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BACKGROUND/AIM: Metastatic colorectal cancer (mCRC) is a heterogeneous disease with distinct molecular subtypes. The BRAFV600E-mutation found in approximately 8-12% of mCRC patients is associated with poor prognosis. Guideline recommendations for this population are mostly based on small cohorts due to lack of clinical data. This retrospective analysis was designed to evaluate (approved) therapeutic approaches and algorithms in BRAFV600E-mutant mCRC prior to approval of the targeted combination encorafenib plus cetuximab in Germany, Austria, and Switzerland. PATIENTS AND METHODS: Anonymized data from BRAFV600E-mutant mCRC patients were analyzed retrospectively regarding 1st-, 2nd- and 3rd-line treatment using descriptive statistics. RESULTS: Forty-two patients were eligible for analysis (mean age 62.1 years, 47.6% female). At initial diagnosis, 20 patients (47.6%) were documented with right-sided tumors. Most patients (81.0%) were tested for BRAF before 1st-line. Four patients (9.5%) showed high microsatellite instability (MSI-H). Based on 94 treatment lines, chemotherapy combined with targeted therapy (TT) was used mostly (61.7%), followed by chemotherapy alone (19.1%). Backbone therapies were most frequently FOLFOXIRI (27.7%), FOLFOX/CAPOX (22.3%), or FOLFIRI (20.2%). Anti-VEGF/VEGFR and anti-EGFR-treatments were used in 45.7% and 23.4% of patients, respectively. Across all treatment lines and types, the predominantly documented reason for discontinuation was lack of efficacy. CONCLUSION: Combined chemotherapy+TT (anti-VEGF/VEGFR and anti-EGFR) played a predominant role in BRAFV600E-mutated mCRC treatment prior to approval of the targeted combination encorafenib plus cetuximab. Since lack of efficacy was the major reason for treatment discontinuation, newly approved therapies including encorafenib plus cetuximab and - for MSI-H tumors - pembrolizumab represent urgently needed options for future mCRC patients.

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BACKGROUND: Purpose of this analysis was to report data of the BEACON CRC trial used in the German Health Technology Assessment (HTA) and previously unpublished data focusing on the dual blockade (encorafenib + cetuximab) and appropriate comparative therapy (ACT/control: cetuximab + irinotecan-based chemotherapy) of patients with BRAFV600E-mutant mCRC. MATERIALS AND METHODS: Analyses included overall survival (OS) and time-to-event analyses of morbidity and safety. RESULTS: A total of 220 patients received encorafenib + cetuximab and 221 patients ACT/control. Median OS was 9.3 (encorafenib + cetuximab) versus 5.9 months (ACT/control) (stratified hazard ratio (HRstrat): 0.61 [95% confidence interval: 0.48-0.77]). Time-to-response (TTR) showed a statistically significant advantage for encorafenib + cetuximab compared to ACT/control (HRstrat [95% CI]: 10.46 [3.75; 29.15]; P < .0001). Median progression-free survival 2, ie, PFS after initiation of subsequent treatment after completion of study treatment, was 8.3 (dual blockade) versus 5.3 months (ACT/control), representing a statistically significant benefit for the dual blockade (HRstrat [95% CI]: 0.62 [0.48; 0.78]; P < .0001). The statistically significant advantage for diarrhea (EORTC QLQ-C30) reached clinical relevance (LS-mean [95% CI]; P-value / Hedges'g [95% CI]: -12.61 [-17.75; -7.47]; P < .0001 / -0.53 [-0.74; -0.31]). The time-to-event analyses showed a statistically significant benefit for the dual blockade for serious adverse events (AE), severe AEs and AEs leading to discontinuation. CONCLUSION: In the HTA, the German G-BA granted a "hint for a considerable additional benefit" of encorafenib + cetuximab compared to the ACT in BRAFV600E-mutant mCRC patients. This treatment is considered the new standard of care for these patients.

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Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms.

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BACKGROUND: Mobile health apps have great potential to support the self-management of chronic conditions such as allergic diseases, which constitute significant challenges in health care. However, the health app market is confusing for users, as it is vast, dynamic, and lacks scientific evidence regarding the effectiveness of the apps on offer. To our knowledge, no health app for pollen-related allergic rhinitis has been evaluated. OBJECTIVE: The aim of our study was to evaluate the Husteblume mobile phone health app, developed in Germany to facilitate the self-management of pollen-related allergic rhinitis. METHODS: We evaluated usability and changes in quality of life, health literacy, and self-efficacy for managing one's chronic disease. We conducted 2 online surveys of registered users of the app, 1 before and 1 after the 2017 pollen season, allowing for the analysis of both cross-sectional and longitudinal data in a field setting. RESULTS: The sample comprised 661 app users at the first measurement point and 143 users at follow-up. The subgroup of study participants at follow-up rated the usability of the app as good or very good. There were no significant changes in patient-reported outcomes such as quality of life, health literacy, and self-efficacy between the 2 measurement points (P>.05). However, those reached at follow-up perceived subjective improvements due to the app: 55.9% (80/143) reported being subjectively better informed about their allergy, 27.3% (39/143) noted improved quality of life, 33.6% (48/143) reported subjectively better coping with their allergy, and 28.0% (40/143) felt better prepared for the consultation with their physician. Finally, 90.9% (130/143) users did not identify any adverse effects of the app. CONCLUSIONS: Despite some methodological caveats, the results of the evaluation of the Husteblume app are encouraging for the subgroup using the app in the long term. However, further studies evaluating the effectiveness of the app are needed. TRIAL REGISTRATION: German Clinical Trials Register DRKS00011897; https://tinyurl.com/yxxrg9av.

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Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death.Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort.Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy.Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." Clin Cancer Res; 23(16); 4805-16. ©2017 AACR.

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After tissue injury, both wound sealing and apoptosis contribute to restoration of tissue integrity and functionality. Although the role of platelets (PLTs) for wound closure and induction of regenerative processes is well established, the knowledge about their contribution to apoptosis is incomplete. Here, we show that PLTs present the death receptor Fas ligand (FasL) on their surface after activation. Activated PLTs as well as the isolated membrane fraction of activated PLTs but not of resting PLTs induced apoptosis in a dose-dependent manner in primary murine neuronal cells, human neuroblastoma cells, and mouse embryonic fibroblasts. Membrane protein from PLTs lacking membrane-bound FasL (FasL(△m/△m)) failed to induce apoptosis. Bax/Bak-mediated mitochondrial apoptosis signaling in target cells was not required for PLT-induced cell death, but increased the apoptotic response to PLT-induced Fas signaling. In vivo, PLT depletion significantly reduced apoptosis in a stroke model and an inflammation-independent model of N-methyl-d-aspartic acid-induced retinal apoptosis. Furthermore, experiments using PLT-specific PF4Cre(+) FasL(fl/fl) mice demonstrated a role of PLT-derived FasL for tissue apoptosis. Because apoptosis secondary to injury prevents inflammation, our findings describe a novel mechanism on how PLTs contribute to tissue homeostasis.

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The Bcl-2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro-survival Bcl-2 proteins control Bax by constant retrotranslocation into the cytosol of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this level of regulation. Here we report that Bak is retrotranslocated from the mitochondria by pro-survival Bcl-2 proteins. Bak is present in the cytosol of human cells and tissues, but low shuttling rates cause predominant mitochondrial Bak localization. Interchanging the membrane anchors of Bax and Bak reverses their subcellular localization compared to the wild-type proteins. Strikingly, the reduction of Bax shuttling to the level of Bak retrotranslocation results in full Bax toxicity even in absence of apoptosis induction. Thus, fast Bax retrotranslocation is required to protect cells from commitment to programmed death.

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