The reaction of seven N-peptidyl-O-acyl hydroxylamines with serine proteinases exhibiting different substrate specificity has been investigated. Depending on the structure of the peptidyl residue of the inhibitors, rapid and complete irreversible inactivation of the enzymes may be achieved. Enzyme-catalyzed turnover of inhibitor to products was detected during reaction of proline-specific endopeptidase with N-Boc-Ala-Pro-O-(4-nitrobenzoyl)hydroxylamine.

Zusammenfassung Hintergrund Die Radiosynoviorthese (RSO) ist eine seit mehr als 70 Jahren bekannte und etablierte Lokaltherapie zur Behandlung entzündlicher Gelenkerkrankungen mit nachgewiesener Synovialitis. Die RSO ist die in Deutschland am häufigsten durchgeführte nuklearmedizinische Behandlung und wird ganz überwiegend von niedergelassenen Nuklearmedizinern durchgeführt. Ziel der Arbeit Dieser Artikel soll interessierten (auch angehenden) Nuklearmedizinern, die bislang noch keine RSO durchführen, einen ersten praxisnahen Überblick über diese faszinierende und von den Patienten gut angenommene Behandlung geben. Material und Methoden Wichtige Aspekte der prätherapeutischen Diagnostik zur korrekten Indikationsstellung und zur Aufklärung des Patienten werden ebenso beschrieben wie das grundlegende Therapieprinzip, die Durchführung der RSO und die möglichen Komplikationen. Ergänzt werden diese Punkte durch praktische organisatorische Hinweise, die einen unkomplizierten und entspannten Therapieablauf ermöglichen sollen. Ergebnisse Die Autoren, Gründungsmitglieder des kürzlich ins Leben gerufenen RSO-Exzellenznetz e. V., möchten mit diesem Artikel das Interesse an der RSO wecken, mögliche Vorurteile und Ängste abbauen und damit zur weiteren Verbreitung dieser effektiven Therapie beitragen. Diskussion Wir würden uns freuen, wenn durch diese Arbeit das Zitat von Hermann Hesse, das in leicht abgewandelter Form als Titel dient, ins Original zurückkehren würde „Jedem Anfang wohnt ein Zauber inne.“

Die Radiosynoviorthese (RSO) ist eine nuklearmedizinische Lokaltherapie entzündlicher Gelenkerkrankungen. Bei der rheumatoiden Arthritis (RA) ist sie indiziert in Gelenken mit therapieresistenter Synovialitis trotz adäquater Basismedikation. Die Arthritis des Ellenbogengelenkes tritt bei bis zu zwei Drittel der Patienten mit RA auf. Die intraartikuläre Bestrahlung der entzündeten Synovialmembran durch den Betastrahler [186Re]Rhenium-Sulfid führt zur Verödung oberflächlicher Schleimhautschichten und damit u. a. zur signifikanten Schmerzlinderung. Der schmerztherapeutische Effekt der RSO bei rheumatischer Cubitalarthritis wurde bislang aber nur in monozentrischen Untersuchungen an kleinen Patientenzahlen beschrieben. In dieser retrospektiven Datenauswertung wurde der schmerztherapeutische Effekt der RSO bei Patienten mit rheumatischer Cubitalarthritis untersucht, die in verschiedenen RSO-Schwerpunktpraxen behandelt wurden. Bei 107 Patienten aus der täglichen Routine wurde vor und nach der RSO die subjektive Schmerzintensität in einer numerischen Skala (NRS) mit Werten von 0 bis 10 erfasst. Eine Veränderung von ≥ −2 gilt als klinisch signifikante Besserung. Der Nachbeobachtungszeitraum betrug im Mittel 14 Monate (mindestens 3, maximal 50 Monate). Vor RSO lag der mittlere NRS-Wert bei 7,3 ± 2,1, nach RSO bei 2,8 ± 2,2. Eine klinisch signifikante Schmerzlinderung trat bei 78,5

Background Radiosynoviorthesis (RSO) is a local radionuclide therapy of inflammatory joint diseases, successfully performed since several decades mainly as an outpatient-protocol in ambulatory health care centers or nuclear medicine practices. Despite of long-term experience in some centers, only very few valuable or comparable data about the procedure itself and/or the clinical results of this treatment are available. Objectives The aim of this online survey is to assess reliable data of the current status in Germany. Materials and Methods A web-based questionnaire was designed to evaluate the status of RSO in Germany including demographic data, training, pretherapeutic diagnostics, clinical procedures, and follow-up.The survey was distributed via the supplier of RSO-nuclides, national nuclear medicine societies, and personal networks. It was available for 28 days and closed on November 30, 2020. Results A total of 78 specialists in nuclear medicine answered the questionnaire, which corresponds to a response rate of 23%. Several differences and concordances in pre-therapeutic diagnostics, in the procedure of RSO itself, and follow-up were documented in this survey for the first time. Most important, less than 70 nuclear medicine specialists in Germany perform more than 75% of all RSO-procedures and most of them are older than 50 years of age. This implies the urgent need of a dedicated advancement of young academics in nuclear medicine and a professional advanced training in RSO to offer this beneficial treatment to future patients. Conclusions To achieve these goals, an association of RSO experts would be useful, through which, among other things, an RSO training curriculum is developed and theoretical and practical trainings are organized. Moreover, possible cooperation agreements between ambulant and inpatient institutions would foster the education of young nuclear medicine specialists interested in RSO.

Die Radiosynoviorthese (RSO) ist eine seit langem bewährte, wenig invasive nuklearmedizinische Therapie entzündlicher Gelenkerkrankungen sowie der pigmentierten villonodulären Synovitis nach vorangegangener chirurgischer Synovektomie und der Gelenkbeteiligung bei Hämophilie. Die RSO ist die häufigste, ambulant durchzuführende Radionuklidtherapie in Deutschland. Es erfolgt eine Darstellung der Methode der RSO sowie eine Erläuterung der Ergebnisse, Grenzen und potentiellen Risiken anhand der aktuellen Literatur. Die prätherapeutische Diagnostik, die Vorbereitung und Durchführung der RSO sowie die Nachsorge nach RSO werden dargestellt. Ziel der RSO ist die Behandlung der betroffenen Synovialmembran durch die lokal wirksame Bestrahlung, um eine Progression zu verhindern. Bei bis zu >80% der behandelten Patienten kommt es nach einer RSO zu einer deutlichen Reduzierung der entzündlichen Veränderungen und Ergussbildung bzw. der Schmerzsymptomatik und damit zu einer Verbesserung der Gelenkfunktion. Die Ansprechrate ist unter anderem abhängig vom Ausmaß der vorhandenen Degenerationen und der Speicherung der Radiokolloide in der Synovialmembran. Neue Studien zeigen eine im Vergleich zu der intra-artilulären Kortikoidapplikation nach der RSO eine signifikant längere Therapieeffizienz. Die RSO ist eine etablierte, sichere und nebenwirkungs-arme Therapieoption insbesondere bei Patienten mit einer Synovialitis. Die Indikationsstellung zur RSO sowie die Nachsorge sollte in enger Zusammenarbeit zwischen Nuklearmediziner und dem Überweiser erfolgen. Radiosynoviorthesis (RSO) is a tried and tested, less invasive nuclear medicine therapy for inflammatory joint diseases as well as pigmented villonodular synovitis after previous surgical synovectomy and joint involvement in hemophilia. The RSO is the most common outpatient radionuclide therapy in Germany. The RSO method is presented as well as an explanation of the results, limits and potential risks based on the current literature. The pre-therapeutic diagnostics, the preparation and implementation of the RSO as well as the follow-up care after RSO are presented. The aim of the RSO is to treat the affected synovial membrane with locally effective radiation to prevent progression. In up to > 80% of the treated patients, there is a significant reduction in inflammatory changes and effusion or pain symptoms and thus an improvement in joint function after a RSO. The response rate depends, among other things, on the extent to which the radiocolloids are stored in the synovial membrane. New studies show a significantly longer therapeutic efficiency compared to intra-articular corticosteroid application after RSO. The RSO is a well established, safe treatment option with only few side effects, especially for patients with synovitis. The indication for RSO and follow-up care should be carried out in close cooperation between the nuclear medicine specialist and the referring physician.

Zusammenfassung Einleitung Die Radiosynoviorthese (RSO) ist eine seit Jahrzehnten eingeführte nuklearmedizinische Lokalbehandlung entzündlicher Gelenkerkrankungen, die überwiegend ambulant in nichtuniversitären Einrichtungen durchgeführt wird. Trotz umfangreicher Erfahrungen in einzelnen Institutionen gibt es kaum fassbare oder vergleichbare Daten über die Durchführung und/oder Erfolge dieser Therapie. Fragestellung Ziel der Untersuchung war es, möglichst belastbare Daten zur RSO in Deutschland zu erhalten. Materialien und Methoden Es wurde ein webbasierter Fragebogen eingesetzt. In ihm wurden demografische Daten, Ausbildung/Erlernen der RSO, prätherapeutischer Diagnostik, klinischer Verfahren und Follow-up abgefragt. Die Umfrage stand 28 Tage lang zur Verfügung und wurde am 30. November 2020 geschlossen. Ergebnisse Insgesamt 78 Fachärzte für Nuklearmedizin beantworteten den Fragebogen, was einer Rücklaufquote von 23 % entspricht. Neben den hier erstmals dokumentierten Unterschieden und Übereinstimmungen bei prätherapeutischer Diagnostik, Durchführung und Nachsorge der RSO zeigt sich, dass weniger als 70 Fachärzte in Deutschland mehr als 75 % aller RSO-Behandlungen durchführen, und dass diese meist älter als 50 Jahre sind. Hieraus ergibt sich die Notwendigkeit einer verstärkten Nachwuchsförderung, um dieses hilfreiche Therapieverfahren auch in Zukunft den Patienten anbieten zu können. Schlussfolgerungen Zum Erreichen dieser Ziele ist ein Zusammenschluss von RSO-Experten sinnvoll, durch die unter anderem ein Ausbildungs-Curriculum RSO erarbeitet wird sowie Fortbildungen und Hospitationsmöglichkeiten organisiert werden. Darüber hinaus wären auch ambulant-stationäre Kooperationsmodelle im Rahmen der Facharztausbildung denkbar.

BackgroundProstate-specific membrane antigen (PSMA) targeting radioligands have transformed treatment of prostate cancer. Radioligand therapy (RLT) with 177Lu-PSMA in metastasized castration resistant prostate cancer (mCRPC) achieves objective response and disease stabilization in roughly two third of patients, whereas one third of patients progress. This study was performed to assess the role of interim PSMA PET/CT after the 2nd cycle of RLT for early prediction of overall survival in patients undergoing RLT with 177Lu-PSMA.Methods38 mCRPC patients (68.9 ± 8.1 y) treated with at least two cycles of RLT at 8 week intervals and interim 68Ga-PSMA PET/CT (PET) at 8–10 weeks after the 2nd cycle of RLT were included in this study. Prostate-specific antigen (PSA) response was evaluated according to the Prostate Cancer Working Group 3 criteria. Radiographic response assessment of soft tissue, lymph node, and bone lesions was performed according to RECIST 1.1 including the PET component. Patients’ data were collected for follow-up from the local Comprehensive Cancer Center Register.ResultsMedian follow-up was 19.7 months (4.7–45.3). PSA response after the 2nd therapy cycle showed partial remission (PR) in 23.7%, stable disease (SD) in 50%, and progressive disease (PD) in 26.3% of patients. In comparison, 52.6, 23.7, and 23.7% of patients showed PR, SD, and PD respectively on PET/CT. The strength of agreement between PSA response and PET/CT response criteria was only fair (kappa 0.346). Median overall survival (OS) was 22.5 months (95% CI: 15.8–29.2). Median OS stratified to PSA/PET response was 25.6/25.6 months for PR, 21.7/30.6 months for SD and 19.4/13.1 months for PD (p = 0.496 for PSA and 0.013 for PET/CT response).ConclusionsInterim PSMA PET/CT based response evaluation at 8–10 weeks after the 2nd cycle of RLT is predictive of overall survival and PD in patients treated with 177Lu-PSMA. On the contrary, PSA appears to have only limited predictive value.

Purpose To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas. Methods Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp( N Me)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure–activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6) 3 . Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. Results Ga-68-Trivehexin showed a high αvβ6-integrin affinity (IC 50 = 0.047 nM), selectivity over other subtypes (IC 50 -based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUV max = 10–13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. Conclusions Ga-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers.

Seit über sechs Jahrzehnten werden Radionuklide für die Schmerztherapie bei Knochen- und Gelenkerkrankungen eingesetzt. Dabei ist das Target bei malignen Knochenprozessen, besonders Knochenmetastasen, das überwiegend osteoblastische Knochengewebe, bei entzündlichen Gelenkerkrankungen dagegen die entzündete Synovialis. Eine hypertrophische und entzündete Synovialis ist bei zahlreichen Gelenkerkrankungen, wie der rheumatoiden Arthritis, Osteoarthritis, Spondylarthritis oder hämophilen Arthropathie, bereits in den Frühstadien die Ursache für eine Schmerzsymptomatik und rezidivierende Gelenkergüsse. Die nuklearmedizinische palliative Schmerztherapie bei malignen Knochentumoren, besonders bei überwiegend osteoblastischen Metastasen, stellt eine nebenwirkungsarme, ergänzende Behandlungsoption im Gesamtspektrum der Schmerztherapie dar.

Aim: Radiosynoviorthesis using intraarticular injection of beta-emitting radiocolloids is increasingly performed throughout Europe in patients with inflammatory joint disease. It is a cost-effective and safe treatment, local complications are very rare with only eight cases mentioned in the literature so far. No recommendations for therapy of tissue necrosis, infection or thromboembolism after radiosynoviorthesis are available. Methods: Using a standardized questionary, 260 nuclear medicine physicians and 20 medical liability insurances were asked for the kind and frequency of complications after radiosynoviorthesis between 1998 and 2003. The survey was terminated after nine months with a response of only 25.7%. Results: A total of 53 severe complications were documented (28 necroses, 12 thromboses, 13 joint infections). Eight other complications were seen but difficult to correlate directly with radiosynoviorthesis. Tissue necroses from yttrium-90 were successfully treated by surgical excision and closure of the defect. Rhenium-186-induced ulcers healed by hyperbaric oxygen therapy in two cases. Lesions from erbium-169 showed restoration by conservative treatment. Thromboembolic events happened after radiosynoviorthesis in joints of the lower limb only, mostly treated by conventional anticoagulation. Intraarticular infections showed restoration after intraarticular antibiotics in the majority of cases. Conclusion: Severe complications after radiosynoviorthesis seem to be rare. However, because of the low return rate, a reliable frequency cannot be calculated. Nevertheless, important advices regarding treatment concepts can be taken from our data.

Radiation synovectomy was developed for local treatment of rheumatoid arthritis. In this study, the long-term efficacy of radiation synovectomy was retrospectively evaluated in patients with osteoarthritis (activated arthrosis) of the digital joints using an algofunctional score.

OBJECTIVE:This prospective multicenter study was performed to assess the reliability of sentinel lymph node (SLN) biopsy in breast cancer and to analyze factors potentially influencing success rates.METHODS:In 21 departments, SLN biopsy and consecutive axillary lymph node dissection were performed in 814 breast cancer patients. The 80 surgeons involved were free in the choice of lymphography technique. The detection rate and the sensitivity, as well as the impact of lymphography technique, patient selection, technical procedure and learning curves, were evaluated.RESULTS:The blue dye technique was used in 137 patients, radiocolloid in 169 patients, and combined blue dye/radiocolloid in 508 patients. The identification rate for the sentinel node was 83.9% for the entire group and showed a significant dependence on the lymphography technique (blue dye, 71.6%; radiocolloid, 78.8%; combined blue dye and radiocolloid, 89.6%). The overall sensitivity in detecting lymph node metastases was 91.3%. Immunostaining for cytoceratine revealed micrometastases in 19 (5.1%) of 374 patients in whom H/E staining was negative. The combined subdermal/peritumoral injection of the colloid showed a significantly higher identification rate than subdermal or peritumoral injection alone (96.8%, 84.6%, 78.6%; p < 0.001). There was also a significant higher detection rate in cases of SLN biopsy performed prior to lumpectomy, compared to SLN biopsy following lumpectomy (94.7% versus 82.8%; p < 0.001). Furthermore, there was a close correlation between the number of performed examinations and the detection rate.CONCLUSION:SLN mapping predicts the axillary lymph node status accurately. Learning curves and several technical features influence the detection rate significantly. However, the false negative rate was independent of experience and injection technique.

Accurate knowledge of lymphatic drainage facilitates planning of surgery for patients with squamous cell carcinoma of the head and neck. The aim of this study was to evaluate the feasibility of a new injection technique for lymph node detection in patients with squamous cell carcinoma of the hypopharynx and larynx, in whom simple peritumoural injection is hampered by the tumour localisation. Computed tomography (CT)-guided lymphoscintigraphy was performed in a total of 13 patients with squamous cell carcinoma of the hypopharynx and larynx who could not be injected by simple visual inspection. In a first step, contrast medium-enhanced axial 5-mm-thick CT slices of the neck were obtained. After tumour localisation on these CT images, 1-2 ml contrast medium and, in the event of appropriate distribution, subsequently 50 MBq technetium-99m colloid were injected at one to three peritumoural sites under CT guidance. Peritumoural tracer distribution was controlled by thin-slice CT. Subsequently, planar scintigrams from anterior, right and left lateral views were obtained. In all patients, peritumoural colloid application was feasible, as shown on control CT scans. Post injection, neither severe nor minor complications were noted. The patients complained of only low pain sensations with an average score of 1.8 on a pain scale from 0 to 10. Lymphatic drainage was identified in nine of the 13 patients, with a total of 14 detected lymph nodes. In six patients, ipsilateral sentinel lymph nodes were visualised; bilateral sentinel lymph nodes were identified in one patient and contralateral lymphatic drainage was observed in two patients. CT-guided lymphoscintigraphy is a feasible and minimally invasive diagnostic tool for sentinel lymph node detection in patients with squamous cell carcinoma of the hypopharynx and the larynx. In contrast to endoscopic colloid injection under general anaesthesia, this technique seems to be a well-tolerated method for lymphatic mapping prior to surgical procedures.

The aim of this study is to investigate the myeloprotective effects of different amifostine regimens in rabbits undergoing high-dose treatment with 186Rhenium-(tin)1,1-hydroxyethylidene diphosphonate (186Re-HEDP) and to analyze the impact of amifostine on the bone uptake of the radiopharmaceutical. All animals were treated with 1000 MBq 186Re-HEDP. Group ReA received 500 mg amifostine prior to radionuclide therapy, group ReA3 received 3 x 200 mg amifostine 24 hours and 30 minutes prior to and 24 hours after radionuclide therapy. Group ReC served as control receiving no amifostine. Scintigrams were acquired to quantify the skeletal uptake of 186Re-HEDP, and platelet and leucocyte counts were measured. The mean decrease in platelets was 36% +/- 2%, 37% +/- 3%, and 61% +/- 5% for ReA, ReA3, and ReC, respectively. The decrease in ReC was significantly higher than in amifostine-treated animals with no difference between ReA and ReA3. For the leucocytes the mean decrease was 75% +/- 12%, 82% +/- 5%, and 73% +/- 4%, with no significant differences between the respective groups. Bone uptake of 186Re-HEDP was significantly reduced by 50% in ReA and ReA3 compared to ReC. Thus, the 3-day amifostine regimen had no advantage over the single dose regimen, with both regimens reducing bone uptake and yielding a platelet-protective but no leucoprotective effect.