Okuno S.,Rochester College |
Bailey H.,University of Wisconsin - Madison |
Mahoney M.R.,Rochester College |
Adkins D.,University of Washington |
And 4 more authors.
Cancer | Year: 2011
BACKGROUND: The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus (CCI-779), a mammalian target of rapamycin in patients with advanced soft tissue sarcomas (STS). METHODS: Patients ≥18 years with measurable advanced STS, no prior chemotherapy for metastatic disease (adjuvant and neoadjuvant chemotherapy allowed), adequate organ function, and performance status of ≤2 were eligible. After premedication with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on Days 1, 8, 15, and 22, repeated every 4 weeks. The primary endpoint was confirmed response rate per Response Evaluation Criteria in Solid Tumors. RESULTS: Between June 2004 and November 2005, a total of 41 patients were enrolled and began treatment; 40 patients are evaluable for response and adverse events. The median age was 62 years (range, 28-72 years) with 56% women. Eighty percent had high-grade STS, and 22% had prior adjuvant chemotherapy. There were 2 patients (5%; 95% confidence interval [CI], 1-17) (undifferentiated fibrosarcoma and uterine leiomyosarcoma) who achieved a confirmed partial response lasting 3 and 17 months, respectively. Thirty-nine (95%) patients have progressed, with a median time to progression of 2.0 months (95% CI, 1.8-3.5). The median overall survival was 7.6 months (95% CI, 6.1-15.9). Forty-three percent experienced grade 3+ adverse events that were possibly related to therapy. CONCLUSIONS: Temsirolimus in this patient population of STS had limited clinical activity and had moderate toxicities. © 2011 American Cancer Societyy.
Doan N.T.Q.,Copenhagen University |
Paulsen E.S.,Copenhagen University |
Sehgal P.,University of Aarhus |
Moller J.V.,University of Aarhus |
And 5 more authors.
Steroids | Year: 2015
The skin irritating principle from Thapsia garganica was isolated, named thapsigargin and the structure elucidated. By inhibiting the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) thapsigargin provokes apoptosis in almost all cells. By conjugating thapsigargin to peptides, which are only substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) prodrugs were created, which selectively affect prostate cancer cells or neovascular tissue in tumors. One of the prodrug is currently tested in clinical phase II. The prodrug under clinical trial has been named mipsagargin ©2014 Elsevier Inc. All rights reserved.
Nicholas S.,University of Maryland, Baltimore |
Nicholas S.,Bunting Blaustein Cancer Research Building |
Mathios D.,Johns Hopkins Hospital |
Mathios D.,Bunting Blaustein Cancer Research Building |
And 3 more authors.
Current Treatment Options in Oncology | Year: 2013
Opinion statement: Malignant melanoma with brain metastases remains a difficult disease to treat. Patients presenting with disease affecting the central nervous system (CNS) have a poor prognosis. Treatment depends on a number of factors, including the size and number of lesions, performance status, comorbidities, and presenting symptoms. Physicians and patients must weigh risks and benefits of treatments, with the main goal of palliating symptoms and decreasing the risk of neurological death. Opinions throughout the country vary, but first-line treatment for brain metastases is local therapy involving either craniotomy or stereotactic radiosurgery (SRS) using CyberKnife or Gamma Knife, with or without whole brain radiation therapy (WBRT). Clinical trials remain another option for patients, with chemotherapy reserved for patients who have exhausted other options. There has been a recent surge in knowledge regarding the pathophysiology and treatment of metastatic melanoma leading to recent FDA approval in 2011 of new drugs: ipilimumab, a novel immune therapy, and vemurafenib, which blocks the MAP Kinase pathway. These drugs have the potential to treat patients with metastatic melanoma to the brain but are still undergoing clinical investigation. Despite these recent advances, the prognosis is poor, with few patients able to achieve durable and long-lasting response. Treatment for patients with brain metastases continues to lag behind treatment of other diseases, partly due to their exclusion from early clinical trials. © 2013 Springer Science+Business Media New York.
Detection of Quiescent Infections with Multiple Elephant Endotheliotropic Herpesviruses (EEHVs), Including EEHV2, EEHV3, EEHV6, and EEHV7, within Lymphoid Lung Nodules or Lung and Spleen Tissue Samples from Five Asymptomatic Adult African Elephants
PubMed | Nashville Zoo at Grassmere, Smithsonian Institution, Fort Worth Zoological Park, Maryland Zoo at Baltimore and 3 more.
Type: Journal Article | Journal: Journal of virology | Year: 2016
More than 80 cases of lethal hemorrhagic disease associated with elephant endotheliotropic herpesviruses (EEHVs) have been identified in young Asian elephants worldwide. Diagnostic PCR tests detected six types of EEHV in blood of elephants with acute disease, although EEHV1A is the predominant pathogenic type. Previously, the presence of herpesvirus virions within benign lung and skin nodules from healthy African elephants led to suggestions that African elephants may be the source of EEHV disease in Asian elephants. Here, we used direct PCR-based DNA sequencing to detect EEHV genomes in necropsy tissue from five healthy adult African elephants. Two large lung nodules collected from culled wild South African elephants contained high levels of either EEHV3 alone or both EEHV2 and EEHV3. Similarly, a euthanized U.S. elephant proved to harbor multiple EEHV types distributed nonuniformly across four small lung nodules, including high levels of EEHV6, lower levels of EEHV3 and EEHV2, and a new GC-rich branch type, EEHV7. Several of the same EEHV types were also detected in random lung and spleen samples from two other elephants. Sanger PCR DNA sequence data comprising 100 kb were obtained from a total of 15 different strains identified, with (except for a few hypervariable genes) the EEHV2, EEHV3, and EEHV6 strains all being closely related to known genotypes from cases of acute disease, whereas the seven loci (4.0 kb) obtained from EEHV7 averaged 18% divergence from their nearest relative, EEHV3. Overall, we conclude that these four EEHV species, but probably not EEHV1, occur commonly as quiescent infections in African elephants.Acute hemorrhagic disease characterized by high-level viremia due to infection by members of the Proboscivirus genus threatens the future breeding success of endangered Asian elephants worldwide. Although the genomes of six EEHV types from acute cases have been partially or fully characterized, lethal disease predominantly involves a variety of strains of EEHV1, whose natural host has been unclear. Here, we carried out genotype analyses by partial PCR sequencing of necropsy tissue from five asymptomatic African elephants and identified multiple simultaneous infections by several different EEHV types, including high concentrations in lymphoid lung nodules. Overall, the results provide strong evidence that EEHV2, EEHV3, EEHV6, and EEHV7 represent natural ubiquitous infections in African elephants, whereas Asian elephants harbor EEHV1A, EEHV1B, EEHV4, and EEHV5. Although a single case of fatal cross-species infection by EEHV3 is known, the results do not support the previous concept that highly pathogenic EEHV1A crossed from African to Asian elephants in zoos.
Keizman D.,Sidney Kimmel Comprehensive Cancer Center |
Zahurak M.,Sidney Kimmel Comprehensive Cancer Center |
Sinibaldi V.,Sidney Kimmel Comprehensive Cancer Center |
Carducci M.,Sidney Kimmel Comprehensive Cancer Center |
And 7 more authors.
Clinical Cancer Research | Year: 2010
Purpose: To evaluate the safety and activity of 6 months of treatment with lenalidomide at 5 or 25 mg/d in nonmetastatic biochemically relapsed prostate cancer. Experimental Design: Sixty men with non-castrate, nonmetastatic, biochemically relapsed prostate cancer were stratified by prostate-specific antigen (PSA) doubling time, surgery/radiation therapy, prior androgen deprivation therapy (ADT), and randomized to lenalidomide 5 mg (n = 26) or 25 mg/d (n = 34) for 3 weeks repeated monthly for 6 months or until dose-limiting toxicity or disease progression. Toxicity was evaluated monthly, and PSAs and X-rays/scans every 6 months. Study size was determined to detect a progression rate of 40% at 6 months in either arm with 85% power (compared with a rate of 80% in the population receiving no treatment). Changes in PSA slopes were calculated using the regression of the log PSA for each patient before and during the initial 6 months and compared by t test. Results: Baseline variables were balanced between arms. Grade 3/4 toxicity rates were 12% (n = 3) with 5 mg and 29% (n = 10) with 25 mg (P = 0.1), most commonly neutropenia (five patients, all on 25 mg). Two patients per arm had thromboembolic events. The change in PSA slope was greater with 25 mg versus 5 mg [-0.172 (-0.24 to -0.11) versus -0.033 (-0.11 to 0.04); P = 0.005]. With a mean follow-up of 31.4 months (range 14-44), five patients on 25 mg and one patient on 5 mg remain on the study. Conclusions: Lenalidomide has acceptable toxicity and is associated with long-term disease stabilization and PSA declines. Randomized studies evaluating conventional clinical disease end points in this patient population are planned. ©2010 AACR.
Keizman D.,Sidney Kimmel Comprehensive Cancer Center |
Eisenberger M.,Bunting Blaustein Cancer Research Building
Current Opinion in Supportive and Palliative Care | Year: 2010
Purpose of review Prognostic clinical, pathological, and molecular parameters identify patients with nonmetastatic prostate cancer that are at risk for the development of future metastatic disease and shorter survival. In metastatic castration-resistant prostate cancer, docetaxel-based chemotherapy prolongs survival and improves quality of life, and is the standard of care. It may be rational to hypothesize that early utilization of chemotherapy may delay the onset of distant metastasis and prolong survival in the earlier nonmetastatic disease. A discussion on ongoing clinical trials and natural history aspects applicable to clinical trials design in this setting are presented herein. Recent findings Preliminary data suggest that chemotherapy is well tolerated, feasible, and potentially active in nonmetastatic prostate cancer. However, results from prospective randomized trials were not published yet. Summary In nonmetastatic prostate cancer, application of chemotherapy remains an open question awaiting prospective validation and should be routinely applied outside of clinical trials. In view of the long natural history, evaluation of conventional endpoints as time to distant metastasis and survival are challenging even in the high-risk patients. Appropriate patient selection based on predictive biomarkers and surrogate endpoints may provide critical information for patient selection and study design. Copyright © Lippincott Williams & Wilkins.
Keizman D.,Bunting Blaustein Cancer Research Building |
Huang P.,Bunting Blaustein Cancer Research Building |
Eisenberger M.A.,Bunting Blaustein Cancer Research Building |
Pili R.,Bunting Blaustein Cancer Research Building |
And 4 more authors.
European Journal of Cancer | Year: 2011
Background: Sunitinib is a standard treatment for metastatic renal cell carcinoma. Angiotensin system inhibitors, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, are widely used in hypertension, kidney disease and heart failure. Data suggests that they may inhibit tumourigenesis. Aims: To study the effect of angiotensin system inhibitors on sunitinib treatment outcome in metastatic renal cell carcinoma. Methods: We performed a retrospective study of an unselected cohort of patients with metastatic renal cell carcinoma who were treated with sunitinib. Patients were divided into angiotensin system inhibitors users (group 1) and non-users (group 2). The effect of angiotensin system inhibitors on objective response, time to disease progression and overall survival, was tested with adjustment for known confounding risk factors through logistic regression model and Cox regression model. Results: Between 2004 and 2010, 127 patients with metastatic renal cell carcinoma were treated with sunitinib, 44 group 1 and 83 group 2. The groups were balanced regarding known clinicopathologic prognostic factors. Objective response was partial response/stable disease 86% versus 72% and progressive disease 14% versus 28% (p = 0.07) in group 1 versus 2, respectively. Median progression free survival was 13 versus 6 months (HR 0.537, p = 0.0055), and median overall survival 30 versus 23 months (HR 0.688, p = 0.21), in favour of group 1. Conclusions: Angiotensin system inhibitors may improve the outcome of sunitinib treatment in metastatic renal cell carcinoma. This should be investigated prospectively, and if validated applied in clinical practise and clinical trials. © 2011 Elsevier Ltd. All rights reserved.
Kelly R.J.,Bunting Blaustein Cancer Research Building
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013
A better understanding of the biology of both thymomas and thymic carcinomas has occurred in recent years thanks to advanced technologies such as comparative genomic hybridization, expression array analysis, and next-generation sequencing. Gene expression profiling and genomic clustering studies have shown that thymic tumors as classified by the 2004 WHO system do have different molecular features. Because of the rarity of these tumors, there is a paucity of high-quality clinical research data, and treatment decisions are often guided by the small amount of prospective trial data, retrospective series, and individual case reports. The literature does report on several advanced thymic tumors that have responded to new targeted agents, indicating that across the spectrum of thymic malignancies there may be clinically relevant molecular subsets. Genomic profiling distinguishes type B3 thymoma and thymic carcinoma from type A and B2 thymomas. Furthermore, type B2 thymomas can be separated from other subgroups in that it has a more distinctly lymphocytic component than the other groups in which epithelial cells predominate. The presence of KIT mutations in thymic carcinomas rather than in thymomas further adds to a growing body of evidence showing that underlying tumor biology may in the future lead to molecular classifications, which may enhance therapies for these rare tumors. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.