Prostate-specific membrane antigen as a target for prostate cancer PET imaging

Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer (PCa) cells. In the last decade, PSMA-targeting positron emission tomography (PET) has gained increasing acceptance for PCa imaging. Among the different available PSMA ligands, theranostic agents that can be labelled with both diagnostic and therapeutic radioisotopes have raised particular interest. Androgen deprivation therapy (ADT) is known to upregulate PSMA expression. However, studies investigating this phenomenon in humans are limited. In the clinical context, while the use of PSMA PET has been established in detecting recurrence after radical treatment, the role of PSMA PET in primary staging was only recently affirmed. The aim of this doctoral thesis was to investigate novel aspects of PSMA PET imaging, from the kinetics of a novel theranostic radiotracer, through the physiology of PSMA expression, to its use for primary staging in the clinical practice. The uptake kinetics of radiohybrid [18F]-rhPSMA-7.3 in PCa lesions and reference tissues were assessed in a prospective Phase I trial and demonstrated dominant irreversible components. The uptake in PCa lesions and lesion-to-reference ratios increased over time, with the optimal visual detection starting from 60 minutes postinjection. Two prospective studies demonstrated a heterogeneous increase in PSMA uptake after short-term ADT (PSMA flare) in treatment-näive PCa patient, most evidently seen in bone metastases. This phenomenon was negatively correlated with glucose metabolism, which suggests that lesions with low or absent flare might be more aggressive. Finally, [ 18F]-PSMA-1007 PET/computed tomography (CT) was prospectively compared to whole body magnetic resonance imaging (WBMRI) and CT in the primary nodal staging of patients with unfavourable intermediate or highrisk PCa. The study demonstrated improved sensitivity and accuracy while maintaining high specificity.Prostataspesifinen membraaniantigeeni eturauhassyövän PET-kuvantamisessa Prostataspesifisen membraaniantigeenin (PSMA) ilmentyminen on voimakkaasti lisääntynyt eturauhassyövän solukalvoilla. Tämän takia PSMA on erinomainen kohde eturauhassyövän positroniemissiotomografia(PET)-kuvaukselle. PSMA PET:n käyttö eturauhassyövän kuvantamisessa on lisääntynyt selvästi viime vuosikymmenen aikana ja PSMA:han sitoutuvia merkkiaineita on kehitetty useita. Erityistä kiinnostusta ovat herättäneet ns. teranostiset merkkiaineet, jossa sama PSMA-ligandi voidaan leimata sekä PET-kuvantamiseen että kehonsisäiseen sädehoitoon tarkoitetuilla isotoopeilla. Androgeenideprivaatioterapia (ADT) tiedetään lisäävän PSMA:n ilmenemistä, mutta tätä ilmiötä on tutkittu hyvin niukasti. Yleisin, kliinisesti vahvistettu PSMA-PET:n käyttöindikaatio on eturauhassyövän hoidon jälkeisen taudin uusiutumisen havaitseminen, mutta myös PSMA-PET:n rooli taudin levinneisyyden selvittämisessä on tarkentumassa. Tämän väitöskirjan tarkoituksena oli tutkia PSMA-PET-kuvauksen uusia näkökohtia, kuten uuden teranostisen merkkiaineen kinetiikkaa, hormonihoidon vaikutusta PSMA-PET:n löydöksiin sekä PSMA-PET:n suorituskyky eturauhassyövän levinneisyyden selvittämisessä. [ 18F]-rhPSMA-7.3:n kinettisen analyysin tulokset osoittivat, että tautipesäkkeiden aktiivisuudet sekä pesäke/vertailukudos-aktiivisuussuhteet voimistuivat ajan myötä ja optimaalinen pesäkkeiden visuaalinen paikallistaminen alkoi 60 minuuttia injektiosta. Kahdessa muussa tutkimuksessa osoitettiin, että PSMA:n ilmentymisen lisääntyminen lyhytaikaisen ADT:n jälkeen (PSMA-flare) on heterogeenista ja voimakkainta luustoetäpesäkkeissä levinnyttä eturauhassyöpää sairastuvilla potilailla. PSMA-flare-ilmiö korreloi negatiivisesti glukoosin aineenvaihduntaan, mikä viittaa siihen, että matala PSMA-flare tai sen puuttuminen on yhteydessä etäpesäkkeiden aggressiivisuuteen. Lisäksi [ 18F]-PSMA1007 PET/tietokonetomografia (TT) verrattiin koko kehon magneettiin ja TT:hen korkean riskin eturauhassyöpäpotilailla. Tutkimus osoitti PSMA-PET/TT:n korkeamman herkkyyden ja tarkkuuden

Historical Perspectives on Property and Land Law. An Interdisciplinary Dialogue on Methods and Research Approaches

This volume aims to investigate, with an interdisciplinary approach, how legal property regimes, land law and land registration systems are intertwined with economic, social, and political spheres; to analyse the social functions and legal and political implications of various land registration systems in different contexts and how, for example, they operated in a colonial framework; to scrutinise the relations between politics and property, as well as the transformation of the property concept, in its meaning and function

Onko nenänielusta löytynyt parillinen sylkirauhanen - päivittyykö ihmisen makroskooppinen anatomia?

Sylkirauhasilla on keskeinen merkitys fysiologisissa toiminnoissa, jotka liittyvät nielemiseen, purentaan, puheen tuottamiseen ja ruuansulatukseen. Ihmisen suurista sylkirauhasista korvasylkirauhanen on kuvattu ajanlaskumme alun aikoihin. Nykyään kolmen suuren parillisen ja lukuisten pienten sylkirauhasten tehtävät, rakenteet ja sijainti tiedetään täsmällisesti. Pieniä sylkirauhasia tai syljentuotantoa nenänielussa ei kuitenkaan yleensä kuvata, vaikka alueelta lähtöisin olevat sylkirauhaskasvaimet tunnetaan. Hollantilainen tutkimusryhmä havaitsi nenänielussa korvatorven aukon läheisyydessä suurena sylkirauhasena pitämänsä parillisen rakenteen potilailla, joita oli molekyylikuvannettu urologisen syövän takia. Nenänielun sylkirauhasiin viittaavat löydökset havaittiin sylkirauhaskudokseen aktiivisesti hakeutuvalla radioaktiivisella lääkeaineella positroniemissiotomografiassa ({PET}). Löydöstä selvitettiin makroskooppisesti ja mikroskooppisesti vainajatutkimuksessa. Siinä ilmeni, että kuvatulla rauhasella on rakenteellisia yhtäläisyyksiä kielenalus- ja pieniin sylkirauhasiin

Single Center Experience with a 4-Week 177Lu-PSMA-617 Treatment Interval in Patients with Metastatic Castration-Resistant Prostate Cancer

Background: 177Lu-PSMA-617 is a promising theragnostic treatment for metastatic castration-resistant prostate cancer (mCRPC). However, both the optimal treatment dose and interval in mCRPC and the rate of identification of responders from non-responders among possible treatment candidates are unknown. Methods: 62 men with mCRPC who were treated with 177Lu-PSMA-617 during 1/2017–2/2019 were included in the study. Treatment responses, overall survival (OS) and progression free survival (PFS) were determined. The median follow-up time was 1.4 years (IQR 0.5–2.2). Tumor volume of metastases (MTV), SUVmax and tumor lesion activity (TLA) were quantitated from pre-treatment PSMA PET/CT images together with pre-treatment PSA. Results: An average of three treatment cycles (2–5) were given within a four-week interval. PFS was 4.9 months (2.4–9.6) and OS was 17.2 months (6–26.4). There were no major adverse events reported. A significant PSA response of >50% was found in 58.7% of patients, which was significantly associated with longer OS, p < 0.004. PSA response was not associated with staging PSMA-derived parameters. Conclusions: 177Lu-PSMA-617 treatment in four-week intervals was safe and effective. Almost 60% of patients had a significant PSA response, which was associated with better OS. Pre-treatment PSA kinetics or staging PSMA PET/CT-derived parameters were not helpful in identifying treatment responders from non-responders; better biomarkers are needed to aid in patient selection.© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).fi=vertaisarvioitu|en=peerReviewed

Hepatic Positron Emission Tomography: Applications in Metabolism, Haemodynamics and Cancer

Evaluating in vivo the metabolic rates of the human liver has been a challenge due to its unique perfusion system. Positron emission tomography (PET) represents the current gold standard for assessing non-invasively tissue metabolic rates in vivo. Here, we review the existing literature on the assessment of hepatic metabolism, haemodynamics and cancer with PET. The tracer mainly used in metabolic studies has been [F-18]2-fluoro-2-deoxy-D-glucose (F-18-FDG). Its application not only enables the evaluation of hepatic glucose uptake in a variety of metabolic conditions and interventions, but based on the kinetics of F-18-FDG, endogenous glucose production can also be assessed. 14(R,S)-[F-18]fluoro-6-thia-Heptadecanoic acid (F-18-FTHA), C-11-Palmitate and C-11-Acetate have also been applied for the assessment of hepatic fatty acid uptake rates (F-18-FTHA and C-11-Palmitate) and blood flow and oxidation (C-11-Acetate). Oxygen-15 labelled water (O-15-H2O) has been used for the quantification of hepatic perfusion. F-18-FDG is also the most common tracer used for hepatic cancer diagnostics, whereas C-11-Acetate has also shown some promising applications in imaging liver malignancies. The modelling approaches used to analyse PET data and also the challenges in utilizing PET in the assessment of hepatic metabolism are presented

Depigmenting potential of lichen extracts evaluated by in vitro and in vivo tests

Melanin is the main pigment of human skin, playing the primary role of protection from ultraviolet radiation. Alteration of the melanin production may lead to hyperpigmentation diseases, with both aesthetic and health consequences. Thus, suppressors of melanogenesis are considered useful tools for medical and cosmetic treatments. A great interest is focused on natural sources, aimed at finding safe and quantitatively available depigmenting substances. Lichens are thought to be possible sources of this kind of compounds, as the occurrence of many phenolic molecules suggests possible effects on phenolase enzymes involved in melanin synthesis, like tyrosinase. In this work, we used four lichen species, Cetraria islandica Ach., Flavoparmelia caperata Hale, Letharia vulpina (L.) Hue, and Parmotrema perlatum (Hudson) M. Choisy, to obtain extracts in solvents of increasing polarity, viz. chloroform, chloroform-methanol, methanol, and water. Cell-free, tyrosinase inhibition experiments showed highest inhibition for L. vulpina methanol extract, followed by C. islandica chloroform-methanol one. Comparable results for depigmenting activities were observed by means of in vitro and in vivo systems, such as MeWo melanoma cells and zebrafish larvae. Our study provides first evidence of depigmenting effects of lichen extracts, from tyrosinase inhibition to cell and in vivo models, suggesting that L. vulpina and C. islandica extracts deserve to be further studied for developing skin-whitening products

Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients

Purpose Short-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [F-18]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism.Methods Twenty-five men with newly diagnosed treatment-naive metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [F-18]PSMA-1007 PET/CT immediately before and 3-4 weeks after ADT initiation (degarelix). Before ADT, [F-18]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as Delta SUVmax.Results All the patients reached castration levels of testosterone at the time of the second [F-18]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (>= 20%) in PSMA uptake, with a median Delta SUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [F-18]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA Delta SUVmax and FDG SUVmax (p Conclusions A heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive.</p

Comparison of reprojected bone SPECT/CT and planar bone scintigraphy for the detection of bone metastases in breast and prostate cancer

Objective The aim of this study was to compare reprojected bone SPECT/CT (RBS) against planar bone scintigraphy (BS) in the detection of bone metastases in breast and prostate cancer patients. Methods Twenty-six breast and 105 prostate cancer patients with high risk for bone metastases underwent Tc-99m-HMDP BS and whole-body SPECT/CT, 1.5-T whole-body diffusion-weighted MRI and F-18-NaF or F-18-PSMA-1007 PET/CT within two prospective clinical trials (NCT01339780 and NCT03537391). Consensus reading of all imaging modalities and follow-up data were used to define the reference standard diagnosis. The SPECT/CT data were reprojected into anterior and posterior views to produce RBS images. Both BS and RBS images were independently double read by two pairs of experienced nuclear medicine physicians. The findings were validated against the reference standard diagnosis and compared between BS and RBS on the patient, region and lesion levels. Results All metastatic patients detected by BS were also detected by RBS. In addition, three metastatic patients were missed by BS but detected by RBS. The average patient-level sensitivity of two readers for metastases was 75% for BS and 87% for RBS, and the corresponding specificity was 79% for BS and 39% for RBS. The average region-level sensitivity of two readers was 64% for BS and 69% for RBS, and the corresponding specificity was 96% for BS and 87% for RBS. Conclusion Whole-body bone SPECT/CT can be reprojected into more familiar anterior and posterior planar images with excellent sensitivity for bone metastases, making additional acquisition of planar BS unnecessary.Peer reviewe

Safety, biodistribution and radiation dosimetry of 18 F-rhPSMA-7.3 in healthy adult volunteers

This first-in-human study investigated the safety, biodistribution and radiation dosimetry of the novel 18F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) positron emission tomography (PET) imaging agent, 18F-rhPSMA-7.3. Methods: Six healthy volunteer subjects (3 males, 3 females) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 minutes after the administration of 18F-rhPSMA-7.3 (mean activity 220; range, 210-228 MBq). PET scans were conducted in three separate sessions and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 hours post-injection to assess metabolite-corrected radioactivity in whole blood, plasma and urine. Quantitative measurements of 18F radioactivity in volumes of interest (VOIs) over target organs were determined directly from the PET images at 8 time points and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results: 18F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18F-rhPSMA-7.3: because of the temporal association with 18F-rhPSMA-7.3 injection, a causal relationship could not be excluded. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-hour voiding interval. The organs with the highest absorbed dose per unit of administered radioactivity were the adrenals (mean absorbed dose, 0.1835 mSv/MBq), the kidneys (mean absorbed dose, 0.1722 mSv/MBq), the submandibular glands (mean absorbed dose, 0.1479 mSv) and the parotid glands (mean absorbed dose, 0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min post-injection), an average of 7.2% (range, 4.4-9.0%) of the injected radioactivity of 18F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution and internal radiation dosimetry 18F-rhPSMA-7.3 are considered favorable for PET imaging