scholarly journals PTEN is a Predictive Biomarker of Trastuzumab Resistance and Prognostic Factor in HER2-overexpressing Gastroesophageal Adenocarcinoma

2021 ◽  
Author(s):  
Daiju Yokoyama ◽  
Shigeo Hisamori ◽  
Yasunori Deguchi ◽  
Tatsuto Nishigori ◽  
Hiroshi Okabe ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Mtor Inhibitor ◽  
Gastroesophageal Junction ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Pten Expression ◽  
Trastuzumab Resistance ◽  
Effective Treatment Option ◽  
Pten Loss

Abstract IntroductionPoor Trastuzumab (Tmab) response in human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is reported to be associated with loss of phosphatase and tensin homolog (PTEN) expression.MethodsIn a multicenter, retrospective observational study, pathological samples of HER2-GEA patients receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. Primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The effect of PI3K pathway inhibitors on HER2-GEA cell lines were evaluated in in-vitro.ResultsAmong 145 HER2-GEA patients, 29 formed the PTEN-loss group and 116 the PTEN-positive group. In patients with target region, DCR was significantly lower in PTEN-loss than in PTEN-positive patients (67% and 87%, respectively, p=0.049). Multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR=1.63, p=0.035) and OS (HR=1.83, p=0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, while Tmab combined with PI3K/mTOR inhibitor NPV-BEZ235 suppressed the proliferation of PTEN knockdown cells which were resistant to Tmab alone.ConclusionIn HER2-GEA patients, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with PI3K/mTOR inhibitor would be an effective treatment option for HER2-GEA with PTEN loss.

scholarly journals PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daiju Yokoyama ◽  
Shigeo Hisamori ◽  
Yasunori Deguchi ◽  
Tatsuto Nishigori ◽  
Hiroshi Okabe ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Mtor Inhibitor ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Pten Expression ◽  
Trastuzumab Resistance ◽  
Pten Loss

AbstractPoor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective observational study, pathological samples of patients with HER2-GEA receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. The primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We assessed the effect of conventional chemotherapy and Tmab alone or combined with PI3K pathway inhibitors in vitro in HER2-GEA cells with or without PTEN expression. Twenty-nine and 116 patients were in the PTEN-loss and PTEN-positive groups, respectively. In patients with the target region, DCR was significantly lower in PTEN-loss patients than in PTEN-positive patients (67% and 87%, respectively, p = 0.049). The multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR = 1.63, p = 0.035) and OS (HR = 1.83, p = 0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, whereas Tmab combined with the PI3K/mTOR inhibitor NPV-BEZ235 suppressed PTEN-knockdown cell proliferation. In patients with HER2-GEA, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with a PI3K/mTOR inhibitor would be effective for HER2-GEA with PTEN loss.

KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

2009 ◽  
Vol 27 (35) ◽  
pp. 5931-5937 ◽  
Author(s):  
Susan D. Richman ◽  
Matthew T. Seymour ◽  
Philip Chambers ◽  
Faye Elliott ◽  
Catherine L. Daly ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Braf Mutation ◽  
Poor Prognosis ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Poor Prognostic Factor ◽  
Minimal Impact ◽  
The Impact

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

scholarly journals BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Carla Azzurra Amoreo ◽  
Isabella Sperduti ◽  
Sara Donzelli ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Promoter ◽  
Predictive Biomarker ◽  
Open Chromatin ◽  
Therapeutic Success ◽  
Rna Pol Ii ◽  
Pten Loss ◽  
Braf Inhibition ◽  
Dependent Mechanism

Abstract Inflammation might substantially contribute to the limited therapeutic success of current systemic therapies in colorectal cancer (CRC). Amongst cytokines involved in CRC biology, the proinflammatory chemokine IL-8 has recently emerged as a potential prognostic/predictive biomarker. Here, we show that BRAF mutations and PTEN-loss are associated with high IL-8 levels in CRC models in vitro and that BRAF/MEK/ERK, but not PI3K/mTOR, targeting controls its production in different genetic contexts. In particular, we identified a BRAF/ERK2/CHOP axis affecting IL-8 transcription, through regulation of CHOP subcellular localization, and response to targeted inhibitors. Moreover, RNA Pol II and an open chromatin status in the CHOP-binding region of the IL-8 gene promoter cooperate towards increased IL-8 expression, after a selective BRAF inhibition. Overall, our data show that IL-8 production is finely and differentially regulated depending on the tumor genetic context and might be targeted for therapeutic purposes in molecularly defined subgroups of CRC patients.

Effect of the leukocyte chemoattractant chemerin on PTEN via CMKLR1 in human prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 282-282
Author(s):  
Russell Kent Pachynski ◽  
Robert Crowder ◽  
William Shin ◽  
Keith Rennier
Keyword(s):  
Tumor Cell ◽  
Immune Cell ◽  
Pten Expression ◽  
Intrinsic Activity ◽  
Dependent Manner ◽  
In Vitro Proliferation ◽  
Immune Effector ◽  
Pten Loss ◽  
Protein Levels

282 Background: Recent data in preclinical models has shown that phosphatase and tensin homolog (PTEN) loss correlated with decreased tumor immune cell infiltration as well as decreased response to T cell-based immunotherapy. Chemerin ( RARRES2) is a recently identified endogenous leukocyte chemoattractant shown to recruit innate immune cells through its G-protein coupled receptor CMKLR1. RARRES2 is commonly downregulated in prostate and other cancers (eg sarcoma) compared to their normal tissue counterparts. Our previous preclinical studies showed that forced overexpression of chemerin in tumors was capable of recruiting immune effector cells into the tumor microenvironment and suppressing tumor growth. Methods: Here, we investigate the effects of chemerin on tumor cell intrinsic processes by exposing prostate and sarcoma tumor lines to exogenous recombinant chemerin in vitro. Evaluation of PTEN was performed at both the mRNA and protein levels, using both quantitative PCR as well as Western blotting. PTEN immunoprecipitation by and Malachite Green assays were used to determine PTEN activity. In vitro invasion assays were performed to investigate the functional impact of chemerin exposure on tumor intrinsic activity. Knockdown of CMKLR1 using siRNA was performed to determine its role in tumor response. Results: Using both prostate and sarcoma tumor lines, we found exogenous chemerin was able to significantly upregulate PTEN expression at both the mRNA and protein levels in a dose-dependent manner. PTEN phosphatase activity was also significantly increased by chemerin. Exposure to chemerin did not result in increased apoptosis or altered in vitro proliferation. Importantly, chemerin treatment significantly decreased in vitro tumor invasion. Knockdown of CMKLR1 resulted in loss of chemerin-induced PTEN and PTEN activity and restored tumor migration, suggesting a link between this GPCR and PTEN. Conclusions: For the first time to our knowledge, we have shown a link between chemerin and PTEN expression and activity in both prostate and sarcoma tumor lines. This work has potential clinical implications on both tumor cell intrinsic and extrinsic responses to chemerin-based immunotherapeutic strategies.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) patients who received taxane plus trastuzumab treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 637-637
Author(s):  
Yeon Hee Park ◽  
Hyun Ae Jung ◽  
Won Jin Chang ◽  
Moon Ki Choi ◽  
Jung Yong Hong ◽  
...  
Keyword(s):  
Metastatic Breast ◽  
Progression Free Survival ◽  
Pi3k Pathway ◽  
Pten Expression ◽  
Her2 Positive ◽  
Pten Loss ◽  
Trastuzumab Treatment ◽  
First Line Therapy ◽  
Predictive And Prognostic Biomarker

637 Background: The HER3 receptor is a key member of ErbB family and preferentially signals through the PI3K pathway. Formation of dimers between HER3 and HER2 seems to be crucial for HER2-driven signals in HER2 overexpressing tumors. Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 activity may contribute to the resistance of trastuzumab. PTEN plays a well-established role in the negative regulation of the PI3K pathway. Our aim of this study was to investigate the role of HER3 and PTEN expression in patients with HER2 overexpressed MBC. Methods: One-hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as the first line therapy were included in this analysis. Immunohistochemical stainings (IHC) with HER3 and PTEN antibody were conducted retrospectively. Results: Median age was 48 years. HER3 IHC was graded from 0 to 3. PTEN IHC was scored as multiplication of intensity and proportion from 0 to 300. The patients who had negative HER3 stain showed better progression free survival (PFS) to taxane plus trastuzumab chemotherapy than those positive HER3 stain (p=0.001, median PFS 21 vs. 11 mo.). The patients who had PTEN score of more than 20 showed longer PFS than those PTEN score of 20 or less than 20 (p=0.006, median PFS 13 vs. 9 mo.). The patients who had PTEN score of more than 20 showed longer overall survival (OS) than those PTEN score of 20 or less than 20 (p=0.005, median OS 48 vs. 25 mo.). HER3 negativity and PTEN loss were identified as independent risk factors for PFS [Hazard Ratio (HR) 0.4 (95% CI 0.3-0.8 for HER3 negativity; HR 2.1 (95% CI 1.2-3.7) for PTEN loss]. However, PTEN loss (HR 3.1 [95% CI 1.6-6.3]) was identified as an independent risk factor for OS. Conclusions: HER3 and PTEN expression may be predictive markers for trastuzumab treatment in HER2-positive MBCs. PTEN expression may have a potential predictive and prognostic biomarker for trastuzumab treatment.

FOCUS4: A prospective molecularly stratified, adaptive multicenter program of randomized controlled trials for patients with colorectal cancer (CRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3645-TPS3645
Author(s):  
Kai-Keen Shiu ◽  
Tim Maughan ◽  
Richard H. Wilson ◽  
Richard A. Adams ◽  
Cheryl Pugh ◽  
...  
Keyword(s):  
Randomised Trial ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Double Blind ◽  
Interim Analyses ◽  
Pten Loss ◽  
Molecular Stratification ◽  
Multi Stage ◽  
New Strategy

TPS3645 Background: Targeted therapies based on somatic gene mutations or activated pathways have inhibited progression of some cancers. However, although various targets are identifiable in CRC, KRAS mutation is currently the only validated predictive biomarker for selection of a targeted therapy. FOCUS4 is a rolling phase II-III trial for testing in a staged way both the utility of molecular stratification and the efficacy of novel agents in subpopulations of mCRC patients. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type using a Multi-Arm, Multi-Stage design. Methods: The study population consists of subjects with newly diagnosed inoperable mCRC. Subjects receive first-line chemotherapy for 16 weeks. During this time the tumour is tested for BRAF/PIK3CA/KRAS/NRAS mutations and PTEN loss. Subjects with responding or stable disease on CT, who would normally be candidates for a treatment break, are then randomised to four coherent biomarker-based subgroups: FOCUS4-A: BRAF mutant, FOCUS4-B: PIK3CA mutant or complete loss of PTEN on IHC, FOCUS4-C: KRAS or NRAS mutant, FOCUS4-D: All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS). For each subgroup, a relevant novel agent or combination is to be tested in an adaptive double-blind placebo controlled randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity. There will also be a 5thsubgroup FOCUS4-N testing maintenance capecitabine for unclassifiable tumours or for patients whose marker defined cohort is temporarily suspended. The primary endpoint is progression free survival. Promising results in any biomarker defined cohort will then be tested for response in cohorts without the biomarker. Within the overall trial, biomarker developments can be accommodated with changes in the distribution of the cohorts or testing of new targeted agents. Enrolment will commence in May 2013. Upto 3400 patients will be registered over a 4-5 year period depending on which cohorts pass their staged interim analyses and proceed to later stages, including an overall survival endpoint. Clinical trial information: 2012-005111-12.

SLFN11 expression (exp) in castration-resistant prostate cancer (CRPC) patients (pts) to predict response to platinum-based chemotherapy (PLT).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5065-5065
Author(s):  
Vincenza Conteduca ◽  
Loredana Puca ◽  
Sheng-Yu Ku ◽  
Judy Hess ◽  
Megan Kearney ◽  
...  
Keyword(s):  
Cox Regression ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Median Number ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Cox Regression Analysis ◽  
Platinum Based Chemotherapy

5065 Background: Schlafen family member 11 (SLFN11) sensitizes tumor cells to DNA-damaging agents and has been investigated as a potential predictive biomarker of response to PLT and PARP inhibitors, especially in small cell lung cancer (Lok, CCR 2017; Pietanza, JCO 2018). We aimed to explore the predictive/prognostic role of SLFN11 in PLT-treated CRPC. Methods: We assessed tumor exp of SLFN11 in PLT-treated, metastatic CRPC pts by RNAseq (N=27) and/or CTCs (N=20) (via the Epic Sciences platform). In addition, tumor morphology for neuroendocrine (NE) features and genomic status of select genes (ie, AR, TP53, RB1, BRCA2, BRCA1, ATM) by whole exome sequencing were evaluated. Statistical comparisons used Cox regression analysis and Kaplan Meier method for the association with overall/radiographic progression free survival (OS/rPFS). A dose response curve with PLT was performed in patient-derived organoids using Cell Title Glo according to the manufacturer’s protocol. Results: 41 CRPC (including 20 CRPC-NE) treated with PLT monotherapy (N=3) or PLT combination therapy (N=38) between August 2013 and December 2017 were evaluated. Median age was 67.1 years (range 51-91). Median number of prior therapies was 2 (range 1-7). A longer median rPFS was observed in all SLFN11+ pts treated with PLT (regardless of histology, RB1, TP53, PTEN, or DNA repair status) compared to SLFN11- [5.2 vs 2.3 months, HR 3.5, 95%CI 1.6-7.7, P<0.0001]. No association was reported for OS. On multivariable analysis (Table), SLFN11 was an independent factor associated with rPFS. Organoids derived from patient tumors expressing SLFN11 showed sensitivity to PLT in vitro. Conclusions: SLFN11 exp identifies both CRPC and CRPC-NE pts with a better response to PLT. Patient-derived organoids expressing SLFN11 confirmed increased sensitivity to PLT. Larger prospective evaluation of therapy decisions based on SLFN11 exp is now required. [Table: see text]

PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic Colorectal Cancer

2009 ◽  
Vol 27 (16) ◽  
pp. 2622-2629 ◽  
Author(s):  
Fotios Loupakis ◽  
Luca Pollina ◽  
Irene Stasi ◽  
Annamaria Ruzzo ◽  
Mario Scartozzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Pten Expression ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Pten Loss ◽  
Egfr Inhibition ◽  
Paired Samples

PurposePTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC).Patients and MethodsA cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated.ResultsOne-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001).ConclusionPTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.

Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6028-6028 ◽  
Author(s):  
Barbara Burtness ◽  
Ju-Whei Lee ◽  
Donghua Yang ◽  
Fang Zhu ◽  
Joaquin J. Garcia ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Small Sample ◽  
Pten Expression ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Pik3ca Mutations ◽  
Pten Loss

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.

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