184

European Journal of -20-1367 Oxford, UK Oxford, Oxfordshire,UKand 1 Radu Mihai parathyroid allotransplantation treatments andfutureprospectsfor Postsurgical :current MANAGEMENT OFENDOCRINEDISEASE . Whenitbecameapparent thatthisprocedure received thefirstrecorded allotransplantofparathyroid A victimofatramaccident was usedasdonor, andAlbert was aninsufficiency oftheparathyroid glandfunction. in Vienna inearly1920s,theinitialworkingdiagnosis fractures, wasadmittedunderthecareofDrFelixMandle When Albert, a 34 years old man with multiple recent Introduction symptomatic protractedpost-surgicalhypoparathyroidismiswarranted. Conclusion for immunosuppressionandlong-termoutcomesarereviewed. selection ofdonors,parathyroidcellpreparationbeforeallotransplantation,siteandtimingtransplantation, need allotransplantation ofparathyroidtissuebetweensiblings,thereisrenewedinterestinthistechnique.Dataon and concernsrelatedtotheriskofdevelopmentosteosarcoma.Basedonrecentcasereportssuccessful , Forsteo®)hasbeenassessedinmulticentretrials,buttheuseofthismedicationisrestrictedbycosts emergency admissions.ReplacementtherapywithsyntheticPTHcompounds(PTH1-34,Natpara®andPTH1-84, analogues butasignificantproportionofpatientscontinuetoexperienceseveresymptomsrequiringrepeated Results parathyroid allotransplantation. Methods as seizuresandlaryngospasm. burden thehealthcareprovisionthroughcomplexneedsformedicationandtreatmentofspecificcomplications,such bilateral thyroidsurgerydevelopPOSH.Thisleadstoamultitudeofsymptomsthatdecreasethequalitylifeand in generalandofthyroidsurgeryparticular.Dependingondiagnosticcriteria,upto10%patientsundergoing Background Abstract Department ofEndocrineSurgery,ChurchillCancerCentre,OxfordUniversityHospitalsNHSFoundationTrust, https://doi.org/ https://eje.bioscientifica.com Review : Inmostpatients,POSHiscontrolledwithregularuseofcalciumsupplementsandactivevitaminD : NarrativereviewofcurrentmedicaltreatmentsforPOSHandtheexperienceaccumulatedwith : Aprospectivetrialtoassesstheefficacyofparathyroidallotransplantationinpatientswithseverely 10.1530/EJE : Permanentpostsurgicalhypoparathyroidism(POSH)isamajorcomplicationofanteriornecksurgery 1 and -20-1367 Rajesh V Thakker 2 Academic EndocrineUnit,RadcliffeDepartment of ,UniversityOxford, 5 R MihaiandVThakker Published by Bioscientifica Ltd. 2 Printed inGreat Britain © 2021Theauthors (PTalloT) will becomepartofthesurgicalpractice. be thatinafurther decade parathyroidallotransplantation one ofthemostcommonendocrine operations.Itcould is for primary parathyroid ( ofparathyroidsurgery started thehistory Albert’s neckandthisfirstsuccessfulparathyroidectomy had noclinicalimpact,DrMandledecidedtoexplore hypoparathyroidism Treatment ofpostsurgical Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at09/28/202109:04:27PM (2021) Endocrinology European Journalof [email protected] Email to RMihai should be addressed Correspondence 184 184 :5 , R165–R175 Creative Commons

1 ). Currently, R165 –R175 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com is diagnosedafterfullbiochemical reassessmentat6or 24 haftertheoperation).Similarly, permanenthypoPT hypocalcaemia, orlowPTH levelswithin4hor the lowerlimitofnormal range,orsymptomatic different definitionsareused (e.g.calciumlevelsunder The reportedincidenceofPOSHvarieswidelybecause Epidemiology ofpostsurgicalhypoPT of theirvascularsupplycanreducetheriskPOSH( for identificationofparathyroidglandsandassessment expected thattheintraoperativeuseof(auto)fluorescence autotransplantation ( lymph nodedissectionandtheroutineuseofparathyroid bleeding, theneedforassociatedcentralcompartment POSH. Incontrast,longeroperations,reoperationfor of parathyroid glands ( routine parathyroid identification and several operativefactors.Highsurgicalvolume( isinfluencedby The riskofPOSHafterthyroidsurgery tumours is a rare cause of POSH (under 5% of cases). after parathyroid surgery. Radical resection of laryngeal 80% ofpatients.About10–15%POSHcasesoccur exposure ( (e.g. iron/copperoverload)orbyionisingradiation hypoPTcausedbyrareinfiltrativedisorders secondary inadvertent excision.Itisraretoencounterpatientswith compromising vascularsupply, or thermicinjury totheparathyroidglandsthrough intraoperative injury represented by postsurgicalhypoPT(POSH), caused by parathyroid function. hypoPT due to impaired common secondary/acquired within theparathyroidglands,andmuchmore hypoPT duetointrinsicgeneticandautoimmunedefects absent PTH levels. The condition is divided into primary levelsinthepresenceofinappropriatelylow/ Hypoparathyroidism (hypoPT)isdefinedaslowserum hypoparathyroidism (hypoPT) Causes ofpostsurgical hypoparathyroidism. symptomatic refractory role of allotransplantation in patients with severely background forapotentialclinicaltrialexploringthe options forhypoparathyroidismandaimstocreatethe Review Bilateral surgery is the cause of POSH in over Bilateral thyroid surgery hypoPTare The vastmajorityofcasessecondary This paperisanarrativereviewofcurrenttherapeutic 2 ). 6 ) increasetheriskofPOSH.Itis 5 ) are all reducing the risk of

R MihaiandVThakker in situ preservation preservation 3 , 7 ). 4 ), these ledtothe17-itemscoringsystem( symptoms wereidentifiedduringitemgenerationand concentration/focus (43%).Atotalof17majorsignsand ability tohaveaconversation(50%),andlack of (57%),impaired dysfunction (86%),impairedmemory muscle (86%),physicalfatigue(83%),cognitive such astingling,numbnessandparesthesia(88%), experienced physicalsymptomsattributedtohypoPT, hundred percentoftheconceptelicitationpatientgroup peryear. Surgeonsmightnotbeaware and thoseoperatedincenterswithavolumeof parathyroidautotransplantation patients whounderwent of POSHamongwomen,patientsovertheage60years, POSH. Inamultivariableanalysis,therewashigherrisk based onthisdefinition,938patients(12.5%)developed and active for more than 1 year after surgery hypoPT wasdefinedastreatmentwithcalciumand/or inSwedenfrom2005to2015.Permanent atotal on analysisof7852patientswhounderwent most recent report on the incidence of POSH is based to occurinup5%ofcases(discussed( defined aslastingmorethan6months,isestimated patients after neck surgery, whereas permanent POSH, population studies. (e.g. osteoporosis)arenotalwaysexcludedinlarge calcium/vitamin Dsupplementsforotherindications 12 monthsaftertheoperation,andpatientswhotake Only 4%ofpatientsnever experiencedfatigueor for ,and4.5±1.9 for lowsenseofwell-being. highest scores for severity of symptoms were 4.8 ± 1.8 UK (nowParathyroidUK) patient supportgroup,the this questionnaireshouldnowbetestedinlargecohorts. for patient-reported outcomes in hypoPT ( Scale-Symptom hasbeendevelopedasaspecifictool Recently, theHypoparathyroidismPatientExperience Consequences ofpostsurgicalhypoPT future decades. worldwide, theprevalenceofPOSHislikelytoincreasein increasing numberofthyroidoperationsperformed (discussed in( the prevalenceofPOSHwasestimatedas22/100000 with POSH( quality registeronlyidentified178ofthese938patients of mostthesecasesastheirself-reporteddatafromthe hypoparathyroidism Treatment ofpostsurgical Transient POSHisestimatedtooccurin25–80%of In our own survey of252memberstheHypoPara In ourownsurvey Using datafromtheDanishNationalPatientRegistry, 4 ). 2 )). Onthebackgroundofconstantly Downloaded fromBioscientifica.com at09/28/202109:04:27PM 184 8 :5 ). Thevalidityof 8 2 ). One )). The R166 < 100 via freeaccess

European Journal of Endocrinology 1. therapeutic optionsexist: management of thesepatients ( guidelines highlightsomeofthedifficultiesin QoL andreducethemorbidity. Recent European in thelongterm,treatmentaimstoimprove reduce symptoms,hospitalstayandreadmissions,while In the short term, the goals of medical are to surgical hypoPT Current managementofpost- 1.04–4.20) ( hypoPT aftertotalthyroidectomy(HR:2.09,95%CI: was significantly higher among patients with permanent dataitwasfoundthattheriskofdeath same registry and forcardiovascularevents(HR:1.88)( insufficiency (HR:4.88),foranymalignancy2.15) follow-up of 4.5 years they had an increased risk for renal foundthatafteramean Parathyroid, andAdrenalSurgery from theScandinavianQualityRegisterforThyroid, A studyof239patientswithpermanenthypoPTidentified including ,epilepsyandsofttissuecalcification. hypoPT experiencesignificantlong-termmorbidity 6 months( required emergencyadmissiontohospitalwithinthelast UK patients, where 93% of responders reported that they ( required emergencydepartmentorhospitaladmissions experienced symptomsdespitetreatmentand79%had patients with hypoPT showed that 75% of sufferers quality oflife( use ofmedicationandthisimpactsevenmoreontheir experiencing symptomatichypocalcaemiadespiteregular with patients’self-ratedsymptomseverity( therapy and207caregivers,caregivers’burdenincreased hypoPT notadequatelycontrolledonconventional Inastudyof398patientswithchronic health services. extends totheircarers,andthisamplifiestheimpacton described inliterature( patients listedamyriadofassociatedsymptomsrarely these symptomsalmostallthetime.Inaddition,149 numbness/tingling sensations,while30–35%experienced 11 Review supplements toallpatients for4–6weeksafter effective approachistoprescribe routinecalcium the standardtreatmentof hypoPT. Themost cost- Oral calciumandvitaminD supplementation ). This mirrors the results of our survey ofHypoPara ). Thismirrorstheresultsofoursurvey In additiontotheirimpairedQoL,patientswith Interestingly, themajorityofpatientsarestill The burdenofthediseaseonindividualpatients 9 13 ). ). 9 ). Arecentpopulationstudyof374adult 9 ). R MihaiandVThakker 14 ). Several medical 12 10 ). Usingthe ). represent

daily injections.PTH(1-34) deliveredbyinsulinpump, further downsideofPTHreplacement isthatitrequires have tobeslowlyweaned overseveralweeks( as thiscouldleadtosevere hypocalcemiaandpatients Importantly, PTH(1-34) cannotbediscontinuedabruptly, 2. more widelyintheUSA. Alfacalcidol isusedmoreintheUK,Rocaltrol then adjusteduptotheusualdoseof0.5–1 administered orallyataninitialdoseof250 physiologically-active analogueofvitaminD,andis (Rocaltrol®, 1,25(OH) patients withPOSHinadoseof1–3µg/day. D analogue,isroutinelyincludedinthemedicationof Alfacalcidol (1-Alpha-Hydroxycholecalciferol),avitamin mended andthisrequiresregularcalciummeasurements. Daily dosesofupto1200–2000mgcalciumarerecom hypoparathyroidism Treatment ofpostsurgical early measurementofPTHinthepostoperativeperiod and/or thedynamicoftheirPTHlevels.Currently, based on their symptoms, their slope of calcium changes select patientswhoaregivencalciumsupplements calcium levelsduringin-hospitaladmissionandto intense medicaltreatment( parathyroid functionismorelikelyafteraperiodof in Barcelona, of whohypothesisedthattherecovery been labelledas‘parathyroidsplinting’byresearchers symptomatic hypocalcaemia( The numberneededtotreatwas4(95%CI:3–6)for treatment basedonmeasurementofcalciumlevels. and biochemical(RD-0.24)hypocalcaemiathan lower riskofsymptomatic(riskdifference(RD) supplementation withcalcium meta-analysis of15studieswith3037patients,routine function anddecideonlong-termmanagement.Ina before reassessing parathyroid bilateral thyroid surgery and thephysicalmentalfunctioning( PTH(1-84) improvethebone-remodellingdynamics( USA in 2015 and in the EU in 2017. Both PTH(1-34) or for usebytheFoodandDrugAdministration(FDA), available norroutinelyused.Thedrugwasaccepted hormonal failure,butthismedicationisnotwidely Synthetic PTH length ofhospitalstay. symptomatic hypocalcemiaandavoidingprolonged the postoperativeperiod,reducingincidenceof and Vitamin D replacement can be initiated early in (reviewed in ( at riskofhypocalcemiafollowingtotalthyroidectomy is widelyacceptedasthebestwaytoidentifypatients Historically, mostsurgeonspreferredtomonitor would be the ideal replacement for a 6 )). In this way prophylactic calcium 2 vitaminD),isthesynthetic Downloaded fromBioscientifica.com at09/28/202109:04:27PM 16 https://eje.bioscientifica.com ). 15 + vitamin D3offereda ). Thisstrategyhas 184 :5 µg/day. While ng daily, and 18 ). R167 19 − 0.25) ). A 17 via freeaccess ) -

European Journal of Endocrinology https://eje.bioscientifica.com is approx. £10. Vitamin D supplements (alfacalcidol: 1 µg/ (1 gr calcium carbonate two-three times daily for 4 weeks) are cheapandcanbebought overthecounter. Calchichew costs relatedtodailymedication. Calciumsupplements for acutecomplicationsofhypoPT. , northelikelycostsrelatedtohospitalisation outpatient clinics,hospitals,emergencydepartments, or the studydidnotquantifycostsrelatedtoutilisation of ( estimated tobeaboutthreetimesthatforhealthypatients yearly costofmedicalcareforpatientswithhypoPTwas In apopulation-basedstudyfromMinnesota,USAthe medication regimes Cost analysisofcurrent safety-information-identified-fda-adverse january-march-2019-potential-signals-serious-risksnew- and-answers-fdas-adverse-event-reporting-system-faers/ and calciphylaxis( Event ReportingSystemlistedcutaneouscalcification bones arestillgrowing.Furthermore,theFDAAdverse and prohibitsitsuseinchildrenyoungadultswhose of the2-yearmaximumlifetimedurationtreatment media/77492/download from FDA,USA(August2013, the mostrecentguidanceonFORTEO®(teriparatide) described byclinicaltrialsinhumans( rats but,thusfar, skeletalmalignancieshavenotbeen established. Ariskofosteosarcoma wasreportedin yet beendemonstratedanditssafetyprofileisnotfully clinical development( Based onthesedatathedrugwilladvanceintophase2 demonstrated aneffectivehalf-lifeofapproximately60h. healthy adultswasgenerallywelltoleratedandfreePTH placebo-controlled studyTransCon PTHadministeredto designed toreleasePTH(1-34).Inaphase1,randomised, inactive prodrugtransientlyboundtoaninertcarrier, (TransCon PTH)thatisasustained-release,essentially ( of deliveringteriparatideorally, usingnanoemulsion treatment more ‘user-friendly’. The first is the possibility profile ( and proven to achieve a physiological biochemical of hypoPTthathasbeenusedinadultsandchildren represents an important advance in the management 22 2 ). Thishowevermightbeasignificantunderestimate,as Review ). Thesecondistheuseofachemicalderivative As asimplifiedfinancialmodel somecalculateonlythe The long-termbenefitsofsyntheticPTHhavenot Two recentdevelopmentsinthisfieldmightmake 20 , 21 ). https://www.fda.gov/drugs/questions- 23 ) informshealthcareproviders ). R MihaiandVThakker https://www.fda.gov/ 24 ). ). Nevertheless,

are reimplantedduringthesameprocedureintoamuscle that arerecognisedtohavebeeninadvertentlyremoved As partofroutinesurgicalpractice,parathyroidglands Parathyroid transplantation of £6500for28doses. but thepriceonEuropeancontinentisinregion 100 µg/dose).ThecostofthedruginUKisnotavailable, dose cartridgecontainingdifferentdosagestrengths(25– ct2/show/NCT03324880 used inthe‘BALANCE’study( day) anditcosts£326.PTH1-84(Natpara®)iscurrently dispensed asa2.4mLpre-filledpen(equivalentof20µg/ but couldbeobtainedonnamedpatientbasis.Itis (teriparatide, Forsteo®)isnotlicensedforuseinhypoPT calcitriol (100capsules,250µg)inUSAis$35.PTH1-34 day for 1 month) costs under £10. Average retail price for could bejustified.Morerecently, theintraoperativeuse is nonviable,hencethedecision ofautotransplanting the bloodsupplyhasbeen compromised andthegland experience, oneexpectsto beabletorecognisewhen of aglanddeemeddevascularised. With increasing surgical more difficultscenarioistodecideonautotransplantation need/benefit ofautotransplantationiseasilyaccepted. A inadvertently removedwiththethyroidspecimen, thyroidectomy in1926. performed parathyroidautotransplantation during a One ofpioneersthyroidsurgery, DrFrankLahey, first Parathyroid autotransplantation immunosuppression medication. downside ofallotransplantationistheneedforlife-long the recipient,basedonHLAandblood-groups.Themain process ofthedonorsfollowedbystrictmatchingwith transplantable organsthrougharigorousselection This reliesonusingapotentiallylargesource of term usedtodescribethisprocessisallotransplantation. reimplanted surgicallyinapatient(therecipient).The retrieved from another individual (the donor) being or aheart-lungtransplant,onereferstousinganorgan replacing adeficientorgan,suchaskidneytransplant the patient’s owntissueistransplanted. function. Theprocedureiscalledautotransplantation,as supply andsubsequentlywillmaintaintheirsecretory pocket, with theexpectation that they willregain vascular hypoparathyroidism Treatment ofpostsurgical When one(ormore)parathyroidgland(s)are In contrast,whendiscussingotherproceduresof Downloaded fromBioscientifica.com at09/28/202109:04:27PM ) andisavailableasmultiple- https://clinicaltrials.gov/ 184 :5 R168 via freeaccess European Journal of Endocrinology Care ofpatientswithgeneticsyndromes Techniques forreducingtheincidence of Use ofsyntheticPTHastreatmentfor Epidemiology ofhypoPT Topic identified on Table 1 PARADIGM studyfromUniversityofCalifornia(Pancreatic on hypoPT are summarised in PTalloT. The topics explored by recent and ongoing trials successfulPTalloTwho underwent ( report ofa32-year-oldfemalewithintractablehypoPT patients withPOSH,afterhopeswereraisedbyacase been increasinglydiscussedasapossibletreatmentfor Recently, parathyroidallotransplantation(PTalloT) has Parathyroid allotransplantation hypoPT ( hypoPT butasubsequentreductioninratesofpermanent performed, itisthoughttobeassociatedwithatransient of parathyroidtissueinbufferedsaline( (as describedbyWells ( reimplanting 10–20smallslices/fragmentsofthegland based onpersonalexperience,withachoicebetween function. as thishastheaddedbenefitofeasiermonitoringgraft expected ifre-implantationisperformedintheforearm sternocleidomastoid muscle. Similaroutcomesare other unitsremainstobedeterminedinfutureyears. early-adopters ofthistechnologycouldbereplicatedin findings fromthe enthusiastic groupinGeneva who were least onewell-perfused parathyroid . Whether these and supplementation with calcium in patients with at need forpostoperativemeasurementofcalciumandPTH, vascularisation oftheparathyroidglandsandobviates In theirexperience,ICGangiographyreliablypredictsthe hypoparathyroidism onPOD1,andsix10–15( gland couldbeidentifiedbyangiography, presentedwith of the50patientsinwhomnowell-perfusedparathyroid of theoperation.Inastudyincluding196patients,11 been toassessperfusionofparathyroidglandsattheend of autofluorescencewithICG(indocyaninegreen)has Review associated withhypoPT post-thyroidectomy hypoPT hypoPT There are no registered clinical trials involving The techniqueusedforautotransplantationis The preferredsiteforautotransplantationisthe 26 Topics addressedbystudiesonhypoparathyroidism ). clinicaltrials.gov 25 registry(accessedon1May2020). )) orinjectionofasuspension Table 1 R MihaiandVThakker 27 ). . Intriguingly, the Number ofstudies 26 30 14 26 ). When 5

7 ). • 1. Selectionofdonorsparathyroidtissue PTalloT: pancreatic islets. when co-transplanted with the engraftment and survival such cells will induce neoangiogenesis and promote islet endothelial progenitorcellsthatresidewithinPTG,and routinely inthemuscle,canprovideCD34+vascular a richlyvascularisedorganthatcanbetransplanted The hypothesisexploredisthattheparathyroidglands, allogeneic parathyroid cells with adult pancreatic islets. to assess the effectiveness of co-transplantation of Identifier: NCT03977662,registeredin2019),aims for Treatment ofType 1Diabetes,ClinicalTrials.gov Islets andParathyroidGlandCo-transplantation • • • hypoparathyroidism Treatment ofpostsurgical • • • • Germany, describeda32-year-oldfemalewho Living to upperrangeofnormalcalcium levels.Reassuringly, cells ifthedonorhadanadenoma withasetpointclose (CaSR). Suchcellscouldrepresent areasonablesource of abnormal expressionofthe calcium-sensingreceptor the monoclonalexpansion ofparathyroidcellswith isonlyminimallyshiftedtothe right by PTH curve raised calciumlevelsandtheirset-pointforthecalcium- donors. ManypatientswithPHPThaveminimally attractive, becauseofthelargenumberpotential published overthreedecadesago( hyperparathyroidism (PHPT) Adenomatous glandsfrom patientswithprimary transplanted inapatientwithnormalrenalfunction. should returntonormalfunctiononcesuccessfully chronic renalfailure,itispostulatedthatsuchglands response tothebiochemicalabnormalitiestriggeredby date. Becausemultiglandhyperplasiaisaphysiological viable parathyroidtissuefortransplantationreportedto hyperparathyroidism Hyperplastic gland(s)from patientswithsecondary transplantation fromabrain-deaddonor( combinedkidney/parathyroid who underwent failure andaprevioustotalparathyroidectomy Belgium, describedawomanwithterminalrenal Brain- patient ( donor nephrectomyandtransplantedintothesame simultaneous additionalsurgicalprocedureduring ( two healthyparathyroidglandsfromherbrother aliving-donorallotransplantationof underwent 27 Several factors have to be considered when planning ). Similarly, parathyroidtissuewasretrievedasa d ead d onors 28 , d onors 29 : AcasereportfromtheRegensburg, ). : AsinglecasereportfromAntwerp, isthemostcommonsource of Downloaded fromBioscientifica.com at09/28/202109:04:27PM : Thefirstcasereportwas https://eje.bioscientifica.com 184 31 :5 ). Thisoptionis 30 ). R169 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com At theBezmialemVakif University, Istanbul,Turkey, and thegraftfunctionedfor atleast20months( sodium alginatewasused formicroencapsulation immunosuppression ( membrane. Thiscouldallowallotransplantationwithout immunologic responsebycoatingitwithasemipermeable based onprotectingthetissuetobetransplantedfrom h ofcoldischaemia( PTH releaseandtoprotectCaSRfunctionalityforup24 patent andisreportedtosupportcellularviability for parathyroid tissue transplantation. This has a pending Vakif University, Istanbul,Turkey, wasdesignedspecifically cold ischemiatimeof14h( example, some reported successful transplantation with viability of thecells. Several solutions have been explored. is ensuringareasonablecellyieldandmaintainingthe parathyroidfunctionafterPTalloTCritical topreserving before allotransplantation 2. Parathyroidcellpreparation • This approachraisesconcernsthatasuccessful • Review not available. attractiveoptionbutatthispointsuchcellsare a very progress in this field could make allotransplantation architectural structurefor theirfunction( and parathyroidcellsdonothaverequirementforan each cellcontainsthecompletefunctionsoforgan, cell lines patients couldhavethegraftremoved. more distressingthantheinitialhypoparathyroidism, range). Furthermore,ifhyperparathyroidismbecomes normal (i.e.donorswithcalciumlevelsjustabove parathyroid adenomaswithacalciumthresholdcloseto reported and the risk could be mitigated by using suffering withhypoparathyroidism.Thishasnotbeen (and itsassociatedmorbidity)inapatientpreviously allotransplantation couldinducehyperparathyroidism but suchdataisyettobepublishedforallografts. without anyreportedmalignanttransformation( showed nohistologicalchangesduringfollow-up xenografts fromparathyroidadenomasintorabbits Parathyroid-like stem cellsderived from humanembryonic In areportfromtheUniversity ofChile,commercial Microencapsulation of parathyroid tissue Parathyroid University OfWisconsin wouldbeoptimalforcellularreplacement,as t ransport ransport 34 35 ). s ). olution s olution 30 ). reportedfromBezmialem R MihaiandVThakker iscommonlyused.For is a technique 33 ). Future 36 32 ). ) tissues ( confirmed thesuccessfultransplantationofparathyroid PTH levelwasrestoredbyjustover50%andhistology Hallym University, Chuncheon,Korea.Onday70,the gel format37°C)wasmanufacturedbyresearchers atthe polyalanine-co-phenylalanine (PEG-PAF) (solformat4°C, PTalloT ( selection oftheoptimalbioartificalgraftforhuman tissue revealeddifferencesinfunctionandthusfacilitated Preoperative evaluationofmicroencapsulatedparathyroid were microencapsulatedwithamitogenicBa(2+)alginate. Germany, tissueparticlesandsinglecells/cellclusters than 1year( parathyroid cells showedthefunctionality for more generated withcalciumchloride.Microencapsulated performed withultrapurealginateandspheroidswere microencapsulation ofculturedparathyroidcellswas hyperparathyroidism were fragmented quicklyinthe resected fromtheliving donorswithsecondary function formorethan2months ( 95%. In 64patients the allografts retained their endocrine class IIpositivecells.Theviabilityofculturedcellswas HLA (HLA)classIABCexpressionandwerefreeof freezing, the parathyroidcellsdecreased their normal parathyroid cells.After6weeksofcultivationand 116allotransplantationsof cultured underwent after culturingofcells( Academy, Warsaw, Poland, describedallotransplantation The initialpaper, publishedin1996fromtheMedical 4. Timingoftransplantation clinical applicability. PTalloT, buttheseexperimentaldatawouldhavelimited adrenal glands( tissue ( centres usedlaparoscopictransplantationintheomental deltoid muscles( The commonlyusedmethodisinjectionintotheleft 3. Siteoftransplantation activity ( followedbyatleast3monthsoffunctional femoral polyvinylidine difluoride and implanted into the deep was constructedbyresearchers inMinsk,Belarususing hypoparathyroidism Treatment ofpostsurgical Macrocapsule Thermoreversible In amorerecentreport, the parathyroidglands 37 39 40 38 ). Inanimalmodels,thethymus( ). ). Noothergrouphasreplicatedthistechnique. ). 37 containing20–30×10 43 41 ). At the University of Wurzburg, ) appeartobeaprivilegedsitesfor ) andforearmmuscles( gel madeofpolyethyleneglycol- Downloaded fromBioscientifica.com at09/28/202109:04:27PM 44 ). Inthatreport,85patients 45 184 ). 6 parathyroidcells :5 27 42 ), butsome ) andthe R170 via freeaccess European Journal of Endocrinology Allotransplantation Autotransplantation Synthetic PTH Oral calciumandvitaminD Table 2 secretion for2years( side effectsandfouroutoffivegraftsmaintainedPTH México, noneofthepatientshadimmunosuppression of 6 months was used by researchers from Guadalajara, recipient ( parathyroidtissueinakidneytransplant of cryopreserved used byagroupinCleveland,USA,forallotransplantation after allotransplantation( another reportmethylprednisolonewasusedfor1month month and lasting over 1 year ( with a rapid return to normal calcium levels within 1 postop) hasbeenusedintwosuccessfulallotransplants PTalloT ( Some centreshavenotusedimmunosuppressionafter parathyroid allotransplantation 6. Useofimmunosuppressionafter recipients remainednegativeforPRA( novo test Xmatch). Two out four patients were negative for (panel reactive antibodies), and CXM tests (compatibility and onelivingdonorwereevaluatedforHLA-typing,PRA unrelated recipientswhosegraftsfunctioned1–4years of extensive immunological tests beforePTalloT. Four successful PTalloT. Onlyonestudyevaluatedtherole Surprisingly, HLA-matchingmightnotbesignificantfor parathyroid allotransplantation 5. ImpactofHLAtypingonsuccess muscles ofthetworecipients( operation roombeforebeinginjectedintotheleftdeltoid Review supplements Tacrolimus, mycophenolate mofetil and were donorspecificantibodiesandthreeoutoffourthe 46 Comparisons ofcurrentmedicaltherapyforpermanenthypoparathyroidism. 49 ). Metylprednisolone as a short course (2 days ). When an immunosuppressive regimen 50 ). 48 Could berepeated Potentially unlimitedsourceof donorcells No needforimmunosuppression Easy toperform Very effectivewhenadministeredwithapump Ideal hormonalreplacement Safe Cheap, easilyavailable Advantages ). 41 R MihaiandVThakker ). 41 , 37 47 ). ). Similarly, in de Chvostek andTrousseau’s signsdisappearedinover90% correlation in thyroid surgery and reported that the correlation in thyroid surgery Surgeons reviewedtheevidenceforvolume-outcome volume units.In2019,theEuropeanSocietyofEndocrine incidence byensuringsuchoperationsaredoneinhigh management, thereisgrowingpressuretoreduceits surgery. Inparallelwitheffortstoimproveitsmedical common anddebilitatingcomplicationofthyroid Permanent hypoparathyroidismiscurrentlythemost Final comments possible beforetransplantation( without havingsignsofhypocalcaemia,whichwasnot outbasicdailyactivities of patientsandmostcouldcarry reported theimpactonsymptomsrelatedtoPOSH( The recentsystematicreviewfoundthatonlytwostudies 8. Symptomaticbenefitsafterallotransplantation was46%(95%CI11–80%)( graft survival patients were followed up followed-up for up to 1-year. In further five studies, followed-up for of 47% (95% CI 24–71%) when patients were survival evidence fromfivestudiesandreportedameanallograft normal calcium/PTHlevels3yearslater( had aliving-donorallotransplantationandremainswith Hospital Regensburg,Germany, wherea32-year-oldfemale reportedtodateisfromtheUniversity The longestsurvival parathyroid allotransplantation 7. Expectedlong-termoutcomesafter hypoparathyroidism Treatment ofpostsurgical A recentsystematicliteraturereviewsummarisedthe Need forgraftmonitoring Cost ofHLAmatchingandthe surgical procedure Alleged needforimmunosuppression Unpredictable survivalorpreserved tissue Need forcryopreservationfacilities Restricted useupto2yearsdueconcerns Not suitableforneedle-phobicpatients Long termunknown Expensive Ineffective inmanypatients Need forregularbloodtests Disadvantages regarding developmentofosteosarcoma < 6monthsand41%(2.3–80%)when Downloaded fromBioscientifica.com at09/28/202109:04:27PM > 12 months and the mean https://eje.bioscientifica.com 51 ). 184 :5 27 51 ). ). R171 51 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com transplant survival of12monthsisunlikelytobea transplant survival this asaviabletherapeutic option. Islikelythatamean compared withtheenthusiasmofclinicianstoconsider smallnumberofunits. remained restrictedtoavery are deemedasunconvincingandthereforePTalloT has so farregardinglong-termoutcomeofallotransplantation high,dataavailable with poorlycontrolledhypoPTisvery the clinicalneedforaneweffective treatment inpatients symptomatic hypoPTaresummarisedin under theacronymGIRFT( forendocrinesurgery delivery a nationalreviewofservice expected soon in the United Kingdom after completion of operations/year ( be centralisedinunitsperformingatleast50thyroid forthyroidcancershould at least25/yearandsurgery thyroid cases should be operated in centres performing yearly. TheESESrecommendsthereforethatroutine when thesurgeonperformsmorethan30operations andhypocalcaemia/hypoparathyroidism)islower injury nerve incidence ofcomplications(recurrentlaryngeal hypoparathyroidism. parathyroid allotransplantation forpatientswithsevere Proposed strategyforrecruitment intoaprospectivetrialof Figure 1 Review Patients’ expectationsremaindisproportionate The optionsavailableforpatientswithseverely 52 ). Similarrecommendationsare get itrightfirsttime R MihaiandVThakker Table 2 ). . Though co-stimulation blockeriscalimab (Novartis)mighttrigger nosupressants (tacrolimus, everolimus) oreventhenew remains likelythatdailymedication withstandardimmu plantation without long-term immunosuppression as it is encouragingthatsomereportedsuccessfulallotrans be exploredprospectivelyinarandomisedfashion. It a forearmmusclepocket. for ashortperiodof1–2days,beforetransplantationinto forviability andfunction and assessedinthelaboratory from theresectedparathyroidadenomascouldbecultured because thepoolofdonorswouldbelargeenough.Cells hyperparathyroidism from patientswithsecondary with mildhyperparathyroidismorhyperplasticglands of parathyroidcellsshouldbeadenomasfrompatients showed enthusiasmwiththetechnique. procedure restrictedtoasmallnumberofunitswho follow-up, PTalloT willremainasan experimental is convincinglydemonstratedinastudywith3–5years the experience of single centers. Until its effectiveness a prospectivemulticenterstudythatshouldbuildon medical therapy. Thisapproachcanonlybeassessedin patients whoremainseverelysymptomaticdespiteintense of PTalloT. a needtodefinebetterthebenefitsandlimitations compelling prospectforpatients.Thereis,therefore, Proposed designforarandomisedtrialofparathyroid Figure 2 hypoparathyroidism Treatment ofpostsurgical allotransplantation. The needandextentofimmunesuppressionshould Based onthedataavailable,ourviewisthatsource At thispoint,PTalloT shouldbeofferedonlyfor Downloaded fromBioscientifica.com at09/28/202109:04:27PM 184 :5 R172 via freeaccess - -

European Journal of Endocrinology References Both authorshavecontributedtotheplanningandwritingofthisreview. Author contributionstatement (NIHR) OxfordBiomedicalResearchCentre(BRC)Programme(toRVT). This workwassupported bytheNationalInstitute for Health Research Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest a groupofpatientswithdebilitatingchroniccondition. surgeons couldmakeasignificantimpactonthecareof collaboration betweenendocrinologistsandthyroid reports, should be the next step in this process and such is sustainable. the improvementin quality of life becomes apparent and biochemical parameters,suchastudyshoulddetermineif and benefitsofPTalloT ( in aclinicaltrialthatwouldexplorethefeasibility of 252respondentsexpressedaninterestparticipating views ofmembersHypoParaUKgroup,atleast40% and proposed designofsuchatrialareoutlinedin reducing theuseofcalcium-vitaminDsupplements. side effectsthatcouldoutweighthebenefitsofavoiding/ 5 4 3 2 1 Review Lorente-Poch L, Sancho JJ,Ruiz S& Sitges-Serra A. Importanceofin Anneback M, Hedberg J,Almquist M,Stalberg P&Norlen O.Risk Thomusch O, Machens A,Sekulla C,Ukkat J,Brauckhoff M& Clarke BL, Brown EM,Collins MT, Juppner H,Lakatos P, Levine MA, Niederle BE, Schmidt G,Organ CH&Niederle B.AlbertJandhis 1002/bjs.9676) ofSurgery British Journal ofparathyroidglandsduringtotalthyroidectomy.situ preservation SLA.0000000000003800) Sweden. benign disease:anationwidepopulation-basedcohortstudyFrom of permanenthypoparathyroidismAftertotalthyroidectomyfor (https://doi.org/10.1067/msy.2003.61) analysis of5846consecutivepatients. amultivariate hypoparathyroidism inbilateralthyroidsurgery: Dralle H. Theimpactofsurgicaltechniqueonpostoperative doi.org/10.1210/jc.2015-3908) Clinical EndocrinologyandMetabolism Epidemiology anddiagnosisofhypoparathyroidism. Mannstadt MM, Bilezikian JP, Romanischen AF&Thakker RV. doi.org/10.1016/j.jamcollsurg.2005.03.036) oftheAmericanCollegeSurgeons Journal surgeon: ahistoricalreevaluationofthefirstparathyroidectomy. 2 A prospective cohort trial, rather than more case Recruitment ofpatientsintosuchatrialandthe , respectively. Inourrecentpaperinvestigatingthe Annals ofSurgery 2015 2020Inpress. 102 9 ). Inadditiontoanalysing 359–367. 2016 R MihaiandVThakker Surgery (https://doi.org/10.1097/ 2006 101 (https://doi.org/10. 2003 202 2284–2299. 181–190. 133 Journal of Journal 180–185. (https:// (https:// Figs 1

hypoparathyroidism Treatment ofpostsurgical 18 11 10 19 16 15 14 13 12 17 9 8 7 6 Cusano NE, Rubin MR,McMahon DJ,Zhang C,Ives R,Tulley A, Hadker N, Egan J,Sanders J,Lagast H&Clarke BL.Understanding Siggelkow H, Clarke BL,Germak J,Marelli C,Chen K,Dahl- Stevenson A &Mihai R.Patients’viewsaboutparathyroid Brod M, Waldman LT, Smith A&Karpf D.Assessingthepatient Vidal Fortuny J,Sadowski SM,Belfontali V, Guigard S, Poncet A, Edafe O, Antakia R,Laskar N,Uttley L&Balasubramanian SP. Gafni RI, Guthrie LC,Kelly MH,Brillante BA, Christie CM, Cusano NE, Rubin MR,McMahon DJ,Irani D,Tulley A, Sliney Jr Sitges-Serra A. ThePGRISandparathyroidsplintingconceptsfor Sanabria A, Rojas A&Arevalo J.Meta-analysisofroutinecalcium/ Bollerslev J, Rejnmark L,Marcocci C, Shoback DM,Sitges-Serra A, Almquist M, Ivarsson K,Nordenstrom E&Bergenfelz A.Mortality Bergenfelz A, Nordenstrom E&Almquist M.Morbidityinpatients org/10.1111/cen.14128) caregiver survey. patientand hypoparathyroidism: findingsfroma13-country et al. Hansen H, Glenister E,Bent-Ennakhil N,Judge D,Mycock K org/10.1007/s00423-018-1693-y) Langenbeck’s Archives ofSurgery transplantation forpost-thyroidectomyhypoparathyroidism. s40271-019-00388-5) symptom). hypoparathyroidism patientexperiencescale-symptom(HPES- experience ofhypoparathyroidismsymptoms:developmentthe org/10.1002/bjs.10783) surgery. green fluorescencepredictingparathyroidfunctionafterthyroid intraoperative parathyroidglandangiographywithindocyanine Ris F, Karenovics W&Triponez F. Randomizedclinicaltrialof 307–320. thyroidectomy hypocalcaemia. Systematic reviewandmeta-analysisofpredictorspost- 2015 therapy inhypoparathyroidism. synthetic parathyroidhormone1–34 (hPTH1–34)replacement calcium andcalcitriolrequirements After discontinuationofhuman Reynolds JC, Yovetich NA, James R& Collins MT. Transient increased hypoparathyroidism. J &Bilezikian JP. Theeffectof PTH(1–84)onqualityoflifein 137–144. and safety. with PTH(1–84):aprospectivefour-yearinvestigationofefficacy Sliney Jr J,Cremers SC&Bilezikian JP. Therapyofhypoparathyroidism Surgery the analysisandprognosisofprotractedhypoparathyroidism. org/10.1002/bjs.11216) ofSurgery British Journal strategy topreventpostoperativehypocalcaemiaafterthyroidectomy. vitamin D3supplementationversusserumcalciumlevel-based EJE-15-0628) Endocrinology of chronichypoparathyroidisminadults. European SocietyofEndocrinologyClinicalGuideline:treatment van Biesen W, Dekkers OM&EuropeanSocietyofEndocrinology. (https://doi.org/10.1002/bjs.10843) thyroidectomy. in patientswithpermanenthypoparathyroidismaftertotal surg.2019.06.056) Surgery with permanenthypoparathyroidismaftertotalthyroidectomy. 671–679. among patientsinthePARADOX study. the burdenofillnessassociatedwithhypoparathyroidismreported 2013 Burdenofillnessinnotadequatelycontrolledchronic 30 98 2017 2020 2112–2118. 2356–2361. British Journal ofSurgery British Journal (https://doi.org/10.1210/jc.2012-2984) (https://doi.org/10.1002/bjs.9384) (https://doi.org/10.4158/EP13328.OR) Journal ofClinicalEndocrinologyandMetabolism Journal Patient 6 167 2015 S86–S93. British Journal ofSurgery British Journal 124–128. Clinical Endocrinology 2020 173 (https://doi.org/10.1002/jbmr.2555) (https://doi.org/10.1210/jc.2013-1239) Journal ofClinicalEndocrinologyandMetabolism Journal G1–G20. 2019 (https://doi.org/10.21037/gs.2017.07.16) 13 Downloaded fromBioscientifica.com at09/28/202109:04:27PM 151–162. (https://doi.org/10.1016/j. 106 2018 2018 British Journal ofSurgery British Journal Journal ofBoneandMineralResearchJournal (https://doi.org/10.1530/ 1126–1137. https://eje.bioscientifica.com 403 (https://doi.org/10.1007/ 105 2020 2018 Endocrine Practice 623–629. 350–357. European Journal of European Journal 184 92 105 (https://doi. 159–168. :5 1313–1318. (https://doi. (https://doi. 2014 2013 (https://doi. 2014

R173 101 98 Gland 20

via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

31 34 33 32 30 29 28 27 26 25 24 23 22 21 20 Review Goncu B, Yucesan E, Ozdemir B,Basoglu H,Kandas NO, Bingham EL, Cheng SP, Woods Ignatoski KM &Doherty GM. Aysan E, Duzkoylu Y, Can Chapelle T, Meuris K,Roeyen G,DeGreef K,Van Beeumen G, Giulianotti PC, D’Amico G,Tzvetanov I&Benedetti E.Living Garcia-Roca R, Garcia-Aroz S, Tzvetanov IG,Giulianotti PC, Agha A, Scherer MN,Moser C,Karrasch T, Girlich C,Eder F, Hicks G, George R&Sywak M.Shortandlong-termimpactof Wells Jr SA,Gunnells JC,Shelburne JD,Schneider AB & Marcucci G, DellaPepa G&Brandi ML.Drugsafetyevaluation Mortensen E,Kovoor E,Markova D Karpf DB, Pihl S,Mourya S, Altaani BM, Almaaytah AM,Dadou S,Alkhamis K,Daradka MH& Winer KK, Sinaii N,Reynolds J,Peterson D,Dowdy K& Winer KK, Fulton KA,Albert PS&Cutler JrGB.Effectsof Duarte B, Mozes MF, John E,Aronson I,Pollak R&Jonasson O. allotransplantation: effectsoncellviability andcalcium-sensing Akbas F &Aysan E. Anewtransportsolutionforparathyroid doi.org/10.1089/scd.2008.0337) phenotype. stem cellstoaparathyroid-like Differentiation ofhumanembryonic turkjsurg.2017.3427) Turkish ofSurgery Journal isolated fromparathyroidadenomastonormocalcemicrabbits. parathyroidtissue Xenotransplantation ofhumancryopreserved 1072–1076. hypoparathyroidism. idiopathic primary Parathyroid allotransplantationinthetreatmentofcomplicated org/10.1016/j.transproceed.2008.12.026) case report. allotransplantation fromasingledonorafter20yearsoftetany: Bosmans JL &Ysebaert D.Simultaneouskidney-parathyroid 2014 procurement inakidneytransplantrecipient. donor parathyroidallotransplantationwithrobotictransaxillary doi.org/10.1097/TP.0000000000001042) review ofliterature. kidney andparathyroidallotransplantation:firstcasereport Campara M, Oberholzer J&Benedetti E.Simultaneouslivingdonor s12893-016-0165-y) a casereport. hypoparathyroidism inanontransplantrecipient–threeyearresults: postsurgical persistent allotransplantation fortherapy-refractory Jung EM, Schlitt HJ&Schaeffler A.Living-donorparathyroid org/10.21037/gs.2017.09.15) total thyroidectomy. parathyroid autotransplantationonfunctionafter clinical indicationsandresults. TransplantationSherwood LM. oftheparathyroidglandsinman: (https://doi.org/10.1080/14740338.2017.1311322) hypoparathyroidism. of parathyroidhormoneforhypocalcemiainpatientswith org/10.1002/jbmr.4016) of BoneandMineralResearch human Phase1trialofTransCon PTHinhealthyadults. & Leff JA.Arandomizeddouble-blindplacebo-controlledfirst-in- Research system: design,invitroandvivoevaluation. Hananeh W. ofteriparatideusingananoemulsion Oraldelivery doi.org/10.1210/jc.2009-2464) Clinical EndocrinologyandMetabolism parathyroid hormone1–34versuscalcitriolandcalcium. hypoparathyroidism: arandomizedtrialcomparingsynthetichuman Cutler Jr GB.Long-termtreatmentof12childrenwithchronic hypoparathyroidism. parathyroid hormone1–34inchildrenwithseverecongenital ofsynthetic pump versustwice-dailyinjectiondelivery 27 2020 e43–e45. Transplantation Proceedings Stem CellsandDevelopment BMC Surgery 37 80. (https://doi.org/10.1111/tri.12269) Transplantation Gland Surgery (https://doi.org/10.1007/s11095-020-02793-0) Expert Opinion on Drug Safety OpiniononDrug Expert Pediatrului Jurnalul 2017 2016 i &Buyukpinarbasili N. 2020 33 Surgery 16 91–95. 35 2017 51. 2016 1430–1440. 2010 R MihaiandVThakker 2009 1975 2009 (https://doi.org/10.1186/ 2014 6 (https://doi.org/10.5152/ 100 Surgery S75–S85. 95 41 78 18 1318–1321. 2680–2688. 165 Transplant International 599–600. 34–44. 1071–1080. Pharmaceutical Pharmaceutical 1985 (https://doi. 2017 556.e1–563.e1. (https://doi. 98 16 Journal Journal Journal of Journal (https://doi.

(https://

(https:// 617–625. (https://

hypoparathyroidism Treatment ofpostsurgical 39 38 37 36 35 48 47 46 45 44 43 42 41 40 Park HS, Jung SY, Kim HY, Ko DY, Chung SM,Jeong B&Kim HS. Moskalenko V, Ulrichs K,Kerscher A,Blind E,Otto C, Yucesan E, Goncu B,Ozdemir B,Idiz O,Ersoy YE&Aysan E. Cabane P, Gac P, Amat J,Pineda P, Rossi R,Caviedes R&Caviedes P. Hasse C, Bohrer T, Barth P, Stinner B,Cohen R,Cramer H, Aysan E, Yucesan E, Idiz UO&Goncu B.Dischargingapatient Kunori T, Tsuchiya T, Itoh J,Watabe S, Arai M,Satomi T, Takakura K Hasse C, Klock G,Schlosser A,Zimmermann U&Rothmund M. Nawrot I, Wozniewicz B, Tolloczko T, Sawicki A,Gorski A, Wozniewicz B, Migaj M,Giera B,Prokurat A,Tolloczko T, Sawicki A, Kukreja SC, Johnson PA, Ayala G, Bowser EN&Williams GA. Gao Z, Xing Z&Zhu Y. ofthethymusas observation Preliminary Yucesan E, Goncu B,Basoglu H,OztenKandas N,Ersoy YE,Akbas F &Ghoussein Y.Khryshchanovich V Allotransplantationof injection ofparathyroidautotransplantation. Feasibility ofinjectablethermoreversiblegelsforuseinintramuscular j.1432-2277.2007.00496.x) Transplant International optimal bioartificialgraftforhumanparathyroidallotransplantation. microencapsulated humanparathyroidtissueaidsselectionofthe Hamelmann W, Demidchik Y&Timm S. Preoperativeevaluationof (https://doi.org/10.1016/j.imbio.2019.05.007) parathyroid allotransplantation. Importance ofHLAtyping,PRAandDSAtestsforsuccessful transproceed.2009.06.211) Proceedings postsurgical hypoparathyroidism:acasereport. Allotransplant ofmicroencapsulatedparathyroidtissueinsevere 1361–1366. clinically suitablealginate. long-term invivofunctionfollowingmicroencapsulationwitha without immunosuppressioninexperimentalhypoparathyroidism: Zimmermann U &Rothmund M.Parathyroidxenotransplantation doi.org/10.1089/bio.2018.0008) receptors. hospitalized for3.5yearswithpermanent hypoparathyroidism: treated withparathyroidallotransplantation afterhavingbeen 33–40. rejection therapy. repeated allotransplantationofparathyroid tissuewithoutanti- & Yamaguchi H. Improvementofpostoperativehypocalcemiaby 6736(05)62473-7) Lancet Parathyroid allotransplantationwithoutimmunosuppression. 83 without immunosuppression:clinicalresults. et al. Chudzinski W, Wojtaszek M, Grzesiuk W, Sladowski D,Karwacki J 3542–3544. without immunosuppression. preparation ofhumanparathyroidcellsforallotransplantation Nawrot I, Gorski A,Zabitkowska T&Kossakowska AE.Cellculture 559–560. and transplantationintotheadrenalgland. Allotransplantation ofratparathyroidglands:effectsorganculture Chinese MedicalSciencesJournal a privilegedsiteforparathyroidglandallotransplantationinrats. 2017 term immunosuppression:1-yearfollow-up. & Aysan E. Freshtissueparathyroidallotransplantation withshort- 4947.2016.21.3.1130) Medicine postsurgical hypoparathyroidism:casereport. macroencapsulated parathyroidcellsasatreatmentofsevere s00405-016-3990-9) Oto-Rhino-Laryngology 734–740. Allotransplantationofculturedparathyroidprogenitorcells 31 e13086 1997 (https://doi.org/10.1620/tjem.165.33) 2016 (https://doi.org/10.1007/BF01922771) Biopreservation andBiobanking Biopreservation 2009 (https://doi.org/10.1007/s002680010225) 350 (https://doi.org/10.1097/01.tp.0000258601.17505.9d) 36 1296–1297. 41 . 143–147. (https://doi.org/10.1111/ctr.13086) Tohoku ofExperimentalMedicine Journal 3879–3883. 2016 2007 Downloaded fromBioscientifica.com at09/28/202109:04:27PM World ofSurgery Journal (https://doi.org/10.5144/0256- 273 20 (https://doi.org/10.1016/S0140- Transplantation Proceedings 1993 3827–3834. 688–696. (https://doi.org/10.1016/j. Immunobiology 8 246–247. 2018 (https://doi.org/10.1111/ 184 Experientia (https://doi.org/10.1007/ Clinical Transplantation Transplantation European Archives of 16 Annals ofSaudi 2019 :5 Transplantation 278–284. 2000 224 1979 24 1996 1991 485–489.

(https://

35 2007 R174 28 165

via freeaccess

European Journal of Endocrinology

50 49 Review Hermosillo-Sandoval JM, Leonher-Ruezga KL,Jimenez-Gomez JA, &Milas M. Flechner SM, Berber E,Askar M,Stephany B,Agarwal A 188–192. Allogeneic parathyroid:2-yearfollow-up. Fuentes-Orozco C, Gonzalez-Ojeda A&Ramirez-Gonzalez LR. 6143.2010.03234.x) Transplantation inarenaltransplantrecipient. parathyroidtissueforsevere Allotransplantation ofcryopreserved (https://doi.org/10.1016/j.transproceed.2019.03.036) a casereport. (https://doi.org/10.1016/j.circir.2015.05.002) Transplantation Proceedings 2010 10 2061–2065. (https://doi.org/10.1111/j.1600- R MihaiandVThakker 2019 Cirugia yCirujanos Cirugia American Journal of American Journal 51 3186–3188. 2015 83

Accepted 17February2021 Revised versionreceived14January2021 Received 27November2020

hypoparathyroidism Treatment ofpostsurgical 52 51 Lorenz K, Raffaeli M,Barczynski M, Lorente-Poch L&Sancho J. Parameswaran R, Samuel M,Satish RL,Kripesh A,Moorthy V, 020-01907-x) Surgery Surgeons (ESES)positionalstatement. an evidence-basedanalysis-EuropeanSocietyofEndocrine Volume, outcomes,andqualitystandardsinthyroidsurgery: surge.2020.06.008) a reviewofcasestudies. allotransplantation totreatpost-thyroidectomyhypoparathyroidism: Vajjhala R, Ng XL,Yip GW, Voon FCT &Chandran M.Parathyroid 2020 405 401–425. Surgeon Downloaded fromBioscientifica.com at09/28/202109:04:27PM (https://doi.org/10.1007/s00423- 2020. https://eje.bioscientifica.com (https://doi.org/10.1016/j. Langenbeck’s Archives of 184 :5

R175

via freeaccess