Potential therapeutic strategies for lymphatic metastasis

Physiologically, the lymphatic system regulates fluid volume in the interstitium and provides a conduit for immune cells to travel to lymph nodes, but pathologically, the lymphatic system serves as a primary escape route for cancer cells. Lymphatic capillaries have a thin discontinuous basement membrane, lack pericyte coverage and often contain endothelial cell gaps that can be invaded by immune cells (or tumor cells). In addition, tumor cells and stromal cells in the tumor microenvironment secrete factors that stimulate lymphangiogenesis, the growth of lymphatic endothelial cells and the sprouting of lymphatic capillaries. As a result, many tumors are surrounded by large, hyperplastic, peri-tumoral lymphatic vessels and less frequently are invaded by intra-tumoral lymphatic vessels. Carcinoma cells commonly metastasize through these lymphatic vessels to regional lymph nodes. The presence of metastatic cells in the sentinel lymph node is a prognostic indicator for many types of cancer, and the degree of dissemination determines the therapeutic course of action. Lymphangiogenesis is currently at the frontier of metastasis research. Recent strides in this field have uncovered numerous signaling pathways specific for lymphatic endothelial cells and vascular endothelial cells. This review will provide an overview of tumor lymphangiogenesis and current strategies aimed at inhibiting lymphatic metastasis. Novel therapeutic approaches that target the tumor cells as well as the vascular and lymphatic endothelial compartments are discussed.     

转移性肝癌的治疗

转移性肝癌的治疗是肿瘤治疗中十分棘手的难题,治疗方法虽然较多,但迄今疗效不甚满意.转移性肝癌的预后取决于原发肿瘤的部位、恶性程度、肝受累范围、有无肝外转移灶和患者的全身情况.对已有肝转移的晚期肿瘤,只有在尽可能切除原发灶的情况下,采取以手术为主的综合治疗的方法,才有可能最大限度地使患者病情缓解,提高生活质量,延长生存期.本文综述了各种转移性肝癌的治疗进展.     

Emerging therapeutic strategies for obesity

The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss.     

Potential emerging therapeutic strategies to prevent restenosis in the peripheral vasculature.

Despite the availability of antiplatelet and antithrombotic therapies, recent advances in catheter and stent technology and improved operator skill, restenosis remains the most frequent problem associated with percutaneous and surgical revascularization interventions for both coronary and peripheral arterial disease. Prevention of restenosis in the coronary vasculature has been demonstrated with cilostazol, trapidil, probucol, tranilast, nitric oxide donors, and clopidogrel. Given the similarities in revascularization procedures and in the pathophysiology of restenosis, it is possible that these results may be extrapolated to the setting of restenosis in the peripheral vasculature, making trials with these agents imperative. Several new agents have shown promising preliminary results for the prevention of restenosis in the peripheral vasculature, including cilostazol, low-molecular-weight heparins, and elastase. Several nonpharmacologic treatment modalities are also under study to prevent peripheral and coronary restenosis and have shown favorable initial results. These include endovascular radiation brachytherapy, arterial gene therapy, photoangioplasty, and several novel treatment delivery systems.     

Emerging therapeutic strategies for myelodysplastic syndrome

Increasing understanding of the pathophysiology of myelodysplastic syndromes (MDS) and a greater appreciation of the large impact that marrow failure has on the symptomatology and outcome of MDS have led to new treatment approaches. We describe recent developments of methods to manage marrow failure, suppress the MDS clone, and widen the applicability of curative treatment with allogeneic stem cell transplants.     

Current therapeutic strategies for HCV-associated cryoglobulinemia

Cryoglobulinemia refers to the presence in serum of immunoglobulins, that reversibly precipitate at low temperatures. Cryoglobulins are classified according to their immunochemical properties as type I, composed of a single monoclonal immunoglobulin, and types II and III, referred as mixed cryoglobulinemia (MC), composed by a mixture of monoclonal (type II) and polyclonal (type III) IgM that have rheumatoid factor activity and bind to polyclonal IgGs. MC is a systemic vasculitis with cutaneous and multiple organ involvement including chronic hepatitis, membrano-proliferative glomerulonephritis, and peripheral neuropathy. In more than 90% of patients, MC is associated with chronic hepatitis C virus (HCV) infection, which is considered the triggering factor of the disease. Patients with HCV-related MC may be managed by means of etiological, pathogenetic or symptomatic therapeutic modalities. The choice of the more appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement. This paper reviews the currently available therapeutic strategies for MC syndrome, emphasizing the importance of HCV eradication, and the safety/efficacy of new biologic therapies for selective control of cryoglobulin-producing B-cells.     

RNAi-based therapeutic strategies for metabolic disease

RNA interference (RNAi) is a robust gene silencing mechanism that degrades mRNAs complementary to the antisense strands of double-stranded, short interfering RNAs (siRNAs). As a therapeutic strategy, RNAi has an advantage over small-molecule drugs, as virtually all genes are susceptible to targeting by siRNA molecules. This advantage is, however, counterbalanced by the daunting challenge of achieving safe, effective delivery of oligonucleotides to specific tissues in vivo. Lipid-based carriers of siRNA therapeutics can now target the liver in metabolic diseases and are being assessed in clinical trials for the treatment of hypercholesterolemia. For this indication, a chemically modified oligonucleotide that targets endogenous small RNA modulators of gene expression (microRNAs) is also under investigation in clinical trials. Emerging 'self-delivery' siRNAs that are covalently linked to lipophilic moieties show promise for the future development of therapies. Besides the liver, inflammation of the adipose tissue in patients with obesity and type 2 diabetes mellitus may be an attractive target for siRNA therapeutics. Administration of siRNAs encapsulated within glucan microspheres can silence genes in inflammatory phagocytic cells, as can certain lipid-based carriers of siRNA. New technologies that combine siRNA molecules with antibodies or other targeting molecules also appear encouraging. Although still at an early stage, the emergence of RNAi-based therapeutics has the potential to markedly influence our clinical future.     

肝肺综合征的诊治对策

肝肺综合征(HPS)是肝病和/或门静脉高压患者常见的肺部并发症,其特征表现为肺内血管扩张引起的动脉氧合异常。HPS发病机制复杂,临床上早期诊断率低,预后差。目前HPS尚缺乏有效治疗药物,肝移植是唯一根本治疗手段。现就HPS发病机制、临床表现、诊断及治疗进行概述,旨在进一步提高临床筛查和诊治HPS的水平。     

Novel therapeutic strategies for large vessel vasculitis

Giant cell arteritis and Takayasu's arteritis are systemic vasculitides that cause inflammation of large arteries and their branches. Both have similar histology, but differ in their age of onset. Corticosteroids have been the mainstay of treatment for the past 50 years but are limited by the potential toxicity that may occur in almost 60% of patients. This limitation has lead to the investigation of alternative agents for the treatment of these diseases.     

Medication therapeutic strategies for gastro-esophageal reflux disease

Gastroesophageal reflux disease (GERD) is a common condition in industrialised countries. According to a recently published, globally accepted definition and classification of GERD, clinical presentations include oesophageal and extraoesophageal syndromes, with extraoesophageal syndromes divided into established and proposed associations. Proton pump inhibitors (PPI) are the drug class of choice for all patients with GERD, irrespective of the severity. The individual strategy of treatment (e. g., dose and duration of PPI) depends on the clinical presentation. As a rule, the magnitude of acid control gained by PPIs is related to clinically meaningful outcome parameters: speed and extent of symptom control, healing of reflux oesophagitis, maintenance of symptomatic and endoscopic remission of the disease. In individual cases, the efficacy of PPI therapy can be improved by switching from one compound to another and by increasing the frequency of dosing. Current evidence suggests that PPI therapy is remarkably safe without any relevant differences between the PPIs on the market.     

Current therapeutic strategies for acute myeloid leukaemia

Improvements in survival in adult acute myeloid leukaemia (AML) have yet to be gleaned from either refinements in the understanding of the pathophysiology of the disease or from the expanding pool of targeted therapies. Outcomes have remained particularly dismal in older patients. Ongoing and planned trials will assess the effects of drugs targeting biological pathways whose clinical importance may vary as a function of the unique genotype and phenotype of each case of AML. The success of these ventures will ultimately require well-designed clinical trials in subsets of patients with risk being dependent not only on age and cytogenetics, but on additional, increasingly quantifiable biological variables. Inhibitors of fms-like tyrosine kinase-3, farnesyl transferase, apoptotic and angiogenic pathways are being studied alone and in combination with chemotherapy. Biological therapies, including monoclonal antibodies, peptide vaccines and interleukin-2, are undergoing evaluation. The role of autologous as well as allogeneic myeloablative and reduced-intensity transplantation continues to be defined. Several potentially useful new cytotoxic agents are being introduced. Critically important to advancing the field in light of such an increasing number of choices is a reassessment of traditional phase II trial designs so that more efficient evaluation of new therapies may take place, even as well-designed phase III trials continue to be performed.     

Treatment strategies for hepatic metastasis from colorectal cancer

Hepatic micrometastases of the parenchyma adjacent to a macroscopic lesion were detected in 17 of 31 resected liver metastases. Fifty-nine micrometastatic lesions were detected in total; 26 lesions were situated in the portal vein (PV), 22 in the central vein (CV), 5 in the bile duct (BD), and 6 in the sinusoid (SS). A histological study confirmed the direct invasion of the macrometastatic cancer cells into the adjacent PV, CV, BD, and SS. According to the tumor doubling time, the mean diameter of the macrometastases in 19 remnant livers was calculated to have been 0.57±0.87 cm at the time of the primary resection. The calculated diameter of 3 of these 19 macrometastases was found to be less than 0.01 cm, the minimum implantable size, indicating that the cancer recurrence in these specimens may have developed from macroscopic metastatic lesions as a satellite, and not from the primary tumor. In 13 patients who received doses of 5250 mg or more of 5 fluorouracil (FU) via the hepatic artery, the cumulative disease-free rate 2 years postoperatively was 100%; this value was 47.6% in 11 patients who received less than 5250 mg of 5 FU via the hepatic artery, and 0% in 39 patients who received no chemotherapy (P<0.005). These results suggest that anatomical hepatic resection for satellite lesions, combined with prophylactic hepatic arterial chemotherapy for micrometastases, decreases the recurrence rate of hepatic metastases in the remnant liver.     

Remodeling the therapeutic pyramid: evolving therapeutic strategies for rheumatoid arthritis

The approach to treatment of rheumatoid arthritis (RA) is undergoing dramatic change, With a prevalence of 1% of the general population. RA is the most common cause of disability that is potentially reversible if correct management of the disease is begun in the early phases. While the traditional therapeutic pyramid model has been in place for the past 25 years, evolving therapeutic strategies suggest that it is appropriate primarily for patients with benign synovitis, and an inverted pyramid is necessary to treat aggressive synovitis, control inflammation early and to prevent rapid joint destruction, disability and early death. Important principals underlying the remodeling of the therapeutic pyramid and evolving therapeutic strategies include: identifying patients with benign and aggressive synovitis: early control of inflammation to stabilize functional status at near normality; need for combination therapy in aggressive synovitis until a major breakthrough or ‘magic’ bullet becomes available; awareness that drugs that control inflammation in a more fundamental manner, such as disease-modifying anti-rheumatic drugs, are more effective in pain control and disability than non-steroidal anti-inflammatory drugs; and, most importantly, education of patients, primary and managing care physicians, health maintenance organizations, insurance companies, and government officials that two-thirds of the cost of RA lies in the complications of the disease and that providing resources for early aggressive therapy is a good investment for all. Successful treatment of rheumatoid arthritis is best accomplished by a coordinated team of a consultant rheumatologist and a managing primary care physician. Much like an early consultation with an oncologist when cancer is suspected, an early consultation with a rheumatologist can help separate benign and aggressive synovitis. If the latter, the rheumatologist can help identify important co-morbid conditions and recommend appropriate therapy. Follow-up programs can then be outlined to maintain control of inflammation at all times, utilize appropriate pharmacologic and non-pharmacologic physical and occupational therapy modalities for mechanical pain, and highlight potential toxicities to be monitored. This program, initiated early, will help prevent administration of toxic drugs to patients with benign synovitis. And, just as important for patients with aggressive synovitis, this strategy is designed to reduce the high incidence of morbidity and mortality and the costly episodes of hospitalizations and salvage surgery that can be so devastating to patients and their families.     

Advanced therapeutic strategies for HBV-related acute-on-chronic liver failure

BACKGROUND: Acute-on-chronic liver failure(ACLF) is increasingly recognized as a distinct clinical entity and is associated with a high short-term mortality. The most common cause of ACLF is chronic hepatitis B worldwide. Currently, there is no standardized approach for the management of ACLF and the efficacy and safety of therapeutic modalities are uncertain.DATA SOURCES: Pub Med and Web of Science were searched for English-language articles. The search criteria focused on clinical trials and observational studies on the treatment of patients with HBV-related ACLF.RESULTS: Therapeutic approaches for ACLF in patients with chronic hepatitis B included nucleos(t)ide analogues, artificial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation. All of these therapeutic approaches have shown the potential to improve liver function and increase patients' survival rate, but most of the studies were not randomized or controlled.CONCLUSION: Substantial challenges for the treatment of HBV-related ACLF remain and further basic research and randomized controlled clinical trials are needed.