Cemiplimab-induced cytokine-release syndrome: second case reported and review of the literature.

Cemiplimab, a human monoclonal antibody directed against PD-1, has provided more options in the treatment of locally advanced or metastatic cutaneous squamous-cell carcinoma at an unresectable state. Immune checkpoint inhibitors can induce several unfavorable reactions generally referred to as immune-related adverse effects. Cytokine-release syndrome is an immune-related adverse event that is infrequent and not well known. Diagnosis is difficult because of the unspecific symptoms (e.g., fever, hypotension) but it can also be life threatening. The authors report the case of a 62-year-old treated by cemiplimab for a cutaneous squamous-cell carcinoma of the diaper fold with iliac and inguinal lymph node extension. He presented with severe cytokine-release syndrome, concluding with the discontinuation of cemiplimab.

Immunotherapy has become an increasingly important part of cancer treatment. This treatment has many side effects, mainly linked with immune system activation. Cytokine-release syndrome is one of the rare complications; it causes hyperthermia, hypotension and biological inflammation. Diagnosis of this syndrome is critical, as it can be life threatening. Diagnosis and early management, including stopping immunotherapy and administering corticosteroids and, in some cases, anti-IL- 6, leads to a favorable outcome in the majority of cases. The authors report the second case of cytokine-release syndrome after cemiplimab infusion used in the first-line treatment of cutaneous unresectable squamous-cell carcinoma.

Pharmaco-mechanical catheter-directed thrombolysis versus recanalization and stenting for post thrombotic syndrome after lower limb deep vein thrombosis: a comparative study.

Background: Endovenous interventional procedures can be used in addition to therapeutic anticoagulation to treat deep vein thrombosis in selected patients with proximal vein involvement (vena cava, iliac and/or common femoral). The aim of this study was to compare venous patency and the post-thrombotic syndrome (PTS) in patients treated with pharmaco-mechanical catheter-directed thrombolysis (PMT) versus recanalization-stenting for PTS after a proximal lower limb deep vein thrombosis. Methods: Between January 2014 and December 2020, this retrospective and monocentric study included patients with very symptomatic acute iliofemoral deep vein thrombosis treated with PMT within 21 days after diagnosis (PMT group) and patients with PTS caused by chronic venous obstruction treated with recanalization and stenting (CRS group). Results: A total of 116 patients were included (26 PMT, 90 CRS). The rate of primary patency was 81.8% (18/22 patients) in the PMT group and 78.4% (69/88) in the CRS group (P>0.99). The rate of venous patency at the last follow-up was 76.9% (20/26) in the PMT group and 82.2% (74/90) in the CRS group (P=0.57). The median number of stents was 2 (range, 0-5) in the PMT group and 3 (range, 0-7) in the CRS group (P<0.001). The median stent length was 150 mm (range, 60-390 mm) and 280 mm (range, 120-820 mm), respectively (P<0.001). The median last Villalta score was 2 (range, 0-10) in the PMT group and 2 (range, 0-21) in the CRS group (P=0.55). The rate of venous claudication at the last follow-up was 19.0% (4/21) in the PMT group and 12.0% (10/83) in the CRS group (P=0.47). Conclusions: In this study, there was no difference in venous patency and in the rate and severity of PTS between the PMT and CRS groups. The number of stent and their length were significantly lower in the PMT group compared with the CRS group.

Prevalence of post-thrombotic syndrome in a cohort of upper extremity vein thrombosis.

OBJECTIVE: Post-thrombotic syndrome (PTS) is one of the main complications that occurs after venous thrombosis. There are few data on the proportion of patients that will develop upper extremity PTS (UE-PTS) after upper extremity venous thrombosis (UEVT). The main objective of the study was to assess the prevalence of PTS in a UEVT cohort and to identify predictive factors of UE-PTS. METHODS: This study included patients with a history of proximal or arm UEVT, diagnosed on duplex ultrasound examination, between January 1, 2015, and December 31, 2017, in a university hospital. After UEVT, each patient was evaluated by a prospective standardized recording of clinical manifestations and duplex ultrasound examination in case of upper limb symptoms. UE-PTS was defined as a modified Villalta score of 4 or higher. RESULTS: Ninety-two patients were included; 68 (73.9%) had deep vein thrombosis (DVT) and 24 (19.2%) arm superficial vein thrombosis. Thirteen patients had PTS (14.1%), 12 (17.6%) in the DVT group and 1 (4.2%) in the superficial vein thrombosis group. There was a history of DVT in 92.3% of the cases of PTS. PTS was more frequent in patients with strokes with limb movement reduction (P = .01). On multivariate Cox analysis, a history of stroke (hazard ratio, 5.4; 95% confidence interval, 1.46-20.22; P = .01) was predictive of UE-PTS. CONCLUSIONS: UE-PTS occurred in 14.1% of cases after UEVT. Stroke with a decrease in limb movement was a predictor of developing PTS. Diagnostic criteria should be established for UE-PTS and prospective studies are needed to improve the description and management of UE-PTS.

Risk factors for symptomatic vascular events in giant cell arteritis: a study of 254 patients with large-vessel imaging at diagnosis.

AIMS: To identify factors associated with vascular events in patients with giant cell arteritis (GCA). METHODS: We performed a retrospective study of GCA patients diagnosed over a 20-year-period, who all underwent vascular imaging evaluation at diagnosis. Symptomatic vascular events were defined as the occurrence of any aortic event (aortic dissection or symptomatic aortic aneurysm), stroke, myocardial infarction, limb or mesenteric ischemia and de novo lower limbs arteritis stage 3 or 4. Patients with symptomatic vascular event (VE+) and without were compared, and risk factors were identified in a multivariable analysis. RESULTS: Thirty-nine (15.4%) of the 254 included patients experienced at least one symptomatic vascular event during follow-up, with a median time of 21.5 months. Arterial hypertension, diabetes, lower limbs arteritis or vascular complication at diagnosis were more frequent in VE+ patients (p < 0.05), as an abnormal computed tomography (CT)-scan at diagnosis (p = 0.04), aortitis (p = 0.01), particularly of the descending thoracic aorta (p = 0.03) and atheroma (p = 0.03). Deaths were more frequent in the VE+ group (37.1 versus 10.3%, p = 0.0003). In multivariable analysis, aortic surgery [hazard ratio (HR): 10.46 (1.41-77.80), p = 0.02], stroke [HR: 22.32 (3.69-135.05), p < 0.001], upper limb ischemia [HR: 20.27 (2.05-200.12), p = 0.01], lower limb ischemia [HR: 76.57 (2.89-2027.69), p = 0.009], aortic atheroma [HR: 3.06 (1.06-8.82), p = 0.04] and aortitis of the descending thoracic aorta on CT-scan at diagnosis [HR: 4.64 (1.56-13.75), p = 0.006] were independent predictive factors of a vascular event. CONCLUSION: In this study on GCA cases with large vessels imaging at diagnosis, aortic surgery, stroke, upper or lower limb ischemia, aortic atheroma and aortitis of the descending thoracic aorta on CT-scan, at GCA diagnosis, were independent predictive factors of a vascular event. PLAIN LANGUAGE SUMMARY: Risk factors for symptomatic vascular events in giant cell arteritisThis study was performed to identify the risk factors for developing symptomatic vascular event during giant cell arteritis (GCA) because these are poorly known.We performed a retrospective study of GCA patients diagnosed over a 20-year-period, who all underwent vascular imaging evaluation at diagnosis.Patients with symptomatic vascular event (VE+) and without (VE-) were compared, and risk factors were identified in a multivariable analysis.Thirty-nine patients experienced at least one symptomatic vascular event during follow-up, with a median time of 21.5 months.Arterial hypertension, diabetes, lower limbs arteritis or vascular complication at diagnosis were significantly more frequent in VE+ patients, as an abnormal CT-scan at diagnosis, aortitis, particularly of the descending thoracic aorta and atheroma. Deaths were more frequent in the VE+ group.Among 254 GCA patients, 39 experienced at least one vascular event during follow-up.Aortic surgery, stroke, upper and lower limb ischemia were vascular event risk factors.Aortic atheroma and descending thoracic aorta aortitis on CT-scan were vascular event risk factors.This study on GCA cases with large vessels imaging at diagnosis, showed that aortic surgery, stroke, upper or lower limb ischemia, aortic atheroma and aortitis of the descending thoracic aorta on CT-scan, at GCA diagnosis, were independent predictive factors of a vascular event.

Large-vessel involvement is predictive of multiple relapses in giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis. Relapses are frequent. The aim of this study was to identify relapse risk factors in patients with GCA with complete large-vessel imaging at diagnosis. METHODS: Patients with GCA followed in our institution between April 1998 and April 2018 were included retrospectively. We included only patients who had undergone large vascular imaging investigations at diagnosis by computed tomography (CT)-scan and/or positron emission tomography (PET)-scan and/or angio-magnetic resonance imaging (MRI). Clinical, biological, and radiological data were collected. Relapse was defined as the reappearance of GCA symptoms, with concomitant increase in inflammatory markers, requiring treatment adjustment. Relapsing patients (R) and non-relapsing patients (NR) were compared. Relapse and multiple relapses (>2) risk factors were identified in multivariable Cox analyses. RESULTS: This study included 254 patients (73.2% women), with a median age of 72 years at diagnosis and a median follow up of 32.5 months. At diagnosis, 160 patients (63%) had an inflammatory large-vessel involvement on imaging, 46.1% (117 patients) relapsed at least once, and 21.3% (54 patients) had multiple relapses. The median delay of first relapse after diagnosis was 9 months. The second relapse delay was 21.5 months. NR patients had more stroke at diagnosis than R (p = 0.03) and the brachiocephalic trunk was involved more frequently on CT-scan (p = 0.046), as carotids (p = 0.02) in R patients. Multivariate Cox model identified male gender [hazard ratio (HR): 0.51, confidence interval (CI) (0.27-0.96), p = 0.04] as a relapse protective factor, and peripheral musculoskeletal manifestations [HR: 1.74 (1.03-2.94), p = 0.004] as a relapse risk factor. Peripheral musculoskeletal manifestations [HR: 2.78 (1.23-6.28), p = 0.014], negative temporal artery biopsy [HR: 2.29 (1.18-4.45), p = 0.015], large-vessel involvement like upper limb ischemia [HR: 8.84 (2.48-31.56), p = 0.001] and inflammation of arm arteries on CT-scan [HR: 2.39 (1.02-5.58), p = 0.04] at diagnosis were risk factors of multiple relapses. CONCLUSION: Male gender was a protective factor for GCA relapse and peripheral musculoskeletal manifestations appeared as a relapsing risk factor. Moreover, this study identified a particular clinical phenotype of multi-relapsing patients with GCA, characterized by peripheral musculoskeletal manifestations, negative temporal artery biopsy, and large-vessel involvement with upper limb ischemia or inflammation of arm arteries. PLAIN LANGUAGE SUMMARY: At giant cell arteritis diagnosis, large-vessel inflammatory involvement is predictive of multiple relapses 46.1% of patients with GCA relapse, and 21.3% undergo multiple relapses;Male gender appears as a protective factor for relapsing in GCA;Peripheral musculoskeletal manifestations are a relapse and multiple relapses risk factor;A negative temporal artery biopsy is predictive of multiple relapses;Large-vessel involvement is predictive of multiple relapses.

Predictive factors of venous recanalization in upper-extremity vein thrombosis.

BACKGROUND: Upper extremity venous thrombosis (UEVT) represents about 10% of venous thrombo-embolic disease. This is mainly explained by the increasing use of central venous line, for oncologic or nutritional care. The factors associated with venous recanalization are not known. OBJECTIVE: The aim of this study was to investigate prognosis factor associated with venous recanalization after UEVT. METHODS: This study included patients with UEVT diagnosed with duplex ultra-sonography (DUS) from January 2015 to December 2017 with DUS evaluations during follow-up. A multivariate Cox proportional-hazards-model analysis was performed to identify predictive factors of UEVT complete recanalization. RESULTS: This study included 494 UEVT, 304 proximal UEVT and 190 distal UEVT. The median age was 58 years, 39.5% were women. Clinical context was: hematological malignancy (40.7%), solid cancer (14.2%), infectious or inflammatory context (49.9%) and presence of venous catheters or pacemaker leads in 86.4%. The rate of recanalization without sequelae of UEVT was 38%. For all UEVT, in multivariate analysis, factors associated with complete vein recanalization were: thrombosis associated with central venous catheter (CVC) (HR:2.40, [1.45;3.95], p<0.001), UEVT limited to a venous segment (HR:1.94, [1.26;3.00], p = 0.003), occlusive thrombosis (HR:0.48 [0.34;0.67], p<0.0001), the presence of a PICC Line (HR:2.29, [1.48;3.52], p<0.001), a thrombosis of deep and distal topography (HR:1.70, [1.10;2.63], p = 0.02) or superficial thrombosis of the forearm (HR:2.79, [1.52;5.12], p<0.001). For deep and proximal UEVT, non-occlusive UEVT (HR:2.23, [1.49;3.33], p<0.0001), thrombosis associated with CVC (HR:1.58, [1.01;2.47], p = 0.04) and infectious or inflammatory context (HR:1.63, [1.10;2.41], p = 0.01) were factors associated with complete vein recanalization. CONCLUSION: In this study, factors associated with UEVT recanalization were UEVT limited to a venous segment, thrombosis associated with CVC, a thrombosis of deep and distal thrombosis topography and superficial thrombosis of the forearm. Occlusive thrombosis was associated with the absence of UEVT recanalization.

Digital ischaemia aetiologies and mid-term follow-up: A cohort study of 323 patients.

ABSTRACT: Upper extremity digital ischaemia (UEDI) is a rare heterogeneous condition whose frequency is 40 times less than that of toe ischaemia. Using a large cohort, the aim of this study was to evaluate aetiologies, prognosis and midterm clinical outcomes of UEDI.All patients with UEDI with or without cutaneous necrosis in a university hospital setting between January 2000 to December 2016 were included. Aetiologies, recurrence of UEDI, digital amputation and survival were analyzed retrospectively.Three hundred twenty three patients were included. UEDI due to cardio-embolic disease (DICE) was the highest occurring aetiology with 59 patients (18.3%), followed by DI due to Systemic Sclerosis (SSc) (16.1%), idiopathic causes (11.7%), Thromboangiitis obliterans (TAO) (9.3%), iatrogenic causes (9.3%), and cancer (6.2%). DICE patients tended to be older and featured more cases with arterial hypertension whereas TAO patients smoked more tobacco and cannabis. During follow-up, recurrences were significantly more frequent in SSc than in all other tested groups (P < .0001 vs idiopathic and DICE, P = .003 vs TAO) and among TAO patients when compared to DICE patients (P = .005). The cumulated rate of digital amputation was higher in the SSc group (n = 18) (P = .02) and the TAO group (n = 7) (P = .03) than in DICE (n = 2).This retrospective study suggests that main aetiologies of UEDI are DICE, SSc and idiopathic. This study highlights higher frequency of iatrogenic UEDI than previous studies. UEDI associated with SSc has a poor local prognosis (amputations and recurrences) and DICE a poor survival. UEDI with SSc and TAO are frequently recurrent.

Effect of cannabis consumption on characteristics and evolution of thromboangitis obliterans.

Background: Thromboangiitis obliterans (TAO) is a distal non atherosclerotic thrombotic vasculitis affecting tobacco smokers. The role of cannabis co-exposure remains controversial. The study aims to assess how cannabis consumption influences clinical presentation and outcome of TAO in tobacco smokers. Patients and methods: TAO patients, according to Papa's criteria, were included in a retrospective bicentric study between the 1st January 2003 and the 1st march 2020. Clinical characteristics, arterial involvement at TAO diagnosis, vascular event and amputations during follow-up were analyzed according to cannabis consumption. Results: Seventy-three patients with TAO patients were included. Forty-five patients were in Tobacco group (T) and 28 in Tobacco and cannabis group (T&C). Tobacco exposure was less important in T&C group than in T group (19.4±11.3 vs 31.6±16.6 pack-years) (p=0.005) and patients in T&C group were younger at TAO diagnosis than in T group (p=0.008). Patients in T&C group presented more claudication (33.3% vs 8.9%, p=0.01) and less upper limbs resting ischemia (25.9% vs 51.1%, p=0.04) than patients in the T group. No differences were found between groups with regard to arterial distribution. Amputation rate for patients who had at least one major or minor amputation did not differ between T and T&C group (25% vs 14.8%, p=0.38). Conclusions: Cannabis consumption was associated with a younger age of TAO onset. However, it does not affect amputation-free survival, Tobacco exposure is less important in T&C patients; data of this bicentric study suggest that cannabis could be a cofactor of tobacco which accelerates TAO onset.

Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2 . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).

A STROBE cohort study of 755 deep and superficial upper-extremity vein thrombosis.

Upper extremity vein thrombosis (UE-VT) are more and more frequent pathologies and yet little studied. The aim is to describe the clinical and ultrasound features, UE-VT-related diseases, and the prevalence of pulmonary embolism (PE) and associated deaths.All UE-VT patients diagnosed by Doppler-ultrasound in Nantes University Hospital, from January 2015 to December 2017, were included retrospectively. UE-VT suspicion patterns, clinical features, UE-VT topography, and prevalence of PE and death were analyzed.Seven hundred and fifty-five UE-VT were analyzed, including 427 deep thrombosis (UE-DVT) and 328 superficial thrombosis (UE-SVT). In 86.2% (n = 651) UE-VT were related to endovascular devices. Among these thrombosis, one third is in connection with a PICC LINE and one quarter with a peripheral venous line. Forty nine percent (n = 370) of the patients had solid neoplasia or hematological malignancies. An inflammatory or systemic infectious context was found in 40.8% (n = 308) of the cases. The most frequently observed clinical sign at the UE-VT diagnosis was edema (28.6%). Among the UE-SVT it was the presence of an indurated cord (33.2%) and among the UE-DVT the indication of the Doppler-ultrasound was mainly a suspicion of infection on endovascular device (35.1%). In 10.6% (n = 80) of the cases the UE-VT were asymptomatic. The most frequently thrombosed veins were brachial basilic veins (16.7% of all thrombosed segments) followed by jugular (13%) and subclavian (12.3%) veins; 61.3% (n = 463) of UE-VT were in the right upper extremity; 63.3% (n = 478) UE-VT were occlusive. The occurrence of PE is 4% and the death rate is 10.2%, mainly related to the severe comorbidities of patients with UE-VT.UE-VT occurs in particular clinical contexts (hematological malignancies, solid cancers, systemic infections) and in the majority of endovascular devices (86.2%). The occurrence of PE is low.

Comparison of idiopathic (isolated) aortitis and giant cell arteritis-related aortitis. A French retrospective multicenter study of 117 patients.

OBJECTIVES: The aim of the study was to compare clinical/imaging findings and outcome in patients with idiopathic (isolated aortitis, IA) and with giant cell arteritis (GCA)-related aortitis. METHODS: Patients from 11 French internal medicine departments were retrospectively included. Aortitis was defined by aortic wall thickening >2mm and/or an aortic aneurysm on CT-scan, associated to inflammatory syndrome. Patients with GCA had at least 3 ACR criteria. Aortic events (aneurysm, dissection, aortic surgeries) were reported, and free of aortic events-survival were compared. RESULTS: Among 191 patients with non-infectious aortitis, 73 with GCA and 44 with IA were included. Patients with IA were younger (65 vs 70 years, p=0.003) and comprised more past/current smokers (43 vs 15%, p=0.0007). Aortic aneurisms were more frequent (38% vs 20%, p=0.03), and aortic wall thickening was more pronounced in IA. During follow-up (median=34 months), subsequent development of aortic aneurysm was significantly lower in GCA when compared to IA (p=0.009). GCA patients required significantly less aortic surgery during follow-up than IA patients (p=0.02). Mean age, sex ratio, inflammatory parameters, and free of aortic aneurism survival were equivalent in patients with IA ≥ 60 years when compared to patients with GCA-related aortitis. CONCLUSIONS: IA is more severe than aortitis related to GCA, with higher proportions of aortic aneurism at diagnosis and during follow-up. IA is a heterogeneous disease and its prognosis is worse in younger patients <60 years. Most patients with IA ≥ 60 years share many features with GCA-related aortitis.