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We identified a new estrogen receptor (ER)-targeting ligand with picomolar affinity serving as vehicle for radioiodines. This ligand is a potential radiotheranostics for ER+ male tumours.

The optimal first-line treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) diagnosed in early stages is largely undefined. We therefore analyzed 100 NLPHL patients (early-stage favorable: 85 patients; early-stage unfavorable: 15 patients) treated within the randomized HD16 (early-stage favorable) and HD17 (early-stage unfavorable) studies. These studies investigated the omission of consolidation radiotherapy (RT) in patients with a negative interim positron emission tomography (iPET) (defined as a Deauville score < 3) at the end of chemotherapy (HD16: 2xABVD; HD17: 2xBEACOPPescalated plus 2xABVD). Patients with NLPHL treated within the HD16 and HD17 studies had 5-year progression-free survival (PFS) rates of 90.3% (95%-CI: 83.8%-96.7%) and 92.9% (95%-CI: 79.4%-100%), respectively. Thus, the 5-year PFS did not differ significantly from patients with classical Hodgkin lymphoma treated within the same studies (p=0.88 for HD16; p=0.50 for HD17). Patients with early-stage favorable NLPHL who had a negative iPET after 2xABVD and did not undergo consolidation RT (n=25) tended to have a worse PFS than iPET-negative patients who received consolidation RT (n=21) (5-year PFS: 83% (95%-CI: 67.8%-98.2%) vs 100%; p=0.05). Overall, there were 10 cases of NLPHL recurrence (HD16: 9 patients; HD17: 1 patient). However, no NLPHL patient died during follow-up. Hence, the 5-year overall survival rate was 100%. Taken together, contemporary HL-directed treatment approaches result in excellent outcomes for patients with newly diagnosed early-stage NLPHL and thus represent valid treatment options. In patients with early-stage favorable NLPHL, consolidation RT appears necessary after 2xABVD to achieve the optimal disease control irrespective of the iPET result.

The short half-life of existing prostate-specificmembraneantigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Because of its longer half-life, the 89Zr-labeled ligand 89Zr-PSMA-DFO allows acquisition of PET scans up to 6 d after injection, thereby overcoming the above limitation. We investigated whether 89Zr-PSMA-DFO allowed more sensitive detection of weak PSMA-positive prostate cancer lesions. Methods: We selected 14 prostate cancer patients with biochemical recurrence who exhibited no PSMA-positive lesions on a PET scan acquired with existing PSMA tracers (68Ga-PSMA-11, 18F-JK-PSMA-7). Within 5 wk after the negative scan result, we obtained a second PSMA PET scan using 89Zr-PSMA-DFO (117 6 16 MBq, PET acquisition within 6 d of injection). Results: 89Zr-PSMADFO detected 15 PSMA-positive lesions in 8 of 14 patients, who had a PET-negative reading of their initial PET scans with existing tracers. In these 8 patients, the new scans revealed localized recurrence of disease (3/8), metastases in lymph nodes (3/8), or lesions at distant sites (2/8). On the basis of these results, patients received lesiontargeted radiotherapies (5/8), androgen deprivation therapies (2/8), or no therapy (1/8). The plausibility of 14 of 15 lesions was supported by histology, clinical follow-up after radiotherapy, or subsequent imaging. Furthermore, comparison of the 15 89Zr-PSMA-DFO–positive lesions with their correlates on the original PET scan revealed that established tracers exhibited mild accumulation in 7 of 15 lesions; however, contrast-to-noise ratios were too low for robust detection of these lesions (contrast-to-noise ratios, 2.4 6 3.7 for established tracers vs. 10.2 6 8.5 for89Zr-PSMA-DFO, P 5 0.0014). The SUVmax of the 15 89ZrPSMA-DFO–positive lesions (11.5 6 5.8) was significantly higher than the SUVmax on the original PET scans (4.7 6 2.8, P5 0.0001). Kidneys were the most exposed organ, with doses of 3.3 6 0.7 mGy/MBq. The effective dose was 0.15 6 0.04 mSv/MBq. Conclusion: In patients with weak PSMA expression, a longer period of time might be needed for ligand internalization than that offered by existing PSMA tracers to make lesions visible on PET/CT scans. Hence, 89ZrPSMA-DFO might be of significant benefit to patients in whom the search for weak PSMA-positive lesions is challenging. Radiation exposure should be weighed against the potential benefitof metastasis-directed therapy or salvage radiotherapy, which weinitiated in 36% (5/14) of our patients based on their 89Zr-PSMA-DFO PET scans.

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

Background: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). Methods: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18–60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1–3, 100 mg/m2 oral procarbazine on days 1–7, 40 mg/m2 oral prednisone on days 1–14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. Findings: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7–61·2), 5-year progression-free survival was 97·3% (95% CI 94·5–98·7) in the standard combined-modality treatment group and 95·1% (92·0–97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226–1·211]). The between-group difference was 2·2% (95% CI −0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. Interpretation: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. Funding: Deutsche Krebshilfe.

Purpose: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (ΔMTV and ΔTLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. Patients and Methods: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 × N-AVD) and 4 × nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. Results: At interim restaging, we determined a mean ΔMTV and ΔTLG of −99.8% each in arm A after 2 × N-AVD, compared with −91.4% and −91.9%, respectively, for treatment group B undergoing 4 × nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. Conclusions: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

Purpose PSMA imaging is frequently used for monitoring of androgen deprivation therapy (ADT) in prostate cancer. In a previous study, [18F]-JK-PSMA-7 exhibited favorable properties for tumor localization after biochemical recurrence. In this retrospective study, we evaluated the performance of [18F]-JK-PSMA-7 under ADT. Procedures We examined the performance of [18F]-JK-PSMA-7 in 70 patients (first cohort) with increasing or detectable PSA values under ADT (PSA < 2 ng/ml for 21/70 patients). We further analyzed 58 independent patients with PSA levels < 2 ng/ml under ADT, who were imaged with [68Ga]PSMA-11 or [18F]DCFPyL (second cohort). Finally, we compared detection rates between [18F]-JK-PSMA-7, [68Ga]PSMA-11, and [18F]DCFPyL. Results In the first cohort, we detected [18F]-JK-PSMA-7-positive lesions in 63/70 patients. In patients with PSA levels ≥ 2 ng/ml, the detection rate was 100 % (49/49). In patients with PSA < 2 ng/ml, the detection rate was significantly lower (66.7 %, 14/21, p = 9.7 × 10−5) and dropped from 85.7 % (12/14, PSA levels between 0.3 and 2.0 ng/ml) to 28.6 % (2/7) for PSA levels < 0.3 ng/ml (p = 1.73 × 10−2). In the second cohort (PSA < 2 ng/ml), the detection rate was 79.3 % (46/58) for [68Ga]PSMA-11 or [18F]DCFPyL. Again, the detection rate was significantly higher (p = 1.1 × 10−2) for patients with PSA levels between 0.3 and 2.0 ng/ml (87.0 %, 40/46) relative to those with PSA levels < 0.3 ng/ml (50 %, 6/12). No significant difference was found between [18F]-JK-PSMA-7 and [68Ga]PSMA-11 or [18F]DCFPyL in patients with PSA levels < 2 ng/ml (p = 0.4295). Conclusion [18F]-JK-PSMA-7 PET showed a high detection rate in patients with PSA levels ≥ 0.3 ng/ml under ADT. The lower PSA threshold of 0.3 ng/ml for high detection rates was consistent across the three PSMA ligands. Thus, PSMA imaging is suitable for clinical follow-up of patients with increasing PSA levels under ADT.

in press A consensus statement about indications for post-surgical radioiodine therapy (RIT) in differentiated thyroid cancer patients (DTC) was recently published by the European Thyroid Association (ETA) 1. This publication discusses indications for RIT on the basis of an individual risk assessment. Many of the conclusions of this consensus statement are well founded and accepted across the disciplines involved. However, especially from the perspective of nuclear medicine, as the discipline responsible for indicating and executing RIT, some of the recommendations may require further clarification with regard to their compatibility with established best practice and national standards of care. Assessment of the indications for RIT is strongly dependent on the weighing up of benefits and risks. On the basis of longstanding clinical experience in nuclear medicine, RIT represents a highly specific precision medicine procedure of proven efficacy with a favorable side-effect profile. This distinguishes RIT significantly from other adjuvant oncological therapies and has resulted in the establishment of this procedure as a usually well-tolerated, standard safety measure. With regard to its favorable risk/benefit ratio, this procedure should not be unnecessarily restricted, in the interest of offering reassurance to the patients. Both patients' interests and regional/national differences need to be taken into account. We would therefore like to comment on the recent consensus from the perspective of authors and to provide recommendations based on the respective published data.

The aim of our study was to address the prevalence of oligometastatic recurrent prostate cancer (PCa) on PSMA-PET and the associated practice of metastasis-directed therapy (MDT). Next, we aimed to determine a PSA threshold below which most patients had local and/or oligometastatic recurrence on PSMA-PET.One hundred and ten consecutive patients with biochemical recurrence (BCR) after radical prostatectomy (RP) ± radiation were referred forThirty-four patients (30.9%) had a PSMA-negative scan, while 17 (15.5%) had local recurrence and 59 (53.6%) had metastatic recurrence on PSMA-PET. ROC analysis revealed a cut-off of ≤3 metastatic lesions on PSMA-PET for the steering of treatment decisions towards MDT rather than solely systemic therapy (AUC: 0.88). Defined as 3 or fewer metastatic lesions, oligometastatic recurrent PCa was found in up to 30% (33/110) of all patients. At PSA levels below 3.5 ng/ml, the rate of PSMA-positive disease that was locally confined or oligometastatic was 76% (45/59), dropping significantly to 29.4% (5/17) above this threshold (p0.001) as polymetastatic findings became more frequent.The detection of ≤3 oligometastases on PSMA-PET encouraged the consecutive pursuit of MDT instead of systemic therapy alone. PSMA-PET predominantly captured patients at recurrence stages amenable to localized treatment when initiated at PSA levels below 3.5 ng/ml.ZIEL: Ziel unserer Studie war es, die Prävalenz des oligometastatisch rezidivierten Prostatakarzinoms (PCa) in der PSMA-PET sowie die damit verbundene Praxis der Metastasen-gerichteten Therapie (MDT) zu untersuchen. Anschließend sollte ein PSA-Schwellenwert ermittelt werden, unterhalb dem die Patienten in der Regel ein lokales und/oder oligometastatisches Rezidiv in der PSMA-PET aufwiesen.110 konsekutive Patienten mit biochemischem Rezidiv (BCR) nach radikaler Prostatektomie (RP) ± Bestrahlung wurden zur34 Patienten (30,9 %) hatten einen PSMA-negativen Scan, während 17 (15,5 %) ein lokales Rezidiv und 59 (53,6 %) ein metastasiertes Rezidiv in der PSMA-PET hatten. In der ROC-Analyse erwies sich eine Anzahl von ≤3 Metastasen in der PSMA-PET als Schwellenwert für die Verfolgung einer MDT statt einer ausschließlich systemischen Therapie (AUC: 0,88). Definiert als 3 oder weniger Metastasen wurde das oligometastatisch rezidivierte PCa bei bis zu 30% (33/110) aller Patienten vorgefunden. Bei PSA-Werten unter 3,5 ng/ml lag die Rate der PSMA-positiven Befunde, die lokal begrenzt oder oligometastatisch waren, bei 76 % (45/59) und sank signifikant auf 29,4 % (5/17) oberhalb dieses Grenzwerts (p0,001), da polymetastatische Befunde zunahmen.Der Nachweis von ≤3 PCa-Oligometastasen in der PSMA-PET ermutigte zur Verfolgung einer lokalen, Metastasen-gerichteten anstelle einer rein systemischen Therapiestrategie. Die PSMA-PET erfasste die Patienten in Rezidivstadien, die einer lokalen Therapie zugänglich waren, vor allem dann, wenn die Bildgebung bei PSA-Werten unter 3,5 ng/ml veranlasst wurde.

PurposeWe present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands.ProceduresThe precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [177Lu]Lu-PSMA-617. The ligand [89Zr]Zr-PSMA-DFO was compared with [68Ga]Ga-PSMA-11 and [18F]F-JK-PSMA-7in vitroby determination of theKdvalue, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, andin vivoby small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [89Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [18F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously.Results[89Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very highin vitrostability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization,in vitroand comparable tumor uptake in biodistribution experiments during the first 5 h. The [89Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [68Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [18F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p in vivothat tumor visualization with [89Zr]Zr-PSMA-DFO is comparable to [68Ga]Ga-PSMA-11 or [18F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [89Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUVmax13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides.Conclusion[89Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation.

Background 18F -fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the staging and response assessment of lymphoma patients. Our aim was to explore the predictive relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with early stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD16 trial. Methods 18F-FDG PET/CT images were available for MTV and TLG analysis in 107 cases from the HD16 trial. We calculated MTV and TLG using three different threshold methods (SUV4.0, SUV41% and SUV140%L), and then performed receiver-operating-characteristic analysis to assess the predictive impact of these parameters in predicting an adequate therapy response with PET negativity after 2 cycles of chemotherapy. Results All three threshold methods analyzed for MTV and TLG calculation showed a positive correlation with the PET response after 2 cycles chemotherapy. The largest area under the curve (AUC) was observed using the fixed threshold of SUV4.0 for MTV- calculation (AUC 0.69 [95% CI 0.55–0.83]) and for TLG-calculation (AUC 0.69 [0.55–0.82]). The calculations for MTV and TLG with a relative threshold showed a lower AUC: using SUV140%L AUCs of 0.66 [0.53–0.80] for MTV and 0.67 for TLG [0.54–0.81]) were observed, while with SUV41% an AUC of 0.61 [0.45–0.76] for MTV, and an AUC 0.64 [0.49–0.80]) for TLG were seen. Conclusions MTV and TLG do have a predictive value after two cycles ABVD in early stage Hodgkin lymphoma, particularly when using the fixed threshold of SUV4.0 for MTV and TLG calculation. Trial registration ClinicalTrials.gov NCT00736320.

In preclinical trials, the recently developed tracer 2-methoxy-18F-DCFPyL (18F-JK-prostate-specific membrane antigen [PSMA]-7) has shown favorable properties regarding clinical performance and radiochemical accessibility. The aim of this study was to evaluate the clinical utility of 18F-JK-PSMA-7 for PET/CT imaging of patients with prostate cancer. Methods: In an Institutional Review Board–approved pilot study, the initial clinical utility of PET/CT imaging with 18F-JK-PSMA-7 was directly compared with 68Ga-PSMA-11 PET/CT in a group of 10 patients with prostate cancer. The 2 PSMA tracers were administered to each patient less than 3 wk apart. Next, we analyzed the data of 75 consecutive patients who had undergone clinical 18F-JK-PSMA-7 PET/CT imaging for tumor localization of biochemical recurrence (BCR). Results: The pilot study in 10 patients who were examined with both PSMA tracers demonstrated that 18F-JK-PSMA-7 was at least equivalent to 68Ga-PSMA-11. All unequivocally 68Ga-PSMA-11–positive lesions could be also detected using 18F-JK-PSMA-7, and in 4 patients additional suspected PSMA-positive lesions were identified (1 patient changed from PSMA-negative to PSMA-positive). In patients with BCR (after prostatectomy or radiotherapy), the capacity of 18F-JK-PSMA-7 PET/CT to detect at least one PSMA-positive lesion was 84.8%. The prostate-specific antigen (PSA)–stratified detection rate of 18F-JK-PSMA-7 after prostatectomy varied among 54.5% (6/11 patients; PSA < 0.5 μg/L), 87.5% (14/16 patients; PSA 0.5–2 μg/L), and 90.9% (20/22 patients; PSA > 2 μg/L). Conclusion: The tracer 18F-JK-PSMA-7 was found to be safe and clinically useful. We demonstrated that 18F-JK-PSMA-7 was not inferior when directly compared with 68Ga-PSMA-11 in a pilot study but indeed identified additional PSMA-avid suspected lesions in oligometastasized patients with BCR. In a subsequent analysis of a clinical cohort of BCR patients, 18F-JK-PSMA-7 was useful in tumor localization. 18F-JK-PSMA-7 is recommended for future prospective trials.

ZusammenfassungDie Version 5 der Verfahrensanweisung für die Iod-131 Ganzkörperszintigrafie beim differenzierten Schilddrüsenkarzinom ist ein Update der Version 4, publiziert durch die Deutsche Gesellschaft für Nuklearmedizin (DGN). Diese Verfahrensanweisung beschreibt mit primärer Zielsetzung die fachgerechte Durchführung der Ganzkörperszintigrafie nach Applikation einer diagnostischen bzw. einer therapeutischen I-131 Aktivität. Die Verfahrensanweisung wurde von einer repräsentativen Expertengruppe im Konsensverfahren verabschiedet. Sie entspricht damit einer Verfahrensanweisung der ersten Stufe (S1) nach den Kriterien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF).

Hashimoto's thyroiditis is a common disease that also affects pregnant women. We analyzed to what extent the inflammatory process of Hashimoto's thyroiditis changes with iodine prophylaxis in pregnant women. The target for immunologic activity was levels of thyroid antibodies (TPO). The data were collected retrospectively from 20 consecutive, pregnant patients who had been diagnosed with Hashimoto's thyroiditis between 01.12.2012 and 01.12.2014 and had received iodine supplementation with 100 µg (n = 1) or 150 µg (n = 19). At least two measurements of TPO antibody levels taken during pregnancy and one after pregnancy were evaluated for each patient in the study group. At the end of pregnancy, the average TPO antibody level for the 20 patients studied was 137 IU/ml (+/-214 IU/ml), the lowest being 16 IU/ml and the highest 1000 IU/ml. Despite iodine prophylaxis, levels of TPO antibodies decreased in 18 patients during pregnancy, falling below the reference value of 35 IU/ml in 5 cases. However, in one patient TPO antibodies increased from 60 IU/ml to 237 IU/ml during pregnancy while in another, levels remained constant at 1000 IU/ml. Iodine prophylaxis in pregnant women, taken at a dose of 100 or 150 μg daily was shown to have no negative systemic effects on Hashimoto's thyroiditis in a group of pregnant women with increased TPO levels, and can therefore be recommended for expectant mothers, including those with this disease.ZIEL: Die Hashimoto-Thyreoiditis ist eine häufige Erkrankung, welche auch schwangere Frauen betrifft. Wir haben untersucht, in welchem Ausmaß sich der Entzündungsprozess einer Hashimoto-Thyreoiditis unter Jodprophylaxe bei schwangeren Frauen verändert. Zielgröße hierfür war der Verlauf der Thyreoperoxidase-Antikörper (TPO). Die Daten wurden retrospektiv von 20 schwangeren Patienteninnen erhoben, bei denen im Zeitraum vom 01.12.2012 bis zum 01.12.2014 eine Hashimoto-Thyreoiditis diagnostiziert worden war und die eine Jodprophylaxe mit 100 µg (n = 1) oder 150 µg (n = 19) erhalten haben. Für die eingeschlossenen Patientinnen wurden mindestens 2 Werte der TPO-Antikörper in der Schwangerschaft sowie mindestens ein Wert der TPO-Antikörper nach der Schwangerschaft ausgewertet. Am Ende der Schwangerschaft lag der durchschnittliche TPO-Antikörper-Wert der 20 Patientinnen bei 137 IU/ml (+/–214 IU/ml), der niedrigste Wert lag bei 16 IU/ml und der höchste Wert bei 1000 IU/ml. Bei 18 Patientinnen waren die Werte der TPO-Antikörper trotz Jodprophylaxe in der Schwangerschaft gesunken, bei 5 Patientinnen unter den Referenzwert von 35 IU/ml. Bei einer Patientin waren die TPO-Antikörper während der Schwangerschaft von 60,3 IU/ml auf 237 IU/ml gestiegen und bei einer Patientin bei 1000 IU/ml konstant geblieben. Die übliche Jodprophylaxe bei schwangeren Frauen mit einer Dosierung zwischen 100 und 150 μg täglich zeigte keine systematisch negativen Auswirkungen auf die Hashimoto-Thyreoiditis in einer Gruppe von Schwangeren mit erhöhten TPO-Antikörpern und kann daher auch für werdende Mütter mit dieser Diagnose empfohlen werden.

The short half-life of existing prostate-specific membrane antigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Because of its longer half-life, the

Summary Background The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. Methods HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18–60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1–3], 100 mg/m2 oral procarbazine [day 1–7], 40 mg/m2 oral prednisone [day 1–14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov , NCT00515554 , and is completed. Findings Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI −1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [–5·9 to 6·2]). Interpretation Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. Funding Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. Translation For the German translation of the abstract see Supplementary Materials section.

Objective The reliability of visual and quantitative response assessment may be impaired owing to inconsistent scanning protocols and image reconstruction methods of 2-deoxy-2-[F-18]fluoro-d-glucose (F-18-FDG) PET. Hence, this study investigates the effect of contrast-enhanced computed tomography (CT) attenuation correction in patients with Hodgkin lymphoma. Patients and methods In 10 consecutive patients undergoing either staging or response assessment, F-18-FDG PET images were attenuation-corrected once on the basis of unenhanced CT and additionally using contrast-enhanced CT. Reconstruction was performed in both cases with ordered subset expectation maximization (OSEM) and ultra-high definition (UHD) algorithm. While maximum and peak standardized uptake value (SUV) were obtained from tumour tissue (lesionSUV(max) and lesionSUV(peak)), maximum and mean SUVs were determined within the background regions liver (liverSUV(max) and liverSUV(mean)) and mediastinal blood pool (mbpSUV(max) and mbpSUV(mean)). Results After switching to contrast-enhanced CT attenuation correction, lesionSUV(max) and lesionSUV(peak) increased on average by 2.55 +/- 3.24 (P=0.018) and 3.64 +/- 3.22% (P=0.008), respectively, with OSEM and by 4.59 +/- 5.49 (P=0.005) and 3.84 +/- 5.65% (P=0.005), respectively, with UHD reconstruction. LiverSUV(max) and liverSUV(mean) showed a mean rise of 7.15 +/- 4.27 (P=0.005) and 6.97 +/- 2.18% (P=0.005), respectively, in the OSEM data sets and of 7.24 +/- 6.59 (P=0.017) and 6.29 +/- 2.83% (P=0.005), respectively, in the UHD images. The average increases of mbpSUV(max) and mbpSUV(mean) were 10.82 +/- 4.89 (P=0.005) and 12.40 +/- 3.73% (P=0.005), respectively, after OSEM, compared with 13.11 +/- 14.93 (P=0.005) and 11.50 +/- 12.19% (P=0.005), respectively, after UHD reconstruction. Conclusion As the use of CT contrast fluids results in a stronger SUV increase within the liver and mediastinal blood pool than within lymphoma tissue, this may have clinical consequences regarding visual and quantitative response assessment. Ideally, CT scans for PET attenuation correction should therefore be performed in the absence of a contrast agent.

Since the mid-1990s, 18F-fluorodeoxglucose (FDG)-positron emission tomography (PET) in combination with computed tomography has come to play a prominent role in the management of malignant lymphomas. One of the first PET applications in oncology was the detection of lymphoma manifestations at staging, where it has shown high sensitivity. Nowadays, this imaging modality is also used during treatment to evaluate the individual chemosensitivity and adapt further therapy accordingly. If the end-of-treatment PET is negative, irradiation in advanced-stage Hodgkin lymphoma patients can be safely omitted after highly effective chemotherapy. Thus far, lymphoma response assessment has mainly been performed using visual criteria, such as the Deauville five-point scale, which became the international standard in 2014. However, novel measures such as metabolic tumor volume or total lesion glycolysis have recently been recognized by several working groups and may further increase the diagnostic and prognostic value of FDG-PET in the future.

Prostate-specific membrane antigen (PSMA), expressed by most prostate carcinomas (PCa), is a promising target for PCa imaging. The application of PSMA-specific (18)F-labeled PET probes such as (18)F-DCFPyL and (18)F-PSMA-1007 considerably improved the accuracy of PCa tumor detection. However, there remains a need for further improvements in sensitivity and specificity. The aim of this study was the development of highly selective and specific PSMA probes with enhanced imaging properties, in comparison with (18)F-DCFPyL, (18)F-PSMA-1007, and (68)Ga-PSMA-11. Methods: Eight novel (18)F-labeled PSMA ligands were prepared. Their cellular uptake in PSMA-positive LNCaP C4–2 and PSMA-negative PC-3 cells was compared with that of (18)F-DCFPyL. The most promising candidates were additionally evaluated by small-animal PET in healthy rats using PSMA-positive peripheral ganglia as a model for small PCa lesions. PET images of the ligand with the best outcome, (18)F-JK-PSMA-7, were compared with those of (18)F-DCFPyL, (18)F-PSMA-1007, and (68)Ga-PSMA-11 with respect to key image-quality parameters for the time frame 60–120 min. Results: Compared with (18)F-DCFPyL, (18)F-JK-PSMA-7 demonstrated increased PSMA-specific cellular uptake. Although target-to-background ratios of (18)F-DCFPyL and (18)F-PSMA-1007 were comparable, this parameter was higher for (18)F-JK-PSMA-7 and lower for (68)Ga-PSMA-11. Image acutance was significantly higher for (18)F-JK-PSMA-7 and (18)F-PSMA-1007 than for (18)F-DCFPyL and (68)Ga-PSMA-11. Image resolution was similar for all 4 tracers. (18)F-PSMA-1007 demonstrated significantly higher blood protein binding and bone uptake than the other tracers. Conclusion: (18)F-JK-PSMA-7 is a promising candidate for high-quality visualization of small PSMA-positive lesions. Excellent preclinical imaging properties justify further preclinical and clinical studies of this tracer.

Adjuvant radioiodine therapy (RITh) for differentiated thyroid carcinoma is performed either with thyroid hormone withdrawal or with administration of recombinant human thyroid-stimulating hormone (rhTSH). Heterogeneous results have been obtained on the impact of the method of patient preparation on thyroid uptake and whole-body effective half-life. A higher radiation exposure using thyroid hormone withdrawal for several weeks compared with rhTSH was reported in prior studies. It was the aim to examine whether these findings are reproducible in a modern protocol with a short interval between surgery and RITh. Methods: A retrospective study was performed on patients admitted for adjuvant RITh for differentiated thyroid carcinoma at the University Hospital of Cologne over a 5-y period from 2010. Dose rate measurements were analyzed for 366 patients, and subgroup analyses were performed for papillary thyroid cancer (n = 341) and follicular thyroid cancer (n = 25) patients, sex, length of hypothyroidism, and normal versus decreased glomerular filtration rate (GFR). Results: The median interval between surgery and RITh was 18 d for thyroid hormone withdrawal and 25 d for rhTSH (P < 0.01). The mean thyroid uptake was 4.2% ± 1.8% for the 300 hypothyroid patients versus 3.8% ± 1.6% (P = 0.12) for the 66 rhTSH patients. Whole-body half-life in the hypothyroid group was significantly longer at 19.3 ± 7.7 h versus 16.4 ± 4.6 h in the rhTSH group (P < 0.01). Results were predominantly influenced by data from the largest subgroup, that is, female papillary thyroid cancer patients. Within this group, whole-body half-life was significantly shorter in the rhTSH treatment arm. Duration of hypothyroidism and a decrease in GFR less than 60 mL/min/1.73 m2 significantly influenced results, with an increased whole-body half-life occurring in the hypothyroid group. When patients returned for whole-body scintigraphy, thyroid, half-life, and whole-body half-life were significantly shorter in the rhTSH groups, resulting in a low thyroid and remaining-body dose. Conclusion: With a shortening of the time between surgery and adjuvant RITh, thyroid uptake is not significantly changed but whole-body half-life becomes longer in the hypothyroid group. Radiation exposure for most patients is not significantly different. However, patients with a hypothyroid phase of more than 4 wk, and in particular those with a decreased GFR, experience higher radiation exposure.

Klagt Ihr Patient, dass er schwitzt, nervos ist und Gewicht verloren hat, sollten Sie eine Schilddrusenuberfunktion abklaren. Das wichtigste Screeninginstrument ist dabei der TSH-Test. Wie es danach in der Hausarztpraxis weitergeht, fasst der nachfolgende Beitrag zusammen.

Our aim was to evaluate the benefit of early (1 h post-injection (p.i.)) and late (3 h p.i.) [68Ga]PSMA-HBED-CC positron emission tomography (PET)/x-ray computed tomography (CT) imaging for detection of biochemical recurrence (BCR) of prostate cancer (PCa). Seventy patients with BCR of the PCa and prostate-specific antigen (PSA) levels of less than 2.0 μg/l were subjected to [68Ga]PSMA-HBED-CC PET (mean injected activity 180 MBq). While early imaging contained whole body scans, late imaging was confined to the pelvis and the lower abdomen. Uptake in suspicious lesions was analyzed by peak and maximum standardized uptake values (SUVpeak/max). Tumor-to-background ratios were calculated for all lesions in which the liver served as reference organ. The Wilcoxon matched-pair signed-rank test was used to compare the uptake in suspicious lesions between early and late imaging. Follow-up data were used to validate the existence of the additionally detected lesions. Forty-four of the 70 patients thus examined were interpreted as PSMA-positive in early and/or late scans while 26 remained without suspicion of PSMA tracer uptake. A total of 70 suspicious lesions were analyzed. Ten tumor-suspicious lesions from seven different patients were better or exclusively visible in the late measurements while three tumor-suspicious lesions from three different patients were better or exclusively visible in the early images. A validation by follow-up data was possible for 11 of these 13 additionally detected lesions. In direct comparison between early and late imaging, the mean SUVmax in PSMA-positive lesions was 74 % higher (p

ZusammenfassungDie Version 4 der Verfahrensanweisung für die Iod-131-Ganzkörperszintigraphie beim differenzierten Schilddrüsenkarzinom ist ein Update der Version 3, die im Jahr 2007 durch die Deutsche Gesellschaft für Nuklearmedizin (DGN) und die Deutsche Gesellschaft für Medizinische Physik (DGMP) publiziert wurde. Diese Verfahrensanweisung beschreibt mit primärer Zielsetzung die fachgerechte Durchführung der Ganzkörperszintigraphie nach Applikation einer diagnostischen bzw. therapeutischen I-131-Aktivität. Die aktualisierten Indikationen zur I-131-Ganzkörperszintigraphie werden in der Verfahrensanweisung aufgelistet. Neue Erkenntnisse bezüglich der Beziehung zwischen verabreichter Aktivität und Bildqualität wurden in der aktualisierten Verfahrungsanweisung berücksichtigt. Die Verfahrensanweisung wurde von einer repräsentativen Expertengruppe im Konsensverfahren verabschiedet. Sie entspricht damit einer Verfahrensanweisung der ersten Stufe (S1) nach den Kriterien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Zusätzlich wurden Indikationsstellung, Zeitpunkt und Aktivitätswahl für die diagnostische Ganzkörperszintigraphie im erweiterten Kollegenkreis am 30. November 2012, am 19. April 2013 und am 23. April 2015 bei Tagungen der Arbeitsgemeinschaft Schilddrüse der Deutschen Gesellschaft für Nuklearmedizin ausführlich diskutiert.

Rationale: (18F)fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumour volume (MTV) as baseline risk factor. Our aim was to analyse the prognostic impact of MTV measurements, obtained by different means in advanced-stage Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD18 trial. Methods: Within the German Hodgkin Study Group trial HD18, 310 patients underwent 18F-FDG PET/CT scanning for staging which was available to the central review panel for quantitative analysis. We calculated the MTV by four different thresholding methods and performed receiver operating characteristic (ROC) analysis to evaluate the potential for prediction of early response determined by PET after two cycles (PET-2) dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival (PFS) and overall survival (OS). Results: All different MTV calculations used predicted PET-2 response to a moderate and comparable degree (area under the curve = 0.62-0.63, P = 0.01-0.06). With none of the measuring methods did the ROC curves point to any unique cut-off values, but indicated a wide range of possible cut-offs. However, none of the MTV measurements was prognostic for PFS (Hazard ratio 1.2-1.5, P = 0.15-0.52) or OS (Hazard ratio 1.0-1.5, P = 0.95 - 0.27). Conclusion: Baseline MTV as determined by different means, is a predictive factor for early response to eBEACOPP after two cycles. However, value as a prognostic factor after highly effective PET-2 adapted treatment strategy could not be observed.