Research Spotlight

Sannino, A., S. Potluri, B. Pollock, G. Filardo, A. Gopal, R. C. Stoler, M. Szerlip, A. Chowdhury, M. J. Mack and P. A. Grayburn (2019). “Impact of Mitral Stenosis on Survival in Patients Undergoing Isolated Transcatheter Aortic Valve Implantation.” Am J Cardiol Jan 25. [Epub ahead of print].

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This study was performed to investigate the prevalence and impact on survival of baseline mitral stenosis (MS) in patients who underwent transcatheter aortic valve implantation (TAVI) due to the presence of severe symptomatic aortic stenosis. This retrospective study included 928 consecutive patients with severe, symptomatic aortic stenosis who underwent TAVI in 2 institutions, from January 2012 to August 2016. Mean follow-up was 40.8 +/- 13.9 months. Based on the mean mitral gradient (MMG) at baseline, 3 groups were identified: MMG <5 mm Hg (n=737, 81.7%); MMG >/=5 and <10 mm Hg (n=147, 16.3%); MMG >/=10 mm Hg (n=17, 1.9%). These latter were more frequently women, with a smaller body surface area, a higher prevalence of atrial fibrillation, chronic obstructive pulmonary disease, and previous history of coronary-artery bypass graft/percutaneous coronary intervention. At baseline, patients with MMG >/=10 mm Hg compared with >/=5 and <10 mm Hg and <5 mm Hg patients had a lower mitral valve area (2.4 +/- 0.94 vs 2.1 +/- 0.86 vs 1.5 +/- 0.44 cm(2)), a lower prevalence of MR >/=2+ (5.9% vs 28.6% and 15.6%, p <0.0001), a higher prevalence of severe mitral annular calcium (70.6% vs 45.6% and 13.0%, p <0.0001) and a higher systolic pulmonary arterial pressure (50.6 +/- 12.1 vs 47.2 +/- 14.5 and 41.6 +/- 14.4, p <0.0001). Despite the low prevalence of MMG >/=10 mm Hg, these patients had higher 5-year mortality compared with the other groups (adjusted hazard ratio 2.91, 95% confidence interval 1.17 to 7.20, p=0.02). In conclusion, severe calcific MS is uncommon in patients who underwent TAVI. Its presence is associated with higher long-term mortality whereas moderate MS is not.

Saif, M. W., L. Rosen, M. A. Rudek, W. Sun, D. R. Shepard, C. Becerra, F. Yamashita, P. Bebeau and R. Winkler (2019). “Open-label study to evaluate trifluridine/tipiracil safety, tolerability and pharmacokinetics in patients with advanced solid tumours and hepatic impairment (PI: Dr Saif).” Br J Clin Pharmacol Jan 9. [Epub ahead of print].

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AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, non-randomised study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged >/=18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m(2) orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n=8) and mild (n=10) and moderate (n=6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least one adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, five of six patients experienced grade >/=3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve (AUC) at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI AUC. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.

Rolfes, M. A., B. Flannery, J. Chung, A. O’Halloran, S. Garg, E. A. Belongia, M. Gaglani, R. Zimmerman, M. L. Jackson, A. S. Monto, N. B. Alden, E. Anderson, N. M. Bennett, L. Billing, S. Eckel, P. D. Kirley, R. Lynfield, M. L. Monroe, M. Spencer, N. Spina, H. K. Talbot, A. Thomas, S. Torres, K. Yousey-Hindes, J. Singleton, M. Patel, C. Reed and A. M. Fry (2019). “Effects of Influenza Vaccination in the United States during the 2017-2018 Influenza Season.” Clin Infect Dis Feb 2. [Epub ahead of print].

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Background: The severity of the 2017-2018 influenza season in the U.S. was high with influenza A(H3N2) viruses predominating. We report influenza vaccine effectiveness (VE) and estimate the number of vaccine prevented influenza-associated illnesses, medical visits, hospitalizations, and deaths for the 2017-2018 influenza season. Methods: We used national age-specific estimates of 2017-2018 influenza vaccine coverage and disease burden. We estimated VE, and 95% confidence intervals (CI), against medically-attended RT-PCR confirmed influenza virus infection, in the ambulatory setting, using a test-negative design. We estimated influenza type/subtype-specific burden using multipliers applied to population-based rates of influenza-associated hospitalizations. We used a compartmental model to estimate numbers, with 95% credible intervals (CrI), of influenza-associated outcomes prevented by vaccination. Results: The VE against outpatient medically-attended, laboratory-confirmed influenza was 38% (95% CI: 31-43%) including 22% (95% CI: 12-31%) against influenza A(H3N2), 62% (95% CI: 50-71%) against influenza A(H1N1)pdm09, and 50% (95% CI: 41-57%) against influenza B. We estimated that influenza vaccination prevented 7.1 million (95% CrI: 5.4 million-9.3 million) illnesses, 3.7 million (95% CrI: 2.8 million-4.9 million) medical visits, 109,000 (95% CrI: 39,000-231,000) hospitalizations, and 8,000 (95% CrI: 1,100-21,000) deaths. Vaccination prevented 10% of expected hospitalizations overall and 41% among young children (6 months-4 years). Conclusions: Despite 38% VE, influenza vaccination reduced a substantial burden of influenza-associated illness, medical visits, hospitalizations, and deaths in the U.S. during the 2017-2018 season. Our results demonstrate the benefit of current influenza vaccination and the need for improved vaccines.

Reichard, C. A., Y. A. Nyame, D. Sundi, J. Tosoian, L. Wilkins, R. Alam, M. F. Achim, X. Wang, A. J. Stephenson, E. A. Klein, A. E. Ross, J. W. Davis and B. F. Chapin (2019). “Does time from diagnosis to treatment of high or very high risk prostate cancer affect outcome?” BJU Int Jan 17. [Epub ahead of print].

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OBJECTIVE: To determine whether time from diagnosis to treatment impacted outcomes in a multi-center cohort of high and very high risk (VHR) prostate cancer (PCa) patients undergoing radical prostatectomy (RP). SUBJECTS AND METHODS: 1392 patients from three tertiary centers who underwent RP for either high risk or VHR disease from 2005-2015 were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer specific mortality (PCSM) were calculated for each tertile. Kaplan-Meier method was used to evaluate for differences in all cause mortality (ACM) among tertiles. Competing risks regression models as well as cox proportional hazards regression models were fit to assess association between time-to-event outcomes and patient characteristics. RESULTS: Median time from biopsy to radical prostatectomy was 68 days (IQR 50-94). Median follow up was 31 months (IQR 12.1-55.7). Cumulative incidence of BCR (p=0.14), metastasis (p=0.15), and PCSM (p=0.69) did not differ among time to treatment tertiles of VHR patients. Kaplan-Meier estimates of ACM (p=0.53) also did not differ among time to treatment tertiles. BCR, metastasis, PCSM, and ACM also did not significantly differ among time to treatment tertiles in multivariable modeling. CONCLUSION: In this pooled meta-dataset of patients with high or VHR prostate cancer, time from diagnosis to radical prostatectomy did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials.

Raymond, G. V. and R. Schiffmann (2019). “Cerebrotendinous xanthomatosis: The rare “treatable” disease you never consider.” Neurology 92(2): 61-62.

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Cerebrotendinous xanthomatosis (CTX; Online Mendelian Inheritance in Man No. 213700) is an autosomal recessive disorder due to pathogenic variant in the CYP27A1 gene resulting in a defect in the mitochondrial enzyme sterol 27-hydroxylase. The enzyme catalyzes multiple hydroxylation reactions involved in cholesterol metabolism and bile acid synthesis. When affected, it results in decreased synthesis of bile acids, with the resultant production of cholestanol and cholesterol affecting all tissues . . . In this issue of Neurology®, Stelten et al. examined whether early treatment could prevent the development of neurologic findings. They examined a Dutch cohort of 56 individuals with long-term follow-up and evaluated CDCA treatment in relation to the clinical neurologic outcomes. The mean age at diagnosis was 25.6 years, but the authors emphasize that, with the application of a clinical suspicion index, individuals could have been diagnosed 8 years earlier with a mean age of 17.3 years. They go on to demonstrate that those treated before 24 years of age had better outcomes and that neurologic deterioration was seen only in those treated after this age. While earlier treatment improved function, neurologic symptoms were seen before the age of 24 (25% vs 88%), with pyramidal and cerebellar symptoms being the most common. In this early treated group, these findings completely disappeared in those adherent to therapy, and none developed new neurologic symptoms. Some degree of intellectual impairment was seen in 50% of individuals diagnosed and treated before 24 years, but again, with early treatment, this stabilized. In those treated later in life, 61% worsened, with parkinsonism developing as a treatment-resistant feature of the disease. Experience in this large cohort of treated patients with CTX followed up for up to 35 years demonstrates that the age at diagnosis and initiation of CDCA therapy correlates with prognosis and that the routine delay in testing for the condition adversely affects the affected individual. Many questions will of course remain with a rare disorder, but it is clear that diagnosis and subsequent treatment are not occurring in a timely fashion. Faster, earlier diagnosis matters to these people in getting them treatment. Strategies to improve diagnosis with a clinical suspicion index, while admirable, have clearly not been effective. Most clinicians are not even aware that they should be suspicious. Improved detection is necessary, but this will most likely take a multiprong strategy to implement. Ordering cholestanol should become as routine, easy, and reflexive as ordering amino acids on any child seen in the clinic. It should become incorporated into all of the diagnostic DNA panels for cataracts, gastrointestinal disorders, and the multitude of neurologic and psychiatric diseases. We also need to imbue residents and fellows with the necessity of testing because they will ultimately change clinical practice. The proposed universal detection through newborn blood spots has challenges but may yet prove to be the most appropriate strategy. Until that time, however, it is imperative that we continue to improve detection and treatment. (Excerpt from text of this editorial, p. 61-62; abstract not available.)