Discovery Category Highlights

An Unexpected Journey: How Cancer Immunotherapy Has Paved the Way for an HIV-1 Cure

Abstract: Over 30 million people worldwide are currently infected with human immunodeficiency virus type-1 (HIV-1). While HIV-1 infection was initially thought to be a death sentence, the advent of combination antiretroviral therapy (cART) in the mid-1990's resulted in decreases in viremia and an extended lifespan for infected persons. Despite this, long-term control of the virus in the absence of drug therapy has yet to be achieved, owing to the rebound in viral load and resumption of disease progression that follows removal of the patient from cART. Currently, the most promising candidates for an HIV-1 cure are immunotherapies that harness the patient's own immune system and induce cytotoxic T lymphocyte (CTL)-mediated clearance of infected cells. Most of these approaches were developed and optimized in the cancer setting and have had varying degrees of success, the findings from which have wide applications to various disease models. In this review, we evaluate the past successes and failures of cancer immunotherapy and how the findings have shaped our journey toward an HIV-1 cure. ... Read more

Immune Effects of Targeted Radiation Therapy for Cancer

Abstract: Radiation therapy plays an important role in the treatment of the majority of cancers, and is commonly used to treat both localized and metastatic disease. Immunotherapy has recently been firmly integrated into the treatment of metastatic melanoma, and holds significant promise in treating a variety of other cancers. Although large field radiation has historically been appreciated for its immunosuppressive ability, targeted radiation can induce substantial changes in the tumor microenvironment beyond cellular cytotoxicity that evoke innate and adaptive immune responses. Previous studies have highlighted radiation-induced changes in proinflammatory cytokines, chemokines, effector, and immunosuppressive T cell subsets, as well as in immune receptors on tumor cells. Some of these changes in localized and systemic immune mediators have been linked to expansion of tumor-reactive T cells, improved clinical responses, and increased overall survival in preclinical and clinical models. Taken together, this evidence suggests that targeted radiation therapy can impact anti-tumor immune responses, and may potentially be combined with immunotherapy for synergistic effect. ... Read more

Advances in Hematopoietic Cell Transplantation in Chronic Myeloid Leukemia

Abstract: The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic myeloid leukemia (CML) patients who fail or are intolerant to TKIs. Its long-term cost effectiveness compared to TKIs, however, has maintained its use as front-line treatment in some areas. Advances in HCT, including the development of intravenous busulfan and plasma assays permitting dose adjustment, have improved results of HCT in CML. Improved supportive care has lowered the incidence of non-relapse mortality and improved survival. The availability of reduced-intensity preparative regimens, molecular typing of unrelated donors, and the use of cord blood and haploidentical donors has expanded the application of HCT to nearly any patient with an appropriate indication. From 2006 to 2010, approximately one thousand HCTs are performed annually in patients with CML. Better understanding of recent advances will improve the appropriate use and results of HCT in patients with CML. ... Read more

Functional Imaging in Radiation Therapy

Abstract: The advent of functional imaging facilitates the acquisition of patient-specific tumor characteristics, including its metabolic state and regional oxygen tension. Recent advances promote incorporating this information with data obtained from current imaging techniques, such as MRI and CT, to manage various malignancies. Functional imaging's vital roles progressively evolved to include: aiding in diagnosis, improving radiation treatment planning, differentiating tumor volume from surrounding normal tissues which enables dose escalation to the former while improving sparing of the latter, adapting radiation therapy regimens according to a tumor's response to initial treatment, and assessing radiation therapy response and toxicity. This review explores functional imaging in radiation oncology in the context of these five applications, as well as its comparison to, and integration with, existing imaging modalities. In parallel with advances in functional imaging and understanding of tumor microbiology, the emergence of diverse tracers provides a plethora of options to distinguish and manage malignancies on the basis of specific metabolic processes and changing microenvironmental cues. Current limitations, potential concerns, and future innovations of functional imaging are also discussed. ... Read more

Safety and Efficacy of Rivaroxaban Versus Warfarin in Patients Undergoing Catheter Ablation of Atrial Fibrillation: a Meta-analysis of Observational Studies

Abstract: The safety and efficacy of rivaroxaban in the periprocedural anticoagulation for patients undergoing catheter ablation of atrial fibrillation is not well established. We sought to systematically review this evidence using data from multiple studies. A thorough literature search was conducted in MEDLINE, EMABSE, Web of knowledge,, and the Cochrane library up to November 2014. Studies of at least 100 patients in rivaroxaban and warfarin groups were included. Nine observational studies were identified enrolling a total of 4,334 patients (1,210 treated with rivaroxaban and 3,124 with warfarin). The primary outcomes were thromboembolic events and major bleeding. The fixed-effects model meta-analysis was performed and risk ratios (RRs) were calculated. No significant differences were found between patients treated with rivaroxaban and warfarin with regard to thromboembolic events (0.25% rivaroxaban vs. 0.29% warfarin; RR: 0.61; 95%CI: 0.21-1.76; P=0.36) and major bleeding (1.03% rivaroxaban vs. 1.83% warfarin; RR: 0.51; 95%CI: 0.26-1.00; P=0.05). This meta-analysis suggests that patients treated with rivaroxaban have a similar incidence of thromboembolic events and major bleeding compared to warfarin. Signals were seen favoring rivaroxaban; however, considering low events rates, more high-quality studies are necessary to thoroughly compare the two strategies. ... Read more

New Concepts on Functional Chronic Pelvic and Perineal Pain: Pathophysiology and Multidisciplinary Management

Abstract: The management of chronic pelvic and perineal pain has been improved by a better understanding of the mechanisms of this pain and an optimized integrated multidisciplinary approach to the patient. The concept of organic lesions responsible for a persistent nociceptive factor has gradually been replaced by that of dysregulation of nociceptive messages derived from the pelvis and perineum. In this setting, painful diseases identified by organ specialists are usually also involved and share several common denominators (triggering factors, predisposing clinical context). These diseases include painful bladder syndrome, irritable bowel syndrome, vulvodynia, and chronic pelvic pain syndrome. The painful symptoms vary from one individual to another and according to his or her capacity to activate pain inhibition/control processes. Although the patient often attributes chronic pain to a particular organ (with the corollary that pain will persist until the organ has been treated), this pain is generally no longer derived from the organ but is expressed via this organ. Several types of clinical presentation of complex pelvic pain have therefore been pragmatically identified to facilitate the management of treatment failures resulting from a purely organ-based approach, which can also reinforce the patient's impression of incurability. These subtypes correspond to neuropathic pain, central sensitization (fibromyalgia), complex regional pain syndrome, and emotional components similar to those observed in post-traumatic stress disorder. These various components are also often associated and self-perpetuating. Consequently, when pelvic pain cannot be explained by an organ disease, this model, using each of these four components associated with their specific mechanisms, can be used to propose personalized treatment options and also to identify patients at high risk of postoperative pelvic pain (multi-operated patients, central sensitization, post-traumatic stress disorder, etc.), which constitutes a major challenge for prevention of these types of pain that have major implications for patients and society. ... Read more

Genetic Causes of Pituitary Hormone Deficiencies

Abstract: In recent decades, dozens of genes that cause isolated and combined pituitary hormone deficiencies have been discovered. We will review the clinically relevant genes known to cause isolated and combined pituitary hormone deficiencies in humans. This review will address genetic causes of adrenocorticotropic hormone deficiency, thyroid stimulating hormone deficiency, growth hormone deficiency, hypogonadotropic hypogonadism, and diabetes insipidus. Additionally, we will discuss genetic causes of combined pituitary hormone deficiency, septo-optic dysplasia, holoprosencephaly, and multisystemic syndromes in which hypopituitarism is a significant component. With the widespread clinical availability of next generation sequencing and ongoing identification of new disease causing genes, genetic diagnoses are determined for increasing numbers of patients. With new insights into mechanisms of disease resulting from multiple gene interactions, an increasingly nuanced understanding of the underlying genetic etiology of pituitary hormone deficiencies is possible. ... Read more

Dendritic-Tumor Fusion Cells in Cancer Immunotherapy

Abstract: A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen-presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC-tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines. ... Read more

Advances in Mechanisms, Diagnosis, and Treatment of Pernicious Anemia

Abstract: Pernicious anemia (PA) is an entity initially described in 1849 as a condition that consisted of pallor, weakness, and progressive health decline. Since then several advances led to the conclusion that PA is an autoimmune disease characterized by the deficient absorption of dietary cobalamin. It is currently recognized as the most common cause of cobalamin deficiency worldwide. We hereby review the current understanding of the disease and its neurological, hematological, and biochemical manifestations with emphasis on the diagnostic approach, treatment, and monitoring strategies. We propose an algorithm for the diagnostic approach considering the current performance and limitations of the available diagnostic tools for evaluation of cobalamin status and the presence of autoimmune chronic atrophic gastritis (CAG). Patients with PA require lifelong treatment with cobalamin replacement therapy. The current widely available treatment can be provided through enteral or parenteral cobalamin supplements, with comparable efficacy and tolerability. ... Read more

Pathogenesis, Newly Recognized Etiologies, and Management of Idiopathic Anaphylaxis

Abstract: Idiopathic anaphylaxis (IA) is a life-threatening allergic disease and the most common diagnosis given to patients following an anaphylactic event. The inability of the healthcare provider and the patient to identify the trigger for anaphylaxis makes standard allergen avoidance measures ineffectual. IA is diagnosed after other causes of anaphylaxis have been excluded. Mast cell activation syndromes (MCAS), mastocytosis, IgE to galactose-alpha-1,3-galactose (α-gal), and certain medications have recently been recognized as causes of anaphylaxis that were previously labeled idiopathic. This review will describe the epidemiology and proposed theories of pathogenesis for IA, its diagnostic approach, its clinical management, and examine newly recognized disorders that were previously labeled as idiopathic anaphylaxis. ... Read more

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