Annual Review of Medicine - Volume 61, 2010

The genomic era is changing the understanding of cancer, although translation of the vast amount of data available into decision-making algorithms is far from reality. Molecular profiling of hepatocellular carcinoma (HCC), the most common cause of death among cirrhotic patients and a fast-growing malignancy in Western countries, is enabling the advancement of novel approaches to disease diagnosis and management. Most HCCs arise on a cirrhotic liver, and predictably, an accurate genomic characterization will allow the identification of procarcinogenic signals amenable to selective targeting by chemopreventive strategies. Molecular diagnosis is currently feasible for small tumors, but it has not yet been formalized by scientific guidelines. Molecular treatment is a reality: Sorafenib confers unprecedented survival benefits in patients at advanced stages. Genomic information from tumor and nontumoral tissue will aid prognosis prediction and facilitate the identification of oncogene addiction loops, providing the opportunity for more personalized medicine.

Kidney cancer is not a single disease; it is made up of a number of cancers that occur in the kidney, each having a different histology, following a different clinical course, responding differently to therapy, and caused by a different gene. Study of the genes underlying kidney cancer has revealed that it is fundamentally a metabolic disorder. Understanding the genetic basis of cancer of the kidney has significant implications for diagnosis and management of this disease. VHL is the gene for clear cell kidney cancer. The VHL protein forms a complex that targets the hypoxia-inducible factors for ubiquitin-mediated degradation. Knowledge of this pathway provided the foundation for the development of novel therapeutic approaches now approved for treatment of this disease. MET is the gene for the hereditary form of type 1 papillary renal carcinoma and is mutated in a subset of sporadic type 1 papillary kidney cancers. Clinical trials are currently ongoing with agents targeting the tyrosine kinase domain of MET in sporadic and hereditary forms of papillary kidney cancer. BHD is the gene for the hereditary type of chromophobe kidney cancer. It is thought to be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. Hereditary leiomyomatosis renal cell carcinoma, a hereditary form of type 2 papillary renal carcinoma, is caused by inactivation of a Krebs cycle enzyme due to mutation. Knowledge of these kidney cancer gene pathways has enabled new approaches in the management of this disease and has provided the foundation for the development of targeted therapeutics.

Myelodysplastic syndromes (MDS) represent a collection of stem cell disorders characterized by impaired hematopoiesis resulting in low peripheral blood counts. The majority of patients with MDS present with symptoms related to anemia; however, bleeding and infection are the most common causes of death. The median age of diagnosis is 72 and the median survival is 2.5 years. Lenalidomide, azacitidine, and decitabine are all FDA-approved agents to treat MDS; however, the only potential cure for MDS remains stem cell transplantation.

Surgery is currently the most effective and widely used procedure in treating human cancers, and the single most important predictor of patient survival is a complete surgical resection. Major opportunities exist to develop new and innovative technologies that could help the surgeon to delineate tumor margins, to identify residual tumor cells and micrometastases, and to determine if the tumor has been completely removed. Here we discuss recent advances in nanotechnology and optical instrumentation, and how these advances can be integrated for applications in surgical oncology. A fundamental rationale is that nanometer-sized particles such as quantum dots and colloidal gold have functional and structural properties that are not available from either discrete molecules or bulk materials. When conjugated with targeting ligands such as monoclonal antibodies, peptides, or small molecules, these nanoparticles can be used to target malignant tumor cells and tumor microenvironments with high specificity and affinity. In the “mesoscopic” size range of 10–100 nm, nanoparticles also have large surface areas for conjugating to multiple diagnostic and therapeutic agents, opening new possibilities in integrated cancer imaging and therapy.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor.

Several gastrointestinal (GI) operations that were designed to promote weight loss can powerfully ameliorate type 2 diabetes mellitus (T2DM). Although T2DM is traditionally viewed as a chronic, relentless disease in which delay of end-organ complications is the major treatment goal, GI surgery offers a novel endpoint: complete disease remission. Ample data confirm the excellent safety and efficacy of conventional bariatric operations—especially Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding—to treat T2DM in severely obese patients. Use of experimental procedures as well as conventional bariatric operations is increasingly being explored in less obese diabetic patients, with generally favorable results, although further assessment of risk:benefit profiles is needed. Mounting evidence indicates that certain operations involving intestinal diversions improve glucose homeostasis through varied mechanisms beyond reduced food intake and body weight, for example by modulating gut hormones. Research to elucidate such mechanisms should facilitate the design of novel pharmacotherapeutics and dedicated antidiabetes GI manipulations. Here we review evidence regarding the use and study of GI surgery to treat T2DM, focusing on available published reports as well as results from the Diabetes Surgery Summit (DSS) in Rome and the World Congress on Interventional Therapies for T2DM in New York City.

Acute pancreatitis and chronic pancreatitis are complex inflammatory disorders of the pancreas with unpredictable severity, complications, and clinical courses. Growing evidence for genetic risk and modifying factors, plus strong evidence that only a minority of patients with these disorders are heavy alcohol drinkers, has revolutionized our concept of these diseases. Once considered a self-inflicted injury, pancreatitis is now recognized as a complex inflammatory condition like inflammatory bowel disease. Genetic linkage and candidate gene studies have identified six pancreas-targeting factors that are associated with changes in susceptibility to acute and/or chronic pancreatitis, including cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), serine protease inhibitor Kazal 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsinogen C (CTRC) and calcium-sensing receptor (CASR). Patients with mutations in these genes are at increased risk of pancreatitis caused by a variety of stresses including hyperlipidemia and hypercalcemia. Multiple studies are reporting new polymorphisms, as well as complex gene × gene and gene × environmental interactions.

Anorexia nervosa (AN) is a serious mental illness categorized by a failure to maintain a minimally normal weight, a fear of gaining weight or becoming fat, and preoccupations about body shape or weight. AN is associated with significant morbidity and a mortality rate as high as that seen in any psychiatric illness. Biological factors, including genetic predisposition, appear to play a role in the development of AN. Treatment is challenging both because interventions with clear empirical support have not been identified and because individuals affected by AN are typically reluctant to undergo weight restoration. Preliminary studies suggest that family-based treatment may be useful for younger patients with AN. Treatment development for adults with AN and pursuit of neurobiological correlates of AN remain high-priority research areas.

During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with “paired-end” methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.

The delivery of combat casualty care poses numerous challenges including austere conditions, limited supplies and medical personnel, and multiple simultaneous patients. However, the exigent circumstances of the battlefield compel the development of research and the advancement of adaptive, practical medical technologies to support and sustain military health. In Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), modern changes in medical management, coupled with improved protective gear and evacuation capabilities, have facilitated the highest survival rate in combat history.

The Medicare Modernization Act was intended to improve access to prescription drugs for millions of seniors, by providing a range of benefit packages with different prices and different formularies for beneficiaries to choose from. The major challenge for physicians has been to recognize when a Medicare beneficiary has coverage versus when that patient is in the “doughnut hole” where Medicare beneficiaries do not have coverage and therefore have to pay the full cost of the drugs out-of-pocket. A second challenge is that different Medicare beneficiaries are enrolled in different drug plans, and drugs that are covered in some plans are not covered in other plans.