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Introduction Immunotherapy with checkpoint inhibitors (CPIs) has revolutionised cancer treatment but has no convincing effect in metastatic castration-resistant prostate cancer (mCRPC). It has been suggested that a combination of CPI and hypofractionated stereotactic body radiotherapy (SBRT) may work synergistically, and recent trials have supported this. We hypothesise that adding SBRT to CPI treatment can improve response rates in patients with mCRPC. Methods and analysis The CheckPRO trial is an open-label, randomised, two-stage, phase II trial. We aim to enrol and randomise 80 evaluable patients with mCRPC who progressed following ≥2 lines of treatment. Enrolment started in November 2019 with 38 months expected enrolment period. The participants receive treatment for 52 weeks including four cycles of ipilimumab and nivolumab with or without concomitant SBRT (24 Gray in three fractions) to a single soft tissue or bone metastasis, followed by 10 cycles of nivolumab. Participants are followed until progression, death, or for 12 months after the end of treatment. Co-primary endpoints are the objective response rate and prostate-specific antigen (PSA) response rate. Secondary endpoints include safety, radiographic progression-free survival, clinical benefit rate, duration of response, PSA-progression-free survival beyond 12 weeks, quality of life and overall survival. Exploratory endpoints include translational analyses of tumour biopsies and consecutive blood samples. Biopsies from metastatic sites are collected at baseline, before the third treatment and at the end of treatment. Blood sampling for immune monitoring and circulating tumour DNA is performed consecutively at baseline and every radiographic assessment. Ethics and dissemination This study follows the Helsinki Declaration and is approved by the Danish Ethics Committee System (journal no. H-19016100). All participants must receive written and oral information and provide a signed informed consent docume

Background: The effect of routine imaging in melanoma surveillance is unknown. In 2016, Denmark was the first country in the world to implement routine imaging with positron emission tomography-computed tomography with fluorodeoxyglucose (FDG PET-CT) in a nationwide, population-based surveillance program. This study aimed to determine the impact of surveillance with routine FDG PET-CT on hazard, cumulative incidence, and absolute risk of overall, locoregional, and distant recurrence detection in patients with stage IIB to IIID cutaneous melanoma. Methods: This retrospective, population-based, nationwide cohort study used prospectively collected data from five national health registries to compare hazard, cumulative incidence, and absolute risk of recurrence in patients with cutaneous melanoma diagnosed in 2008–2010 (cohort 1, followed with clinical examinations) and patients with cutaneous melanoma diagnosed in 2016–2017 (cohort 2, followed with clinical examinations and routine FDG PET-CT at 6, 12, 24, and 36 months). Results: The study included 1480 patients with stage IIB to IIID cutaneous melanoma. Cumulative incidences of overall and distant recurrence were higher in cohort 2, with a peak difference at three years (32.3 % vs 27.5 % and 25.8 % vs. 18.5 %, respectively). The hazard of recurrence was higher in cohort 2 during the first two years, with hazard rates for overall and distant recurrence of 1.16 (95 % confidence interval [CI], 0.93–1.44) and 1.51 (95 % CI, 1.16–1.96), respectively. The patterns persisted in absolute risk estimates. Conclusions: Patients with stage IIB to IIID melanoma followed with routine FDG PET-CT had a 51 % increased hazard of distant recurrence detection within the first two years of surveillance. Future studies must determine whether this earlier recurrence detection translates into improved survival.

Routine [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) may help predict clinical outcomes after response to immunotherapy. With a European Medicines Agency-recommended treatment length until disease progression or unacceptable toxicity, the optimal duration of immunotherapy remains to be defined. In a retrospective study, we retrieved from the Danish Metastatic Melanoma Database (DAMMED), all patients that were annotated as a partial or complete response based on the computed tomography (CT) of serial FDG-PET-CT scans. Patients treated with an anti-Programmed Death (PD)-1-containing regimen for <18 months, and ≥4 months without disease progression after halting anti-PD-1 were included. Cases were divided into an “elective” and a “toxicity” group based on the reason for treatment discontinuation. A total of 140 patients were included. At 29.3 months of median follow-up, a higher proportion of patients remained alive in the “elective” group (93% vs 75%, P =.0031) with an improved melanoma-specific (HR 0.07, 95% CI 0.02-0.32, P =.0041) survival (MSS). Patients without FDG-avid lesions at the time of treatment discontinuation had an improved MSS (HR 0.03, 95% CI 0.01-0.17, P =.0002), and the absence of FDG-avid lesions was the only independent predictive feature of improved MSS in multivariate analysis. In conclusion, patients with metastatic melanoma who obtain an early response and early discontinue immunotherapy have an excellent prognosis, especially in the absence of FDG-PET avid lesions when discontinuing treatment. These data support the option of early discontinuation, limiting possible overtreatment and thereby toxicity, health and economic expenses and improving logistics.

Objective To evaluate the diagnostic accuracy of observers with different levels of experience in reading F-18-sodium fluoride (NaF) PET/CT images for the diagnosis of bone metastases in prostate cancer (PCa) patients. Methods Nine observers with varying NaF PET/CT experience, ranging from no experience to 2000+ examinations, evaluated 211 NaF PET/CT scans from PCa patients participating in one of four prospective trials. Each observer evaluated each NaF PET/CT on a patient level using a trichotomous scale: M0 (no bone metastases), Me (equivocal for bone metastases) and M1 (bone metastases). Subsequently, a dichotomous evaluation was conducted (M0/M1). The final diagnosis was retrieved from the original study. For each observer, ROC curves and the diagnostic accuracy were calculated based on dichotomous and trichotomous scales; in the latter case, Me was first regarded as M1 and then M0. Results Across all experience levels, the sensitivity, specificity and accuracy using the dichotomous scale ranged from 0.81 to 0.89, 0.93 to 1.00 and 0.91 to 0.94, respectively. Employing the trichotomous scale, novice and experienced observers chose Me in up to 20 vs. 10% of cases, respectively. Considering Me as M0, the sensitivity, specificity and accuracy ranged from 0.78 to 0.89, 0.95 to 1.00 and 0.91 to 0.95, respectively. Considering Me as M1, the sensitivity, specificity and accuracy ranged from 0.86 to 0.92, 0.71 to 0.96 and 0.77 to 0.94, respectively. Conclusion Novice observers used the equivocal option more frequently than observers with NaF PET/CT experience. However, on the dichotomous scale, all observers exhibited high and satisfactory accuracy for the detection of bone metastases, making NaF PET/CT an effective imaging modality even in unexperienced hands.

PURPOSE: Despite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this treatment. We evaluated the use of vemurafenib, a small-molecule BRAF inhibitor with immunomodulatory properties, as priming before TIL harvest and adoptive T cell therapy in a phase I/II clinical trial. METHODS: 12 patients were treated with vemurafenib for 7 days before tumor excision and during the following weeks until TIL infusion. TILs were grown from tumor fragments, expanded in vitro and reinfused to the patient preceded by a lymphodepleting chemotherapy regimen and followed by interleukin-2 infusion. Extensive immune monitoring, tumor profiling and T cell receptor sequencing were performed. RESULTS: No unexpected toxicity was observed, and treatment was well tolerated. Of 12 patients, 1 achieved a complete response, 8 achieved partial response and 3 achieved stable disease. A PR and the CR are ongoing for 23 and 43 months, respectively. In vitro anti-tumor reactivity was found in TILs from 10 patients, including all patients achieving objective response. Serum and tumor biomarker analyses indicate that baseline cytokine levels and the number of T cell clones may predict response to TIL therapy. Further, TCR sequencing suggested skewing of TCR repertoire during in vitro expansion, promoting certain low frequency clonotypes. CONCLUSIONS: Priming with vemurafenib before infusion of TILs was safe and feasible, and induced objective clinical responses in this cohort of patients with checkpoint inhibitor-resistant metastatic melanoma. In this trial, vemurafenib treatment seemed to decrease attrition and could be considered to bridge the waiting time while TILs are prepared.

Introduction: The use of routine imaging with 18F-FDG PET-CT (PET-CT) in melanoma surveillance is debated and evidence of its diagnostic value and yield in asymptomatic patients is limited. Denmark introduced nationwide routine surveillance with PET-CT in high-risk patients in 2016. The aim of this study was to examine the sensitivity, specificity, negative and positive predictive values, numbers-needed-to-scan and clinical impact of routine PET-CT in the surveillance of asymptomatic stage IIB-III melanoma patients. Materials and methods: Data was retrieved from the population-based Danish Melanoma Database and patient records. All patients diagnosed with stage IIB-III melanoma at two University Hospitals in 2016 and 2017 were included. Patients underwent surveillance with clinical examinations and PET-CT scans at 6, 12, 24 and 36 months. Results: In 138 patients, 243 routine PET-CTs were performed within a median follow-up time of 17.7 months. Routine PET-CT detected recurrence at least once in 25 patients (18.1%), including distant recurrence in 19 patients (13.8%). Stage IIB patients had the lowest recurrence rate (11.1%). Numbers-needed-to-scan to detect one distant recurrence was 12.8 patients and median time-to-recurrence was 6.8 months. Sensitivity was 100%, specificity was 94.7% and negative and positive predictive values were 100% and 74.4%, respectively. False positive findings prompted 22 additional investigations (of which ten invasive) in 17 patients (12.3%). Conclusion: Routine PET-CT has a high sensitivity and specificity when used in high-risk melanoma surveillance. Time-to-recurrence and stage-specific recurrence rates indicate high gain of early routine imaging at six months especially for stage IIC and III patients.

BACKGROUND: Melanoma-related limb lymphoedema is a well-known late effect following sentinel node biopsy (SNB), and lymph node dissection (LND) in patients treated of melanoma. However, data on associated risk factors are sparse. This study aimed to investigate factors associated with melanoma-related limb lymphoedema.METHODS: The present cross-sectional single-center clinical study included patients between 18 and 75 years with American Joint Committee on Cancer Stages I-III melanoma treated with wide local excision (WLE) and unilateral axillary or inguinal SNB and/or completion LND (CLND) or therapeutic LND (TLND). The diagnosis of secondary unilateral limb lymphoedema was based on the history, symptoms, and physical examination and staged according to the International Society of Lymphology (ISL). Data on factors associated with lymphoedema were analysed with binary logistic regression models.RESULTS: In total, 642 patients were eligible, of which 435 (68%) patients participated in the study. Among these 431 patients, 109 (25%) had lymphoedema of which 48 (44%), and 61 (56%) were classified with ISL Stages I and II-III, respectively. Multivariate analyses identified primary tumour on the limb (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.17-4.56; p value .017), inguinal surgery (OR, 6.91; 95% CI, 3.49-14.11; p value <.0001), LND (OR, 6.45; 95% CI, 3.18-13.57; p value <.0001), and persistent pain at the site of lymph node surgery as factors associated with lymphoedema (OR, 3.52; 95% CI, 1.54-8.19; p value .003). Multivariable analysis of ISL Stage II-III lymphoedema further identified limb cellulitis to be associated with lymphoedema (OR 5.74; 95% CI, 2.11-15.99; p value .0006).CONCLUSIONS: Melanoma-related limb lymphoedema is associated with inguinal surgery, LND, primary tumour on the limb, persistent pain at the site of lymph node surgery, and cellulitis of the limb. This study highlights the importance of increasing awar

Prostate-specific membrane antigen (PSMA)-based radioligands for positron emission tomography (PET)/computed tomography (CT) studies represent the gold standard for detection of recurrent prostate cancer (PCa). [68Ga]PSMA-HBED-CC is a PET radiotracer suitable for detection of PCa, and its clinical use has become widespread over the last few years. In this contribution, we detail our GMP-compliant production of [68Ga]PSMA-HBED-CC using the Trasis miniAllinOne radiosynthesizer and report synthetic and clinical data for the first 100 productions of 2019. Additionally, we detail our efforts towards a GMP-compliant production of the radiotherapeutic [177Lu]PSMA-I&T using the same synthesis module. PSMA-based radioligand therapy (RLT) offers a possible future treatment in cases of metastatic castration-resistant PCa, and GMP-compliant routine production methods are therefore called for. This report highlights how PSMA-based agents for theranostic purposes can be conveniently produced at a single radiochemistry Good Manufacturing Practice (GMP) site, thereby facilitating optimized detection and treatment of PCa.

The aim of this study was to determine if additional 18F-sodium fluoride PET/CT (NaF PET/CT) improves the prognostic accuracy in the initial staging of prostate cancer patients with normal bone scintigraphy undergoing prostatectomy. Methods: A prospective cohort study examined NaF PET/CT in intermediate- or high-risk prostate cancer with negative bone scintigraphy who were scheduled for prostatectomy. Biochemical response: PSA levels > 0.2 ng/mL at 6 wk and 6 mo postoperatively, PSA level < 0.2 ng/mL was biochemical failure. Results: Eighty-one patients were included in the study; 75 patients (93%) achieved biochemical responses, 6 patients had biochemical failure. NaF PET/CT indicated bone metastasis in 1 patient (1.2%), was equivocal in 7 patients (8.6%), without bone metastases in 73 patients (90.1%). Eight patients with bone metastases or equivocal results on NaF PET/CT exhibited biochemical responses. All patients with biochemical failure had negative NaF PET/CT and bone scintigraphy for bone metastases. Conclusion: NaF PET/CT has no added value for bone staging in intermediate- and high-risk prostate cancer patients with normal bone scintigraphy results undergoing prostatectomy.

Background: Electrochemotherapy is an established treatment for cutaneous tumors. This study aimed at determining efficacy of electrochemotherapy in recurrent head and neck cancer. Methods: Phase II clinical trial in patients with recurrent head and neck carcinomas with no curative treatment options. Electrochemotherapy was performed under general anesthesia. Primary endpoint was tumor response (CT scanning) evaluated at week 8. Secondary endpoints included biopsy results, MRI and fluorodeoxyglucose-positron emission tomography scanning, safety, toxicity, pain score, and quality-of-life questionnaires. Results: Of 26 patients treated, 5 (19%) achieved complete response, 10 (39%) partial response, resulting in an objective response of 58%. Two responders remain without recurrence. No serious adverse events occurred during treatment. Four events occurred posttreatment: one bleeding episode, two episodes with mucosal swelling, and one patient died due to disease progression. Conclusion: Electrochemotherapy is efficient against local recurrence of head and neck cancer with an overall response rate of 58%.

Objectives: To determine the diagnostic accuracy of 68 gallium prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) in comparison with 18 F-fluoride-based PET/CT (NaF-PET/CT) and whole-body magnetic resonance imaging (WB-MRI) for the detection of bone metastases in patients with prostate cancer. Methods: Sixty patients with prostate cancer were included in the period May 2016 to June 2017. The participants underwent three scans (index tests) within 30 days: a NaF-PET/CT, a WB-MRI and a PSMA-PET/CT. Experienced specialists assessed the scans. In the absence of a histological reference standard, the final diagnosis was determined as a panel diagnosis. Measures of the diagnostic performances of the index tests were calculated from patient-based dichotomous outcomes (0 or ≥ 1 bone metastasis) and pairwise compared (McNemar test). For each index test, the agreement with the final diagnosis with regard to the number of bone metastases detected (0, 1–5, > 5) and the inter-reader agreement was calculated (kappa coefficients). Results: Fifty-five patients constituted the final study population; 20 patients (36%) were classified as having bone metastatic disease as their final diagnosis. The patient-based diagnostic performances were (sensitivity, specificity, overall accuracy) PSMA-PET/CT (100%, 100%, 100%), NaF-PET/CT (95%, 97%, 96%) and WB-MRI (80%, 83%, 82%). The overall accuracy of PSMA-PET/CT was significantly more favourable compared to WB-MRI (p = 0.004), but not to NaF-PET/CT (p = 0.48). PSMA-PET/CT classified the number of bone metastases reliably compared to the final diagnosis (kappa coefficient 0.97) and with an “almost perfect” inter-reader agreement (kappa coefficient 0.93). Conclusions: The overall accuracy of PSMA-PET/CT was significantly more advantageous compared to WB-MRI, but not to NaF-PET/CT. Key Points: • PSMA-PET/CT assessed the presence of bone metastases correctly in a

INTRODUCTION: The clinical assessment of unilateral limb lymphedema is commonly based on measurements of interlimb volume differences. Reference values for interlimb percentage differences of the volume, fat mass, and lean mass measured with dual-energy X-ray absorptiometry (DXA) scan are, however, not established. The aim of the study was to establish and categorize these reference values in normal limbs.METHODS AND RESULTS: DXA scans of the normal arms of 167 and normal legs of 196 melanoma patients (aged 18-75 years, body mass index <40), respectively, were performed. The interlimb percentage difference is calculated as follows: ("Limb-of-interest"-contralateral)/contralateral × 100. The interlimb percentage differences for the limb-of-interest were stratified to upper (according to handedness) and lower limbs and categorized as none/mild, moderate, or severe, respectively, based on whether the value is below, in between, or above the two prediction limits. The prediction limits for interlimb total volume percentage difference were 6% and 10%, 0% and 4%, and 3% and 6% for the dominant arm, nondominant arm, and leg, respectively. Further data are given for interlimb percentage differences of regional (upper arm, lower arm, hand, thigh, lower leg, and foot) and total volume, fat mass, and lean mass, respectively.CONCLUSIONS: The provided clinical reference values allow for identifying and categorizing pathophysiological differences of limbs-of-interest and evaluating tissue composition.