Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors

This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine...

Full description

Saved in:
Bibliographic Details
Published in:OncoTargets and therapy 2017-01, Vol.10, p.3177-3186
Main Authors: Yao, James C, Chan, Jennifer A, Mita, Alain C, Kundu, Madan G, Hermosillo Reséndiz, Karina, Hu, Ke, Ravichandran, Shoba, Strosberg, Jonathan R, Wolin, Edward M
Format: Article
Language:English
Subjects:
Analysis
Cancer
Cardiac arrhythmia
Care and treatment
Control
Development and progression
Diagnosis
Drug dosages
Heart rate
Laboratories
Metastasis
Neuroendocrine tumors
Original Research
Overdose
Patient outcomes
Patients
Pharmacodynamics
Pharmacokinetics
Studies
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c507t-27a61d108cafc85adf8e6b86f389e689f14dc5ecb7a77afeb216ef633bc884743
cites
container_end_page 3186
container_issue
container_start_page 3177
container_title OncoTargets and therapy
container_volume 10
creator Yao, James C
Chan, Jennifer A
Mita, Alain C
Kundu, Madan G
Hermosillo Reséndiz, Karina
Hu, Ke
Ravichandran, Shoba
Strosberg, Jonathan R
Wolin, Edward M
description This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis. A total of 29 patients were treated with 80 mg (n=13) and 120 mg (n=16) doses. Most common primary tumor sites included small intestine (44.8%), pancreas (24.1%), and lung (17.2%). No protocol-defined dose-limiting toxicities were observed in the study; however, in post hoc analysis, a higher incidence of bradycardia (heart rate [HR]
doi_str_mv 10.2147/OTT.S128547
format article
fullrecord <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5499931</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A534206780</galeid><sourcerecordid>A534206780</sourcerecordid><originalsourceid>FETCH-LOGICAL-c507t-27a61d108cafc85adf8e6b86f389e689f14dc5ecb7a77afeb216ef633bc884743</originalsourceid><addsrcrecordid>eNptkl1rFDEYhQdRbK1eeS8Dgggya74mydwIpdhaKFRwvQ6ZzJudlJlkTTJK_71ZutZdkVzk63lPkpNTVa8xWhHMxMfb9Xr1DRPZMvGkOsVYyIZ3FD09GJ9UL1K6Q4hzSdjz6oRIQTDi4rRSX0edoL6uh5CggWT0pLMLvk55Ge7rYOsp-E2jTXZ-U291chFCdgPUzpdpduBzqn-5PNYelhjAD8FE56HOyxxielk9s3pK8Grfn1XfLz-vL740N7dX1xfnN41pkcgNEZrjASNptDWy1YOVwHvJLZUdcNlZzAbTgumFFkJb6AnmYDmlvZGSCUbPqk8Putuln2Ew5VpRT2ob3azjvQraqeMd70a1CT9Vy7quo7gIvN8LxPBjgZTV7JKBadIewpIU7giiHSVMFvTtP-hdWKIvz1OEMNK2jCP6l9roCZTzNpRzzU5UnbeUkWK_RIVa_YcqbYDZmeDBurJ-VPDuoGAEPeUxhWnZfVo6Bj88gCaGlCLYRzMwUrvgqBIctQ9Ood8c-vfI_kkK_Q3sMr4a</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2242554603</pqid></control><display><type>article</type><title>Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors</title><source>Taylor &amp; Francis Open Access</source><source>Publicly Available Content Database</source><source>PubMed Central</source><creator>Yao, James C ; Chan, Jennifer A ; Mita, Alain C ; Kundu, Madan G ; Hermosillo Reséndiz, Karina ; Hu, Ke ; Ravichandran, Shoba ; Strosberg, Jonathan R ; Wolin, Edward M</creator><creatorcontrib>Yao, James C ; Chan, Jennifer A ; Mita, Alain C ; Kundu, Madan G ; Hermosillo Reséndiz, Karina ; Hu, Ke ; Ravichandran, Shoba ; Strosberg, Jonathan R ; Wolin, Edward M</creatorcontrib><description>This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis. A total of 29 patients were treated with 80 mg (n=13) and 120 mg (n=16) doses. Most common primary tumor sites included small intestine (44.8%), pancreas (24.1%), and lung (17.2%). No protocol-defined dose-limiting toxicities were observed in the study; however, in post hoc analysis, a higher incidence of bradycardia (heart rate [HR] &lt;40 beats per minute [bpm]) was observed with 120 mg (31.3%) vs 80 mg (0%). Two partial responses (PRs) were observed, both in the 120 mg dose cohort. Pasireotide concentrations correlated with tumor shrinkage, although the association was not statistically significant ( =0.08). Among the biomarkers analyzed, insulin-like growth factor 1 (IGF-1) showed a decreasing trend with increasing pasireotide concentration, while chromogranin A (CgA) and neuron-specific enolase (NSE) levels did not show any dose-response relationship. The most common adverse events in any dose group were hyperglycemia, fatigue, and nausea. MTD was defined at 120 mg for pasireotide LAR in patients with advanced NETs. Although objective radiographic responses were rarely observed with somatostatin analogs, two PRs were observed among 16 patients in the 120 mg cohort. Bradycardia (HR &lt;40 bpm) appears to be a dose-limiting effect; however, the mechanism and clinical significance are uncertain. This study was registered with clinicaltrials.gov (NCT01364415).</description><identifier>ISSN: 1178-6930</identifier><identifier>EISSN: 1178-6930</identifier><identifier>DOI: 10.2147/OTT.S128547</identifier><identifier>PMID: 28721067</identifier><language>eng</language><publisher>New Zealand: Dove Medical Press Limited</publisher><subject>Analysis ; Cancer ; Cardiac arrhythmia ; Care and treatment ; Control ; Development and progression ; Diagnosis ; Drug dosages ; Heart rate ; Laboratories ; Metastasis ; Neuroendocrine tumors ; Original Research ; Overdose ; Patient outcomes ; Patients ; Pharmacodynamics ; Pharmacokinetics ; Studies</subject><ispartof>OncoTargets and therapy, 2017-01, Vol.10, p.3177-3186</ispartof><rights>COPYRIGHT 2017 Dove Medical Press Limited</rights><rights>2017. This work is licensed under https://creativecommons.org/licenses/by-nc/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Yao et al. This work is published and licensed by Dove Medical Press Limited 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c507t-27a61d108cafc85adf8e6b86f389e689f14dc5ecb7a77afeb216ef633bc884743</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2242554603/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2242554603?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25752,27923,27924,37011,37012,44589,53790,53792,74997</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28721067$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yao, James C</creatorcontrib><creatorcontrib>Chan, Jennifer A</creatorcontrib><creatorcontrib>Mita, Alain C</creatorcontrib><creatorcontrib>Kundu, Madan G</creatorcontrib><creatorcontrib>Hermosillo Reséndiz, Karina</creatorcontrib><creatorcontrib>Hu, Ke</creatorcontrib><creatorcontrib>Ravichandran, Shoba</creatorcontrib><creatorcontrib>Strosberg, Jonathan R</creatorcontrib><creatorcontrib>Wolin, Edward M</creatorcontrib><title>Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors</title><title>OncoTargets and therapy</title><addtitle>Onco Targets Ther</addtitle><description>This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis. A total of 29 patients were treated with 80 mg (n=13) and 120 mg (n=16) doses. Most common primary tumor sites included small intestine (44.8%), pancreas (24.1%), and lung (17.2%). No protocol-defined dose-limiting toxicities were observed in the study; however, in post hoc analysis, a higher incidence of bradycardia (heart rate [HR] &lt;40 beats per minute [bpm]) was observed with 120 mg (31.3%) vs 80 mg (0%). Two partial responses (PRs) were observed, both in the 120 mg dose cohort. Pasireotide concentrations correlated with tumor shrinkage, although the association was not statistically significant ( =0.08). Among the biomarkers analyzed, insulin-like growth factor 1 (IGF-1) showed a decreasing trend with increasing pasireotide concentration, while chromogranin A (CgA) and neuron-specific enolase (NSE) levels did not show any dose-response relationship. The most common adverse events in any dose group were hyperglycemia, fatigue, and nausea. MTD was defined at 120 mg for pasireotide LAR in patients with advanced NETs. Although objective radiographic responses were rarely observed with somatostatin analogs, two PRs were observed among 16 patients in the 120 mg cohort. Bradycardia (HR &lt;40 bpm) appears to be a dose-limiting effect; however, the mechanism and clinical significance are uncertain. This study was registered with clinicaltrials.gov (NCT01364415).</description><subject>Analysis</subject><subject>Cancer</subject><subject>Cardiac arrhythmia</subject><subject>Care and treatment</subject><subject>Control</subject><subject>Development and progression</subject><subject>Diagnosis</subject><subject>Drug dosages</subject><subject>Heart rate</subject><subject>Laboratories</subject><subject>Metastasis</subject><subject>Neuroendocrine tumors</subject><subject>Original Research</subject><subject>Overdose</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Studies</subject><issn>1178-6930</issn><issn>1178-6930</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNptkl1rFDEYhQdRbK1eeS8Dgggya74mydwIpdhaKFRwvQ6ZzJudlJlkTTJK_71ZutZdkVzk63lPkpNTVa8xWhHMxMfb9Xr1DRPZMvGkOsVYyIZ3FD09GJ9UL1K6Q4hzSdjz6oRIQTDi4rRSX0edoL6uh5CggWT0pLMLvk55Ge7rYOsp-E2jTXZ-U291chFCdgPUzpdpduBzqn-5PNYelhjAD8FE56HOyxxielk9s3pK8Grfn1XfLz-vL740N7dX1xfnN41pkcgNEZrjASNptDWy1YOVwHvJLZUdcNlZzAbTgumFFkJb6AnmYDmlvZGSCUbPqk8Putuln2Ew5VpRT2ob3azjvQraqeMd70a1CT9Vy7quo7gIvN8LxPBjgZTV7JKBadIewpIU7giiHSVMFvTtP-hdWKIvz1OEMNK2jCP6l9roCZTzNpRzzU5UnbeUkWK_RIVa_YcqbYDZmeDBurJ-VPDuoGAEPeUxhWnZfVo6Bj88gCaGlCLYRzMwUrvgqBIctQ9Ood8c-vfI_kkK_Q3sMr4a</recordid><startdate>20170101</startdate><enddate>20170101</enddate><creator>Yao, James C</creator><creator>Chan, Jennifer A</creator><creator>Mita, Alain C</creator><creator>Kundu, Madan G</creator><creator>Hermosillo Reséndiz, Karina</creator><creator>Hu, Ke</creator><creator>Ravichandran, Shoba</creator><creator>Strosberg, Jonathan R</creator><creator>Wolin, Edward M</creator><general>Dove Medical Press Limited</general><general>Taylor &amp; Francis Ltd</general><general>Dove Medical Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170101</creationdate><title>Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors</title><author>Yao, James C ; Chan, Jennifer A ; Mita, Alain C ; Kundu, Madan G ; Hermosillo Reséndiz, Karina ; Hu, Ke ; Ravichandran, Shoba ; Strosberg, Jonathan R ; Wolin, Edward M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c507t-27a61d108cafc85adf8e6b86f389e689f14dc5ecb7a77afeb216ef633bc884743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Analysis</topic><topic>Cancer</topic><topic>Cardiac arrhythmia</topic><topic>Care and treatment</topic><topic>Control</topic><topic>Development and progression</topic><topic>Diagnosis</topic><topic>Drug dosages</topic><topic>Heart rate</topic><topic>Laboratories</topic><topic>Metastasis</topic><topic>Neuroendocrine tumors</topic><topic>Original Research</topic><topic>Overdose</topic><topic>Patient outcomes</topic><topic>Patients</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yao, James C</creatorcontrib><creatorcontrib>Chan, Jennifer A</creatorcontrib><creatorcontrib>Mita, Alain C</creatorcontrib><creatorcontrib>Kundu, Madan G</creatorcontrib><creatorcontrib>Hermosillo Reséndiz, Karina</creatorcontrib><creatorcontrib>Hu, Ke</creatorcontrib><creatorcontrib>Ravichandran, Shoba</creatorcontrib><creatorcontrib>Strosberg, Jonathan R</creatorcontrib><creatorcontrib>Wolin, Edward M</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>ProQuest Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>OncoTargets and therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yao, James C</au><au>Chan, Jennifer A</au><au>Mita, Alain C</au><au>Kundu, Madan G</au><au>Hermosillo Reséndiz, Karina</au><au>Hu, Ke</au><au>Ravichandran, Shoba</au><au>Strosberg, Jonathan R</au><au>Wolin, Edward M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors</atitle><jtitle>OncoTargets and therapy</jtitle><addtitle>Onco Targets Ther</addtitle><date>2017-01-01</date><risdate>2017</risdate><volume>10</volume><spage>3177</spage><epage>3186</epage><pages>3177-3186</pages><issn>1178-6930</issn><eissn>1178-6930</eissn><abstract>This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis. A total of 29 patients were treated with 80 mg (n=13) and 120 mg (n=16) doses. Most common primary tumor sites included small intestine (44.8%), pancreas (24.1%), and lung (17.2%). No protocol-defined dose-limiting toxicities were observed in the study; however, in post hoc analysis, a higher incidence of bradycardia (heart rate [HR] &lt;40 beats per minute [bpm]) was observed with 120 mg (31.3%) vs 80 mg (0%). Two partial responses (PRs) were observed, both in the 120 mg dose cohort. Pasireotide concentrations correlated with tumor shrinkage, although the association was not statistically significant ( =0.08). Among the biomarkers analyzed, insulin-like growth factor 1 (IGF-1) showed a decreasing trend with increasing pasireotide concentration, while chromogranin A (CgA) and neuron-specific enolase (NSE) levels did not show any dose-response relationship. The most common adverse events in any dose group were hyperglycemia, fatigue, and nausea. MTD was defined at 120 mg for pasireotide LAR in patients with advanced NETs. Although objective radiographic responses were rarely observed with somatostatin analogs, two PRs were observed among 16 patients in the 120 mg cohort. Bradycardia (HR &lt;40 bpm) appears to be a dose-limiting effect; however, the mechanism and clinical significance are uncertain. This study was registered with clinicaltrials.gov (NCT01364415).</abstract><cop>New Zealand</cop><pub>Dove Medical Press Limited</pub><pmid>28721067</pmid><doi>10.2147/OTT.S128547</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1178-6930
ispartof OncoTargets and therapy, 2017-01, Vol.10, p.3177-3186
issn 1178-6930
1178-6930
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5499931
source Taylor & Francis Open Access; Publicly Available Content Database; PubMed Central
subjects Analysis
Cancer
Cardiac arrhythmia
Care and treatment
Control
Development and progression
Diagnosis
Drug dosages
Heart rate
Laboratories
Metastasis
Neuroendocrine tumors
Original Research
Overdose
Patient outcomes
Patients
Pharmacodynamics
Pharmacokinetics
Studies
title Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T18%3A07%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phase%20I%20dose-escalation%20study%20of%20long-acting%20pasireotide%20in%20patients%20with%20neuroendocrine%20tumors&rft.jtitle=OncoTargets%20and%20therapy&rft.au=Yao,%20James%20C&rft.date=2017-01-01&rft.volume=10&rft.spage=3177&rft.epage=3186&rft.pages=3177-3186&rft.issn=1178-6930&rft.eissn=1178-6930&rft_id=info:doi/10.2147/OTT.S128547&rft_dat=%3Cgale_pubme%3EA534206780%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c507t-27a61d108cafc85adf8e6b86f389e689f14dc5ecb7a77afeb216ef633bc884743%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2242554603&rft_id=info:pmid/28721067&rft_galeid=A534206780&rfr_iscdi=true