Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept.

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.

Androgens, QT, sex and ventricular repolarization-a double-edged sword: A case series.

The prevalence and incidence of cardiac pro-arrhythmic disorders are often influenced by sex due to specific effects on the QT interval. Androgens shorten QT, which may be protective against acquired long QT syndromes and their related arrhythmias in men such as torsade de pointes (TdP). On the other hand, androgens can potentiate Brugada and early repolarization syndromes, which are most prevalent in men. In this case series, we highlight four male patients with aborted SCD in the setting of abnormal testosterone status; two patients with TdP in a setting of testosterone deprivation (of which one drug-induced) and 2 patients with ventricular fibrillation associated with exogenous androgenic booster (Tribulus terrestris) intake. From this case series, we review the current available literature of the effects of androgen as a double-edged sword on the QTc interval and emphasize the importance of QTc monitoring in this subset of patients.

From cardio-oncology to cardio-onco-pharmacology: Towards a multidisciplinary approach in the understanding and management of cardiotoxicity.

Cardio-oncology is an emerging field that transformed the medical management of patients with cancer. It encompasses the prevention and treatment of cardiovascular toxicities related to cancer treatments, aiming to reduce cardiac adverse events among cancer survivors. Cardiovascular toxicities related to cancer treatments are described through data collected during phase I to phase III therapeutic trials, and post-marketing surveillance (phase IV). Pharmacovigilance analyses, based on datamining from these extensive databases, allowed to understanding and identifying new adverse drug reactions, some recently made available, such as immunotherapy or inhibitor of Bruton tyrosine kinase (IBTK).

Role of Cardiac Imaging in the Diagnosis of Immune Checkpoints Inhibitors Related Myocarditis.

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 (<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.

Development and clinical validation of a simple and fast UPLC-ESI-MS/MS method for simultaneous quantification of nine kinase inhibitors and two antiandrogen drugs in human plasma: Interest for their therapeutic drug monitoring.

Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter- and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and vemurafenib; two active metabolites of them: N-desmethyl imatinib, N-oxide sorafenib; and two AAs: abiraterone and enzalutamide; with short pre-treatment and run time in order to be easily used in clinical practice for their therapeutic drug monitoring (TDM) and facilitating pharmacokinetics and pharmacokinetics/pharmacodynamics studies. Plasma samples were prepared by a single-step protein precipitation. Analytes were separated on a Waters Acquity UPLC® T3 HSS C18 column by non-linear gradient elution; with subsequent detection by Xevo® TQD triple quadrupole tandem mass spectrometer in a positive ionization mode. Analysis time was 2.8 min per run, and all analytes eluted within 1.46-1.97 minutes. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-500 ng/mL for abiraterone, dasatinib and ibrutinib; 5-500 ng/mL for cobimetinib and palbociclib; 10-5,000 ng/mL for imatinib, N-desmethyl imatinib, nilotinib, sorafenib, N-oxide sorafenib and ruxolitinib; 100-50,000 ng/mL for enzalutamide and 100-100,000 ng/mL for vemurafenib with coefficient of correlation above 0.995 for all analytes. This novel method was successfully applied to TDM in clinical practice.

Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19.

BACKGROUND: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. METHODS: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2. RESULTS: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs). CONCLUSION: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.

Pharyngeal motility in patients submitted to type I thyroplasty.

INTRODUCTION: Type 1 thyroplasty is performed to improve glottis closure as well as dysphagic symptoms in patients with unilateral vocal fold immobility. OBJECTIVES: This study aims to compare the motility of the pharynx and upper esophageal sphincter in patients with unilateral vocal fold immobility before and after thyroplasty Type I. METHODS: We prospectively studied 15 patients with unilateral vocal fold immobility who underwent thyroplasty Type I. Subjects were divided according to the topography of vagal injury and presence of dysphagia. High resolution manometry was performed before and 30 days after surgery. Time and pressure manometric parameters at the topography of the velopharynx, epiglottis and upper esophageal sphincter were recorded. RESULTS: Dysphagia was present in 67% of patients. 63% had lower vagal injuries. Manometric parameters did not change after thyroplasty for the whole population. The group of dysphagic patients, however, had an increase in residual pressure at the upper esophageal sphincter after thyroplasty (1.2 vs. 5.2mmHg; p=0.05). Patients with low vagal injury developed higher peak pressure (100 vs. 108.9mmHg p≤0.001), lower rise time (347 vs. 330ms p = 0.04), and higher up stroke (260 vs. 266.2mmHg/ms p=0.04) at the topography of the velopharynx after thyroplasty. CONCLUSION: Pharyngeal motility is affected by thyroplasty Type I in patients with dysphagia and low vagal injury.

High-Resolution Manometry Evaluation of Pressures at the Pharyngo-upper Esophageal Area in Patients with Oropharyngeal Dysphagia Due to Vagal Paralysis.

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.

Importance of esophageal manometry and pH monitoring for the evaluation of otorhinolaryngologic (ENT) manifestations of GERD. A multicenter study.

BACKGROUND/AIMS: Patients with otorhinolaryngologic (ear, nose, and throat-ENT) symptoms attributed to gastroesophageal reflux disease (GERD) are usually treated with medication based on the findings of nasal endoscopy and laryngoscopy only. This study aims to determine sensitivity and specificity of symptoms, nasal endoscopy, and laryngoscopy for the diagnosis of GERD as compared to pH monitoring. METHODS: We studied 79 patients (mean age 53 years, 38 % males) in whom ENT symptoms were assumed to be secondary to GERD. All patients underwent a transnasal laryngoscopy by the ENT team and upper endoscopy and esophageal function tests by the surgical team. GERD was defined by a pathological pH monitoring. RESULTS: Pathologic reflux by pH monitoring was documented in 36 of the 79 patients (46 %), with a mean DeMeester score of 44. In 25 of the 36 patients (69 %), distal and proximal reflux was present. Among patients with negative pH monitoring, one patient was diagnosed with achalasia. ENT symptom sensitivity for globus, hoarseness and throat clearing was respectively 11, 58, and 33 %; specificity was respectively 77, 42, and 58 %. Positive predictive value for nasal endoscopy and laryngoscopy was 46 %. Among patients with positive pH monitoring, 13 (36 %) had a hypotensive lower esophageal sphincter (p < 0.01) and 27 (34 %) had abnormal peristalsis (p < 0.01). CONCLUSIONS: In conclusion, the results of this study showed that (a) ENT symptoms were unreliable for the diagnosis of GERD and (b) laryngoscopy had a low positive predictive value for the diagnosis of GERD. These data confirm the importance of esophageal manometry and pH monitoring in any patient with suspected ENT manifestations of GERD before starting empiric therapy with acid-reducing medications since pathologic reflux by pH monitoring was confirmed in less than half of the patients with suspected GERD.

Histological analysis of autologous fascia graft implantation into the rabbit voice muscle.

UNLABELLED: The ideal approach for the treatment of glottal insufficiency remains a challenge for laryngologists. AIM: This experimental study assessed the histological changes and fibrosis caused by autologous fascia lata grafts into the rabbit voice muscle. STUDY DESIGN: A clinical and experimental study. METHODS: A 0.2 × 0.2 cm fragment of autologous fascia lata was grafted into the right voice muscle of 14 adult rabbits. Animals were euthanized 30 or 60 days post-procedure and histology of the excised vocal folds was carried out. RESULTS: No extensive edema, necrosis or foreign body-type reaction was observed at any time. No significant inflammatory reaction or fibrosis was seen at 30 or 60 days. CONCLUSION: The presence of fascia lata in the rabbit voice muscle had no significant influence on inflammation, and does not increase fibrosis. Rabbit voice muscle shows good tolerance to fascia lata grafting.

Histological analysis of autologous fascia graft implantation into the rabbit voice muscle / Análise histológica em músculo vocal de coelhos submetidos a implante de fáscia lata autóloga

The ideal approach for the treatment of glottal insufficiency remains a challenge for laryngologists. AIM: This experimental study assessed the histological changes and fibrosis caused by autologous fascia lata grafts into the rabbit voice muscle. STUDY DESIGN: A clinical and experimental study. METHODS: A 0.2 × 0.2 cm fragment of autologous fascia lata was grafted into the right voice muscle of 14 adult rabbits. Animals were euthanized 30 or 60 days post-procedure and histology of the excised vocal folds was carried out. RESULTS: No extensive edema, necrosis or foreign body-type reaction was observed at any time. No significant inflammatory reaction or fibrosis was seen at 30 or 60 days. CONCLUSION: The presence of fascia lata in the rabbit voice muscle had no significant influence on inflammation, and does not increase fibrosis. Rabbit voice muscle shows good tolerance to fascia lata grafting.

A apropriada abordagem no tratamento da insuficiência glótica causada por paralisa, cicatriz e atrofia de prega vocal é um desafio ao laringologista. OBJETIVO: O presente estudo avaliou as alterações histológicas e fibrose desencadeadas pelo enxerto autólogo de fáscia lata no músculo vocalde coelhos. FORMA DE ESTUDO: Clínico e Experimental. MATERIAL E MÉTODO: Foi realizado um estudo experimental com 14 coelhos adultos que foram submetidos a implante de fáscia lata autóloga medindo 0,2 x 0,2cm, no músculo vocal direito. Os animais foram sacrificados após 30 e 60 dias do procedimento, suas laringes removidas e submetidas a estudo histológico. RESULTADOS: Não foi observado edema extenso, área de necrose ou reação inflamatória do tipo corpo estranho. A reação inflamatória observada após 30 e 60 dias foi leve, bem como a fibrose desencadeada. CONCLUSÃO: A presença de fáscia lata autóloga no músculo vocal de coelho não desencadeou fibrose e resposta inflamatória significativa.

Comparação entre a telelaringoscopia e a laringoscopia de suspensão no diagnóstico das lesões benignas das pregas vocais / Comparison between telelaryngoscopy and suspension laryngoscopy in the diagnosis of benign vocal fold lesions

O correto diagnóstico das lesões benignas da laringe ainda causa dúvida em laringologistas experientes, apesar dos avanços diagnósticos. OBJETIVO: O objetivo desse estudo foi comparar a telelaringoscopia (pré-operatória) com a laringoscopia de suspensão (intra-operatória) no diagnóstico das lesões benignas das pregas vocais. MATERIAL E MÉTODO: Foi realizado um estudo retrospectivo através da análise de 79 prontuários de pacientes acompanhados em um hospital universitário. Em todos os prontuários havia pelo menos uma hipótese diagnóstica ambulatorial sugerida pela telelaringoscopia, que posteriormente foi comparada aos achados intra-operatórios da laringoscopia de suspensão. RESULTADOS: Quase dois terços dos pacientes eram do gênero feminino, com idade variando de 12 aos 66 anos (média de 37 anos). Dos 79 pacientes estudados, foram diagnosticadas 95 lesões com a telelaringoscopia e 124 com a laringoscopia de suspensão. A lesão benigna mais freqüente foi pólipo vocal em ambos os métodos. Em 64,5 por cento dos casos, o diagnóstico das lesões feito no ambulatório foi o mesmo dos achados cirúrgicos. CONCLUSÃO: O laringologista deve estar preparado para alterar seu planejamento cirúrgico e abordagens terapêuticas devido às mudanças diagnósticas que ocorrem no intra-operatório.

Proper diagnosis of laryngeal benign lesions still brings doubts among experienced laryngologists, despite current diagnostic progress. AIM: the goal of this study was to compare telelaryngoscopy (preoperative) with suspension laryngoscopy (intraoperative) on the diagnosis of vocal fold benign lesions. MATERIALS AND METHODS: We carried out a restrospective study analyzing 79 charts from patients followed up in a University Hospital. In all the charts there was at least diagnostic hypothesis suggested by telelaryngoscopy, which was later on compared to intraoperative findings of suspension laryngoscopy. RESULTS: Almost two-thirds of the patients were females, with ages varying between 12 and 66 years (mean of 37 years). Of the 79 patients studied, we diagnosed 95 lesions with telelaryngoscopy and 124 with suspension laryngoscopy. The most frequently found benign lesion was the vocal polyp in both methods. In 64.5 percent of the cases the diagnosis of the lesions in the outpatient ward was the same as those in the surgical findings. CONCLUSION: Laryngologists must be prepared to alter their surgical planning and treatment approaches because of diagnostic changes that may happen during surgery.

Comparison between telelaryngoscopy and suspension laryngoscopy in the diagnosis of benign vocal fold lesions.

UNLABELLED: Proper diagnosis of laryngeal benign lesions still brings doubts among experienced laryngologists, despite current diagnostic progress. AIM: The goal of this study was to compare telelaryngoscopy (preoperative) with suspension laryngoscopy (intraoperative) on the diagnosis of vocal fold benign lesions. MATERIALS AND METHODS: We carried out a restrospective study analyzing 79 charts from patients followed up in a University Hospital. In all the charts there was at least diagnostic hypothesis suggested by telelaryngoscopy, which was later on compared to intraoperative findings of suspension laryngoscopy. RESULTS: Almost two-thirds of the patients were females, with ages varying between 12 and 66 years (mean of 37 years). Of the 79 patients studied, we diagnosed 95 lesions with telelaryngoscopy and 124 with suspension laryngoscopy. The most frequently found benign lesion was the vocal polyp in both methods. In 64.5% of the cases the diagnosis of the lesions in the outpatient ward was the same as those in the surgical findings. CONCLUSION: Laryngologists must be prepared to alter their surgical planning and treatment approaches because of diagnostic changes that may happen during surgery.

Estudo de paralisias faciais traumáticas: análise de casos clínicos e cirúrgicos / Traumatic facial paralysis's study: clinical and surgical review

As paralisias faciais traumáticas são a segunda causa mais freqüente de Paralisia Facial Periférica, ficando somente atrás dos casos ditos idiopáticos. FORMA DE ESTUDO: Clínico retrospectivo. MATERIAL E MÉTODO: Foram estudados retrospectivamente 82 pacientes atendidos no período de janeiro de 1990 a janeiro de 1999 no ambulatório de ORL da Escola Paulista de Medicina. RESULTADO: Deste grupo 54, eram do sexo masculino (65.8 por cento) e 28 do sexo feminino (34.2 por cento). A idade média foi de 30.9 anos (variando de 2 a 75 anos). Quanto ao tipo de trauma, obtivemos: 15 (18.22 por cento) iatrogênicos, 2 (2.44 por cento) por ferimentos cortantes da face, 50 (60.97 por cento) pós-traumas crânio-encefálicos, 14 (17.07 por cento) ferimentos por projéteis de arma de fogo e 1 (1.22 por cento) ao nascimento. Quanto ao tipo de aparecimento, observamos: 71 (86.5 por cento) de início súbito, 10 (12.3 por cento) progressivos e 1 (1.2 por cento) ao nascimento. Quanto aos testes elétricos iniciais, observamos: 32 (43.84 por cento) com exames que foram simétricos e 41 (56.16 por cento) com exames inescitáveis. Dos 32 casos com simetria, observamos 24 com recuperação total, 6 com 80 por cento de recuperação e 2 com 60 por cento; já nos casos inexcitáveis, dos 41 casos apenas 5 evoluíram para a recuperação total. CONCLUSÃO: Frente aos resultados concluímos que: 1. Houve predomínio da incidência no sexo masculino; 2. Houve predomínio dos casos súbitos e estes evoluíram proporcionalmente melhor que os progressivos; 3. Houve predomínio dos casos de etiologia por TCE e estes evoluíram proporcionalmente melhor que as outras etiologias; 4. Os testes elétricos realizados puderam prever com bom grau de acerto a evolução dos pacientes; 5. O tipo de tratamento realizado foi proporcionalmente mais agressivo quanto mais intensa era a paralisia, com bons resultados.