Weill Medical College of Cornell University

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Transplantation-Oncology Infectious Diseases:

Translational Research: Walsh, Soave, helfgott, Petraitiene, Petraitis. Infectious diseases are important causes of morbidity and mortality in immunocompromised patients with cancer and those undergoing transplantation. The mission of the transplantation-oncology infectious diseases program is to develop new strategies for diagnosis, treatment, and prevention of life-threatening infections in immunocompromised children and adults with transplantation and neoclassic diseases through multidisciplinary translational research. The tools of this research include epidemiology, pathogenesis, antimicrobial pharmacology, immunopharmacology, molecular diagnostic microbiology, and studies of innate host defenses.

laboratory animal models, phase I-II clinical trials, and, where applicable to multicenter phase III clinical trials. Our clinical trials are conducted with consortia composed of seasoned clinical investigators with expertise in immunocompromised patients. Among the pediatric and adult patient populations studied within the Program are those hematological malignancies, aplastic anemia, myelodysplasia, hematopoietic stem cell transplantation, and solid organ transplantation. Our strategy for translational research is predicated on an iterative process of bedside to bench to bedside with an emphasis on the critical role of the physician-scientist in this process. These studies are conducted in collaboration with our colleagues in Pediatrics, Oncology, Hematology, Nephrology, Hepatobiliary Surgery, Clinical Microbiology, Pharmacology, and Microbiology & Immunology. We have a long and successful tradition of mentoring the future leaders in the field of infections in immunocompromised patients.

Invasive Fungal Infections: Recognizing the severe morbidity and mortality cause by invasive mycoses, the study of invasive fungal infections with specific emphasis on Candida spp., Aspergillus spp., the Mucorales (Zygomycetes), and emerging pathogens such as Fusarium spp., Scedosporium spp., is a critical element of our mission. We conduct translational research in three major areas of medical mycology: antifungal pharmacology, molecular diagnosis, and innate host defenses. Among the recent advances in 2011-2012, are the identification of the critical role of antifungal therapy in improving survival in patients with severe aplastic anemia, the combination antifungal therapy of Candida biofilms, transcriptional profiles and immunomodulatory activity of lipid formulations of amphotericin B on human monocytes, development and validation of the first multispecies PCR system for Aspergillus spp to be made available in a U.S. reference laboratory, plasma pharmacokinetics of posaconazole, largest case series of Candida osteomyelitis (collaboration with Hospital for Special Surgery), in vitro and in vivo interspecies analysis of virulence in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers, sporangiospore germination and hyphal metabolism. Ongoing clinical trials include pharmacokinetic studies of novel triazoles and diagnostic biomarkers in immunocompromised children and adults.

Resistant Bacterial Infections: The Program is developing new strategies for pharmacodynamically rational methods for administration of existing antibacterial agents, as well as development of new compounds. We have characterized the epidemiology of carbapebem-resistant Enterobacteriaciae in patients with hematological malignancies. We are currently investigating molecular diagnostic approaches to rapid identification of resistant bacteria as a guide to management of critically-ill patients. As Clostridium difficile represents a serious threat to our patients, international trials are being initiated in the immunocompromised Transplant Oncology Program.

Viral Infections: The epidemiology and risk factors for development of human rhinovirus (HRV) respiratory tract infections have been characterized in HSCT recipients. An ongoing prospective observational study is characterizing the molecular epidemiology of these HRV infections. Studies of anti-influenza and parainfuenza compounds (especially in collaboration with Dr. Moscona in Pediatrics) will provide our patients with new agents that may improve outcome from these serious infections in our immunocompromised population. The epidemiology of respiratory viral infections in these patients continues to evolve and will be the subject of further study. Finally, the Program will be initiating studies of the efficacy and the immunologic response of antiviral vaccines.

• Chatzimoschou A, Katragkou A, Simitsopoulou M, Antachopoulos C, Georgiadou E, Walsh TJ, and Roilides E. Activities of triazole-echinocandin combinations against Candida species in biofilms and as planktonic cells. Antimicrob Agents Chemother. 2011;55:1968- 74.
• Cornely OA, Helfgott D, Langston A, Heinz W, Vehreschild JJ, Vehreschild MJ, Krishna G, Ma L, Huyck S, McCarthy MC. Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection. Antimicrob Agents Chemother. 2012;56:2652-58.
• Gamaletsou MN, Kontoyiannis DP, Sipsas NV, Moriyama B, Alexander E, Roilides E, Brause B and Walsh TJ. Candida osteomyelitis: analysis of 216 pediatric and adult cases. Clin Infect Dis (in press).
• Luong ML, Clancy CJ, Vadnerkar A, Kwak EJ, Silveira FP, Wissel MC, Grantham KJ, Shields RK, Crespo M, Pilewski J, Toyoda Y, Kleiboeker SB, Pakstis D, Reddy SK, Walsh TJ, Nguyen MH. Comparison of an Aspergillus real-time polymerase chain reaction assay with galactomannan testing of bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in lung transplant recipients. Clin Infect Dis. 2011;52:1218-26.
• Petraitis V, Petraitiene R, Antachopoulos C, Hughes JE, Cotton MP, Kasai M, Harrington S, Gamaletsou MN, Bacher JD, Kontoyiannis DP, Roilides E, and Walsh TJ. Increased virulence of Cunninghamella bertholletiae in experimental pulmonary mucormycosis: correlation with circulating molecular biomarkers, sporangiospore germination and hyphal metabolism. Medical Mycol (in press).
• Simitsopoulou M, Roilides E, Georgiadou E, Paliogianni F and Walsh TJ. Differential transcriptional profiles induced by amphotericin B formulations on human monocytes during response to hyphae of Aspergillus fumigatus. Medical Mycol. 2011;49:176-85.
• Valdez JM, Scheinberg P, Nunez O, Wu CO, Young NS, and Walsh TJ. Decreased infection-related mortality and improved survival in severe aplastic anemia in the past two decades. Clin Infect Dis. 2011;52:726-35.
• Walsh TJ, Wissel MC, Grantham KJ, Petraitiene R, Petraitis V, Kasai M, Francesconi A, Cotton MP, Hughes JE, Greene L, Bacher JD, Manna P, Salomoni M, Kleiboeker SB, Reddy SK. Molecular diagnosis and species-specific identification of medically important Aspergillus species by real time PCR in experimental invasive pulmonary aspergillosis. J Clin Microbiol. 2011;49:4150-57.