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World Journal of Clinical CasesWorld J Clin Cases 2017 January 16; 5(1): 1-26

ISSN 2307-8960 (online)

EDITORS-IN-CHIEFGiuseppe Di Lorenzo, NaplesJan Jacques Michiels, RotterdamSandro Vento, AstanaShuhei Yoshida, Chiba

ASSOCIATE EDITORMohammed Hassan Moghadasian, Winnipeg

GUEST EDITORIAL BOARD MEMBERSHung-Yang Chang, HsinchuNing-Chia Chang, KaohsiungYao-Lung Chang, Tao YuanChang-Han Chen, KaohsiungKuen-Bao Chen, TaichungShao-Tsu Chen, HualienYen-Hsu Chen, KaohsiungYi-Ming Arthur Chen, TaipeiChi-Chun Chin, TaoyuanI-Ching Chou, Taichung Jun-Te Hsu, Tao YuanShu-Pin Huang, KaohsiungChi-Wen Juan, ChanghuaChih-Yuan Lin, TaipeiChiung-Chyi Shen, TaichungJim Jinn-Chyuan Sheu, TaiChungBing-wen Soong, TaipeiHwei-Fang Tien, TaipeiRong Kung Tsai, HualienHan-Ping Wu, TaichungHsu-Heng Yen, Changhua

MEMBERS OF THE EDITORIAL BOARD

AfghanistanDavid Bludovsky, Plzen

Ivo A Marik, Prague

AlbaniaRidvan Hamid Alimehmeti, Tirana

AustraliaJian Yuan Cheng, ClaytonDevang J Desai, ToowoombaManuel B Graeber, SydneyGulam Khandaker, SydneyFinlay A Macrae, VictoriaHarunor Rashid, SydneyHarrison S Weisinger, Geelong

AustriaIva Brcic, Graz

BangladeshForhad H Chowdhury, DhakaMd. Jafrul Hannan, ChittagongAliya Naheed, Dhaka

BelgiumGuy C Cheron, BrusselsYves Jacquemyn, EdegemJean-Yves Reginster, Liege

BrazilEverson LDA Artifon, Sao PauloJuliano J Cerci, Sao PauloDaniel Cesar, Rio de JaneiroJose Mario F de Oliveira, Rio de JaneiroFabio Francesconi do Valle, ManausMarcio A Lopes, PiracicabaHelio AG Teive, CuritibaEduardo N Trindade, Porto AlegreFlavia M Valente, Sao Paulo

BulgariaPlamen K Nedev, Varna

CanadaMark O Baerlocher, BarrieYu Chen, FrederictonAli Izadpanah, MontrealGang Li, VancouverAbdul Q Rana, TorontoHabib U Rehman, ReginaConsolato M Sergi, EdmontonRashmi R Singh, VancouverJennifer L Spratlin, EdmontonTed L Tewfik, MontrealSam M Wiseman, Vancouver

WJCC|www.wjgnet.com I January 7, 2017

Editorial Board2017-2020

The World Journal of Clinical Cases Editorial Board consists of 509 members, representing a team of worldwide experts in clinical medical research. They are from 57 countries, including Afghanistan (2), Albania (1), Australia (7), Austria (1), Bangladesh (3), Belgium (3), Brazil (9), Bulgaria (1), Canada (12), China (46), Colombia (2), Croatia (3), Egypt (5), France (3), Germany (12), Greece (15), Hungary (2), India (54), Indonesia (1), Iran (13), Iraq (1), Ireland (1), Israel (5), Italy (57), Japan (34), Jordan (1), Kazakhstan (1), Kuwait (1), Lebanon (2), Malaysia (1), Mexico (1), Morocco (2), Nepal (1), Netherlands (2), New Zealand (2), Nigeria (1), Oman (1), Pakistan (1), Peru (1), Poland (4), Portugal (3), Qatar (1), Romania (3), Saudi Arabia (4), Serbia (4), Singapore (3), Slovakia (2), Slovenia (1), South Korea (27), Spain (9), Sudan (1), Thailand (2), Trinidad and Tobago (1), Tunisia (1), Turkey (29), United Kingdom (22), United States (82).

ChinaShiu-yin Cho, Hong KongLian Duan, BeijingDavid Harold Garfield, ShanghaiYong-Song Guan, Chengdu Guo-Rong Han, NanjingBin Jiang, BeijingAlice Pik Shan Kong, Hong KongFung Yee Janet Lee, Hong KongJian-Jun Li, BeijingDezhi Mu, ChengduSimon SM Ng, Hong KongHuai-Yin Shi, BeijingSu-Sheng Shi, BeijingXue-Ying Sun, HarbinXue-Rui Tan, Shantou Feng Wang, ShanghaiGang Wang, Chengdu Niansong Wang, ShanghaiGe Xiong, BeijingZheng-Feng Yin, ShanghaiShao-Ping Yu, DongguanQing Zhang, JingzhouMing-Hua Zheng, WenzhouJun Zhong, ShanghaiYan-Ming Zhou, Xiamen

ColombiaCarlos A Calderon-Ospina, BogotaIvan Dario Velez Bernal, Medellin

CroatiaSrdana Culic, SplitTomislav Kulis, ZagrebZvonimir Lovric, Zagreb

EgyptRA Ali, MansouraFarid S El-Askary, Cairo Sherifa A Hamed, Assiut Ahmad Abd-Elgawad Nofal, ZagazigMohamed I Seleem, Cairo

FranceIsabelle Andrée Chemin, LyonJean-Francois Emile, BoulogneChristophe Martinaud, Clamart

GermanySebastian Decker, HannoverMichael Froehner, DresdenArndt Hartmann, ErlangenDirk M Hermann, EssenKarl-Anton Kreuzer, Berlin

Wolf C Mueller, LeipzigAndres HM Neuhaus, BerlinIngo S Nolte, MannheimMartin P Schencking, WittenHans-Joachim Schmoll, HalleAndreas G Schreyer, RegensburgMathias Z Strowski, Berlin

GreeceAndrew P Andonopoulos, PatrasDimitrios Daoussis, PatrasIoanna Dimopoulou, AthensMoses S Elisaf, IoanninaCostas Fourtounas, Rio-PatrasOlga-Elpis Kolokitha, ThessalonikiMarilita M Moschos, AthensNikolaos Papanas, AlexandroupolisAthanasios G Papatsoris, AthensPanagiotis Peitsidis, AthensZervoudis Stephane, AthensKonstantinos Tepetes, LarissaApostolos Tsapas, ThessalonikiMichail N Varras, AthensDimitrios Vavilis, Thessaloniki

HungaryAndreas M Fette, BudapestTibor Hortobagyi, Debrecen

IndiaSubrat K Achaya, New DelhiAmit A Agrawal, NasikHena A Ansari, AligarhM S Ansari, MeerutAshu S Bhalla, New DelhiLaxminarayan Bhandari, CalicutSachin A Borkar, New DelhiBhuvan Chanana, New DelhiKanishka Das, BangaloreReena Das, ChandigarhDeep Dutta, DelhiMimi Gangopadhyay, SiliguriRakesh Garg, New DelhiSandeep Grover, ChandigarhMeena Gupta, New DelhiMahendra S Hada, KotaProdul Hazarika, ManipalSachin B Ingle, LaturS Jayaprakash, KeralaParwez S Khan, SrinagarVivek Balkrishna Kute, AhmedabadAmol Lunkad, PuneNikhil Marwah, JaipurAmit K Mishra, IndoreSoma Mukherjee, BombayDeb S Nag, JamshedpurKushal Naha, ManipalJanardhanan C Narayanaswamy, BangaloreSoubhagya R Nayak, MangaloreNarendra Pamidi, Karnataka

Samir K Praharaj, KarnatakaPeralam Y Prakash, ManipalC S Pramesh, MumbaiKishore Puthezhath, KeralaHarbans S Randhawa, DelhiMuthukumaran Rangarajan, CoimbatoreSayantan Ray, KolkataBharat Rekhi, BombayDhananjaya Sabat, New DelhiB Saha, CalcuttaSachin C Sarode, PuneJ Sharma, UdaipurHakim Irfan Showkat, DelhiRikki Singal, MullanaDeepak K Singh, JaipurShyam Sundar, VaranasiNaveen S Tahasildar, ChandigarhDevinder M Thappa, PondicherryPradeep Vaideeswar, BombayMurali P Vettath, KozhikodeMukul Vij, ChennaiRajesh Vijayvergiya, ChandigarhSanjay Vikrant, ShimlaB Viswanatha, Bangalore

IndonesiaCoen Pramono, Surabaya

IranMasoud Amiri, ShahrekordSeyyed A Ayatollahi Mousavi, KermanMostafa Ghanei, TehranSetareh Mamishi, TehranAfshin Mohammadi, UrmiaTaher Mohammadian, TehranMohammad T Rajabi, South KargarAmin Saburi, TehranMaryam Sahebari, MashhadIman Salahshourifar, TehranPayman Vahedi, TehranAmir R Vosoughi, Shiraz

IraqBassim I Mohammad, Al-Qadisiya

IrelandRobbie SR Woods, Dublin

IsraelNimer Assy, SafedGil Bar-Sela, HaifaItzhak Braverman, HaderaGary M Ginsberg, JerusalemEyal Itshayek, Jerusalem

WJCC|www.wjgnet.com II January 7, 2017

ItalyGiovanni Addolorato, RomePiero L Almasio, PalermoFrancesco Angelico, RomeMarialuisa Appetecchia, RomeValeria Barresi, MessinaGabrio Bassotti, San SistoPaolo Boffano, AostaMaria Luisa Brandi, FlorenceMichelangelo Buonocore, PaviaGiovanni Cammarota, RomeAndrea Ciorba, FerraraLucio Cocco, BolognaCarlo Colosimo, RomeAlfredo Conti, MessinaGiovanni Conzo, NapoliGennaro Cormio, BariFabrizio D'Ascenzo, TurinLuigi De Gennaro, RomeElia De Maria, ModenaIsidoro Di Carlo, CataniaAlessandro Federico, NaplesGabriella M Ferrandina, CampobassoDavide Firinu, CagliariFrancesco Formica, Monza Caterina Foti, BariGennaro Galizia, NaplesSilvio Garattini, MilanGiampietro Gasparini, RomaGiorgio Ghilardi, MilanDomenico Girelli, VeronaCarlo Lajolo, RomeAlessandro Landi, RomeSalvatore Leonardi, CataniaCarmela Loguercio, NaplesMarianna Luongo, PotenzaRoberto Manfredini, FerraraAnnunziato Mangiola, RomeMarco Mazzocchi, RomeRoberto L Meniconi, RomeMarco Milone, NaplesPaolo Nozza, GenoaPier P Panciani, BresciaDesire' Pantalone, FirenzeIlaria Peluso, RomeRaffaele Pezzilli, BolognaGiorgina B Piccoli, TorinoRoberto Pola, RomeMarco Romano, NaplesGianantonio Saviola, MantuaStefania Scala, NaplesLeonardo A Sechi, UdineLeonello Tacconi, TriesteMatteo Tebaldi, FerraraRiccardina Tesse, BariTiziano Testori, MilanoMaddalena Zippi, RomeGianvincenzo Zuccotti, Milan

JapanUkei Anazawa, ChibaJunichi Asaumi, Okayama

Takashi Asazuma, Saitama-kenNorihiro Furusyo, Fukuoka Kunihiko Hiraiwa, ShizuokaMasaru Ishida, TokyoTatsuaki Ishiguro, TokyoHajime Isomoto, NagasakiKeita Kai, SagaTerumi Kamisawa, TokyoTatsuo Kanda, Niigata Yuichi Kasai, Tsu city Shigeyuki Kawa, MatsumotoKazushi Kishi, WakayamaSatoru Kyo, IshikawaNozomi Majima, TakatsukiKenji Miki, TokyoK Mizumoto, FukuokaRyuichi Morishita, SuitaAtsushi Nakajima, YokohamaYuzuru Niibe, KanagawaRui Niimi, Mie PrefectureMasaharu Nomura, TokyoYosuke Sato, NiigataBoban Stanojevic, Nagasaki Mitsushige Sugimoto, ShigaHaruhiko Sugimura, HamamatsuKeisuke Uehara, AichiManabu Watanabe, TokyoTakayuki Yamamoto, MieJunkichi Yokoyama, TokyoYoshihito Yokoyama, AomoriKiyoshi Yoshino, Osaka

JordanKhaled M Sarraf, Amman

KazakhstanSandro Vento, Astana

KuwaitNaorem G Singh, Jahra

LebanonKassem A Barada, BeirutRaja Sawaya, Beirut

MalaysiaMohamad N Shafiee, Kuala Lumpur

MexicoErnesto Roldan-Valadez, Mexico

MoroccoAlae El Koraichi, Rabat

Faycal Lakhdar, Rabat

NepalLaxmi V Ghimire, Kathmandu

NetherlandsJan Jacques Michiels, RotterdamPaul E Sijens, Groningen

New ZealandRita R Krishnamurthi, AucklandK Yun, Dunedin

NigeriaShamsideen A Ogun, Ikorodu

OmanItrat Mehdi, Muscat

PakistanSabiha Anis, Karachi

PeruEduardo Gotuzzo, Lima

PolandLukasz S Matuszewski, LublinTadeusz Robak, LodzAdam Wysokinski, LodzWitold A Zatonski, Warsaw

PortugalJorge Alves, BragaGustavo M Rocha, OportoZacharoula Sidiropoulou, Lisbon

QatarFahmi Y Khan, Doha

RomaniaSimona Gurzu, Targu MuresDoina Piciu, ClujMugurel C Rusu, Bucharest

Saudi ArabiaAhmed Alkhani, Riyadh

WJCC|www.wjgnet.com III January 7, 2017

Iqbal A Bukhari, Al KhobarMohamed F Ibrahim, RiyadhYashpal Singh, Al Qassim

SerbiaIvona M Djordjevic, NishJelena L Lazic, BelgradeMomcilo Pavlovic, SuboticaMihailo I Stjepanovic, Belgrade

SingaporeWei-Sheng Chong, SingaporeKhek-Yu Ho, SingaporeYong Kuei Lim, Singapore

SlovakiaMichal Mego, BratislavaPavel Skok, MariborIvan Varga, Bratislava

South KoreaYoung-Seok Cho, SeoulTae Hyun Choi, SeoulYeun-Jun Chung, SeoulKi-Baik Hahm, SeongnamSeung-Jae Hyun, Gyeonggi DoSoo Bin Im, Kyungki DoSoung Won Jeong, SeoulChoun-Ki Joo, SeoulChang Moo Kang, SeoulByung-Wook Kim, IncheonGwi Eon Kim, SeoulGyeong-Moon Kim, SeoulHahn Young Kim, SeoulMyoung Soo Kim, SeoulSeung Taik Kim, CheongjuWon Seog Kim, SeoulYoon Jun Kim, SeoulYun-Hee Kim, SeoulSun-Young Lee, SeoulSang-Chul Lim, KwangjuSeung Sam Paik, SeoulJae Yong Park, TaeguJong-Ho Park, GoyangJun-Beom Park, SeoulChan Sup Shim, SeoulHae Ryong Song, SeoulHwa-Seung Yoo, Daejeon

SpainManuel Benito, MadridVicente Carreno, MadridRosa Corcoy, BarcelonaExuperio Díez-Tejedor, MadridCarlos Alberto Dussan Luberth, TorreviejaSergio Fernandez-Pello Montes, Gijon

Luis I Gonzalez-Granado, MadridJuan D Molina Martin, MadridTomas Sobrino, Compostela

SudanSamir MH Shaheen, Khartoum

ThailandSarunyou Chusri, SongkhalWeekitt Kittisupamongkol, Bangkok

Trinidad and TobagoDale A Maharaj, Trincity

TunisiaMakram Koubaa, Sfax

TurkeySami Akbulut, MalatyaTamer Akca, MersinCengiz Akkaya, BursaAhmet Baydin, KurupelitHasan Belli, IstanbulSerbülent G Beyaz, SakaryaGüldeniz K Cakmak, Kozlu ZonguldakTurgay Celik, AnkaraYasemin B Cihan, KayseriOmür Dereci, AnkaraMehmet Doganay, KayseriAylin T Ermertcan, ManisaKadir Ertem, MalatyaAydin Gulses, AnkaraMustafa K Gumus, KayseriF. Neslihan Inal-Emiroglu, IzmirRamazan Kahveci, KirikkaleSaadettin Kilickap, AnkaraFatih Kucukdurmaz, IstanbulAslihan Kucuker, AnkaraNuray B Muluk, CankayaOrhan V Ozkan, SakaryaZeynep Ozkurt, IstanbulMustafa Sahin, AnkaraIbrahim Sakcak, AnkaraFeyzi B Sarica, AdanaIlke Sipahi, IstanbulSelim Sozen, KayseriMurat Ugurlucan, Istanbul

United KingdomHenry DE Atkinson, LondonIoannis G Baraboutis, PeterboroughI Beegun, LondonRoy G Beran, LiverpoolRicky H Bhogal, Birmingham

Kuntal Chakravarty, EssexDeyaa Elsandabesee, Great YarmouthRadwan Faraj, South YorkshireBabatunde A Gbolade, LeedsSanju George, BirminghamDavid JA Goldsmith, LondonNadey S Hakim, LondonKoshy Jacob, ManchesterAndrew RL Medford, LeicesterRahul T Rao, LondonFrancis P Rugman, PrestonCrispin Schneider, NottinghamYousef Shahin, HullBadri M Shrestha, SheffieldJagdeep S Virk, HarrowJames CL Wong, ManchesterKimia Ziahosseini, Liverpool

United StatesDoru T Alexandrescu, New YorkNaim Alkhouri, ClevelandMohammad M Alsolaiman, LehiBhupinder S Anand, HoustonSuresh J Antony, El PasoNormadeane Armstrong, New YorkWilbert S Aronow, ValhallaHossam M Ashour, DetroitRajendra Badgaiyan, BuffaloJoseph R Berger, LexingtonDennis A Bloomfield, New YorkNeil F Box, AuroraJeffrey A Breall, IndianapolisSusana M Campos, BostonRobert Carter III, San AntonioKaisorn L Chaichana, BaltimoreAntonio J Chamoun, ThorndaleVince P Clark, AlbuquerqueC. Donald Combs, NorfolkSuzanne M Crumley, HoustonAlain Cruz Portelles, PlantationParakkal Deepak, EvanstonDale Ding, CharlottesvilleYuchuan Ding, DetroitKonstantin H Dragnev, LebanonCecilia L Dragomir, New YorkKonstantinos P Economopoulos, BostonJames M Ford, StanfordYun Gong, HoustonZeba H Hafeez, Las VegasArdeshir Hakam, TampaT. Patrick Hill, New BrunswickHitoshi Hirose, PhiladelphiaElias Jabbour, HoustonRobert T Jensen, BethesdaHuanguang Jia, GainesvilleZhong Jiang, WorcesterTheodoros Kelesidis, Los AngelesKusum K Kharbanda, OmahaPraveen Kumar, ChicagoJulius GS Latorre, SyracuseGuojun Li, HoustonSophia Lionaki, Chapel Hill

WJCC|www.wjgnet.com IV January 7, 2017

Yaling Liu, RochesterMarios-Nikolaos Lykissas, New YorkKenneth Maiese, NewarkMahdi Malekpour, DanvilleSerge P Marinkovic, LafayetteCharles C Matouk, New HavenKapil Mehta, HoustonZaher Merhi, BrooklynAyse L Mindikoglu, BaltimoreMajaz Moonis, WorcesterAssad Movahed, GreenvilleMohammad R Movahed, TucsonSrinivasan Paramasivam, New York

Edwin M Posadas, Los AngelesXiaofa Qin, WestfieldMichel E Rivlin, JacksonJae Y Ro, HoustonBruce S Rudy, HersheyAbdulaziz Sachedina, CharlottesvilleRavi P Sahu, IndianapolisMichael W Schlund, BaltimoreEric L Scott, IndianapolisVolney L Sheen, BostonHerrick J Siegel, BirminghamSubbaya Subramanian, MinneapolisJessica D Sun, South San Francisco

Ulas Sunar, BuffaloJohn A Tayek, TorranceScott Tenner, BrooklynDiana O Treaba, ProvidenceRichard G Trohman, ChicagoMing C Tsai, New YorkVassiliy Tsytsarev, BaltimoreJun Yao, ChicagoShahram Yazdani, Los AngelesPanitan Yossuck, MorgantownStanley Zaslau, MorgantownSheng Zhang, New HavenXinmin Zhang, Philadelphia

WJCC|www.wjgnet.com V January 7, 2017

World Journal ofClinical CasesW J C C

Contents Monthly Volume 5 Number 1 January 16, 2017

IWJCC|www.wjgnet.com January 16, 2017|Volume 5|Issue 1|

ORIGINAL ARTICLE

Basic Study

1 InversecorrelationbetweenCD8+inflammatorycellsandE-cadherinexpressioningallbladdercancer:

Tissuemicroarrayandimaginganalysis

Kai K, Masuda M, Aishima S

CASE REPORT9 Cardiacpapillaryfibroelastoma:Theneedforatimelydiagnosis

Yandrapalli S, Mehta B, Mondal P, Gupta T, Khattar P, Fallon J, Goldberg R, Sule S, Aronow WS

14 Intra-abdominalabscessandintractablesinus-ararelatecomplicationaftersplenectomy

Shrestha B, Hampton J

18 Localadvancedrectalcancerperforationinthemidstofpreoperativechemoradiotherapy:Acasereport

andliteraturereview

Takase N, Yamashita K, Sumi Y, Hasegawa H, Yamamoto M, Kanaji S, Matsuda Y, Matsuda T, Oshikiri T, Nakamura T, Suzuki S,

Koma YI, Komatsu M, Sasaki R, Kakeji Y

LETTERS TO THE EDITOR24 Conscienceimperativeofprovidinginformationandknowledgeinhepatology:ThePortugueseapproach

Macedo G, Silva M

ContentsWorld Journal of Clinical Cases

Volume 5 Number 1 January 16, 2017

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Xiang Li Responsible Science Editor: Fang-Fang JiResponsible Electronic Editor: Dan Li Proofing Editorial Office Director: Xiu-Xia SongProofing Editor-in-Chief: Lian-Sheng Ma

Shuhei Yoshida, MD, PhD, Division of Gastroenter-ology, Beth Israel Deaconess Medical Center, Dana 509, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States

EDITORIALBOARDMEMBERSAll editorial board members resources online at http://www.wjgnet.com/2307-8960/editorialboard.htm

EDITORIALOFFICEXiu-Xia Song, DirectorWorld Journal of Clinical CasesBaishideng Publishing Group Inc8226 Regency Drive, Pleasanton, CA 94588, USATelephone: +1-925-2238242Fax: +1-925-2238243E-mail: [email protected] Desk: http://www.wjgnet.com/esps/helpdesk.aspxhttp://www.wjgnet.com

PUBLISHERBaishideng Publishing Group Inc8226 Regency Drive, Pleasanton, CA 94588, USATelephone: +1-925-2238242Fax: +1-925-2238243E-mail: [email protected]

Help Desk: http://www.wjgnet.com/esps/helpdesk.aspxhttp://www.wjgnet.com

PUBLICATIONDATEJanuary 16, 2017

COPYRIGHT© 2017 Baishideng Publishing Group Inc. Articles published by this Open Access journal are distributed under the terms of the Creative Commons Attribu-tion Non-commercial License, which permits use, dis-tribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.

SPECIALSTATEMENTAll articles published in journals owned by the Baishideng Publishing Group (BPG) represent the views and opinions of their authors, and not the views, opinions or policies of the BPG, except where other-wise explicitly indicated.

INSTRUCTIONSTOAUTHORShttp://www.wjgnet.com/bpg/gerinfo/204

ONLINESUBMISSIONhttp://www.wjgnet.com/esps/

IIWJCC|www.wjgnet.com

ABOUT COVER

AIM AND SCOPE

INDExING/ABSTRACTING

January 16, 2017|Volume 5|Issue 1|

NAMEOFJOURNALWorld Journal of Clinical Cases

ISSNISSN 2307-8960 (online)

LAUNCHDATEApril 16, 2013

FREQUENCYMonthly

EDITORS-IN-CHIEFGiuseppe Di Lorenzo, MD, PhD, Professor, Geni-tourinary Cancer Section and Rare-Cancer Center, Uni-versity Federico II of Napoli, Via Sergio Pansini, 5 Ed. 1, 80131, Naples, Italy

Jan Jacques Michiels, MD, PhD, Professor, Primary Care, Medical Diagnostic Center Rijnmond Rotterdam, Bloodcoagulation, Internal and Vascular Medicine, Eras-mus University Medical Center, Rotterdam, Goodheart Institute and Foundation, Erasmus Tower, Veenmos 13, 3069 AT, Erasmus City, Rotterdam, The Netherlands

Sandro Vento, MD, Department of Internal Medicine, University of Botswana, Private Bag 00713, Gaborone, Botswana

EditorialBoardMemberofWorldJournalofClinicalCases,FengWang,MD,PhD,AssociateProfessor,DepartmentofNephrology,ShanghaiJiaoTongUniversityAffiliatedSixthPeople'sHospital,Shanghai200233,China

World Journal of Clinical Cases (World J Clin Cases, WJCC, online ISSN 2307-8960, DOI: 10.12998) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians.

The primary task of WJCC is to rapidly publish high-quality Autobiography, Case Re-port, Clinical Case Conference (Clinicopathological Conference), Clinical Management, Diagnostic Advances, Editorial, Field of Vision, Frontier, Medical Ethics, Original Ar-ticles, Clinical Practice, Meta-Analysis, Minireviews, Review, Therapeutics Advances, and Topic Highlight, in the fields of allergy, anesthesiology, cardiac medicine, clinical genetics, clinical neurology, critical care, dentistry, dermatology, emergency medicine, endocrinol-ogy, family medicine, gastroenterology and hepatology, geriatrics and gerontology, he-matology, immunology, infectious diseases, internal medicine, obstetrics and gynecology, oncology, ophthalmology, orthopedics, otolaryngology, pathology, pediatrics, peripheral vascular disease, psychiatry, radiology, rehabilitation, respiratory medicine, rheumatology, surgery, toxicology, transplantation, and urology and nephrology.

World Journal of Clinical Cases is now indexed in PubMed, PubMed Central.

I-V EditorialBoardFLYLEAF

Keita Kai, Masanori Masuda, Shinichi Aishima

ORIGINAL ARTICLE

� January �6, 20�7|Volume 5|Issue �|WJCC|www.wjgnet.com

Inverse correlation between CD8+ inflammatory cells and E-cadherin expression in gallbladder cancer: Tissue microarray and imaging analysis

Basic Study

Keita Kai, Shinichi Aishima, Department of Pathology, Saga University Hospital, Saga 849-8501, Japan

Masanori Masuda, Shinichi Aishima, Department of Pathology and Microbiology, Saga University Faculty of Medicine, Saga 849-8501, Japan

Author contributions: Kai K is the main author of this article and performed the data correction and statistical analyzes; Masuda M contributed to the data collection; Aishima S reviewed the manuscript; all authors have read and approved the final manuscript.

Institutional review board statement: The study protocol was approved by the Ethics Committee of the Faculty of Medicine at Saga University (approval no. 27-19).

Informed consent statement: Written informed consent for the use of resected tissue and clinical information was obtained from all patients.

Conflict-of-interest statement: The authors declare that they have no conflicts of interest.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Invited manuscript

Correspondence to: Dr. Keita Kai, Department of Pathology, Saga University Hospital, Nabeshima 5-1-1, Saga 849-8501, Japan. [email protected]: +81-952-343264Fax: +81-952-342055

Received: June 22, 2016

Peer-review started: June 27, 2016First decision: August 11, 2016Revised: August 27, 2016Accepted: October 25, 2016Article in press: October 27, 2016Published online: January 16, 2017

AbstractAIMTo investigated the association between the tumor cells’ expression of E-cadherin and the numbers of several types of inflammatory cells infiltrating into the invasive portion of gallbladder cancer (GBC).

METHODSWe analyzed 50 GBC cases for which a sufficient amount of tumor tissues for tissue microarray (TMA) had been saved. Three tissue cores (3.0 mm) of invasive lesion from each case were used for the TMA. The 4-μm cut sections on slides were immunostained using primary antibodies including E-cadherin for cancer cells, leukocyte common antigen for leukocyte, myeloperoxidase for neutrophils, CD3 for T cells, CD4 for helper T cells, CD8 for killer T cells, CD20 for B cells and CD68 for macrophages. The immunostained slides were digitally analyzed by imaging analysis software.

RESULTSA significant inverse correlation between the number of infiltrating CD8+ cells at invasive areas and the ex-pression of E-cadherin by cancer cells was observed (P = 0.0001), although the degree of this correlation was relatively weak (R = 0.32). The number of CD8+ cells and the cancer cells’ E-cadherin expression were also significantly correlated with tumor differentiation (well-differentiated vs poorly differentiated) (P = 0.0467 and P = 0.0294, respectively). Inverse correlation of T-stage

Submit a Manuscript: http://www.wjgnet.com/esps/Help Desk: http://www.wjgnet.com/esps/helpdesk.aspxDOI: �0.�2998/wjcc.v5.i�.�

World J Clin Cases 20�7 January �6; 5(�): �-8 ISSN 2307-8960 (online)

© 20�7 Baishideng Publishing Group Inc. All rights reserved.


2 January �6, 20�7|Volume 5|Issue �|WJCC|www.wjgnet.com

Kai K et al . E-cadherin and CD8+ lymphocyte in GBC

and the number of CD8+ cell infiltration was observed with statistical significance in comparison of T2 and T3 cases (P = 0.0324).

CONCLUSIONOur findings indicate an inverse correlation of CD8+ T cell infiltration and cancer cells’ E-cadherin expression at invasive areas of GBC. Further analyses are essential to test these findings.

Key words: E-cadherin; Inflammation; CD8; Gallbladder cancer; Tissue microarray

© The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: We analyzed the association between the expression of E-cadherin in tumor cells and the type and amount of inflammatory cells infiltrating into the invasive portion of gallbladder cancer, using tissue microarray and imaging analyses. The results indicated an inverse correlation of CD8+ T cell infiltration and E-cadherin expression by cancer cells at invasive areas of gallbladder cancer. Further analyses are essential to test these results.

Kai K, Masuda M, Aishima S. Inverse correlation between CD8+ inflammatory cells and E-cadherin expression in gallbladder cancer: Tissue microarray and imaging analysis. World J Clin Cases 2017; 5(1): 1-8 Available from: URL: http://www.wjgnet.com/2307-8960/full/v5/i1/1.htm DOI: http://dx.doi.org/10.12998/wjcc.v5.i1.1

INTRODUCTIONGallbladder cancer (GBC) often shows the dedifferentiation or clustering of tumor cells (tumor budding) at the areas of infiltration, and a high degree of inflammatory response usually accompanies these findings[1]. Dedifferentiation is often associated with increased aggressiveness of a tumor. Although genetic heterogeneity, genome instability and epithelialmesenchymal transition are considered mechanisms of dedifferentiation, the mechanism of dedifferentiation has not been established[2,3]. The concept of tumor budding was first established in colorectal cancer and was considered to be associated with the initial phase of tumor invasion and then with metastatic activity and prognostic outcome in various types of solid tumors[1,4,5], but the mechanism underlying tumor budding has not been clearly demonstrated.

Cellcell adhesion participates in histogenesis and the maintenance of cell polarity and tissue structure. It has long been known that the mutual adhesiveness of cancer cells is significantly weaker than that of the corresponding normal cells[6,7]. Reduced cellcell adhesiveness allows cancer cells to destruct of the histological structure of tumor tissue, resulting in the dedifferentiation of the tumor. Ecadherin is a wellknown cell adhesion molecule

composed of a series of components, each comprised of approximately 110 amino acid residues. Ecadherin forms a complex with three cytoplasmic proteins (alpha, beta and gammacatenins), and the Ecadherincatenin complex plays a key role in cellular adhesion; the loss of this function has been associated with tumor dedifferentiation and metastasis[8].

The microenvironment of cancer changes dramatically in relation to invasion into the stroma due to the changes of blood flow, metabolism and the direct interaction of inflammatory cells. We speculated that the type or amount of inflammatory cells that infiltrate into invasive areas may play some roles in the loss of Ecadherin function, and that tumorinfiltrating inflammatory cells thus contribute to the dedifferentiation of GBC. The purpose of this study was to determine the association between the expression of Ecadherin in tumor cells and the type and amount of inflammatory cells infiltrating into the invasive portion of GBC.

MATERIALS AND METHODSPatients and tissue microarray preparationWe selected a total of 50 GBC cases for which a sufficient amount of formalinfixed, paraffinembedded tumor tissues for tissue microarray (TMA) had been saved from resection of the primary lesion at Saga University Hospital between 1994 and December 2010. Three tissue cores (3.0 mm) of the invasive lesion from each case were used for the TMA. Written informed consent for the use of resected tissue and clinical information was obtained from all patients, and the study protocol was approved by the Ethics Committee of the Faculty of Medicine at Saga University (approval No. 2719). Clinical and histopathological staging were based on the TNM Classification of Malignant Tumors by the International Union against Cancer (7th edition)[9].

The inflammatory cell analysis strategy and immunohistochemical stainsThe inflammatory cell analysis strategy is summarized in Figure 1. The labels that were initially considered for inflammatory cells were as follows: Leukocyte common antigen (LCA) for leukocytes, myeloperoxidase (MPO) for

Strategy of inflammatory cell analysis

Leukocyte(LCA)

Neutrophil (MPO)

Lymphocyte

Macrophage (CD68)

Dendritic cell (CD1a)

T cell (CD3)

B cell (CD20)

Helper T cell (CD4)

Killer T cell (CD8)

NK-T cell (CD56)

Plasma cell (CD38)

Figure 1 The inflammatory cell analysis strategy. Gray filled shows items which was not able to analyze by Tissue studio (because of positive stain of tumor cells). LCA: Leukocyte common antigen; MPO: Myeloperoxidase.


neutrophils, CD3 for T cells, CD4 for helper T cells, CD8 for killer T cells, CD56 for natural killer T cells, CD20 for B cells, CD38 for plasma cells, CD68 for macrophages and CD1a for dendritic cells. Among them, CD56, CD38 and CD1a were excluded from the analysis because the imaging analysis software could not accurately detect inflammatory cells due to positive staining of the tumor cells. The primary antibodies used are summarized in Table 1. The 4μm cut sections on slides were heated in EDTA (pH 9.0) by a microwave for antigen retrieval. The Envision+® System (Dako Cytomation, Glostrup, Denmark) was used as the secondary antibody. The slides were visualized by diaminobenzidine tetrahydrochloride, and nuclei were counterstained with hematoxylin. An Autostainer plus® automatic stainer (Dako Cytomation) was used for staining.

Imaging analysisImmunostained tissue microarray slides were digitally scanned by the NanoZoomer 2.0HT digital slide scanner (Hamamatsu Photonics, Hamamatsu, Japan) with 20× magnification for the imaging analysis. The numbers of positively stained inflammatory cells were automatically counted by the imaging analysis software, Tissue Studio (Definiens, München, Germany) (Figure 2). The membranous expression of Ecadherin was assessed by the histological score that was automatically calculated by Tissue Studio (Figure 3). Tissue Studio digitally evaluated the membranous expression of Ecadherin and categorized the expression into three grades (high, medium and low), and the histological score was calculated by the following formula: 1 × %Low + 2 × %Medium + 3 × %High.

Statistical analysisWe used JMP ver. 12 software (SAS Institute, Cary, NC, United States) for all statistical analyses. The comparisons of two groups were performed using a simple linear regression analysis, and each pair was analyzed using Student’s t-test as appropriate. Probability values < 0.05 were considered significant.

RESULTSThe population of inflammatory cells at the invasive sites of GBCThe numbers of inflammatory cells per TMA core are

summarized in Table 2. Many acute inflammatory cells such as MPO+ neutrophils and CD68+ macrophages (average numbers/core were 2692.39 and 2452.99, respectively) were infiltrated into invasive sites of the GBCs. Regarding the composition of infiltrating lymphocytes, CD8+ killer T cells showed the largest number, followed by CD4+ helper T cells; CD20+ B cells were the least in number (avg. nos./core were 919.44, 583.01 and 467.95). All of the types of inflammatory cells showed a large standard deviation, indicating that the number and composition of inflammatory cells were quite different in each case.

Correlation between E-cadherin expression and the type of inflammatory cellsThe results of our single linear regression analysis between E-cadherin expression and the type of inflammatory cells are summarized in Table 3. The immunohistochemical markers of inflammatory cells that were shown to be significantly correlated with the expression of E-cadherin were LCA (P = 0.0482), CD3 (P = 0.011) and CD8 (P = 0.0001). The linear regression models of these factors are demonstrated in Figure 4. An inverse correlation between the number of CD8+ cells and the expression of Ecadherin was observed, but the degree of this correlation was relatively weak (R = 0.32).

Clinicopathological data and correlations with pathologically assessed differentiationThe clinicopathological data, number of CD8+ cells (means of analyzable cores in each case) and Ecadherin histological score (means of analyzable cores in each cases) of the 50 GBC cases are presented in Table 4. The numbers of cases in which the pathologically assessed differentiation of invasive front was observed were as follows. G1 (well-differentiated), 16 cases (32.0%); G2 (moderately differentiated), 19 cases (38.0%); G3 (poorly differentiated), 15 cases (30.0%). The median ± SD of CD8+ cells was 580.0 ± 1154.5, and the E-cadherin histological score was 114.3 ± 37.8.

Figure 5 illustrates the correlations of pathologically assessed differentiation with the number of infiltrating

Antibody Dilution Clone Manufacturer

LCA Prediluted PD7/26, 2B�� Nichirei Biosciences, TokyoMPO �:200 Polyclonal DakoCytomation, Glostrup,

DenmarkCD3 Prediluted PS� Nichirei BiosciencesCD4 Prediluted 4B�2 Nichirei BiosciencesCD8 �:50 C8/�44B DakoCytomationCD20 �:50 L26 DakoCytomation

Table 1 The primary antibodies used for immunohistochemistry

LCA: Leukocyte common antigen; MPO: Myeloperoxidase. 100 μm

A B

Figure 2 Images of CD8+ lymphocytes. A: Original image of CD8-immunostained slide of an invasive area; B: The software Tissue Studio detects the positive cells and counts them automatically.



CD8+ cells in each case or with the Ecadherin histological score in each case, with each pair analyzed by Student’s ttest. A significant difference was observed in the comparison

of G1 and G3 cases according to the number of CD8+

cells (P = 0.0467) and according to the Ecadherin histological score (P = 0.0294).

Maximun positive cell counts/core Minimun positive cell counts/core Average/core Standard deviation/core No. of analyzable cores

LCA �3962 73 3�08.27 2734.79 �36MPO �09�� 388 2692.39 �830.47 �3�CD3 �4702 74 �967.06 2058.45 �30CD4 6583 0 583.0� 934.52 �34CD8 5572 �0 9�9.44 �034.35 �3�CD20 7097 4 467.95 834.74 �33CD68 ��355 97 2452.99 2043.92 �35

Table 2 The numbers of inflammatory cells per tissue microarray core

LCA: Leukocyte common antigen; MPO: Myeloperoxidase.

Cells Regression equation Adjusted R2 R Standard error P value

LCA EHS = 117.67879 − 0.0029223 × LCA 0.02�6 0.�5 46.5793 0.0482CD20 EHS = 112.37344 − 0.0083497 × CD20 0.0�53 0.�2 45.8466 0.083CD3 EHS = 119.86794 − 0.0050479 × CD3 0.042� 0.2� 45.7�07 0.0��CD4 EHS = 109.63264 − 0.0003939 × CD4 < 0.000� n/a 47.�9�3 0.9285CD8 EHS = 121.37735 − 0.0146326 × CD8 0.�0�� 0.32 43.6707 0.000�MPO EHS = 104.23773 + 0.0012811 × MPO −0.00523 n/a 46.9647 0.570�CD68 EHS = 113.83072 − 0.0023317 × CD68 0.0029 0.05 46.8666 0.24�2

Table 3 Single linear regression analysis of the relationship between E-cadherin expression and the type of inflammatory cells

EHS: E-cadherin histological score; n/a: Not available; LCA: Leukocyte common antigen; MPO: Myeloperoxidase.

A B

C D

Figure 3 Images of E-cadherin expression in cancer cells. A: Low-magnification image of an E-cadherin-immunostained TMA core; B: Low-magnification image of E-cadherin-immunostained TMA core analyzed by Tissue Studio; C: High-magnification (× 400) image of an E-cadherin-immunostained TMA core; D: High-magnification (× 400) image of an E-cadherin-immunostained TMA core analyzed by Tissue Studio. The membranous expression of E-cadherin was assigned to three categories of the degree of expression: High (brown), medium (orange) and low (yellow). The histological score was calculated by the following formula: 1 × %Low + 2 × %Medium + 3 × %High. TMA: Tissue microarray.



Relationship between TMN-stage and E-cadherin expression or CD8+ cell infiltrationNo distant metastasis (M1) case was involved in this study. The mean ± SD of number of infiltrating CD8+ cells with T2, T3 and T4 tumors were 1489.05 ± 1607.22, 747.33 ± 719.87 and 506.92 ± 336.37, respectively. The mean ± SD of E-cadherin histological score with T2, T3 and T4 tumors were 101.69 ± 37.90, 108.27 ± 37.04 and 133.75 ± 42.30, respectively. Figure 6 illustrates the correlations of Tstage with the Ecadherin histological score in each case or with the number of infiltrating CD8+

cells in each case. A significant difference was observed in the comparison of T2 and T3 cases according to the number of CD8+ cells (P = 0.0324).

The mean ± SD of number of infiltrating CD8+ cells of N0 and N1 cases was 1109.10 ± 1618.16 and 936.39 ± 849.25, respectively. The mean ± SD of E-cadherin histological score of N0 and N1 cases was 117.73 ± 9.11 and 102.90 ± 6.54, respectively. Figure 7 illustrates the Nstage with the Ecadherin histological score in each case or with the number of infiltrating CD8+ cells in each case. No significant difference was observed in each comparison.

DISCUSSIONThis study analyzed the association between the expression of E-cadherin at tumor cells and inflammatory cells infiltrating into the invasive area of GBC, using the TMA technique and imaging analysis software. Our observation that relatively large numbers of acute inflam-matory cells such as neutrophils and macrophages had infiltrated into invasive areas seems reasonable, since the gallbladder frequently develops acute inflammation manifested as acute cholecystitis. Although neutrophils have the potential for cell damage/destruction by the degranulation of their arsenal of cytotoxic chemicals

Age Mean ± SD 68.7 ± 8.4Gender Male �5 (30.0)

Female 35 (70.0)Differentiation of invasive front G� �6 (32.0)

G2 �9 (38.0)G3 �5 (30.0)

T-stage T2 �8 (36.0)T3 28 (56.0)T4 4 (8.0)

N N0 �7 (34.0)N� 33 (66.0)

No. of CD8-positive cells (means of analyzable cores in each case)

Median ± SD 580.0 ± ��54.5

E-cadherin histological score Median ± SD ��4.3 ± 37.8

Table 4 Clinicopathologic features of the patients with gallbladder cancer (n = 50) n (%)

250

200

150

100

50

0E-ca

dher

in h

isto

logi

cal s

core

cel

ls

0 2000 4000 6000 8000 10000 14000

P = 0.0482|R| = 0.15

LCA nucleus positive

250

200

150

100

50

0E-ca

dher

in h

isto

logi

cal s

core

cel

ls

0 2000 4000 6000 8000 10000 14000

P = 0.011|R| = 0.21

CD3 nucleus positive

250

200

150

100

50

0

E-ca

dher

in h

isto

logi

cal s

core

0 1000 2000 3000 4000 5000 6000

P = 0.0001|R| = 0.32

CD8 nucleus positive

A B C

Figure 4 The single linear regression models of the relationship between E-cadherin expression (histological score) and the numbers of cells. The cells were positively immunostained by LCA (A), CD3 (B) and CD8 (C) antibodies.

2000

1500

1000

500

0

No.

of

CD8

posi

tive

cells

G1 G2 G3

P = 0.0467

Differentiation

P = 0.1364

P = 0.5392

200

150

100

50

E-ca

dher

in h

isto

logi

cal s

core

G1 G2 G3

P = 0.0294

Differentiation

P = 0.4707P = 0.1112

A

B

Figure 5 The box-and-whisker plots regarding pathologically assessed differentiation and the number of CD8+ cells (A) and the E-cadherin histological score (B). Significant differences were observed in the comparison of G1 and G3 cases according to the number of CD8+ cells (P = 0.0467) and according to the E-cadherin histological score (P = 0.0294), respectively.



and enzymes[10], we observed no association between neutrophil infiltration and the Ecadherin expression of the tumor cells in this study.

Among the analyzed inflammatory cells, significant associations with Ecadherin expression by tumor cells were observed in the infiltration of leukocytes (LCA), T cells (CD3) and CD8+ T cells. In light of the degree of statistical correlation and theoretical considerations, we interpret our present findings as showing that CD8+ T cells are involved in the loss or attenuation of Ecadherin expression in GBC.

Generally, CD8+ T cells have been considered manifestations of host immune reactions against cancer cells, and favorable prognostic impacts of CD8+ T cells have been found in a wide variety of solid cancer tissues[1118]. Regarding GBC, the prognostic impact of CD8+ T cell has been less investigated, and it remains controversial[19,20]. Herein we investigated the correlation between the invasion of CD8+ T cells or Ecadherin expression of tumor cells and the prognosis of GBC cases (disease free survival, overall survival and disease specific survival), and no significant relationship was found (data not shown).

It is interesting finding that the number of infiltrating CD8+ cells were significantly fewer in T3 cases than that of T2 cases. Although it is not statistically significant, the number of infiltrating CD8+ cells were fewer in T4 cases than that of T3 cases. Similar results, namely

inverse correlation of Tstage and the density of CD8+ cell infiltration has been reported in colorectal cancer[21]. It is hypothesized that progressive decrease of CD8+ cell densities along with tumor invasion could indicate a progressive immune escape and the magnitude of the immune reaction at the early stage of the disease could be a major determinant for controlling the evolution of colorectal cancer[21].

Same as other sites of cancer, a reduced expression of Ecadherin by cancer cells compared to nontumorous epithelium has been reported in GBC[22]. The major find-ing of the present study is the inverse correlation of CD8+ Tcell infiltration and Ecadherin expression by cancer cells. This result might be interpreted in the following two ways. The first interpretation is that the expression of Ecadherin by tumor cells is initially reduced by unknown causes, and then the tumor invaded stroma and CD8+ T-cell infiltration is an immune response to the invading tumor. If this is so, it gives rise to the hypothesis that the more reduced the Ecadherin expression of the tumor is, the greater the amount of CD8+ T cells attracted will be.

A second interpretation of the results of the present study is that infiltrating CD8+ T cells affects the reduced expression of Ecadherin. The mechanisms of the inactivation of the E-cadherin are: (1) a consequence of genetic alterations of Ecadherin; (2) genetic alterations of betacatenin; and (3) a loss of the interaction of betacatenin and Ecadherin due to the tyrosine phosphorylation

7000600050004000300020001000

0-1000

No.

of

CD8

posi

tive

cells

T1 T2 T3

P = 0.1172

T-stage

P = 0.0324P = 0.6880

A

150

100

50

E-ca

dher

in h

isto

logi

cal s

core

T2 T3 T4

P = 0.1307

T-stage

P = 0.5666

P = 0.2123

B

Figure 6 The box-and-whisker plots regarding T-stage and the number of CD8+ cells (A) and the E-cadherin histological score (B). A significant difference was observed in the comparison of T2 and T3 cases according to the number of CD8+ cells (P = 0.0324).

7000

6000

5000

4000

3000

2000

1000

0

-1000

No.

of

CD8

posi

tive

cells

N0 N1

P = 0.6213

N-stage

A

200

150

100

50E-ca

dher

in h

isto

logi

cal s

core

N0 N1

P = 0.1924

N-stage

B

Figure 7 The box-and-whisker plots regarding N-stage and the number of CD8+ cells (A) and the E-cadherin histological score (B). No significant difference was observed in each comparison.



of betacatenin[8]. If CD8+ T cells reduce Ecadherin expression, the focus of investigation should be to determine whether CD8+ T cells affect any or all of the abovedescribed mechanisms for the inactivation of Ecadherin.

Either way, our results do not adequately establish the relationship between CD8+ T cell and Ecadherin expression. It also remains in doubt whether the results of a TMA analysis truly reflect the status of the entire tumor. In addition, the microenvironment of a tumor is not composed of only inflammatory cells but also extracellular matrix and surrounding blood vessels; a degree of hypoxia and tumorassociated fibroblasts also contribute to the tumor microenvironment and interact with each other in a complex manner. We found no study in the English literature that provides evidence that the loss of Ecadherin expression promotes CD8+ T-cell infiltration, or evidence that CD8+ T cells reduce the Ecadherin expression in cancer cells, which would support our results. Therefore, a prudent validation by different research methods is essential to establish the correlation between CD8+ T cells and Ecadherin expression in cancer cells.

In conclusion, the results of the present study indicate an inverse correlation of CD8+ Tcell infiltration and Ecadherin expression by cancer cells at invasive areas of GBC. However, our data are not enough to establish the above interaction, and further experimental and clinicopathological analyses are needed to test our results.

COMMENTSBackgroundGallbladder cancer (GBC) often shows the dedifferentiation or clustering of tumor cells at the areas of infiltration. The author speculated that the type or amount of inflammatory cells that infiltrate into invasive areas of GBC may play some roles in the loss of E-cadherin function, and that tumor-infiltrating inflammatory cells thus contribute to the dedifferentiation of GBC.

Research frontiersThis study quantitatively assessed the type and amount of inflammatory cells infiltrating into invasive front of GBC using tissue microarray technique and latest imaging analysis software.

Innovations and breakthroughsThe results of present study indicate an inverse correlation of CD8+ T cell infiltration and cancer cells’ E-cadherin expression at invasive areas of GBC. No previous study in the English literature provides evidence that the loss of E-cadherin expression promotes CD8+ T cell infiltration, or evidence that CD8+ T cells reduce the E-cadherin expression in cancer cells. Their results also indicate the inverse correlation of T-stage and the number of CD8+ T cell infiltration.

ApplicationsThe goal of the study is to clarify the correlation of CD8+ T cell infiltration and E-cadherin expression of cancer cells. These results would be applicable to clarify the mechanism of dedifferentiation and metastasis of cancer. However, further analyses are essential for conclusive result for the correlation of CD8+ T cell infiltration and E-cadherin expression of cancer cells.

TerminologyE-cadherin is a well-known cell adhesion molecule and the E-cadherin-catenin complex plays a key role in cellular adhesion; the loss of this function has been associated with tumor dedifferentiation and metastasis. A CD8+ T cell was known

as cytotoxic T cell or killer T cell that kills cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways.

Peer-reviewThis study investigates the association between the expression of E-cadherin and the numbers of several types of inflammatory cells infiltrating into the invasive portion of GBC.

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P- Reviewer: Ding HG, Peng Y, Wang DH S- Editor: Qiu S L- Editor: A E- Editor: Li D


Srikanth Yandrapalli, Bella Mehta, Pratik Mondal, Tanush Gupta, Pallavi Khattar, John Fallon, Randy Goldberg, Sachin Sule, Wilbert S Aronow

CASE REPORT

� January 16, 2017|Volume 5|Issue 1|WJCC|www.wjgnet.com

Cardiac papillary fibroelastoma: The need for a timely diagnosis

Srikanth Yandrapalli, Bella Mehta, Pratik Mondal, Tanush Gupta, Randy Goldberg, Sachin Sule, Department of Internal Medicine, New York Medical College at Westchester Medical Center, Valhalla, NY 10595, United States

Pallavi Khattar, John Fallon, Department of Pathology, New York Medical College at Westchester Medical Center, Valhalla, NY 10595, United States

Wilbert S Aronow, Department of Cardiology, New York Medical College at Westchester Medical Center, Valhalla, NY 10595, United States

Author contributions: Yandrapalli S, Mehta B, Mondal P, Gupta T and Goldberg R identified the cases, collected patient data, and drafted a preliminary report; Khattar P and Fallon J were involved in the pathological diagnoses, provided histopathological slides and provided guidance regarding the pathological aspects of the condition; Sule S and Aronow WS reviewed the paper and made critical changes.

Institutional review board statement: This manuscript is exempt from institutional review board committee approval.

Informed consent statement: Any information which can lead to identification of the cases has been removed.

Conflict-of-interest statement: None of the authors report any conflicts of interest.


Manuscript source: Invited manuscript

Correspondence to: Wilbert S Aronow, MD, FACC, FAHA, Professor of Medicine, Department of Cardiology, New York

Medical College at Westchester Medical Center, Macy Pavilion, Room 141, Valhalla, NY 10595, United States. [email protected]: +1-914-4935311Fax: +1-914-2356274

Received: June 21, 2016Peer-review started: June 24, 2016First decision: August 11, 2016Revised: September 3, 2016Accepted: October 25, 2016Article in press: October 27, 2016Published online: January 16, 2017

AbstractCardiac papillary fibroelastomas (CPFs) are the second most common primary cardiac tumors and the most common cardiac valvular tumors. Although they are histologically benign and usually asymptomatic, CPFs can lead to serious and life-threatening complications like myocardial infarction, stroke, pulmonary embolus, cardiac arrest etc. CPFs represent a rare entity in clinical medicine and literature regarding their management is limited. We report two cases which illustrate such com-plications arising from undiagnosed CPFs on the aortic valve. We further stress on the importance of identifying CPFs early so that they can be managed appropriately based on recommendations from the available literature.

Key words: Lambl’s excrescences; Aortic valve; Cardiac tumors; Cardiac papillary fibroelastoma; Sudden cardiac death


Core tip: The cases illustrate serious complications that can arise from an undiagnosed cardiac papillary fibroelastoma. The importance of continued investigation

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World J Clin Cases 2017 January 16; 5(1): �-13 ISSN 2307-8�60 (online)

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10 January 16, 2017|Volume 5|Issue 1|WJCC|www.wjgnet.com

Yandrapalli S et al . Life-threatening complications of cardiac papillary fibroelastoma

with a transesophageal echo when there is high clinical suspicion is explained. Current management strategies have been outlined based on available literature.

Yandrapalli S, Mehta B, Mondal P, Gupta T, Khattar P, Fallon J, Goldberg R, Sule S, Aronow WS. Cardiac papillary fibroelastoma: The need for a timely diagnosis. World J Clin Cases 2017; 5(1): 9-13 Available from: URL: http://www.wjgnet.com/2307-8960/full/v5/i1/9.htm DOI: http://dx.doi.org/10.12998/wjcc.v5.i1.9

INTRODUCTIONPrimary cardiac tumors are rare and have a very low prevalence of based on 22 large autopsy studies[1]. Cardiac papillary fibroelastomas (CPFs) are the second common primary cardiac tumors[2]. For decades, CPFs were thought to be asymptomatic and incidental autopsy findings. However, in the past two decades they have gained importance as they have the potential to cause fatal and life-threatening complications. They represent a rare entity in clinical medicine and literature regarding their management is limited. We report two cases of CPFs presenting with cardiovascular and neurological complications and outline the importance of having a clinical suspicion for these tumors, in an effort to prevent further serious complications.

CASE REPORTCase 1A 64-year-old man was transferred to our institution for further management of congestive heart failure, acute kidney injury and lower gastrointestinal bleeding. He initially presented to the other institution with worsening dyspnea and orthopnea. His medical history was sig-nificant for hypertension, congestive heart failure, and non-ST elevation myocardial infarction (NSTEMI). Prior coronary angiography was significant for non-obstructive coronary artery disease (CAD). At the other institution, a chest roentgenogram showed moderately large right-sided effusion. Transthoracic echocardiography (TTE) showed moderately reduced left ventricular systolic func-tion with an ejection fraction of 35%-40% and severely reduced right ventricular systolic function. A diagnosis of acute decompensated heart failure was made and he was started on intravenous furosemide. Hospital course was complicated by acute kidney injury and lower gastrointestinal bleeding. The patient refused blood product transfusion as he was a Jehovah’s Witness. He did not improve clinically and was transferred to our institution. At the time of transfer to our institution, his hemoglobin was 6.3 g/dL and blood pressure was 90/40 mmHg. In our institution, ECG did not reveal ischemic changes, troponin Ⅰ was elevated at 1.10 ng/mL, and brain natriuretic peptide level was elevated at 533 pg/mL.

He was admitted to the medical intensive care unit for further management. Approximately 4 h after admission he developed severe hypotension which rapidly progressed to cardiac arrest with asystole. Despite resuscitative mea-sures, patient expired.

Autopsy showed cardiomegaly (750 g), old inferior wall infarct and healing acute right ventricular myocardial infarct. There was a large bulky tan-white non-en-capsulated, rubbery, firm lesion with short pedicle and multiple papillary fronds on the aortic valve measuring 1.5 cm × 1.0 cm in size, completely occluding the right coronary ostium (Figure 1). Histological section of the mass shows benign papillary lesion comprised of a single layer of endocardial cells overlies a thin layer of mucopolysaccharide matrix and underlying, almost acellular, avascular stroma composed predominantly of elastic fibers. Elastin stain reveals concentric elastin fibres within the papillary excrescences (Figure 2). Imm-unohistochemical stains reveal lining endothelial cells are positive for S100, CD34 and Factor Ⅷ. Coronary artery atherosclerosis of the left anterior descending artery (10%-20% occlusion), the left circumflex artery (10%-20%), and the right coronary artery (20%-30% occlusion) was seen. Coronary emboli were not noted. Based on the autopsy findings, the immediate cause of death was acute myocardial infarction secondary to papillary giant fibroelastoma of aortic valve completely occluding the right coronary ostium.

Case 2A 53-year-old female with a history of diabetes mellitus and NSTEMI presented with sudden onset tingling and numbness on her left side of her face, mouth, upper and lower extremities. Symptoms resolved spontaneously in one hour with no sequelae. Computed tomography (CT) scan of the head and CT angiography of cerebral and carotid arteries were unremarkable. Magnetic reso-nance imaging of the brain did not show signs of acute infarction. Based on these findings, she was diagnosed

Weight: 750 g1.5 cm × 1.0 cm

Figure 1 Autopsy specimen of the heart demonstrating a cardiac papillary fibroelastoma on the aortic valve. Note the large bulky tan-white non-encapsulated, rubbery, firm lesion with short pedicle and multiple papillary fronds on the aortic valve measuring 1.5 cm × 1.0 cm in size, completely occluding the right coronary ostium (blue circle).


with a transient ischemic attack (TIA). Further stroke workup with a TTE showed a mobile mass on the aortic valve (Figure 3) which was later confirmed by a transesophageal echocardiography (TEE). A mobile, pedunculated, 1.2 cm round mass on the aortic side of the non-coronary cusp of a tri-leaflet aortic valve was seen in the TEE, with an appearance most consistent with a fibroelastoma. She was afebrile and blood cultures were negative, ruling out endocarditis. Attributing the TIA symptoms to embolization from the fibroelastoma, she was referred for surgical removal. Pathological exam of the resected mass confirmed a fibroelastoma. She was discharged and remained symptom free.

DISCUSSIONThe first case illustrates a fatal outcome associated with an undiagnosed CPF, and the second case illustrates the benefit of early detection of a CPF to prevent further complications.

Primary cardiac tumors are very rare and have an approximate prevalence of 0.02% based on autopsy studies[1]. Myxomas were reported to be the most com-mon, and CPFs stand second[2]. Gowda et al[3] used the term “papillary fibroelastoma” for the first time in a case

report of myocardial infarction in the absence of coronary atherosclerosis.

CPFs, the most common cardiac valvular tumors, are benign endocardial papillomas, with highest prevalence in the 6th to 8th decade of life[3,4]. CPFs are predominantly valvular with 80% arising from the valvular endocardium. The aortic valve is the most commonly involved with prevalence between 35% and 63%, followed by the mitral valve (9% to 35%), the tricuspid valve (6%-15%), and the pulmonary valve (0.5%-8%)[3-5]. In a large single center review of highly-selected referral population, CPF was more prevalent (0.089% of all echocardiograms) than cardiac myxoma[4]. The pathogenesis of CPF is unclear. Papillary fibroelastomas have been described as neoplasms, hamartomas, organizing thrombi, or post-traumatic tumors[6]. Some authors believe that CPFs represent gaint form of Lambl’s excrescence, evolving from a thrombotic phenomenon due to traumatization of the endothelial cells at the level of the valves which have an increased pressure gradient[5]. Grossly, CPFs have a sea anemone appearance with a gelatinous surface and a stalk with multiple papillary projections[5]. Microscopically, CPFs are avascular and are composed of collagen, elastic, and reticulin[5].

Most patients with CPFs are asymptomatic and these are incidental findings during echocardiography, cardiac surgery, or autopsies[3]. However, the past three decades have witnessed reported cases with life-threatening cardiac and neurological symptoms, including TIA, angina, syncope, stroke, blindness, myocardial infarction and sudden death, heart failure, among many others. Cerebrovascular events are the most common presenting symptom in symptomatic patients[4]. In their meta-analysis of 725 CPF cases, Gowda et al[3] postulated that tumor mobility was the only independent predictor of CPF related death or nonfatal embolization. However, in the study by Tamin et al[4] echocardiographic characteristics of CPFs (size, location, and mobility) were not significantly associated with a cerebrovascular accident. CPFs can cause symptoms by embolization of either the tumor

A B

Figure 2 Microscopic photograph of the cardiac papillary fibroelastoma. A: Histological section of the mass shows benign papillary lesion comprised of a single layer of endocardial cells overlies a thin layer of mucopolysaccharide matrix and underlying, almost acellular, avascular stroma composed predominantly of elastic fibers; B: Elastin stain reveals concentric elastin fibres within the papillary excrescences.

59 bpm

PG

R1.4 2.8

FR 149 Hz15 cm2D 60%C 47P highHPen

Dist 0.828 cm

0 P

M3

Figure 3 Transthoracic echocardiogram showing a cardiac papillary fibroelastoma on the aortic valve (marked).



fragments or a thrombus that has formed on the surface of the tumor. This mechanism can explain the TIA symptoms in our second case. Direct obstruction by the tumor mass resulting in acute myocardial infarction can also occur, as in our first case. Our first patient had a NSTEMI prior to this admission with non-obstructive CAD on prior cardiac catheterization. Autopsy revealed an old inferior wall infarct and non-obstructive CAD. These findings suggest that the aortic valve CPF was causing intermittent obstruction of the right coronary ostium resulting in recurrent myocardial infarction and subsequent heart failure.

The advent of higher-resolution imaging especially TEE facilitates rapid ante-mortem diagnosis in symptomatic patients. Currently, depending on symptoms and tumor mobility either surgical resection or anticoagulation/antiplatelet agents are offered to patients. Based on available data, surgical resection is strongly recom-mended in symptomatic patients to prevent further cardiovascular or embolic events[3,7]. This was the rationale for surgical resection of the CPF in our second patient. She had a mobile, pedunculated fibroelastoma on her aortic valve causing a TIA (Figure 3). Curative surgical resection was done to prevent further complications. In asymptomatic patients, there is a debate between anticoagulation vs surgical excision. Increased cerebrova-scular accidents and mortality were observed in patients with echocardiographically suspected CPF who did not undergo surgical removal[4]. Ikegami et al[7] recommend surgical excision in asymptomatic patients with incidental CPF finding taking into account the friability, mobility and location of the CPF. Literature suggests that successful complete resection of CPF is curative with an excellent long-term prognosis and a lower stroke risk[3,4].

Given the potential to cause fatal outcomes and the availability of successful therapies, CPF should be a diag-nostic consideration in elderly patients with myocardial infarction with normal coronaries or non-obstructive CAD after other potential causes of myocardial injury and other confounding diagnoses have been ruled out. Diagnostic evaluation begins with a TTE, but it is advisable to further evaluate with TEE when clinical suspicion for CPF is high, as TTE can miss a third of CPF’s evident on a TEE[4]. It must be noted that the TTE of our first patient did not reveal a CPF. Surgical resection should be offered for symptomatic patients and also to asymptomatic patients with high risk CPFs. Close monitoring and follow-up is recommended if medical management is pursued. Randomized studies are needed to make valid recommendations as most of the available studies are single center experiences.

COMMENTSCase characteristics Case 1: A 64-year-old man with sudden cardiac arrest; Case 2: A 53-year-old female with sudden onset tingling and numbness on her left side of her face, mouth, upper and lower extremities.

Clinical diagnosis Case 1: Acute myocardial infarction leading to sudden cardiac arrest; Case 2:

Acute cerebrovascular event/transient ischemic attack (TIA).

Differential diagnosis Case 1: Coronary thromboembolism from atherosclerosis, acute blood loss anemia causing cardiac demand ischemia, coronary occlusion secondary to vasculitis/arteritis, aortic dissection, with retrograde involvement of the coronary arteries, coronary artery emboli, secondary to cholesterol, air, or the products of sepsis, drugs (cocaine, etc.); Case 2: Endocarditis, cardiac myxoma, cardiac papillary fibroelastomas (CPFs), organized thrombus, valvular lipoma, etc.

Laboratory diagnosis Case 1: Acute myocardial infarction; Case: All labs were within normal limits.

Imaging diagnosis Case 2: Transthoracic echocardiography (TTE) showing a cardiac papillary fibroelastoma on the aortic valve.

Pathological diagnosis CPF.

Treatment Case 2: Complete surgical excision of the CPF.

Related reports Traditionally though to be asymptomatic, the past three decades have witnessed reported cases of CPFs with life-threatening cardiac and neurological symptoms, including TIA, angina, syncope, stroke, blindness, myocardial infarction and sudden death, heart failure, among many others.

Term explanation CPFs are benign endocardial papillomas and are the most common cardiac valvular tumors. They have the propensity to cause life-threatening cardiac and neurologic complications. Surgical resection should be considered in symptomatic patients and in asymptomatic patients with high risk feautures.

Experiences and lessons TTE can miss a third of the CPFs. A transesophageal echocardiography should be considered when there is high clinical suspicion. Early detection is necessary to prevent life-threatening cardiac and neurologic complications. Surgical resection can be curative.

Peer-review The paper is well written.

REFERENCES1 Reynen K. Frequency of primary tumors of the heart. Am J

Cardiol 1996; 77: 107 [PMID: 8540447 DOI: 10.1016/S0002- 9149(97)89149-7]

2 Steger CM, Hager T, Ruttmann E. Primary cardiac tumours: a single-center 41-year experience. ISRN Cardiol 2012; 2012: 906109 [PMID: 22792486 DOI: 10.5402/2012/906109]

3 Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart J 2003; 146: 404-410 [PMID: 12947356 DOI: 10.1016/S0002-8703(03)00249-7]

4 Tamin SS, Maleszewski JJ, Scott CG, Khan SK, Edwards WD, Bruce CJ, Oh JK, Pellikka PA, Klarich KW. Prognostic and Bioepidemiologic Implications of Papillary Fibroelastomas. J Am Coll Cardiol 2015; 65: 2420-2429 [PMID: 26046736 DOI: 10.1016/j.jacc.2015.03.569]

5 Darvishian F, Farmer P. Papillary fibroelastoma of the heart: report of two cases and review of the literature. Ann Clin Lab Sci 2001; 31: 291-296 [PMID: 11508834]

6 Abu Saleh WK, Al Jabbari O, Ramlawi B, Reardon MJ. Cardiac Papillary Fibroelastoma: Single-Institution Experience with 14

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Surgical Patients. Tex Heart Inst J 2016; 43: 148-151 [PMID: 27127431 DOI: 10.14503/THIJ-14-4889]

7 Ikegami H, Andrei AC, Li Z, McCarthy PM, Malaisrie SC.

Papillary fibroelastoma of the aortic valve: analysis of 21 cases, including a presentation with cardiac arrest. Tex Heart Inst J 2015; 42: 131-135 [PMID: 25873822 DOI: 10.14503/THIJ-14-4262]

P- Reviewer: Kataoka H, Lee TM, Peteiro J, Petix NR S- Editor: Qiu S L- Editor: A E- Editor: Li D


Badri Shrestha, James Hampton

CASE REPORT


Intra-abdominal abscess and intractable sinus - a rare late complication after splenectomy

Badri Shrestha, James Hampton, Sheffield Teaching Hospitals NHS Trust, Sheffield S5 7AU, United Kingdom

Author contributions: Both authors contributed to the acquisition of data, writing, and revision of this manuscript.

Institutional review board statement: This case report was exempt from the Institutional Review Board standards at Sheffield Teaching Hospitals NHS Trust.

Informed consent statement: The patient involved in this study gave his written informed consent authorizing use and disclosure of her protected health information.

Conflict-of-interest statement: All the authors have no conflicts of interests to declare.


Manuscript source: Unsolicited manuscript

Correspondence to: Badri Shrestha, MD, FRCS, FACS, Sheffield Teaching Hospitals NHS Trust, Herries Road, Sheffield S5 7AU, United Kingdom. [email protected]: +44-79-49354709Fax: +44-11-42714604

Received: August 15, 2016 Peer-review started: August 16, 2016 First decision: September 28, 2016Revised: October 2, 2016 Accepted: November 1, 2016Article in press: November 2, 2016Published online: January 16, 2017

AbstractIntra-abdominal abscess and an intractable abdominal wall sinus forty years after splenectomy is rare, which has not been described previously in the surgical litera-ture. We report the management of a patient who had presented with an intractable sinus on his left hypochondrium forty years after having undergone splenectomy and cholecystectomy, which persisted for more than two years despite repeated surgery and courses of antibiotics and compromised quality of life significantly from pain. A sinogram and computerised tomographic scan followed by exploration and laying open of the sinus delivered multiple silk sutures used for ligation of splenic pedicle, led to complete resolution of the sinus. It is important to avoid using non-absorbable silk sutures during splenectomy when splenectomy is undertaken in a contaminated field. Appropriate imaging and exploration is mandatory for its resolution.

Key words: Abscess; Intractable; Late presentation; Splenectomy; Sinus


Core tip: An intra-abdominal abscess and a sinus 40 years following splenectomy is rare, which should be investigated with a computerised tomographic scan and a sinogram and treated by exploration. Non-absorbable silk sutures, which act as nidus for bacteria, should be avoided if splenectomy is undertaken simultaneously with surgery on a hollow viscus.

Shrestha B, Hampton J. Intra-abdominal abscess and intractable sinus - a rare late complication after splenectomy. World J Clin Cases 2017; 5(1): 14-17 Available from: URL: http://www.wjgnet.com/2307-8960/full/v5/i1/14.htm DOI: http://dx.doi.

Submit a Manuscript: http://www.wjgnet.com/esps/Help Desk: http://www.wjgnet.com/esps/helpdesk.aspxDOI: 10.12998/wjcc.v5.i1.14

World J Clin Cases 2017 January 16; 5(1): 14-17 ISSN 2307-8960 (online)




Shrestha B et al . Intra-abdominal abscess and intractable sinus

org/10.12998/wjcc.v5.i1.14

INTRODUCTIONSplenectomy is performed for a wide range of medical conditions such as haematological disorders, portal hypertension and trauma, which can be attended by complications, principally infectious and thromboembolic[1]. Splenectomy is also performed in association with surgery of other abdominal viscera, particularly in multiply injured trauma victims, where contamination of abdominal cavity is present[2]. Chronic intraabdominal sepsis can compromise the quality of life significantly and be challenging from diagnostic and treatment perspectives. We describe the management challenges posed by the late presentation of a patient with intraabdominal abscess followed by an intractable abdominal wall sinus 40 years after splenectomy and review pertinent literature.

CASE REPORTA 62yearold male was referred to our general surgical clinic from the dermatology department for a second opinion and management of a persistently discharging sinus on the left hypochondrium of two years duration, which was associated with severe eczematous changes on the skin around the sinus, unresponsive to topical steroid creams. He experienced continuous pain in the left upper abdomen, which compromised his sleep and work, and was on regular diazepam 5 mg nocte, morphine sulphate solution 510 mg PRN, sustainedrelease morphine sulphate (Zomorph®) 10 mg 12 hourly and oral phenoxymethylpenicilln 250 mg twice daily.

Aged 19, he had undergone a cholecystectomy and splenectomy for gallstones and portal hypertension through an upper midline incision. Forty years after the surgery, he presented with a painful lump on his left hypochondrium with clinical features suggestive of an intraabdominal abscess. The abscess, containing thick pus, was drained through a transverse subcostal incision. Although the operation record described that the omentum was herniating through a 1 cm diameter defect in the muscles, which was closed with interrupted 0 prolene sutures; in retrospect, the omentum was walling off the abscess, which was mistaken for an incisional hernia. After four weeks, a discharging sinus developed through the middle of the scar, which refused to heal despite debridement on three occasions, regular dressings and courses of flucloxacilln. Over the following two years, the pain and the sinus persisted and caused severe disability. Due to the extensive excoriation of the skin surrounding the sinus, he was referred to a dermatology clinic.

On examination, the skin around the sinus showed severe eczematous changes and the sinus was adherent to the left costal margin in the midaxillary line the white blood cell count was 16 × 109/L and the

Creactive protein was 21 units/mL culture of the pus grew Staphylococcus aureus sensitive to flucloxacilln. A plain computerised tomographic (CT) scan showed a septated extraperitoneal collection in the left upper abdomen measuring 85 mm × 25 mm × 20 mm with adjacent inflammatory changes (Figure 1A). A sinogram delineated the tract under the ribs towards the upper quadrant. There was no communication with the bowel. A CT scan of the abdomen, following the sinogram, after the administration of oral water and intravenous contrast, showed the contrast in the cavity (5 cm × 15 cm in maximum axial dimensions) lying in the extraperitoneal space, which extended from the opening under lower edge of the rib cage to the under surface of the diaphragm cranially. The splenic flexure and the descending colon lay close to the cavity without communication between them (Figure 1B).

The sinus was explored under general anaesthesia. Using a 6 Fr feeding tube, methylene blue dye was injected into the cavity. Through a generous subcostal incision, the sinus tract was followed cranially keeping the dissection close to the rib cage and laid it fully open. The cavity contained thick pus and freefloating braided black silk sutures (15 in number), it was thoroughly curetted with a Volkmann’s spoon and washed with copious amount of saline and hydrogen peroxide solution. The wound was closed in layers after inserting a 16 Fr Robinson’s drain, which was removed after 7 d and the patient was discharged home. The specimens from the sinus contained multiple pieces of fibrous tissue, largest measuring 20 mm in maximum dimension. The histology of the sinus tract showed chronically inflamed fibrous tissue with no evidence of granulomatous inflammation or neoplastic disease. On a routine followup after three weeks, the wound has healed with no sign of recurrence of the sinus. The patient has stopped taking analgesia or tranquillizers. On a telephone enquiry two years following the surgery, he remained well, pain free and not on any drugs, with no signs of recurrence of sinus.

DISCUSSIONThe spleen is crucial in regulating immune homoeostasis through its ability to link innate and adaptive immunity and in protecting against infections[3]. Asplenic patients have a lifelong risk of overwhelming postsplenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells[4]. Immunisation and prophylactic antibiotics help preventing postsplenectomy opportunistic infections.

Presentation with an intraabdominal abscess and a nonhealing sinus, 40 years following splenectomy, is rare and unreported in the surgical literature. Surgical treatment of acute cholecystitis or appendicitis, is known to be associated with a higher risk of late abscess formation, due to retained stones in the abdominal cavity/wall or contamination of the wound at the time of surgery, respectively[5,6]. The differential diagnosis of a nonhealing sinus includes tuberculosis, malignancy, presence


of foreign bodies and communication with abdominal organs to the skin surface. Moreover, mesh repair of an incisional or inguinal hernia, as well as the use of silk yarn in surgical sutures, are associated with late abscess formation. The silk acts as a foreign body and a nidus for latent infection, which can manifest with sinuses several years after the primary surgery as in our case[7].

Intraabdominal abscesses can also occur due to injury to the stomach, pancreas or intestine during splenectomy, but the incidence reported is less than 1 percent and the presentation is usually early during the postoperative period[8,9]. Splenectomy performed for splenic abscess can present with intraabdominal abscess due to contamination of peritoneal cavity and postsplenectomy immunosuppressed state[10]. Bacterial translocation is the invasion of indigenous intestinal bacteria through the gut mucosa to normally sterile tissues and internal organs, which could lead to delayed infection as in our case[11].

Our patient had undergone a splenectomy with ligation of the splenic vessels with silk sutures and a cholecystectomy in the same sitting. It is highly likely that contamination of the splenic bed containing silk sutures with the organisms present in the gall bladder had led to this delayed presentation with a splenic bed abscess and persistent sinus. Resolution of the sinus after removal of the infected silk sutures, emphasises the need for avoidance of using braided silk sutures during surgery, particularly, when splenectomy is performed together with resection of hollow abdominal viscera or when an immunosuppressed state is likely to follow, such as after splenectomy and organ transplantation. Utilisation of absorbable and nonbraided sutures can potentially prevent this complication. Polyglactin 910 is considered to be the optimum suture in preventing the formation of adhesions and abscesses[12]. A sinogram and CT scan followed by early exploration, removal of the sutures and complete excision of the sinus tract through adequate surgical access are essential for a permanent cure and amelioration of prolonged suffering of the patient.

COMMENTSCase characteristics A 62-year-old man with history of undergoing splenectomy 40 years ago

presented with presented with a 2-year history of a sinus following drainage of an intra-abdominal abscess, which refused to heal despite repeated surgical interventions.

Clinical diagnosis A discharging sinus on the left hypochondrium with excoriation of skin.

Differential diagnosis A chronic sinus due to tuberculosis, malignancy, presence of foreign body or a fistula communicating to intra-abdominal organs.

Laboratory diagnosis There was leucocytosis and raised C-reactive protein. Staphylococcus aureus was isolated from the discharge emanating from the sinus.

Imaging diagnosis A plain computerised tomographic (CT) scan showed a septated extraperitoneal collection in the left upper abdomen measuring 85 mm × 25 mm × 20 mm with adjacent inflammatory change. A sinogram delineated the tract under the ribs towards the upper quadrant. There was no communication with the bowel.

Pathological diagnosis The histology of the sinus tract showed chronically inflamed fibrous tissue with no evidence of granulomatous inflammation or neoplastic disease.

Treatment Exploration of the sinus, removal of retained silk sutures and curettage of the sinus led to complete healing.

Related reports Intra-abdominal abscess and infections following use of non-absorbable sutures have been reported in the past. But a case like this presenting 40 years after having undergone splenectomy has not been reported in the past.

Experiences and lessons The case emphasizes the need for appropriate investigations with a sinogram and CT imaging followed by early exploration of the sinus. Use of non-absorbable sutures should be avoided to prevent such complications.

Peer-review This is a very rare case indeed. The case report is correctly structured, well written, the case is well and completely described. It is indeed useful as a case report for clinical practice.

REFERENCES1 Buzelé R, Barbier L, Sauvanet A, Fantin B. Medical complications

A B

Figure 1 Contrast in the sinus tract extending up into the left upper quadrant (arrow) (A) and abscess cavity in the left upper quadrant (arrow) (B).

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following splenectomy. J Visc Surg 2016; 153: 277-286 [PMID: 27289254 DOI: 10.16/j.jviscsurg.2016.04.013]

2 Weledji EP. Benefits and risks of splenectomy. Int J Surg 2014; 12: 113-119 [PMID: 24316283 DOI: 10.1016/j.ijsu.2013.11.017]

3 Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet 2011; 378: 86-97 [PMID: 21474172 DOI: 10.1016/S0140-6736(10)61493-6]

4 Cameron PU, Jones P, Gorniak M, Dunster K, Paul E, Lewin S, Woolley I, Spelman D. Splenectomy associated changes in IgM memory B cells in an adult spleen registry cohort. PLoS One 2011; 6: e23164 [PMID: 21829713 DOI: 10.1371/journal.pone.0023164]

5 van Rossem CC, Bolmers MD, Schreinemacher MH, van Geloven AA, Bemelman WA. Prospective nationwide outcome audit of surgery for suspected acute appendicitis. Br J Surg 2016; 103: 144-151 [PMID: 26509648 DOI: 10.1002/bjs.9964]

6 Sista F, Schietroma M, Santis GD, Mattei A, Cecilia EM, Piccione F, Leardi S, Carlei F, Amicucci G. Systemic inflammation and immune response after laparotomy vs laparoscopy in patients with acute cholecystitis, complicated by peritonitis. World J Gastrointest Surg 2013; 5: 73-82 [PMID: 23717743 DOI: 10.4240/wjgs.v5.i4.73]

7 Calkins CM, St Peter SD, Balcom A, Murphy PJ. Late abscess

formation following indirect hernia repair utilizing silk suture. Pediatr Surg Int 2007; 23: 349-352 [PMID: 17333211 DOI: 10.1007/s00383-007-1894-x]

8 O’Sullivan ST, Reardon CM, O’Donnell JA, Kirwan WO, Brady MP. “How safe is splenectomy?”. Ir J Med Sci 1994; 163: 374-378 [PMID: 8002263]

9 Barmparas G, Lamb AW, Lee D, Nguyen B, Eng J, Bloom MB, Ley EJ. Postoperative infection risk after splenectomy: A prospective cohort study. Int J Surg 2015; 17: 10-14 [PMID: 25779211]

10 Han SP, Galketiya K, Fisher D. Primary splenic abscess requiring splenectomy. ANZ J Surg 2016 [PMID: 26991530 DOI: 10.1111/ans.13537]

11 Lima Kde M, Negro-Dellacqua M, Dos Santos VE, de Castro CM. Post-splenectomy infections in chronic schistosomiasis as a consequence of bacterial translocation. Rev Soc Bras Med Trop 2015; 48: 314-320 [PMID: 26108010 DOI: 10.1590/0037-8682-0042-2015]

12 Ishikawa K, Sadahiro S, Tanaka Y, Suzuki T, Kamijo A, Tazume S. Optimal sutures for use in the abdomen: an evaluation based on the formation of adhesions and abscesses. Surg Today 2013; 43: 412-417 [PMID: 22797960 DOI: 10.1007/s00595-012-0249-y]

P- Reviewer: Elpek GO, Surlin VM S- Editor: Ji FF L- Editor: A E- Editor: Li D


Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yu-Ichiro Koma, Masato Komatsu, Ryohei Sasaki, Yoshihiro Kakeji

CASE REPORT


Local advanced rectal cancer perforation in the midst of preoperative chemoradiotherapy: A case report and literature review

Nobuhisa Takase, Kimihiro Yamashita, Yasuo Sumi, Hiroshi Hasegawa, Masashi Yamamoto, Shingo Kanaji, Yoshiko Matsuda, Takeru Matsuda, Taro Oshikiri, Tetsu Nakamura, Satoshi Suzuki, Yoshihiro Kakeji, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Yu-Ichiro Koma, Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 657-8501, Japan

Masato Komatsu, Division of Diagnostic Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 657-8501, Japan

Masato Komatsu, Department of Surgery, Hyogo Cancer Center, Akashi 673-8558, Japan

Ryohei Sasaki, Department of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe 657-8501, Japan

Author contributions: Yamashita K and Sumi Y operated on the patient and designed the report; Hasegawa H, Yamamoto M, Kanaji S, Matsuda Y, Matsuda T, Oshikiri T, Nakamura T and Suzuki S drafted the paper; Koma YI, Komatsu M, Sasaki R and Kakeji Y critically revised the paper with an important conceptual and editorial input.

Institutional review board statement: This case report was exempt from the Institutional review board standards at Kobe University Graduate School of Medicine and Hospital, Kobe, Japan.

Informed consent statement: The patient participant to the study provided informed written consent.

Conflict-of-interest statement: The authors declare no conflict of interest associated with this manuscript.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external

reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/


Correspondence to: Kimihiro Yamashita, MD, PhD, Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. [email protected]: +81-78-3825925Fax: +81-78-3825939

Received: August 24, 2016Peer-review started: August 25, 2016First decision: October 28, 2016Revised: November 11, 2016Accepted: December 1, 2016Article in press: December 2, 2016Published online: January 16, 2017

AbstractStandard chemoradiotherapy (CRT) for local advanced rectal cancer (LARC) rarely induce rectal perforation. Here we report a rare case of rectal perforation in a patient with LARC in the midst of preoperative CRT. A 56-year-old male was conveyed to our hospital exhibiting general malaise. Colonoscopy and imaging tests resulted in a clinical diagnosis of LARC with direct invasion to adjacent organs and regional lymphadenopathy. Preo-perative 5-fluorouracil-based CRT was started. At 25 d after the start of CRT, the patient developed a typical fever. Computed tomography revealed rectal






Takase N et al . Preoperative CRT-related rectal cancer perforation

perforation, and he underwent emergency sigmoid colostomy. At 12 d after the surgery, the remaining CRT was completed according to the original plan. The histopathological findings after radical operation revealed a wide field of tumor necrosis and fibrosis without lymph node metastasis. We share this case as important evidence for the treatment of LARC perforation in the midst of preoperative CRT.

Key words: Local advanced rectal cancer; Preoperative chemoradiotherapy; Rectal perforation; 5-fluorouracil; Tumor necrosis


Core tip: Standard chemoradiotherapy (CRT) for local advanced rectal cancer (LARC) rarely induces rectal perforation. This case report presents a case of rectal perforation in a patient with LARC in the midst of 5-fluo-rouracil-based preoperative CRT. We decided to com-plete CRT according to the original plan after supporting emergency recovery. The histopathological findings after radical operation revealed a wide field of tumor necrosis and fibrosis without lymph node metastasis, suggesting the efficacy of the CRT. We believe that establishing a standard treatment for CRT-related LARC perforation may improve the prognosis of such cases.

Takase N, Yamashita K, Sumi Y, Hasegawa H, Yamamoto M, Kanaji S, Matsuda Y, Matsuda T, Oshikiri T, Nakamura T, Suzuki S, Koma YI, Komatsu M, Sasaki R, Kakeji Y. Local advanced rectal cancer perforation in the midst of preoperative chemoradiotherapy: A case report and literature review. World J Clin Cases 2017; 5(1): 18-23 Available from: URL: http://www.wjgnet.com/2307-8960/full/v5/i1/18.htm DOI: http://dx.doi.org/10.12998/wjcc.v5.i1.18

INTRODUCTIONCurrently, the best proven approach to local advanced rectal cancer (LARC) is a combination of surgery and preoperative chemoradiotherapy (CRT)[1,2]. Compared to preoperative radiotherapy (RT) alone, the incidence of local recurrence at 5 years was significantly lower in the preoperative CRT group[3]. We previously reported that the pathological response to preoperative 5-fluorouracil (FU)-based CRT may be a useful predictor of LARC survival[4]. However, preoperative CRT is associated with various adverse effects that can be life-threatening. Among the life-threatening side effects, CRT-related per-foration of colorectal cancer is not well understood. We herein report a case of perforated LARC associated with preoperative CRT.

CASE REPORTA 56-year-old Japanese male was transported to our

facility with chief complaints of fever and general ma-laise. Though he had had anemia 3 years prior, he did not seek medical attention. He had used alcohol for at least 34 years. His serum level of carcino embryonic antigen was increased to 21.0 ng/mL (normal < 2.5). The colonoscopy examination revealed a low anterior circumferential rectal lesion (Figure 1A).

An endoscopic biopsy histologically confirmed the clinical diagnosis of adenocarcinoma. Magnetic resonance imaging (MRI) findings revealed LARC with involvement of perirectal fat, the prostate and the seminal vesicles (Figure 1B). Some of the lymph nodes in the tumor area were enlarged (Figure 1C) and 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) showed metabolically active foci in the left obturator lymph node (Figure 1D). No evidence of distant spread was seen.

The patient was scheduled for preoperative 5-FU-based CRT. Administration of a fixed dose of tegafur/uracil (UFT) (300 mg/body per day) and leucovorin (LV) (75 mg/body per day) was planned for days 1-28. Concurrent RT administration to the whole pelvis (Figure 2A) was planned in fractions of 1.8 Gy/d, 5 d a week for 5 wk (45 Gy in 25 fractions). However, the patient developed a typical fever at 25 d after starting CRT (36 Gy in 20 fractions received). The CT findings revealed rectal perforation with air-fluid around the left side of the seminal vesicle adjacent to the rectum (Figure 2B), and the colonoscopic examination also showed the perfora-tion of the tumor wall (Figure 2C). The patient underwent construction of a sigmoid colostomy as an emergency surgery.

At 12 d after the surgery with no inflammatory findings, the remaining CRT was commenced, and was completed safely according to plan. The patient underwent abdominoperineal resection of the rectum including the prostate and seminal vesicle with a laparo-scopic technique as minimally invasive surgery. The histopathological findings revealed that a wide area of tumor tissue had been replaced by necrotic tissue and fibrous tissue, suggesting that chemoradiation had been effective (Figure 3). The Union for International Cancer Control (UICC) TNM staging[5] of the tumor was pT3, N0 (0/34), M0. No evident disease recurrence has been ob-served in the patients for 8 mo.

DISCUSSIONRT is one of the useful modalities for various cancers including rectal cancer. Currently, more than 50% of cancer patients receive RT with or without chemotherapy[6]. RT gives rise to various cellular responses including both DNA and membrane damage[7]. The DNA damage leads to cell cycle arrest, apoptosis, stress and the activation of DNA repair processes through coordinating intracellular signal pathways involving poly ADP ribose polymerase, ERK1/2, p53 and ataxia telangiectasia mutated[7,8]. Concerning pelvic RT with concurrent 5-FU-based chemotherapy, 5-FU can increase radiation sensitivity[3,9]. However, RT


causes various side effects that damage healthy cells and tissues near the treatment area.

Radiation-related tissue injuries are well known to occur in the gastrointestinal tract. Acute radiation-related small bowel toxicity often occurs during RT for LARC. The overall incidence of acute Grade 3-4 diarrhea was 16%-39% in prospective studies of preoperative RT[10]. Concerning the rectum, radiation proctitis is generally classified as acute or chronic phase by the timeframe of the symptoms, and chronic proctitis may include acute proctitis defined as an inflammatory process. However, the detailed pathogenesis of RT-induced proctitis is not yet clear. Acute proctitis including symptoms of diarrhea, nausea, cramps, tenesmus, urgency, mucus discharge and minor bleeding occurs within 6 wk after the start of RT[11]. Severe bleeding, strictures, perforation, fistula and bowel obstruction occur in the chronic phase, which may not become apparent for months to years[12]. Concerning pelvic RT with concurrent 5-FU-based chemo-therapy, severe acute small-bowel toxicity was found to be associated with radiation in a dose-dependent manner[13,14].

Colorectal perforation is a life-threatening compli-cation. The causes of rectal perforation include fecal impaction, enema, and cancer and its therapy, including RT, chemotherapy and molecular-targeted therapy. Among them, rectal perforation from pelvic RT is an extremely rare adverse event. The mechanisms of radiation-related perforation, especially the difference in responses between normal rectal tissue and LARC tissue,

remain elusive. RT-induced normal tissue perforation is generally caused by accumulation of radiation-induced irreversible ischemic mechanisms with submucosal fibrosis and obliteration of small blood vessels[15]. In addition to the ischemic change, cancer tissue with high radiation sensitivity results in massive necrotic death, which in turn triggers an inflammatory reaction analogous to a wound-healing response[15-17].

There is general agreement that radiation-induced gastrointestinal injuries are associated with the dose of radiation. Late normal tissue reactions are more dependent on the dose per fraction than acute reactions[18]. Still, Do et al[12] reported that a total dose of 45 to 50 Gy delivered to the pelvis for adjuvant or neoadjuvant treatment for rectal malignancies generally causes very few acute and late morbidities.

However, total treatments of > 70 Gy cause sig-nificant and long-standing injury to the surrounding area[12,19]. In the present case, the main cause of the standard 5-FU-based CRT-related rectal perforation was thought to be not direct radiation morbidity but a secondary effect of the tumor necrosis. In addition to excessive treatment effects of CRT, the potential risks for CRT-related LARC perforation may include the presence of diverticula, collagenosis and tumor ulceration. Khan et al[20] also argue that the biological behavior of the tumor may have a large influence on whether an event occurs because all transrectal tumors have the potential for perforation. Pathological and immunohistochemical analyses of various factors in colorectal tumor perforation

F

P P

L

0.00

45 × PET

3.3

-999999.000000

3.3 mm/3.3 sp

m = 0.00 M = 6.00 g/mL

A B

C D

Figure 1 Evaluation of clinical findings. Colonoscopy showed a circumferential mass at the lower rectum (A); Sagittal magnetic resonance imaging (MRI) of the pelvis showed rectal mass with involvement prostate and seminal vesicles (red arrows) (B), and perirectal fat (C); The enlarged lymph node in the left obturator detected by coronal MRI (red arrow) showed obvious metabolically active foci 18-fluorodeoxyglucose-positron emission tomography/computed tomography evaluation (D).

215

P 243



compared with non-perforated tumor showed significant associations of tumor location and cell differentiation[21].

We searched all common literature search engines (PubMed, Medline, Google Scholar). To our knowledge, only 6 cases of perforated LARC associated with 5-FU-

based preoperative CRT have been reported[20,22,23] (Table 1). Among them, the cases of perforation in the midst of preoperative CRT were only 2 in number. Furthermore, completion of preoperative CRT according to the original plan after supporting emergency recovery for CRT-related rectal perforation has never before been described.

In recent years, various molecularly targeted agents have been used clinically for colorectal cancer. However, the spread of molecularly targeted therapies including combination RT has resulted in more cases of agent-induced gastrointestinal perforation[24,25]. Gastrointestinal perforation has occurred in both non-tumor tissue and tumor tissue including rectal cancer[26]. To avoid severe complications related to CRT, such as LARC perforation, regimens of chemotherapy as well as methods of radiation therapy should be carefully considered.

In conclusion, we documented an extremely rare case of LARC that developed preoperative rectal perforation in the midst of 5-FU-based preoperative CRT. We share this case as important evidence for the treatment for

Case Ref. Sex Time to perforation Surgical intervention (additional surgery) TNM Outcome

Age Total dose of RT (Gy/fr) Classification1

1 Lee et al[22] F 5 D after planned CRT LAR cT4, NX, MX Alive67 50 Gy/28 fr pT4, N2, M0

2 Lee et al[22] F Immediately after planned CRT Ileostomy cT4, NX, MX Alive78 54 Gy/unknown

3 Lee et al[22] M 2 W in the middle of planned CRT Colostomy cT3, NX, MX Perioperativedeath72 21.6 Gy/unknown

4 Lee et al[22] M 4 W in the middle of planned CRT Colectomy with ileostomy cT3, NX, MX Perioperativedeath76 36 Gy/unknown

5 Khan et al[20] M 1 W after planned CRT LAR cT3, N1, M0 Alive47 50.45 Gy/28 fr pT3, N2, M0

6 ElGendy et al[23] F 2 W after planned CRT LAR cT3, N1, M0 Alive55 45 Gy/unknown pT3, N2, M0

7 Our case M 25 D in the middle of planned CRT Colectomy (APR after remaining planned CRT) cT4, N2, M0 Alive56 36 Gy/20 fr pT3, N0, M0

Table 1 Characteristics of perforated local advanced rectal cancer associated with 5-fluorouracil-based preoperative chemoradiotherapy

1According to the TNM classification by Union for International Cancer Control (UICC)[5]. The following cases searched common literature search engines (PubMed, Medline, Google Scholar) through August 2016, using search terms related to rectal cancer, perforation and chemoradiotherapy. LAR: Low anterior resection; APR: Abdominoperineal resection; CRT: Chemoradiotherapy; RT: Radiotherapy; F: Female; M: Male.

Figure 3 Histological findings of the resected specimen showed a wide field of tumor necrosis with fibril formation (H-E stain).

1 mm


P

R L

A B C

Figure 2 Rectal tumor perforation suggestive of chemoradiationdamage. Radiotherapy was delivered to the whole pelvis through three (one posterior-anterior and two lateral) or four (one anterior-posterior, one posterior-anterior and two lateral) fields using a 10-MV linear accelerator in the prone position (A); Coronal computed tomography findings showed a small bubble of extra-luminal gas (red arrow) (B); Preoperative colonoscopicfindings for radical surgery showed excavation with mucosa necrosis (red arrow) suggestive of chemoradiationdamage in the rectal tumor (C).

H


LARC perforation in the midst of preoperative CRT. Our case findings imply that completing preoperative CRT after supporting emergency recovery may enhance the anti-tumor effect, resulting in a better prognosis for such cases.

COMMENTSCase characteristicsA 56-year-old male with locally advanced rectal cancer (LARC) developed preoperative rectal perforation in the midst of 5-fluorouracil (FU)-based pre-operative chemoradiotherapy (CRT).

Clinical diagnosisColonoscopy and imaging tests resulted in a clinical diagnosis of LARC with direct invasion to adjacent organs and regional lymphadenopathy.

Differential diagnosisInflammatory associated rectal perforation.

Laboratory diagnosisPreoperative serum level of carcino embryonic antigen was increased to 21.0 ng/mL (normal < 2.5).

Imaging diagnosisThe computed tomography findings revealed rectal perforation with air-fluid around the left side of the seminal vesicle adjacent to the rectum.

Pathological diagnosisA wide area of tumor tissue was replaced by necrotic tissue and fibrous tissue, suggesting that chemoradiation had been effective.

TreatmentThe patient completed preoperative CRT after supporting emergency recovery.

Related reportsTo our knowledge, only 6 cases of perforated LARC associated with 5-FU-based preoperative CRT have been reported.

Experiences and lessonsThe authors share this case as important evidence for the treatment of LARC perforation in the midst of preoperative CRT.

Peer-reviewThis case report demonstrated that completing preoperative CRT after supporting emergency recovery may enhance the anti-tumor effect, resulting in a better prognosis.

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P- Reviewer: Rasmussen SL, Trevisani L S- Editor: Qi Y L- Editor: A E- Editor: Li D


Guilherme Macedo, Marco Silva

LETTERS TO THE EDITOR


Conscience imperative of providing information and knowledge in hepatology: The Portuguese approach

Guilherme Macedo, Marco Silva, Department of Gastroenterology, the Centro Hospitalar São João, WGO Training Center, Faculty of Medicine, University of Porto, 4200319 Porto, Portugal

Author contributions: Macedo G drafted and final approval of the manuscript; Silva M drafted of the manuscript.

Conflict-of-interest statement: All authors declare that there is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.

Open-Access: This article is an openaccess article which was selected by an inhouse editor and fully peerreviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/licenses/bync/4.0/


Correspondence to: Guilherme Macedo, MD, Professor, Department of Gastroenterology, the Centro Hospitalar São João, WGO Training Center, Faculty of Medicine, University of Porto, Hernâni Monteiro, 4200319 Porto, Portugal. [email protected]: +351225512100Fax: +351225025766

Received: June 20, 2016Peer-review started: June 20, 2016First decision: August 11, 2016Revised: September 21, 2016Accepted: October 25, 2016Article in press: October 27, 2016Published online: January 16, 2017

AbstractThe last 25 years have been a thrilling time for the Portuguese hepatologists. Our national meetings have

been providing the forum for the exchange of scientific ideas and the presentation of clinical research in clinical Hepatology, a growing world of knowledge in medical care. Bridging the gaps between technology and clinical daily practice, the latest development and the almost humble bedside care, has been a challenge for the increasing numbers of doctors devoted to the diagnostic and treatment of liver disease. We have been trying to be very persuasive among the Portuguese medical community in demonstrating that cultural vectors may influence the origin and pattern of liver disease among us. Viral hepatitis and alcoholic liver disease are para-digms of this assumption. Chronic liver disease is responsible for 3% of the deaths in Portugal, which accounts for the top ten causes of death in our country. The recognition by public health authorities of this fact along with the national net of hepatology outpatient consultation in public hospitals, has brought liver dis-eases under the lights of doctors concerns and an increased public awareness of its dimension.

Key words: Alcohol; Cirrhosis; Hepatology; Liver; Public health


Core tip: The last 25 years have been a thrilling time for the Portuguese Hepatologists. Nowadays our main efforts are devoted both at the level of training and pregraduate teaching, especially in the large university hospitals but also in addressing the public directly, aiming essentially in giving information on three major topics: Alcohol, viral hepatitis and the obesity epidemics.

Macedo G, Silva M. Conscience imperative of providing information and knowledge in hepatology: The Portuguese approach. World J Clin Cases 2017; 5(1): 2426 Available from: URL: http://www.wjgnet.com/23078960/full/v5/i1/24.htm DOI: http://dx.doi.org/10.12998/wjcc.v5.i1.24






Macedo G et al . Information and knowledge in hepatology

TO THE EDITORThe last 25 years have been a thrilling time for the portuguese hepatologists. Our national meetings, either the portuguese association for the study of liver disease annual meeting or the portuguese digestive disease week, have been providing the forum for the exchange of scientific ideas and the presentation of clinical research in clinical hepatology, a growing world of knowledge in medical care. Bridging the gaps between technology and clinical daily practice, the latest development and the almost humble bedside care, has been a challenge for the increasing numbers of doctors devoted to the diagnostic and treatment of liver disease.

Nowadays our main efforts are devoted both at the level of training and pregraduate teaching, especially in the large University Hospitals but also in addressing the public directly, aiming essentially in giving information on three major topics: Alcohol, viral hepatitis and the obesity epidemics.

We have been trying to be very persuasive among the Portuguese medical community in demonstrating that cultural vectors may influence the origin and pattern of liver disease among us. Viral hepatitis and alcoholic liver disease are paradigms of this assumption. Chronic liver disease is responsible for 3% of the deaths in Portugal, which accounts for the top ten causes of death in our country[1]. The recognition by Public Health authorities of this fact along with the national net of hepatology outpatient consultation in public hospitals, has brought liver diseases under the lights of doctors concerns and an increased public awareness of its dimension. Furthermore, although liver transplantation only begun 20 years ago, there are about 250 patients yearly transplanted, in 3 centers, serving a ten million population[2].

It is true that alcoholic liver disease is a dominant concern in this country and several reasons may contribute to this fact: Portugal, with temperate climate from Atlantic and Mediterranean origins, has a rich tradition in wine processing, and for years, many rural communities were actively involved in those processes. Alcohol consumption is thus a widespread habit, and in the traditional goodeatinganddrinking land (many times advertised abroad), it became a deep cultural characteristic lasting for decades. This creates a great challenge for us doctors, while trying to explain everyone, the risks, the facts and the fancies about chronic alcohol consumption.

If we accept WHO reports claiming for recent evidence suggesting association between alcohol abuse induced disorders and HIV/AIDS[3,4], it is easy to extrapolate that this may also play a role and background for viral hepatitis liver injury. Binge drinking for example is associated with nonprotected, unexpected and multiple partners sex behaviour[3]. So prevention has been a major task for public health authorities concerning alcohol abuse, under the judicious guidance and advice of hepatologists. The social and individual impact of more than 50 alcoholinduced disorders, obviously remain as a

leading topic for medical attention.Interestingly many other features related to viral

hepatitis have had a significant change in the last years in Portugal. If we take hepatitis A, 25 years ago, we had a high level of endemicity, and several reports showed that the adult anti hepatitis A virus (HAV) prevalence was above 90%: Infection was almost universal at around 56 years old[5,6]. The profound changes in basic hygienic and sanitary conditions of both urban and rural population, made now a different reality, with only a seroprevalence less than 35% of anti HAV in modern adolescents[5]. Although we know that if acquired in adult it may have a fulminant course with 2% mortality[1], in the meantime universal vaccination and its inclusion in the National Vaccination Program has not been advocated. Our policy is checking antiHAV previously to vaccination, if considered after the age of 15.

Hepatitis B also has changed recently among us. At the end of the millennium, HBsAg prevalence was shown to the 1.25%[6], bringing Portugal to a low prevalence area. Recently it has been claimed to be less than 1%, in a national serological survey[7], with an anti HBs prevalence of 47%, reflecting the vaccination policy adopted years ago. The overall prevalence of antiHBc is now of 6%[8]. Among us, hepatitis B virus vaccine is included in the National Vaccination Program since 1993 for adolescents aged 1013, and for all newborns since year 2000. The ongoing strategy is vaccination, of all newborns and adolescents, with additional recommendation of risk group vaccination as defined by regulatory ministerial documentation. Recent challenges however have been brought up by the intensive immigration from eastern European countries where Hbs Ag prevalence shifts between 1%7%[9] reproducing the same scenario as 40 years ago, when Angola and Mozambique citizens came back to mainland.

Still the predominant form of chronic hepatitis B is the negative chronic hepatitis, accounting for more than 80% of the cases, as a recent nationwide hospital survey showed, underlining our Mediterranean connections[1]. Despite the vaccination Program regularly undertaken, the fact is that there is a growing interest on this topic, related to the increased identification of long standing “carriers”, now truly reclassified as chronic hepatitis patients, and to the questions raised by the immunosuppressive drugs regimen (e.g., biologics, chemotherapy), urging the need for appropriate prophylaxis.

Hepatitis C also, has clearly gained full media and patient attention in recent years. Our estimated antihepatitis C virus (HCV) prevalence (based on blood donors statistics, and many clinical observations ranges between 1% and 1.5% (100000150000 subjects)[2]. Interesting cultural and historical facts made a significant contribution for this: Sports, for example. Portuguese people share with Brazilians not only the language and many cultural roots, but also an overriding enthusiasm about soccer. It is the national Portuguese sport, practiced all over the country, with passionate supporters following major Portuguese teams’ performances and


successes in European champion leagues. After thorough questionnaires and observations, we found several cases of young, otherwise healthy adults who had, as a single risk factor for HCV infection, the sharing of needles or glass reusable syringes by the paramedics of amateur soccer clubs in the eighties and nineties[1]. This occurred whenever multivitamin complexes were intravenously administered (sometimes weekly!) or when antiinflammatory drugs were repeatedly given intramuscularly. We found that it was a widespread habit, to strengthen athletes’ performance. However, other sources for percutaneous transmission of HCV, such as contaminated instruments and equipment, should always be kept in mind when we deal with our patients. Many Portuguese, as young people, had prolonged sojourns in Africa and were involved in the colonial war of late 1960s and early 1970s. ln those days, mass vaccination programs for prophylaxis in Portuguese troops going to Africa, did not use disposable needles, and tattooing with device sharing was also very common. Also, in the wake of the 1974 Portuguese Revolution, almost 1 million people returned from Africa, creating new sociological challenges in main land, at the same time fuelled by proper stimuli from the brave new world of musical scene which paved the way for youth contestation movements to include the adoption of highrisk behaviours such as sporadic (nowadays “forgotten”) intravenous drug use. Furthermore, bizarre and folk medical practices such as intravenous gammaglobulin use for “immune strength” or as “memory inducers” and intravenous calcium for chronic asthenia and tetany, without proper aseptic use of needles and syringes, may have given a significant contribution to the estimated 150000 infected people[2]. Nowadays, special attention has been given on the risk of further iatrogenic exposures to the transmission of HCV infection, beyond the overall care of health providers and the educational tools given to those involved in cosmetic procedures (tattooing, body piercing), trying to avoid what has been seen recently in developed countries from Europe, United Stated or Australia: Preparation and delivery of injectable medications, particularly in the anaesthetics setting, has been intensively addressed by those concerned with HCV epidemiological new unexpected features.

Portuguese Hepatologists have been trying to discuss the viability of creating a National Strategy Plan for prevention and control of hepatitis C. This ambitious plan stands on the tripod base of quality information, reinforced prevention and costeffective modalities, and intend to gather many society vectors like health related authorities, scientific societies - beyond the conventional gastroenterology and hepatology association pharmaceutical companies, patients organizations, and of course, politicians and the media. This tremendous effort set the stage and the pace for a unique agreement

between health authorities and Industry, allowing the recent access of thousands of patients exclusively to alloral hepatitis c treatment agents.

Step by step we have managed to reach public interest and media attention: In 2010 spring time, we promoted the “Liver on Tour”, a special Project devoted to increase public awareness on Liver health and Liver disease. All counties in Portugal were visited in a road show, with lots of simple, reliable and practical information on liver problems. Members of the Portuguese Association for the study of liver diseases board of directors were literally on the road, claiming for attention and protection for the liver. In 2011-2015 another several “out of the box” meetings addressed this anthropological insight of liver Health: Sports and the liver (along with major conferences from wellknown Portuguese sportsmen), sexuality and liver health, with two more symposia on the liver and Social Exclusion, showing how liver diseases promote exclusion and how exclusion itself is a vector for liver diseases.

Building these projects, we show clearly that silence will not be an option for those devoted in Portugal in caring for liver problems: Information and knowledge will remain to be, as demonstrated in these busy and passionate last years, a conscience imperative.

REFERENCES1 LaBrecque D, Cohen H. World Digestive Health Day: Viral

Hepatitis. World Health Organization, 2007. Available from: URL: http://www.worldgastroenterology.org/UserFiles/events/WDHD/2007/2007_wgn_newsletter.pdf

2 Anjo J, Café A, Carvalho A, Doroana M, Fraga J, Gíria J. The burden of hepatitis C in Portugal. GE J Port Gastrenterol 2014; 21: 4454 [DOI: 10.1016/j.jpg.2014.03.001]

3 Shuper PA, Neuman M, Kanteres F, Baliunas D, Joharchi N, Rehm J. Causal considerations on alcohol and HIV/AIDSa systematic review. Alcohol Alcohol 2010; 45: 159166 [PMID: 20061510 DOI: 10.1093/alcalc/agp091]

4 Rehm J. The risks associated with alcohol use and alcoholism. Alcohol Res Health 2011; 34: 135143 [PMID: 22330211]

5 Speidel A, Malaba N, Marques R, Alves J, Veríssimo R, Valente C. Prevalência do anticorpo contra o VHA numa população numa população na região centro de Portugal. Revista Portuguesa de Doenças Infeciosas 2010; 6: 95

6 Lecour H, Ribeiro AT, Amaral I, Rodrigues MA. Prevalence of viral hepatitis markers in the population of Portugal. Bull World Health Organ 1984; 62: 743747 [PMID: 6334572 DOI: 10.1007/BF01644446]

7 Mota A, Areias J, Cardoso MF. [Hepatitis B genotype distribution in Portugal and worldwide]. Acta Med Port 2011; 24: 587594 [PMID: 22521016]

8 Santos A, Carvalho A, Tomaz J, Rodrigues V, Coxinho L, Bento D, Sá R, Porto A. [Prevalence of markers of hepatitis B infection in the adult population of the district of Coimbra]. Acta Med Port 2000; 13: 167171 [PMID: 11155483]

9 Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of agespecific HBsAg seroprevalence and endemicity. Vaccine 2012; 30: 22122219 [PMID: 22273662 DOI: 10.1016/j.vaccine.2011.12.116]

P- Reviewer: Jamall IS, Jin B, Sipos F S- Editor: Qiu S L- Editor: A E- Editor: Li D

Macedo G et al . Information and knowledge in hepatology


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