An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.

Value of PET imaging for radiation therapy.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Using immuno-PET imaging to monitor kinetics of T cell-mediated inflammation and treatment efficiency in a humanized mouse model for GvHD.

PURPOSE: Hematopoietic stem cell transplantation is the only curative treatment for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of graft-versus-host disease (GvHD) after transplantation is a severe complication with high morbidity and mortality. The aim of this study was to image human T cells during GvHD development and their migration into GvHD-related organs. By using a radiolabeled anti-human CD3 monoclonal antibody (mAb), we were able to visualize GvHD progression in a humanized mouse model. METHODS: Human peripheral blood mononuclear cells (PBMC) were transferred into immunodeficient mice (initially n = 11 mice/group) to induce GvHD. One group additionally received regulatory T cells (Treg) for prevention of GvHD. T cell migration was visualized by sequential small animal PET/MRI using 89Zr-labeled anti-human CD3 mAb. Flow cytometry and immunohistochemistry were used to measure T cell frequencies in relevant organs at different time points after engraftment. RESULTS: Using radiolabeled anti-CD3 mAb, we successfully visualized human T cells in inflamed organs of mice by 89Zr-anti-CD3-PET/MRI. Upon GvHD progression, we observed increased numbers of CD3+ T cells in the liver (22.9% on day 3; 94.2% on day 10) and the spleen (4.4% on day 3; 58.8% on day 10) which correlated with clinical symptoms. The liver showed distinct spot-like lesions representing a strong focal accumulation of T cells. Administration of Treg prior GvHD induction reduced T cell accumulation in the liver from 857 ± 177 CD3+ cells/mm2 to 261 ± 82 CD3+ cells/mm2 and thus prevented GvHD. CONCLUSION: 89Zr-labeled anti-human CD3 mAb can be used as a proof of concept to detect the exact spatio-temporal distribution of GvHD-mediating T cells. In the future, radiolabeled T cell-specific mAb could be employed as a predictive early biomarker during the course of GvHD maybe even before clinical signs of the disease become evident. Furthermore, monitoring T cell migration and proliferation might improve tailored GvHD therapy.

Evaluation of a novel monoclonal antibody against tumor-associated MUC1 for diagnosis and prognosis of breast cancer.

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on healthy epithelial cells thus enabling the generation of breast tumor-specific radiolabeled immune therapeutic tools. Methods: MAb GGSK-1/30 was used for immunohistochemical analysis of human breast cancer tissue. Its desferrioxamine (Df')-conjugate was synthesized and labelled with 89Zr. [89Zr]Zr-Df'-GGSK-1/30 was evaluated as a potential PET tracer. Binding and pharmacokinetic properties of [89Zr]Zr-Df'-GGSK-1/30 were analyzed in vitro using human and murine cell lines that express tumor-associated MUC1. Self-generated primary murine breast cancer cells expressing human tumor-associated MUC1 were transplanted subcutaneously in wild type and human MUC1-transgenic mice. The pharmacology of [89Zr]Zr-Df'-GGSK-1/30 was investigated using breast tumor-bearing mice in vivo by PET/MRT imaging as well as by ex vivo organ biodistribution analysis. Results: The mAb GGSK-1/30 stained specifically human breast tumor tissue and can be possibly used to predict the severity of disease progression based on the expression of the tumor-associated MUC1. For in vivo imaging, the Df'-conjugated mAb was radiolabeled with a radiochemical yield of 60 %, a radiochemical purity of 95 % and an apparent specific activity of 6.1 GBq/µmol. After 7 d, stabilities of 84 % in human serum and of 93 % in saline were observed. In vitro cell studies showed strong binding to human tumor-associated MUC1 expressing breast cancer cells. The breast tumor-bearing mice showed an in vivo tumor uptake of >50 %ID/g and clearly visible specific enrichment of the radioconjugate via PET/MRT. Principal conclusions: Tumor-associated MUC1 is a very important biomarker for breast cancer next to the traditional markers estrogen receptor (ER), progesterone receptor (PR) and HER/2-neu. The mAb GGSK-1/30 can be used for the diagnosis of over 90% of breast cancers, including triple negative breast cancer based on biopsy staining. Its radioimmunoconjugate represents a promising PET-tracer for breast cancer imaging selectively targeting breast cancer cells.

Comparison of Linear and Hyperbranched Polyether Lipids for Liposome Shielding by 18F-Radiolabeling and Positron Emission Tomography.

Multifunctional and highly biocompatible polyether structures play a key role in shielding liposomes from degradation in the bloodstream, providing also multiple functional groups for further attachment of targeting moieties. In this work hyperbranched polyglycerol ( hbPG) bearing lipids with long alkyl chain anchor are evaluated with respect to steric stabilization of liposomes. The branched polyether lipids possess a hydrophobic bis(hexadecyl)glycerol membrane anchor for the liposomal membrane. hbPG was chosen as a multifunctional alternative to PEG, enabling the eventual linkage of multiple targeting vectors. Different hbPG lipids ( Mn = 2900 and 5200 g mol-1) were examined. A linear bis(hexadecyl)glycerol-PEG lipid ( Mn = 3000 g mol-1) was investigated as well, comparing hbPG and PEG with respect to shielding properties. Radiolabeling of the polymers was carried out using 1-azido-2-(2-(2-[18F]fluoroethoxy)ethoxy)ethane ([18F]F-TEG-N)3 via copper-catalyzed alkyne-azide cycloaddition with excellent radiochemical yields exceeding 95%. Liposomes were prepared by the thin-film hydration method followed by repeated extrusion. Use of a custom automatic extrusion device gave access to reproducible sizes of the liposomes (hydrodynamic radius of 60-94 nm). The in vivo fate of the bis(hexadecyl)glycerol polyethers and their corresponding assembled liposome structures were evaluated via noninvasive small animal positron emission tomography (PET) imaging and biodistribution studies (1 h after injection and 4 h after injection) in mice. Whereas the main uptake of the nonliposomal polyether lipids was observed in the kidneys and in the bladder after 1 h due to rapid renal clearance, in contrast, the corresponding liposomes showed uptake in the blood pool as well as in organs with good blood supply, that is, heart and lung over the whole observation period of 4 h. The in vivo behavior of all three liposomal formulations was comparable, albeit with remarkable differences in splenic uptake. Overall, liposomes shielded by the branched polyglycerol lipids show a favorable biodistribution with greatly prolonged blood circulation times, rendering them promising novel nanovesicles for drug transport and targeting.

Inclusion of PET-CT into planning of primary or neoadjuvant chemoradiotherapy of esophageal cancer improves prognosis.

BACKGROUND: PET-CT is widely used for both the staging and planning of primary or neoadjuvant chemoradiotherapy for esophageal cancer. Inclusion of PET-CT information into radiotherapy planning often leads to substantial modifications of the target volume. In the case of detection of distant metastases, it may also result in a switch to a palliative treatment approach. This spares patients from therapy-related toxicities that provide no clinical benefit. However, due to a lack of studies, it is currently unclear whether the advantages of PET-CT also translate into a measurable improvement in patient survival. PATIENTS AND METHODS: A retrospective analysis assessed the survival data of 145 patients with esophageal carcinoma stages I (eight patients; 5%), II (45; 31%), III (79; 55%), IV (8; 5%) and unknown (5; 4%). Patients were treated between 1999 and 2014 either with primary chemoradiation (n = 101) or neoadjuvant chemoradiation at the Department of Radiation Oncology, University Medical Center Mainz, followed by transabdominal or transthoracic tumor resection (n = 44). Of the 145 patients, 64 (44%) had undergone PET-CT. RESULTS: Univariate analysis showed the use of PET-CT to be associated with significantly longer local recurrence-free survival (p = 0.006) and tended to translate into a measurable improvement of overall survival (p = 0.071). Since more patients underwent surgery in the group planned using PET-CT (20% vs. 44%; p = 0.002), we carried out a multivariate Cox regression analysis to adjust for this possible confounding factor. Surgery (p = 0.042; HR 0.55; 95% confidence interval: 0.31-0.98) as well as the use of PET-CT (p = 0.048; HR 0.60; 95% confidence interval: 0.36-0.99) nearly halved the risk of local recurrence. It was only in the group of patients with PET-CT that a trend towards a shorter overall survival was evident in lymph node-positive patients (p = 0.16), whereas nodal stage did not impact on survival in patients staged without PET-CT (p = 0.97). CONCLUSION: To the best of our knowledge these data suggest for the first time that the use of PET-CT in the framework of staging and planning of primary or neoadjuvant chemoradiotherapy for esophageal cancer has a favorable impact on patient survival.

Bone scintigraphy predicts bisphosphonate-induced osteonecrosis of the jaw (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC).

OBJECTIVES: The aim of this study was to evaluate the role of bone scintigraphy (BS) in early prediction of clinically asymptomatic bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIAL AND METHODS: BS of mCRPC patients treated with BP was evaluated for pathologic tracer uptake of the jaws in BS suspicious for BRONJ. Results were compared to development of clinically evident BRONJ. Sensitivity, specificity and predictive values of BS for the detection of BRONJ as well as time from beginning of BP therapy to pathologic tracer uptake in BS and time from pathologic tracer uptake in BS to clinically evident BRONJ were determined. RESULTS: Thirty BP-treated patients were included. Nine patients (30%) had pathologic BS lesions of the jaws. Six patients (20%) developed BRONJ. Sensitivity and specificity of BS for BRONJ prediction were 67 and 79%. Median time from the start of BP treatment to pathologic tracer uptake in BS was 28 months (range 10-33) and from pathologic tracer uptake in BS to clinically evident BRONJ 6.5 months (range 2-19). Pathologic tracer uptake in BS was significantly more often observed in patients who developed BRONJ compared to patients who did not (p = 0.049; OR 7.6). CONCLUSIONS: Patients with pathologic tracer uptake in the jaws in BS significantly more often develop BRONJ. An unsuspicious BS is predictive for absence of BRONJ in the future. CLINICAL RELEVANCE: We conclude that when BS has been performed, it should not only be used to assess tumour stage and treatment response but also to check for pathologic tracer uptake in the jaws in BS to detect BRONJ at an early stage in mCRPC patients receiving bisphosphonates.

Fate of linear and branched polyether-lipids in vivo in comparison to their liposomal formulations by 18F-radiolabeling and positron emission tomography.

In this study, linear poly(ethylene glycol) (PEG) and novel linear-hyperbranched, amphiphilic polyglycerol (hbPG) polymers with cholesterol (Ch) as a lipid anchor moiety were radiolabeled with fluorine-18 via copper-catalyzed click chemistry. In vivo investigations via positron emission tomography (PET) and ex vivo biodistribution in mice were conducted. A systematic comparison to the liposomal formulations with and without the polymers with respect to their initial pharmacokinetic properties during the first hour was carried out, revealing remarkable differences. Additionally, cholesterol was directly labeled with fluorine-18 and examined likewise. Both polymers, Ch-PEG27-CH2-triazole-TEG-(18)F and Ch-PEG30-hbPG24-CH2-triazole-TEG-(18)F (TEG: triethylene glycol), showed rapid renal excretion, whereas the (18)F-cholesten displayed retention in lung, liver, and spleen. Liposomes containing Ch-PEG27-CH2-triazole-TEG-(18)F revealed a hydrodynamic radius of 46 nm, liposomal Ch-PEG30-hbPG24-CH2-triazole-TEG-(18)F showed a radius of 84 nm and conventional liposomes with (18)F-cholesten 204 nm, respectively. The results revealed fast uptake of the conventional liposomes by liver, spleen, and lung. Most importantly, the novel hbPG-polymer stabilized liposomes showed similar behavior to the PEG-shielded vesicles. Thus, an advantage of multifunctionality is achieved with retained pharmacokinetic properties. The approach expands the scope of polymer tracking in vivo and liposome tracing in mice via PET.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives.

The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

Impact of mediastinal tumor burden and lymphatic spread in locally advanced non-small-cell lung cancer: A secondary analysis of the multicenter randomized PET-Plan trial.

PURPOSE: The aim of this secondary analysis of the prospective randomized phase 2 PET-Plan trial (ARO-2009-09; NCT00697333) was to evaluate the impact of mediastinal tumor burden and lymphatic spread in patients with locally advanced non-small-cell lung cancer (NSCLC). METHODS: All patients treated per protocol (n = 172) were included. Patients received isotoxically dose-escalated chemoradiotherapy up to a total dose of 60-74 Gy in 30-37 fractions, aiming as high as possible while adhering to normal tissue constraints. Radiation treatment (RT) planning was based on an 18F-FDG PET/CT targeting all lymph node (LN) stations containing CT positive LNs (i.e. short axis diameter > 10 mm), even if PET-negative (arm A) or targeting only LN stations containing PET-positive nodes (arm B). LN stations were classified into echelon 1 (ipsilateral hilum), 2 (ipsilateral station 4 and 7), and 3 (rest of the mediastinum, contralateral hilum). The endpoints were overall survival (OS), progression-free survival (PFS), and freedom from local progression (FFLP). RESULTS: The median follow-up time (95 % confidence interval [CI]) was 41.1 (33.8 - 50.4) months. Patients with a high absolute number of PET-positive LN stations had worse OS (hazard ratio [HR] = 1.09; 95 % CI 0.99 - 1.18; p = 0.05) and PFS (HR = 1.12; 95 % CI 1.04 - 1.20; p = 0.003), irrespective of treatment arm allocation. The prescribed RT dose to the LNs did not correlate with any of the endpoints when considering all patients. However, in patients in arm B (i.e., PET-based selective nodal irradiation), prescribed RT dose to each LN station correlated significantly with FFLP (HR=0.45; 95 % CI 0.24-0.85; p = 0.01). Furthermore, patients with involvement of echelon 3 LN stations had worse PFS (HR = 2.22; 95 % CI 1.16-4.28; p = 0.02), also irrespective of allocation. CONCLUSION: Mediastinal tumor burden and lymphatic involvement patterns influence outcome in patients treated with definitive chemoradiotherapy for locally advanced NSCLC. Higher dose to LNs did not improve OS, but did improve FFLP in patients treated with PET-based dose-escalated RT.

Emerging frontiers in androgen receptor research for prostate Cancer: insights from the 2nd international androgen receptor Symposium.

Continued exploration of the androgen receptor (AR) is crucial, as it plays pivotal roles in diverse diseases such as prostate cancer (PCa), serving as a significant therapeutic focus. Therefore, the Department of Urology Dresden hosted an international meeting for scientists and clinical oncologists to discuss the newest advances in AR research. The 2nd International Androgen Receptor Symposium was held in Dresden, Saxony, Germany, from 26-27.04.2024, organised by Dr. Holger H.H. Erb. Following the format of the first meeting, more than 35 scientists from 8 countries attended the event to discuss recent developments, research challenges, and identification of venues in AR research. An important new feature was the involvement of PhD students and young investigators, acknowledging the high scientific quality of their work. The symposium included three covers: new advances from clinical research, basic and translational research, and novel strategies to target AR. Moreover, based on its increasing clinical relevance, a PSMA theranostic mini-symposium was added at the end of the AR symposium to allow the audience to discuss the newest advances in PSMA theranostic. This report focuses on the highlights and discussions of the meeting.

High incidence of extraadrenal paraganglioma in families with SDHx syndromes detected by functional imaging with [18F]fluorodihydroxyphenylalanine PET.

PURPOSE: Knowledge of the genetic backgrounds of hereditary syndromes, which are increasingly being characterized, enables genetic screening of family members of affected patients. Upon detection of a mutation, genetic counselling and clinical screening including imaging modalities and biochemical analyses are commonly performed. METHODS: Unaffected, mutation-positive relatives of index patients with hereditary paraganglioma syndromes were offered PET imaging with [(18)F]fluorodihydroxyphenylalanine and the incidence of pathological findings was retrospectively analysed in relation to mutations of the succinate dehydrogenase enzyme complex. PET only or PET/CT was performed in 21 individuals from eight families with SDHD, one family with SDHC and two families with SDHB mutations. Screening was offered every 2 to 5 years. RESULTS: Of the 21 individuals, 14 showed paraganglioma during screening. In particular, in only 2 of 15 patients with a SDHD mutation were the findings completely unremarkable on PET screening. However, false-negative lesions for abdominal manifestations in two SDHD-positive patients were detected. CONCLUSION: FDOPA PET is a sensitive imaging modality which should be offered to patients with a detected SDHx (SDHD) mutation, preferably using a hybrid technique.

Up-Regulation of PSMA Expression In Vitro as Potential Application in Prostate Cancer Therapy.

Possibilities to improve the therapeutic efficacy of Lu-177-PSMA-617 radionuclide therapy by modulation of target expression are being investigated. Knowledge on regulatory factors that promote prostate cancer (PCa) progression may contribute to targeting prostate cancer more effectively. We aimed at the stimulation of PCa cell lines using the substances 5-aza-2'-deoxycitidine (5-aza-dC) and valproic acid (VPA) to achieve increased prostate-specific membrane antigen (PSMA) expression. PC3, PC3-PSMA, and LNCaP cells were incubated with varying concentrations of 5-aza-dC and VPA to investigate the cell-bound activity of Lu-177-PSMA-617. Stimulation effects on both the genetically modified cell line PC3-PSMA and the endogenously PSMA-expressing LNCaP cells were demonstrated by increased cellular uptake of the radioligand. For PC3-PSMA cells, the fraction of cell-bound radioactivity was enhanced by about 20-fold compared to that of the unstimulated cells. Our study reveals an increased radioligand uptake mediated by stimulation for both PC3-PSMA and LNCaP cell lines. In perspective of an enhanced PSMA expression, the present study might contribute to advanced radionuclide therapy approaches that improve the therapeutic efficacy, as well as combined treatment options.

Genetic Code Expansion for Site-Specific Labeling of Antibodies with Radioisotopes.

Due to their target specificity, antibody-drug conjugates─monoclonal antibodies conjugated to a cytotoxic moiety─are efficient therapeutics that can kill malignant cells overexpressing a target gene. Linking an antibody with radioisotopes (radioimmunoconjugates) enables powerful diagnostics and/or closely related therapeutic applications, depending on the isotope. To generate site-specific radioimmunoconjugates, we utilized genetic code expansion and subsequent conjugation by inverse electron-demand Diels-Alder cycloaddition reactions. We show that, using this approach, site-specific labeling of trastuzumab with either zirconium-89 (89Zr) for diagnostics or lutetium-177 (177Lu) for therapeutics yields efficient radioimmunoconjugates. Positron emission tomography imaging revealed a high accumulation of site-specifically 89Zr-labeled trastuzumab in tumors after 24 h and low accumulation in other organs. The corresponding 177Lu-trastuzumab radioimmunoconjugates were comparably distributed in vivo.

PET/CT reading for relapse in non-small cell lung cancer after chemoradiotherapy in the PET-Plan trial cohort.

BACKGROUND: Current studies indicate that fluorine-18-fluorodeoxyglucose positron emission tomography/ computed tomography ([18F]FDG PET/CT) is the most accurate imaging modality for the detection of relapsed locally advanced non-small cell lung cancer (NSCLC) after curatively intended chemoradiotherapy. To this day, there is no objective and reproducible definition for the diagnosis of disease recurrence in PET/CT, the reading of which is relevantly influenced by post radiation inflammatory processes. The aim of this study was to evaluate and compare visual and threshold-based semi-automated evaluation criteria for the assessment of suspected tumor recurrence in a well-defined study population investigated during the randomized clinical PET-Plan trial. METHODS: This retrospective analysis comprises 114 PET/CT data sets of 82 patients from the PET-Plan multi-center study cohort who underwent [18F]FDG PET/CT imaging at different timepoints for relapse, as suspected by CT. Scans were first analyzed visually by four blinded readers using a binary scoring system for each possible localization and the associated reader certainty of the evaluation. Visual evaluations were conducted repeatedly without and with additional knowledge of the initial staging PET and radiotherapy delineation volumes. In a second step, uptake was measured quantitatively using maximum standardized uptake value (SUVmax), peak standardized uptake value corrected for lean body mass (SULpeak), and a liver threshold-based quantitative assessment model. Resulting sensitivity and specificity for relapse detection were compared to the findings in the visual assessment. The gold standard of recurrence was independently defined by prospective study routine including external reviewers using CT, PET, biopsies and clinical course of the disease. RESULTS: Overall interobserver agreement (IOA) of the visual assessment was moderate with a high difference between secure (ĸ = 0.66) and insecure (ĸ = 0.24) evaluations. Additional knowledge of the initial staging PET and radiotherapy delineation volumes improved the sensitivity (0.85 vs 0.92) but did not show significant impact on the specificity (0.86 vs 0.89). PET parameters SUVmax and SULpeak showed lower accuracy compared to the visual assessment, whereas threshold-based reading showed similar sensitivity (0.86) and higher specificity (0.97). CONCLUSION: Visual assessment especially if associated with high reader certainty shows very high interobserver agreement and high accuracy that can be further increased by baseline PET/CT information. The implementation of a patient individual liver threshold value definition, similar to the threshold definition in PERCIST, offers a more standardized method matching the accuracy of experienced readers albeit not providing further improvement of accuracy.

Late-Onset Prosthetic Endocarditis with Paraaortic Abscess Caused by Cutibacterium acnes.

Cutibacterium acnes, an integral component of the skin's customary bacterial flora, represents a Gram-positive anaerobic bacterium characterized by its low virulence. Despite its low virulence, the pathogen can cause profound-seated infections as well as infections linked to medical devices. We report a case study of a prosthesis endocarditis accompanied by a paraaortic abscess caused by C. acnes, a development occurring five years prior to composite aortic root and valve replacement. At the point of admission, the patient presented with a combination of symptoms hinting at a subacute progression, such as weight loss, chest pain, and limitations of cardiopulmonary functionality. An anaerobic pathogen, namely C. acnes, was detected in a singular blood culture vial. Since first-line imaging modalities such as echocardiography did not reveal any signs of inflammation, and in the case of a suspected diagnosis for IE, did not show high pretest probability, further diagnostic imaging such as 18F-FDG PET CT was put to use. Here, a highly elevated glucose metabolism around the aortic valve ring was detected, pointing to an inflammatory process. The patient received adjusted intravenous antibiotic therapy over a course of six weeks; he then underwent surgical therapy via re-replacement of the aortic root and valve using a composite conduit. Advanced microbiological analyses, including the amplification of PCR and valve sequencing via 16S rDNA, mainly detected one pathogen: C. acnes. Delayed onset with mild symptoms and laboratory findings is characteristic of infective endocarditis by C. acnes. Due to its high rate of complications, mortality, and morbidity, an infection should not be disregarded as contamination. Recommendations from different studies underline a combination of a positive blood culture and microbiological evidence to differentiate between contamination and true infection in the case of an infection involving C. acnes. Serial blood cultures with prolonged incubation, advanced microbiological analyses, and modified Duke criteria including second-line imaging techniques should be utilized for further evaluation.

Real-Life Experience in the Treatment of Intrahepatic Cholangiocarcinoma by 90Y Radioembolization: A Multicenter Retrospective Study.

Limited treatment options in patients with intrahepatic cholangiocarcinoma (iCCA) demand the introduction of new, catheter-based treatment options. Especially, 90Y radioembolization may expand therapeutic abilities beyond surgery or chemotherapy. Therefore, the purpose of this study was to identify factors associated with an improved median overall survival (mOS) in iCCA patients receiving radioembolization in a retrospective study at 5 major tertiary-care centers. Methods: In total, 138 radioembolizations in 128 patients with iCCA (female, 47.7%; male, 52.3%; mean age ± SD, 61.1 ± 13.4 y) were analyzed. Clinical data, imaging characteristics, and radioembolization reports, as well as data from RECIST, version 1.1, analysis performed 3, 6, and 12 mo after radioembolization, were collected. mOS was compared among different subgroups using Kaplan-Meier curves and the log-rank test. Results: Radioembolization was performed as first-line treatment in 25.4%, as second-line treatment in 38.4%, and as salvage treatment in 36.2%. In patients receiving first-line, second-line, and salvage radioembolization, the disease control rate was 68.6%, 52.8%, and 54.0% after 3 mo; 31.4%, 15.1%, and 12.0% after 6 mo; and 17.1%, 5.7%, and 6.0% after 1 y, respectively. In patients receiving radioembolization as first-line, second-line, and salvage treatment, mOS was 12.0 mo (95% CI, 7.6-23.4 mo), 11.8 mo (95% CI, 9.1-16.6 mo), and 8.4 mo (95% CI, 6.3-12.7 mo), respectively. No significant differences among the 3 groups were observed (P = 0.15). Hepatic tumor burden did not significantly influence mOS (P = 0.12). Conclusion: Especially in advanced iCCA, second-line and salvage radioembolization may be important treatment options. In addition to ongoing studies investigating the role of radioembolization as first-line treatment, the role of radioembolization in the later treatment stages of the disease demands further attention.

Alpha emitting nuclides in nuclear medicine theranostics.

Theranostic applications with radio-isotopes currently are rapidly progressing and expand nuclear medicine application in clinical routine. Alpha emitting isotopes, in particular, have long been hypothesized to achieve relevant advances for the treatment of malignancies. Here, an overview of their properties and the knowledge of radiobiology is reviewed in view of clinical translation. Clinical evidence of radiopharmaceuticals based on alpha emitters is summarized with a focus on recent developments for treatment of metastasized castration resistant prostate cancer.