Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

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The motility of the pharynx, upper esophageal sphincter (UES), and proximal esophagus in patients with oropharyngeal dysphagia is still not entirely understood. High-resolution manometry (HRM) was recently added to the armamentarium for the study of this area. This study aims to describe HRM findings in patients with vagal paralysis. Sixteen patients (mean age 54 years, 69% females) with oropharyngeal dysphagia due to unilateral vagal paralysis were prospectively studied. All patients underwent HRM. Motility of the UES and at the topography of the velopharynx and epiglottis were recorded. (1) UES relaxation is compromised in a minority of patients, (2) epiglottis pressure does not follow a specific pattern, (3) vellum is hypotonic in half of the patients, (4) dysphagia is related to a low pharyngeal pressure, not to a flow obstruction at the level of the UES, and (5) aspiration is related to low pressures at the level of the UES and epiglottis and higher pressures at the level of the vellum. Pharyngeal motility is significantly impaired in patients with oropharyngeal dysphagia and unilateral vagal paralysis. In half of the cases, UES resting pressure is preserved due to unilateral innervation and relaxation is normal in most patients. Dysphagia therapy in these patients must be directed toward improvement in the oropharyngeal motility not at the UES.

Background: Immune-checkpoint inhibitors (ICI) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, troponin-I (cTnI), troponin-T (cTnT) and creatine-kinase (CK) are used for diagnosis. However, the temporal elevation of these biomarker elevations with course of disease and their association with outcomes have not been established. Methods: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT and CK in ICI-myocarditis (n=61) in two cardio-oncology units (APHP.Sorbonne, France & Heidelberg, Germany). Major adverse cardio-myotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular/sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and related death. Diagnostic performances of troponins were also assessed in an international ICI-myocarditis registry (n=244 independent cases, 13 countries). Results: On presentation, cTnT, cTnI or CK were increased compared to upper reference limit (URL) in 51/52 (98%), 28/34 (82%, p=0.009 vs. cTnT), 33/48 (69%, p<0.0001 vs. cTnT), respectively. This higher rate of positivity for cTnT vs. cTnI was independently confirmed in an international registry. In patients surviving to 30 days, cTnI and CK had normalized in 20/34(59%) and 30/35(86%), respectively, while cTnT had reached normal values in only 5/42(12%), (p<0.0001). The highest value of cTnT/URL within the first 72h of admission performed best in predicting MACE (AUC:0.82) vs. CK/URL (AUC:0.74) and cTnI/URL (AUC:0.67), even after adjustment for age and sex. Maximal value of cTnT/URL≥32 within ≤72h of diagnosis was the best predictor cut-off for MACE (Hazard-ratio=9.4(95% CI 3.1, 28.3), p<0.0001) over a median follow-up of 4 months. cTnT was increased in all patients just before MACE (22/22, 100%) while cTnI and CK values were normal in 3/21(14%) and 6/24(25%) of patients (p<0.0001). Conclusions. Significant discrepancies between cTnT (compared to cTnI, and CK) circulating levels exist in ICI-myocarditis. cTnT is the best predictor of MACE and most suitable for diagnosis and surveillance. A ratio of cTnT/URL<32 within ≤72h of diagnosis identifies a subgroup at low-risk of MACE.

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Immune checkpoint inhibitors (ICI) have constituted a paradigm shift in the management of patients with cancer. Their administration is associated with a new spectrum of immune-related toxicities that can affect any organ. In patients treated with ICI, cardiovascular toxicities, particularly myocarditis, occur with a low incidence (&lt;1%) but with a high fatality rate (30−50%). ICI-related myocarditis has been attributed to an immune infiltration, comprising of T-cells that are positive for CD3+, CD4+, CD8+, and macrophages that are positive for CD68. The diagnosis remains challenging and is made based on clinical syndrome, an electrocardiogram (ECG), biomarker data, and imaging criteria. In most clinical scenarios, endomyocardial biopsy plays a pivotal role in diagnosis, while cardiac magnetic resonance imaging (cMRI) has limitations that should be acknowledged. In this review, we discuss the role of medical imaging in optimizing the management of ICI related myocarditis, including diagnosis, prognostication, and treatment decisions.

This study aims to evaluate the upper esophageal sphincter (UES) motility in patients with gastroesophageal reflux disease (GERD) as compared to healthy volunteers. We retrospectively studied the HRM tests of 44 patients (median age: 61 years, 54% females) under evaluation for GERD. The manometric UES parameters of these patients were compared to 40 healthy volunteers (median age: 27 years, 50% females). Almost half of the patients had a short and hypotonic UES. Patients with extraesophageal symptoms had a higher proportion of hypotonic UES as compared to patients with esophageal symptoms. Reflux pattern did not influence manometric parameters. Proximal reflux (any number of episodes) was present in 37(84%) patients (median number of proximal episodes = 6). Manometric parameters are similar in the presence or absence of proximal reflux. There is not a correlation between the UES length and UES basal pressure. In conclusion, our results show that: (1) the manometric profile of the UES in patients with GERD is characterized by a short and hypotonic UES in half of the patients; (2) this profile is more pronounced in patients with extraesophageal symptoms; and (3) neither the presence of proximal reflux nor reflux pattern bring a different manometric profile.