Three Metachronous Osteosarcomas within 22 Years without Pulmonary Metastases: A Case Report and Review of the Literature

Introduction. We present the extremely rare case of a patient with three metachronous osteosarcomas within 22 years without evident pulmonary manifestation of disease 30 years after first diagnosis. Case Presentation. In 1983, a high-grade osteosarcoma of the left distal femur was diagnosed in an 18-year-old Caucasian male. He received rotationplasty accompanied by pre- and postoperative chemotherapy. Ten years later, an osteoblastic osteosarcoma occurred in TH12. En bloc resection and pre- and postoperative chemotherapy followed. In 2005, the patient developed another high-grade osteosarcoma in his right distal femur. Treatment included a wide resection and reconstruction with a tumour endoprosthesis as well as (neo)adjuvant chemotherapy. After the third tumour occurrence, cytogenetic and molecular genetic examinations (p53, rb1) were performed, showing a normal genetic pattern. Screening for metastases never showed clinical evidence of extraskeletal tumour manifestation. Discussion. In patients presenting metachronous osteosarcoma, identification of their lesions clonality (second primary tumour or metastases) could lead to a better understanding of tumour development and help to filter patients who need extended long-term followup due to a higher risk of late occurring sarcoma recurrence

Qualitätskultur. Ein Blick in die gelebte Praxis der Hochschulen. Beiträge zur 4. AQ Austria Jahrestagung 2016

Die Publikation zur AQ Austria Jahrestagung 2016 präsentiert in den einzelnen Beiträgen vielfältige Perspektiven, Ansätze, Beispiele und Erfahrungen mit Qualitätskultur und ermöglicht somit einen Blick in die gelebte Praxis der Qualitätskultur an Hochschulen. Die Frage, ob wir eine Qualitätskultur brauchen und was dafür oder dagegen spricht, [wird] in einleitenden Thesen [bearbeitet]. In fünf Foren wurden Kernfragen in Zusammenhang mit Zweck, Bedingungen und Ausgestaltung der Qualitätskultur diskutiert. Es geht u. a. um das Verständnis und den Stellenwert von Qualitätskultur ,das Wechselspiel mit internen und externen Rahmenbedingungen und um die Frage, wie Einstellungen und Werthaltungen der Mitarbeiterinnen und Mitarbeiter im Sinne einer Qualitätskultur gefördert werden können. Weitere Beiträge befassen sich mit dem Verhältnis von Qualitätskultur und externer Qualitätssicherung und damit, wie wirkungsvoll oder auch wirkungslos Qualitätskultur von Hochschulen eingeschätzt wird. (Autor

Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL

Altered membrane rigidity via enhanced endogenous cholesterol synthesis drives cancer cell resistance to destruxins

Destruxins, secondary metabolites of entomopathogenic fungi, exert a wide variety of interesting characteristics ranging from antiviral to anticancer effects. Although their mode of action was evaluated previously, the molecular mechanisms of resistance development are unknown. Hence, we have established destruxin-resistant sublines of HCT116 colon carcinoma cells by selection with the most prevalent derivatives, destruxin (dtx)A, dtxB and dtxE. Various cell biological and molecular techniques were applied to elucidate the regulatory mechanisms underlying these acquired and highly stable destruxin resistance phenotypes. Interestingly, well-known chemoresistance-mediating ABC efflux transporters were not the major players. Instead, in dtxA- and dtxB-resistant cells a hyper-activated mevalonate pathway was uncovered resulting in increased de-novo cholesterol synthesis rates and elevated levels of lanosterol, cholesterol as well as several oxysterol metabolites. Accordingly, inhibition of the mevalonate pathway at two different steps, using either statins or zoledronic acid, significantly reduced acquired but also intrinsic destruxin resistance. Vice versa, cholesterol supplementation protected destruxin-sensitive cells against their cytotoxic activity. Additionally, an increased cell membrane adhesiveness of dtxA-resistant as compared to parental cells was detected by atomic force microscopy. This was paralleled by a dramatically reduced ionophoric capacity of dtxA in resistant cells when cultured in absence but not in presence of statins. Summarizing, our results suggest a reduced ionophoric activity of destruxins due to cholesterol-mediated plasma membrane re-organization as molecular mechanism underlying acquired destruxin resistance in human colon cancer cells. Whether this mechanism might be valid also in other cell types and organisms exposed to destruxins e.g. as bio-insecticides needs to be evaluated

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients