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Background This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra‐rare sarcoma, marked by WWTR1‐CAMTA1 or YAP1‐TFE3 fusions. Methods Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan‐Meier method. Results Overall, 73 patients were included; 21 had more than one treatment. Thirty‐three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m‐) PFS and m‐OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m‐PFS and m‐OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m‐PFS and m‐OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF‐α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m‐PFS and m‐OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported. Conclusion Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed. Anthracycline‐based regimens, the standard first line treatment in advanced soft tissue sarcomas, paclitaxel and pazopanib have a very limited activity in advanced, progressive epithelioid haemangioendothelioma. In the absence of available, potentially active medical therapies, epithelioid haemangioendothelioma remains today an unmet clinical need.

Résumé Le congrès Targeted Anticancer Therapies (TAT) s’est déroulé cette année du 2 au 4 mars à Paris. Encore une fois l’immunothérapie y était à l’honneur avec les anticorps anti-PD-1/PD-L1, les anticorps anti-CSF-1R, l’immunothérapie adoptive et le développement de combinaisons d’immunothérapies. Le challenge actuel reste de parvenir à identifier les patients susceptibles d’en retirer le plus grand bénéfice. Parmi les molécules prometteuses présentées par ailleurs, on peut citer les agents ciblant les cyclines dépendantes kinases (CDK) ou les empreintes épigénétiques ainsi que les inhibiteurs de PARP et des systèmes de réparation de l’ADN tels qu’ATR. Enfin, une troisième génération d’inhibiteurs de tyrosines-kinases (ITK) est actuellement en cours d’évaluation afin de contourner les résistances acquises aux premiers ITK ; comme le rociletinib actif sur la mutation de résistance T790M dans les cancers bronchiques. Sur le plan des techniques, le criblage moléculaire affirme son intérêt en routine clinique dans le cadre du développement de la médecine personnalisée avec les résultats de l’essai MOSCATO-01, et de nouveaux critères radiologiques et « radiomics » d’évaluation de la réponse tumorale sont en cours de validation pour s’adapter notamment à l’immunothérapie et aux thérapies ciblées.

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization’s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) ≥ 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design.

Despite the high efficacy of antiretroviral therapies, people living with HIV remain more susceptible to infections, cancers, and autoimmune diseases than the general population. [...]a higher incidence of immune-related adverse events, a lower antitumoral efficacy, and induction of inflammatory syndromes with the use of immune checkpoint inhibitors in people living with HIV compared with those without HIV were feared. A review of 176 people living with HIV on immune checkpoint inhibitors, mainly from retrospective studies, reported that 20 (12·1%) of 165 had severe adverse events (ie, Common Terminology Criteria for Adverse Events grade >2), which is similar to the incidence observed in the general population.2 This finding was supported by the results of three phase 1/2 trials of durvalumab (none of 20 patients had severe adverse events), nivolumab (one [6·3%] of 16), and pembrolizumab (seven [23·3%] of 30) in virally suppressed people living with HIV who have cancer.3–5 Of note, one patient given pembrolizumab for a Kaposi sarcoma-associated herpesvirus infection developed associated lethal polyclonal B-cell-lymphoproliferation, but this remains the only case reported to date.5 Importantly, none of these studies reported a negative immunovirological effect of immune checkpoint inhibitors on HIV viral load and CD4 cell count. [...]the safety profile of immune checkpoint inhibitors combined with chemotherapy or tyrosine-kinase inhibitors in people living with HIV has not yet been established, and physicians should have access to multidisciplinary boards of experts, such as the French national CANCERVIH network, to provide optimal treatment to people living with HIV and prevent disparities.

Autoimmune myocarditis is a rare but often fatal complication of immune checkpoint inhibitor therapy for cancer. A case of glucocorticoid-refractory myocarditis in the course of nivolumab treatment for lung cancer was resolved with the use of the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) agonist abatacept.

Immune checkpoint inhibitors (ICI) widely improved the treatment of solid and hematologic malignancies. Yet, a remarkable proportion of patients receiving ICI develop immune related adverse events (irAEs) which are difficult to define as treatment-related. This underlines the need to develop a biomarker to guide irAE diagnosis. We developed a novel flow cytometry assay combining measurement of anti-PD-1 (programmed cell death protein-1) occupancy and evaluation of remaining PD-1 receptor availability with anti-IgG4 PE and anti-PD-1 BV421. We prospectively collected blood and biological fluids samples from patients treated by IgG4 anti-PD-1 therapy (nivolumab or pembrolizumab), with (n=18) or without (n=12) current irAE. We analyzed PD-1+ and IgG4+ staining pattern and MFI values of these parameters on CD4 and CD8 T cells, and IgG4+/PD-1+ MFI ratios are calculated. A higher mean fluorescence intensity IgG4+/PD-1+ ratio was measured on peripheral CD4+ T cells of irAE cases, when compared to controls (p=0.003). ICI-related toxicity is therefore associated with increased therapeutic antibody occupancy of PD-1 receptors on CD4+ T cells. Furthermore, in one case of ICI-related pneumonitis, binding of therapeutic antibody was stronger on lung CD4+ T cell than in blood. In another case of ICI-related encephalitis, the PD-1 receptor occupancy was total on CSF CD4 T cells, but only partial on peripherical CD4 T cells. Our results suggest that flow cytometry monitoring of ICI occupancy can be used in patients treated with monoclonal ICI to guide irAE diagnosis.

Background Vinorelbine is commonly used to treat metastatic breast cancer (mBC), while thiotepa is known for its ability to cross the blood–brain barrier. Methods Our retrospective study aimed to compare the efficacy and safety of vinorelbine with or without thiotepa in patients with HER2‐negative mBC. We used propensity score inverse probability of treatment weighting to ensure comparability between groups. Results Vinorelbine‐thiotepa was not significantly associated with improved median progression‐free survival (PFS) (4.9 vs. 3.0 months, p = 0.138) or median overall survival (OS) (11.8 vs. 11.9 months, p = 0.961) compared to vinorelbine. However, in the central nervous system (CNS) metastasis subgroup, vinorelbine‐thiotepa was associated with a longer median PFS (4.9 vs. 2.1 months, p = 0.013) and CNS‐PFS (6.12 vs. 2.20 months, p = 0.007). The combination was also associated with a higher rate of grade ≥ 3 adverse events (54.3% vs. 37.9%, p = 0.021). Conclusion While no overall benefit in PFS or OS was found, vinorelbine‐thiotepa may be associated with improved PFS in mBC patients with CNS metastasis. Comparative analysis of thiotepa plus vinorelbine versus vinorelbine alone in patients with HER2‐negative metastatic breast cancer, using a propensity score emulated target trial. While no progression‐free survival benefit was observed in the overall population, vinorelbine–thiotepa was associated with significantly improved median progression‐free survival in patients with central nervous system metastases.

Immunotherapies and immune checkpoint inhibitors (ICI) represent the latest revolution in oncology. Several studies have reported an association between the use of corticosteroids and poorer outcomes for patients treated with ICIs. However, it has been never established whether corticoid-induced tumor progression under ICI treatment could be reversible. We report herein transient tumor progression induced by dexamethasone for a patient treated with pembrolizumab for metastatic bladder cancer. An 82-year-old man was treated with pembrolizumab as a second-line treatment for metastatic urothelial carcinoma with stable disease for 8 months as the best tumoral response. He experienced severe coronavirus disease 2019 (COVID-19) infection and was treated with high-dose dexamethasone for ten days according to the RECOVERY protocol. Following this episode, radiological CT-scan evaluation showed tumor progression. Pembrolizumab was maintained, and subsequent radiological evaluation showed tumor shrinkage. This case highlights that the antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Clinicians should be aware that tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients. Insights: The antagonistic effect of glucocorticoids with ICI efficacy is transient and can be reverted when corticoids are withdrawn. Tumor progression in the context of the intercurrent use of systemic corticosteroids can be temporary and should be interpreted with caution, and ICI continuation could be considered for some patients.