Research Spotlight

Kim, H. T., K. W. Ahn, Z. H. Hu, M. S. Davids, V. O. Volpe, J. H. Antin, M. L. Sorror, M. Shadman, O. Press, J. Pidala, W. Hogan, R. Negrin, S. Devine, J. Uberti, E. Agura . . . and J. R. Brown (2019). “Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients: Center for International Blood and Marrow Transplant Research Report.” Clin Cancer Res Jun 28. [Epub ahead of print].

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Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or >/=5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

Kennedy, L., H. Francis, P. Invernizzi, J. Venter, N. Wu, M. Carbone, M. E. Gershwin, F. Bernuzzi, A. Franchitto, D. Alvaro, M. Marzioni, P. Onori, E. Gaudio, A. Sybenga, L. Fabris, F. Meng, S. Glaser and G. Alpini (2019). “Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.” FASEB Jun 28. [Epub ahead of print].

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Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-beta receptor II (dnTGF-betaRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5-27, for 1 wk. dnTGF-betaRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-betaRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-betaRII mice, there was increased microRNA-125b/TGF-beta1/TGF-beta receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC.-Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.

Kelly, R. J., R. Turner, Y. W. Chen, J. R. Rigas, A. W. Fernandes and S. Karve (2019). “Complications and Economic Burden Associated With Obtaining Tissue for Diagnosis and Molecular Analysis in Patients With Non-Small-Cell Lung Cancer in the United States.” J Oncol Pract Jun 25. [Epub ahead of print].

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PURPOSE: With an increase in biomarker-directed therapies, tissue biopsy to identify targetable genomic and immunologic alterations has become the mainstay of managing patients with non-small-cell lung cancer (NSCLC); however, little is known about the associated economic impact and complication rate. This study assesses the frequency, complications, and costs of diagnostic and postprogression biopsy. METHODS: This retrospective, observational study was conducted using administrative claims data from more than 30 million commercially insured individuals in the United States (2006 to 2014). Data were analyzed for the overall population and by time of biopsy (diagnostic or postprogression biopsy). RESULTS: Of 20,013 eligible patients, 13,411 (67%) received a diagnostic biopsy, whereas only 2,056 (10%) received a postprogression biopsy (mean cost, $9,977 and $16,806, respectively). Complication rates were similar at diagnosis and after progression, on the day of biopsy (10% v 7%, respectively) and within 30 days (63% v 61%, respectively). Mean costs were higher among patients with a complication compared with those without a complication on the day of biopsy (diagnostic biopsy, $12,030 v $6,508, respectively; postprogression biopsy, $22,593 v $7,812, respectively), within 7 days of biopsy (diagnostic biopsy, $13,657 v $7,765, respectively; postprogression biopsy, $23,969 v $8,932, respectively), and within 30 days of biopsy (diagnostic biopsy, $24,968 v $15,988, respectively; postprogression biopsy, $30,293 v $12,494, respectively; P < .001 for all comparisons). CONCLUSION: From 2006 to 2014, postprogression biopsies were not common practice in NSCLC. Complication rates were similar at diagnosis and after progression, with mean costs higher among patients with a complication than those without a complication. With increasing demands for effective novel targeted therapies and safe testing methods, these data may be valuable in determining the budget impact and comparing complication rates with newer, less invasive molecular testing methods, including plasma circulating tumor DNA testing.

Huntley, G. D., K. M. Tecson, S. Sodhi, J. Saef, K. S. White, P. A. Ludbrook, A. M. Cedars and J. M. Ko (2019). “Cardiac Denial and Expectations Associated With Depression in Adults With Congenital Heart Disease.” Am J Cardiol 123(12): 2002-2005.

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Depression in adults with congenital heart disease is highly prevalent and strongly associated with adverse prognosis. Better management of risk factors for depression may improve clinical outcomes in this population. We conducted a single-site, cross-sectional study of 78 adults with congenital heart disease followed at Washington University School of Medicine. Data considered in the analyses included retrospectively obtained clinical information and patients’ self-assessed psychosocial functioning and health status. To identify the clinical and psychosocial variables associated with depression, we built a stepwise multivariate model to measure the relative contribution of these variables to depression status. The prevalence of depression in our sample was 26%. Our model accounted for approximately 67% of the variability in depression scores. The final model consisted of the Cardiac Denial of Impact Scale, expectations domain of Barriers to Care, and the energy and social domains of the Rand 36-Item Short Form Health Survey. Clinical variables did not predict variability in depression scores. In conclusion, greater cardiac denial and negative expectations of the healthcare team were associated with increased depression symptoms in ACHD.

Hollander, P. A., J. Kiljanski, E. Spaepen and C. J. Harris (2019). “The Risk of Clinically Relevant Hypoglycaemia in Patients with Type 2 Diabetes Self-titrating Insulin Glargine U-100.” Diabetes Obes Metab Jul 2. [Epub ahead of print].

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AIMS: We evaluated risk factors for clinically relevant hypoglycaemia (blood glucose <3 mmol/L) in patients with type 2 diabetes during insulin glargine self-titration. Data was from two clinical trials in which patients were able to improve their glycaemic control by self-titration of insulin glargine with a simple algorithm. PATIENTS AND METHODS: We performed post hoc analyses of pooled treatment groups from each of 2 Phase 3 studies comparing LY2963016 with LANTUS(R): ELEMENT-2 (double-blind) and ELEMENT-5 (open label). Clinically relevant hypoglycaemia was analysed by category of HbA1c (<7%, 7-8.5%, >8.5%) at Week 12 (titration period) and at Week 24 (overall study), and subgroups of age (<65, >/=65 yrs) and previous insulin use (naive or not). RESULTS: In ELEMENT-2 (N=756), there were no overall differences in rate or incidence of hypoglycaemia among HbA1c categories. In ELEMENT-5 (N=493), patients with HbA1c >8.5% had lower rate and incidence of hypoglycaemia throughout the study compared to those in the lower HbA1c categories. In both studies, patients >/=65 yrs of age (vs <65 yrs) had a higher rate and incidence of hypoglycaemia during the titration phase, and had lower baseline HbA1c, smaller increases in dose, and no differences in HbA1c post-baseline. The rate and incidence of hypoglycaemia was similar between naive patients and patients previously on basal insulin, across all levels of glycaemic control. With the exception of the older subgroup, hypoglycaemia rates were similar during titration and maintenance periods. CONCLUSIONS: Our results support broader use of self-titration algorithms in patients with type 2 diabetes.