Randomised phase II trial of stereotactic body radiotherapy in combination with checkpoint inhibitors in metastatic castration-resistant prostate cancer (CheckPRO): a study protocol.

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 document prior to inclusion. The study results will be published in an international peer-review journal. TRIAL REGISTRATION NUMBER: EudraCT number: 2018-003461-34. CLINICALTRIALS: gov ID NCT05655715.

Randomized Trial of Surgical Left Atrial Appendage Closure: Protection Against Cerebrovascular Events.

Following open-heart surgery, atrial fibrillation and stroke occur frequently. Left atrial appendage closure added to elective open-heart surgery could reduce the risk of ischemic stroke. We aim to examine if routine closure of the left atrial appendage in patients undergoing open-heart surgery provides long-term protection against cerebrovascular events independently of atrial fibrillation history, stroke risk, and oral anticoagulation use. Long-term follow-up of patients enrolled in the prospective, randomized, open-label, blinded evaluation trial entitled left atrial appendage closure by surgery (NCT02378116). Patients were stratified by oral anticoagulation status and randomized (1:1) to left atrial appendage closure in addition to elective open-heart surgery vs standard care. The primary composite endpoint was ischemic stroke events, transient ischemic attacks, and imaging findings of silent cerebral ischemic lesions. Two neurologists blinded for treatment assignment adjudicated cerebrovascular events. In total, 186 patients (82% males) were reviewed. At baseline, mean (standard deviation (SD)) age was68 (9) years and 13.4% (n = 25/186) had been diagnosed with atrial fibrillation. Median [interquartile range (IQR)] CHA2DS2-VASc was 3 [2,4] and 25.9% (n = 48/186) were receiving oral anticoagulants. Mean follow-up was 6.2 (2.5) years. The left atrial appendage closure group experienced fewer cerebrovascular events; intention-to-treat 11 vs 19 (P = 0.033, n = 186) and per-protocol 9 vs 17 (P = 0.186, n = 141). Left atrial appendage closure as an add-on open-heart surgery, regardless of pre-surgery atrial fibrillation and oral anticoagulation status, seems safe and may reduce cerebrovascular events in long-term follow-up. More extensive randomized clinical trials investigating left atrial appendage closure in patients without atrial fibrillation and high stroke risk are warranted.

Outstanding Response to Sorafenib in a Patient with Metastatic Gastrointestinal Stromal Tumour.

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (PDGFRA). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at PDGFRA exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case.

Imaging for Target Delineation in Head and Neck Cancer Radiotherapy.

The definition of tumor involved volumes in patients with head and neck cancer poses great challenges with the increasing use of highly conformal radiotherapy techniques eg, volumetric modulated arc therapy and intensity modulated proton therapy. The risk of underdosing the tumor might increase unless great care is taken in the process. The information gained from imaging is increasing with both PET and MRI becoming readily available for the definition of targets. The information gained from these techniques is indeed multidimensional as one often acquire data on eg, metabolism, diffusion, and hypoxia together with anatomical and structural information. Nevertheless, much work remains to fully exploit the available information on a patient-specific level. Multimodality target definition in radiotherapy is a chain of processes that must be individually scrutinized, optimized and quality assured. Any uncertainties or errors in image acquisition, reconstruction, interpretation, and delineation are systematic errors and hence will potentially have a detrimental effect on the entire radiotherapy treatment and hence; the chance of cure or the risk of unnecessary side effects. Common guidelines and procedures create a common minimum standard and ground for evaluation and development. In Denmark, the treatment of head and neck cancer is organized within the multidisciplinary Danish Head and Neck Cancer Group (DAHANCA). The radiotherapy quality assurance group of DAHANCA organized a workshop in January 2020 with participants from oncology, radiology, and nuclear medicine from all centers in Denmark, treating patients with head and neck cancer. The participants agreed on a national guideline on imaging for target delineation in head and neck cancer radiotherapy, which has been approved by the DAHANCA group. The guidelines are available in the Supplementary. The use of multimodality imaging is being recommended for the planning of all radical treatments with a macroscopic tumor. 2-[18F]FDG-PET/CT should be available, preferable in the treatment position. The recommended MRI sequences are T1, T2 with and without fat suppression, and T1 with contrast enhancement, preferable in the treatment position. The interpretation of clinical information, including thorough physical examination as well as imaging, should be done in a multidisciplinary setting with an oncologist, radiologist, and nuclear medicine specialist.

Adding left atrial appendage closure to open heart surgery provides protection from ischemic brain injury six years after surgery independently of atrial fibrillation history: the LAACS randomized study.

BACKGROUND: Open heart surgery is associated with high occurrence of atrial fibrillation (AF), subsequently increasing the risk of post-operative ischemic stroke. Concomitant with open heart surgery, a cardiac ablation procedure is commonly performed in patients with known AF, often followed by left atrial appendage closure with surgery (LAACS). However, the protective effect of LAACS on the risk of cerebral ischemia following cardiac surgery remains controversial. We have studied whether LAACS in addition to open heart surgery protects against post-operative ischemic brain injury regardless of a previous AF diagnosis. METHODS: One hundred eighty-seven patients scheduled for open heart surgery were enrolled in a prospective, open-label clinical trial and randomized to concomitant LAACS vs. standard care. Randomization was stratified by usage of oral anticoagulation (OAC) planned to last at least 3 months after surgery. The primary endpoint was a composite of post-operative symptomatic ischemic stroke, transient ischemic attack or imaging findings of silent cerebral ischemic (SCI) lesions. RESULTS: During a mean follow-up of 3.7 years, 14 (16%) primary events occurred among patients receiving standard surgery vs. 5 (5%) in the group randomized to additional LAACS (hazard ratio 0.3; 95% CI: 0.1-0.8, p = 0.02). In per protocol analysis (n = 141), 14 (18%) primary events occurred in the control group vs. 4 (6%) in the LAACS group (hazard ratio 0.3; 95% CI: 0.1-1.0, p = 0.05). CONCLUSIONS: In a real-world setting, LAACS in addition to elective open-heart surgery was associated with lower risk of post-operative ischemic brain injury. The protective effect was not conditional on AF/OAC status at baseline. TRIAL REGISTRATION: LAACS study, clinicaltrials.gov NCT02378116 , March 4th 2015, retrospectively registered.

A prospective study comparing whole-body skeletal X-ray survey with 18F-FDG-PET/CT, 18F-NaF-PET/CT and whole-body MRI in the detection of bone lesions in multiple myeloma patients.

BACKGROUND: For decades, the most widely used imaging technique for myeloma bone lesions has been a whole-body skeletal X-ray survey (WBXR), but newer promising imaging techniques are evolving. PURPOSE: To compare WBXR with the advanced imaging techniques 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), 18F-sodium fluoride (NaF) PET/CT and whole-body magnetic resonance imaging (WB-MRI) in the detection of myeloma bone lesions. MATERIAL AND METHODS: Fourteen patients with newly diagnosed multiple myeloma were prospectively enrolled. In addition to WBXR, all patients underwent FDG-PET/CT, NaF-PET/CT, and WB-MRI. Experienced specialists performed blinded readings based on predefined anatomical regions and diagnostic criteria. RESULTS: In a region-based analysis, a two-sided ANOVA test showed that the extent of detected skeletal disease depends on the scanning technique (P < 0.0001). Tukey's multiple comparison test revealed that WB-MRI on average detects significantly more affected regions than WBXR (P < 0.005), FDG-PET/CT (P < 0.0001), and NaF-PET/CT (P < 0.05). In a patient-based analysis, a Cochran's Q test showed that there are no significant differences in the proportion of patients with bone disease detected by the different scanning techniques (P = 0.23). Determination of intrareader variability resulted in Kappa coefficients corresponding to moderate (FDG-PET/CT) and substantial agreement (WB-MRI, WBXR, NaF-PET/CT). CONCLUSION: WB-MRI detects on average significantly more body regions indicative of myeloma bone disease compared to WBXR, FDG-PET/CT, and NaF-PET/CT. The lack of significance in the patient-based analysis is most likely due to the small number of study participants.

[Treatment of central nervous system lymphoma following transplantation using monoclonal antibody and ganciclovir]. / Behandling af centralnervesystemlymfom efter transplantation med monoklonalt antistof og ganciclovir.

A 35-year-old female was diagnosed with a primary central nervous system posttransplant Epstein-Barr-virus-associated lymphoproliferative disorder three years after a renal transplantation. The histological diagnosis of the brain tumour was a diffuse large B-cell lymphoma. The patient had had diabetes mellitus for 28 years and was treated with four weekly doses of the monoclonal antibody rituximab, the antiviral drug ganciclovir and high-dose prednisolone, and the immune suppression was reduced. After four weeks of treatment, a control magnetic resonance image showed complete regression of the central nervous system lesion.