In-vitro und in-vivo Untersuchungen mit dem Antiemetikum Aprepitant

Aprepitant, ein Neurokinin-1-Rezeptorantagonist, wird zur Therapie des Zytostatika induzierten Erbrechen eingesetzt. Besonders hohe Wirksamkeit erzielt man gegen die verzögerte Emesis. Für Patienten die eine hoch bis moderat emetogene Chemotherapie erhalten ist eine Kombinationstherapie aus Aprepitant, einem 5-HT3-Antagonisten und einem Glucocorticoid Methode der Wahl. Während der Therapie mit Aprepitant wird CYP3A4 gehemmt, nach Beendigung der Therapie wird vorübergehend eine Induktion von CYP3A4 und CYP2C9 erzeugt. Für den Metabolismus von Aprepitant spielt CYP3A4 die Hauptrolle. Untersucht wurden Plasmaproben die von Patienten stammen die Aprepitant erhielten. Die Proben wurden nach Festphasenextraktion mittels HPLC analysiert. Chromatographiert wurde mit einem binären Gradienten. Der erste Eluent enthielt 70% (V/V) Methanol, der zweite 95% (V/V). Als detektiert wurde mit einem Diodenarraydetektor bei 220 nm. Anhand der erhaltenen Daten wurde eine Plasmaspiegelkurve erstellt. In einem in vitro Versuch wurde Aprepitant mit dem Isoenzym CYP3A4 über eine Laufzeit von 6 Stunden behandelt um die Abbaugeschwindigkeit und die entstehenden Metaboliten zu quantifizieren. Vor der Analyse wurde eine Proteinfällung gemacht um die Enzymaktivität zu beenden. Als Analysenmethode wurde wieder eine HPLC gewählt, ein UV/Vis-Detektor wurde verwendet um bei 220 nm die Spektren aufzunehmen

Survival prediction using temporal muscle thickness measurements on cranial magnetic resonance images in patients with newly diagnosed brain metastases.

OBJECTIVES: To evaluate the prognostic relevance of temporal muscle thickness (TMT) in brain metastasis patients. METHODS: We retrospectively analysed TMT on magnetic resonance (MR) images at diagnosis of brain metastasis in two independent cohorts of 188 breast cancer (BC) and 247 non-small cell lung cancer (NSCLC) patients (overall: 435 patients). RESULTS: Survival analysis using a Cox regression model showed a reduced risk of death by 19% with every additional millimetre of baseline TMT in the BC cohort and by 24% in the NSCLC cohort. Multivariate analysis included TMT and diagnosis-specific graded prognostic assessment (DS-GPA) as covariates in the BC cohort (TMT: HR 0.791/CI [0.703-0.889]/p < 0.001; DS-GPA: HR 1.433/CI [1.160-1.771]/p = 0.001), and TMT, gender and DS-GPA in the NSCLC cohort (TMT: HR 0.710/CI [0.646-0.780]/p < 0.001; gender: HR 0.516/CI [0.387-0.687]/p < 0.001; DS-GPA: HR 1.205/CI [1.018-1.426]/p = 0.030). CONCLUSION: TMT is easily and reproducibly assessable on routine MR images and is an independent predictor of survival in patients with newly diagnosed brain metastasis from BC and NSCLC. TMT may help to better define frail patient populations and thus facilitate patient selection for therapeutic measures or clinical trials. Further prospective studies are needed to correlate TMT with other clinical frailty parameters of patients. KEY POINTS: • TMT has an independent prognostic relevance in brain metastasis patients. • It is an easily and reproducibly parameter assessable on routine cranial MRI. • This parameter may aid in patient selection and stratification in clinical trials. • TMT may serve as surrogate marker for sarcopenia

Docetaxel plus cetuximab biweekly is an active regimen for the first-line treatment of patients with recurrent/metastatic head and neck cancer

For patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (SCCHN) limited therapeutic options exist. Only a subset of patients is suitable for combination chemotherapy regimens. Biweekly docetaxel plus cetuximab might be an alternative option. Thus, we performed this retrospective analysis in unselected patients in order to investigate the efficacy and safety of this regimen. Thirty-one patients receiving off protocol docetaxel (50mg/m2) plus cetuximab (500mg/m2) biweekly were included. Data collection included baseline demographic, response rate (ORR), disease control rate (DCR), overall survival (OS), progression free survival (PFS) as well as toxicity. OS and PFS were 8.3 months (95% CI 4.811.8) and 4.0 months (95% CI 1.07.0), respectively. Three (9.7%) patients achieved a complete response and one patient (3.2%) a partial response. The DCR was 41.9% and we observed an ORR of 12.9%. The one-year survival rate was 25.8%. The therapy was well tolerated and the most common grade 3/4 adverse events were neutropenia (19.4%), hypomagnesaemia (12.9%) and acne-like rash (9.7%). Biweekly cetuximab/docetaxel is an effective regimen and well tolerated in R/M SCCHN patients not suitable for platinum doublet treatment. Further evaluation of this regimen in prospective clinical trials is warranted.(VLID)468855

Survival prediction using temporal muscle thickness measurements on cranial magnetic resonance images in patients with newly diagnosed brain metastases

Objectives To evaluate the prognostic relevance of temporal muscle thickness (TMT) in brain metastasis patients. Methods We retrospectively analysed TMT on magnetic resonance (MR) images at diagnosis of brain metastasis in two independent cohorts of 188 breast cancer (BC) and 247 non-small cell lung cancer (NSCLC) patients (overall: 435 patients). Results Survival analysis using a Cox regression model showed a reduced risk of death by 19% with every additional millimetre of baseline TMT in the BC cohort and by 24% in the NSCLC cohort. Multivariate analysis included TMT and diagnosis-specific graded prognostic assessment (DS-GPA) as covariates in the BC cohort (TMT: HR 0.791/CI [0.7030.889]/p<0.001; DS-GPA: HR 1.433/CI [1.1601.771]/p=0.001), and TMT, gender and DS-GPA in the NSCLC cohort (TMT: HR 0.710/CI [0.6460.780]/p<0.001; gender: HR 0.516/CI [0.3870.687]/p<0.001; DS-GPA: HR 1.205/CI [1.0181.426]/p=0.030). Conclusion TMT is easily and reproducibly assessable on routine MR images and is an independent predictor of survival in patients with newly diagnosed brain metastasis from BC and NSCLC. TMT may help to better define frail patient populations and thus facilitate patient selection for therapeutic measures or clinical trials. Further prospective studies are needed to correlate TMT with other clinical frailty parameters of patients. Key Points TMT has an independent prognostic relevance in brain metastasis patients. It is an easily and reproducibly parameter assessable on routine cranial MRI. This parameter may aid in patient selection and stratification in clinical trials. TMT may serve as surrogate marker for sarcopenia.(VLID)355034

Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds : a randomized Phase 1 trial (MARSYAS I)

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5106 PBMCs and a high-dose group (B) receiving an equivalent of 25106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.(VLID)460739