A Mitogen-activated protein kinase controls differentiation of bloodstream forms of Trypanosoma brucei

African trypanosomes undergo differentiation in order to adapt to the mammalian host and the tsetse fly vector. To characterize the role of a mitogen-activated protein (MAP) kinase homologue, TbMAPK5, in the differentiation of Trypanosoma brucei, we constructed a knockout in procyclic (insect) forms from a differentiation-competent (pleomorphic) stock. Two independent knockout clones proliferated normally in culture and were not essential for other life cycle stages in the fly. They were also able to infect immunosuppressed mice, but the peak parasitemia was 16-fold lower than that of the wild type. Differentiation of the proliferating long slender to the nonproliferating short stumpy bloodstream form is triggered by an autocrine factor, stumpy induction factor (SIF). The knockout differentiated prematurely in mice and in culture, suggestive of increased sensitivity to SIF. In contrast, a null mutant of a cell line refractory to SIF was able to proliferate normally. The differentiation phenotype was partially rescued by complementation with wild-type TbMAPK5 but exacerbated by introduction of a nonactivatable mutant form. Our results indicate a regulatory function for TbMAPK5 in the differentiation of bloodstream forms of T. brucei that might be exploitable as a target for chemotherapy against human sleeping sickness.

Exophytic mass of the gingiva as the first manifestation of metastatic pulmonary adenocarcinoma

BACKGROUND: Metastasis of a malignant tumor to the oral cavity is rare, but it can be the first manifestation of a primary tumor. METHODS: The clinicopathologic features of a gingival metastasis originating from lung adenocarcinoma in a female patient are described. A 57-year-old woman showed a rapidly growing, painless, exophytic mass in the left mandibular gingiva. The whole lesion was excised, and histologic and immunohistochemical analyses were performed. RESULTS: The histopathologic sections showed a proliferation of poorly differentiated spindle and pleomorphic cells. Because the differentiation between carcinoma and sarcoma of spindle cell tumors was difficult, additional immunohistochemical evaluation was performed. The intraoral healing after tumor removal was uneventful. The discrepancy between the histopathologic results and the clinical findings led to a thorough examination by the patient's physician. Finally, a biopsy of the lungs confirmed a poorly differentiated adenocarcinoma with multiple metastases, including the oral cavity. CONCLUSIONS: An exophytic lesion on the gingiva can be the first sign of metastatic adenocarcinoma to the oral mucosa. This case emphasizes that even apparently benign-looking gingival lesions in anamnestically healthy patients need to be examined histopathologically.

Frequent ventricular tachycardias: antiarrhythmic drug treatment or catheter ablation?

Antiarrhythmic drugs are used in at least 50% of patients who received an implantable cardioverter defibrillator (ICD). The potential indications for antiarrhythmic drug treatments in patients with an ICD are generally the following: reduction of the number of ventricular tachycardias (VTs) or episodes of ventricular fibrillation and therefore reduction of the number of ICD therapies, most importantly, the number of disabling ICD shocks. Accordingly, the quality of life should be improved and the battery life of the ICD extended. Moreover, antiarrhythmic drugs have the potential to increase the tachycardia cycle length to allow termination of VTs by antitachycardia pacing and reduction of the number of syncopes. In addition, supraventricular arrhythmias can be prevented or their rate controlled. Recently published or reported trials have shown the efficacy of amiodarone, sotalol and azimilide to significantly reduce the number of appropriate and inappropriate ICD shocks in patients with structural heart disease. However, the use of antiarrhythmic drugs may also have adverse effects: an increase in the defibrillation threshold, an excessive increase in the VT cycle length leading to detection failure. In this situation and when antiarrhythmic drugs are ineffective or have to be stopped because of serious side effects, catheter ablation of both monomorphic stable and pleomorphic and/or unstable VTs using modern electroanatomic mapping systems should be considered. The choice of antiarrhythmic drug treatment and the need for catheter ablation in ICD patients with frequent VTs should be individually tailored to specific clinical and electrophysiological features including the frequency, the rate, and the clinical presentation of the ventricular arrhythmia. Although VT mapping and ablation is becoming increasingly practical and efficacious, ablation of VT is mostly done as an adjunctive therapy in patients with structural heart disease and ICD experiencing multiple shocks, because the recurrence and especially the occurrence of "new" VTs after primarily successful ablation with time and disease progression have precluded a widespread use of catheter ablation as primary treatment.

Current management options for liposarcoma and challenges for the future

Liposarcoma (LS) represents one of the most common soft tissue sarcomas. There are three major subtypes, namely, well/dedifferentiated, myxoid/round cell and pleomorphic LS. In general, LS is known to be a relatively chemo-resistant sarcoma subtype with the exception of the myxoid variant. Conventional chemotherapy with doxorubicin and ifosfamide represents the mainstay of systemic treatment in the first line. Other active cytotoxic agents include gemcitabine and docetaxel and the marine-derived compounds trabectedin. Recent progress in molecular diagnostics of each single LS subtype has improved the knowledge of the molecular characteristics and has led to two recent treatment targets: the amplification of mouse double minute 2 homolog and cyclin-dependent kinase-4 in well- and dedifferentiated LS. Thus far, only early-phase trials are reported and no new drugs have been introduced in daily clinical practice. The focus of this review is on current systemic treatment options, including novel strategies.

Polymorphous oligodendroglioma of Zülch revisited: a genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation.

A polymorphous variant of oligodendroglioma was described by K.J. Zülch half a century ago, and is only very sporadically referred to in the subsequent literature. In particular, no comprehensive analysis with respect to clinical or genetic features of these tumors is available. From a current perspective, the term polymorphous oligodendroglioma (pO) may appear as contradictory in terms, as nuclear monotony is a histomorphological hallmark of oligodendrogliomas. For the purpose of this study, we defined pO as diffusely infiltrating gliomas felt to be of oligodendroglial rather than astrocytic differentiation and characterized by the presence of multinucleate tumor giant cells and/or nuclear pleomorphism. In a total of nine patients, we identified tumors consistent with this working definition. All tumors were high-grade. We characterized these with respect to clinical, histomorphological and genetic features. Despite clinical and genetic heterogeneity, we identified a subset of tumors of bona fide oligodendroglial differentiation as characterized by combined loss of heterozygosity of chromosome arms 1p and 19q (LOH 1p19q). Those tumors that lacked LOH 1p19q showed a high frequency of IDH1 mutations and loss of alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) immunoreactivity, indicating a possible phenotypic convergence of true oligodendrogliomas and gliomas of the alternative lengthening of telomeres (ALT) pathway. p53 alterations were common irrespective of the 1p19q status. Histomorphologically, the tumors featured interspersed bizarre multinucleate giant tumor cells, while the background population varied from monotonous to significantly pleomorphic. Our findings indicate, that a rare polymorphous - or "giant cell" - variant of oligodendroglioma does indeed exist.