A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors.

BACKGROUND: Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. METHODS: In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). RESULTS: Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event. CONCLUSION: SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

Detection of cell-free tumor DNA in cerebrospinal fluid as a diagnostic biomarker for leptomeningeal melanoma metastasis: A case series.

Leptomeningeal melanoma metastases (LMM) are associated with poor survival. Diagnosis is based on clinical presentation, brain MRI and cerebrospinal fluid (CSF) analysis. Inconclusive findings at initial presentation can delay treatment. In this single-center case series, detection of BRAFV600- and NRASQ61-mutant cell-free tumor DNA (cfDNA) in CSF was evaluated as a complementary diagnostic biomarker. In 12 patients with clinical suspicion of LMM, a retrospective analysis of MRI, CSF cytology and cfDNA analysis on 1 mL of CSF using the Idylla® platform was carried out. Nine patients displayed MRI abnormalities suggesting LMM. CSF analysis identified malignant cells in three patients (including one without MRI abnormalities). BRAFV600- or NRASQ61-mutant cfDNA was detected in CSF of nine patients (eight with and one without MRI abnormalities; all patients with positive CSF cytology). Subsequent follow-up confirmed LMM in all patients with positive and in one patient with a negative CSF cfDNA analysis (sensitivity 81.8%; specificity 100%). Our findings suggest that analyzing BRAFV600- and NRASQ61-mutant cfDNA in CSF using the Idylla® platform holds promise as a sensitive and specific complementary diagnostic biomarker for LMM, particularly in case of inconsistency between imaging and CSF cytology. The 110-min analysis can facilitate urgent treatment decisions.

Emotional Distress, Cognitive Complaints, and Care Needs among Advanced Cancer Survivors Treated with Immune Checkpoint Blockade: A Mixed-Method Study.

BACKGROUND: There is a need for a better understanding of survivorship-related issues in advanced cancer survivors treated with immune checkpoint blockade (ICB). The purpose of this study was to identify survivorship-related issues, with a focus on psychological distress, cognitive complaints, physical sequelae, impact on family dynamics, and care needs in unresectable, advanced cancer survivors treated with ICB. METHODS: Semi-structured interviews and patient-reported outcome measures (PROMs) were conducted in survivors followed up at the University Hospital Brussels. We performed content analysis on the semi-structured interviews and analyzed the PROMs descriptively. RESULTS: 70 cancer survivors (71.4%) consented to participate between July 2022 and November 2023. Clinical fear of cancer recurrence (FCR) was present in 54.3% of the cancer survivors, and 18.6% had elevated cognitive complaints. We identified triggers related to clinically important psychological distress, such as immune-related adverse events, the progression/recurrence of disease, difficulties in adjusting to life after treatment, and co-existing life stressors, alongside persistent physical issues and unmet psychological and nutritional care needs. CONCLUSION: Our results indicate the existence of persistent psychological, physical, and cognitive issues, and support the need for routine screening for FCR. The identified triggers related to severe psychological distress can aid clinicians in timely referring the patient, thereby enhancing survivorship care.

Regorafenib in patients with pretreated advanced melanoma: a single-center case series.

Melanoma patients failing all approved treatment options have a poor prognosis. The antimelanoma activity of regorafenib (REGO), a multitargeted kinase inhibitor, has not been investigated in this patient population. The objective response rate and safety of REGO treatment in advanced melanoma patients was investigated retrospectively. Twenty-seven patients received REGO treatment. All patients had progressed on anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibition and BRAF/MEK inhibitors (in case of a BRAF V600 mutation). REGO was administered in continuous dosing and combined (upfront or sequentially) with nivolumab ( n  = 5), trametinib ( n  = 8), binimetinib ( n  = 2), encorafenib ( n  = 1), dabrafenib/trametinib ( n  = 9), or encorafenib/binimetinib ( n  = 7). The best overall response was partial response (PR) in five patients (18.5%) and stable disease in three patients (11.1%). Three of seven (42.8%) BRAF V600mut patients treated with REGO in combination with BRAF/MEK inhibitors obtained a PR (including regression of brain metastases in all three patients). In addition, PR was documented in a BRAF V600mut patient treated with REGO plus anti-PD-1, and a NRASQ61mut patient treated with REGO plus a MEK inhibitor. Common grade 3-4 treatment-related adverse events included arterial hypertension ( n  = 7), elevated transaminase levels ( n  = 5), abdominal pain ( n  = 3), colitis ( n  = 2), anorexia ( n  = 1), diarrhea ( n  = 1), fever ( n  = 1), duodenal perforation ( n  = 1), and colonic bleeding ( n  = 1). Median progression-free survival was 11.0 weeks (95% confidence interval, 7.1-14.9); median overall survival was 23.1 weeks (95% confidence interval, 13.0-33.3). REGO has a manageable safety profile in advanced melanoma patients, in monotherapy as well as combined with BRAF/MEK inhibitors or PD-1 blocking monoclonal antibodies. The triplet combination of REGO with BRAF/MEK inhibitors appears most active, particularly in the BRAF V600mut patients.

Primary splenic angiosarcoma: a case series of a rare oncological entity and diagnostic challenge.

BACKGROUND AND PURPOSE: Primary angiosarcoma of the spleen (PAS), an exceptionally rare and aggressive neoplasm with high metastatic risk (70%-85%), is frequently diagnosed in an advanced or metastatic stage. It presents diagnostic challenges due to its nonspecific symptomatology and resemblance to benign vascular lesions in various imaging modalities. PATIENTS AND METHODS: This case series aims to clarify the diagnostic difficulties by comparing imaging characteristics (CT-scan, MRI, and [18F]FDG-PET/CT) as well as pathological findings of three PAS cases diagnosed in different stages of the diseases (localized, metastatic, and metastatic with organ failure). Furthermore, a brief review on diagnostic and therapeutic features is included. RESULTS AND INTERPRETATION: We suggest [18F]FDG-PET/CT as a differentiating tool between benign and malignant splenic lesions and propose a flowchart of a diagnostic algorithm for PAS. For treatment, we advocate for early splenectomy and when systemic therapy is warranted, paclitaxel emerges as a viable first-line option. While it is crucial to acknowledge that further trial data is required to evaluate the efficacy of emerging treatment regimens, designing and conducting trials for PAS is challenging given its scarcity and aggressive behavior. Therefore case reporting remains important.

Intratumoral administration of the immunologic adjuvant AS01B in combination with autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells plus ipilimumab and intravenous nivolumab in patients with refractory advanced melanoma.

BACKGROUND: Patients with advanced melanoma who progress after treatment with immune checkpoint-inhibitors (ICI) and BRAF-/MEK-inhibitors (if BRAF V600 mutated) have no remaining effective treatment options. The presence of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment correlates with pre-existing immune recognition and responsiveness to immune checkpoint blockade. The synthetic saponin-based immune adjuvant AS01B enhances adaptive immunity through the involvement of myDC. METHODS: In this first-in-human phase I clinical trial, patients with metastatic melanoma refractory to ICI and BRAF-/MEK inhibitors (when indicated) were recruited. Patients received an intravenous administration of low-dose nivolumab (10 mg, every 2 weeks) plus an intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01B (every 2 weeks). All myDC, isolated from blood, were injected on day 2 into the same metastatic lesion. Tumor biopsies and blood samples were collected at baseline and repeatedly on treatment. Multiplex immunohistochemistry (mIHC) was performed on biopsy sections to characterize and quantify the IT and peritumoral immune cell composition. RESULTS: Study treatment was feasible and well tolerated without the occurrence of unexpected adverse events in all eight patients. Four patients (50%) obtained a complete response (CR) in the injected lesions. Of these, two patients obtained an overall CR, and one patient a partial response. All responses are ongoing after more than 1 year of follow-up. One additional patient had a stable disease as best response. The disease control rate was 50%. Median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration, with a reduced mean distance between T cells and tumor cells. Peripheral blood immune cell composition did not significantly change during study treatment. CONCLUSIONS: Combining an intratumoral injection of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myDC with repeated IT administration of ipilimumab and AS01B and systemic low-dose nivolumab is safe, feasible with promising early results, worthy of further clinical investigation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03707808.

Successful Treatment with Dabrafenib/Trametinib of a Malignantly Transformed and Metastasized BRAF V600E Mutant Pleiomorphic Xanthoastrocytoma: A Case Report and Review of the Literature.

Introduction: Pleiomorphic xanthoastrocytoma (PXA) is considered a low-grade glioma with a favorable prognosis following surgical resection. We present a case report of a BRAFV600E mutant malignantly transformed and disseminated PXA that was successfully treated with BRAF-/MEK-targeted therapy (dabrafenib/trametinib). Case Presentation: At the age of 16 years, our patient underwent an initial subtotal resection of a right occipital PXA. Six months later, a reintervention for an asymptomatic tumor recurrence was performed and complete resection was achieved. The patient has been followed up by MRI for 14 years without arguments for recurrence but was lost to follow-up thereafter. At 38 years of age, he presented with a symptomatic local recurrence with extra-cerebral soft tissue extension, for which a third surgical resection was performed. Anatomopathological examination reported a grade 3 anaplastic PXA (aPXA); molecular analysis detected a BRAFV600E mutation. Three months later, before the initiation of radiotherapy, a local tumor recurrence was diagnosed, for which he underwent a fourth surgical resection. Radiotherapy was performed following the surgical debulking. One month after completion of radiotherapy, disease progression was documented including multiple sites of extracranial metastases (skeletal, lung, cervical lymph node, and subcutaneous metastases). Systemic treatment with a combination of BRAF-/MEK-inhibitors (dabrafenib/trametinib) was initiated and resulted in a rapid and deep tumor response (partial response according to RECISTv1.1) and absence of BRAFV600E mutant ctDNA in plasma at 6 weeks after treatment initiation. A near-complete metabolic remission was documented on [18F]FDG-PET/CT 3 months after starting systemic therapy. Conclusion: We present a rare case of malignant transformation and systemic dissemination of a BRAFV600E mutant PXA, occurring 20 years after the initial diagnosis. This case highlights the importance of long-term follow-up of patients diagnosed with these rare central nervous system tumors that initially are considered benign and also illustrates that BRAF/MEK inhibition can be an effective therapy for BRAFV600E mutated PXA, underscoring the importance of performing molecular genetic profiling of these tumors.

Development and Validation of a Predictive Model for Metastatic Melanoma Patients Treated with Pembrolizumab Based on Automated Analysis of Whole-Body [18F]FDG PET/CT Imaging and Clinical Features.

BACKGROUND: Antibodies that inhibit the programmed cell death protein 1 (PD-1) receptor offer a significant survival benefit, potentially cure (i.e., durable disease-free survival following treatment discontinuation), a substantial proportion of patients with advanced melanoma. Most patients however fail to respond to such treatment or acquire resistance. Previously, we reported that baseline total metabolic tumour volume (TMTV) determined by whole-body [18F]FDG PET/CT was independently correlated with survival and able to predict the futility of treatment. Manual delineation of [18F]FDG-avid lesions is however labour intensive and not suitable for routine use. A predictive survival model is proposed based on automated analysis of baseline, whole-body [18F]FDG images. METHODS: Lesions were segmented on [18F]FDG PET/CT using a deep-learning approach and derived features were investigated through Kaplan-Meier survival estimates with univariate logrank test and Cox regression analyses. Selected parameters were evaluated in multivariate Cox survival regressors. RESULTS: In the development set of 69 patients, overall survival prediction based on TMTV, lactate dehydrogenase levels and presence of brain metastases achieved an area under the curve of 0.78 at one year, 0.70 at two years. No statistically significant difference was observed with respect to using manually segmented lesions. Internal validation on 31 patients yielded scores of 0.76 for one year and 0.74 for two years. CONCLUSIONS: Automatically extracted TMTV based on whole-body [18F]FDG PET/CT can aid in building predictive models that can support therapeutic decisions in patients treated with immune-checkpoint blockade.

Low-Dose Bevacizumab for the Treatment of Focal Radiation Necrosis of the Brain (fRNB): A Single-Center Case Series.

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5-7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

Auto-immune hemolytic anemia and hemophagocytic lymphohistiocytosis as immune-related adverse event in patients with metastatic melanoma and concurrent chronic lymphocytic leukemia: a case series and literature review.

Auto-immune hemolytic anemia (AIHA) and hemophagocytic lymphohistiocytosis (HLH) are both rare immune-related adverse events (irAEs) following treatment with immune checkpoint inhibitors. Consensus treatment guidelines are currently lacking. Patients with a solid malignancy and a concurrent lymphoproliferative disorder, such as chronic lymphocytic leukemia (CLL), might be more prone to develop hematological irAEs. We report the case history of two patients, diagnosed with CLL, who during treatment for metastatic melanoma with nivolumab, a PD-1 immune checkpoint blocking mAb, developed AIHA and HLH in combination with AIHA. Furthermore, we provide a review of the literature on published cases of immune-related AIHA and HLH and their correlation with CLL.

Trajectory of neutrophilic responses in a mouse model of pollutant-aggravated allergic asthma.

Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust particles (DEP) is implicated in both exacerbation and development of asthma. Since exposure to DEP is associated with a neutrophilic component, we aimed to investigate how exposure to the combination of allergens and DEP modulates neutrophilic responses. Human bronchial epithelial cells (HBEC) were exposed to house dust mite (HDM), DEP or HDM + DEP in vitro to determine the expression of neutrophil-recruiting chemokines. Female (C57BL/6 J) mice were intranasally instilled with saline, DEP, HDM or combined HDM + DEP for 3 weeks (subacute) or 6 weeks (chronic). The neutrophilic responses were determined in lung tissue and bronchoalveolar lavage fluid (BALF). Simultaneous exposure to HDM + DEP resulted in increased CXCL1 and CXCL8 mRNA expression by HBEC in vitro. In mice, subacute exposure to HDM + DEP induced a strong mixed eosinophilic/neutrophilic inflammation in BALF and lung and was associated with higher expression of neutrophil-attracting chemokines and NET formation compared to the sole exposures. After chronic HDM + DEP exposure, a similar neutrophilic response was observed, however the NET formation was less pronounced. Interestingly, the increase of BALF eosinophils was also significantly attenuated after chronic HDM + DEP exposure compared to the subacute exposure. Subacute and chronic HDM + DEP exposure induced goblet cell hyperplasia and airway hyperresponsiveness. Our data suggest a role for neutrophils and NETs in pollutant-aggravated eosinophilic allergic asthma. Moreover, subacute exposure to HDM + DEP induces a mixed eosinophilic/neutrophilic response whereas upon chronic HDM + DEP exposure there is a shift in inflammatory response with a more prominent neutrophilic component.

Lymphadenopathy after COVID-19 vaccination in patients with endocrine cancer: two case reports.

Summary: The Covid-19 vaccination has been rapidly implemented among patients with cancer. We present two cases of patients with endocrine tumours who developed lymphadenopathy following a Covid-19 vaccination. In the case of a patient with multiple endocrine neoplasia (MEN) 1 syndrome, an 18-fluorodeoxyglucose (18FDG)-PET/CT showed positive axillary lymph nodes. Further work-up with fine needle aspiration showed a reactive pattern following a Covid-19 vaccination in the ipsilateral arm shortly before the 18FDG-PET/CT. A second patient, in follow-up for thyroid cancer, developed clinical supraclavicular lymphadenopathy after a Covid-19 vaccination. Follow-up ultrasound proved the lesion to be transient. These cases demonstrate lymphadenopathy in response to a Covid-19 vaccination in two patients susceptible to endocrine tumours and metastatic disease. With growing evidence about the pattern and occurrence of lymphadenopathy after mRNA Covid-19 vaccination, recommendations for scheduling and interpretation of imaging among cancer patients should be implemented to reduce equivocal findings, overdiagnosis, and overtreatment, while maintaining a good standard of care in oncological follow-up. Learning points: Reactive lymphadenopathy is very common after an mRNA vaccination against Covid-19 and should be part of the differential diagnosis in patients with endocrine tumours who recently received a Covid-19 mRNA vaccination and present with an ipsilateral lymphadenopathy. A good vaccine history is essential in assessing the risk for lymphadenopathy and if possible, screening imaging in patients with endocrine tumours should be postponed at least 6 weeks after the previous vaccination. For now, a multidisciplinary care approach is recommended to determine the necessary steps in the diagnostic evaluation of lymphadenopathy in the proximity of a Covid-19 vaccination.