Malignant Hypercalcemia Vim Lub Ectopic Production Ntawm Calcitriol Los Ntawm Lub plab Liposarcoma

Abstract

Hypercalcemia ntawm malignancy (HM) yog ib hom kab mob paraneoplastic uas cuam tshuam nrog kev ua tsis zoo ntawm tus kab mob. Hauv cov qog nqaij hlav, HM tshwm sim feem ntau yog los ntawm kev tsim cov tshuaj parathyroid hormone-related peptides (PTHrP). Peb nthuav tawm ib rooj plaub ntawm 60- txiv neej hnub nyoog muaj 25 cm retroperitoneal liposarcoma kuaj pom tias muaj mob hnyav hypercalcemia (16.8 mg / dL) los ntawm kev kuaj ntshav ua ntej. Kev ua haujlwm hypercalcemia tau pom tias muaj cov tshuaj tiv thaiv kab mob parathyroid (PTH), ib txwm muaj PTHrP, thiab siab 1, 25-dihydroxy vitamin D (1,25 (OH) 2D) qib ntshav.

Nyem rau cistanche deserticola vs tubulosa rau testosterone

Tom qab phais, hypercalcemia thiab calcitriol qib normalized. Immunohistochemical tsom xam ntawm cov qog pom tau tias 1 -hydroxylase qhia los ntawm qog hlwb. Rau peb txoj kev paub, qhov no yog thawj kis ntawm liposarcoma-koom nrog hypercalcemia tshwm sim tshwj xeeb los ntawm ectopic ntau lawm ntawm calcitriol. Txawm hais tias nws yog ib qho tsis tshua muaj ua rau hypercalcemia, ntsuas 1,25 (OH) 2D yuav tsum raug txiav txim siab hauv kev ua haujlwm ntawm tus neeg mob uas muaj cov calcium ntau ntau, suppressed PTH, thiab PTHrP ib txwm.

Taw qhia

Hypercalcemia tshwm sim txog li 30 feem pua ​​​​ntawm cov neeg mob uas muaj malignancy, raug cuam tshuam nrog cov kab mob siab heev thiab tsis zoo [1]. Nws yog ib qho ntawm feem ntau hom kab mob paraneoplastic syndromes, nrog rau qhov tshwm sim ntawm 15 tus neeg rau 100,000 neeg hauv ib xyoos [2]. Hypercalcemia ntawm malignancy (HM) tshwm sim hauv ntau hom mob qog noj ntshav, nrog ntau zaus hauv kev mob qog noj ntshav mis, mob ntsws cancer, thiab ntau yam myeloma [3].

Muaj ntau lub luag haujlwm rau HM, uas suav nrog kev tso tawm ntau ntxiv ntawm parathyroid hormone-related peptide (PTHrP), hauv zos osteolytic hypercalcemia, ntau dhau lawm ntawm 1,25-dihydroxy vitamin D (1,25 (OH)2D), thiab thawj lossis ectopic secretion ntawm parathyroid hormone (PTH) [1]. PTHrP-mediated hypercalcemia suav txog 80 feem pua ​​​​ntawm HM cov neeg mob thiab feem ntau cuam tshuam nrog squamous cell carcinomas ntawm lub ntsws, lub taub hau, caj dab, thiab txoj hlab pas los yog nrog rau lub mis, lub raum, prostate, thiab zais zis mob qog noj ntshav, tab sis zoo li, ib qho qog tuaj yeem ua rau tus mob no. [4].

Kev tso tawm ntawm 1,25 (OH) 2D tso nyiaj rau kwv yees li 1 feem pua ​​​​ntawm cov neeg mob HM [1]. Nws yog feem ntau cuam tshuam nrog hematologic malignancies xws li Hodgkin thiab non-Hodgkin lymphoma tab sis kuj tau tshaj tawm hauv qee cov qog nqaij hlav xws li zes qe menyuam dysgerminoma, plab hnyuv qog (GIST), thiab seminomas [1,5]. Ntawm no, peb nthuav qhia tus neeg mob plab liposarcoma thiab HM tshwm sim los ntawm kev tsim tawm ntawm 1,25 (OH) 2D.

Case Presentation

Ib tug txiv neej muaj hnub nyoog 60- xyoo, uas tsis muaj keeb kwm kho mob, tau kuaj pom thaum Lub Rau Hli 2019 nrog qhov loj ntawm 25 cm retroperitoneal tom qab muaj kev nce ntxiv hauv cov pob txha thiab plab hnyuv ntau tshaj rau lub hlis (Daim duab 1). Kev suav tomography (CT)-kev coj noj coj ua biopsy tau qhia txog liposarcoma, thiab kev phais tau npaj.

Kev kuaj ntshav ua ntej pom cov calcium hauv cov ntshav ntawm 16.8 mg / dL (ib txwm muaj (NR): 8.4-10.2 mg / dL), uas ua rau muaj kev xa mus sai rau peb lub tuam tsev. Nws pib hloov cov kua dej ntau, voj diuretics, thiab glucocorticoids. Electrocardiogram yog qhov qub. Kev kho nrog bisphosphonate tsis tau ua txij li qhov kwv yees glomerular pom tus nqi (eGFR) yog 21.7 mL / feeb / 1.73 m2. Nws tau tshaj tawm cov tsos mob tsis tshwj xeeb xws li qaug zog, myalgia, anorexia, thiab lub siab hloov pauv hauv ob peb lub lis piam dhau los.

Drug-induced hypercalcemia raug cais tawm thaum nws tsis kam noj cov tshuaj ua ntej nkag. Kev tshawb nrhiav thawj zaug pom tau tias albumin kho calcium qib ntawm 16.8 mg / dL, phosphorous ntawm 6.3 mg / dL (NR: 2.3-4.7 mg / dL), PTH< 3 pg/mL (NR: 12-65 pg/mL), 25-hydroxyvitamin D (25(OH)D) of 18 ng/mL (NR: 8-56 ng/mL), and alkaline phosphatase of 91 UI/L (NR: 40-150 UI/L) (Table 1). Bone scan scintigraphy was negative, and multiple myeloma was excluded by serum and urine protein electrophoresis. 

Nyob rau lub sijhawm no, ntshav qab zib PTHrP thiab 1,25 (OH) 2D qib tau thov, tab sis cov txiaj ntsig tsis muaj txog li ob peb lub lis piam tom qab. Tom qab tsib hnub, nws tau tawm hauv tsev kho mob nrog cov tshuaj calcium hauv cov ntshav ntawm 12.3 mg / dL, kho mob asymptomatic, thiab nrog kev pom zoo kom nce cov kua hauv qhov ncauj.

Ob lub lis piam tom qab, nws tau raug lees paub vim tias kho calcium qib ntawm 19.2mg / dL. Lub sijhawm no, nws yws yws ntawm qaug zog, mob musculoskeletal, anorexia, thiab cem quav. Kev ntsuam xyuas electrocardiographic yog qhov qub. Txij li thaum nws tswj tau eGFR <30 mL / feeb / 1.73 m2, denosumab 120 mg tau muab tshuaj subcutaneously rau hnub 1, 8, 15, thiab 29 thiab tom qab ntawd txhua plaub lub lis piam.

Tom qab plaub hnub ntawm thawj thawj coj, cov tshuaj calcium hauv cov ntshav tau txo qis rau 11.6 mg / dL, thiab tus neeg mob tau tawm hauv tsev kho mob. Nws tau tswj xyuas qhov kev soj ntsuam ze ntawm peb lub tsev kho mob, nrog cov tshuaj calcium hauv cov ntshav ntawm 11.6 mg / dL thiab 15.8 mg / dL (Daim duab 2). Qhov txiaj ntsig kawg no tau tshwm sim ntawm qhov thib ob thiab thib peb kev tswj hwm ntawm denosumab, thiab lub sijhawm no, tus neeg mob tau muab cov tshuaj prednisolone 40 mg ntawm qhov ncauj rau peb hnub, kom txog rau thaum kev tswj hwm tom ntej ntawm denosumab, thiab cov calcium uas txo qis rau 12.1 mg. /dL. Cov txiaj ntsig ntawm kev ua haujlwm thawj zaug tau tshwm sim, qhia txog PTHrP ntawm 0.9 pmol / L (NR: PTHrP < 2.5 pmol / L) thiab nce ntxiv 1,25 (OH) 2D qib ntshav ntawm 224 pg / mL (NR: {{19). }} pg/mL).

Kev phais phais ntawm cov qog tau ua nyob rau lub Cuaj Hli 2019, thiab cov kab mob tau nthuav tawm cov liposarcoma dedifferentiated ntsuas 45 × 40 × 29 cm (Daim duab 3A). Tam sim ntawd tom qab kev phais mob, cov tshuaj calcium hauv cov ntshav thiab 1,25 (OH) 2D qib poob mus rau qhov qub (8.66 mg / dL thiab 54 pg / mL, feem). Kev kho mob tom qab phais tau pom tias muaj qhov rov ua tiav, thiab tom qab kev soj ntsuam, tsis muaj pov thawj ntawm tus kab mob mus txog 33 lub hlis tom qab (yuav luag peb xyoos), thaum hypercalcemia rov qab los (11.9 mg / dL), thiab CT scan pom qhov tshwm sim hauv zos ntawm cov qog. .

Kev tshawb nrhiav ntxiv pom phosphorus ntawm 3.8 mg / dL, PTH < 3 pg / mL, 25 (OH) D ntawm 34 ng / mL, 1,25 (OH) 2D ntawm 169 pg / mL, thiab PTHrP < 0. 5 pmol / L. Zoledronic acid 3.3 mg (hloov kho rau eGFR ntawm 49 mL / feeb) tau txhaj tshuaj intravenously, nrog kev txhim kho hauv cov ntshav calcium (9.9 mg / dL) xya hnub tom qab kho. Intravenous doxorubicin 75 mg / m2 tau pib hauv kev kho mob monotherapy, txhua 21 hnub, tab sis raug txiav tawm tom qab tsib lub voj voog, thaum kawg ntawm Lub Xya Hli, vim tias muaj kab mob. Cov qib calcium hauv cov ntshav tseem nyob hauv qhov qub, tab sis kev tswj hwm thib ob ntawm zoledronic acid yog xav tau nyob rau lub Yim Hli, vim yog cov calcium hauv cov ntshav ntawm 12.5 mg / dL. Kev kho thib ob nrog trabectedin 1.5 mg / m2 yog tam sim no tab tom xav txog.

Immunohistochemistry rau 1 -hydroxylase

Cov kab mob qog nqaij hlav tau stained nrog antiserum tsa tawm tsam luav raum 1 -hydroxylase los ntawm Ventana BenchMark ULTRA IHC system (Roche Diagnostics, Basel, Switzerland). Thawj cov tshuaj tiv thaiv antiCYP27B1 (polyclonal reference PA5-26065, 1:15/28 feeb) (Thermo Fisher Scientific, Waltham, MA, USA) thiab anti-MDM2 (reference MAD-000682QD-7 , PD/16 feeb) (Vitro Master Diagnostic Mouse Monoclonal IF2) tau siv nrog cov txheej txheem peroxidase-indirect-polymer Ventana Optiview DAB refª 760-700. Ntu 3 μm tuab tau txiav mus rau Superfrost ntxiv rau cov swb los ntawm paraffin-embedded cov ntaub so ntswg niaj hnub.

Lub tshav kub-mediated antigen retrieval yog Ventana CC1 rau 64 feeb rau anti-CYP27B1 thiab 48 feeb rau antiMDM2 (Daim duab 3B). Rau kev tswj qhov zoo thiab tsis zoo, lub raum thiab tonsil tau siv, raws li. Immunohistochemical tsom xam nrog cov tshuaj antiserum rau 1 -hydroxylase qhia kev qhia rau cov enzyme hauv liposarcoma hlwb (Daim duab 3C) thiab lub raum proximal tubule epithelial hlwb (Daim duab 3D). Los ntawm qhov sib txawv, tsis muaj staining rau 1 -hydroxylase tau pom nyob rau hauv cov ntaub so ntswg (cov ntaub ntawv tsis qhia).

Kev sib tham

Ntawm no, peb piav qhia txog ib rooj plaub ntawm tus neeg mob uas muaj tus kab mob liposarcoma dedifferentiated thiab HM cuam tshuam nrog kev tsim khoom tshwj xeeb ntawm 1,25 (OH) 2D. Feem ntau ntawm HM yog tshwm sim los ntawm kev tso tawm ntawm PTHrP los yog los ntawm osteolytic pob txha metastasis [3]. Kev tsim tawm ectopic ntawm 1,25 (OH) 2D yog ib qho tsis tshua muaj tshwm sim ntawm HM thiab tuaj yeem tshwm sim hauv sarcoidosis thiab lwm yam kab mob uas tsis yog granulomatosis, nrog rau cov kab mob malignancy, xws li hauv Hodgkin thiab non-Hodgkin lymphomas [3,4]. Muaj ob peb kis nyob rau hauv cov ntaub ntawv ntawm HM txuam nrog sarcomas [6-9].

Kev tsim tawm ntawm 1,25 (OH) 2D raws li qhov ua rau HM tau tshaj tawm nyob rau hauv ib kis ntawm dedifferentiated plab liposarcoma, nyob rau hauv uas muaj ib tug coproduction ntawm ob leeg 1,25 (OH) 2D thiab PTHrP los ntawm cov qog [10]. Hauv peb cov ntaub ntawv tshawb fawb, qhov kev kho mob ntawm hypercalcemia yog kev phais ntawm cov qog. Txog thaum muaj kev cuam tshuam kev phais, hypercalcemia hnyav tau tswj hwm nrog denosumab txij li bisphosphonates yog contraindicated rau cov neeg mob uas muaj lub raum tsis zoo. Hu et al. pom tias denosumab tuaj yeem siv los txo cov calcium hauv cov neeg mob uas muaj bisphosphonate-refractory HM [11].

Raws li txoj kev tshawb no, peb siv tib txoj kev kho mob, nrog rau kev txhim kho cov calcium ntau ntau tom qab plaub hnub ntawm kev pib denosumab. Txawm li cas los xij, ntawm kev tswj hwm, cov qib calcium hauv cov ntshav tau nce siab, ua qhov tsis zoo rau kev txhim kho nrog kev ntxiv ntawm prednisolone, uas ua rau muaj kev cuam tshuam calcitriol ectopic ntau lawm. Qhov tseeb mechanism ntawm kev tsim khoom ntawm 1,25 (OH) 2D hauv HM tsis paub thiab tau kawm. Hauv peb tus neeg mob, qhov kev daws teeb meem tseem ceeb ntawm hypercalcemia tom qab kev phais resection nyiam qhov kev xav tias cov qog harbored lub hlwb lub luag hauj lwm rau cov calcitriol-mediated hypercalcemia, thiab cov immunohistochemical qhia ntawm 1 -hydroxylase nyob rau hauv cov qog hlwb lees paub nws (Daim duab 3C).

Hewison et al. tshaj tawm ib rooj plaub ntawm tus txiv neej muaj hnub nyoog 75- xyoo uas muaj hypercalcemia thiab Hodgkin lymphoma uas tau xa mus rau splenectomy nrog kev daws teeb meem ntawm hypercalcemia [12]. Immunohistochemical tsom xam ntawm splenic cov ntaub so ntswg tau qhia tsis zoo rau 1 -hydroxylase nyob rau hauv lymphoma thiab ib txwm spleen hlwb tab sis zoo nyob rau hauv ib puag ncig macrophages.

Evans et al. kuj tau kawm txog kev qhia ntawm 1 -hydroxylase nyob rau hauv ib phau ntawm 12 dysgerminomas los ntawm RT-PCR tsom xam, enzyme assays, thiab immunolocalization kev tshawb fawb, tag nrho cov ntawm lawv qhia tau hais tias muaj zog qhia ntawm no enzyme nyob rau hauv ob lub qog hlwb thiab infiltrated macrophages [13]. Txawm hais tias qhov cuam tshuam ntawm qhov kev qhia ntawm 1 -hydroxylase ntawm cov qog tsis paub, nws tau tshaj tawm tias nws yuav yog ib feem ntawm kev tiv thaiv qog nqaij hlav endogenous, txij li calcitriol muaj cov tshuaj tiv thaiv kab mob rau cov hlwb ntawm lub cev tiv thaiv kab mob [9,13] .

Cov lus xaus

Peb tau nthuav tawm cov xwm txheej tshwj xeeb ntawm HM cuam tshuam nrog kev tsim cov calcitriol los ntawm ib qho dedifferentiated liposarcoma uas tau daws ib ntus los ntawm qog resection. Hauv peb tus neeg mob, hypercalcemia sawv cev rau qhov tseeb biomarker ntawm cov qog rov ua haujlwm yuav luag peb xyoos tom qab kev phais thawj zaug. Txawm hais tias nws yog ib qho tsis tshua muaj ua rau hypercalcemia, ectopic 1,25 (OH) 2D ntau lawm yuav tsum nco ntsoov txiav txim siab hauv kev ua haujlwm ntawm HM thaum PTHrP ntau lawm tau raug cais tawm.

Lub mechanism ntawm Cistanche boosts testosterone nyhuv

Cistanche tau pom los txhawb qib testosterone hauv ntau txoj hauv kev. Ua ntej, nws muaj cov tebchaw hu ua echinacoside thiab acteoside, uas tau pom tias txhim khu kev tsim cov tshuaj luteinizing hormone (LH) hauv pituitary caj pas. LH txhawb nqa Leydig hlwb hauv cov qe ntshav los tsim cov testosterone. Cistanche kuj tseem muaj cov polysaccharides thiab phenylethanoid glycosides, uas tau pom tias muaj cov tshuaj tua kab mob antioxidant thiab tiv thaiv kab mob. Qhov no tuaj yeem pab txo qis oxidative kev nyuaj siab thiab mob hauv cov qog nqaij hlav, uas tuaj yeem cuam tshuam rau testosterone ntau lawm Tsis tas li ntawd, Cistanche tau pom tias yuav ua rau kom muaj kev qhia ntawm cov noob koom nrog hauv testosterone synthesis thiab txo cov haujlwm ntawm cov enzymes uas ua rau testosterone, xws li {{1} }alpha-reductase. Zuag qhia tag nrho, kev sib xyaw ua ke ntawm cov txheej txheem no tau xav tias yuav pab txhawb rau Cistanche's testosterone-boosting teebmeem.

Cov ntaub ntawv

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