Johns Hopkins Medical Institutions
Johns Hopkins Medical Institutions
Lindsay M.E.,Johns Hopkins Medical Institutions |
Lindsay M.E.,McKusick Nathans Institute of Genetic Medicine |
Dietz H.C.,McKusick Nathans Institute of Genetic Medicine |
Dietz H.C.,Howard Hughes Medical Institute
Nature | Year: 2011
Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-Î 2 cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies. © 2011 Macmillan Publishers Limited. All rights reserved.
Mease R.C.,Johns Hopkins Medical Institutions
Current Topics in Medicinal Chemistry | Year: 2010
Prostate cancer (PCa) is the second leading cause of cancer deaths in American men. Early detection of PCa by blood tests for elevated levels of prostate-specific-antigen (PSA) has lead to early treatment and a reduction in death rates. However, PSA level alone does not distinguish between PCa and normal conditions that cause elevated PSA. Further more, because PCa can be a very slow growing cancer, even confirmation of PCa cells in a biopsy gives no indication whether the PCa will progress into active disease within the individual's lifetime. As a result many patients receive treatment that they may not need. Imaging is an attractive modality for the detection and characterization of disease because most techniques are non- or minimally invasive, nondestructive, provide dynamic real-time data, and allow for repeat measurements. In PCa, advanced imaging techniques could be useful for accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions, and predicting the aggressiveness of the disease. This paper reviews the radionuclide based imaging agents for planar, single photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging currently used in the clinic and those under development for PCa. The former includes the bone agents technetium diphosphonates and F-18 fluoride, the metabolic agents 2-[18F]fluoro-2-deoxy-D-glucose (FDG), and receptor targeted radiolabeled monoclonal antibodies including ProstaScint. The latter agents include C-11 acetate, C-11 and F-18 choline, C-11 and F-18 labeled 1-aminocyclobutane-1-carboxylic acid, radiolabeled androgen receptor binding compounds, radiolabeled peptides and small molecules for receptors over expressed either on prostate cancer itself or on the associated tumor neovasculature. Coregistration of PET or SPECT images with CT or MRI scans, improvements in imaging cameras, and image reconstruction algorithms have improved the quality of the images to the point where dual modality (radionuclide/CT or MRI) imaging with several agents can now be considered for staging of PCa. In addition, the high selectivity and rapid localization of many of the new agents under development portends promise for a greater use of radionuclide imaging for prostate cancer detection, characterization, and treatment monitoring. © 2010 Bentham Science Publishers Ltd.
Maldonado L.,Johns Hopkins Medical Institutions
Science translational medicine | Year: 2014
About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8(+) T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNβ), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation.
Fader A.N.,Johns Hopkins Medical Institutions
Obstetrics and gynecology | Year: 2013
To examine clinicopathologic variables associated with survival among women with low-grade (grade 1) serous ovarian carcinoma enrolled in a phase III study. This was an ancillary data analysis of Gynecologic Oncology Group protocol 182, a phase III study of women with stage III-IV epithelial ovarian carcinoma treated with carboplatin and paclitaxel compared with triplet or sequential doublet regimens. Women with grade 1 serous carcinoma (a surrogate for low-grade serous disease) were included in the analysis. Among the 3,686 enrolled participants, 189 had grade 1 disease. The median age was 56.5 years and 87.3% had stage III disease. The median follow-up time was 47.1 months. Stratification according to residual disease after primary surgery was microscopic residual in 24.9%, 0.1-1.0 cm of residual in 51.3%, and more than 1.0 cm of residual in 23.8%. On multivariate analysis, only residual disease status (P=.006) was significantly associated with survival. Patients with microscopic residual had a significantly longer median progression-free (33.2 months) and overall survival (96.9 months) compared with those with residual 0.1-1.0 cm (14.7 months and 44.5 months, respectively) and more than 1.0 cm of residual disease (14.1 months and 42.0 months, respectively; progression-free and overall survival, P<.001). After adjustment for other variables, patients with low-grade serous carcinoma with measurable residual disease had a similar adjusted hazard ratio for death (2.12; P=.002) as their high-grade serous carcinoma counterparts with measurable disease (2.31; P<.001). Surgical cytoreduction to microscopic residual was associated with improved progression-free and overall survival in women with advanced-stage low-grade serous ovarian carcinoma. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00011986. II.
Isaacs J.T.,Johns Hopkins Medical Institutions
Science | Year: 2013
Prostate cancer development and metastasis is driven by invasion of the tumor by the nervous system.
Iacobuzio-Donahue C.A.,Johns Hopkins Medical Institutions
Gut | Year: 2012
Pancreatic cancer is a disease caused by the accumulation of genetic alterations in specific genes. Elucidation of the human genome sequence, in conjunction with technical advances in the ability to perform whole exome sequencing, have provided new insight into the mutational spectra characteristic of this lethal tumour type. Most recently, exomic sequencing has been used to clarify the clonal evolution of pancreatic cancer as well as provide time estimates of pancreatic carcinogenesis, indicating that a long window of opportunity may exist for early detection of this disease while in the curative stage. Moving forward, these mutational analyses indicate potential targets for personalised diagnostic and therapeutic intervention as well as the optimal timing for intervention based on the natural history of pancreatic carcinogenesis and progression.
Wu K.C.,Johns Hopkins Medical Institutions
Journal of Cardiovascular Magnetic Resonance | Year: 2012
Microvascular obstruction (MO) or no-reflow phenomenon is an established complication of coronary reperfusion therapy for acute myocardial infarction. It is increasingly recognized as a poor prognostic indicator and marker of subsequent adverse LV remodeling. Although MO can be assessed using various imaging modalities including electrocardiography, myocardial contrast echocardiography, nuclear scintigraphy, and coronary angiography, evaluation by cardiovascular magnetic resonance (CMR) is particularly useful in enhancing its detection, diagnosis, and quantification, as well as following its subsequent effects on infarct evolution and healing. MO assessment has become a routine component of the CMR evaluation of acute myocardial infarction and will increasingly play a role in clinical trials of adjunctive reperfusion agents and strategies. This review will summarize the pathophysiology of MO, current CMR approaches to diagnosis, clinical implications, and future directions needed for improving our understanding of this common clinical problem. © 2012 Wu; licensee BioMed Central Ltd.
Sharma K.,Johns Hopkins Medical Institutions |
Kass D.A.,Johns Hopkins Medical Institutions
Circulation Research | Year: 2014
The clinical syndrome comprising heart failure (HF) symptoms but with a left ventricular ejection fraction (EF) that is not diminished, eg, HF with preserved EF, is increasingly the predominant form of HF in the developed world, and soon to reach epidemic proportions. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common comorbidities. Importantly, its morbidity and mortality are on par with HF with reduced EF, and as the list of failed treatments continues to grow, HF with preserved EF clearly represents a major unmet medical need. The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and redirect our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists. Here, we review recent translational and clinical research into HF with preserved EF and give perspectives on its evolving demographics and epidemiology, the role of multiorgan deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions. © 2014 American Heart Association, Inc.
Kelly R.J.,Johns Hopkins Medical Institutions |
Smith T.J.,Johns Hopkins Medical Institutions
The Lancet Oncology | Year: 2014
Cancer costs continue to increase alarmingly despite much debate about how they can be reduced. The oncology community needs to take greater responsibility for our own practice patterns, especially when using expensive tests and treatments with marginal value: we cannot continue to accept novel therapeutics with very small benefits for exorbitant prices. Patients, payers, and pharmaceutical communities should be constructively engaged to communicate medically and economically possible goals, and eventually, to reduce use and costs. Diagnostic tests and treatments should have to show true value to be added to existing protocols. In this article, we discuss three key drivers of costs: end-of-life care patterns, medical imaging, and drugs. We propose health-care models that have the potential to decrease costs and discuss solutions to maintain clinical benefit at an affordable price. © 2014 Elsevier Ltd.
Spivak J.L.,Johns Hopkins Medical Institutions
Annals of Internal Medicine | Year: 2010
The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus. © 2010 American College of Physicians.