Research Spotlight

Posted June 15th 2016

Adrenal cortical carcinoma with pulmonary emboli: A unique presentation of a rare tumor with extensive tumor thrombus and inferior vena cava extension.

Giuliano Testa M.D.

Giuliano Testa M.D.

Fernandez, H. T., P. T. W. Kim and G. Testa (2016). “Adrenal cortical carcinoma with pulmonary emboli: A unique presentation of a rare tumor with extensive tumor thrombus and inferior vena cava extension.” International Journal of Hepatobiliary and Pancreatic Diseases 6: 30-33.

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Introduction: Adrenal cortical carcinoma (ACC) is rare, and presenting symptoms vary widely depending on functional or non-functional endocrine status. These tumors are most commonly treated with surgical resection and postoperative mitotane administration. Case Report: This is an unusual presentation of a 23-year-old female with no significant past medical history, admitted to the hospital with syncope and dyspnea. Computed tomography angiography (CTA) demonstrated extensive bilateral pulmonary embolisms, with an associated 16-cm assumed right lobe hepatic mass with suprahepatic vena cava tumor thrombus extension beyond the level of the hepatic veins. The patient underwent a complete resection of the right adrenal mass, with inferior vena cava resection, thrombectomy, and placement of caval interposition graft without the use of bypass. Pathology was consistent with adrenal cortical carcinoma. Conclusion: This case of an adrenal cortical carcinoma, with a rare presentation of bilateral pulmonary embolisms, was treated with a surgical R0 resection. This included a right adrenalectomy with IVC resection and interposition graft. Tumors with IVC involvement and tumor thrombus can be treated with surgical resection and IVC grafting, without the use of bypass.


Posted June 15th 2016

Moxifloxacin’s limited efficacy in the hollow-fiber model of mycobacterium abscessus disease.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Ferro, B. E., S. Srivastava, D. Deshpande, J. G. Pasipanodya, D. van Soolingen, J. W. Mouton, J. van Ingen and T. Gumbo (2016). “Moxifloxacin’s limited efficacy in the hollow-fiber model of mycobacterium abscessus disease.” Antimicrob Agents Chemother 60(6): 3779-3785.

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Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (kel) of 0.11 +/- 0.05 h(-1) (mean +/- standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emax was 3.15 +/- 1.84 log10 CFU/ml on day 3, and the exposure mediating 50% of Emax (EC50) was a 0- to 24-h area under the concentration time curve (AUC0-24)-to-MIC ratio of 41.99 +/- 31.78 (r(2) = 0.99). The EC80 was an AUC0-24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC0-24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC80 in /=12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin’s efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.


Posted June 15th 2016

Women with cardiogenic shock derive greater benefit from early mechanical circulatory support: An update from the cvad registry.

Susan M. Joseph M.D.

Susan M. Joseph M.D.

Joseph, S. M., M. A. Brisco, M. Colvin, K. L. Grady, M. N. Walsh and J. L. Cook (2016). “Women with cardiogenic shock derive greater benefit from early mechanical circulatory support: An update from the cvad registry.” J Interv Cardiol 29(3): 248-256.

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OBJECTIVES: The aim of this analysis was to assess survival differences between men and women supported with Impella 2.5 (Abiomed Inc., Danvers) in the setting of acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). BACKGROUND: Data on sex differences in outcomes of CS with mechanical circulatory support are sparse. METHODS: Patients enrolled in the cVAD Registry who underwent percutaneous coronary intervention (PCI) and Impella 2.5 support for CS complicating an AMI were included. Differences between men and women were examined. RESULTS: In total, 180 patients were analyzed. Women (n = 49, 27.2%) were older (71.0 +/- 12.8 years vs 63.8 +/- 13.0, P = 0.001), smaller (BSA 1.82 +/- 0.22 vs 2.04 +/- 0.24 m(2) , P < 0.001), and had a higher STS mortality risk score than men (27.9 +/- 17.0 vs. 20.8 +/- 16.8 P = 0.01). There was no difference in survival to discharge (P = 0.3). Patients receiving the Impella 2.5 pre-PCI had significantly lower inpatient mortality than those who received support post-PCI (P = 0.003). However, the magnitude of the survival benefit was significantly greater in women who received the Impella pre-PCI as compared to men. Overall, 68.8% of women survived with pre-PCI Impella 2.5 versus 24.2% post-PCI (P = 0.005) whereas 54.2% of men survived with pre-PCI Impella 2.5 versus 40.3% post-PCI (P = 0.1, p-interaction = 0.07). No differences in timing to intervention were found between men and women. CONCLUSIONS: Early initiation of hemodynamic support prior to PCI with Impella 2.5, in the setting of AMI complicated by CS, was associated with a greater survival benefit to hospital discharge in women compared to men, despite a higher predicted risk of mortality and a greater revascularization failure rate for women.


Posted June 15th 2016

Thioridazine as chemotherapy for mycobacterium avium complex diseases.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Deshpande, D., S. Srivastava, S. Musuka and T. Gumbo (2016). “Thioridazine as chemotherapy for mycobacterium avium complex diseases.” Antimicrob Agents Chemother: May 2016 [Epub ahead of print].

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Mycobacterium avium-intracellulare complex (MAC) causes an intractable intracellular infection that presents as chronic pulmonary disease. Currently, therapy consists of ethambutol and macrolides and takes several years to complete. The neuroleptic phenothiazine, thioridazine, kills mycobacteria by inhibiting the electron transport chain. In several experiments of bacterial populations up to 1012 CFU/mL we failed to isolate any bacteria resistant to 3 times the MIC, suggesting absence of resistant mutants at bacterial burdens several-fold higher than encountered in patients. In the hollow fiber model of intracellular MAC (HFS-MAC), thioridazine achieved an extracellular half-life of 16.8 hours and an intracellular half-life of 19.7 hours. Thioridazine concentrations were >28,000-fold higher inside infected macrophages compared to HFS-MAC central compartment (equivalent to “plasma”). Thioridazine maximal kill was 5.20+/-0.75 log10 CFU/mL on day 7 (r2= 0.96) and 7.19+/-0.31 log10 CFU/mL on day 14 (r2=0.99), the highest seen with any drug in the system. Dose-fractionation studies revealed that thioridazine efficacy and acquired drug resistance were driven by peak-to-MIC ratio, with an EC50 of 2.78+/-0.44 for microbial kill. Acquired drug resistance was encountered by day 21 with suboptimal doses, demonstrating that fluctuating drug concentrations drive evolution faster than static concentrations in mutation frequency studies. However, the thioridazine EC50 changed 16.14-fold when fetal bovine serum was changed from 0% to 50%, suggesting that intracellular potency could be heavily curtailed by protein binding. Efficacy in patients will depend on the balance between trapping of the drug in the pulmonary system and the massive intracellular concentrations versus very high protein binding of thioridazine.


Posted June 15th 2016

Incidence and predictive factors for recovery of ovarian function in amenorrheic women in their 40s treated with letrozole.

Joyce O'Shaughnessy M.D.

Joyce O’Shaughnessy M.D.

Krekow, L. K., B. A. Hellerstedt, R. P. Collea, S. Papish, S. M. Diggikar, R. Resta, S. J. Vukelja, F. A. Holmes, P. K. Reddy, L. Asmar, Y. Wang, P. S. Fox, S. R. Peck and J. O’Shaughnessy (2016). “Incidence and predictive factors for recovery of ovarian function in amenorrheic women in their 40s treated with letrozole.” J Clin Oncol 34(14): 1594-1600.

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PURPOSE: This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS: Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for >/= 1 year were treated with letrozole (2.5 mg) daily for >/= 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS: The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naive patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION: These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.