This study aimed to analyze survival outcomes in patients with differentiated thyroid cancer (DTC) compared to the general population, with particular focus on sex distribution, UICC staging, and age-specific mortality patterns. A retrospective survival analysis was conducted on 3186 DTC patients with extended follow-up. Overall survival (OS) and relative survival (RS; observed survival in patients/expected survival in population) were compared to age- and sex-matched general population data, using Monte-Carlo simulation. Multivariate Cox regression analysis was performed to identify independent prognostic factors. Female predominance was confirmed in younger age groups with balanced distribution in the 40- to < 55-year cohort. DTC patients demonstrated superior OS compared to the general population, with improving RS over time. Female patients showed better survival outcomes than males and exceeded general population survival, while male patients achieved comparable survival. UICC stage I showed significantly lower mortality than all other stages. Only stage IVb consistently demonstrated worse outcomes than the general population. All age groups showed equal to superior survival compared to the general population, with patients ≥ 55 years demonstrating significantly improved RS from 5 years onward. Multivariate analysis identified sex, age at diagnosis, and UICC stage as independent prognostic factors for death. This analysis confirms generally favorable prognosis for DTC patients, demonstrating superior survival compared to the general population, due to increased health consciousness but also reflects the highly effective therapeutic regimen. Only patients ≥ 55 years with distant metastases (UICC stage IVb) consistently showed worse survival than the general population, emphasizing the critical importance of preventing disease progression.

BACKGROUND:Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([177Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs. METHODS:This phase 3, open-label, superiority trial included patients aged 18 years or older with treatment-naive or previously treated unresectable or metastatic (or both) grade 1-2 GEP NETs. Patients were enrolled from 49 specialist neuroendocrine tumour treatment centres across 14 countries in Africa, Europe, North America, and Oceania and randomised (2:1) to intravenous [177Lu]Lu-edotreotide (7·5 ± 0·7 GBq every 3 months, maximum four cycles) or oral everolimus (10 mg/day) for up to 30 months. Random assignment was via a central, web-based randomisation system (block size of 6) and stratified by primary tumour origin and previous therapy. The primary endpoint was progression-free survival, assessed via blinded independent central review in all randomly assigned patients at 30 months. Harms were assessed in all enrolled patients who received at least one dose of a study drug. This study was registered with ClinicalTrials.gov (NCT03049189) and is no longer recruiting. FINDINGS:Between April 13, 2017, and June 20, 2022, 324 patients were enrolled and 309 patients (including 168 [54%] male patients and 141 [46%] female patients) were randomly assigned to treatment: 207 to the [177Lu]Lu-edotreotide group and 102 to the everolimus group. The median follow-up for progression-free survival was 27·5 months (IQR 19·6-30·4) for the [177Lu]Lu-edotreotide group and 21·2 months (8·9-29·4) for the everolimus group. Median progression-free survival was significantly longer with [177Lu]Lu-edotreotide versus everolimus (23·9 months [95% CI 18·7-30·0] vs 14·1 months [9·2-20·9]; stratified hazard ratio 0·67 [95% CI 0·48-0·95]; p=0·022). Treatment-related adverse events occurred in 178 (82%) of 217 patients in the [177Lu]Lu-edotreotide group and 96 (97%) of 99 patients in the everolimus group. 40 (18%) patients in the [177Lu]Lu-edotreotide group and 40 (40%) in the everolimus group had at least one treatment-related grade 3-4 adverse event. The most common treatment-related adverse events in the [177Lu]Lu-edotreotide group were diarrhoea and nausea (both 79 [36%] patients) and asthenia (66 [33%] patients), whereas those in the everolimus group were diarrhoea (45 [45%] patients), asthenia (36 [36%] patients), and anaemia (27 [27%] patients). No treatment-related deaths occurred in either study group. INTERPRETATION:[177Lu]Lu-edotreotide led to statistically significant and clinically meaningful improvements in progression-free survival. Efficacy and harms results support the use of [177Lu]Lu-edotreotide in early lines of therapy in patients with advanced, progressive GEP NETs. FUNDING:ITM Solucin.

High expression of prostate-specific membrane antigen (PSMA) is not limited to prostate cancer but can be found in other tumor entities, such as hepatocellular carcinoma (HCC), and could possibly be used for theranostic purposes. Our aim was to investigate the diagnostic potential of the hepatobiliary excreted radiotracer [18F]PSMA-1007 on initial staging of HCC. Methods: This prospective clinical study (NCT05547919) included 10 participants (9 men, 1 woman) with treatment-naïve, histopathologically proven PSMA-positive HCC. All participants underwent [18F]PSMA-1007 PET with unenhanced low-dose CT. All scans were analyzed visually and quantitatively. We assessed the SUVmax of the primary tumor and the SUVmean of nonaffected liver parenchyma and calculated tumor-to-background ratios (i.e., SUVmax HCC/SUVmean liver) for each patient. In addition, we assessed possible eligibility for PSMA-directed radiopharmaceutical therapy according to the PROMISE criteria. The presence of local lymph nodes and distant metastases was noted for [18F]PSMA-1007 PET/CT and compared with the results of contrast-enhanced CT of the trunk and MRI of the upper abdomen. Possible prognostic implications of PSMA expression on immunohistochemistry and on [18F]PSMA-1007 PET/CT were compared with progression-free survival (defined as clinical progression, radiographic progression, or death from any cause) using Cox regression. Results: [18F]PSMA-1007 PET showed high uptake in 7 of 10 patients (PROMISE score 2, n = 4; PROMISE score 3, n = 3); mediocre or missing uptake was found in 3 participants (PROMISE score 0, n = 1; PROMISE score 1, n = 2). The median tumor-to-background ratio was 2.7 (interquartile range, 2.65). [18F]PSMA-1007 PET did not reveal new distant metastatic lesions compared with contrast-enhanced CT. In 1 patient, local lymph node metastases were considered PSMA-negative despite high uptake in the primary tumor. Whether assessed ex vivo or in vivo, PSMA expression did not correlate with progression-free survival. Conclusion: [18F]PSMA-1007 can be used depict untreated HCC and shows high uptake relative to background, indicative of excellent image contrast. High tracer accumulation in 70% of the participants suggests a possible use for PSMA-directed radiopharmaceutical therapy in an end-stage setting. However, PSMA expression was not prognostic for outcome, possibly because of the small sample size.

Aim:This review aims to explore the evolving field of theranostics in oncology, focusing on its potential application to head and neck squamous cell carcinoma (HNSCC). Specifically, it examines the integration of molecular imaging and radionuclide therapy in the context of theranostics. Methods:A comprehensive review of current literature was conducted to evaluate the state-of-the-art theranostic approaches in HNSCC. The review includes an analysis of established and emerging molecular targets relevant to HNSCC, as well as the potential for future theranostic developments. Results:The integration of theranostic principles into head and neck oncology is gaining momentum, with increasing interest in novel targets in the context of theranostics. Although [18F]FDG PET/CT still remains the dominant imaging modality in HNSCC, the application of novel radiotracers for imaging and radionuclide therapy holds considerable promise. Conclusion:Theranostics represents a promising future for head and neck oncology, offering the potential for personalized, biology-driven diagnostic and therapeutic strategies. While many emerging approaches are still under investigation, the combination of molecular imaging and targeted radionuclide therapy may significantly enhance the treatment of HNSCC, providing more precise and effective patient care in the future.1.

Purpose: To establish the extent, distribution and frequency of in-vivo vessel wall [68Ga]Ga-PentixaFor uptake and to determine its relationship with calcified atherosclerotic plaque burden (CAP) and cardiovascular risk factors (CVRF). Methods: 65 oncological patients undergoing [Ga-68]Ga-PentixaFor PET/CT were assessed. Radiotracer uptake (target-to-background ratio [TBR]) and CAP burden (including number of CAP sites, calcification circumference and thickness) in seven major vessel segments per patient were determined. We then investigated associations of vessel wall uptake with CAP burden, cardiovascular risk (CVRF and European Society of Cardiology [ESC] SCORE2/SCORE2-OP risk chart) and image noise (determined by coefficient of variation [CoV] from unaffected liver parenchyma). Results: We identified 1292 sites of high focal [Ga-68]Ga-PentixaFor uptake (PentixaFor+ sites) in the vessel wall in 65/65 (100%) patients, with concomitant calcification in 385/1292 (29.8%) sites. There were no significant associations between vessel wall uptake and CAP burden (number of PentixaFor+ sites: r <= 0.18, P >= 0.14; PentixaFor+ TBR: r <= 0.08, P >= 0.54). The number of PentixaFor+ sites showed a moderate correlation with cardiovascular risk (ESC SCORE2/SCORE2-OP, r = 0.30; number of CVRF, r = 0.26; P = 0.04, respectively), but failed to reach significance for PentixaFor+ TBR (r <= 0.18, P >= 0.22). In univariable regression analysis, body mass index (odds ratio [OR] 1.08, 95%-confidence interval [CI] 1.02-1.14) and CoV (OR, 1.07; CI, 1.05-1.10) were linked to TBR and the number of PentixaFor+ sites (P < 0.01, respectively), while injected activity was only associated with the latter imaging parameter (OR, 0.99; CI, 0.98-1.00; P = 0.04). In multivariable regression, injected activity (OR, 1.00; CI, 0.99-1.00) and CoV (OR, 1.06; CI, 1.06-1.07) remained significantly associated with the number of PentixaFor+ sites (P < 0.01, respectively). CoV, however, was the only parameter significantly linked to PentixaFor+ TBR on multivariable analysis (OR, 1.02; CI, 1.01-1.03; P < 0.01). Conclusion: On a visual and quantitative level, high focal [Ga-68]Ga-PentixaFor uptake in the arterial tree was not consistently linked to vessel wall calcification or cardiovascular risk. Image noise, however, may account for a substantial portion of apparent vessel wall uptake.

BACKGROUND:We aim to report on somatostatin receptor (SSTR)-targeted molecular imaging and therapy in patients with advanced esthesioneuroblastoma (ENB). PATIENTS AND METHODS:Five patients with ENB [Kadish stage D in 5/5 (100%); Hyams grade 2 in 2/5 (40%), grade 3 in 2/5 (40%), undetermined in 1/5 (20%)] underwent SSTR-directed PET/CT. We quantified SSTR-avid tumor volume (TV), maximum SUV (SUV max ), and target-to-background ratios (TBR). Based on imaging, peptide receptor radionuclide therapy (PRRT) along with dosimetry was also conducted. We recorded nephrotoxicity and hematotoxicity, including estimated glomerular filtration rate (eGFR), hemoglobin, leukocytes, and thrombocytes at baseline and after the last treatment cycle. We determined adverse events following Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response and progression-free survival (PFS) was also evaluated. RESULTS:All 5 patients were rated positive on SSTR-PET/CT. On a lesion-based level, we identified 32 SSTR-avid tumor sites with a median TV of 11.7±10.8 and SUV max of 24.3±12.8. TBR was 19.8±9.7, indicating excellent image contrast. After median 4 (range, 2-6) cycles with a median of 7.7 GBq per cycle per patient, we observed no CTCAE grade 3 or 4 toxicity for leukocytes and thrombocytes and no significant CTCAE events for renal function. One patient (20%), however, developed reversible grade 3 anemia. Up to 11.8 Gy in tumor lesions were achieved. Partial response was recorded in 3/5 (60%), stable disease in 1/5 (20%), and progressive disease in 1/5 (20%). The median PFS was 29 weeks. CONCLUSIONS:SSTR-directed PET provided high image contrast in ENB, suggesting good read-out capabilities in this tumor type. PRRT was also feasible, along with an acceptable safety profile, thereby rendering SSTR-targeted theranostics a potential treatment option in advanced disease.

We report on a patient diagnosed with Hodgkin Lymphoma who was scheduled for [18F]FDG PET/CT as part of routine follow-up after treatment with two cycles of chemotherapy and mediastinal external beam radiation. Although the patient was advised to fast for at least four hours, an energy drink (Red Bull ) was ingested right after radiotracer administration, which led to increased uptake in the large skeletal muscles, thereby rendering this scan as non-diagnostic. After strictly following respective dietary recommendations, the repeated scan then provided excellent image quality and revealed response to treatment. In the present case report, we discuss the impact of major ingredients (sugar, caffeine, taurine, glucuronolactone) of Red Bull on large muscle uptake, which may also apply to "sugar-free" types of this popular energy drink. Moreover, this case reports demonstrates the importance to inform patients that they should avoid intake of energy drinks not only prior to but also after injection of [18F]FDG.

Desmoplastic small round blue cell tumor (DSRCT) is a highly aggressive fatal sarcoma without evidence-based therapeutic guidelines. We present here seven patients with DSRCT including immunohistochemistry combined with fluorescence in situ hybridization (FISH), next generation sequencing (NGS, n = 6) as well as OncoScan array (n = 3) analyses and show consecutive therapeutic approaches. All seven DSRCT patients presented with an extended abdominal mass; median age at diagnosis was 24.8 years. NGS analyses revealed five class 4 or 5 sequence variants. Remarkably, OncoScan and targeted analyses by FISH identified genomic gains of CCND1 in two cases. Cyclin D1 expression was present in all seven tumors as shown by immunohistochemical staining. Multimodal therapeutic concepts included systemic therapies, resection, and radiation. Six patients were treated as first-line therapy with conventional chemotherapy. All except one patient had a dismal therapy response. Subsequent therapy lines consisted of chemotherapeutic combinations followed by targeted therapies. Due to Cyclin D1 expression, the CDK4/6 inhibitor palbociclib was applied to four patients. The median therapy duration until disease progression in these patients was 4.5 months (range, 1.5-5 months). So, CCND1 genomic gain and Cyclin D1 expression are common features pointing to cell-cycle deregulation as a possible therapeutic target.

In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [68Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters. We identified 41 metastasized ACC patients imaged with [68Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded. After [68Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1–96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95

C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in a multitude of cancers, including neoplasms of hematopoietic origin. This feature can be leveraged by a theranostic approach, which provides a read-out of the actual CXCR4 expression in vivo, followed by CXCR4-targeted radioligand therapy (RLT) exerting anti-cancer as well as myeloablative efficacy. In a recent meeting of hematooncology and nuclear medicine specialists, statements on the current clinical practice and future perspectives of this innovative concept were proposed and summarized in this opinion article. Experts concluded that i) CXCR4-directed [68Ga]Ga-PentixaFor PET/CT has the potential to improve imaging for patients with marginal zone lymphoma; ii) CXCR4-targeted RLT exerts anti-lymphoma efficacy and myeloablative effects in patients with advanced, treatment-refractory T-cell lymphomas; iii) prospective trials with CXCR4-based imaging and theranostics are warranted.

Introduction: The use of ciltacabtagen autoleucel (cilta-cel) in RRMM patients within the CARTITUDE-1 study has exposed previously unknown late onset neurotoxicities, referred to as movement, neurocognitive treatment emergent events (MNT) (Cohen, A et al., 2022). In addition to their late occurrence, MNTs are characterized by their failure to respond to standard therapy such as corticosteroids. Hence, this patient population (5.0 % in CARTITIUDE-1) is at high risk of severe and persistent neurological complications evoking the necessity for further research into the yet poorly understood pathophysiology of MNTs. So far, CAR-T “on-target-off-tumor”-toxicity due to BCMA expression in the basal ganglia has been proposed as one of the driving pathomechanisms of MNTs (Van Oekelen, O et al., 2021). We report the case of a 63-year-old male patient with IgA-kappa myeloma, who received 7 prior lines of treatment. Besides prolonged CRS °I, which was successfully managed by a single dose of tocilizumab, no other adverse events or signs of neurotoxicity occurred immediately post CAR-T infusion. Patient case and methods: 14 days post CAR-T infusion the patient presented with shakiness, subjective slowing of motor skills and concentration disorders. However, it was not until a second hospitalization period 30 days post CAR-T, when neurological examination confirmed a clinical syndrome of parkinsonism including bradykinesia, rigor, tremor and postural instability. Consistent with the clinical presentation, 123I-FP-CIT-SPECT-imaging revealed reduced presynaptic dopamine transporter density in the striatum. On day 54 after CAR-T, the patient developed a massive deterioration of parkinsonism reflected by an increased MDS-UPDRS part III score of 65. Ultimately, the patient was treated with intrathecal chemotherapy, dasatinib orally, cyclophosphamide and corticosteroids. From 149 days post CAR-T a slight improvement of parkinsonism was observed (MDS-UPDRS part III score of 32) following levodopa/benserazide delivery via PEG, and after achieving CAR-T eradication with prior therapies. Multimodal analysis, including flow cytometry, and simultaneous scRNA- and scTCR-seq, was performed on peripheral blood (PB) and cerebrospinal fluid (CSF) longitudinally to the course of illness. Results: CAR-T expansion in PB peaked in the first month post CAR-T (day 17: 7966.7 CAR-T/µl, day 30: 8299.6 CAR-T/µl), while peak infiltration of the CSF occurred at day 57 (367 cells/µl) coinciding with parkinsonism deterioration. Throughout the patient's course, CAR-T were the most abundant cell population in the CSF, with CD4+ CAR-T dominating at the beginning (day 17-30). We performed scRNA-seq and scTCR-seq on 7 longitudinally collected samples (d20-d143 post CAR-T) of the patient's CSF and 6 matched PB samples, collectively representing 74603 cells. CAR-T as well as non-CAR-T cells were present in the CSF with CAR-T proportions decreasing over time. CD8+ as well as CD4+ CAR-T showed marked expression of cytotoxicity associated genes (PRF1, granzymes, GNLY). While CAR-T did not clonally expand, scTCR-seq revealed clonally expanded CD8+ non-CAR-T in the CSF concurring with the deterioration of parkinsonism. Major CD8+ non-CAR-T clones were detectable from day 30 post CAR-T, albeit at low numbers, and were also detectable in the PB. Phenotypically, these clones were marked by the expression of cytotoxicity genes, and tissue residency markers (ZNF683). Cell-cell interaction inference indicated activating signaling of CD4+ CAR-T towards clonally expanded CD8+ non-CAR-T in CSF. Furthermore, we observed an increased interferon response in the CSF that preceded the deterioration of the patient, which was absent in PB. Notably, the interferon response was abrogated after treatment with dasatinib, consistent with reduced activation of CAR-T and non-CAR-T as determined by flow cytometry. Conclusion: Our longitudinal case study shows for the first time that CD4+ CAR-T are most likely the initiators of MNTs and that clonally expanded CD8+ non-CAR-T cells could drive the deterioration of parkinsonism. These findings are consistent with recent reports that CD8+ T cells promote neurodegeneration in other diseases. The coincidence of an interferon response with clinical worsening and the potential abrogation of this response by dasatinib requires further investigation.