Research Spotlight

Blanco, P., H. Ueno and N. Schmitt (2016). “T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis.” Eur J Immunol 46(2): 281-290.

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Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to self. The autoantibodies generated in SLE are directed against nuclear components, with which they form immune complexes (ICs). ICs play key roles in organ and tissue damage, as well as in the activation of the innate and adaptive immune system during the disease course. Therefore, it is of prime importance to understand the mechanisms responsible for the development of B cells producing these pathogenic autoantibodies. There is compelling evidence that T follicular helper (Tfh) cells play a fundamental role in this process. In this review, we will summarize the current knowledge regarding the involvement of Tfh cells in SLE pathogenesis, and discuss potential strategies to target Tfh cells and/or molecules as a therapeutic modality of SLE.

Solomon, S. D., B. Claggett, A. S. Desai, M. Packer, M. Zile, K. Swedberg, J. L. Rouleau, V. C. Shi, R. C. Starling, O. Kozan, A. Dukat, M. P. Lefkowitz and J. J. McMurray (2016). “Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.” Circ Heart Fail 9(3): e002744.

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BACKGROUND: The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril. METHODS AND RESULTS: Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) less than of equal to 40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95). CONCLUSIONS: In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Shalowitz, D. I., M. A. Spillman and M. A. Morgan (2016). “Interactions with Industry under the Sunshine Act: An Example from Gynecologic Oncology.” Am J Obstet Gynecol. Feb 20. [Epub ahead of print]

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THE PROBLEM: Clinicians may be unaware that industry payments to physicians are now publicly searchable under the Physician Payments Sunshine Act. Furthermore, the extent of industry’s financial involvement in subspecialty practice has not been previously accessible. As an example, 6,948 direct, research-unrelated payments totaling $1,957,004 were made to 765 gynecologic oncologists in 2014, the first full year of data available. 153 companies reported at least one payment; however, the ten manufacturers reporting the highest total payment amount accounted for 82% of all payments to physicians. 48 gynecologic oncologists received more than $10,000 from manufacturers, accounting for $1,202,228, or 61% of total payments. A SOLUTION: Obstetrician-gynecologists, including gynecologic oncologists, should be aware of their publicly reported payments from industry and ensure reports’ accuracy. Professional organizations, including the Society for Gynecologic Oncology, should strongly consider proactively developing guidelines regarding interactions with industry for their general memberships.

Porta, C., G. Tortora, J. M. Larkin and T. E. Hutson (2016). “Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions.” Future Oncol 12(4): 533-549.

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Targeted therapies have substantially improved outcomes in metastatic renal cell carcinoma (mRCC). As expected, poor-risk patients have the worst outcomes. Temsirolimus is currently the only agent licensed for treatment of poor-risk mRCC patients. It is associated with meaningful improvements in survival and quality of life, highlighting the importance of correctly stratifying risk in mRCC patients so they receive optimal treatment. Currently, data for other targeted therapies in poor-risk patients are relatively sparse. Optimizing outcomes in these patients is the subject of ongoing research, including studies of biomarkers and studies to elucidate the role of nephrectomy and neoadjuvant targeted therapy in poor-risk mRCC patients. The impacts of novel combinations including temsirolimus have also been explored to further improve outcomes.

Pearson, E., L. McGarry, S. Gala, C. Nieset, M. Nanavaty, M. Mwamburi and Y. Levy (2016). “Disease-related mortality exceeds treatment-related mortality in patients with chronic myeloid leukemia on second-line or later therapy.” Leuk Res 43: 1-8.

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Treatment of newly-diagnosed patients with chronic-phase chronic myeloid leukemia (CP-CML) with tyrosine kinase inhibitors (TKIs) results in near-normal life expectancy. However, CP-CML patients resistant to initial TKIs face a poorer prognosis and significantly higher CML-related mortality. We conducted a systematic literature review to evaluate the specific causes of deaths (diseases progression versus drug-related) in CP-CML patients receiving second- or third-line therapy. We identified eight studies based on our criteria that reported causes of death. Overall, 5% of second-line and 10% of third-line patients died during the study follow-up period. For second-line, (7 studies, n=1926), mortality was attributed to disease progression for 41% of deaths, 2% to treatment-related causes, 3% were treatment-unrelated, and 50% were unspecified adverse events (AEs), not likely related to study drug. In third-line, (2 studies, n=144), 71% deaths were attributed to disease progression, 7% treatment-related AEs, 14% treatment-unrelated and 7% unspecified AEs. Annual death rates for second- and third-line therapy were significantly higher than for general population in similar age group. Our findings suggest death attributed to disease progression is approximately 10 times that due to treatment-related AEs in patients with CP-CML receiving second- or third-line therapy. Therefore, the potential benefits of effective treatment for these patients with the currently available TKIs outweigh the risks of treatment-induced AEs.