Fever and neutropenia: still a challenge

Neutropenia is a double-edged sword. Fever may be the only manifestation of serious bacterial and fungal infection in neutropenic patients, and untreated occult infection can rapidly progress to septic shock and death.     

Alcohol liver disease: A review of current therapeutic approaches to achieve long-term abstinence

Harmful alcohol drinking may lead to significant damage on any organ or system of the body. Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe. In ALD, only alcohol abstinence was associated with a better long-term survival. Therefore, current effective therapeutic strategy should be oriented towards achieving alcohol abstinence or a significant reduction in alcohol consumption. Screening all primary care patients to detect those cases with alcohol abuse has been proposed as population-wide preventive intervention in primary care. It has been suggested that in patients with mild alcohol use disorder the best approach is brief intervention in the primary care setting with the ultimate goal being abstinence, whereas patients with moderate-to-severe alcohol use disorder must be referred to specialized care where detoxification and medical treatment of alcohol dependence must be undertaken.     

Acquired hemophilia: current diagnostic and therapeutic approaches

PURPOSE: Acquired haemophilia is a rare disease, occurring most frequently in elderly patients, caused by the development of autoantibodies against factor VIII. CURRENT KNOWLEDGE AND KEY POINTS: The disease is characterised by spontaneous haemorrhagic complications which can be fatal in 15-20% of the patients. However spontaneous remission is possible and in fact natural evolution and aetiology are still partly unknown. Acquired haemophilia may arise in association with auto-immune diseases, lymphoproliferative malignancy, pregnancy and also as a drug reaction. The aims of the treatment are first to treat the bleeding which is the most common cause of morbidity and mortality, and second to eliminate the inhibitor by immunosuppression. However no consensus exists for these two parts of the treatment. Bleeding may be controlled by prothrombin complex concentrates, recombinant factor VIIa or porcine factor VIII. The inhibitor is abolished in up 70% of patients using prednisone and cyclophosphamide. Other combinations of prednisone with azathioprine or with cyclophosphamide and vincristine or the use of high-dose immunoglobulin or double-filtration plasmapheresis have also proven effective in some patients. FUTURE AND PROJECTS: The rare occurrence of the disease, the associated with various diseases, and lack of consensus about treatment, require multicentric prospective studies.     

COPD: current therapeutic interventions and future approaches.

Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-alpha. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B(4) antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema. More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.     

Use of colony-stimulating factors for chemotherapy-associated neutropenia: review of current guidelines

Chemotherapy-associated neutropenia is often dose-limiting and may compromise treatment efficacy. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) are increasingly used to prevent febrile neutropenia (FN) or to increase dose-density. This review discusses recent changes in treatment guidelines for chemotherapy-associated neutropenia. Primary prophylactic use of CSFs is now recommended as a treatment option at an overall risk of FN of 20%, not taking into account cost-effectiveness. To estimate the risk of FN, patient-, disease-, and treatment-related factors predicting an adverse outcome of FN have been determined. Dose-dense chemotherapy has become feasible with the use of CSFs. However, clinical benefit has been shown only for specific chemotherapy regimens in breast cancer, small cell lung cancer (SCLC), and non-Hodgkin's lymphoma (NHL), for the latter particularly for patients above 60 years of age. Strategies are being developed to tailor the use of CSFs to patients with a high risk of adverse outcome of FN.     

Clinical review 158: Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer

One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progress despite surgery, radioiodine, and T(4) suppression of TSH. As knowledge of thyroid cancer biology improves, the potential exists to develop compounds targeted to treat thyroid cancers that do not respond to traditional therapy. Recently, the development of therapies targeted against specific molecular pathways involved in cancer progression has resulted in dramatic responses in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers. A number of compounds are currently being evaluated in clinical trials that alter pathways involved thyroid cancer, and several of these agents have been tested in thyroid cancer in vitro and in vivo. In this review we will discuss the mechanisms of action and preclinical/clinical data for several of these compounds that have the potential to play an important role in the management of thyroid cancer in the future.     

Erythropoietic agents in chemotherapy-induced anemia: a review of recent therapeutic progress, issues, and concerns

Erythropoietic agents are widely used to alleviate anemia in patients with cancer receiving chemotherapy. Over the past decade, the efficacy and safety of these agents in improving hemoglobin levels and reducing transfusion requirements in an oncology setting has been demonstrated in a number of clinical trials. The overall risk-benefit relationship of treatment with erythropoietic agents is favorable, and these agents represent a tremendous advance in anemia management. This review discusses prevalent issues and addresses key questions concerning the use of erythropoietic agents for the treatment of chemotherapy-induced anemia.     

Lung cancer: A review of current therapeutic modalities

This article describes the current approach to the systematic management of both small cell and non-small cell lung cancer (NSCLC). The treatment of stages I, II, and IIIa NSCLC is surgical resection. Although adjuvant chemotherapy in stage I disease offers no survival benefit, the role of adjuvant chemotherapy in stage II and IIIa NSCLC remains controversial. Results of pilot studies using neoadjuvant chemotherapy in stage IIIa NSCLC are encouraging and data from ongoing randomized trials are awaited with interest. For locally advanced NSCLC, chest irradiation remains the standard of care. However, the addition of systemic chemotherapy holds promise. The impact of cisplatin-based regimens on overall survival in stage IV NSCLC remains disappointing. The introduction of newer agents, such as 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), a topoisomerase-I inhibitor, has shown early favorable results.Chemotherapy is the most important therapeutic modality in the management of small cell lung cancer because of this cancer's propensity for early dissemination. In limited stage small cell lung cancer, chest radiotherapy, particularly if used early and concurrently with chemotherapy, may improve survival, but at the expense of increased toxicity. The role of prophylactic brain irradiation remains controversial in limited-stage disease. Chemotherapy is also the most important treatment modality in extensive-stage disease, but its role is only palliative. Radiotherapy is reserved primarily for disease-related complications in patients in whom chemotherapy has failed.     

Trials and tribulations associated with angina and traditional therapeutic approaches

Ischemic heart disease is the foremost cause of death in the United States and the developed countries. Stable angina is the initial manifestation of ischemic heart disease in one half of the patients and becomes a recurrent symptom in survivors of myocardial infarction (MI) and other forms of acute coronary syndromes (ACS). There are multiple therapeutic modalities currently available for treatment of anginal symptoms in patients with stable CAD. These include anti‐anginal drugs and myocardial revascularization procedures such as coronary artery bypass graft surgery (CABGS), percutaneous transluminal coronary angioplasty (PTCA) and percutaneous coronary intervention (PCI). Anti‐anginal drug therapy is based on treatment with nitrates, beta blockers, and calcium channel blockers. A newly approved antianginal drug, ranolazine, is undergoing phase III evaluation. Not infrequently, combination therapy is often necessary for adequate symptom control in some patients with stable angina. Howerever, there has not been a systematic evaluation of individual or combination antianginal grug therapy on hard clinical end points in patients with stable angina. Most revascularization trials that have evaluated treatment with CABGS, PTCA, or PCI in patients with chronic CAD and stable angina have not shown significant improvement in survival or decreased incidence of non‐fatal MI compared to medical treatment. In the CABGS trials, various post‐hoc analyses have identified several smaller subgroups at high‐risk in whom CABGS might improve clinical outcomes. However, there are conflicting findings in different reports and these findings are futher compromised due to the heterogeneous groups of patients in these trials. Moreover, no prospective randomized controlled trial (RCT) has confirmed an advantage of CABGS, compared to medical treatment, in reduction of hard clinical outcomes in any of the high‐risk subgroups. Based on the available data, it appears reasonable to conclude that for most patients (except perhaps in those with presence of left main disease > 50% stenosis) there is no apparent survival benefit of CABGS compared to medical therapy in stable CAD patients with angina. Although these trial have reported better symptom control associated with the revascularization intervention in most patients, this has not been adequately compared using modern medical therapies. Available data from recent studies also suggest treatment with an angiotensin converting enzyme inhibitor (ACEI), a statin and a regular exercise regimen in patients with stable CAD and angina pectoris. Copyright © 2007 Wiley Periodicals, Inc.     

Problems with the right ventricular outflow tract: a review of morphologic features and current therapeutic options

Repair of complex malformations that necessitate restoration of continuity between the right ventricle and the pulmonary arteries can now safely be performed with low morbidity and mortality. Major concerns still remain on the long-term outlook for these patients, and about the durability of the different prostheses used to restore that continuity, whether during initial correction or at the time of reintervention for failure of the conduit or pulmonary regurgitation. In this review, we discuss the salient morphologic features of the right ventricular outflow tract, and then focus on the indications for early and late intervention, current therapeutic options, and outcomes.     

Familial severe congenital neutropenia associated with infantile osteoporosis: a new entity

A new entity manifested by severe congenital neutropenia associated with osteoporosis and recurrent bone fracture is described in a family. A possible role for a new recognized cytokine system involved in bone remodeling, the osteoprotegerin/receptor activator of nuclear factor-kappa B ligand, is suggested.     

The effect of lithium carbonate on chemotherapy-induced neutropenia and thrombocytopenia

Lithium carbonate ameliorates neutropenia associated with cancer chemotherapy. The effect of lithium on platelet suppression has not, however, been well established. In the present study, five patients with ovarian carcinoma received daily lithium during alternate cycles of treatment with hexamethylmelamine, cyclophosphamide, adriamycin, and cis-platinum. Analysis of myelosuppression was performed on 24 paired consecutive cycles given at identical doses, one with and one without lithium. During lithium cycles, nadir leukocyte, neutrophil, and platelet counts were significantly higher (P less than 0.01, less than 0.01, less than 0.05 respectively) and the interval between treatments was shorter (P less than 0.01). One patient who has received 11 cycles of chemotherapy continues to receive 100% doses owing to the beneficial effect of lithium on chemotherapy-induced thrombocytopenia. Lithium was poorly tolerated by some patients because of either tremor or nausea and vomiting, in spite of nontoxic serum lithium levels. The amelioration of drug-induced platelet suppression as well as neutrophil suppression noted in this study suggests that lithium's effect on hematopoiesis is not limited to stimulation of neutrophil production. The ability of lithium to decrease chemotherapy-induced myelosuppression suggests that lithium administration may facilitate escalation of chemotherapy doses in selected patients.     

Delayed-onset neutropenia associated with rituximab therapy

The characteristics of severe neutropenia with a delayed onset following administration of rituximab have been evaluated in 53 consecutively treated patients. All but one patient received rituximab for the treatment of non-Hodgkin's lymphoma. Eight episodes of grade 4 neutropenia were detected between 1 and 5 months after rituximab, when administered alone on five occasions, and on three occasions in combination with chemotherapy, where neutrophil counts had recovered prior to the development of neutropenia. In three episodes, the patients presented with sepsis. Development of neutropenia did not correlate with either the presence of detectable disease or the administration of further treatment. Neutropenia was associated with selective depletion of neutrophil precursors in all but one episode, where it was associated with generalized bone marrow hypoplasia. All episodes developed after a period of either normal or mildly depressed neutrophil counts following treatment with rituximab, and persisted for between several days and several months, before undergoing spontaneous recovery in four instances, and after administration of filgrastim in the remainder. Episodes of neutropenia were associated with disordered immune status manifested by lymphopenia and hypogammaglobulinaemia, raising the possibility that either disturbance of the balance of lymphocyte subsets or an immune dyscrasia induced by rituximab resulted in the development of this type of neutropenia.