Varicocele in the adolescent population: challenges in management

O manejo da varicocele em adolescentes continua sendo um dos tópicos mais interessantes e debatidos. Embora a crescente conscientização do comprometimento testicular induzido por varicocele tenha motivado diversos estudos, algumas das controvérsias na varicocele em adultos, em relação à fisiopatologia, tratamento e problemas de fertilidade, também podem ser transpostas para a população adolescente. Além disso, os adolescentes representam um grupo heterogêneo com desafios no diagnóstico, parâmetros clínicos e preditores de desfecho limitados. O desenvolvimento físico e puberal reflete-se em dificuldades para condutas padronizadas. O objetivo deste artigo é revisar os dados disponíveis da literatura sobre a apresentação, epidemiologia e patogênese da varicocele em crianças e adolescentes. Também abordamos as principais limitações e desafios da avaliação clínica e fornecemos evidências atuais sobre o dilema do tratamento com varicocele nesse subconjunto específico de pacientes. Opções de intervenção e resultados também são discutidos. A presente revisão baseia-se em uma busca eletrônica utilizando as bases de dados Pubmed / MEDLINE e referências dos artigos identificados realizadas entre março e maio de 2018.Management of varicoceles in adolescents remain one of the most interesting and debatable topics. Although the crescent awareness of varicocele-induced testicular impairment has motivated several studies, some of the controversies in adult varicocele, regarding pathophysiology, treatment and fertility issues can also be transposed the adolescent population. Furthermore, adolescents represent a heterogenic group with challenges in diagnosis, clinical parameters, and limited predictors. Physical and pubertal development reflects in difficulties for standard management. The purpose of this article is to review available data from literature regarding the presentation, epidemiology and pathogenesis of varicocele in children and adolescents. We also address major limitations and challenges of clinical evaluation and provide current evidence regarding the dilemma of varicocele treatment in this particular subset of patients. Interventions options and outcomes are also discussed. The current review is based on an electronic search using Pubmed/MEDLINE databases and references of the identified articles performed between March and May of 2018

Fighting tertiary mutations in EGFR-driven lung-cancers: Current advances and future perspectives in medicinal chemistry

Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC). While the application of third-generation inhibitors has represented an effective first- and second-line treatment, the efficacy of this class of inhibitors has been hampered by the novel, tertiary mutation C797S, which may occur after the treatment with osimertinib. More recently, other point mutations, including L718Q, G796D, G724S, L792 and G719, have emerged as mutations mediating resistance to third-generation inhibitors. The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors

Novel targeted strategies to overcome resistance in small-cell lung cancer: focus on PARP inhibitors and rovalpituzumab tesirine

ABSTRACTIntroduction: Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumour, and its outcome is strongly conditioned by the rapid onset of resistance to conventional chemothera..

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

Introduction: Non-small cell lung cancer (NSCLC) is a highly lethal disease. During the past 20 years, the epidermal growth factor receptor (EGFR) has been a relevant target for anticancer drug-design, and a large family of EGFR tyrosine kinase inhibitors (TKI) were designed, which improved therapeutic outcomes compared to conventional chemotherapy in NSCLC patients with specific EGFR mutations. However, resistance to these inhibitors occurs; therefore, the debate on which inhibitor should be used first is still open. Dacomitinib was approved in 2018 for the first-line treatment of NSCLC with EGFR activating mutations. Areas covered: This manuscript reviews the properties of dacomitinib, including the current information from clinical trials and its potential application as stand-alone therapy, or in combination. Expert opinion: Dacomitinib is a second-generation EGFR-TKI that has demonstrated significant improvement in overall survival in a phase III randomized study compared with gefitinib, a first-generation TKI. However, the rapid development and approval of a new generation of TKIs (osimertinib), with better clinical profiles, raises the question of which role can dacomitinib play in NSCLC. Further studies are required to evaluate the efficacy of this drug on brain metastases, as a second-line treatment after third-generation TKIs, or in combination with other types of treatments

Italian multicenter survey to evaluate the opinion of patients and their reference clinicians on the "tolerance" to targeted therapies already available for non-small cell lung cancer treatment in daily clinical practice

INTRODUCTION: The introduction of targeted therapies in non-small cell lung cancer (NSCLC) treatment has led to emerging toxicities, whose management and impact on quality-of-life (QoL) is not clearly defined. Aim of this Italian multicenter survey was to highlight any discrepancy between patients’ and clinicians’ perception of such toxicities in order to improve their management. METHODS: From October 2013 to April 2014, 133 NSCLC advanced patients, treated with targeted therapies, were consecutively enrolled to assess toxicities and QoL with dedicated questionnaires. One hundred and sixteen patients were included in the final analysis, having attended three consecutive evaluations (T0, T1, T2), starting at least 15 days after the biological treatment. The survey required monthly compilation of both physicians and patients’ questionnaires, basing adverse event evaluation on CTCAE version 4.0. RESULTS: Most of the patients received either an EGFR-TKI or an anaplastic lymphoma kinase (ALK) inhibitor as targeted therapy (84.5% and 13.8%, respectively). At every checkpoint (T0, T1, T2) a significant difference in terms of perception of targeted therapies-related toxicities of any type and grade was described (P value =0.0001 in all cases). This difference was more pronounced for skin toxicity, fatigue and diarrhea. Furthermore, also the assessment of QoL revealed contrasting data between patients and clinicians, mainly QoL reported as good by the majority of patients and daily activities considered as slightly influenced by targeted therapies. CONCLUSIONS: In our knowledge, this is the first prospective survey in patients and doctors specifically designed for targeted therapies in advanced NSCLC. The results show an underestimation of toxicities by clinicians when compared with patients, the difference being greater for adverse events more strongly associated with daily life and QoL. Further studies are needed to confirm our first results. The discrepancy in perception of targeted therapies-related toxicities should be a result from which to start thinking about a new approach in their management

The right immune-modulation at the right time: thymosin α1 for prevention of severe COVID-19 in cancer patients

We presented the rationale for the use of thymosin alpha1 as prophylaxis of severe COVID-19 in cancer patients undergoing active treatment, constituting the background for the PROTHYMOS study, a prospective, multicenter, open-label, Phase II randomized study, currently in its start-up phase(Eudract no.2020-006020-13). We aim to offer new hope for this incurable disease, especially to frail patient population, such as patients with cancer. The hypothesis of an effective prophylactic approach to COVID-19 would have immediate clinical relevance, especially given the lack of curative approaches. Moreover, in the 'COVID-19 vaccine race era' both clinical and biological results coming from the PROTHYMOS trials could even support the rationale for future combinatorial approaches, trying to rise vaccine efficacy in frail individuals

Expression Levels of Some Antioxidant and Epidermal Growth Factor Receptor Genes in Patients with Early-Stage Non-Small Cell Lung Cancer

This study was aimed at: (i) investigating the expression profiles of some antioxidant and epidermal growth factor receptor genes in cancerous and unaffected tissues of patients undergoing lung resection for non-small cell lung cancer (NSCLC) (cross-sectional phase), (ii) evaluating if gene expression levels at the time of surgery may be associated to patients' survival (prospective phase). Antioxidant genes included heme oxygenase 1 (HO-1), superoxide dismutase-1 (SOD-1), and -2 (SOD-2), whereas epidermal growth factor receptor genes consisted of epidermal growth factor receptor (EGFR) and v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2 (HER-2). Twenty-eight couples of lung biopsies were obtained and gene transcripts were quantified by Real Time RT-PCR. The average follow-up of patients lasted about 60 months. In the cancerous tissues, antioxidant genes were significantly hypo-expressed than in unaffected tissues. The HER-2 transcript levels prevailed in adenocarcinomas, whereas EGFR in squamocellular carcinomas. Patients overexpressing HER-2 in the cancerous tissues showed significantly lower 5-year survival than the others