Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies.

Chimeric antigen receptor (CAR-) T cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that is thus far considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR-T cell therapy between 01/2020 and 05/2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet, DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose dependent manner (r = -0.44, p = 0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, p < 0.001). We thus hypothesize that fibrinogen synthesis in CRS is upregulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR-T cell therapy and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

Gemcitabine Maintenance Therapy in Patients With Metastasized Soft Tissue Sarcomas.

BACKGROUND: Metastasized soft-tissue sarcomas still pose a significant therapeutic challenge given the limited efficacy of currently available multimodal treatment strategies. Recent progress in molecular characterization of sarcoma subtypes has enabled successful personalized therapy approaches in a minority of selected patients with targetable mutations. However, in the majority of patients with refractory soft tissue sarcomas, long-term survival remains poor. METHODS: We report on three adult patients with various soft tissue sarcomas subjected to Gemcitabine maintenance therapy. Tumor entities included leiomyosarcoma of the pancreas (patient 1), undifferentiated pleomorphic sarcoma of the right femur (patient 2), and peri-aortic leiomyosarcoma (patient 3). Metastatic sites encompassed liver, lung, and bones. All patients received Gemcitabine maintenance therapy until disease progression following prior salvage chemotherapy with Docetaxel and Gemcitabine. Patients were treated outside of clinical trials. Response assessment was based on radiological imaging. RESULTS: In response to salvage chemotherapy with Docetaxel and Gemcitabine, one patient exhibited a partial remission, and two patients showed stable disease. Patient 1 exhibited stable disease for 6 months during Gemcitabine maintenance therapy before suffering rapid progression of hepatic metastases. Patient 2 underwent 21 months of Gemcitabine maintenance therapy, which was discontinued after progressive pulmonary metastases were detected. Patient 3 is still being treated with Gemcitabine maintenance therapy. Remarkably, owing to significant chemotherapy-associated hematotoxicity, the dose of Gemcitabine dose was reduced by two-thirds. Nevertheless, stable disease with constant pulmonary metastases has been maintained in this patient for 14 months. CONCLUSIONS: Gemcitabine maintenance therapy following prior Docetaxel and Gemcitabine chemotherapy is manageable and reveals potential benefits for patients with aggressive metastasized soft tissue sarcomas. Prospective trials evaluating Gemcitabine maintenance therapy are encouraged.

Case Report: Dual Checkpoint Inhibition in Advanced Metastatic Osteosarcoma Results in Remission of All Tumor Manifestations-A Report of a Stunning Success in a 37-Year-Old Patient.

BACKGROUND: Patients with unresectable metastasized osteosarcoma have a poor prognosis. Current treatment options do not offer a chance to cure the disease in this situation. Despite the fact that immunotherapy has expanded its indications continuously over previous years, its use is not yet established in osteosarcoma. There is a lack of randomized controlled studies that could show a significant benefit in this rare tumor entity. So far, efficacy of immunotherapy is only reported in individual cases as well as in mouse models. To predict a response to immunotherapy, testing for programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB) can be useful, but status is not yet clear for most cancer entities. METHODS: Single case study and review of the literature. CASE PRESENTATION: This report presents the case of a 37-year-old patient with metastatic advanced osteosarcoma, who had no more established options for tumor treatment left. PD-L1 expression in the most recent tumor sample was high (tumor proportion score (TPS) 90%, combined positive score (CPS) 92%) but no MSI could be detected. In an individual therapy attempt, an ongoing and profound remission of all tumor manifestations due to four cycles of immunotherapy with ipilimumab and nivolumab was reached. Despite discontinuation of immunotherapy for 3 months due to therapy-related pneumonitis, remission of all tumor manifestations was ongoing, and no detectable relapse in restaging before onset of Nivolumab-maintenance could be observed. CONCLUSION: The present case constitutes the first report of an adult patient with metastasized advanced osteosarcoma who reached a deep remission of disease by immunotherapy with ipilimumab and nivolumab, which continued even though immunotherapy had to be interrupted. To verify whether the high expression of PD-L1, as seen in this patient, is a predictive marker for response to immunotherapy in osteosarcoma, requires further investigation.

The impact of epicardial adipose tissue in patients with acute myocardial infarction.

AIMS: Epicardial adipose tissue (EAT) has been linked to impaired reperfusion success after percutaneous coronary intervention (PCI). Whether EAT predicts myocardial damage in the early phase after acute myocardial infarction (MI) is unclear. Therefore, we investigated whether EAT in patients with acute MI is associated with more microvascular obstruction (MVO), greater ST-deviation, larger infarct size and reduced myocardial salvage index (MSI). METHODS AND RESULTS: This retrospective analysis of a prospective observational study including patients with acute MI (n = 54) undergoing PCI and 12 healthy matched controls. EAT, infarct size and MSI were analyzed with cardiac magnetic resonance imaging, conducted 3-5 days and 12 weeks after MI. Patients with acute MI showed higher EAT volume than healthy controls (46 [25.;75. percentile: 37;59] vs. 24 [15;29] ml, p < 0.001). The high EAT group (above median) showed significantly more MVO (2.22 [0.00;5.38] vs. 0.0 [0.00;2.18] %, p = 0.004), greater ST-deviation (0.38 [0.22;0.55] vs. 0.15 [0.03;0.20] mV×10-1, p = 0.008), larger infarct size at 12 weeks (23 [17;29] vs. 10 [4;16] %, p < 0.001) and lower MSI (40 [37;54] vs. 66 [49;88] %, p < 0.001) after PCI than the low EAT group. After accounting for demographic characteristics, body-mass index, heart volume, infarct location, TIMI-flow grade as well as apnea-hypopnea index, EAT was associated with infarct size at 12 weeks (B = 0.38 [0.11;0.64], p = 0.006), but not with MSI. CONCLUSIONS: Patients with acute MI showed higher volume of EAT than healthy individuals. High EAT was linked to more MVO and greater ST-deviation. EAT was associated with infarct size, but not with MSI.

Erratum to: Resolution of ST deviation after myocardial infarction in patients with and without sleep-disordered breathing.

[This corrects the article DOI: 10.1007/s11818-018-0154-8.].

Association of sleep-disordered breathing and disturbed cardiac repolarization in patients with ST-segment elevation myocardial infarction.

OBJECTIVE: In patients with ST-segment elevation myocardial infarction (STEMI), disturbed cardiac repolarization before percutaneous coronary intervention (PCI) is a risk factor for malignant ventricular arrhythmia. We tested the hypothesis that sleep-disordered breathing (SDB) in patients with STEMI is associated with disturbed cardiac repolarization. METHODS: Thirty-three patients with STEMI who underwent PCI were prospectively enrolled. To assess cardiac repolarization, the heart-rate corrected interval from the peak of the T wave to the end of the T wave (TpTec) and QTc intervals were assessed with 12-lead electrocardiography before PCI, within 24 h after PCI, and 12 weeks after PCI. SDB defined as an apnea-hypopnea index (AHI) ≥15 per hour was diagnosed by polysomnography. RESULTS: Before PCI, patients with SDB had a significantly prolonged TpTec interval compared to patients without SDB (133 vs 104 ms, p = 0.035). Within 24 h after PCI, the TpTec interval was 107 vs 92 ms (p = 0.178). QTc intervals showed a similar pattern (pre-PCI: 443 vs 423 ms, p = 0.199; post-PCI: 458 vs 432 ms, p = 0.115). In multiple linear regression analyses, AHI was significantly associated with prolonged TpTec intervals (pre-PCI: B-coefficient = 1.11, 95% confidence interval (CI) 0.48-1.74, p = 0.001; post-PCI: B = 0.97, 95% CI 0.29-1.65, p = 0.007), prolonged QTc intervals (pre-PCI: B = 1.05, 95% CI 0.20-1.91, p = 0.018; post-PCI: B = 1.37, 95% CI 0.51-2.24, p = 0.003), and higher TpTe/QT-ratios (pre-PCI: B = 0.16, 95% CI 0.05-0.27, p = 0.007; post-PCI: B = 0.13, 95% CI < 0.01-0.25, p = 0.036), independent of known risk factors for cardiac arrhythmia. CONCLUSION: In patients with STEMI, SDB was significantly associated with disturbed cardiac repolarization before and after PCI, independent of known risk factors. These findings suggest that SDB may contribute to the risk of developing malignant ventricular arrhythmia.