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- Volume 66, 2015
Annual Review of Medicine - Volume 66, 2015
Volume 66, 2015
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A Tale of Two Tumors: Treating Pancreatic and Extrapancreatic Neuroendocrine Tumors
Vol. 66 (2015), pp. 1–16More LessDespite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.
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Metformin in Cancer Treatment and Prevention
Vol. 66 (2015), pp. 17–29More LessPatients with diabetes mellitus are at increased risk of cancer development. Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus. Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent. Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism. This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence.
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Neoadjuvant Therapy for Breast Cancer
Vol. 66 (2015), pp. 31–48More LessNeoadjuvant treatment of breast cancer refers to the use of different treatment modalities prior to surgical excision of the tumor. It has been accepted as a treatment option for patients with nonmetastatic disease, because it renders inoperable tumors operable and increases the rates of breast-conserving surgery, while achieving similar long-term clinical outcomes as adjuvant treatment. The neoadjuvant setting is being increasingly perceived as a research platform, where the biologic effects of traditional anticancer agents can be delineated, prognostic and predictive biomarkers can be identified, and the development of targeted agents can be expedited. Surrogate endpoints that can predict long-term clinical outcome and are evaluable early on, such as the pathologic complete response, offer valuable opportunities for rapid assessment of anticancer agents. Additionally, efforts for molecular profiling of the post-neoadjuvant residual disease hold the potential to lead to personalized therapy for breast cancer patients with early-stage high-risk disease.
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Neuroblastoma: Molecular Pathogenesis and Therapy
Vol. 66 (2015), pp. 49–63More LessNeuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Neuroblastoma is the primary cause of death from pediatric cancer for children between the ages of one and five years and accounts for ∼13% of all pediatric cancer mortality. Its clinical impact and unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology are driving the development of new classification schemas. Novel targeted therapeutic approaches include small-molecule inhibitors as well as epigenetic, noncoding-RNA, and cell-based immunologic therapies. In this review, recent insights regarding the pathogenesis and biology of neuroblastoma are placed in context with the current understanding of tumor biology and tumor/host interactions. Systematic classification of patients coupled with therapeutic advances point to a future of improved clinical outcomes for this biologically distinct and highly aggressive pediatric malignancy.
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Pharmacogenetics of Cancer Drugs
Daniel L. Hertz, and James RaeVol. 66 (2015), pp. 65–81More LessThe variability in treatment outcomes among patients receiving the same therapy for seemingly similar tumors can be attributed in part to genetics. The tumor's (somatic) genome largely dictates the effectiveness of the therapy, and the patient's (germline) genome influences drug exposure and the patient's sensitivity to toxicity. Many potentially clinically useful associations have been discovered between common germline genetic polymorphisms and outcomes of cancer treatment. This review highlights the germline pharmacogenetic associations that are currently being used to guide cancer treatment decisions, those that are most likely to someday be clinically useful, and associations that are well known but their roles in clinical management are not yet certain. In the future, germline genetic information will likely be available from tumor genetic analyses, creating an efficient opportunity to integrate the two genomes to optimize treatment outcomes for each individual cancer patient.
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Recent Therapeutic Advances in the Treatment of Colorectal Cancer
Vol. 66 (2015), pp. 83–95More LessMetastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for KRAS, NRAS, BRAF, PIK3CA, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti–programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as BRAF and PI3K inhibitors, and the anti-RAS reovirus Reolysin®.
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Regulation of Tumor Metastasis by Myeloid-Derived Suppressor Cells
Vol. 66 (2015), pp. 97–110More LessAccumulation of pathologically activated immature myeloid cells with potent immune-suppressive activity is one of the major immunological hallmarks of cancer. In recent years, it became clear that in addition to their immune-suppressive activity, myeloid-derived suppressor cells (MDSCs) influence tumor progression in a variety of ways. They are directly implicated in the promotion of tumor metastases by participating in the formation of premetastatic niches, promoting angiogenesis and tumor cell invasion. In this review, we discuss recent data describing various roles of MDSCs in the formation of tumor metastases.
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Targeting HER2 for the Treatment of Breast Cancer
Vol. 66 (2015), pp. 111–128More LessHER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1–4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.
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The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy
Vol. 66 (2015), pp. 129–143More LessCellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.
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Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies
Vol. 66 (2015), pp. 145–159More LessMacrophage activation syndrome (MAS) is an acute episode of overwhelming inflammation characterized by activation and expansion of T lymphocytes and hemophagocytic macrophages. In rheumatology, it occurs most frequently in patients with systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus. The main clinical manifestations include cytopenias, liver dysfunction, coagulopathy resembling disseminated intravascular coagulation, and extreme hyperferritinemia. Clinically and pathologically, MAS bears strong similarity to hemophagocytic lymphohistiocytosis (HLH), and some authors prefer the term secondary HLH to describe it. Central to its pathogenesis is a cytokine storm, with markedly increased levels of numerous proinflammatory cytokines including IL-1, IL-6, IL-18, TNFα, and IFNγ. Although there is evidence that IFNγ may play a central role in the pathogenesis of MAS, the role of other cytokines is still not clear. There are several reports of SJIA-associated MAS dramatically benefiting from anakinra, a recombinant IL-1 receptor antagonist, but the utility of other biologics in MAS is not clear. The mainstay of treatment remains corticosteroids; other medications, including cyclosporine, are used in patients who fail to respond.
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Cardiovascular Disease in Adult Survivors of Childhood Cancer
Vol. 66 (2015), pp. 161–176More LessTreatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.
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Advances in Nanoparticle Imaging Technology for Vascular Pathologies
Vol. 66 (2015), pp. 177–193More LessNanoparticle imaging agents for vascular pathologies are in development, and some agents are already in clinical trials. Untargeted agents, with long circulation, are excellent blood-pool agents, but molecularly targeted agents have significant advantages due to the signal enhancement possible with nanoparticle presentation of the contrast agent molecules. Molecular targets that are accessible directly from the vasculature are optimal for such agents. Targets that are removed from the vasculature, such as those on tumor cell surfaces, have limited accessibility owing to the enhanced permeation and retention effect. Yet, efforts at molecular targeting have tested small molecules, peptides, antibodies, and most recently aptamers as possible targeting ligands. The future is bright for nanoparticle-based imaging of vascular pathologies.
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Vasopressin Receptor Antagonists, Heart Failure, and Polycystic Kidney Disease
Vol. 66 (2015), pp. 195–210More LessThe synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.
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ADAMTS13 and von Willebrand Factor in Thrombotic Thrombocytopenic Purpura
Vol. 66 (2015), pp. 211–225More LessPathogenesis of thrombotic thrombocytopenic purpura (TTP) was a mystery for over half a century until the discovery of ADAMTS13. ADAMTS13 is primarily synthesized in the liver, and its main function is to cleave von Willebrand factor (VWF) anchored on the endothelial surface, in circulation, and at the sites of vascular injury. Deficiency of plasma ADAMTS13 activity (<10%) resulting from mutations of the ADAMTS13 gene or autoantibodies against ADAMTS13 causes hereditary or acquired (idiopathic) TTP. ADAMTS13 activity is usually normal or modestly reduced (>20%) in other forms of thrombotic microangiopathy secondary to hematopoietic progenitor cell transplantation, infection, and disseminated malignancy or in hemolytic uremic syndrome. Plasma infusion or exchange remains the initial treatment of choice to date, but novel therapeutics such as recombinant ADAMTS13 and gene therapy are under development. Moreover, ADAMTS13 deficiency has been shown to be a risk factor for the development of myocardial infarction, stroke, cerebral malaria, and preeclampsia.
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Current Therapies for ANCA-Associated Vasculitis
Vol. 66 (2015), pp. 227–240More LessThe ANCA-associated vasculitides, granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss), are a group of multisystem autoimmune diseases characterized by necrotizing small- to medium-vessel vasculitis and the presence of anti-neutrophil cytoplasmic antibodies. Current therapeutic strategies consist of glucocorticoids in conjunction with either conventional or biologic agents for both induction of remission and remission maintenance. Treatment goals include reducing toxicity of induction therapy, preventing disease relapse, and limiting overall accrual of both disease-related damage and treatment-related morbidity. Future research directions include investigation of the optimal duration and frequency of maintenance therapy as well as development of targeted therapeutic agents, which is enhanced by emerging insights into disease pathogenesis.
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Changing Practice of Anticoagulation: Will Target-Specific Anticoagulants Replace Warfarin?
Vol. 66 (2015), pp. 241–253More LessThe target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.
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The Mechanisms and Therapeutic Potential of SGLT2 Inhibitors in Diabetes Mellitus
Vol. 66 (2015), pp. 255–270More LessThe kidneys in normoglycemic humans filter 160–180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.
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Extranuclear Steroid Receptors Are Essential for Steroid Hormone Actions*
Vol. 66 (2015), pp. 271–280More LessSteroid hormones are produced throughout the phylogenetic tree, from plants to mammals. In the past 40 years, steroid receptors localized to the nucleus have been recognized as being important to mediating steroid action in many organs. This action mainly arises from the regulation of key genes that are important for organ development and function. These include but are not limited to genes influencing the reproductive tract, mammary glands, bone, brain, fat differentiation, pituitary hormone regulation, and metabolic effects in many organs. Unfortunately, steroids also promote the development of hormone-responsive cancers, including breast, uterus, and prostate cancer. It has also been shown that steroid receptors exist outside the nucleus in many organs and cells, with unclear impact for normal development, health, and disease. This review describes the evidence from many laboratories that these receptors exist and function with nuclear receptors to provide the full impact of all steroid hormones.
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Impact of the Obesity Epidemic on Cancer
Vol. 66 (2015), pp. 281–296More LessThere is growing appreciation that the current obesity epidemic is associated with increases in cancer incidence at a population level and may lead to poor cancer outcomes; concurrent decreases in cancer mortality at a population level may represent a paradox, i.e., they may also reflect improvements in the diagnosis and treatment of cancer that mask obesity effects. An association of obesity with cancer is biologically plausible because adipose tissue is biologically active, secreting estrogens, adipokines, and cytokines. In obesity, adipose tissue reprogramming may lead to insulin resistance, with or without diabetes, and it may contribute to cancer growth and progression locally or through systemic effects. Obesity-associated changes impact cancer in a complex fashion, potentially acting directly on cells through pathways, such as the phosphoinositide 3-kinase (PI3K) and Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathways, or indirectly via changes in the tumor microenvironment. Approaches to obesity management are discussed, and the potential for pharmacologic interventions that target the obesity–cancer link is addressed.
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Obesity and Cancer: Local and Systemic Mechanisms
Vol. 66 (2015), pp. 297–309More LessObesity is a leading modifiable risk factor for the development of several epithelial malignancies. In addition to increasing risk, obesity also confers worse prognosis for many cancers. Obesity represents an overall state of energy imbalance frequently associated with systemic effects including insulin resistance, altered hormone signaling, and high circulating levels of proinflammatory mediators. In addition to its systemic effects, obesity causes subclinical white adipose inflammation including increased tissue levels of proinflammatory mediators. Both local and systemic effects are likely to contribute to the development and progression of cancer. An understanding of the interplay between local and systemic alterations involved in the obesity–cancer link provides the basis for developing interventions aimed at mitigating the protumorigenic effects.
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The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention*
Vol. 66 (2015), pp. 311–328More LessThe Janus kinase (JAK)–signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. This pathway provides an elegant and remarkably straightforward mechanism whereby extracellular factors control gene expression. It thus serves as a fundamental paradigm for how cells sense environmental cues and interpret these signals to regulate cell growth and differentiation. Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions. The clinical relevance of the pathway has been confirmed by the emergence of a new class of therapeutics that targets JAKs.
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Management of Postmenopausal Osteoporosis
Vol. 66 (2015), pp. 329–342More LessA hallmark of menopause, which follows the decline in the ovarian production of estrogen, is the aggressive and persistent loss of bone mineral and structural elements leading to loss of bone strength and increased fracture risk. This review focuses on newer methods of diagnosing osteoporosis and assessing fracture risk, as well as on novel management strategies for prevention and treatment. Fracture-risk prediction has been significantly enhanced by the development of methods such as the trabecular bone score, which helps assess bone microarchitecture and adds value to standard bone densitometry, and the Fracture Risk Assessment Tool (FRAX) algorithm techniques. The treatment of osteoporosis, which has the goals of fracture prevention and risk reduction, is moving beyond traditional monotherapies with antiresorptives and anabolic agents into new combination regimens.
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The Gut Microbial Endocrine Organ: Bacterially Derived Signals Driving Cardiometabolic Diseases
Vol. 66 (2015), pp. 343–359More LessThe human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease (CVD) progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact CVD risk. Whether pharmacological interventions at the level of the gut microbial endocrine organ will reduce CVD risk is a key new question in the field of cardiovascular medicine. Here we discuss the opportunities and challenges that lie ahead in targeting meta-organismal endocrinology for CVD prevention.
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H7N9: Preparing for the Unexpected in Influenza*
Vol. 66 (2015), pp. 361–371More LessIn the years prior to 2013, avian influenza A H7 viruses were a cause of significant poultry mortality; however, human illness was generally mild. In March 2013, a novel influenza A(H7N9) virus emerged in China as an unexpected cause of severe human illness with 36% mortality. Chinese and other public health officials responded quickly, characterizing the virus and identifying more than 400 cases through use of new technologies and surveillance tools made possible by past preparedness and response efforts. Genetic sequencing, glycan-array receptor-binding assays, and ferret studies reveal the H7N9 virus to have increased binding to mammalian respiratory cells and to have mutations associated with higher virus replication rates and illness severity. New risk-assessment tools indicate H7N9 has the potential for further mammalian adaptation with possible human-to-human transmission. Vigilant virologic and epidemiologic surveillance is needed to monitor H7N9 and detect other unexpected novel influenza viruses that may emerge.
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Treatment of Recurrent and Severe Clostridium Difficile Infection
J.J. Keller, and E.J. KuijperVol. 66 (2015), pp. 373–386More LessClostridium difficile infection (CDI) is a serious complication of hospitalization and antibiotic use with a high mortality and very high costs. Despite appropriate treatment, a subset of patients develop chronic recurrent CDI. Some other patients develop severe and life-threatening colitis. The risk factors, pathogenesis, and treatment of recurrent CDI and severe CDI are discussed in this review. In particular, fecal microbiota transplantation (FMT) as a treatment strategy is outlined and a treatment algorithm incorporating FMT is described.
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Emerging Technologies for Point-of-Care Management of HIV Infection
Vol. 66 (2015), pp. 387–405More LessThe global HIV/AIDS pandemic has resulted in 39 million deaths to date, and there are currently more than 35 million people living with HIV worldwide. Prevention, screening, and treatment strategies have led to major progress in addressing this disease globally. Diagnostics is critical for HIV prevention, screening and disease staging, and monitoring antiretroviral therapy (ART). Currently available diagnostic assays, which include polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and western blot (WB), are complex, expensive, and time consuming. These diagnostic technologies are ill suited for use in low- and middle-income countries, where the challenge of the HIV/AIDS pandemic is most severe. Therefore, innovative, inexpensive, disposable, and rapid diagnostic platform technologies are urgently needed. In this review, we discuss challenges associated with HIV management in resource-constrained settings and review the state-of-the-art HIV diagnostic technologies for CD4+ T lymphocyte count, viral load measurement, and drug resistance testing.
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Understanding HIV Latency: The Road to an HIV Cure
Vol. 66 (2015), pp. 407–421More LessTreatment with antiretroviral therapy dramatically increases the survival of HIV-infected individuals. However, treatment has to be continued for life because it does not lead to the full eradication of infection. HIV persists in resting CD4+ T cells, and possibly other cell types, and can reemerge from these cells when therapy is interrupted. Here, we review molecular mechanisms that have been proposed to contribute to HIV latency, as well as the relative roles of cis- and trans-acting mechanisms. We also discuss existing and future therapeutic opportunities regarding HIV latency that might lead to a future cure for HIV infection.
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Lessons from the RV144 Thai Phase III HIV-1 Vaccine Trial and the Search for Correlates of Protection
Vol. 66 (2015), pp. 423–437More LessRV144 remains the only HIV-1 vaccine trial to demonstrate efficacy against HIV-1 acquisition. The prespecified analysis of immune correlates of risk showed that antibodies directed against the V1V2 region of gp120, in particular the IgG1 and IgG3 subclass mediating antibody-dependent cell-mediated cytotoxicity, seem to play a predominant role in protection against HIV-1 acquisition and that plasma envelope (Env)-specific IgA antibodies were directly correlated with risk. RV144 and recent nonhuman primate challenge studies suggest that Env is essential, and perhaps sufficient, to induce protective antibody responses against mucosal HIV-1 acquisition. Follow-up clinical trials are ongoing to further dissect the immune responses elicited by the RV144 ALVAC-HIV and AIDSVAX® B/E regimen. The study of gp120 Env immunogens and immune correlates of risk has resulted in the development of improved antigens. Whether the RV144 immune correlates of risk will generalize to other populations vaccinated with similar immunogens with different modes and intensity of transmission remains to be demonstrated. Efficacy trials are now planned in heterosexual populations in southern Africa and men who have sex with men in Thailand.
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T Cell–Mediated Hypersensitivity Reactions to Drugs
Vol. 66 (2015), pp. 439–454More LessThe immunological mechanisms driving delayed hypersensitivity reactions (HSRs) to drugs mediated by drug-reactive T lymphocytes are exemplified by several key examples and their human leukocyte antigen (HLA) associations: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02, allo-purinol and HLA-B*58:01, and both amoxicillin-clavulanate and nevirapine with multiple class I and II alleles. For HLA-restricted drug HSRs, specific class I and/or II HLA alleles are necessary but not sufficient for tissue specificity and the clinical syndrome. Several models have been proposed to explain the immunopathogenesis of severe T cell–mediated drug HSRs, and our increased understanding of the risk factors and mechanisms involved in the development of these reactions will further the development of sensitive and specific strategies for preclinical screening that will lead to safer and more cost-effective drug design.
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Synthetic Lethality and Cancer Therapy: Lessons Learned from the Development of PARP Inhibitors
Vol. 66 (2015), pp. 455–470More LessThe genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline BRCA1 or BRCA2 gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected. Applying the synthetic lethal concept to target non-BRCA-mutant cancers also has clear potential, and we discuss how some of the principles learned in developing PARP inhibitors might also drive the development of additional genetic approaches.
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Lysosomal Storage Diseases: From Pathophysiology to Therapy
Vol. 66 (2015), pp. 471–486More LessLysosomal storage diseases are a group of rare, inborn, metabolic errors characterized by deficiencies in normal lysosomal function and by intralysosomal accumulation of undegraded substrates. The past 25 years have been characterized by remarkable progress in the treatment of these diseases and by the development of multiple therapeutic approaches. These approaches include strategies aimed at increasing the residual activity of a missing enzyme (enzyme replacement therapy, hematopoietic stem cell transplantation, pharmacological chaperone therapy and gene therapy) and approaches based on reducing the flux of substrates to lysosomes. As knowledge has improved about the pathophysiology of lysosomal storage diseases, novel targets for therapy have been identified, and innovative treatment approaches are being developed.
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From De Novo Mutations to Personalized Therapeutic Interventions in Autism
Vol. 66 (2015), pp. 487–507More LessThe high heritability, early age at onset, and reproductive disadvantages of autism spectrum disorders (ASDs) are consistent with an etiology composed of dominant-acting de novo (spontaneous) mutations. Mutation detection by microarray analysis and DNA sequencing has confirmed that de novo copy-number variants or point mutations in protein-coding regions of genes contribute to risk, and some of the underlying causal variants and genes have been identified. As our understanding of autism genes develops, the spectrum of autism is breaking up into quanta of many different genetic disorders. Given the diversity of etiologies and underlying biochemical pathways, personalized therapy for ASDs is logical, and clinical genetic testing is a prerequisite.
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Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics
Vol. 66 (2015), pp. 509–523More LessKetamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent antidepressant effects of ketamine in treatment-resistant depression. Moreover, preclinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. This article discusses the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants.
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Previous Volumes
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Volume 75 (2024)
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