Hepatic breast cancer dissemination after an iatrogenic hepatic laceration during talc pleurodesis: a case report

<p>Abstract</p> <p>Background</p> <p>Talc pleurodesis is an effective treatment for malignant pleural effusion. We present a case of an asymptomatic hepatic laceration that occurred during pleurodesis in a breast cancer patient and led to hepatic tumor dissemination.</p> <p>Discussion</p> <p>Pleurodesis is a relatively safe procedure, although previous studies have described malignant invasion of scar tissue.</p> <p>Conclusion</p> <p>To our knowledge, this is the first case report of tumor spread due to a liver puncture during talc pleurodesis in a breast cancer patient.</p

Alucinaciones visuales y dolor inusual en relación a hipomagnesemia en un paciente con cáncer avanzado

Hypomagnesemia has been related to high accumulated doses of cisplatin, and its clinical presence is characterized by neuromuscular and cardiovascular alterations. We present the case of an advanced cancer patient who had received successive lines of chemotherapy and who was receiving opioid treatment for cancer pain. During his hospital stay, he experienced visual hallucinations and very intense, unexplained pain in one shoulder. Symptoms reverted with the normalization of his plasma magnesium levels, which were low. We consider that plasma magnesium levels should be monitored in oncology patients with neurological or psychiatric symptoms or with unusual pain

Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients

COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain

Primary bone lymphoma of the mandible and thyroid incidentaloma identified by 18FDG PET/CT: a case report

The mandible is a rare site for the occurrence of primary bone lymphoma (PBL), a non-Hodgkin lymphoma. We report herein a case of an incidentally diagnosed thyroid incidentaloma by (18)Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in a patient with a previous diagnosis of PBL. Therapeutic options are reviewed and discussed

Ethics competences in the undergraduate medical education curriculum: the Spanish experience

Aim To investigate if there are differences in medical ethics education between different schools of medicine in Spain, specifically between private and public schools and between recently founded schools and older ones. Method The curricula of medical degrees from all Spanish faculties were reviewed for the 2014/2015 academic year, identifying subjects concerning bioethics, deontology, and ethics. We identified the type of teaching, format and method of the course, the number of credits and hours, and the school year of each subject. An analysis with descriptive parameters and the Cohen’s coefficient (d) was performed. Results All medical schools in Spain (n = 44) were included. A mean of 3.64 European Credit Transfer and Accumulation System (ECTS) credits was specifically devoted to ethical values teaching in Spain. Private medical schools offered more credits than public ones (6.51 ECTS vs 2.88 ECTS, relevant difference: d = 2.06>>0.8), and the 10 most recently founded medical schools offered more credits than the 10 oldest (5.86 ECTS vs 2.63 ECTS, relevant difference: d = 1.43 > 0.8). A mean of 36.75 hours was dedicated to ethics education. Conclusions Although ethics education is incorporated into the training of future Spanish physicians, there is still notable heterogeneity between different medical schools in the time devoted to this topic

LungBEAM: A prospective multicenter study to monitor stage IV NSCLC patients with EGFR mutations using BEAMing technology

Mutacions de l'EGFR; Biòpsia líquida; Carcinoma de pulmó de cèl·lules no petitesMutaciones de EGFR; Biopsia liquida; Carcinoma de pulmón de células no pequeñasEGFR mutations; Liquid biopsy; Non-small cell lung carcinomaObjectives The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non-small cell lung cancer (NSCLC) patients treated with first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. Methods Stage IV NSCLC patients with locally confirmed EGFR-TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first- or second-generation EGFR-TKI as first-line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression-free survival (PFS) event or until study completion (72-week follow-up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing. Results A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty-six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow-up, preceding radiologic progression with a median of 76 (interquartile ratio: 54–111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48–2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01–7.36; p < 0.001). Conclusion Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients.This work was supported by Sysmex Inostics GmbH. The sponsor and the study coordinating investigators were involved in the study design and data interpretation. Writing and editorial assistance was funded by Sysmex Inostics GmbH

La vía de la insulina y el factor de crecimiento similar a la insulina, una nueva diana terapéutica en oncología

La biología molecular del cáncer ha permitido identificar nuevas dianas para atacar las células tumorales. Recientemente se ha propuesto la vía de señalización de la insulina y el factor de crecimiento similar a la insulina como una de estas dianas. En esta revisión se describe su función biológica, los datos de laboratorio y estudios poblacionales que alertan de su papel en el cáncer y se describen los elementos claves de esta vía de señalización: los ligandos (insulina, IGF1, IGF2), sus receptores y la cascada de señales intracelular que desencadena su activación. Así mismo se revisan las distintas estrategias que se están investigando para bloquearla, algunas de las cuales ya se encuentran en estudios avanzados fase III. Los datos preliminares indican que los fármacos diseñados para bloquear esta vía pueden ser una nueva arma terapéutica para los pacientes oncológicos en un futuro próximo.The molecular biology of cancer has made it possible to identify new targets for attacking tumourous cells. One of these recently proposed targets is the insulin and insulin-like growth factor signaling pathway. This review describes its biological function, laboratory data, population studies that warn of its role in cancer, and the key elements of this signaling pathway: the ligands (insulin, IGF1, IGF2), its receptors and the cascade of intracellular signals that trigger its activation. Also reviewed are the different strategies under investigation for blocking it, some of which are already in phase III advanced studies. The preliminary data indicate that the medicines designed for blocking this pathway might be a new thera

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline

Metformin-induced preferential killing of breast cancer initiating CD44+CD24−/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts

Trastuzumab-refractory breast cancer stem cells (CSCs) could explain the high rate of primary resistance to single-agent trastuzumab in HER2 gene-amplified breast cancer patients. The identification of agents with strong selective toxicity for trastuzumab-resistant breast CSCs may have tremendous relevance for how HER2+ breast cancer patients should be treated. Using the human breast cancer cell line JIMT-1, which was established from the pleural metastasis of a patient who was clinically resistant to trastuzumab ab initio, we examined whether preferential killing of the putative CD44+CD24 −/low breast CSC population might be sufficient to overcome primary resistance to trastuzumab in vivo. Because recent studies have shown that the anti-diabetic biguanide metformin can exert antitumor effects by targeted killing of CSC-like cells, we explored whether metformin's ability to preferentially kill breast cancer initiating CD44+CD24 −/low cells may have the potential to sensitize JIMT-1 xenograft mouse models to trastuzumab. Upon isolation for breast cancer initiating CD44+CD24 −/low cells by employing magnetic activated cell sorting, we observed the kinetics of metformin-induced killing drastically varied among CSC and non-CSC subpopulations. Metformin's cell killing effect increased dramatically by more than 10-fold in CD44+CD24 −/low breast CSC cells compared to non-CD44+CD24 −/low immunophenotypes. While seven-weeks treatment length with trastuzumab likewise failed to reduce tumor growth of JIMT-1 xenografts, systemic treatment with metformin as single agent resulted in a significant two-fold reduction in tumor volume. When trastuzumab was combined with concurrent metformin, tumor volume decreased sharply by more than four-fold. Given that metformin-induced preferential killing of breast cancer initiating CD44+CD24 −/low subpopulations is sufficient to overcome in vivo primary resistance to trastuzumab, the incorporation of metformin into trastuzumab-based regimens may provide a valuable strategy for treatment of HER2+ breast cancer patients

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (alpha-glucosidase/alpha-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols