progressively more parsimonious models. The ACSD data (July 2014 to December 2016) were used to assess model calibration and to compare discrimination with previous STS risk models. RESULTS: Calibration in the validation sample was excellent for all models except mediastinitis/deep sternal wound infection, which slightly underestimated risk and will be recalibrated in feedback reports. The c-indices of new models exceeded those of the last published STS models for all populations and endpoints except stroke in valve patients. CONCLUSIONS: New STS ACSD risk models have generally excellent calibration and discrimination and are well suited for risk adjustment of STS performance metrics.

Mull, H. J., L. A. Graham, M. S. Morris, A. K. Rosen, J. S. Richman, J. Whittle, E. Burns, T. H. Wagner, L. A. Copeland, T. Wahl, C. Jones, R. H. Hollis, K. M. F. Itani and M. T. Hawn (2018). “Association of Postoperative Readmissions With Surgical Quality Using a Delphi Consensus Process to Identify Relevant Diagnosis Codes.” JAMA Surg. Apr 18. [Epub ahead of print].

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Importance: Postoperative readmission data are used to measure hospital performance, yet the extent to which these readmissions reflect surgical quality is unknown. Objective: To establish expert consensus on whether reasons for postoperative readmission are associated with the quality of surgery in the index admission. Design, Setting, and Participants: In a modified Delphi process, a panel of 14 experts in medical and surgical readmissions comprising physicians and nonphysicians from Veterans Affairs (VA) and private-sector institutions reviewed 30-day postoperative readmissions from fiscal years 2008 through 2014 associated with inpatient surgical procedures performed at a VA medical center between October 1, 2007, and September 30, 2014. The consensus process was conducted from January through May 2017. Reasons for readmission were grouped into categories based on International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Panelists were given the proportion of readmissions coded by each reason and median (interquartile range) days to readmission. They answered the question, “Does the readmission reason reflect possible surgical quality of care problems in the index admission?” on a scale of 1 (never related) to 5 (directly related) in 3 rounds of consensus building. The consensus process was completed in May 2017 and data were analyzed in June 2017. Main Outcomes and Measures: Consensus on proportion of ICD-9-coded readmission reasons that reflected quality of surgical procedure. Results: In 3 Delphi rounds, the 14 panelists achieved consensus on 50 reasons for readmission; 12 panelists also completed group telephone calls between rounds 1 and 2. Readmissions with diagnoses of infection, sepsis, pneumonia, hemorrhage/hematoma, anemia, ostomy complications, acute renal failure, fluid/electrolyte disorders, or venous thromboembolism were considered associated with surgical quality and accounted for 25521 of 39664 readmissions (64% of readmissions; 7.5% of 340858 index surgical procedures). The proportion of readmissions considered to be not associated with surgical quality varied by procedure, ranging from to 21% (613 of 2331) of readmissions after lower-extremity amputations to 47% (745 of 1598) of readmissions after cholecystectomy. Conclusions and Relevance: One-third of postoperative readmissions are unlikely to reflect problems with surgical quality. Future studies should test whether restricting readmissions to those with specific ICD-9 codes might yield a more useful quality measure.

Molina, A. M., T. E. Hutson, D. Nosov, P. Tomczak, O. Lipatov, C. N. Sternberg, R. Motzer and T. Eisen (2018). “Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study.” Eur J Cancer 94: 87-94.

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BACKGROUND: Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). METHODS: Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. FINDINGS: Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3-12.7) and median overall survival was 21.6 months (95% CI: 17.0-27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade >/=3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. INTERPRETATION: This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.

McKenna Iii, J., D. Kapfhamer, J. M. Kinchen, B. Wasek, M. Dunworth, T. Murray-Stewart, T. Bottiglieri, R. A. Casero, Jr. and M. J. Gambello (2018). “Metabolomic studies identify changes in transmethylation and polyamine metabolism in a brain-specific mouse model of tuberous sclerosis complex.” Hum Mol Genet. Apr 9. [Epub ahead of print].

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Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and the quintessential disorder of mTORC1 dysregulation. Loss of either causative gene, TSC1 or TSC2, leads to constitutive mTORC1 kinase activation and a pathologically anabolic state of macromolecular biosynthesis. Little is known about the organ-specific metabolic reprogramming that occurs in TSC-affected organs. Using a mouse model of TSC in which Tsc2 is disrupted in radial glial precursors and their neuronal and glial descendants, we performed an unbiased metabolomic analysis of hippocampi to identify Tsc2-dependent metabolic changes. Significant metabolic reprogramming was found in well-established pathways associated with mTORC1 activation, including redox homeostasis, glutamine/TCA cycle, pentose and nucleotide metabolism. Changes in two novel pathways were identified: transmethylation and polyamine metabolism. Changes in transmethylation included reduced methionine, cystathionine, S-adenosylmethionine (SAM – the major methyl donor), reduced SAM/SAH ratio (cellular methylation potential), and elevated betaine, an alternative methyl donor. These changes were associated with alterations in SAM-dependent methylation pathways and expression of the enzymes methionine adenosyltransferase 2A (MAT2A) and cystathionine beta synthase (CBS). We also found increased levels of the polyamine putrescine due to increased activity of ornithine decarboxylase, the rate-determining enzyme in polyamine synthesis. Treatment of Tsc2+/- mice with the ornithine decarboxylase (ODC) inhibitor 2-difluoromethylornithine (DFMO), to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAM-dependent methylation reactions and polyamine metabolism in TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.