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Menorrhagia, mechanisms and targeted therapies.

PURPOSE OF REVIEW: Efficient treatment options for the increasing complaint of heavy menstrual bleeding are required to avoid the morbidity associated with major surgery. This review summarizes recent developments in the nonsurgical approach to treating menorrhagia. RECENT FINDINGS: Even though the mechanism of menstruation has still not been fully elucidated, there have been promising developments in the attempt to reduce menstrual blood loss. The levonorgestrel-releasing intrauterine system has proven very efficient, and there is a frameless device suitable for enlarged uterine cavities. The side effect of breakthrough bleeding has been the main reason for discontinuing treatment. Recent studies have investigated options of concomitant therapy with antiprogestogens to counter this effect. Another group of novel compounds are selective progesterone receptor modulators, which thus far have been shown to reduce menstrual bleeding without the unwanted effect of unscheduled bleeding episodes. SUMMARY: As menorrhagia is largely a subjective complaint, it is important for successful therapy to be based on an informed patient's choice. Currently, lack of evidence-based practice, poor compliance and unpleasant side effects limit the success of medical therapies contributing to the amount of major surgery performed for this indication. If concomitant therapies succeeded in minimizing the episodes of breakthrough bleeding with the levonorgestrel-releasing intrauterine system, its recommendation as a first choice treatment may be confounded. Further research is needed into efficiency and safety of selective progesterone receptor modulators, which appear to have great potential in reducing menstrual blood loss.

Contraceptive Agents, Female↗

Podocyte injury and targeting therapy: an update.

PURPOSE OF REVIEW: Podocyte injury is a central event in the development of glomerulosclerosis. This review highlights contributions from the past year to our understanding of mechanisms of podocyte injury and implications for potential treatment strategies of glomerular disease. RECENT FINDINGS: Rearrangement of the actin cytoskeleton, the backbone linking the slit diaphragm, apical domain and sole plate, serves as a common denominator during foot process effacement. Reports on the role of synaptopodin and CDK5 on actin dynamics as well as cathepsin L and B7.1 in subsequent cell migration have expanded our understanding of the podocyte response to injury. Mounting evidence supports an expanding role of the slit diaphragm in signal transduction to mediate downstream cellular responses, including prosurvival effects of the integral proteins nephrin and CD2AP. The discovery that TRPC6 localizes to the slit diaphragm and identification of specific mutations of the transport channel in kindreds of familial focal segmental glomerulosclerosis implicate a causal role for aberrant calcium signaling in podocyte injury. Disruption of the dystroglycan complex, which anchors the podocyte to the underlying basement membrane, in states of foot process effacement may have implications for the recent finding of viable podocytes in the urine in glomerular disease. SUMMARY: The resurgence of research in podocyte biology over the past decade underscores the importance of this unique cell in preserving glomerular structure and function. A greater understanding of the complex signaling mechanisms governing podocyte biology in health and disease will ultimately lead to novel therapeutic avenues for treating disorders of the podocyte.

Angiotensin-Converting Enzyme Inhibitors↗

Possibilities for tailored and targeted therapy in paediatric acute myeloid leukaemia.

The clinical outcome of acute myeloid leukaemia (AML) in children has improved considerably using intensive chemotherapy and/or stem cell transplantation. This leads to cure in 50-70% of patients, and also results in significant morbidity and mortality. Hence, we need other ways to improve the cure rate. This review discusses possibilities for tailored therapy, reviewing in vitro cellular drug sensitivity data. The results provide suggestions regarding the adaptation of clinical protocols in certain AML subgroups, although further clinical studies will show whether this is effective. Secondly, we review type 1 genetic abnormalities (such as receptor tyrosine kinase mutations) that result in enhanced survival and proliferation of leukaemic cells, which can be detected in approximately 50% of paediatric AML samples, and are non-randomly associated with French-American-British type and cytogenetic subgroups. FLT3 internal tandem duplication is associated with poor clinical outcome, and may be used for risk-group stratification. The first results with small molecule inhibitors in adult AML do not suggest their use in children as yet. International collaboration is needed to further improve outcome by developing treatment protocols for subgroups of paediatric AML.

Acute Disease↗

Towards targeted therapy for infant acute lymphoblastic leukaemia.

Despite the greatly improved treatment regimes for childhood acute lymphoblastic leukaemia (ALL) in general, resulting in long-term survival in approximately 80% of cases, current therapies still fail in >50% of ALL cases diagnosed within the first year of life (i.e. in infants). Therefore, more adequate treatment strategies are urgently needed to also improve the prognosis for these very young patients with ALL. Here we review the current acquaintance with the biology of infant ALL and describe how this knowledge may lead to innovative therapeutic approaches.

Age of Onset↗

Epidermal growth factor receptor targeted therapy with gefitinib in locally advanced and metastatic primary lung adenocarcinoma.

OBJECTIVE: To describe the efficacy of monotherapy with the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib in patients with locally advanced and metastatic primary lung adenocarcinoma. METHODS: A retrospective analysis was undertaken of patients who had locally advanced or metastatic lung adenocarcinoma treated with gefitinib 250 mg orally once daily until disease progression. All patients had either been previously treated with systemic cytotoxic chemotherapy and/or radiotherapy or had declined chemotherapy or were medically not fit for cytotoxic chemotherapy. RESULTS: A total of 23 patients (13 men) (15 never smokers) with a median age of 51 years (range 35-79 years) received gefitinib monotherapy. Disease control occurred in 14 patients (61%); there was a reduction in the size of the primary and/or metastatic tumours (partial response (PR)) in 11 patients (48%), and 3 patients (13%) had stable disease. The response rate was significantly higher in those who had never smoked (10 of 15 (67%)) compared with that of smokers (1 of 8 (13%)) (odds ratio (95% confidence interval), 14.0 (1.33-147.43) P=0.027). In total, 11 of 18 patients (61%) with a WHO performance status 1 or 2 showed a PR, whereas none with a performance status 3 or 4 responded (P=0.037). Response was not affected by the patient's age, gender, disease stage, prior chemotherapy treatment, interval between diagnosis and commencement of gefitinib or the development of skin toxicity. The median time to symptom improvement was 1.5 (range 0.5-6) weeks. The median progression-free survival time was: 60 (range 15-138) weeks in patients with PR and 34 (range 7-38) weeks in patients with stable disease (P=0.368). CONCLUSION: When given alone, gefitinib showed significant antitumour activity in patients with locally advanced and metastatic primary lung adenocarcinoma. An objective response was observed more frequently in never smokers and exclusively in patients with good performance status.

Adenocarcinoma↗

Tumor angiogenesis and molecular target therapy in ovarian carcinomas.

Growth of solid tumors depends on angiogenesis, the process by which new blood vessels develop from the endothelium of a pre-existing vasculature. Tumors promote angiogenesis by secreting various angiogeneic factors, and newly formed blood vessels induce tumor cell proliferation and invasiveness. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. The degree of angiogenesis of ovarian carcinomas may directly influence the clinical course of the disease. Although a growing body of evidence indicates that angiogenic intensity may play a prognostic role in gynecological malignancies including ovarian carcinomas, the related biological mechanisms remain to be further elucidated. In this review, we describe current knowledge pertaining to mechanisms and regulation of angiogenesis in ovarian carcinomas with special reference to our recent research results.

Angiogenesis Inducing Agents↗

The 2005 International Symposium on Advances in Targeted Therapies: what have we learned in the 2000s and where are we going?

This essay summarises a personal perspective on where we have got to in the five years since the turn of the last century. The focus is on advances in knowledge of antitumour necrosis factor (anti-TNF) therapy of rheumatoid arthritis and other chronic immune-inflammatory rheumatic diseases. The accumulating knowledge is clarifying the scope and limitations of efficacy, safety, and durability of these agents. It is defining the unmet needs of patients and communities worldwide for the future. The call is for progress in providing more cost-effective advances in therapeutics that not only interrupt the disease process long term but also reverse the anatomical and functional consequences of disease and the impairment in quality of life.

Antirheumatic Agents↗