T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva (TM)): Mechanisms of action

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis. Copyright (C) 2004 S. Karger AG, Basel

A bibliometric study of the top 100 most-cited randomized controlled trials, systematic reviews and meta-analyses published in endodontic journals

Aim To identify and analyse the main features of the top 100 most‐cited randomized controlled trials, systematic reviews and meta‐analyses published in endodontic journals from 1961 to 2018. Methodology The Clarivate Analytics’ Web of Science ‘All Databases’ was used to search and analyse the 100 most frequently cited randomized controlled trials, systematic reviews and meta‐analyses having ‘randomized’, ‘randomised’, ‘randomized controlled’, ‘randomised controlled’, ‘randomized controlled trial’, ‘randomized controlled trials’, ‘clinical trial’, ‘systematic’, ‘systematic review’, ‘meta‐analysis’, and ‘meta‐analyses’ in the title section. The ‘International Endodontic Journal’, ‘Journal of Endodontics’, ‘Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology’, ‘Australian Endodontic Journal’, ‘Endodontics & Dental Traumatology’, ‘Endo‐Endodontic Practice Today’ and ‘European Endodontic Journal’ were included in the publication name section. After ranking the articles in a descending order based on their citation counts, each article was cross‐matched with the citation counts in Elsevier's Scopus and Google Scholar. The articles were analysed, and information on citation counts, citation density, year of publication, contributing authors, institutions and countries, journal of publication, study design, topic of the article and keywords was extracted. Results The citation counts of the 100 most‐cited articles varied from 235 to 20 (Web of Science), 276 to 17 (Scopus) and 696 to 1 (Google Scholar). The year in which the top 100 articles were published was 2010 (n = 13). Among 373 authors, the greatest number of articles was associated with three individuals namely Reader A (n = 5), Beck M (n = 5) and Kvist T (n = 5). Most of the articles originated from the United States (n = 24) with the greatest contribution from Ohio State University (USA) (n = 5). Randomized controlled trials were the most frequent study design (n = 45) followed by systematic reviews (n = 30) with outcome studies of root canal treatment being the major topic (n = 35). The Journal of Endodontics published the largest number of included articles (n = 70) followed by the International Endodontic Journal (n = 27). Among 259 unique keywords, meta‐analysis (n = 23) and systematic review (n = 23) were the most frequently used. Conclusion This study has revealed that year of publication had no obvious impact on citation count. The bibliometric analysis highlighted the quantity and quality of research, and the evolution of scientific advancements made in the field of Endodontology over time. Articles before 1996, that is prior to the CONSORT statement that encouraged authors to include specific terms in the title and keywords, may not have been included in this electronic search

Chemotherapy in Cutaneous Melanoma: Is There Still a Role?

Purpose of review: In the preceding decade, the management of metastatic cutaneous melanoma has been revolutionised with the development of highly effective therapies including immune checkpoint inhibitors (specifically CTLA-4 and PD-1 inhibitors) and targeted therapies (BRAF and MEK inhibitors). The role of chemotherapy in the contemporary management of melanoma is undefined. Recent findings: Extended analyses highlight substantially improved 5-year survival rates of approximately 50% in patients with metastatic melanoma treated with first-line therapies. However, most patients will progress on these first-line treatments. Sequencing of chemotherapy following failure of targeted and immunotherapies is associated with low objective response rates and short progression-free survival, and thus, meaningful benefits to patients are minimal. Chemotherapy has limited utility in the contemporary management of cutaneous melanoma (with a few exceptions, discussed herein) and should not be the standard treatment sequence following failure of first-line therapies. Instead, enrolment onto clinical trials should be standard-of-care in these patients. Summary: Chemotherapy has limited utility in the contemporary management of cutaneous melanoma (with a few exceptions, discussed herein) and should not be the standard treatment sequence following failure of first-line therapies. Instead, enrolment onto clinical trials should be standard-of-care in these patients

Biomarkers in melanoma

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques--DNA and RNA microarrays--have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers--lactate dehydrogenase, S100B and melanoma-inhibiting activity--as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the futur

The impact of COVID-19 on cancer care and oncology clinical research: an experts’ perspective

COVID-19; Cancer care; Clinical researchCOVID-19; Cura del càncer; Recerca clínicaCOVID-19; Cuidado del cancer; Investigación clínicaThe coronavirus disease-19 (COVID-19) pandemic promises to have lasting impacts on cancer clinical trials that could lead to faster patient access to new treatments. In this article, an international panel of oncology experts discusses the lasting impacts of the pandemic on oncology clinical trials and proposes solutions for clinical trial stakeholders, with the support of recent data on worldwide clinical trials collected by IQVIA. These lasting impacts and proposed solutions encompass three topic areas. Firstly, acceleration and implementation of new operational approaches to oncology trials with patient-centric, fully decentralized virtual approaches that include remote assessments via telemedicine and remote devices. Geographical differences in the uptake of remote technology, including telemedicine, are discussed in the article, focusing on the impact of the local adoption of new operational approaches. Secondly, innovative clinical trials. The pandemic has highlighted the need for new trial designs that accelerate research and limit risks and burden for patients while driving optimization of clinical trial objectives and endpoints, while testing is being minimized. Areas of considerations for clinical trial stakeholders are discussed in detail. In addition, the COVID-19 pandemic has exposed the underrepresentation of minority groups in clinical trials; the approach for oncology clinical trials to improve generalizability of efficacy and outcomes data is discussed. Thirdly, a new problem-focused collaborative framework between oncology trial stakeholders, including decision makers, to leverage and further accelerate the innovative approaches in clinical research developed during the COVID-19 pandemic. This could shorten timelines for patient access to new treatments by addressing the cultural and technological barriers to adopting new operational approaches and innovative clinical trials. The role of the different stakeholders is described, with the aim of making COVID-19 a catalyst for positive change in oncology clinical research and eventually in cancer care

Biomarkers in melanoma

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques—DNA and RNA microarrays—have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers—lactate dehydrogenase, S100B and melanoma-inhibiting activity—as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future

Osteoblasts contribute to a protective niche that supports melanoma cell proliferation and survival

Melanoma is the deadliest form of skin cancer; a primary driver of this high level of morbidity is the propensity of melanoma cells to metastasize. When malignant tumours develop distant metastatic lesions the new local tissue niche is known to impact on the biology of the cancer cells. However, little is known about how different metastatic tissue sites impact on frontline targeted therapies. Intriguingly, melanoma bone lesions have significantly lower response to BRAF or MEK inhibitor therapies. Here, we have investigated how the cellular niche of the bone can support melanoma cells by stimulating growth and survival via paracrine signalling between osteoblasts and cancer cells. Melanoma cells can enhance the differentiation of osteoblasts leading to increased production of secreted ligands, including RANKL. Differentiated osteoblasts in turn can support melanoma cell proliferation and survival via the secretion of RANKL that elevates the levels of the transcription factor MITF, even in the presence of BRAF inhibitor. By blocking RANKL signalling, either via neutralizing antibodies, genetic alterations or the RANKL receptor inhibitor SPD304, the survival advantage provided by osteoblasts could be overcome

Perturbing resistance: a network perspective

The recent convergence of high-dimensional molecular datasets with small-molecule inhibitor pipelines allows for selective targeting of aberrantly regulated pathways in many cancer types. But intra-tumor heterogeneity, paradoxical activation, intrinsic or acquired therapeutic resistance, and non-linear pathway interactions confound most simple targeting strategies(Widmer et al., 2015). For instance, MAPK signaling is activated by hot-spot mutations in BRAF, which are found in about 40-50% of melanoma cases. This article is protected by copyright. All rights reserved

The Prognostic Value of a Single, Randomly Timed Circulating Tumor DNA Measurement in Patients with Metastatic Melanoma

Simple Summary In this study, we investigated the associations of circulating tumor DNA (ctDNA), measured at a random time point during the patient’s treatment, with tumor progression and routine blood markers (protein S100, lactate dehydrogenase (LDH), and C-reactive protein (CRP)) in a cohort of patients with metastatic melanoma. Detectable ctDNA was associated with the presence of extracerebral disease, tumor progression, and poorer overall survival (OS). Elevated S100 and CRP was correlated with detectable ctDNA, whereas LDH was not. Our results further support the use of ctDNA in the clinical management of patients with metastatic melanoma. Abstract Melanoma currently lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Circulating tumor DNA (ctDNA), originating from tumor cells and detectable in plasma, has emerged as a possible biomarker in patients with metastatic melanoma. In this retrospective, single-center study, we collected 129 plasma samples from 79 patients with stage IIIB–IV melanoma as determined by the American Joint Committee on Cancer (AJCC, 8th edition). For the determination of ctDNA levels, we used eight different assays of droplet digital polymerase chain reaction (ddPCR) to detect the most common hotspot mutations in the BRAF and NRAS genes. The aim of the study was to investigate the association of the detectability of ctDNA at a non-prespecified time point in a patient’s treatment with tumor progression, and to correlate ctDNA with commonly used biomarkers (protein S100, LDH, and CRP). Patients with detectable ctDNA progressed more frequently in PET-CT within 12 months than those without detectable ctDNA. Detectability of ctDNA was associated with shorter OS in univariate and multivariate analyses. ctDNA was detectable in a statistically significantly larger proportion of patients with distant metastases (79%) than in patients with no distant metastases or only intracranial metastases (32%). Elevated protein S100 and CRP correlated better with detectable ctDNA than LDH. This study supports the potential of ctDNA as a prognostic biomarker in patients with metastatic melanoma. However, additional prospective longitudinal studies with quantitative assessments of ctDNA are necessary to investigate the limitations and strengths of ctDNA as a biomarker. Keywords: ctDNA; melanoma; tumor progression; PET-CT; S100; biomarke