Case Report: Sudden very late-onset near fatal PD1 inhibitor-associated myocarditis with out-of-hospital cardiac arrest after >2.5 years of pembrolizumab treatment

IntroductionImmune checkpoint inhibitors have advanced the outcomes of many different types of cancer. A rare but extraordinarily severe complication of these agents resembles immune checkpoint inhibitor-related myocarditis, which typically occurs within the first few weeks after treatment initiation with a mortality of 25%–50%.Case reportA 57-year-old woman had uneventfully received pembrolizumab for metastatic non-small cell lung cancer for over 2.5 years and was admitted after an out-of-hospital cardiac arrest due to ventricular fibrillation. After successful cardiopulmonary resuscitation, the initial diagnostic work-up showed elevated cardiac enzymes and a limited left-ventricular ejection fraction, while coronary angiography did not show relevant stenosis. Despite cardiac MRI being unsuggestive of myocarditis, myocardial biopsies were obtained and histologically confirmed anti-PD-1 antibody-associated myocarditis. After the initiation of prednisone at 1 mg/kg body weight, the patient gradually recovered and was discharged three weeks later with markedly improved cardiac function.ConclusionThis case resembles the first description of a very late onset irMyocarditis, occurring over 2.5 years after the start of treatment. It demonstrates the importance of contemplating that severe immune-related toxicities with a sudden onset clinical presentation may occur even after long uneventful periods of anti-PD-1 immune checkpoint inhibitor treatment. Furthermore, it underlines the critical importance of myocardial biopsies in this setting, especially when cardiac MRI remains inconclusive. Moreover, it demonstrates the necessity and benefits of early immunosuppressive treatment if immune-related myocarditis is considered a differential diagnosis

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity

Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities

A Comparative Study of Incidents Investigation methods

[[abstract]]事故災害的發生，往往造成事業單位人員傷亡、財產設備損失與企業商譽受損，因此事故調查的過程就顯為重要，事故調查的基本目的是對於事故進行檢討，找出事故發生的原因，並從事故原因提出防範對策，如何經過事故調查過程找出正確事故原因，需透過事故分析手法，不同分析手法會因為執行調查人員身份與調查方法，而產生不同調查結果。事業單位發生事故災害未達法令規定需回報政府機關，一般事故皆由事業單位自行調查，無法比照國內重大事故調查與美國事故調查單位（CSB）有強大專業學術後盾的專家進行事故調查，有鑑於此，需要有一套符合事業單位背景條件的事故分析手法工具，以此事故分析手法工具提出事故原因與防範對策。 因此，本研究將探討由日本學者所提的失敗學分析手法、勞動檢查機關現行的國內重大事故分析手法與光電廠區內部的事故案例分析手法，經由三項不同型式分析手法，由事故實例分析的過程與結果，析分不同手法的差異處，並提出適合一般事業適用的事故分析工具。期盼依此事故分析工具協助事業單位使用，能夠避免事故一再發生，使員工在安全的環境下作業，以保障企業持續發展與永續經營。[[abstract]]The happening of the accident always cause casualties, property loss and the enterprise goodwill is impaired. For those reasons, the process of accident investigations is the most important thing and it is the basic purpose of a review to find out the reason for accidents. We could follow the procedure of accident investigations to figure out the primary causes for the accident and get the countermeasures in advance for other issues by the accident analysis technique. We will get different results by diverse analysis methods and unlike identity of investigators. Accident disasters institution of law needs to return the government organs. Whereas, the general accident investigation by the institutions themselves, not according to the domestic major accident investigation. The accident investigation unit (the CSB) has strong professional academic backing experts in accident investigation. In light of this, we need to have a meet the requirements for the institution background of accident analysis tools, to put forward the cause of the accident and accident analysis technique tool preventive countermeasures. Therefore, this research will be discussed by the Japanese scholar failure analysis technique, labor inspection office of the current domestic major accident analysis technique and photoelectric factory internal accident case analysis technique. Via those three different types of analysis technique, following the process and results from divers’ accident case study will get multiple analysis point and methods for accident analysis tools. Wish this accident analysis tool is useful for enterprises to avoid the accident happen again and again, give employees a safe working environment, and ensure enterprises sustainable development

Ocular diseases in metastatic cutaneous melanoma: review of 108 consecutive patients in two German tertiary centers

Purpose To analyze the incidence and spectrum of ocular disease in patients with metastatic cutaneous melanoma. Methods One hundred and eight consecutive patients with metastatic cutaneous melanoma were screened for ocular diseases using standardized eye examination, including measurement of visual acuity and intraocular pressure, slit-lamp examination, funduscopy in mydriasis, and spectral-domain optical coherence tomography (SDOCT) of the retina. Selected cases with atypical findings underwent electrophysiological studies. One patient was examined for hypercortisolism by a dexamethasone suppression test. Results Ocular diseases were found in 65 out of 108 patients (60 %) with metastatic cutaneous melanoma, significantly more often in older patients (p=0.004). Cataract was present in 27 patients (25 %), pseudophakia in 22 patients (20 %), macular disease in 29 patients (28 %), diabetic retinopathy in ten patients (9 %), hypertensive retinal disease in 14 patients (13 %), retinal venous and arterial occlusive disease in three patients (3 %), optic neuropathy in four patients (4 %), and uveitis in one patient (1%). Eight patients (8%) had choroidal or iridal nevi, one patient (1 %) choroidal hemangioma, and one patient (1 %) choroidal metastasis. No patient had periocular neoplastic lesions. Paraneoplastic retinopathy manifesting as acute exudative polymorphous vitelliform maculopathy (AEPVM)-like disease was diagnosed in two patients (2 %) with multifocal central serous chorioretinopathy and development of vitelliform or fibrin-like subretinal deposits in one patient. Conclusions Patients with metastatic cutaneous melanoma reveal ocular diseases with a spectrum similar to the normal population of this age range. Very rarely, uveal metastasis as well as paraneoplastic retinopathy can occur

Comparison of high resolution melting analysis, pyrosequencing, next generation sequencing and immunohistochemistry to conventional Sanger sequencing for the detection of p.V600E and non-p.V600E BRAF mutations

Background: The approval of vemurafenib in the US 2011 and in Europe 2012 improved the therapy of not resectable or metastatic melanoma. Patients carrying a substitution of valine to glutamic acid at codon 600 (p.V600E) or a substitution of valine to leucine (p.V600K) in BRAF show complete or partial response. Therefore, the precise identification of the underlying somatic mutations is essential. Herein, we evaluate the sensitivity, specificity and feasibility of six different methods for the detection of BRAF mutations. Methods: Samples harboring p.V600E mutations as well as rare mutations in BRAF exon 15 were compared to wildtype samples. DNA was extracted from formalin-fixed paraffin-embedded tissues by manual micro-dissection and automated extraction. BRAF mutational analysis was carried out by high resolution melting (HRM) analysis, pyrosequencing, allele specific PCR, next generation sequencing (NGS) and immunohistochemistry (IHC). All mutations were independently reassessed by Sanger sequencing. Due to the limited tumor tissue available different numbers of samples were analyzed with each method (82, 72, 60, 72, 49 and 82 respectively). Results: There was no difference in sensitivity between the HRM analysis and Sanger sequencing (98%). All mutations down to 6.6% allele frequency could be detected with 100% specificity. In contrast, pyrosequencing detected 100% of the mutations down to 5% allele frequency but exhibited only 90% specificity. The allele specific PCR failed to detect 16.3% of the mutations eligible for therapy with vemurafenib. NGS could analyze 100% of the cases with 100% specificity but exhibited 97.5% sensitivity. IHC showed once cross-reactivity with p.V600R but was a good amendment to HRM. Conclusion: Therefore, at present, a combination of HRM and IHC is recommended to increase sensitivity and specificity for routine diagnostic to fulfill the European requirements concerning vemurafenib therapy of melanoma patients

Table1_Case Report: Sudden very late-onset near fatal PD1 inhibitor-associated myocarditis with out-of-hospital cardiac arrest after >2.5 years of pembrolizumab treatment.docx

IntroductionImmune checkpoint inhibitors have advanced the outcomes of many different types of cancer. A rare but extraordinarily severe complication of these agents resembles immune checkpoint inhibitor-related myocarditis, which typically occurs within the first few weeks after treatment initiation with a mortality of 25%–50%.Case reportA 57-year-old woman had uneventfully received pembrolizumab for metastatic non-small cell lung cancer for over 2.5 years and was admitted after an out-of-hospital cardiac arrest due to ventricular fibrillation. After successful cardiopulmonary resuscitation, the initial diagnostic work-up showed elevated cardiac enzymes and a limited left-ventricular ejection fraction, while coronary angiography did not show relevant stenosis. Despite cardiac MRI being unsuggestive of myocarditis, myocardial biopsies were obtained and histologically confirmed anti-PD-1 antibody-associated myocarditis. After the initiation of prednisone at 1 mg/kg body weight, the patient gradually recovered and was discharged three weeks later with markedly improved cardiac function.ConclusionThis case resembles the first description of a very late onset irMyocarditis, occurring over 2.5 years after the start of treatment. It demonstrates the importance of contemplating that severe immune-related toxicities with a sudden onset clinical presentation may occur even after long uneventful periods of anti-PD-1 immune checkpoint inhibitor treatment. Furthermore, it underlines the critical importance of myocardial biopsies in this setting, especially when cardiac MRI remains inconclusive. Moreover, it demonstrates the necessity and benefits of early immunosuppressive treatment if immune-related myocarditis is considered a differential diagnosis.</p

Treatment monitoring of immunotherapy and targeted therapy using FET PET in patients with melanoma and lung cancer brain metastases: Initial experiences.

Background: Due to the lack of specificity of contrast-enhanced (CE) MRI, the differentiation of progression from pseudoprogression (PsP) following immunotherapy using checkpoint inhibitors (IT) or targeted therapy (TT) may be challenging, especially when IT or TT is applied in combination with radiotherapy (RT). Similarly, for response assessment of RT plus IT or targeted therapy (TT), the use of CE MRI alone may also be difficult. For problem solving, the integration of advanced imaging methods may add valuable information. Here, we evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in comparison to CE MRI for these important clinical situations in patients with brain metastases (BM) secondary to malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Methods: From 2015-2018, we retrospectively identified 31 patients with 74 BM secondary to MM (n = 20 with 42 BM) and NSCLC (n = 11 with 32 BM) who underwent 52 FET PET scans during the course of disease. All patients had RT prior to IT or TT initiation (61%) or RT concurrent to IT or TT (39%). In 13 patients, FET PET was performed for treatment response assessment of IT or TT using baseline and follow-up scans (median time between scans, 4.2 months). In the remaining 18 patients, FET PET was used for the differentiation of progression from PsP related to RT plus IT or TT. In all BM, metabolic activity on FET PET was evaluated by calculation of tumor/brain ratios. FET PET imaging findings were compared to CE MRI and correlated to the clinical follow-up or neuropathological findings after neuroimaging. Results: In 4 of 13 patients (31%), FET PET provided additional information for treatment response evaluation beyond the information provided by CE MRI alone. Furthermore, responding patients on FET PET had a median stable clinical follow-up of 10 months. In 10 of 18 patients (56%) with CE MRI findings suggesting progression, FET PET detected PsP. In 9 of these 10 patients, PsP was confirmed by a median stable clinical follow-up of 11 months. Conclusions: FET PET may add valuable information for treatment monitoring in individual BM patients undergoing RT in combination with IT or TT

Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study

Background: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. Methods: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. Results: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0–65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0–65.0). The median PFS was 3.0 months (95% CI 2.4–3.6). The median OS was estimated to 16.1 months (95% CI 12.9–19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). Conclusions: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials

Treatment Monitoring of Immunotherapy and Targeted Therapy using 18 F-FET PET in Patients with Melanoma and Lung Cancer Brain Metastases: Initial Experiences

Purpose: We investigated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive. Methods: We retrospectively identified 40 patients with 107 BM secondary to melanoma (n = 29 with 75 BM) or non-small cell lung cancer (n = 11 with 32 BM) treated with ICI or TT who had 18F-FET PET (n = 60 scans) for treatment monitoring from 2015-2019. The majority of patients (n = 37; 92.5%) had radiotherapy during the course of disease. In 27 patients, 18F-FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, 18F-FET PET was performed for response assessement to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic 18F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference. Results: A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P = 0.003). Metabolic responders to ICI or TT on 18F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P = 0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P = 0.019). Conclusion: 18F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT