Michaela Liedtke

All Publications

• A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma. British journal of haematology Dunn, T. J., Dinner, S., Price, E., Coutré, S. E., Gotlib, J., Hao, Y., Berube, C., Medeiros, B. C., Liedtke, M. 2016; 173 (2): 253-259

  Abstract

  Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

  View details for DOI 10.1111/bjh.13946

  View details for PubMedID 27040320

• NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016. Journal of the National Comprehensive Cancer Network Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Reu, F. J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2016; 14 (4): 389-400

  Abstract

  These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

  View details for PubMedID 27059188

• First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction. Journal of clinical oncology Gertz, M. A., Landau, H., Comenzo, R. L., Seldin, D., Weiss, B., Zonder, J., Merlini, G., Schönland, S., Walling, J., Kinney, G. G., Koller, M., Schenk, D. B., Guthrie, S. D., Liedtke, M. 2016; 34 (10): 1097-1103

  Abstract

  Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264).Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria.Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease.Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

  View details for DOI 10.1200/JCO.2015.63.6530

  View details for PubMedID 26858336

• Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia & lymphoma Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

  Abstract

  The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

  View details for DOI 10.3109/10428194.2015.1091930

  View details for PubMedID 26374199

• Recurrent Subepidermal Blistering Dermatosis Heralding Disease Relapse in IgA Kappa Multiple Myeloma: Report of a Case and a Review of the Literature. Clinical lymphoma, myeloma & leukemia Leatham, H. W., Novoa, R., Liedtke, M., Kwong, B. Y. 2016; 16 (1): e1-5

  View details for DOI 10.1016/j.clml.2015.11.007

  View details for PubMedID 26708980

• Multiple Myeloma, Version 2.2016 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Atanackovic, D., Biermann, J. S., Chandler, J. C., Costello, C., Djulbegovic, B., Fung, H. C., Gasparetto, C., Godby, K., Hofmeister, C., Holmberg, L., Holstein, S., Huff, C. A., Kassim, A., Krishnan, A. Y., Kumar, S. K., Liedtke, M., Lunning, M., Raje, N., Singhal, S., Smith, C., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Shead, D. A., Kumar, R. 2015; 13 (11): 1398-1435

  View details for Web of Science ID 000364277500010

• CD93 Marks a Non-Quiescent Human Leukemia Stem Cell Population and Is Required for Development of MLL-Rearranged Acute Myeloid Leukemia CELL STEM CELL Iwasaki, M., Liedtke, M., Gentles, A. J., Cleary, M. L. 2015; 17 (4): 412-421

  View details for DOI 10.1016/j.stem.2015.08.008

  View details for Web of Science ID 000365693800008

• Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma CANCER IMMUNOLOGY RESEARCH Hansmann, L., Blum, L., Ju, C., Liedtke, M., Robinson, W. H., Davis, M. M. 2015; 3 (6): 650-660

  View details for DOI 10.1158/2326-6066.CIR-14-0236-T

  View details for Web of Science ID 000357430000010

• Outcomes After Heart Transplantation for Amyloid Cardiomyopathy in the Modern Era AMERICAN JOURNAL OF TRANSPLANTATION Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

  Abstract

  We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

  View details for DOI 10.1111/ajt.13025

  View details for Web of Science ID 000349977700013

• Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia LEUKEMIA RESEARCH Liedtke, M., Dunn, T., Dinner, S., Coutre, S. E., Berubea, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

  View details for DOI 10.1016/j.leukres.2014.09.018

  View details for Web of Science ID 000345614400011

• Indolent T-lymphoblastic Proliferation With Disseminated Multinodal Involvement and Partial CD33 Expression AMERICAN JOURNAL OF SURGICAL PATHOLOGY Ohgami, R. S., Sendamarai, A. K., Atwater, S. K., Liedtke, M., Fleming, M. D., Natkunam, Y., Warnke, R. A. 2014; 38 (9): 1298-1304

  Abstract

  Although indolent T-lymphoblastic proliferations (iT-LBP) are rare, this diagnosis should be excluded in any patient with an extrathymic proliferation of immature TdT+T cells. Unlike T-lymphoblastic leukemia/lymphoma, patients with iT-LBP do not require chemotherapy. We report a case of iT-LBP with disseminated multinodal involvement in an otherwise healthy 49-year-old woman. Multiple lymph node biopsies were performed over the course of several months demonstrating persistent and anatomically diffuse involvement. Over 18 months, and without therapy, she has remained healthy, and her lymphadenopathy significantly improved. No bone marrow or peripheral blood involvement was ever identified. Atypical T cells showed an immunophenotypic spectrum of T-cell antigen expression with partial CD33 on a subset of T cells detected by both flow cytometry and immunohistochemistry. Both T-cell clonality and Human Androgen Receptor Assay (HUMARA) studies, performed on lymph node biopsy specimens, were negative. This case represents the first detailed clinical, morphologic, molecular, and immunophenotypic description of disseminated multinodal involvement by nonclonal iT-LBP with partial CD33 expression on T cells.

  View details for Web of Science ID 000341096800017

  View details for PubMedID 24618611

• Current therapy and novel agents for relapsed or refractory acute lymphoblastic leukemia LEUKEMIA & LYMPHOMA Dinner, S., Lee, D., Liedtke, M. 2014; 55 (8): 1715-1724

  Abstract

  Despite high rates of complete remission in newly diagnosed adult acute lymphoblastic leukemia (ALL), rates of long-term leukemia-free survival are disappointingly low. Treatment of relapsed disease with chemotherapy, even in patients able to pursue consolidation with allogeneic stem cell transplant, has demonstrated limited success. There are no established standards of care in this setting and few standard treatment options. Novel agents targeting antigens on the lymphoblast cell surface offer unique side effect and anti-leukemic profiles which suggest that their use alone or in combination with chemotherapy may achieve improved outcomes for relapsed or refractory ALL.

  View details for DOI 10.3109/10428194.2013.856428

  View details for Web of Science ID 000340224100006

  View details for PubMedID 24251864

• Effects of serum and plasma matrices on multiplex immunoassays IMMUNOLOGIC RESEARCH Rosenberg-Hasson, Y., Hansmann, L., Liedtke, M., Herschmann, I., Maecker, H. T. 2014; 58 (2-3): 224-233

  Abstract

  Multiplexed fluorescence or electrochemiluminescence immunoassays of soluble cytokines are commonly performed in the context of human serum or plasma, to look for disease biomarkers and to monitor the immune system in a simple and minimally invasive way. These assays provide challenges due to the complexities of the matrix (serum or plasma) and the presence of many cytokines near the limit of detection of the assay. Here, we compare the readout of matched serum and plasma samples, which are generally correlated. However, a subset of cytokines usually have higher levels in serum, and the non-specific background is significantly increased in serum versus plasma. Presumably as a result of this non-specific background, disease-related decreases in low-abundance cytokines can sometimes be detected in plasma but not in serum. We further show, through spike recovery experiments, that both serum and plasma inhibit the readout of many cytokines, with some variability between donors, but with serum causing greater inhibition than plasma in many cases. Standard diluents from different vendors can partially reverse this inhibition to varying degrees. Dilution of samples can also partly overcome the inhibitory effect of the matrix. We also show that dilution is nonlinear and differentially affects various cytokines. Together, these data argue that (1) plasma is a more sensitive matrix for detecting changes in certain low-abundance cytokines; (2) calculation of concentrations in serum or plasma matrices is inherently inaccurate; and (3) dilution of samples should not be assumed to be linear, i.e., all comparisons need to be made among similarly diluted samples.

  View details for DOI 10.1007/s12026-014-8491-6

  View details for Web of Science ID 000336333700008

• Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

  View details for DOI 10.1016/j.hrthm.2013.10.026

  View details for Web of Science ID 000329119200027

• A single-center experience of the nationwide daunorubicin shortage: substitution with doxorubicin in adult acute lymphoblastic leukemia LEUKEMIA & LYMPHOMA Patel, S., Liedtke, M., Ngo, D., Medeiros, B. C. 2013; 54 (10): 2231-2235

  Abstract

  Due to a national shortage of daunorubicin we evaluated the effects of substituting doxorubicin 1:1 in the induction phase for adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). We identified 10 patients receiving doxorubicin instead of daunorubicin as part of their induction on Cancer and Leukemia Group B (CALGB) 9511 or CALGB10403 and retrospectively compared them to 83 patients who received treatment on the same protocols with daunorubicin. Response rates were similar, independent of anthracycline received, with either CALGB9511 or CALGB10403. In either regimen, doxorubicin resulted in longer absolute neutrophil count (ANC) recovery time and hospitalization. Doxorubicin as part of CALGB9511 resulted in greater than three-fold higher mucositis. Sepsis and death during induction were significantly more frequent in patients who received doxorubicin on CALGB10403. While remission rates were similar, the use of doxorubicin was associated with prolonged neutropenia, higher risk of mucositis, infection and sepsis, and prolonged hospitalization. Higher induction mortality observed with doxorubicin substitution in this analysis needs further study.

  View details for DOI 10.3109/10428194.2013.772606

  View details for Web of Science ID 000324589800026

  View details for PubMedID 23383599

• Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement HAEMATOLOGICA Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

  Abstract

  Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

  View details for DOI 10.3324/haematol.2013.084574

  View details for Web of Science ID 000328543400020

  View details for PubMedID 23716538

• AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Penchala, S. C., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H., Liedtke, M., Witteles, R. M., Powers, E. T., Reixach, N., Chan, W. K., Wilson, I. A., Kelly, J. W., Graef, I. A., Alhamadsheh, M. M. 2013; 110 (24): 9992-9997

  Abstract

  The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

  View details for DOI 10.1073/pnas.1300761110

  View details for Web of Science ID 000320930100085

  View details for PubMedID 23716704

• The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

  Abstract

  The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

  View details for DOI 10.1111/bjh.12269

  View details for Web of Science ID 000317602300009

• Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia HAEMATOLOGICA Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

  Abstract

  There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ≥ 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

  View details for DOI 10.3324/haematol.2012.076414

  View details for Web of Science ID 000319897700026

  View details for PubMedID 23242596

• Multiple Myeloma, Version 1.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Cohen, A. D., Devine, S., Djulbegovic, B., Faber, E. A., Gasparetto, C., Hernandez-Illizaliturri, F., Huff, C. A., Kassim, A., Krishnan, A. Y., Liedtke, M., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Weber, D., Yahalom, J., Yunus, F., Shead, D. A., Kumar, R. 2013; 11 (1): 11-17

  Abstract

  These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

  View details for Web of Science ID 000313575200004

• Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049603073

• Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia AMERICAN JOURNAL OF HEMATOLOGY Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A., Bates, J., Sekeres, M. A., Coutre, S., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. 2012; 87 (10): 957-960

  Abstract

  We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ?350 cells/?L at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/?L (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ?350 cells/?L on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/?L (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/?L vs. ?350 cells/?L, P ? .0004 for OS and EFS) along with WBC at diagnosis (?6.0 or >30.0 K/?L vs. >6.0-30.0 K/?L, P ? 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

  View details for DOI 10.1002/ajh.23279

  View details for Web of Science ID 000309065700081

  View details for PubMedID 22729847

• Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

  Abstract

  Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

  View details for DOI 10.1038/leu.2011.294

  View details for Web of Science ID 000303883500005

  View details for PubMedID 22033493

• More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

  View details for Web of Science ID 000305415100012

  View details for PubMedID 22652951

• Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

  Abstract

  Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

  View details for DOI 10.1016/j.healun.2011.09.010

  View details for Web of Science ID 000300806500015

  View details for PubMedID 22051505

• Hemophagocytic lymphohistiocytosis in pregnancy: A case report and review of treatment options. Hematology (Amsterdam, Netherlands) Dunn, T., Cho, M., Medeiros, B., Logan, A., Ungewickell, A., Liedtke, M. 2012

  Abstract

  Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory disorder characterized by uncontrolled proliferation and activation of histiocytes with phagocytosis of normal hematopoietic cells. A 41-year-old woman, 19 weeks pregnant with twins, and a history of Still's disease, presented with rash, fever, and headache. Laboratory studies revealed transaminitis, hyperbilirubinemia, and eventually severe neutropenia as well as elevations in ferritin, lactate dehydrogenase, and C-reactive protein. A bone marrow biopsy confirmed HLH. She declined standard HLH-treatment but responded well to high-dose corticosteroids. Her blood counts remained stable following corticosteroid taper, and she delivered healthy twin girls at 30-week gestation. Few cases of HLH during pregnancy have been reported. In some cases, the condition has proved fatal. Therefore recognizing signs and symptoms of HLH is essential to avoid treatment delay. In our case, high-dose corticosteroids alone were a safe and effective therapy for the mother and fetuses resulting in long-term disease control.

  View details for PubMedID 22980356

• Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

  Abstract

  This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

  View details for DOI 10.3324/haematol.2011.045997

  View details for Web of Science ID 000299870500009

  View details for PubMedID 21993685

• The Transcription Factor Encyclopedia GENOME BIOLOGY Yusuf, D., Butland, S. L., Swanson, M. I., Bolotin, E., Ticoll, A., Cheung, W. A., Zhang, X. Y., Dickman, C. T., Fulton, D. L., Lim, J. S., Schnabl, J. M., Ramos, O. H., Vasseur-Cognet, M., de Leeuw, C. N., Simpson, E. M., Ryffel, G. U., Lam, E. W., Kist, R., Wilson, M. S., Marco-Ferreres, R., Brosens, J. J., Beccari, L. L., Bovolenta, P., Benayoun, B. A., Monteiro, L. J., Schwenen, H. D., Grontved, L., Wederell, E., Mandrup, S., Veitia, R. A., Chakravarthy, H., Hoodless, P. A., Mancarelli, M. M., Torbett, B. E., Banham, A. H., Reddy, S. P., Cullum, R. L., Liedtke, M., Tschan, M. P., Vaz, M., Rizzino, A., Zannini, M., Frietze, S., Farnham, P. J., Eijkelenboom, A., Brown, P. J., Laperriere, D., Leprince, D., de Cristofaro, T., Prince, K. L., Putker, M., del Peso, L., Camenisch, G., Wenger, R. H., Mikula, M., Rozendaal, M., Mader, S., Ostrowski, J., Rhodes, S. J., Van Rechem, C., Boulay, G., Olechnowicz, S. W., Breslin, M. B., Lan, M. S., Nanan, K. K., Wegner, M., Hou, J., Mullen, R. D., Colvin, S. C., Noy, P. J., Webb, C. F., Witek, M. E., Ferrell, S., Daniel, J. M., Park, J., Waldman, S. A., Peet, D. J., Taggart, M., Jayaraman, P., Karrich, J. J., Blom, B., Vesuna, F., O'Geen, H., Sun, Y., Gronostajski, R. M., Woodcroft, M. W., Hough, M. R., Chen, E., Europe-Finner, G. N., Karolczak-Bayatti, M., Bailey, J., Hankinson, O., Raman, V., LeBrun, D. P., Biswal, S., Harvey, C. J., DeBruyne, J. P., Hogenesch, J. B., Hevner, R. F., Heligon, C., Luo, X. M., Blank, M. C., Millen, K. J., Sharlin, D. S., Forrest, D., Dahlman-Wright, K., Zhao, C., Mishima, Y., Sinha, S., Chakrabarti, R., Portales-Casamar, E., Sladek, F. M., Bradley, P. H., Wasserman, W. W. 2012; 13 (3)

  Abstract

  Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

  View details for DOI 10.1186/gb-2012-13-3-r24

  View details for Web of Science ID 000308544200009

  View details for PubMedID 22458515

• Cardiac Amyloidosis: Screening Criteria for Heart Transplantation and New Strategies for Post-Transplant Therapy Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2011: S45-S46

  View details for Web of Science ID 000293938700145

• A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML) Pollyea, D. A., Kohrt, H. E., Gallegos, L., Berube, C., Coutre, S., Gotlib, J., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 1347-1347

  View details for Web of Science ID 000289662203619

• Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification Medeiros, B. C., Kohrt, H. E., Rajwanshi, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Zhang, M., Arber, D. A., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1357-1358

  View details for Web of Science ID 000289662203644

• Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

  Abstract

  The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

  View details for DOI 10.1002/ajh.21857

  View details for Web of Science ID 000283568200010

  View details for PubMedID 20872554

• Plasma cell leukemia: concepts and management. Expert review of hematology Liedtke, M., Medeiros, B. C. 2010; 3 (5): 543-549

  Abstract

  Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia. Patients with PCL have a very poor prognosis with median survival measured in months. PCL can present de novo or following a prodrome of plasma cell myeloma. Patients with PCL tend to present with aggressive clinical features, such as extramedullary disease, bone marrow failure, advanced stage disease and expression of distinct immunophenotypic markers, such as lack of CD56 and presence of CD20. Historically, the treatment of PCL has primarily been palliative, with only a small minority of patients achieving a durable remission. The impact of newer agents, such as bortezomib and lenalidomide, in conjunction with autologous and allogeneic stem cell transplantation is uncertain, but emerging data suggest that use of these modalities may help improve the poor prognosis of patients with PCL.

  View details for DOI 10.1586/ehm.10.52

  View details for PubMedID 21083471

• Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6 BLOOD Liedtke, M., Ayton, P. M., Somervaille, T. C., Smith, K. S., Cleary, M. L. 2010; 116 (1): 63-70

  Abstract

  MLL is a common target for chromosomal translocations associated with acute leukemia resulting in its fusion with a large variety of nuclear or cytoplasmic proteins that may activate its oncogenic properties by distinct but poorly understood mechanisms. The MLL-AF6 fusion gene represents the most common leukemogenic fusion of mixed lineage leukemia (MLL) to a cytoplasmic partner protein. Here, we identified a highly conserved Ras association (RA1) domain at the amino-terminus of AF6 as the minimal region sufficient for MLL-AF6 mediated myeloid progenitor immortalization in vitro and short latency leukemogenesis in vivo. Moreover, the ability of RA1 to activate MLL oncogenesis is conserved with its Drosophila ortholog, Canoe. Although the AF6 RA1 domain has previously been defined as an interaction surface for guanosine triphosphate-bound Ras, single amino acid substitutions known to abolish the AF6-Ras interaction did not abrogate MLL-AF6-mediated oncogenesis. Furthermore, fusion of MLL to heterologous RA domains of c-Raf1 or RalGDS, or direct fusion of MLL to constitutively active K-RAS, H-RAS, or RAP1 was not sufficient for oncogenic activation of MLL. Rather, the AF6 RA1 domain efficiently mediated self-association, suggesting that constitutive MLL self-association is a more common pathogenic mechanism for MLL oncogenesis than indicated by previous studies of rare MLL fusion partners.

  View details for DOI 10.1182/blood-2009-09-243386

  View details for Web of Science ID 000279641400012

  View details for PubMedID 20395419

• Therapeutic targeting of MLL BLOOD Liedtke, M., Cleary, M. L. 2009; 113 (24): 6061-6068

  Abstract

  Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.

  View details for DOI 10.1182/blood-2008-12-197061

  View details for Web of Science ID 000267147100009

  View details for PubMedID 19289854

• Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma LEUKEMIA & LYMPHOMA Kohrt, H., Logan, A., Temmins, C., Witteles, R., Liedtke, M., Medeiros, B. 2008; 49 (3): 581-585

  View details for DOI 10.1080/10428190701861702

  View details for Web of Science ID 000253513300029

  View details for PubMedID 18297538

• Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population ANNALS OF ONCOLOGY Liedtke, M., Hamlin, P. A., Moskowitz, C. H., Zelenetz, A. D. 2006; 17 (6): 909-913

  Abstract

  Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment.One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms.Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13).These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.

  View details for DOI 10.1093/annonc/mdl049

  View details for Web of Science ID 000237696000005

  View details for PubMedID 16672295

• Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase ONCOGENE Liedtke, M., Pandey, P., Kumar, S., KHARBANDA, S., Kufe, D. 1998; 17 (15): 1889-1892

  Abstract

  The oncogenic Bcr-Abl variant of the c-Abl tyrosine kinase transforms cells by a mechanism dependent on activation of the stress-activated protein kinase (SAPK). Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress. The present studies demonstrate that Bcr-Abl binds constitutively to SHPTP1. We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites. The functional significance of the Bcr-Abl/SHPTP1 interaction is supported by the finding that SHPTP1 regulates Bcr-Abl-induced SAPK activity. Importantly, SHPTP1 also decreases Bcr-Abl-dependent transformation of fibroblasts. These findings indicate that SHPTP1 functions as a tumor suppressor in cells transformed by Bcr-Abl.

  View details for Web of Science ID 000076423500001

  View details for PubMedID 9788431

• A SITE-DIRECTED MUTAGENESIS STUDY TO IDENTIFY AMINO-ACID-RESIDUES INVOLVED IN THE CATALYTIC FUNCTION OF THE RESTRICTION ENDONUCLEASE ECORV BIOCHEMISTRY SELENT, U., RUTER, T., Kohler, E., Liedtke, M., THIELKING, V., Alves, J., Oelgeschlager, T., Wolfes, H., Peters, F., Pingoud, A. 1992; 31 (20): 4808-4815

  Abstract

  We have used site-directed mutagenesis of the EcoRV restriction endonuclease to change amino acid side chains that have been shown crystallographically to be in close proximity to the scissile phosphodiester bond of the DNA substrate. DNA cleavage assays of the resulting mutant proteins indicate that the largest effects on nucleolytic activity result from substitution of Asp74, Asp90, and Lys92. We suggest on the basis of structural information, mutagenesis data, and analogies with other nucleases that Asp74 and Asp90 might be involved in Mg2+ binding and/or catalysis and that Lys92 probably stabilizes the pentacovalent phosphorus in the transition state. These amino acids are part of a sequence motif, Pro-Asp...Asp/Glu-X-Lys, which is also present in EcoRI. In both enzymes, it is located in a structurally similar context near the scissile phosphodiester bond. A preliminary mutational analysis with EcoRI indicates that this sequence motif is of similar functional importance for EcoRI and EcoRV. On the basis of these results, a proposal is made for the mechanism of DNA cleavage by EcoRV and EcoRI.

  View details for Web of Science ID A1992HW13800010

  View details for PubMedID 1591242