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- Volume 57, 2006
Annual Review of Medicine - Volume 57, 2006
Volume 57, 2006
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Angiogenesis
Vol. 57 (2006), pp. 1–18More LessAngiogenesis inhibitors for the treatment of cancer have now been approved by the Food and Drug Administration in the United States, and in 28 other countries including China. Clinical application of this new class of drugs is informed by certain principles from angiogenesis research. Oncogenic mutations initiate tumorigenesis, but angiogenesis is necessary for expansion of tumor mass. Two angiogenesis inhibitors have been developed that have a broad spectrum of anticancer activity, yet virtually no side effects. Endogenous angiogenesis inhibitors act as tumor suppressor proteins. The angiogenic response in vivo is based on the genetic background of the host. Several types of angiogenesis inhibitors reveal a biphasic, U-shaped curve of efficacy. “Antiangiogenic chemotherapy” is a novel approach to the treatment of drug resistance.
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Advances in Radiation Oncology
Vol. 57 (2006), pp. 19–31More LessAdvances in radiation oncology have been made on three major fronts: biology, physics, and clinical application. Our biological understanding of how radiation kills cells and how malignant cells avoid damage has identified new targets for therapeutic manipulation. Research in physics has yielded sophisticated methods to direct the deposition of radiation energy in ways that enhance target coverage while minimizing dose to normal structures as much as possible. Intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy represent new paradigms in treatment planning and dose delivery. Clinical management of the cancer patient is multidisciplinary. Increasingly, combinations of radiation and chemotherapy, with or without surgery, are enhancing cure rates, often with preservation of organ function. Taken together, these advances have increased the effectiveness of radiation therapy and promise better treatment results in the future.
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Bortezomib: Proteasome Inhibition as an Effective Anticancer Therapy
Vol. 57 (2006), pp. 33–47More LessVELCADE® (bortezomib, Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. Inhibition of the proteasome results in disruption of homeostatic mechanisms within the cell that can lead to cell death. Bortezomib's first indication, for the treatment of relapsed myeloma in patients who have received at least two prior treatments and progressed on their previous treatment, was based in part on the magnitude of activity demonstrated in phase II trials. Bortezomib is currently indicated for patients who have received at least one prior therapy in the United States and European Union, although patients in the European Union must have already undergone bone marrow transplantation or be unsuitable for the procedure. A phase III trial demonstrated the superiority of bortezomib over high-dose dexamethasone in response rate, time to progression, and survival in patients with myeloma who had relapsed after 1–3 prior therapies. Clinical development is ongoing to investigate its activity as monotherapy and in combination regimens for the treatment of non-Hodgkin's lymphoma, solid tumors, and earlier presentations of myeloma.
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Chemoprevention of Prostate Cancer
Vol. 57 (2006), pp. 49–63More LessProstate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. The Prostate Cancer Prevention Trial has provided the first firm evidence that this cancer can be prevented by a relatively nontoxic oral agent. Additional agents, many of which are antioxidants with antiandrogenic effects, are being tested (or soon will be) in large clinical trials. The current body of evidence is insufficient to make a routine recommendation of any dietary or nutritional supplement for the prevention of prostate cancer.
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Effective Cancer Therapy Through Immunomodulation*
Vol. 57 (2006), pp. 65–81More LessMAbs directed toward tumor cells, tumor neovasculature, and host negative immunoregulatory elements (checkpoints) have emerged as useful immunotherapeutic agents against cancer. However, effective active modulation of the immune response with anticancer vaccines will require identifying appropriate tumor-rejection antigens; optimizing the interactions of peptides, antigen-presenting cells, and T cells; and blockading negative immunological checkpoints that impede an effective immune response. Checkpoints being targeted include CTLA-4 and PD1 that are negative signaling receptors expressed on activated T cells, CD4+CD25+ Foxp3-expressing Tregs (suppressor T cells), IL-2-mediated activation-induced cell death (AICD), and the cytokine TGFβ.
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Molecular Approaches in Pediatric Oncology*
Vol. 57 (2006), pp. 83–97More LessThe use of molecular approaches has become part of the standard of care in the management of pediatric cancer patients. Molecular approaches are now included in the initial diagnosis, definition of prognostically distinct patient subgroups, selection of patients for specific therapies, prediction of risk for toxicities to therapy, and monitoring of patients receiving both conventional and novel targeted therapies. This clinical application of molecular medicine has been based on a growing molecular understanding of cancer biology. Studies of pediatric cancers have contributed to this understanding in many ways. We present a model for understanding cancer biology, using specific examples taken from pediatric oncology, and then discuss the application of molecular techniques to the clinical management of pediatric cancer patients.
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Molecular Imaging in the Development of Cancer Therapeutics
Vol. 57 (2006), pp. 99–118More LessResearchers have made great progress in defining genetic and molecular alterations that contribute to cancer. New therapeutic targets have been identified and targeted therapeutic agents have been developed, but our ability to evaluate potential drugs has not kept pace. Molecular imaging technologies that monitor biological processes and/or measure levels of targeted macromolecules can contribute significantly to preclinical and clinical drug evaluation. This article describes the drug discovery process, economic problems facing drug discovery and development, and successes and failures in this realm. We briefly describe the available molecular imaging tools, with emphasis on positron emission tomography. We discuss biological processes that are altered in tumors and can be measured by molecular imaging; examples include gene expression, signal transduction, tumor cell metabolism, proliferation, apoptosis, hypoxia, and angiogenesis. We conclude with a proposal to integrate molecular imaging into the drug development process.
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Pharmacogenomics and Individualized Drug Therapy
Vol. 57 (2006), pp. 119–137More LessPharmacogenetics deals with inherited differences in the response to drugs. The best-recognized examples are genetic polymorphisms of drug-metabolizing enzymes, which affect about 30% of all drugs. Loss of function of thiopurine S-methyltransferase (TPMT) results in severe and life-threatening hematopoietic toxicity if patients receive standard doses of mercaptopurine and azathioprine. Gene duplication of cytochrome P4502D6 (CYP2D6), which metabolizes many antidepressants, has been identified as a mechanism of poor response in the treatment of depression. There is also a growing list of genetic polymorphisms in drug targets that have been shown to influence drug response. A major limitation that has heretofore moderated the use of pharmacogenetic testing in the clinical setting is the lack of prospective clinical trials demonstrating that such testing can improve the benefit/risk ratio of drug therapy.
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Avian Flu to Human Influenza
Vol. 57 (2006), pp. 139–154More LessInfluenza A viral infection causes substantial annual morbidity and mortality worldwide, particularly for infants, the elderly, and the immunocompromised. The virus mainly replicates in the respiratory tract and is spread by respiratory secretions. A growing concern is the recent identification of H5N1 strains of avian influenza A in Asia that were previously thought to infect only wild birds and poultry, but have now infected humans, cats, pigs, and other mammals, often with fatal results, in an ongoing outbreak. A human pandemic with H5N1 virus could potentially be catastrophic because most human populations have negligible antibody-mediated immunity to the H5 surface protein and this viral subtype is highly virulent. Whether an H5N1 influenza pandemic will occur is likely to hinge on whether the viral strains involved in the current outbreak acquire additional mutations that facilitate efficient human-to-human transfer of infection. Although there is no historical precedent for an H5N1 avian strain causing widespread human-to-human transmission, some type of influenza A pandemic is very likely in the near future. The possibility of an H5N1 influenza pandemic has highlighted the many current limitations of treatment with antiviral agents and of vaccine production and immunogenicity. Future vaccine strategies that may include more robust induction of T-cell responses, such as cytotoxic T lymphocytes, may provide better protection than is offered by current vaccines, which rely solely or mainly on antibody neutralization of infection.
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Emerging Therapeutics for Chronic Hepatitis B
Vol. 57 (2006), pp. 155–166More LessHepatitis B is a global health problem. Patients with chronic hepatitis B (CHB) carry a significant risk to eventually develop cirrhotic liver disease. Recent therapeutic advances against CHB offer excellent potential for long-term suppression of hepatitis B virus (HBV) replication during antiviral therapy, and occasionally a durable remission off medication. Selection of appropriate patients for antiviral therapy depends on identification of HBV replication and an elevated alanine aminotransferase level or histologic liver injury. Pegylated interferon alpha offers potent immunomodulatory and antiviral activity with the potential for durability, but also with adverse effects and significant cost. The nucleoside or nucleotide analogs, lamivudine, adefovir, and entecavir, suppress HBV replication and are extremely well-tolerated, but long-term or even lifelong therapy is required. Most experience has been gained with lamivudine, but viral resistance occurs frequently. Newer analogs appear to be relatively free of this problem. Approaches using a combination of agents have promise, but have yet to be proven superior to individual drugs alone.
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The Rotavirus Vaccine Saga
Vol. 57 (2006), pp. 167–180More LessRotavirus is the single most common cause of acute, dehydrating gastroenteritis worldwide. This is a highly contagious and highly democratic disease. The attack rate in infants and young children is similar regardless of sanitation, socioeconomics or geography. Rotavirus vaccine development began in the early 1980s using a “Jennerian” approach based on rotaviruses that normally infect animals. Although these vaccines were found to be generally safe, protection from disease was inconsistent. The second generation of vaccines was based on the same animal viruses configured to carry the relevant coat proteins of human rotaviruses. An attenuated human rotavirus vaccine has also been developed. After close to 20 years of laboratory and clinical studies, safe and effective rotavirus vaccines are approaching regulatory approval.
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West Nile Virus: Epidemiology and Clinical Features of an Emerging Epidemic in the United States*
Vol. 57 (2006), pp. 181–194More LessWest Nile virus (WNV) was first detected in North America in 1999 during an outbreak of encephalitis in New York City. Since then the virus has spread across North America and into Canada, Latin America, and the Caribbean. The largest epidemics of neuroinvasive WNV disease ever reported occurred in the United States in 2002 and 2003. This paper reviews new information on the epidemiology and clinical aspects of WNV disease derived from greatly expanded surveillance and research on WNV during the past six years.
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Prostatitis/Chronic Pelvic Pain Syndrome
Vol. 57 (2006), pp. 195–206More LessWe review the diagnosis, categorization, and treatment of prostatitis/chronic pelvic pain syndrome based on the National Institutes of Health (NIH) classification. Prostatitis is an extremely common syndrome that afflicts 2%–10% of men. Formerly a purely clinical diagnosis, prostatitis is now classified within a complex series of syndromes (NIH category I–IV prostatitis) that vary widely in clinical presentation and response to treatment. Acute bacterial prostatitis (category I) and chronic bacterial prostatitis (category II) are characterized by uropathogenic infections of the prostate gland that respond well to antimicrobial treatment. In contrast, chronic prostatitis/chronic pelvic pain syndrome (category III), which accounts for 90%–95% of prostatitis cases, is of unknown etiology and is marked by a mixture of pain, urinary, and ejaculatory symptoms with no uniformly effective therapy. Asymptomatic inflammatory prostatitis (category IV) is an incidental finding of unknown clinical significance. This review describes the current status of prostatitis syndromes and explores the future prospects of new diagnostic tools and therapies.
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Celiac Disease
Vol. 57 (2006), pp. 207–221More LessCeliac disease is an autoimmune disease that occurs in genetically predisposed individuals as the result of an immune response to gluten. This immune response occurs in both the lamina propria and the epithelium of the small intestine. There is a close link to HLA DQ2 and DQ8, although these HLA genes account for only 40% of the genetic influence. Environmental factors, such as the amount and timing of gluten administration in infancy, as well as breastfeeding, influence the disease. Serologic screening studies that use sensitive and specific antibody tests have revealed the disease to be common, occurring in ∼1% of the population. Clinical presentations are diverse and atypical; the majority of patients lack diarrhea. Therapy is a gluten-free diet that requires avoidance of wheat, rye, and barley, although there is potential for other therapies based on our understanding of the pathophysiology of the disease.
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Amyloidosis
Vol. 57 (2006), pp. 223–241More LessAmyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein. About 23 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic structure although they are associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls, and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. This rarity and the variable involvement of different organs and tissues are often responsible for missed or delayed diagnosis, and amyloidosis remains a considerable clinical challenge. However, recent elucidation of important aspects of pathogenesis, as well as developments in diagnosis, monitoring, and treatment, have greatly improved outcomes, especially when patients are managed in specialist centers.
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Surgical Treatment of Morbid Obesity
Vol. 57 (2006), pp. 243–264More LessObesity is a major epidemic in developed countries. It induces or exacerbates hypertension, diabetes mellitus, obstructive sleep apnea, dyslipidemia, and many other disease processes, which cumulatively contribute to premature mortality on a scale rivaling that of smoking. At present, bariatric surgery is the only therapeutic modality that can produce sustained weight loss and halt or resolve comorbidities. This success results from the ability to perform the operation reliably, usually laparoscopically, with low mortality. The most commonly performed operation is Roux-en-Y gastric bypass. Other bypasses discussed in this review include biliopancreatic diversion with and without duodenal switch. Purely restrictive operations, especially adjustable gastric banding, have a lower risk but are somewhat less effective. We focus on the more controversial aspects of commonly accepted operations, including patient selection, the spectrum and frequency of complications, and the long-term outcome.
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Therapeutic Approaches to Preserve Islet Mass in Type 2 Diabetes
Vol. 57 (2006), pp. 265–281More LessType 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate β-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in β-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet β-cell that lead to stimulation of β-cell replication and inhibition of β-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances β-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands β-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve β-cell mass, although it remains unclear whether TZDs affect β-cell mass via direct mechanisms. Complementary approaches to regeneration of β-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in β-cell mass that is characteristic of the natural history of type 2 diabetes.
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Enzyme Replacement for Lysosomal Diseases*
Vol. 57 (2006), pp. 283–296More LessFollowing the demonstration of the nature of the enzymatic defects in the sphingolipid storage disorders in the mid-1960s, consideration was directed to the development of therapy for patients with these conditions. High on the list of possibilities was enzyme supplementation or replacement. Many years of arduous investigation and the development of novel protein targeting strategies were required to bring this concept to fruition. Enzyme replacement therapy (ERT) was eventually shown to be extraordinarily effective for patients with Gaucher disease, the most prevalent metabolic storage disorder of humans. Demonstration of the benefit of ERT in this disorder led to the extension of this approach to the treatment of other lysosomal storage disorders. This review presents the current status and anticipated developments in this field.
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Genetic Basis of Lipodystrophies and Management of Metabolic Complications
Vol. 57 (2006), pp. 297–311More LessSelective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPARγ), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.
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Nuclear Receptors in Lipid Metabolism: Targeting the Heart of Dyslipidemia
Vol. 57 (2006), pp. 313–329More LessDyslipidemia is the sine qua non of atherosclerosis, but it is also strongly associated with the metabolic syndrome, obesity, diabetes, and fatty liver disease. The molecular basis for future therapies requires understanding the pivotal role of nuclear hormone receptors in lipid and inflammatory homeostasis. This review summarizes evidence that the liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are key transcriptional regulators in lipid metabolism. Additionally, their effects on glucose homeostasis and inflammation make LXR and PPAR signaling networks attractive molecular targets for managing lipid-related diseases.
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Previous Volumes
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Volume 76 (2025)
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 58 (2007)
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Volume 57 (2006)
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Volume 56 (2005)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 44 (1993)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 41 (1990)
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Volume 40 (1989)
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Volume 39 (1988)
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Volume 38 (1987)
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Volume 37 (1986)
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Volume 36 (1985)
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Volume 35 (1984)
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Volume 34 (1983)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 9 (1958)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 5 (1954)
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Volume 4 (1953)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)