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In locally advanced lung cancer, established baseline clinical variables show limited prognostic accuracy and 18F-fluorodeoxyglucose positron emission tomography (FDG PET) radiomics features may increase accuracy for optimal treatment selection. Their robustness and added value relative to current clinical factors are unknown. Hence, we identify robust and independent PET radiomics features that may have complementary value in predicting survival endpoints. A 4D PET dataset (n = 70) was used for assessing the repeatability (Bland-Altman analysis) and independence of PET radiomics features (Spearman rank: |ρ|<0.5). Two 3D PET datasets combined (n = 252) were used for training and validation of an elastic net regularized generalized logistic regression model (GLM) based on a selection of clinical and robust independent PET radiomics features (GLMall). The fitted model performance was externally validated (n = 40). The performance of GLMall (measured with area under the receiver operating characteristic curve, AUC) was highest in predicting 2-year overall survival (0.66±0.07). No significant improvement was observed for GLMall compared to a model containing only PET radiomics features or only clinical variables for any clinical endpoint. External validation of GLMall led to AUC values no higher than 0.55 for any clinical endpoint. In this study, robust independent FDG PET radiomics features did not have complementary value in predicting survival endpoints in lung cancer patients. Improving risk stratification and clinical decision making based on clinical variables and PET radiomics features has still been proven difficult in locally advanced lung cancer patients.

Using reliable techniques for detecting lymph node metastases (LNM) in oral squamous cell carcinoma (OSCC) is crucial for adequate neck treatment. Currently, palpation of the neck, computed tomography, magnetic resonance imaging, ultrasound-guided fine needle aspiration cytology and/or sentinel lymph node biopsy (SLNB) are used to stage the neck in early-stage OSCC. SLNB is a reliable diagnostic technique to detect occult LNM. However, management of the neck with SLNB has its limitations. First of all, SLNB is an invasive procedure with associated morbidity and approximately 20–30% of patients require a subsequent neck dissection. Moreover, performing a subsequent neck dissection is more complex than elective neck dissection, and carries a higher risk of complications. Therefore, it is important to improve patient selection for SLNB. Fluor-18-fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography/computed tomography (PET/CT) has shown promising results for LNM detection. The aim of the PETN0 study, a prospective Dutch multicenter cohort study (registration number NL83442.041.22), is to reduce the need for SLNB by developing scoring criteria for [ 18 F]FDG PET/CT with a high positive predictive value (PPV) in patients with early-stage OSCC. Developing scoring criteria for a high PPV can reduce SLNBs and second-stage neck dissections by performing a neck dissection together with resection of the primary tumor in patients with predicted LNM. When focused on high PPV the sensitivity will probably be lower, but missed LNM will be detected by SLNB when performed after negative [ 18 F]FDG PET/CT. Patients (n = 159) with cT1-3N0 OSCC (8 th TNM edition; only when T3 is assessed based on tumor dimensions of >2 and ≤4 cm, with DOI > 10 mm), candidate for transoral excision and SLNB, are included in the study. [ 18 F]FDG PET/CT will be conducted within a maximum of three weeks before SLNB. A cost-effectiveness analysis will also be performed, together with quality of life assessment using questionnaires.

Background Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29–47%. [ 177 Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [ 177 Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields. Methods The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [ 177 Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [ 177 Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [ 177 Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [ 177 Lu]Lu-PSMA-617. Discussion This is the first prospective study to combine EBRT and ADT with [ 177 Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [ 177 Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments. Trial registration ClinicalTrials, NCT05162573 . Registered 7 October 2021.

Background The majority of patients with head and neck squamous cell carcinoma (HNSCC) receive bilateral elective nodal irradiation (ENI), in order to reduce the risk of regional failure. Bilateral ENI, as compared to unilateral ENI, is associated with higher incidence of acute and late radiation-induced toxicity with subsequent deterioration of quality of life. Increasing evidence that the incidence of contralateral regional failure (cRF) in lateralized HNSCC is very low (< 10%) suggests that it can be justified to treat selected patients unilaterally. This trial aims to minimize the proportion of patients that undergo bilateral ENI, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation. Methods In this one-armed, single-center prospective trial, patients with primary T1-4 N0-2b HNSCC of the oral cavity, oropharynx, larynx (except T1 glottic) or hypopharynx, not extending beyond the midline and planned for primary (chemo) radiotherapy, are eligible. After 99m Tc-nanocolloid tracer injection in and around the tumor, lymphatic drainage is visualized using SPECT/CT. In case of contralateral lymph drainage, a contralateral sentinel node procedure is performed on the same day. Patients without contralateral lymph drainage, and patients with contralateral drainage but without pathologic involvement of any removed contralateral sentinel nodes, receive unilateral ENI. Only when tumor cells are found in a contralateral sentinel node the patient will be treated with bilateral ENI. The primary endpoint is cumulative incidence of cRF at 1 and 2 years after treatment. Secondary endpoints are radiation-related toxicity and quality of life. The removed lymph nodes will be studied to determine the prevalence of occult metastatic disease in contralateral sentinel nodes. Discussion This single-center prospective trial aims to reduce the incidence and duration of radiation-related toxicities and improve quality of life of HNSCC patients, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation. Trial registration ClinicalTrials.gov Identifier: NCT03968679 , date of registration: May 30, 2019.

Background The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177 Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials Two important changes were made to the original protocol: (1) the study will now use 177 Lu-PSMA-617 instead of 177 Lu-PSMA-I&T and (2) responding patients with residual disease on 18 F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177 Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177 Lu-PSMA-617 will also receive an interim 18 F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177 Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020.

Background Radiolabeled [ 195m Pt]cisplatin has been developed as a tool to determine the biodistribution of cisplatin in vivo through SPECT imaging and possibly aid in patient-selection. This feasibility study aimed to evaluate the (radiation) safety, biodistribution, and image quality of [ 195m Pt]cisplatin SPECT/CT in patients with non-small cell lung cancer (NSCLC). [ 195m Pt]Cisplatin was produced under GMP standards. Six patients received 100 MBq [ 195m Pt]cisplatin in their second or third week of chemoradiation therapy. Planar and SPECT/CT imaging were acquired at 1.5, 48, 120 and 168 h post-administration. Segmentation on SPECT for biodistribution and dosimetry was achieved using TotalSegmentator in 3DSlicer, and organ specific time-activity curves were generated through a mono-exponential curve fit. Effective and absorbed doses were obtained with S-values from IDAC-Dose 2.1. Toxicity was assessed using CTCAE criteria. Results Six NSCLC patients received 100.9 ± 3.3 MBq [ 195m Pt]cisplatin at a radioactivity concentration of 11.1 ± 4.9 MBq/mL. No adverse events above grade 2 were observed. [ 195m Pt]Cisplatin had a long retention time with an effective half-life of 74.8 h. Uptake was highest in the liver and kidneys, which also resulted in the highest absorbed dose at 48.6 ± 7.9 mGy and 38.4 ± 7.3 mGy, respectively. Tumor uptake was similar to blood, with a ratio of 1.0 ± 0.05. Conclusion [ 195m Pt]Cisplatin is safe to use for imaging in patients with NSCLC when injecting 100 MBq, reaching a mean effective dose of 14.6 ± 1.5 mSv. The image quality of [ 195m Pt]cisplatin was suitable for SPECT imaging and quantification. Tumor uptake was similar to blood. Trial registration CCMO, NL74272.031.21. Registered 28 January 2022, https://www.onderzoekmetmensen.nl/nl/trial/55147 .

Introduction: Xerostomia is a well-known complication after iodine-131 (131I) therapy for thyroid carcinoma. It is currently insufficiently understood how the dose and biodistribution of 131I relates to salivary gland toxicity, and whether this is consistent for all salivary glands within a single patient. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) was recently introduced as a new tool to evaluate the relative loss of vital acinar cells in individual salivary glands. We aimed to assess gland-specific salivary gland toxicity after 131I-therapy using PSMA PET/CT. Methods: Five patients with differentiated thyroid cancer underwent [68Ga]Ga-PSMA-11 PET/CT to evaluate their eligibility for peptide radioligand therapy with [177Lu]Lu-PSMA-617. Uptake patterns in salivary glands were evaluated visually and quantitatively as an indicator of vital acinar cell loss after prior 131I-therapy. Results: Four of 5 patients demonstrated significant lowered uptake in at least one salivary gland, after receiving at least 2 131I-treatments. Asymmetric loss of vital acinar cells occurred by gland type (parotid/submandibular) and location (right/left). The other salivary glands in these patients and all salivary glands in the fifth patient showed normal uptake, demonstrating high intrapatient and interpatient variability. Conclusions: 131I-therapy can induce salivary gland toxicity with high inter- but also high intrapatient variation among separate gland locations, which can be assessed with PSMA PET/CT. This new technique offers potential to guide further development and evaluation of protective measures in patients receiving 131I-therapy.

Aims In vivo biodistribution imaging of platinum-based compounds may allow better patient selection for treatment with chemo(radio)therapy. Radiolabeling with Platinum-195m ( 195m Pt) allows SPECT imaging, without altering the chemical structure or biological activity of the compound. We have assessed the feasibility of 195m Pt SPECT imaging in mice, with the aim to determine the image quality and accuracy of quantification for current preclinical imaging equipment. Methods Enriched (>96%) 194 Pt was irradiated in the High Flux Reactor (HFR) in Petten, The Netherlands (NRG). A 0.05 M HCl 195m Pt-solution with a specific activity of 33 MBq/mg was obtained. Image quality was assessed for the NanoSPECT/CT (Bioscan Inc., Washington DC, USA) and U-SPECT + /CT (MILabs BV, Utrecht, the Netherlands) scanners. A radioactivity-filled rod phantom (rod diameter 0.85-1.7 mm) filled with 1 MBq 195m Pt was scanned with different acquisition durations (10-120 min). Four healthy mice were injected intravenously with 3-4 MBq 195m Pt. Mouse images were acquired with the NanoSPECT for 120 min at 0, 2, 4, or 24 h after injection. Organs were delineated to quantify 195m Pt concentrations. Immediately after scanning, the mice were sacrificed, and the platinum concentration was determined in organs using a gamma counter and graphite furnace – atomic absorption spectroscopy (GF-AAS) as reference standards. Results A 30-min acquisition of the phantom provided visually adequate image quality for both scanners. The smallest visible rods were 0.95 mm in diameter on the NanoSPECT and 0.85 mm in diameter on the U-SPECT + . The image quality in mice was visually adequate. Uptake was seen in the kidneys with excretion to the bladder, and in the liver, blood, and intestine. No uptake was seen in the brain. The Spearman correlation between SPECT and gamma counter was 0.92, between SPECT and GF-AAS it was 0.84, and between GF-AAS and gamma counter it was0.97 (all p  < 0.0001). Conclusion Preclinical 195m Pt SPECT is feasible with acceptable tracer doses and acquisition times, and provides good image quality and accurate signal quantification.

BackgroundHigh urinary activity in urinary bladder and ureters may hamper interpretation of prostate cancer and regional nodal metastases in prostate-specific membrane antigen (PSMA) PET/CT. The goal of this study was to assess effects of furosemide and choice of tracer on urinary activity in the bladder and ureters, as well as on occurrence of peri-bladder artefacts in PET/CT.MethodsFour cohorts with a total of 202 men staged with PSMA PET/CT for prostate cancer received either 68Ga-PSMA-11 as tracer, with (cohort G+) or without 10mg intravenous furosemide (G−) concurrent with tracer, or 18F-DCFPyL with (F+) or without furosemide (F−). SUVmax of bladder and ureters, presence, type, and severity of peri-bladder artefacts were compared between cohorts. The influence of furosemide and choice of tracer was determined while taking differences in biodistribution time into account.ResultsMedian SUVmax bladder was 43,5; 14,8; 61,7 and 22,8 in cohorts G−, G+, F− and F+, respectively, resulting in significant overall (p < 0.001) and between cohort differences (p adjusted < 0.001 to 0.003) except between G− and F+. Median SUVmax ureter was 6.4; 4.5; 8.1 and 6.0 in cohorts G−, G+, F− and F+, respectively, resulting in significant overall (p < 0.001) and between cohort differences for G+ : F− and F− : F+ (p < 0.001, respectively, 0.019). Significant effects of furosemide and choice of tracer on SUVmax bladder (p < 0.001 resp. p = 0.001) and of furosemide on SUVmax ureter (p < 0.001) were found, whereas differences in biodistribution time had not impacted these results significantly. Peri-bladder artefacts were present in 42/202 (21%) patients and were significantly more frequent in the F− cohort, respectively, less frequent in the G+ cohort (p = 0.001 resp. p < 0.001). Peri-bladder artefacts had a direct positive correlation with SUVmax bladder (p = 0.033).ConclusionsIncreased urinary activity and higher incidence of peri-bladder artefacts were found in 18F-DCFPyL compared to 68Ga-PSMA-11 PET/CT. Effective reduction of urinary activity may be reached through forced diuresis using 10mg intravenous furosemide, which is especially advantageous in 18F-DCFPyL PET/CT.

Background [ 18 F]FDG PET/CT plays a crucial role in evaluating cancer patients and assessing treatment response, including in BRAF-mutated melanoma. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have emerged as promising alternatives to standardized uptake value (SUV)-based measures for tumor assessment. This study evaluates the predictive value of SUVpeak, MTV, and TLG in predicting progression-free survival (PFS) in advanced BRAF-mutated melanoma treated with BRAF/MEK inhibitors. Results Seventy-five patients with metastatic melanoma were enrolled in a multi-center trial and treated with vemurafenib/cobimetinib. [ 18 F]FDG-PET/CT scans were performed at baseline, week-2, and week-7. Imaging analysis included SUVpeak, MTV, and TLG of summed metastases, as well as percentage changes over time (∆). Baseline median PET-parameters were SUVpeak 12.59 (range 3.13–50.59), MTV 159mL (range 0-1897 mL), and TLG 1013 (range 1-13162). Baseline MTV was the strongest predictor (AUC T=6 months =0.714), while early changes in MTV, TLG, and especially week-7 ΔSUVpeak% showed similar or improved performance ( P  = 0.017 vs. baseline SUVpeak). Patients with TLG below the median had significantly prolonged PFS (15.4 vs. 8.5 months, P  = 0.024). MTV above optimal cutoff (45.3 mL) was associated with an increased risk of progression/death, even after adjusting for LDH, ECOG status, and metastatic sites (HR = 2.97, 95% CI 1.17–7.52, P  = 0.022). At week-2, ∆SUVpeak% was not predictive in a multivariable analysis, but became predictive at week-7 (median ∆SUVpeak%: 64), with a more than three-fold hazard of progression for patients with ∆SUVpeak% below 64% ( P  = 0.0014); PFS was 5.0 months (95% CI: 4.3-NA) for patients below the median versus 14.7 months (95% CI: 9.2–20.2) for those above or with non-quantifiable scans ( P  = 0.0002). Median ∆MTV was 95.5% at week-2 and 97.6% at week-7, with significant PFS differences at both time points (week-2: P  = 0.020, week-7: P  < 0.001). As expected, TLG mirrored MTV. Patients with MTV increases at week-7 after an initial response at week-2 had a median PFS of 5.3 vs. 12.6 months for those with stable or declining MTV ( P  = 0.0023). Intra-patient metabolic heterogeneity was also associated with outcome, with early reductions in SUVpeak variation between lesions correlating with better PFS. Conclusion This study supports the use of MTV and TLG as robust predictive markers for PFS in advanced melanoma treated with BRAF/MEK-inhibitors. Monitoring early PET parameters changes can provide valuable insights into therapeutic response and disease progression. Trial registration Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.