Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment

Background: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. Patients and methods: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. Results: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. Conclusions: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.publishedVersio

Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up

Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.publishedVersio

Intracranial Hemorrhage From Dural Arteriovenous Fistulas: Symptoms, Early Rebleed, and Acute Management: A Single-Center 8-Year Experience

Abstract BACKGROUND Cerebral dural arteriovenous fistulas (dAVFs) presenting with hemorrhage are so rare that reports on their characteristics and guidelines for their acute management are scarce. OBJECTIVE To identify characteristics of the clinical and radiological presentation of hemorrhaging dAVFs, and establish their frequency of early rebleed so that implications for their acute management can be drawn. METHODS Retrospective analysis of all patients admitted with intracranial hemorrhage from a dAVF during the years 2011 to 2018. RESULTS Twenty patients (14 males) with a median age of 61 yr (27-75 yr) were included. Thunderclap headache was the presenting symptom in 13 (65%) patients. Rebleed prior to treatment occurred in 35% of the patients at median 7.5 h (range 3-96 h) after the ictus. All dAVFs had retrograde venous drainage and a venous aneurysm with a bleb was the source of hemorrhage in 16 (80%) patients, all of them presenting with headache. In contrast, patients bleeding due to diffuse venous hypertension presented with neurological deficits. Endovascular treatment was successful in 2 cases; hence, definite dAVF treatment was surgical in 18 (90%) patients. At median 7 mo (2-29 mo) after the ictus, 13 (65%) patients were in Glasgow Outcome Scale-Extended 7 or 8. CONCLUSION The typical presentation of hemorrhage from a cranial dAVF is thunderclap headache. The origin of hemorrhage is often a ruptured venous aneurysm with a bleb. The high frequency of early rebleeds warrants management strategies equivalent to those established for aneurysmal subarachnoid hemorrhage. Overall outcome is favorable

Endovascular versus surgical treatment of cranial dural arteriovenous fistulas: a single-center 8-year experience

Abstract Background Cranial dural arteriovenous fistulas (dAVFs) are rare lesions managed mainly with endovascular treatment (EVT) and/or surgery. We hypothesize that there may be subtypes of dAVFs responding better to a specific treatment modality in terms of successful obliteration and cessation of symptoms and/or risks. Methods All dAVFs treated during 2011–2018 at our hospital were analyzed retrospectively. Presenting symptoms, radiological variables, treatment modality, complications, and residual symptoms were related to dAVF type using the original Djindjian classification. Results We treated 112 dAVFs in 107 patients (71, 66% males). They presented with hemorrhage ( n  = 23; 21%), non-hemorrhagic symptoms ( n  = 75; 70%), or were discovered incidentally ( n  = 9; 8%). There were 25 (22%) type I, 29 (26%) type II, 26 (23%) type III, and 32 (29%) type IV fistulas. EVT was the primary treatment modality in 72/112 (64%) dAVFs whereas 40/112 (36%) underwent primary surgery with angiographic obliteration rates of 60% and 90%, respectively. Using a secondary treatment modality in 23 dAVFs, we obtained a final obliteration rate of 93%, including all type III/IV and 26/27 (96%) type II dAVFs. Except for headache, residual symptoms were rare and minor. Permanent neurological complications consisted of five cranial nerve deficits. Conclusions We recommend EVT as first treatment modality in types I, II, and in non-hemorrhagic type III/IV dAVFs. We recommend surgery as first treatment choice in acute hemorrhagic dAVFs and as secondary choice in type III/IV dAVFs not successfully occluded by EVT. Combining the two modalities provides obliteration in 9/10 dAVF cases at a low procedural risk

Heterotopic ossification and clinical outcome in nonconstrained cervical arthroplasty 2 years after surgery: the Norwegian Cervical Arthroplasty Trial (NORCAT)

Purpose Heterotopic ossification is a phenomenon in cervical arthroplasty. Previous reports have mainly focused on various semiconstrained devices and only a few publications have focused on ossification around devices that are nonconstrained. The purpose of this study was to assess the occurrence of heterotopic ossification around a nonconstrained cervical device and how it affects clinical outcome 2 years after surgery. Methods Thirty-seven patients were included from a larger cohort of a randomized controlled trial (NORCAT) which compared single-level cervical arthroplasty with fusion. The occurrence of heterotopic ossification was assessed with a CT scan and two neuroradiologists determined its degree. For grading, we used the Mehren/Suchomel classification system (grade 0–4). The patients were divided by level of ossification, low grade (0–2) or high grade (3–4), and clinical outcomes were compared. Self-rated disability for neck and arm pain (Neck Disability Index), health-related quality of life (the Short Form-36 and EuroQol-5D), and pain (the Numeric Rating Scale 11) were used as clinical outcome measures. Results Heterotopic ossification was encountered in all patients 2 years after surgery. Complete fusion (grade 4) was found in 16 % of participants, and high-grade ossification (grade 3–4) occurred in 62 %. The remaining patients were classified as having low-grade ossification (grade 2). There were no differences in the clinical outcomes of patients with low- and high-grade ossification. Conclusion High-grade heterotopic ossification and spontaneous fusion 2 years after surgery were seen in a significant number of patients. However, the degree of ossification did not influence the clinical outcome

Cholesterol Crystals Induce coagulation Activation through Complement-Dependent Expression of Monocytic Tissue Factor

Cholesterol crystals (CC) are strong activators of complement and could potentially be involved in thromboinflammation through complement-coagulation cross-talk. To explore the coagulation-inducing potential of CC, we performed studies in lepirudin-based human whole blood and plasma models. In addition, immunohistological examinations of brain thrombi and vulnerable plaque material from patients with advanced carotid atherosclerosis were performed using polarization filter reflected light microscopy to identify CC. In whole blood, CC exposure induced a time- and concentration-dependent generation of prothrombin fragment 1+2 (PTF1.2), tissue factor (TF) mRNA synthesis, and monocyte TF expression. Blocking Abs against TF abolished CC-mediated coagulation, thus indicating involvement of the TF-dependent pathway. Blockade of FXII by corn trypsin inhibitor had a significant inhibitory effect on CC-induced PTF1.2 in platelet-free plasma, although the overall activation potential was low. CC exposure did not induce platelet aggregation, TF microparticle induction, or TF on granulocytes or eosinophils. Inhibition of complement C3 by CP40 (compstatin), C5 by eculizumab, or C5aR1 by PMX53 blocked CC-induced PTF1.2 by 90% and reduced TF+ monocytes from 18-20 to 1-2%. The physiologic relevance was supported by birefringent CC structures adjacent to monocytes (CD14), TF, and activated complement iC3b and C5b-9 in a human brain thrombus. Furthermore, monocyte influx and TF induction in close proximity to CC-rich regions with activated complement were found in a vulnerable plaque. In conclusion, CC could be active, releasable contributors to thrombosis by inducing monocyte TF secondary to complement C5aR1 signaling

Cholesterol crystals induce coagulation activation through complement-dependent expression of monocytic tissue factor

Cholesterol crystals (CC) are strong activators of complement and could potentially be involved in thromboinflammation through complement-coagulation cross-talk. To explore the coagulation-inducing potential of CC, we performed studies in lepirudin-based human whole blood and plasma models. In addition, immunohistological examinations of brain thrombi and vulnerable plaque material from patients with advanced carotid atherosclerosis were performed using polarization reflected light microscopy to identify CC. In whole blood, CC exposure induced a time- and concentration-dependent generation of prothrombin fragment 1+2 (PTF1.2), tissue factor (TF) mRNA synthesis, and monocyte TF expression. Blocking Abs against TF abolished CC-mediated coagulation, thus indicating involvement of the TF-dependent pathway. Blockade of FXII by corn trypsin inhibitor had a significant inhibitory effect on CC-induced PTF1.2 in platelet-free plasma, although the overall activation potential was low. CC exposure did not induce platelet aggregation, TF microparticle induction, or TF on granulocytes or eosinophils. Inhibition of complement C3 by CP40 (compstatin), C5 by eculizumab, or C5aR1 by PMX53 blocked CC-induced PTF1.2 by 90% and reduced TF monocytes from 18-20 to 1-2%. The physiologic relevance was supported by birefringent CC structures adjacent to monocytes (CD14), TF, and activated complement iC3b and C5b-9 in a human brain thrombus. Furthermore, monocyte influx and TF induction in close proximity to CC-rich regions with activated complement were found in a vulnerable plaque. In conclusion, CC could be active, releasable contributors to thrombosis by inducing monocyte TF secondary to complement C5aR1 signaling

Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment

Background: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. Patients and methods: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. Results: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. Conclusions: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making