1494 | Brief Communication Discontinuation of the Tyrosine Kinase In- hibitor Sunitinib in Patients with Metastatic Renal Cell Carcinoma: A Case Series Thomas Neuhaus,1 Joachim Luyken,1 Sebastian Stier2 Corresponding Author: Thomas Neuhaus, MD St. Vincenz-Krankenhaus, Auf dem Schafsberg, 65549 Limburg, Germany. Tel: +49 6431 2924331 Fax: +49 6431 2924346 E-mail: t.neuhaus@st-vincenz.de Received October 2012 Accepted July 2013 1 St. Vincenz-Hospital, Limburg, Germany. 2 Private Practice for Hematol- ogy and Oncology, Brühl, Germany. BRIEF COMMUNICATION Purpose:‎Tyrosine‎kinase‎inhibitors‎(TKI)‎play‎a‎pivotal‎role‎in‎the‎modern‎treatment‎of‎ patients‎with‎metastatic‎renal‎cell‎carcinoma‎(mRCC).‎Depending‎on‎the‎course‎and‎the‎ response,‎the‎targeted‎therapy‎may‎last‎for‎years.‎Thus‎the‎question‎arises,‎if‎a‎successful‎ treatment‎leading‎to‎a‎complete‎response‎or‎at‎least‎a‎stable‎disease‎after‎a‎partial‎remission,‎ may‎be‎discontinued.‎ Materials and Methods:‎Here‎we‎present‎3‎patients‎with‎mRCC‎treated‎with‎sunitinib‎for‎at‎ least‎one‎year,‎resulting‎in‎a‎partial‎response,‎followed‎by‎a‎stable‎disease‎for‎several‎years.‎In‎ these‎patients,‎the‎treatment‎was‎interrupted‎for‎different‎medical‎reasons. Results:‎After‎a‎period‎of‎20,‎33‎and‎34‎months,‎respectively,‎the‎metastases‎of‎the‎renal‎cell‎ cancer‎showed‎no‎signs‎of‎progression,‎neither‎clinically‎nor‎in‎computed‎tomography‎scans,‎ but‎the‎side‎effects‎of‎TKI‎or‎the‎medical‎problem‎leading‎to‎treatment‎interruption‎resolved‎ in‎all‎patients‎within‎a‎few‎weeks. Conclusion:‎The‎discontinuation‎of‎the‎treatment‎for‎mRCC‎with‎TKI‎seems‎to‎be‎possi- ble,‎even‎in‎those‎patients‎with‎a‎partial‎response‎only,‎but‎no‎complete‎remission‎has‎been‎ achieved‎before. Keywords:‎carcinoma,‎renal‎cell;‎kidney‎neoplasms;‎protein‎kinase‎inhibitors;‎drug‎therapy;‎ treatment‎outcome;‎antineoplastic‎agents;‎neoplasm‎metastasis. 1495Vol. 11 | No. 02 | March- April 2014 |U R O LO G Y J O U R N A L Discontinuation of Sunitinib in Metastatic RCC | Neuhaus et al INTRODUCTION At‎the‎time‎of‎diagnosis,‎20%‎of‎all‎patients‎with‎renal‎cell‎carcinoma‎(RCC)‎present‎ in‎a‎meta-static‎stage,‎resulting‎in‎a‎median‎survival‎of‎16‎ months‎only‎and‎a‎five-year‎survival‎rate‎of‎less‎than‎10%. (1)‎This‎poor‎prognosis‎was‎mainly‎caused‎by‎the‎low‎ef- ficacy‎of‎the‎former‎treatment‎of‎choice,‎a‎mixture‎of‎inter- feron‎and‎interleukin.(2)‎ Recently‎it‎has‎been‎shown‎that‎the‎use‎of‎multitargeted‎ tyrosine‎kinase‎inhibitors‎(TKI)‎like‎sunitinib‎may‎lead‎to‎ a‎sufficient‎tumor‎control‎in‎patients‎with‎metastatic‎renal‎ cell‎ carcinoma‎ (mRCC).‎The‎ pathophysiological‎ base‎ of‎ their‎efficacy‎lies‎in‎the‎von‎Hippel-Lindau‎hypoxia-induc- ible‎factor‎and‎vascular‎endothelial‎growth‎factor‎(VEGF)‎ axis‎that‎plays‎a‎central‎role‎in‎the‎development‎of‎RCC‎ and‎which‎members‎work‎as‎the‎target‎of‎TKI.(3) In detail, sunitinib‎ is‎ an‎ orally‎ administered‎ TKI,‎ that‎ influences‎ negatively‎ the‎ receptor‎ families‎ of‎ VEGF‎ and‎ platelet- derived‎growth‎factor‎(PDGF)‎as‎well‎as‎FMS-like‎tyros- ine‎kinase-3‎receptor‎(flt-3)‎and‎stem‎cell‎factor‎receptor‎ (c-kit).‎Sunitinib‎shows‎respond‎rates‎of‎40%‎in‎patients‎ with‎mRCC,‎and‎it‎increases‎the‎overall‎survival‎rates‎to‎ more‎than‎2‎years‎and‎the‎progression‎free‎survival‎(PFS)‎ to about one year.(4)‎Although‎in‎certain‎patients‎severe‎side‎ effects‎like‎hypertension,‎leukopenia‎or‎diarrhea‎may‎occur. (5)‎Sunitinib‎became‎one‎of‎the‎standard‎medication‎for‎the‎ first-line‎treatment‎of‎patients‎with‎mRCC.‎ Because‎of‎its‎efficacy,‎the‎tumor‎remission‎reached‎by‎sunitinib‎ or‎other‎TKI‎may‎last‎for‎years.‎Thus‎the‎question‎arises,‎if‎the‎ medication,‎for‎example‎due‎to‎serious‎and‎disturbing‎treatment- associated‎complications,‎but‎also‎because‎of‎its‎high‎costs,‎can‎ be‎stopped,‎at‎least‎in‎case‎of‎a‎complete‎remission.‎ Here‎we‎present‎3‎mRCC-patients‎with‎a‎stable‎disease‎af- ter‎partial‎response‎achieved‎by‎sunitinib,‎in‎whom‎treat- ment‎was‎stopped‎for‎certain‎reasons.‎During‎a‎follow-up‎of‎ 22,‎34‎and‎33‎months,‎respectively,‎no‎signs‎of‎significant‎ tumor‎growth‎could‎be‎found‎neither‎clinically‎nor‎in‎the‎ radiological‎scans‎performed;‎for‎this‎the‎discontinuation‎ will‎be‎prolonged.‎To‎our‎knowledge‎this‎is‎the‎first‎report‎ about‎a‎successful‎interruption‎of‎TKI-therapy‎in‎patients‎ with‎persisting‎evidence‎of‎metastases.‎ MATERIALS AND METHODS Case 1 Patient‎1‎is‎a‎78-year-old‎woman,‎who‎underwent‎a‎left-sid- ed‎nephrectomy‎due‎to‎a‎localized‎RCC‎in‎1990‎(the‎history‎ of‎the‎three‎patients‎presented‎here‎is‎summarized‎in‎Ta- ble).‎At‎this‎time,‎no‎filiae‎were‎described.‎About‎18‎years‎ later,‎in‎May‎2008,‎a‎mass‎was‎found‎in‎the‎right‎breast,‎ and‎surprisingly,‎the‎histological‎examination‎of‎the‎biopsy‎ revealed‎the‎diagnosis‎of‎a‎metastasis‎of‎the‎RCC.‎After- wards,‎a‎complete‎staging‎was‎performed,‎and‎further‎me- tastases‎involving‎the‎pancreas‎and‎both‎sides‎of‎the‎lung‎ were‎detected.‎Because‎the‎filiae‎were‎clinically‎inapparent‎ and‎the‎patient‎presented‎in‎a‎very‎good‎condition,‎just‎the‎ conduction‎of‎controls‎3‎months‎later‎was‎recommended.‎ Since‎ herein‎ a‎ tumor‎ progression‎ of‎ approximately‎ 30%‎ was‎found‎in‎September‎2008,‎we‎decided‎to‎start‎a‎treat- ment‎with‎sunitinib‎by‎using‎the‎regular‎dose‎(50‎mg/day,‎ administered‎orally‎for‎4‎weeks,‎followed‎by‎a‎2-week‎rest- ing‎period).‎Due‎to‎different‎side‎effects‎like‎mucositis,‎ob- stipation,‎headache‎and‎weakness‎the‎dosage‎was‎reduced‎ to‎37.5‎mg/day‎for‎six‎cycles.‎The‎first‎controls,‎performed‎ after‎3‎and‎6‎months,‎revealed‎partial‎responses‎each,‎while‎ in‎the‎following‎computed‎tomography‎(CT)‎scans‎a‎stable‎ disease‎was‎found.‎In‎October‎2009,‎i.e.‎about‎13‎months‎ after‎therapy‎started,‎the‎patient‎developed‎arterial‎hyper- tension,‎probably‎as‎a‎side‎effect‎of‎sunitinib.‎Although‎the‎ doses‎of‎sunitinib‎was‎reduced‎again‎ to‎25‎mg/day‎now‎ and‎a‎combination‎of‎at‎least‎6‎different‎antihypertensive‎ agents‎were‎used,‎the‎elevation‎of‎blood‎pressure‎persist- ed‎and‎became‎symptomatic.‎Thus‎in‎December‎2009,‎15‎ months‎after‎the‎intake‎of‎sunitinib‎started,‎we‎decided‎to‎ stop‎this‎ treatment.‎Within‎a‎few‎weeks,‎ the‎blood‎pres- sure‎improved‎and‎the‎antihypertensive‎medication‎could‎ be‎reduced.‎About‎four‎months‎after‎the‎use‎of‎sunitinib‎ had‎been‎stopped,‎a‎first‎CT‎scan‎was‎performed‎showing‎ no‎signs‎of‎tumor‎growth.‎In‎addition,‎the‎patient‎pointed‎ out‎to‎feel‎much‎better‎after‎treatment‎with‎TKI‎ended‎and‎ thus‎we‎agreed‎to‎continue‎the‎observational‎procedure.‎In‎ another‎CT‎scan,‎performed‎after‎one‎year‎without‎TKI,‎the‎ metastasis‎in‎the‎breast‎even‎became‎smaller‎spontaneous- ly.‎Meanwhile‎the‎therapy‎with‎sunitinib‎was‎stopped‎for‎33‎ 1496 | months,‎however,‎the‎metastases‎kept‎stable‎without‎signs‎ of‎progression‎(Figure,‎a‎and‎d). Case 2 Patient‎2‎is‎an‎87-year-old‎woman‎in‎a‎very‎good‎condition‎ with‎a‎biological‎age‎of‎around‎70‎years.‎In‎1996‎she‎un- derwent‎left‎sided‎nephrectomy.‎Twelve‎years‎later,‎in‎June‎ 2008,‎metastases‎in‎both‎sides‎of‎the‎lung‎and‎in‎the‎soft‎ tissue‎of‎the‎right‎shoulder‎were‎detected.‎After‎confirming‎ the‎diagnosis‎of‎mRCC‎by‎taking‎a‎biopsy,‎the‎lesion‎in‎ the‎area‎of‎the‎right‎shoulder‎was‎treated‎for‎pain‎relief‎by‎ radiotherapy‎till‎August‎2008.‎Thereafter,‎in‎October‎2008,‎ another‎CT‎scan‎was‎performed,‎showing‎a‎growth-rate‎of‎ the‎pulmonary‎filiae‎of‎about‎20-30%;‎thus‎a‎systemic‎ther- apy was initiated by using sunitinib at the regular schedule and‎dosage‎similar‎to‎the‎patient‎1.‎Three‎weeks‎after‎treat- ment‎started,‎disturbing‎side‎effects‎like‎epistaxis,‎pain‎in‎ different‎joints‎and‎general‎weakness‎appeared,‎leading‎to‎ an‎interruption‎of‎the‎treatment.‎Within‎2‎weeks,‎the‎com- plaints‎vanished‎and‎the‎treatment‎could‎be‎continued,‎but‎ by‎using‎sunitinib‎in‎a‎reduced‎dosage‎of‎25‎mg/day.‎Here- with‎the‎treatment‎was‎tolerated‎very‎well,‎and‎radiologi- cal‎controls‎performed‎by‎conventional‎X-rays‎of‎the‎lung‎ every‎3‎months,‎revealed‎partial‎responses‎each.‎At‎last‎the‎ pulmonary‎lesions‎nearly‎disappeared.‎However,‎from‎July‎ 2009,‎the‎patients‎developed‎an‎ulcus‎cruris‎due‎to‎venous‎ insufficiency.‎Although‎professional‎support‎by‎a‎vascular‎ surgeon and a nurse specialized in wound care was used, the lesion‎did‎not‎improve;‎on‎the‎contrary,‎recurrent‎superin- fection‎resulted‎in‎repeating‎antibiotic‎therapies.‎Therefore‎ the‎patient‎asked‎for‎a‎break‎of‎the‎sunitinib‎administration,‎ and‎the‎treatment‎was‎stopped‎after‎a‎15‎months‎period‎in‎ October‎2009.‎The‎controls‎were‎continued‎every‎3‎to‎6‎ months,‎but‎even‎after‎34‎months‎without‎TKI‎no‎new‎filia‎ appeared‎and‎no‎progression‎of‎the‎known‎metastases‎was‎ found,‎thus,‎still‎a‎stable‎disease‎exists‎(Figure,‎b‎and‎e). Case 3 In‎patient‎3,‎a‎60-year-old‎woman,‎a‎left‎sided‎nephrectomy‎ was‎performed‎in‎august‎2005.‎In‎November‎2007‎the‎pa- tient‎developed‎a‎great‎metastasis‎with‎a‎size‎of‎10.7-6.8‎ cm,‎including‎the‎right‎pelvis‎and‎the‎surrounding‎soft‎tis- sue.‎Since‎an‎operative‎approach‎was‎not‎possible,‎radio- therapy‎was‎performed‎from‎December‎2007‎to‎February‎ 2008‎(62‎Gy).‎A‎CT‎scan‎in‎March‎2008‎showed‎a‎reduction‎ of‎the‎vascular‎perfusion,‎but‎the‎size‎of‎the‎filia‎remained‎ stable.‎We‎performed‎a‎CT‎scan‎check‎12‎weeks‎later,‎in‎ which‎the‎tumor‎presented‎with‎little‎signs‎of‎growth‎(10- 15%)‎and‎increasing‎vascular‎perfusion.‎Therefore,‎we‎rec- ommended‎to‎start‎antineoplastic‎treatment‎with‎sunitinib‎ in‎the‎regular‎schedule.‎However,‎due‎to‎hepatic‎side‎effects‎ (jaundice,‎elevation‎of‎liver‎enzymes)‎the‎dosage‎had‎to‎be‎ reduced‎stepwise‎to‎25‎mg/day,‎used‎since‎October‎2008.‎ In‎a‎magnetic‎resonance‎tomography‎of‎the‎pelvis‎region,‎ performed‎in‎January‎2009,‎the‎tumor‎size‎was‎stable,‎but‎ the‎magnetic‎resonance‎imaging‎(MRI)‎conducted‎during‎ the‎ following‎ months,‎ showed‎ changing‎ distributions‎ of‎ contrast‎enhancement‎were‎described,‎and‎for‎this‎we‎as- Figure. Computed tomography scans (a-d) and magnetic reso- nance imaging (e,f ) show the exemplary course of metastases in three patients suffering from renal cell cancer. The scans at the left side were performed directly before the treatment with a TKI was stopped, the scans at the right side 32 (b), 33 (d) and 20 (f ) months later. Brief Communication 1497Vol. 11 | No. 02 | March- April 2014 |U R O LO G Y J O U R N A L sumed‎that‎the‎malignant‎tissue‎was‎still‎vital.‎From‎March‎ 2010‎the‎creatinine‎value‎of‎the‎patient‎increased‎slowly,‎ but‎continuously.‎In‎addition,‎in‎autumn‎2010,‎the‎patient‎ developed‎unspecific,‎but‎disturbing‎symptoms‎like‎tired- ness‎and‎weakness,‎occurring‎while‎taking‎sunitinib,‎and‎ for‎ this‎ the‎ patient‎ asked‎ to‎ stop‎TKI-treatment‎ after‎ 30‎ months‎in‎December‎2010.‎Again,‎MRIs‎were‎performed‎ regularly‎throughout‎the‎following‎21‎months,‎but‎neither‎ the‎size‎nor‎the‎contrast‎distribution‎within‎the‎metastasis‎ altered‎thus‎far‎(Figure,‎c‎and‎f). DISCUSSION The‎development‎of‎TKIs‎led‎to‎a‎fundamental‎change‎in‎ treatment‎procedures‎of‎patients‎with‎mRCC,‎not‎only‎with‎ regard‎to‎the‎good‎tolerance‎of‎these‎agents,‎but‎mainly‎be- cause‎of‎their‎efficacy.‎While‎the‎median‎survival‎achieved‎ by‎ using‎ cytokines‎ did‎ not‎ exceed‎ 10‎ months,‎ TKI‎ like‎ sunitinib‎or‎sorafenib‎may‎at‎least‎double‎this‎period.(3,6)‎ However,‎as‎a‎result‎of‎the‎prolonged‎survival,‎numerous‎ of‎the‎affected‎patients‎may‎need‎to‎take‎a‎TKI‎for‎several‎ years,‎and‎therefore‎questions‎for‎example‎concerning‎the‎ safety‎or‎the‎high‎costs‎of‎its‎long-term‎use‎arise.‎A‎possible‎ answer and approach would be the controlled discontinua- tion‎of‎treatment,‎but‎surprisingly,‎beside‎a‎very‎few‎reports‎ describing‎flare‎ups‎and‎rapid‎angiogenesis‎onset,‎while‎the‎ use‎of‎TKI‎were‎interrupted,(7-9)‎there are only two studies dealing with this subject. The‎ first‎ study‎ that‎ systematically‎ analyzed‎ the‎ outcome‎ of‎discontinuing‎TKI-treatment‎in‎patients‎with‎mRCC‎is‎ published by Johannsen and colleagues.(10)‎ The‎ authors‎ described‎36‎patients‎with‎complete‎remission‎(CR)‎or‎no‎ evidence‎of‎disease‎after‎therapy‎for‎mRCC,‎in‎whom‎the‎ treatment,‎mainly‎consisting‎of‎sunitinib,‎was‎stopped.‎Af- ter‎a‎median‎time‎of‎7‎months,‎the‎carcinoma‎recurred‎in‎ about‎65%‎of‎the‎patients,‎but‎about‎30%‎of‎the‎patients‎ remained‎tumor-free.‎In‎addition,‎Albiges‎and‎colleagues(11)‎ described‎the‎follow-up‎of‎36‎patients‎with‎mRCC,‎after‎a‎ CR‎by‎using‎a‎TKI‎(again‎mainly‎sunitinib)‎was‎achieved.‎ While‎8‎of‎them‎continued‎treatment,‎28‎patients‎stopped‎ taking‎TKI.‎Of‎these‎patients‎61%‎were‎still‎disease‎free‎ with‎a‎median‎follow-up‎of‎8.5‎months;‎this‎percentage‎is‎ superior‎to‎that‎found‎by‎Johannsen‎and‎colleagues.(10) By‎comparing‎these‎results‎with‎our‎limited‎data,‎some‎dif- ferences‎become‎obvious.‎At‎first,‎the‎treatment‎period‎in‎ our‎patients‎ took‎12,‎15‎and‎30‎months‎with‎an‎average‎ of‎19‎months,‎while‎the‎average‎treatment‎duration‎of‎the‎ patients described in the studies by Johannsen and Albiges was‎7.5‎and‎12.5‎months,‎respectively.(10,11)‎Secondly,‎the‎ median‎‎follow-up‎of‎the‎patients‎mentioned‎in‎these‎stud- ies‎was‎12‎and‎8.5‎months,‎respectively,‎but‎these‎medians‎ consisted‎of‎a‎very‎wide‎range‎(3‎to‎31‎months‎and‎0.3‎to‎ 39.1‎months,‎respectively).‎In‎opposite,‎ the‎current‎aver- age‎duration‎of‎progression‎free‎survival‎in‎our‎patients‎is‎ 28‎months,‎however‎these‎3‎patients‎were‎still‎disease-free.‎ Discontinuation of Sunitinib in Metastatic RCC | Neuhaus et al Table . Epidemiological data of the patients presented. Variables Patient 1 Patient 2 Patient 3 Sex Female Female Female Current age (years) 78 87 60 Date of first diagnosis 02/1990 06/1996 08/2005 Initial treatment Nephrectomy Nephrectomy Nephrectomy Date metastases were diagnosed 06/2008 06/2008 11/2007 Systemic treatment before TKI No No No Local treatment No Radiotherapy, for analgetic reason Radiotherapy, for analgetic reason Date TKI-treatment started 09/2008 10/2008 05/2008 Kind of TKI Sunitinib Sunitinib Sunitinib Duration of TKI-treatment (months) 15 12 30 Reason for stopping TKI Hypertension Superinfection, ulcus cruris Weakness, elevated creatinine Progression-free survival (months) * 33 34 22 Key: TKI, tyrosine kinase inhibitor. * Still ongoing. 1498 | Finally,‎ the‎main‎difference‎between‎both‎collectives‎af- fects‎the‎outcome.‎Since‎from‎the‎results‎of‎Johannsen‎and‎ colleagues(10)‎a‎recommendation‎for‎interrupting‎the‎treat- ment‎with‎TKI‎cannot‎be‎deduced,‎our‎data‎as‎well‎as‎the‎ results‎found‎by‎Albiges‎and‎colleagues(11) rather support such‎an‎approach,‎especially‎because,‎like‎Johannsen‎and‎ colleagues‎point‎out,‎most‎of‎the‎patients‎respond‎to‎a‎TKI‎ if‎it‎is‎re-administered‎in‎case‎of‎a‎progression. Since,‎according‎to‎the‎data‎described‎above,‎35‎to‎61%‎of‎ their‎patients‎remained‎to‎be‎tumor-free,‎the‎authors‎tried‎ to‎identify‎factors‎probably‎influencing‎the‎patient´s‎out- come.‎However,‎neither‎the‎length‎of‎treatment‎before‎the‎ break‎nor‎the‎risk‎profile‎nor‎the‎different‎substances‎used,‎ correlate‎with‎the‎further‎course‎of‎the‎patients,‎but‎the‎au- thors‎rightly‎refer‎to‎the‎small‎number‎of‎patients‎included‎ in‎the‎studies,‎which‎hampers‎reaching‎a‎significant‎result.‎ Regarding‎our‎patients‎it‎is‎remarkable‎that‎in‎2‎of‎them‎the‎ RCC‎relapsed‎after‎a‎disease-free‎period‎of‎more‎than‎10‎ years,‎and‎all‎patients‎achieved‎under‎therapy‎a‎stable‎dis- ease‎for‎a‎longer‎period.‎Thus‎it‎could‎be‎assumed‎that‎the‎ tumors‎presented‎here‎show‎a‎reduced‎activity,‎but‎the‎his- tological‎analysis‎of‎the‎metastases‎revealed‎typical‎growth‎ rates‎of‎20‎to‎30%.‎However,‎possibly‎in‎those‎patients,‎in‎ whom‎disease‎is‎stable‎for‎a‎longer‎time,‎either‎before‎or‎ under‎treatment,‎the‎use‎of‎TKI‎may‎be‎stopped‎especially‎ for‎medical‎reasons,‎but‎further‎studies‎are‎urgently‎needed‎ for‎proofing‎this‎thesis.‎ CONCLUSION We‎present‎3‎patients‎suffering‎from‎mRCC,‎in‎whom‎the‎ treatment‎with‎the‎TKI‎sunitinib‎had‎to‎be‎stopped‎because‎ of‎certain‎medical‎reasons.‎Surprisingly‎in‎all‎patients‎the‎ tumor‎did‎not‎relapse‎to‎date,‎resulting‎currently‎in‎a‎pro- gression‎free‎survival‎of‎at‎least‎two‎years.‎While‎there‎are‎ 2‎small‎studies‎with‎72‎patients‎in‎all,‎that‎deal‎with‎the‎ interruption‎of‎TKI-treatment‎after‎achieving‎a‎CR,‎the‎suc- cessful‎ discontinuation‎ of‎ sunitinib‎ in‎ patients,‎ in‎ whom‎ just‎a‎partial‎response‎but‎no‎CR‎has‎been‎achieved‎before,‎ is‎described‎here‎for‎the‎first‎time.‎ ACKNOWLEDGEMENTS We‎ thank‎ Dr.‎ Hess,‎ Radiology‎ Department‎ St.‎ Vincenz- Hospital‎in‎Limburg‎(Germany),‎Dr.‎Wever,‎Radiological‎ practice‎in‎Limburg‎(Germany)‎and‎Dr.‎Steinhardt,‎Radio- logical‎Practice‎in‎Montabaur‎(Germany)‎for‎providing‎the‎ CT-scans. 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