ABSTRACT:Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT. We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multikinase inhibitor dasatinib in adult patients with CBF-AML. Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg daily on days 8 to 21 in induction, and on days 6 to 28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg daily. Primary end point was event-free survival (EFS). Secondary end points included overall survival, relapse-free survival, and cumulative incidence of relapse. A total of 202 patients were randomly assigned to the standard arm (n = 102) and to the dasatinib arm (n = 100). Median age was 49 years (range, 18-77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); and 58 (28.7%) patients had a KIT comutation. There was no statistically significant difference in EFS (hazard ratio, 0.92; 95% confidence interval, 0.63-1.33; P = .66) or secondary end points between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%). In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.ClinicalTrials.gov as NCT02013648.
BackgroundFree light chain kappa (FLCκ) have emerged as a sensitive biomarker to detect intrathecal immunoglobulin synthesis. To evaluate the role of FLCκ in routine cerebrospinal fluid laboratory diagnostics we conducted a prospective nationwide real world diagnostic study for evaluating the integration of kappa free light chain into clinical routine (ORCAS - prospective multicenter validation of a new laboratory workflow integrating the free light chains kappa in CSF analysis).ObjectivesTo determine whether testing for intrathecal synthesis of FLCκ in cerebrospinal fluid (CSF) can predict intrathecal immunoglobulin (Ig) synthesis of total IgG, IgA, IgM or CSF-specific oligoclonal bands (OCB) with high sensitivity.Materials & MethodsFLCκ were measured in 1052 paired CSF and serum samples according to local laboratory standards in six laboratories in Germany. Sensitivity and negative predictive value (NPV) of intrathecal FLCκ synthesis as first line detection of intrathecal Ig synthesis were assessed.ResultsOf the 1052 samples, 624 fulfilled the inclusion criteria. The intrathecal fraction of FLCκ predicted intrathecal Ig synthesis with a sensitivity of 0.87 (CI 0.81-0.93) and a NPV of 0.97 (CI 0.95-0.98). The sensitivity for predicting CSF-specific OCB was 0.93 (CI 0.88-0.98).ConclusionsIn the real world setting this study analyzing FLCk for detecting intrathecal Ig synthesis did not reach its prespecified primary endpoint of sensitivity >0.95. Therefore, FLCκ should not yet be introduced as a stand-alone preselection marker for intrathecal Ig synthesis, but may provide additional value when combined with established diagnostic parameters.
Current data support that metastatic hormone receptor-positive (HR+) and HER2-positive (HER2+) breast cancer offers distinct treatment options targeting both the hormone receptor and the HER2-pathway. This might lead to increased treatment efficacy with the potential of omitting chemotherapy in these patients. The aim of the randomized multicenter phase III DETECT V trial was to analyze the efficacy of chemotherapy free and CDK4/6 inhibitor containing treatment strategies compared to current standard treatment. Between 09/2015 and 11/2022, 271 patients with HER2+ and HR+ MBC in the 1st-3rd line setting were randomized 1:1 to receive trastuzumab and pertuzumab combined with either endocrine therapy or chemotherapy followed by maintenance therapy with dual HER2 targeted and endocrine therapy. Chemotherapy and the endocrine agents could be chosen from a variety of available regimens according to physicians’ choice. In January 2019, the protocol was amended with the addition of the CDK4/6 inhibitor ribociclib to both treatment arms. The primary objective of DETECT V was to compare tolerability between the treatment arms, and secondary objectives comprised the comparison of overall survival (OS), progression-free survival (PFS) and safety, as well as the evaluation of the effect of adding ribociclib to both treatment arms. Here we report results of the final efficacy analyses as based on the modified ITT set of 262 patients (9 patients did not receive any study treatment and were excluded). Of these, 120 patients were recruited before the addition of ribociclib (59 and 61 patients in the chemotherapy-free and chemotherapy-containing treatment arm, respectively), and 142 patients were recruited after the addition of ribociclib (73 and 69 patients in the chemotherapy-free and chemotherapy-containing treatment arm, respectively). Median patient age was 60 years, 202 (77.1%) of patients were in the first line setting and 137 (52.3%) patients had a metastasis-free interval (from primary diagnosis) exceeding 12 months. The overall comparison between all patients receiving chemotherapy-free and chemotherapy-containing treatment showed no significant difference with regard to OS and PFS (median OS not reached vs 46.1 months, HR 0.98, 95% CI 0.60 - 1.59, p = 0.93; median PFS 19.5 vs 23.0 months, HR 1.15, 95% CI 0.82 - 1.62, p = 0.42). However, both OS and PFS were significantly improved by the (non-randomized) addition of ribociclib (OS: median OS not reached vs 46.1 months, HR 0.43, 95% CI 0.26 - 0.72, p = 0.001; PFS: median PFS 29.7 vs 15.6 months, HR 0.48, 95% CI 0.34 - 0.67, p < 0.001). A separate analysis for the two treatment arms showed that the addition of ribociclib to chemotherapy-containing treatment significantly improved both OS (median OS not reached vs 38.7 months, HR 0.30, 95% CI 0.14 - 0.64, p = 0.002) and PFS (median PFS 33.1 vs 15.4 months, HR 0.35, 95% CI 0.21 - 0.59, p < 0.001), while the addition of ribociclib to chemotherapy-free treatment significantly improved PFS (median PFS 27.2 vs 15.6 months, HR 0.61, 95% CI 0.38 - 0.98, p = 0.040) but not OS (median OS not reached in both groups, HR 0.60, 95% CI 0.30 - 1.23, p = 0.163). An exploratory cross-cohort comparison revealed significantly improved outcome for patients receiving chemotherapy-free treatment plus ribociclib vs chemotherapy-containing treatment without ribociclib (OS: median OS not reached vs 38.7 months, HR 0.48, 95% CI 0.24 - 0.94, p = 0.033; PFS: median PFS 27.2 vs 15.4 months, HR 0.53, 95% CI 0.33 - 0.85, p = 0.008). Our results suggest that chemotherapy-free treatment for patients with HER2+ and HR+ MBC may be a valuable and effective treatment alternative, and may improve survival with the addition of ribociclib. W. Janni, T. Fehm, V. Müller, J. Blohmer, A. De Gregorio, T. Decker, A. Hartkopf, N. Ditsch, M. Schmidt, P. Wimberger, T. Engler, M. Banys-Paluchowski, P. A. Fasching, B. Rack, A. Schneeweiss, K. Pantel, T. W. Friedl, F. Schochter, J. Huober. Efficacy Analysis of the Randomized Phase III DETECT V trial: Treatment De-escalation by Omission of Chemotherapy and the Effect of Adding Ribociclib in HER2-positive and Hormone-receptor Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF4-02.
Postpartum hemorrhage (PPH) remains a clinically significant cause of maternal complications and death. Due to the increasing incidence, international recommendations have been implemented, such as the D‑A-CH algorithm, an interdisciplinary and transnational treatment algorithm for Germany, Austria and Switzerland. This study aims to evaluate both the impact of implementing a hemostaseology working group and adopting the internationally recognized D‑A-CH algorithm on the clinical management of PPH in a university hospital. In this single-center retrospective observational study, patient records were reviewed from all patients treated for PPH between March 2003 and July 2021 at the University Hospital Ulm, Germany (n = 341). Data were divided into three groups: (I) patients treated before the implementation of a working group for hemostaseology (n = 40), (II) patients treated after the implementation of a working group for hemostaseology and before the clinical application of the D‑A-CH-algorithm (n = 103) and (III) patients treated after the clinical application of the D‑A-CH algorithm (n = 198). After the implementation of the D‑A-CH-algorithm, a significantly higher amount of fibrinogen (2.0 g, interquartile range, IQR, 0.0–3.0 g in group III vs. 0.0 g, IQR 0.0–2.0 g in group II and 0.0 g, IQR 0.0–0.0 g in group I ; p < 0.0001) and tranexamic acid (1.0 g, IQR 1.0–1.5 g in group III vs. 1.0 g, IQR 0.0–1.0 g in group II and 0.0 g, IQR 0.0–0.0 g in group I; p < 0.0001) was administered. Additionally, transfusion of allogeneic blood products (units of concentrated red cells: 2.0, IQR 0.0–4.0 in group III vs. 3.0, IQR 2.0–5.0 in group II and 3.0, IQR 0.0–7.8 in group I; p = 0.0036), intensive care unit (ICU) stay (3.0 days, IQR 2.0–4.0 days in group III vs. 3.0 days, IQR 2.0–5.0 days in group II and 3.0 days, IQR 2.0–4.3 days in group I; p = 0.0195) and hospital stay (5.0 days, IQR 3.0–7.0 days in group III vs. 7.0 days, IQR 5.0–9.0 days in group II and 7.0 days, IQR 5.0–9.0 days in group I; p < 0.0001) was significantly reduced. Implementation of a hemostaseology working group alone was only associated with increased fibrinogen and tranexamic acid administration. In this retrospective study, application of the D‑A-CH algorithm was associated with improved targeted hemostatic therapy and reduced transfusion requirements as well as shorter ICU and hospital stays, whereas implementation of a hemostaseology working group alone was only associated with increased fibrinogen and tranexamic acid administration. Due to the retrospective design of the study and inherent limitations therein, we were unable to draw a causative effect relationship. Nonetheless, our results warrant further study.
Die Deutsche Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e. V. (DGHNO-KHC) und die Deutsche HNO-Akademie (DAHNO) haben unter Mitwirkung der entsprechenden Arbeitsgemeinschaften Expertenzertifikate für den Teilbereich „Kopf-Hals-Onkochirurgie“ und nun auch den der „Nasennebenhöhlen- und Schädelbasis-Chirurgie“ entwickelt. Ziel ist es, in Analogie zu internationalen Standards, die Expertise der Antragstellenden für den jeweiligen Teilbereich darzustellen. Für die „Kopf-Hals-Onkochirurgie“ wurde das Qualifikationsmerkmal „Tätigkeit in einem von der Deutschen Krebsgesellschaft/DKG zertifizierten Kopf-Hals-Tumorzentrum“ um das Kriterium „oder vergleichbarer Einrichtung (Strukturmerkmale: regelmäßige interdisziplinäre Fallkonferenz und Zusammenarbeit mit Hauptkooperationspartnern mit Vorhaltung definierter Behandlungspfade)“ ergänzt und hinsichtlich Fortbildungs- bzw. Studienteilnahme modifiziert. Für das Expertenzertifikat „Nasennebenhöhlen- und (anteriore) Schädelbasis-Chirurgie“ wurden gemeinsam mit der Arbeitsgemeinschaft Rhinologie/Rhinochirurgie (ARHIN) und der Arbeitsgemeinschaft Schädelbasis- und kraniofasziale Chirurgie (ASKRA) die Kriterien für ein entsprechendes Logbuch entwickelt. Die Zertifikate können zum Nachweis der individuellen Expertise genutzt werden. Die praktische Umsetzung erfolgt durch eine unabhängige Zertifizierungsstelle (ClarCert GmbH) im Auftrag der DGHNO-KHC und beurteilender Mitarbeit der DAHNO sowie der jeweiligen Arbeitsgemeinschaften. Anträge können durch Mitglieder der DGHNO-KHC oder der DAHNO ab sofort für die genannten Expertenzertifikate gestellt werden. Weitere Zertifikate befinden sich in Vorbereitung.
