High-Grade Osteosarcoma of the Foot: Presentation, Treatment, Prognostic Factors, and Outcome of 23 Cooperative Osteosarcoma Study Group COSS Patients

Osteosarcoma of the foot is a very rare presentation of a rare tumor entity. In a retrospective analysis, we investigated tumor- and treatment-related variables and outcome of patients registered in the Cooperative Osteosarcoma Study Group (COSS) database between January 1980 and April 2016 who suffered from primary high-grade osteosarcoma of the foot. Among the 23 eligible patients, median age was 32 years (range: 6-58 years), 10 were female, and 13 were male. The tarsus was the most commonly affected site (n=16). Three patients had primary metastases. All patients were operated: 5 underwent primary surgery and 18 received surgery following preoperative chemotherapy. In 21 of the 23 patients, complete surgical remission was achieved. In 4 of 17 patients, a poor response to neoadjuvant chemotherapy was observed in the resected primary tumors. Median follow-up was 4.2 years (range: 0.4-18.5). At the last follow-up, 15 of the 23 patients were alive and 8 had died. Five-year overall and event-free survival estimates were 64% (standard error (SE) 12%) and 54% (SE 13%), which is similar to that observed for osteosarcoma in general. Event-free and overall survival correlated with primary metastatic status and completeness of surgery. Our findings show that high-grade osteosarcoma in the foot has a similar outcome as osteosarcoma of other sites

Bevacizumab in temozolomide refractory high-grade gliomas: single-centre experience and review of the literature

BACKGROUND: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience. METHODS: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany. RESULTS: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients. CONCLUSIONS: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV

Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide

A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease

A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3

BACKGROUND: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide - version 3 - (CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. METHODS: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. RESULTS: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. CONCLUSIONS: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM

Innovations and applications of the VERA quality control

Quality control (QC) is seen today as an important scientific field to increase the value of observational data. Whereas most QC methods are linked to atmospheric modeling (being part of the data assimilation procedure), in this paper the focus is on the application of a model independent QC method based on data self consistency recently published: VERA-QC. A special challenge is the QC of data in complex terrain which requires special treatment in terms of data selection and data transformation. In this context, some special VERA-QC modules such as the consideration of significant elevation differences of adjacent stations or the consideration of transformed temperature values will be discussed. The system detects gross errors as well as biases and offers objective correction proposals (deviations) for each observation. The essential gross error detection is not only based on the statistical behavior of station specific deviations, but also on the rate of cost function reduction. Beside a two dimensional application, higher dimensionalities may also be chosen, for instance including the time coordinate. Applications and results are discussed for pressure, temperature as well as for precipitation data which needs, however, a very dense observation network. Real time application of VERA-QC allows the production of high quality fields of meteorological parameters, which can be used, e.g. for nowcasting as well as for model unbiased validation of prognostic models

Seltene Variante eines low-grade Osteosarkoms des Sinus sphenoidalis

Einleitung: Osteosarkome im HNO-Bereich sind eine Seltenheit. Von 2-3 Fällen pro 1 Mio. Einwohner pro Jahr sind weniger als 7% im kraniofazialen Bereich lokalisiert. Ein Auftreten im Bereich der Schädelbasis ist eine Rarität. In unserer Poliklinik stellte sich eine Patientin mit gelegentlicher Epistaxis nasi links als einzigem Symptom vor. Methoden: Endonasal zeigte sich eine kugelige Raumforderung an der Concha nasalis media links. Im MRT mit CISS-Sequenz war diese tumorsuspekt im Sinne eines Plattenepithelcarcinoms, da sie das Os sphenoidale, den linken Processus pterygoideus und die Seitenwand des Sinus sphenoidalis links destruierte. Da der Prozess kaum Größenprogress zeigte, wurde von einem niedrig malignen Tumor ausgegangen. Ergebnisse: Eine initiale Biopsie ergab einen riesenzellhaltigen, myxoiden Tumor ohne Malignität. Bei klinisch suspektem Bild mit ossärer Destruktion wurde das Gewebe abgetragen, histologisch zeigte es einen Chondromyxoidfibrom-artigen Tumor mit irregulärer Osteoidbildung. In der Integration mit der Bildgebung bei lokaler Aggressivität wurde der Tumor als seltene Variante eines niedrig malignen Chondromyxoidfibrom-artigen Osteosarkoms eingestuft. Nach Ausschluss von Metastasen erfolgte gemäß Beschluss der interdisziplinären Tumorkonferenz die endonasale Nachresektion in der Keilbeinhöhle links (R0). Die Patientin war in der regelmäßigen Nachsorge beschwerdefrei. Schlussfolgerungen: Da kraniofaziale Osteosarkome extrem seltene Tumore sind, gibt es kein standardisiertes therapeutisches Vorgehen. Literaturdaten legen nahe, dass diese grundsätzlich eine benignere Biologie als konventionelle Osteosarkome haben. Ein möglicher Nutzen für das krankheitsfreie und das Gesamtüberleben durch eine adjuvante Radiatio oder Chemotherapie ist nicht gesichert.Der Erstautor gibt keinen Interessenkonflikt an

Therapy for recurrent high-grade gliomas: results of a prospective multicenter study on health-related quality of life

OBJECTIVE: To assess the impact of therapy on patients' health-related quality of life (HRQoL) in recurrent high-grade glioma (HGG) in an unselected cohort. METHODS: In this prospective multicenter study, we analyzed European Organization for Research and Treatment of Cancer Quality of Life core questionnaire and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Brain Neoplasm module questionnaires of 92 patients within 1 year after diagnosis of tumor recurrence of a HGG and respective treatment. We evaluated the influence of re-radiation, second- and third-line chemotherapies, and number of recurrent surgeries on summary scores for functioning, symptoms, and total score as well as on subscores for functioning and neurologic symptoms using multivariate mixed models and descriptive statistics. RESULTS: After we adjusted for Karnofsky Performance Score and age, different recurrent therapies did not significantly impact HRQoL. Neither re-radiation nor recurrent surgery significantly influenced HRQoL (total score, P = 0.66; P = 0.64). Patients receiving second-line chemotherapy showed moderately better physical and role functioning as well as less motor dysfunction than patients receiving third-line chemotherapy. When we compared HRQoL after second-line chemotherapies, patients receiving intensified temozolomide dosages demonstrated a moderately better outcome for cognitive functioning and less communication deficits (P = 0.055) than patients treated with bevacizumab. Regarding number of recurrent surgeries, we found stable HRQoL scores until second recurrent surgery, whereas after third recurrent surgery HRQoL decreased. CONCLUSIONS: Our results from an unselected cohort of recurrent HGGs show that the currently available treatment options have no negative impact on HRQoL. Thus, treatment decisions can be made individually, without fear of jeopardizing HRQoL for better survival. Only, the third recurrent surgery remains a very individual decision even in younger patients with high Karnofsky Performance Score