Τετάρτη 20 Ιανουαρίου 2021

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

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imagePostapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF- MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials (n = 467), real-world patients (n = 602) had significantly higher age, higher ECOG performance status, more often ≥3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1–10.4) months compared to 7.2 (95% CI, 6.5–7.7) months (P 
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Life-threatening polymyositis with spontaneous hematoma induced by nivolumab in a patient with previously resected melanoma

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imageSingle-agent anti-PD1 antibodies are usually very well tolerated, but serious toxicity can still occur. Despite the PD-1 pathway seems to be relevant in the pathogenesis of immune-related myositis, anti-PD1-related myositis is generally a rare side effect of the treatment and usually not serious. However, its frequency is likely to increase as the use of immune checkpoint blockades. We present here a case of life-threatening polymyositis with associated spontaneous muscular hematoma in a patient treated with single-agent nivolumab in the adjuvant setting. Spontaneous hematoma is an extremely rare complica tion with unclear etiology of idiopathic myositis. Very few cases have been reported in the literature and their outcome has been often fatal. To our knowledge, this is the first case of autoimmune myositis and spontaneous heamatoma associated with the administration of single-agent checkpoint blockade. Anti-PD1 antibodies have changed the treatment landscape for a number of cancer entities in the past few years. When given as single agent they are usually very well tolerated, but serious rare toxicity can still occur. We present here a case of polymyositis with associated spontaneous muscular hematoma in a patient treated with single agent nivolumab.
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Anti-programmed cell death-1 therapy in octogenarian and nonagenarian advanced/metastatic melanoma patients

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imageImmunotherapy with anti-programmed cell death-1 (PD-1) agents is an effective treatment for metastatic melanoma. Octogenarians and nonagenarians represent a significant cohort of melanoma patients. This multicenter retrospective analysis enrolled 499 patients treated with nivolumab or pembrolizumab. Seventy-three patients were aged 80–100, 218 patients were aged 65–79, and 208 patients were
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Safety and efficacy of electrochemotherapy in a series of patients with nonmetastasized primary or recurrent anorectal malignant melanoma

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imageAnorectal malignant melanoma (AMM) is a rare malignant tumor. Surgery remains the gold standard but new adjuvant treatments to allow local sphincter-saving are warranted. Electrochemotherapy (ECT) is an alternative to surgery in selected cohorts of patients. To evaluate safety and efficacy of ECT in a retrospective series of patients with primary or recurrent AMM in terms of local disease control, local progression free and overall survival. Seven primary and one recurrent AMM underwent ECT. Patients were followed at 1 and 2 months and at the longest available follow-up with clinical examination and/or ultrasound. One month after ECT 6/8 (75%) patients showed complete response, 1/8 partial response (12.5%) and 1/8 stable disease (12.5%), confirmed at 2 months. Bleeding stopped in all patients, and pain was absent or mild/moderate in all patients. No serious adverse events were observed. At 1 year of follow-up seven out of eight patients were alive (87.5%), four were disease-free and three were alive with disease. At the longest available follow-up (mean 4.9 ± 2.0 years) five out of eight (62.5%) of patients were still alive. Our study showed that ECT is well tolerated and effective in the treatment of patients with anal melanoma with good local control of disease.
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Clinical outcomes and secondary glaucoma after gamma-knife radiosurgery and Ruthenium-106 brachytherapy for uveal melanoma: a single institution experience

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imageWe retrospectively analyzed data from records of 48 patients (48 eyes) treated with gamma-knife (n = 18) or Ruthenium-106 brachytherapy (n = 30) for uveal melanoma, in our Ocular Oncology Unit between December 2013 and September 2019, with the aim to evaluate treatment outcomes, and incidence and risk factors for secondary glaucoma. Patients demographics and tumor characteristics at diagnosis were recorded. Follow-up data were collected regarding local tumor control, treatment complications, enucleation need, metastases occurrence and survival status. The median follow-up period was 33.7 months in the gamm a-knife group and 26.2 months in the brachytherapy group. The mean tumor thickness, the largest basal diameter and the tumor volume were significantly higher in the gamma-knife group than in the brachytherapy group. The local tumor control rate was 100% in the brachytherapy group and 77.8% in the gamma-knife group. In the gamma-knife group, six patients were enucleated, no patient treated with brachytherapy underwent enucleation. The overall survival rate was 96.7% in the brachytherapy group and 94.44% in the gamma-knife group. Secondary glaucoma occurred in 10 patients after gamma-knife and in one patient after brachytherapy: it should be emphasized that larger lesions were treated with gamma-knife, whereas smaller tumors were selected for brachytherapy. We found a significative correlation of tumor thickness (P value = 0.043) and volume (P value = 0.040) with secondary glaucoma occurrence after gamma-knife treatment. Moreover, secondary glaucoma significantly correlated with radia tion retinopathy in the gamma-knife group (P value = 0.009). This study shows preliminary clinical results that could be useful for further studies with more patients and longer follow-up.
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Morphea following treatment with pembrolizumab for melanoma with metastatic lymph nodes: case report and review of literature

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imagePembrolizumab is a humanized IgG4 isotype mAb that the targets and blocks the programmed cell death protein 1 receptor on lymphocytes. Its use in treating metastatic melanoma is associated with increased overall survival compared to other older immunotherapies. Several adverse effects have been noted including both systemic and cutaneous manifestations. As a relatively novel treatment option, many new cutaneous manifestations are still being observed, occurring at various times after initiation of therapy. Previously noted cutaneous adverse effects include sarcoid-like reactions, rash, and changes in preexisting lesions or scars. Here we present a case in which biopsy-proven morphea developed after completion of pembrolizumab therapy.
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Transcriptional analysis of metastatic uveal melanoma survival nominates NRP1 as a therapeutic target

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imageUveal melanoma is a rare form of melanoma with particularly poor outcomes in the metastatic setting. In contrast with cutaneous melanoma, uveal melanoma lacks BRAF mutations and demonstrates very low response rates to immune-checkpoint blockade. Our objectives were to study the transcriptomics of metastatic uveal melanoma with the intent of assessing gene pathways and potential molecular characteristics that might be nominated for further exploration as therapeutic targets. We initially analyzed transcriptional data from The Cancer Genome Atlas suggesting PI3K/mTOR and glycolysis as well as IL6 associating w ith poor survival. From tumor samples collected in a prospective phase II trial (A091201), we performed a transcriptional analysis of human metastatic uveal melanoma observing a novel role for epithelial-mesenchymal transition associating with survival. Specifically, we nominate and describe initial functional validation of neuropillin-1 from uveal melanoma cells as associated with poor survival and as a mediator of proliferation and migration for uveal melanoma in vitro. These results immediately nominate potential next steps in clinical research for patients with metastatic uveal melanoma.
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Hemophagocytic lymphohistiocytosis of a melanoma patient under BRAF/MEK-inhibitor therapy following anti-PD1 inhibitor treatment: a case report and review to the literature

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Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition. HLH in infants and young children is usually inherited, which is then classified as primary HLH. Secondary HLH, in contrast, is caused by many different conditions such as infections, cancer or medication and affects mostly adults. HLH is a hyperinflammatory condition, which may mimic an acute septic shock. We report on a 68-year-old patient with malignant melanoma with lymph node metastases. Due to the lymphogenic progression, treatment was switched from nivolumab to dabrafenib and trametinib. Twenty-one days after initiation of BRAF/MEK inhibitor therapy, the patient presented to our emergency department with clinical signs of infection such as fever and fatigue. Laboratory tests showed excessi ve inflammation levels without identifying an underlying pathogen. Two days later, the patient developed an increasing pancytopenia. After extending the diagnosis, we found very high ferritin levels, hypertriglyceridemia, hypofibrinogenemia and a soluble CD25 receptor. Based on the laboratory results, prolonged fever and splenomegaly, we were able to diagnose HLH as the underlying condition. We immediately initiated treatment with intravenous prednisone, which remarkably improved the clinical symptoms. After full recovery, we reinitiated anti-tumor treatment with vemurafenib and cobimetinib, which was tolerated without side effects. Due to the relatively nonspecific nature of the clinical signs and symptoms and the significant overlap with other diseases such as sepsis, the diagnosis of HLH is often delayed. This explains, in part, the high morbidity and mortality rate. Our case shows that early treatment with steroids is effective. However, much work remains in order to raise aware ness and improve the understanding of the pathophysiology of this condition.
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MicroRNAs expression associated with aggressive clinicopathological features and poor prognosis in primary cutaneous melanomas

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imageSeveral studies have focused on identifying microRNAs involved in the pathogenesis of melanoma. However, its association with clinicopathological features has been scarcely addressed. The aim of this study is to identify microRNAs expression profiles related to aggressive clinicopathological and molecular features, and to analyze the association with melanoma survival. A retrospective and observational study was performed in a series of 179 formalin-fixed paraffin embedded primary cutaneous melanomas. First, a screening analysis on a discovery set (n = 22) using miRNA gene chip array (Affymetrix, Santa Cl ara, California, USA) was performed. Differentially expressed microRNAs were detected employing the software Partek Genomic Suite. Validation of four microRNAs was subsequently performed in the entire series (n = 179) by quantitative real time PCR (qRT-PCR). MicroRNAs expression screening analysis identified 101 microRNAs differentially expressed according to Breslow thickness (≤1 mm vs. >1 mm), 79 according to the presence or absence of ulceration, 78 according to mitosis/mm2 (
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Infusion reaction to nivolumab in a metastatic melanoma patient. Safe switch to another anti-programmed death-1: a case report

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imageNowadays, anti-programmed death-1 (PD-1) antibodies are the first-line treatment for metastatic malignant melanoma. An infusion reaction is an adverse event that could occur due to monoclonal antibodies administration and requires prompt diagnosis and treatment. In this article, we report on a case of stage IV malignant melanoma treated with nivolumab, in which a severe infusion reaction occurred, manifesting as flushing and hypotension followed by bronchospasm. The switch to pembrolizumab was both a well-tolerated and effective therapeutic alternative.
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Antibody-drug conjugates: an evolving approach for melanoma treatment

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imageMelanoma continues to be an aggressive and deadly form of skin cancer while therapeutic options are continuously developing in an effort to provide long-term solutions for patients. Immunotherapeutic strategies incorporating antibody-drug conjugates (ADCs) have seen varied levels of success across tumor types and represent a promising approach for melanoma. This review will explore the successes of FDA-approved ADCs to date compared to the ongoing efforts of melanoma-targeting ADCs. The challenges and opportunities for future therapeutic development are also examined to distinguish how ADCs may better impact individuals with malignancies such as melanoma.
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The existence of butterfly effect and its impact on the dentinal microhardness and crack formation after root canal instrumentation

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Μέσω Odontology

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Abstract

To compare the microhardness and crack formation in root dentine presented with butterfly effect in lower premolars. Sixty mature lower premolars were selected and divided into the control and experimental groups. Teeth in the experimental group were instrumented up to size 30/.04. The roots were cut horizontally into twelve parts of 1-mm-thick cross-section and were numbered accordingly. They were divided into coronal, middle, and apical root sections. Sections were then viewed under a microscope to determine the presence of butterfly effect and subsequently scored. 8 teeth from both control and experimental groups with the highest and lowest score were selected. Crack formation was inspected and classified into four different types of cracks. Microhardness test was performed using a Vickers hardness test. Higher frequency of butterfly effect was found in the apical root section and root dentine with butterfly effect were harder mesiodistally. The middle and api cal root sections with butterfly effect were harder than the coronal section. No significant difference of dentine hardness between the control and experimental groups. Cracks only occurred in the experimental group and presented in buccolingual direction with a higher rate of Type 1 and Type 2 cracks. Prevalence of butterfly effect in lower premolars increased from coronal to apical with increased hardness mesiodistally. More buccolingual cracks were found in radicular dentine with butterfly effect and most of them exhibited Type 1 and Type 2 cracks. Roots of lower premolar with butterfly effect may be susceptible to a higher rate of vertical root fracture in buccolingual direction, especially after root canal treatment. Thus, special attention should be given not to overload instruments during root canal preparation.

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