Gastric adenocarcinoma presenting as a rheumatoid factor and anti-cyclic citrullinated protein antibody-positive polyarthritis: a case report and review of literature

CASE REPORT published: 24 May 2021 doi: 10.3389/ med.2021.627004 F on ie s in Medicine | www. on ie sin.o g 1May 2021 | Volume 8 | A icle 627004 Edi ed by: Ca l Kie an O , Sain Vincen ’s Uni e si y Hospi al, I eland Re iewed by: Ga i allia Sakella iou, Uni e si y o Pa ia, I aly Paul S udenic, Medical Uni e si y o Vienna, Aus ia *Co espondence: Manuel Sil é io-An ónio [email p o ec ed] Special y sec ion: This a icle was submi ed o Rheuma ology, a sec ion o he jou nal F on ie s in Medicine Recei ed: 07 No embe 2020 Accep ed: 21 Ap il 2021 Published: 24 May 2021 Ci a ion: Sil é io-An ónio M, Pa la o F, Ma ins P, Khmelinskii N, B az S, Fonseca JE and Polido-Pe ei a J (2021) Gas ic Adenoca cinoma P esen ing as a Rheuma oid Fac o and An i-cyclic Ci ullina ed P o ein An ibody-Posi i e Polya h i is: A Case Repo and Re iew o Li e a u e. F on . Med. 8:627004. doi: 10.3389/ med.2021.627004 Gas ic Adenoca cinoma P esen ing as a Rheuma oid Fac o and An i-cyclic Ci ullina ed P o ein An ibody-Posi i e Polya h i is: A Case Repo and Re iew o Li e a u e Manuel Sil é io-An ónio1,2*, Fede ica Pa la o3, Pa ícia Ma ins1,2, Niki a Khmelinskii1,2, Sand a B az3, João Eu ico Fonseca1,2 and Joaquim Polido-Pe ei a1,2 1Rheuma ology Depa men , Hospi al de San a Ma ia, Cen o Hospi ala Uni e si á io Lisboa No e, Lisbon Academic Medical Cen e, Lisbon, Po ugal, 2Rheuma ology Resea ch Uni , Faculdade de Medicina, Ins i u o de Medicina Molecula , Uni e sidade de Lisboa, Lisbon, Po ugal, 3Medicina 2 Depa men , Uni e si y Hospi al Cen e o Lisbon No h, Lisbon, Po ugal A 64-yea -old male p esen ed wi h a 6-mon h his o y o symme ic polya h i is in ol ing p oximal in e phalangeal join s and me aca pophalangeal join s o he hands, w is s, and ankles. Associa ed symp oms included omi ing, p og essi e a igue, and weigh loss. Labo a o y esul s showed mic ocy ic anemia, leukocy osis, h ombocy osis, ele a ed C- eac i e p o ein and e y h ocy e sedimen a ion a e, and heuma oid ac o (RF) and an i-cyclic ci ullina ed p o ein (ACPA) an ibody posi i i y. Join s adiog aphs we e no mal, wi hou e osions. Uppe endoscopy and gas ic endoscopic ul asonog aphy showed a gas ic adenoca cinoma wi h lympha ic in ol emen . In aope a i ely, pe i oneal ca cinoma osis was documen ed, and he pa ien s a ed pallia i e chemo he apy. A pa aneoplas ic se oposi i e a h i is was assumed, and ea men wi h low-dose p ednisolone and hyd oxychlo oquine was s a ed. A h i is emission was achie ed and sus ained up o 18 mon hs o ollow-up, al hough gas ic cance p og ession was documen ed. We desc ibe a unique pheno ype o pa aneoplas ic a h i is (PA) p esen ing as a se oposi i e (RF and ACPA posi i i y) heuma oid a h i is (RA) wi h a good esponse o bo h low dose co icos e oids and hyd oxychlo oquine he apy. We also e iew he li e a u e o PA, mos ly he RA-like pa e n, and he associa ion be ween PA and ACPA posi i i y. This case highligh s he impo ance o conside ing unde lying cance in elde ly male pa ien s, p esen ing wi h polya h i is and sys emic symp oms, e en in hose wi h ACPA-posi i e RA-like a h i is. Keywo ds: pa aneoplas ic synd ome, pa aneoplas ic a h i is, se oposi i e a h i is, heuma oid a h i is, gas ic cance INTRODUCTION Pa aneoplas ic synd omes a e mani es a ions o a malignan disease ha a e no di ec ly caused by he umo i sel and occu dis an om he p ima y umo o me as asis. Tempo al ela ionship is he main c i ical issue o iden i y pa aneoplas ic synd omes, and as a ule, he mani es a ions mus occu du ing a malignan disease o p ecede i by no longe han 2 yea s (1–3). The bes Sil é io-An ónio e al. Gas ic Adenoca cinoma P esen ing as Se oposi i e Polya h i is e idence o he associa ion be ween he clinical mani es a ions and he malignan disease is es ablished e ospec i ely when he symp oms imp o e o comple ely emi wi h he ea men o he unde lining neoplasm (1,2). A spec um o heuma ologic mani es a ions can esul om a pa aneoplas ic p ocess and a e p esen in abou 7–10% o pa ien s wi h cance , including a h i is, lupus-like synd omes, in lamma o y myopa hies, asculi is, and hype ophic os eoa h opa hy (1,3–5). Pa aneoplas ic a h i is (PA) can p esen simila ly o o he in lamma o y a h i is, and some ea u es a e used o dis inguish i om hose diseases. I a ec s mo e o en elde ly men (male/ emale a io o 1.7:1 and a median age o onse o 54 yea s) and was classically desc ibed as a se onega i e and non-e osi e asymme ical oligo-polya h i is in ol ing mos equen ly he knees, ankles, w is s, and hands (5–7). Recen ly, a symme ic polya h i is indis inguishable om heuma oid a h i is (RA) as a p esen ing ea u e o PA has been documen ed, and isola ed case epo s o PA wi h heuma oid ac o (RF) and/o an i- cyclic ci ullina ed pep ide an ibody (ACPA) posi i i y ha e been published (4,8–11). These da a sugges ha a h i is’ pa e n and se ology may no be en i ely eliable in he iden i ica ion o possible cases o PA (4). In his case-based e iew, we epo a gas ic adenoca cinoma p esen ing as RA wi h RF and ACPA posi i i y, and we e iew he li e a u e o PA, mos ly he se oposi i e pa e n. CASE REPORT A 64-yea -old male p esen ed o he eme gency depa men wi h a 6-mon h his o y o g adual onse o join pain, swelling, and mo ning s i ness in ol ing he w is s, me aca pophalangeal (MCP) join s, p oximal in e phalangeal (PIP) join s, and ankles. In addi ion, he complained o occasional omi ing, ano exia, p og essi e a igue, and unin en ional 12 kg o weigh loss. His a h algia was p og essi e and debili a ing, and had a poo esponse o non-s e oidal an i-in lamma o y d ugs (NSAIDs), ace aminophen, and opioid analgesics ( amadol 200 mg daily). His pas medical his o y and medica ion we e i ele an besides being an ex-smoke (10 pack-yea s, s opped 10 yea s ago). He had a amily his o y o gas oin es inal and pulmona y malignancies. He denied any o al ulce s, d y eyes, ash, e e , nigh swea s, gas oin es inal bleeding, o o he complain s. On physical examina ion, a h i is o he w is s, MCP join s, PIP join s, and ankles, and a posi i e me a a sal squeeze es we e no ed. The es o he examina ion was un ema kable. The ini ial labo a o y in es iga ions unco e ed a mic ocy ic and hypoch omic anemia (hemoglobin 7.9 g/dl), leukocy osis (12.7 ×109/L), h ombocy osis (904 ×109/L), and ele a ion o C- eac i e p o ein (CRP; 17.3 mg/dl) and e y h ocy e sedimen a ion a e (ESR; 94 mm/h). Renal and li e p o iles we e no mal, and an in ec ion sc een was nega i e. An anemia in es iga ion showed low se um i on (9.6 µg/dl) and ans e in sa u a ion (4%), and no mal e i in (74.1 ng/dl), cyanocobalamin (465 pg/ml), and ola e (5 ng/ml) le els. Radiog aphic e alua ion o he a ec ed join s and ches was un ema kable. The RF and ACPA we e signi ican ly FIGURE 1 | Gas ic mass on (A) uppe gas oin es inal endoscopy and (B) abdomen compu ed omog aphy ( ed a ow). ele a ed a 215 IU/ml (0–14 IU/ml) and 156.9 IU/ml (<20 IU/ml), espec i ely. Uppe gas oin es inal endoscopy exhibi ed on he lesse cu a u e and an um o he s omach a ha d and iable mass wi h a eas o nec osis ha condi ioned luminal s enosis (Figu e 1A). Endoscopy ul asound o he uppe gas oin es inal ac e ealed a mass ex ending 17 mm o he se osa laye wi h egional in ol emen o ou lymph nodes. Endoscopy biopsy specimens showed a gas ic adenoca cinoma wi h poo di e en ia ion. Con as -enhanced ches –abdomen–pel is compu ed omog aphy con i med he gas ic mass wi h no e idence o o he adenopa hy o dis an me as asis (Figu e 1B), and he umo was a ed T3N2M0, G3. Ches e alua ion showed sligh changes compa ible wi h emphysema. Du ing he hospi aliza ion, while he malignancy wo kou was ongoing, polya h i is was ea ed wi h a sho cou se o co icos e oids (dexame hasone 5 mg daily) wi h good clinical esponse, and he dose was quickly ape ed. Howe e , a ew weeks la e , his symp oms ecu ed, and he was eadmi ed due o se e e polya h i is wi h disabling gai . Co icos e oid he apy was ein oduced (p ednisolone 20 mg daily), and F on ie s in Medicine | www. on ie sin.o g 2May 2021 | Volume 8 | A icle 627004 Sil é io-An ónio e al. Gas ic Adenoca cinoma P esen ing as Se oposi i e Polya h i is FIGURE 2 | Timeline disease ac i i y o a h i is and ela ion wi h chemo he apy d ugs, co icos e oids, and hyd oxychlo oquine. DAS28 3 -PCR, Disease Ac i i y Sco e o 28 join s wi h h ee a iables ( ende join coun , swollen join coun , and C- eac i e p o ein); DEXA, dexame hasone; HCQ, hyd oxychlo oquine; PDN, p ednisolone. hyd oxychlo oquine (200 mg daily) was also added. Howe e , ull adhe ence o he he apeu ic egimen was only possible a e a ew mon hs and only hen was a comple e esolu ion o polya h i is achie ed (Figu e 2). He was e e ed o oncology and p oposed o gas ec omy. Du ing he lapa o omy p ocedu e, ex ensi e pe i oneal ca cinoma osis was de ec ed, whe eby he unde wen gas ojejunos omy. The pa ien s a ed pallia i e chemo he apy wi h cispla in and luo ou acil, and a e HER2 o e exp ession was documen ed, as uzumab was added. Cispla in and luo ou acil we e s opped a e 8 mon hs, bu cance p og ession was documen ed and we e ein oduced la e on, wi h li le e ec on a h i is con ol. A e 18 mon hs o ollow-up, he emained ali e, wi h sus ained a h i is emission o o e 9 mon hs (documen ed clinically and using ul asound) and wi hou adiological de ec able e osions, unde ea men wi h low-dose p ednisolone (<7.5 mg daily) and hyd oxychlo oquine (300 mg daily), despi e he absence o a cu a i e cance ea men . DISCUSSION O e all, pa ien s wi h RA a e a an inc eased isk o cance compa ed wi h he gene al popula ion. Howe e , gas ic cance has a lowe incidence in RA pa ien s, which can be explained by he inc eased use o NSAIDs in his popula ion (12–15). The incidence o RA in pa ien s wi h gas ic cance is no known. A wide a ie y o solid and hema ological malignancies has been associa ed wi h PA, wi h lung adenoca cinoma being he TABLE 1 | T adi ional cha ac e is ics o pa aneoplas ic a h i is [adap ed om S umm oll e al. (5), La son e al. (8), Caldwell and McCallum (19), and P i zenmeye e al. (20)]. 1. Close empo al ela ionship (12 mon hs) be ween he onse o a h i is and malignancy 2. Olde age 3. Join in ol emen in an asymme ic dis ibu ion 4. P edominance o lowe ex emi y in ol emen 5. Explosi e onse 6. Absence o amily his o y o heuma ic disease 7. Absence o heuma oid nodules 8. Absence o cha ac e is ic adiog aphic lesions o RA 9. Absence o RF 10. Non-speci ic his opa hologic appea ance o he syno ial lining RA, heuma oid a h i is; RF, heuma oid ac o . mos equen (3,9). Thus, a , only ou pa ien s wi h PA we e epo ed ha ing gas ic umo s, none wi h a se oposi i e RA-like pa e n (3,16–18). Based on he e iew o case epo s, PA was adi ionally desc ibed as a se onega i e asymme ic oligoa h i is wi h p edominan in ol emen o he lowe limb join s (Table 1). Howe e , a symme ic polya h i is indis inguishable om RA is now ecognized o be he mos equen pa e n, in a ew cases associa ed wi h RF o ACPA. F on ie s in Medicine | www. on ie sin.o g 3May 2021 | Volume 8 | A icle 627004 Sil é io-An ónio e al. Gas ic Adenoca cinoma P esen ing as Se oposi i e Polya h i is TABLE 2 | New cha ac e is ic ea u es p oposed o he diagnosis o pa aneoplas ic a h i is [adap ed om Mo el e al. (3)]. 1. A e age ime be ween a h i is and neoplasia diagnosis <6 mon hs 2. Men age >50 yea s 3. Polya h i is (symme ic o asymme ic) 4. Absence o heuma oid nodules 5. Absence o e osions on adiog aphy 6. Absence o RF 7. Deg ada ion o gene al heal h s a us 8. High CRP le el 9. Reg ession o a h i is a e speci ic an i- umo al he apy CRP, C- eac i e p o ein; RF, heuma oid ac o . Classic PA ea u es we e de ailed by Kisacik e al. (7) by compa ing pa ien s wi h PA (n=65) wi h pa ien s diagnosed wi h ea ly RA (n=50). In his s udy, he PA g oup was de ined by using p e iously desc ibed adi ional ea u es, and he inclusion c i e ia we e apid disease onse and symme ic o asymme ic disease mos ly a ec ing he lowe ex emi ies and usually spa ing he small join s o he hands. Consequen ly, pa ien s wi h RA-like a h i is we e excluded om he PA g oup, which o igina ed an unin en ional bias in he desc ip ion o PA cha ac e is ics. An ea lie s udy by Mo el e al. be e cha ac e ized his ype o a h i is, in a case se ies o 26 pa ien s wi h PA, using a less es ic i e a h i is pa e n—oligo-polya h i is e ol ing o a maximum o 2 yea s be o e cance diagnosis (3). Despi e con i ming mos o he adi ional ea u es, such as he absence o RF and adiologic lesions, hey concluded ha he majo i y o pa ien s displayed ea u es o RA, being symme ic polya h i is, in ol ing w is s and hands, he mos equen a icula pa e n (85%). The e o e, hey p oposed a new g oup o cha ac e is ic ea u es o he diagnosis o PA (Table 2). A e iew by Wa son e al. also included se e al pa ien s wi h PA wi h symme ic dis ibu ion and in ol emen o he w is s, small join s o he hands, and knees, esembling RA. Con a y o p e ious epo s, some o hese pa ien s we e posi i e o bo h RF and ACPA (9). Ou pa ien p esen ed wi h an RA-like pa e n and high i e o bo h RF and ACPA mee ing he 2010 Ame ican College o Rheuma ology/Eu opean League Agains Rheuma ism classi ica ion c i e ia o RA. To he bes o ou knowledge, his is he six h case desc ibed in he li e a u e classi iable as a PA wi h RF and ACPA posi i i y (Table 3). O in e es , ou o hese pa ien s also had an RA-like pa e n, wi h e osi e a h i is p esen in one o hem. Mos o he pa ien s esponded well o low- dose co icos e oid he apy, bu due o he ad anced s age o he malignancies, umo he apy was cu a i e in a single pa ien , and only in his case, a comple e esolu ion o he PA occu ed. None o he epo ed cases men ions he p esc ip ion o disease- modi ying an i- heuma ic d ugs (DMARDs), which may be explained by he concomi an chemo he apy o p edic able poo gene al condi ion o a pa ien wi h ad anced neoplas ic disease. Despi e he ac ha PA was classically desc ibed as e ac o y o co icos e oids and NSAIDs, he s udy by Mo el e al. showed some con adic o y in o ma ion. NSAIDs and co icos e oids we e e ec i e, espec i ely, in 45 and 91% o he pa ien s, bu wi hou ob aining a sus ained emission. DMARDs (sul asalazine and me ho exa e) we e only e ec i e in one ou o i e ea ed pa ien s. Two s udies analyzed a se ies o pa ien s wi h pa aneoplas ic heuma ologic synd omes and showed ha he majo i y o PA we e ACPA nega i e (7,21). ACPA ha e simila sensi i i y as RF o RA bu wi h a highe speci ici y (90–95%), hus, allowing mo e accu a e diagnosis o RA, especially in cases o ea ly undi e en ia ed a h i is (8,9). Howe e , his es is no 100% speci ic, and ACPA posi i i y has been epo ed in a a ie y o diseases (21–25). As his case highligh s, he p esence o ACPA in he con ex o a polya h i is should no exclude au oma ically o he diagnos ic en i ies, pa icula ly in elde ly pa ien s wi h consump i e symp oms. O e looking his migh delay he diagnosis and ea men o unde lying cance (8,9). ACPAs a e o med agains ci ullina ed an igens ha appea a e enzyme-ca alyzed pep ide ans o ma ion by pep idyla ginine deiminase (PAD) enzymes. In RA, hese an igens a e ound in in lamma o y syno ial memb anes, and ACPAs ha e been shown o pe pe ua e join in lamma ion and co ela e wi h mo e agg essi e disease (26). In hema ological and solid umo s, PAD enzymes a e up egula ed and ha e been implica ed in he ca cinogenesis p ocess (27). In 2014, Handy e al. p oposed a possible associa ion be ween ACPA posi i i y and PA (4). They sugges ed ha ACPA could appea due o he o e exp ession o PAD enzymes in malignan diseases, gene a ing ci ullina ed pep ides, which a e hen exposed o he immune sys em. Howe e , his hypo hesis does no explain all PA cases (as mos a e ACPA nega i e) no o e s a comple e mechanis ic elucida ion o he PA phenomena. In he p esen case, he onse o a symme ic polya h i is in an elde ly man, associa ed wi h cons i u ional symp oms and i on de iciency anemia led us o an addi ional wo kup. In ou opinion, he cha ac e is ic ea u es p oposed by Mo el e al. (3) (Table 2) a e mo e ep esen a i e o he ull spec um o PA and should be p e e ed in clinical p ac ice. Cance p og ession was seen in ou pa ien and was accompanied by la es o polya h i is, despi e ongoing chemo he apy. We should no e ha some chemo he apy d ugs can imp o e RA clinical mani es a ions, namely, cispla in and luo ou acil, which we e used in his pa ien (28,29). Howe e , in his case, chemo he apy d ugs did only ha e a modes e ec , and a h i is emission was only possible when ull adhe ence o hyd oxychlo oquine and p ednisolone was achie ed. Since he e ec o hyd oxychlo oquine in mono he apy in RA is qui e modes when compa ed wi h o he classic DMARDs, especially in double se oposi i e RA, i is p obable ha in ou pa ien , he a h i is emission was achie ed due o he combina ion o hyd oxychlo oquine, p ednisolone, and chemo he apy (30). Acco dingly, we belie e ou case ep esen s a se oposi i e PA, being he i s case ela ed o gas ic malignancy. Un o una ely, he s aging o ou pa ien s’ malignan disease de e mined pallia i e su ge y and chemo he apy, and he likelihood o cu a i e ea men is e y low. We canno , hus, conclude i a h i is would emi wi h he ea men o unde lying cance . F on ie s in Medicine | www. on ie sin.o g 4May 2021 | Volume 8 | A icle 627004 Sil é io-An ónio e al. Gas ic Adenoca cinoma P esen ing as Se oposi i e Polya h i is TABLE 3 | Cha ac e is ic ea u es o published cases o RF and ACPA-posi i e pa aneoplas ic a h i is. Re e ence Age/sex Type o malignancy Du a ion o symp oms p eceding cance diagnosis (mon hs) Family his o y o cance A h i is loca ion and pa e n Onse Anemia ESR (mm/h)/ CPR (mg/dl) RF (IU/ml) /ACPA (IU/ml) Join adiog aphs Response o NSAIDs Response o co icos e oids Cance ea men used ( esponse o e olu ion) Kuma e al. (11) 58/M Panc ea ic cance 2 N.M. No a h i is; a h algia in ol ing hands, w is s, elbows, shoulde s, lowe back, and neck; asymme ic and in e mi en G adual Yes ++/N.M. + + +/++ N.E. N.M. Yes None (died) Raja e al. (10) 40/M Lymphoma oid g anuloma osis 3–4 No W is s, knees, and ankles; symme ic G adual No –/+ ++/++ N.E. N.M. Yes (pa ial) None (died) La son e al. (8) 45/F Lung adenoca cinoma 3 No PIP, MCP, elbows, and knees; symme ic N.M. No –/+ ++/+N.E. No Yes (pa ial) None (died) Handy e al. (4) 61/F T cell lymphoblas ic leukemia 1–2 No MCP, w is s, knees, and ankles; symme ic Acu e Yes + + +/++ + + +/++ E osions No No Hype -CVAD CMT ( e ac o y) Wa son e al. (9) 80/F B eas papilla y cance 1 N.M. Shoulde a h i is; a h algia in ol ing w is s, shoulde s, and knees; asymme ic and mig a o y Acu e Yes –/++ +/+N.E. No Yes CMT (N.M) and RT ( emission) P esen case 64/M Gas ic adenoca cinoma 6 Yes (GI and lung) PIP, MCP, w is s, and ankles; symme ic G adual Yes ++/+ + + ++/++ N.E. No Yes 5-FU and CIS CMT (no cu a i e) CPR, C- eac i e p o ein; ESR, e y h ocy e sedimen a ion a e; ACPA, an i-cyclic ci ullina ed pep ide an ibodies; RF, heuma oid ac o ; NSAIDs, non-s e oidal an i-in lamma o y d ugs; F, emale; M, male; GI, gas oin es inal; MCP, me aca pophalangeal join s; PIP, p oximal in e phalangeal join s; 5-FU, luo ou acil; CIS, cispla in; hype CVAD, cyclophosphamide, inc is ine, doxo ubicin, and dexame hasone; CMT, chemo he apy; RT, adio he apy; N.E., no e osions; N.M., no men ioned. ESR: – i <30, +i ≥30, and <60, ++ i ≥60 and <100, +++i ≥100. CPR: +i ≥0.5 and <5.0, ++ i ≥5.0 and <15.0, +++i ≥15.0. RF i e : +i ≥14 and <100, ++ i ≥100 and <300, + + + i ≥300. ACPA: +i ≥20 and <100, ++ i ≥100 and <300, +++i ≥300. F on ie s in Medicine | www. on ie sin.o g 5May 2021 | Volume 8 | A icle 627004 Sil é io-An ónio e al. Gas ic Adenoca cinoma P esen ing as Se oposi i e Polya h i is In conclusion, ou case illus a es ha physicians should be awa e and ule ou cance in an ACPA- posi i e RA-like polya h i is in pa ien s wi h cons i u ional symp oms and/o wi h labo a o y ea u es showing se e e anemia, h ombocy osis, and e y high CRP. DATA AVAILABILITY STATEMENT The o iginal con ibu ions p esen ed in he s udy a e included in he a icle/supplemen a y ma e ial, u he inqui ies can be di ec ed o he co esponding au ho /s. ETHICS STATEMENT E hical e iew and app o al was no equi ed o he s udy on human pa icipan s in acco dance wi h he local legisla ion and ins i u ional equi emen s. The pa ien s/pa icipan s p o ided hei w i en in o med consen o pa icipa e in his s udy. 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An open-label, phase I/II s udy o 5- luo ou acil plus leuco o in in he ea men o heuma oid a h i is. J Rheuma ol. (2002) 29:1109–10. 30. Smolen JS, Landewé RBM, Bijlsma JWJ, Bu mes e GR, Dougados M, Ke schbaume A, e al. EULAR ecommenda ions o he managemen F on ie s in Medicine | www. on ie sin.o g 6May 2021 | Volume 8 | A icle 627004 Sil é io-An ónio e al. Gas ic Adenoca cinoma P esen ing as Se oposi i e Polya h i is o heuma oid a h i is wi h syn he ic and biological disease-modi ying an i heuma ic d ugs: 2019 upda e. Ann Rheum Dis. (2020) 79:685– 99. doi: 10.1136/ann heumdis-2019-216655 Con lic o In e es : The au ho s decla e ha he esea ch was conduc ed in he absence o any comme cial o inancial ela ionships ha could be cons ued as a po en ial con lic o in e es . Copy igh © 2021 Sil é io-An ónio, Pa la o, Ma ins, Khmelinskii, B az, Fonseca and Polido-Pe ei a. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. F on ie s in Medicine | www. on ie sin.o g 7May 2021 | Volume 8 | A icle 627004