Research Spotlight

Posted March 15th 2016

Disease-related mortality exceeds treatment-related mortality in patients with chronic myeloid leukemia on second-line or later therapy.

Moshe Y. Levy M.D.

Moshe Y. Levy M.D.

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.


Posted March 15th 2016

Progestin treatment decreases CD133+ cancer stem cell populations in endometrial cancer.

Monique A. Spillman M.D.

Monique A. Spillman, M.D.

Guy, M. S., L. Qamar, K. Behbakht, M. D. Post, J. Sheeder, C. A. Sartorius and M. A. Spillman (2016). “Progestin treatment decreases CD133+ cancer stem cell populations in endometrial cancer.” Gynecol Oncol 140(3): 518-526.

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OBJECTIVES: Endometrial cancer is a hormonally responsive malignancy. Response to progestins is associated with estrogen receptor (ER) and progesterone receptor (PR) status. CD133 is a marker of endometrial cancer stem cells. We postulated that CD133+ cells express ER and PR and that progestin therapy differentially regulates CD133+ cells. METHODS: The Ishikawa (ER/PR positive) and KLE (ER/PR negative) cell lines were examined for the presence of CD133 populations. Cell lines were treated with 30.4muM medroxyprogesterone 17-acetate (MPA) for 6days. After treatment, cell counts, apoptosis assays and CD133+ populations were examined. In a clinical project, we identified 12 endometrial cancer patients who were treated with progestin drugs at our institution. Using immunohistochemistry, CD133, ER, PR, and androgen receptor (AR) expression was scored and evaluated for change over time on serial biopsies. RESULTS: CD133+ populations were identified in Ishikawa and KLE cell lines. MPA treatment resulted in a significant reduction in the percentage of live cells (Ishikawa, P=0.036; KLE, P=0.0002), significant increase in apoptosis (Ishikawa, P=0.01; KLE, P=0.0006) and significant decrease in CD133+ populations (Ishikawa, P<0.0001; KLE, P=0.0001). ER, PR, AR and CD133 were present in 96.4%, 96.4%, 89.3% and 100% of patient samples respectively. Paralleling the in vitro results, CD133 expression decreased in patients who had histologic response to progestin treatment. CONCLUSION: CD133+ populations decreased after treatment with MPA in an in vitro model and in patients responding to treatment with progestins. Progestin treatment differentially decreases CD133+ cells.


Posted March 15th 2016

Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy.

Michael Kuperman M.D.

Michael Kuperman, M.D.

Atta, M. G., M. M. Estrella, K. L. Skorecki, J. B. Kopp, C. A. Winkler, W. G. Wasser, R. Shemer, L. C. Racusen, M. Kuperman, M. C. Foy, G. M. Lucas and D. M. Fine (2016). “Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy.” Clin J Am Soc Nephrol 11(2): 262-270.

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BACKGROUND AND OBJECTIVES: Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high-risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation. RESULTS: The addition of APOL1 genotype to HIV-related risk factors for kidney disease in a predictive model improved the prediction of non-HIV-associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology. CONCLUSIONS: APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.


Posted March 15th 2016

The Carpentier-Edwards Perimount Magna mitral valve bioprosthesis: intermediate-term efficacy and durability.

Aldo E. Rafael M.D.

Aldo E. Rafael, M.D.

Loor, G., A. Schuster, V. Cruz, A. Rafael, W. J. Stewart, J. Diaz and K. McCurry (2016). “The Carpentier-Edwards Perimount Magna mitral valve bioprosthesis: intermediate-term efficacy and durability.” J Cardiothorac Surg 11(1): 20.

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BACKGROUND: The Carpentier-Edwards Perimount Magna mitral valve bioprosthesis (Edwards Lifesciences, Irvine, CA) is a low-profile version of the earlier Perimount valve that uses the ThermaFix process for enhanced calcium removal. The Magna valve has been in use since 2008, yet no publication, until now, has verified its intermediate-term safety and efficacy. METHODS: From 2008 through 2011 (our 4-year study period), 70 Magna valves were implanted in the mitral position at a single institution (the Cleveland Clinic). Echocardiograms were prospectively interpreted. For this study, we reviewed patients’ charts; endpoints included hemodynamic measurements, in-hospital morbidity and mortality, valve-related events, resource utilization, and 5-year survival rates. RESULTS: The mean patient age was 68 years; 43 % of the patients had New York Heart Association (NYHA) class III or IV disease, and 51.4 % had moderately severe, or worse, mitral regurgitation (MR). For 43 % of the patients, the Magna valve implantation was a reoperation. For 83 %, the Magna valve implantation also included a concomitant cardiac procedure. The median survival rate was 4.7 years and 90 % of patients were free from significant structural valve degeneration at 5 years. Preoperative atrial fibrillation, ischemic MR, intraaortic balloon pump placement, cardiogenic shock, cardiac arrest, and renal failure were associated with increased mortality. Right ventricular systolic pressure decreased from 50 mmHg preoperatively to 40 mmHg postoperatively, according to our matched-pair analysis (P = 0.003). Per their final echocardiogram during our study period, 98 % of surviving patients had trivial or no MR, one patient had mild MR, and one patient had severe MR. CONCLUSIONS: Our 5-year experience indicates that the Magna valve offers excellent intermediate-term durability and substantial echocardiographic improvement; its low-profile design make it ideal for reoperations and for concomitant cardiac procedures, including valve replacement.


Posted March 15th 2016

Ischiofemoral impingement: defining the lesser trochanter-ischial space.

Hal David Martin D.O.

Hal David Martin, D.O.

Kivlan, B. R., R. L. Martin and H. D. Martin (2016). “Ischiofemoral impingement: defining the lesser trochanter-ischial space.” Knee Surg Sports Traumatol Arthrosc. Jan; 32(1):13-8.

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PURPOSE: The purpose of this study was to define changes in the ischial-lesser trochanteric space associated with medial and lateral hip rotation in neutral and 10 degrees of extension and adduction. METHODS: Twenty-five hip joints from 14 embalmed cadavers (7 males and 7 females) were used for this study. The pelvic region of each cadaver was skeletonized, and the hip capsule released distally. With the hip joint in 0 degrees flexion-extension/abduction-adduction, the distance between the lesser trochanter and ischium was measured in: neutral rotation, 40 degrees medial rotation, and 60 degrees lateral rotation. A one-way ANOVA with post hoc analysis determined the difference in the ischiofemoral space in these three positions. An additional position was then tested by laterally rotating the femur with the hip joint positioned in 10 degrees extension and adduction. RESULTS: The average distance between the lesser trochanter and ischium was different (p < .0005) in neutral rotation, 40 degrees medial rotation, and 60 degrees lateral rotation at 2.8 cm (SD 1.1), 4.3 cm (SD 1.2), and 1.4 cm (SD 0.7), respectively. With the hip joint laterally rotated from a starting position of 10 degrees extension and adduction, 21 of 25 (84 %) hips made contact between the lesser trochanter and ischium at an average position of 29 degrees (SD 20) of lateral rotation. CONCLUSIONS: The lesser trochanter is closest to the ischium in lateral rotation and is furthest away in medial rotation when the hip is in neutral flexion-extension/abduction-adduction. The lesser trochanter approximates the ischium when the hip is laterally rotated in 10 degrees extension and adduction. The information gained through this investigation helps to define the pathomechanics associated with ischiofemoral impingement and validate clinical tests to diagnose ischiofemoral impingement.