Positron emission tomography in the diagnosis and staging of pancreatic and neuroendocrine tumors

Tutkimuksen tausta ja tavoitteet: Viimeaikaisesta perinteisten kuvantamismenetelmien kehityksestä huolimatta sekä haima- että neuroendokriinisten (NE) kasvaimien diagnostiikka on haastavaa. Uudentyyppinen kuvantamismenetelmä, fuusio positroniemissiotomografia-tietokonetomografia (PET/TT), on lupaava näiden kasvainten erotusdiagnostiikassa ja levinneisyyden arvioinnissa. Huolimatta alustavista lupaavista tutkimustuloksista, PET/TT:n rooli on toistaiseksi vielä epäselvä sekä haima- että NE-kasvaimissa eikä se näin ollen ole vakiintunut kliiniseen hoitokäytäntöön. Väitöskirjatyön tavoitteena oli selvittää PET/TT -menetelmän käyttökelpoisuutta haima- ja NE-kasvaimien diagnostiikassa. Kahden ensimmäisen osatyön prospektiivisessa tutkimuksessa potilaat, joilla epäiltiin haimakasvainta, kuvannettiin PET/TT:llä käyttäen merkkiaineena fluorideoxyglukoosia (18F-FDG) kasvaimen aineenvaihdunnan arvioimiseksi ja kasvaimen verenvirtausta arviointiin käyttäen merkkiaineena radiovettä (15O-H2O). Kolmen muun osatyön tavoitteena oli selvittää dihydroxyfenylalaniini (18F-DOPA) PET -menetelmää erilaisten NE-kasvaimien diagnostiikassa ja levinneisyyden arvioinnissa. Tulokset: Haimakasvaimien ensivaiheen diagnostiikassa 18F-FDG-PET/TT:llä oli korkeampi diagnostinen tarkkuus verrattuna titokoneleike- (TT) ja magneettikuvantamiseen (MK) (89% vs. 76% ja 79%). Etenkin pahanlaatuiseksi epäillyn sappitiehytahtauman erotusdiagnostiikassa 18F-FDG-PET/TT:n positiivinen ennustearvo (92%) oli korkea. Haimasyövän levinneisyyden arvioinnissa 18F-FDG-PET/TT:n herkkyys oli huono (30%) paikallisen taudin osoittamisessa. Sen sijaan etäpesäkkeiden osoittamisessa 18F-FDG-PET/TT oli merkittävästi herkempi menetelmä verrattuna TT ja magneettikuvantamiseen (88% vs. 38%). Verrattaessa erilaisten haimakasvaimien ja normaalin haimakudoksen aineenvaihduntaa ja verenvirtausta, aineenvaihdunta/verenvirtaus suhde oli merkittävästi korkeampi pahanlaatuisissa haimakasvaimissa (P18F-DOPA-PET löysi seitsemän kahdeksasta insulinoomasta ja oli positiivinen myös kahdella potilaalla, joilla todettiin haiman saarakesoluhyperplasia. Perustuen alustaviin tuloksiin, rutiinikäytössä oleva karbidopa esilääke ennen 18F-DOPA-PET kuvantamista peitti insulinooma löydöksen kahdella potilaalla kolmesta. NE-kasvaiminen diagnostiikassa 82 potilaan aineisto osoitti 18F-DOPA PET kuvantamisen tarkkuudeksi 90%. Etenkin feokromosytoomien ensivaiheen diagnostiikassa ja NE-kasvaimen uusiutumaa epäiltäessä menetelmän tarkkuus oli korkea. Kokonaisuudessaan 59%:lla aineiston potilaista 18F-DOPA-PET kuvantamisella oli vaikutusta kliinisiin hoitoratkaisuihin. Johtopäätökset: PET/TT käyttäen merkkiaineena 18F-FDG:tä ja radiovettä osoittautui käyttökelpoiseksi menetelmäksi haimakasvaimien erotusdiagnostiikassa. Lisäksi 18F-FDG-PET/TT oli hyödyllinen haimasyövän etäpesäkkeiden arvioinnissa. Tutkimus osoitti myös 18F-DOPA-PET kuvantamisen olevan luotettava menetelmä insulinoomien ja muiden vatsan alueen NE-kasvaimien ensivaiheen diagnostiikassa sekä levinneisyyden arvioinnissa, etenkin muiden kuvantamislöydösten ollessa ristiriitaisia. PET kuvantamisella oli merkittävä vaikutus potilaiden kliiniseen hoitokäytäntöön sekä haima- että NE-kasvaimissa.Siirretty Doriast

Endokriinisten sairauksien PET-kuvantaminen

Neuroendokriiniset (NE) kasvaimet ovat yleistyneet, ja niiden kokonaisennuste on hyvä. Somatostatiinireseptorin kuvantaminen PET-menetelmällä on avainasemassa kaikkien hyvin erilaistuneiden NE-kasvainten primaaridiagnostiikassa, levinneisyyden ja hoitovasteen arvioinnissa. Huonosti erilaistuneissa NE-kasvaimissa, ja jos Ki-67 indeksi ylittää 20 %, käytetään 18F-FDG:tä merkkiaineena. GLP-1R-agonisti, eksendiini, on uusi merkkiaine somatostatiinireseptorinegatiivisen insulinooman paikantamiseen. 18F-LDOPA:n käyttö on vähentynyt mutta sillä on edelleen käyttöaiheena feokromosytooma ja medullaarinen kilpirauhassyöpä. Tulevaisuudessa on tärkeätä saada pidemmällä puoliintumisajalla (positronisäteilijä) leimattu somatostatiiniagonisti- tai antagonisti käyttöön, mikä mahdollistaa PET-menetelmän laajemman käytön NE-kasvainten kuvantamisessa

TKTL1 as a Prognostic Marker in Pancreatic Ductal Adenocarcinoma and Its Correlation with FDG-PET-CT

Introduction: Glucose metabolism in cancer cells differs from noncancerous cells. The expression of transketolase-like protein 1 (TKTL1), a key enzyme in the glucose metabolism of cancer cells, predicts poor prognosis in several cancer types. We studied TKTL1 as a prognostic tool and whether TKTL1 expression correlates with 18F-FDG-PET-CT among patients with pancreatic ductal adenocarcinoma (PDAC). Methods: This retrospective study examined two PDAC patient cohorts: 168 patients operated on at Helsinki University Hospital between 2001 and 2011, and 20 patients with FDG-PET-CT results available from the Auria Biobank. We used immunohistochemistry for TKTL1 expression, combining results with clinicopathological data. Results: Five-year disease-specific survival (DSS) was slightly but not significantly better in patients with a high versus low TKTL1 expression, with DSS of 28.0 versus 17.3%, respectively (p = 0.123). TKTL1 served as a marker of a better prognosis in patients over 65 years old (p = 0.012) and among those with TNM class M1 (p = 0.018), stage IV disease (p = 0.027), or perivascular invasion (p = 0.008). Conclusions: Our study shows that TKTL1 cannot be used as a prognostic factor in PDAC with the exception of elderly patients and those with advanced disease. The correlation of TKTL1 with 18F-FDG-PET-CT requires further study in a larger patient cohort.Peer reviewe

Haimasyövän nykyhoito

VertaisarvioituToteamishetkellä vain 10–20 % haimasyövistä voidaan hoitaa radikaalileikkauksella. Ennustetta pyritään parantamaan kehittämällä varhaisdiagnostiikkaa ja keskittämällä leikkaushoitoa. Jopa puolet leikkauspotilaista saa komplikaatioita, mutta suuri osa on hoidettavissa ilman uusintaleikkausta. Leikkauskuolleisuus on alle 4 %. Leikkausta edeltävän solunsalpaajahoidon käyttö on lisääntynyt. Prospektiivisten tutkimusten tuloksia odotetaan.Peer reviewe

Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

Peer reviewe

Correlation of Somatostatin Receptor 1–5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal

Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

Abstract Background Predicting the aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PNET) remains controversial. We wanted to explore, in a prospective setting, whether the diagnostic accuracy can be improved by dual-tracer functional imaging 68Ga-DOTANOC and 18F-FDG-PET/CT in patients with NF-PNETs. Methods Thirty-one patients with NF-PNET (90% asymptomatic) underwent PET-imaging with 18F-FDG and 68Ga-DOTANOC, followed by surgery (n = 20), an endoscopic ultrasonography and fine-needle biopsy (n = 2) or follow-up (n = 9). A focal activity on PET/CT greater than the background that could not be identified as physiological activity was considered to indicate tumor tissue. The imaging results were compared to histopathology. The mean follow-up time was 31.3 months. Results Thirty-one patients presented a total of 53 lesions (40 histologically confirmed) on PET/CT. Thirty patients had a 68Ga-DOTANOC-positive tumor (sensitivity 97%) and 10 patients had an 18F-FDG-positive tumor. In addition, one 68Ga-DOTANOC-negative patient was 18F-FDG-positive. 18F-FDG-PET/CT was positive in 19% (3/16) of the G1 tumors, 63% (5/8) of the G2 tumors and 1/1 of the well-differentiated G3 tumor. 68Ga-DOTANOC-PET/CT was positive in 94% of the G1 tumors, 100% of the G2 tumors and 1/1 of the well-differentiated G3 tumor. Two out of six (33%) of the patients with lymph node metastases (LN+) were 18F-FDG-positive. The 18F-FDG-PET/CT correlated with tumor Ki-67 (P = 0.021). Further, the Krenning score correlated with tumor Ki-67 (P = 0.013). 18F-FDG-positive tumors were significantly larger than the 18F-FDG-negative tumors (P = 0.012). 18F-FDG-PET/CT showed a positive predictive value of 78% in the detection of potentially aggressive tumors (G2, G3, or LN + PNETs); the negative predictive value was 69%. Conclusions 18F-FDG-PET/CT is useful to predict tumor grade but not the LN+ of NF-PNETs. Patients with 18F-FDG-avid NF-PNETs should be referred for surgery. The 68Ga-DOTANOC-PET/CT also has prognostic value since the Krenning score predicts the histopathological tumor grade. Trial registration The study has been registered at ClinicalTrials.gov; Non-functional Pancreatic NET and PET imaging, NCT02621541

Correlation of Somatostatin Receptor 1–5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms

Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal

Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, F-18-labeled [Nle(14),Lys(40)]exendin-4 analog, shows promise for clinical imaging

Background: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for beta cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label beta cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. F-18-labeled [Nle(14), Lys(40)] exendin-4 analog ([F-18] exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [F-18] exendin-4 was assessed with ex vivo organ.-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of F-18 radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats. Results: [F-18] exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [F-18] exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [F-18] exendin-4. Conclusions: [F-18] exendin-4 showed promise as a tracer for clinical imaging of pancreatic beta cells, due to its high specific uptake in native beta cells and its concomitant low kidney radioactivity uptake.Peer reviewe

Obesity associated blunted subcutaneous adipose tissue blood flow after meal is improved after bariatric surgery

Background and aims: GIP and meal ingestion increase subcutaneous adipose tissue (SAT) perfusion in healthy subjects. Effects of GIP and meal on visceral adipose tissue (VAT) perfusion is unclear. Our aim was to investigate the effects of meal and GIP on VAT and SAT perfusion in obese subjects with type 2 diabetes (T2DM) before and after bariatric surgery.Materials and methods: We recruited 10 obese subjects with T2DM scheduled for bariatric surgery and 10 control subjects. Subjects were studied under two stimulations: meal ingestion and GIP infusion. SAT and VAT perfusion was measured using 15O-H2O PET-MRI at three time points: baseline, 20min and 50min after start of stimulation. Obese subjects were studied before and after bariatric surgery.Results: Before bariatric surgery the responses of SAT perfusion to meal (p=0.04) and GIP-infusion (p=0.002) were blunted in the obese subjects compared to the controls. VAT perfusion response did not differ between obese and control subjects after meal or GIP-infusion.After bariatric surgery SAT perfusion response to meal was similar to that of control subjects. SAT perfusion response to GIP administration remained lower in operated than control subjects. There was no change in VAT perfusion response after bariatric surgery.Conclusions: The vasodilating effects of GIP and meal are blunted in SAT but not in VAT in obese subjects with T2DM. Bariatric surgery improves the effects of meal on SAT perfusion, but not the effects of GIP. Postprandial increase in SAT perfusion after bariatric surgery seems to be regulated in a GIP independent manner.</p