BH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) was considered for a long time one of the most hostile leukemia that was incurable for most of the patients, predominantly due to the extreme resistance to chemotherapy. Part of the resistance to cell death (apoptosis) is the result of increased levels of anti-apoptotic and decreased levels of pro-apoptotic member of the BCL-2 family induced by the BCR-ABL1 oncoprotein. BCR-ABL1 is a constitutively active tyrosine kinase responsible for initiating multiple and oncogenic signaling pathways. With the development of specific BCR-ABL1 tyrosine kinase inhibitors (TKIs) CML became a much more tractable disease. Nevertheless, TKIs do not cure CML patients and a substantial number of them develop intolerance or become resistant to the treatment. Therefore, novel anti-cancer strategies must be developed to treat CML patients independently or in combination with TKIs. Here, we will discuss the mechanisms of BCR-ABL1-dependent and -independent resistance to TKIs and the use of BH3-mimetics as a potential tool to fight CML.

Communication in radiology: evaluation of terminology and TNM descriptor use at a cancer center.

Objective: The purpose of our study was to evaluate the transmission of information from radiologists to physicians, focusing on the level of certainty and the use of imaging descriptors from the tumor-node-metastasis (TNM) staging system. Materials and Methods: Radiologists (n = 56) and referring physicians (n = 50) participated in this questionnaire-based, singlecenter study, conducted between March 20, 2020, and January 21, 2021. Participants were presented with terms commonly used by the radiologists at the institution and were asked to order them hierarchically in terms of the level of certainty they communicate regarding a diagnosis, using a scale ranging from 1 (most contrary to) to 10 (most favoring). They then assessed TNM system descriptors and their interpretation. Student's t-tests and the kappa statistic were used in order to compare the rankings of the terms of certainty. Items related to T and N staging were analyzed by Fisher's exact test. The confidence level was set to 97% (p < 0.03). Results: Although overall agreement among the radiologists and referring physicians on term ranking was poor (kappa = 0.10- 0.35), the mean and median values for the two groups were similar. Most of the radiologists and referring physicians (67% and 86%, respectively) approved of the proposal to establish a standard lexicon. Such a lexicon, based on the participant responses, was developed and graphically represented. Regarding the TNM system descriptors, there were significant differences between the two groups in the reporting of lymph node numbers, of features indicating capsular rupture, and of vessel wall irregularities, as well as in the preference for clear descriptions of vascular involvement. Conclusion: Our findings indicate that ineffective communication and differences in report interpretation between radiologists and referring physicians are still prevalent in the fields of radiology and oncology. Efforts to gain a better understanding of those impediments might improve the objectivity of reporting and the quality of care.

Objetivo: O propósito do nosso estudo foi analisar a transmissão das informações de radiologistas para médicos assistentes, com foco no nível de certeza e uso de descritores de imagem do sistema de estadiamento tumor­nódulo­metástase (TNM). Materiais e Métodos: Radiologistas (n = 56) e médicos assistentes (n = 50) participaram neste estudo unicêntrico, baseado em questionários respondidos entre 20 de março de 2020 e 21 de janeiro de 2021. Os participantes ordenaram hierarquicamente termos comumente usados por radiologistas da instituição para descrever o nível de certeza utilizando uma escala que variou de 1 (mais contrário) a 10 (mais favorável). Em seguida, foram avaliados os descritores relacionados ao sistema TNM e sua interpretação. O teste t de Student e o coeficiente de correlação kappa foram empregados para comparar a classificação dos termos. Os itens relacionados aos estadiamentos T e N foram analisados pelo teste exato de Fisher. O nível de confiança foi fixado em 97% (p < 0,03). Resultados: A concordância geral entre radiologistas e médicos assistentes na classificação hierárquica dos termos foi baixa (kappa = 0,10­0,35), porém, os valores médios e medianos dos dois grupos foram semelhantes. A maioria dos médicos (86%) e radiologistas (67%) foi receptiva à introdução de um léxico padronizado. Uma proposta de léxico foi elaborada com base nas respostas dos participantes e representada graficamente. Em relação aos descritores do sistema TNM, diferenças estatisticamente significativas foram observadas nos seguintes itens: forma de relatar o número de linfonodos; menção a características indicativas de ruptura capsular nodal; menção de irregularidades nas paredes vasculares; e preferência por descrições sucintas para comprometimento de estruturas vasculares. Conclusão: Falhas de comunicação e diferenças na interpretação de laudos entre radiologistas e médicos assistentes ainda são prevalentes em radiologia e oncologia. Esforços para melhor compreendê-los podem melhorar a objetividade do laudo radiológico e a qualidade do atendimento médico.

Communication in radiology: evaluation of terminology and TNM descriptor use at a cancer center / Comunicação em radiologia: avaliação da terminologia e uso dos descritores TNM em um centro oncológico

Abstract Objective: The purpose of our study was to evaluate the transmission of information from radiologists to physicians, focusing on the level of certainty and the use of imaging descriptors from the tumor-node-metastasis (TNM) staging system. Materials and Methods Radiologists (n = 56) and referring physicians (n = 50) participated in this questionnaire-based, single-center study, conducted between March 20, 2020, and January 21, 2021. Participants were presented with terms commonly used by the radiologists at the institution and were asked to order them hierarchically in terms of the level of certainty they communicate regarding a diagnosis, using a scale ranging from 1 (most contrary to) to 10 (most favoring). They then assessed TNM system descriptors and their interpretation. Student's t-tests and the kappa statistic were used in order to compare the rankings of the terms of certainty. Items related to T and N staging were analyzed by Fisher's exact test. The confdence level was set to 97% (p < 0.03). Results: Although overall agreement among the radiologists and referring physicians on term ranking was poor (kappa = 0.10-0.35), the mean and median values for the two groups were similar. Most of the radiologists and referring physicians (67% and 86%, respectively) approved of the proposal to establish a standard lexicon. Such a lexicon, based on the participant responses, was developed and graphically represented. Regarding the TNM system descriptors, there were significant differences between the two groups in the reporting of lymph node numbers, of features indicating capsular rupture, and of vessel wall irregularities, as well as in the preference for clear descriptions of vascular involvement. Conclusion: Our findings indicate that ineffective communication and differences in report interpretation between radiologists and referring physicians are still prevalent in the fields of radiology and oncology. Efforts to gain a better understanding of those impediments might improve the objectivity of reporting and the quality of care.

Resumo Objetivo: O propósito do nosso estudo foi analisar a transmissão das informações de radiologistas para médicos assistentes, com foco no nível de certeza e uso de descritores de imagem do sistema de estadiamento tumor-nódulo-metástase (TNM). Materiais e Métodos: Radiologistas (n = 56) e médicos assistentes (n = 50) participaram neste estudo unicêntrico, baseado em questionários respondidos entre 20 de março de 2020 e 21 de janeiro de 2021. Os participantes ordenaram hierarquicamente termos comumente usados por radiologistas da instituição para descrever o nível de certeza utilizando uma escala que variou de 1 (mais contrário) a 10 (mais favorável). Em seguida, foram avaliados os descritores relacionados ao sistema TNM e sua interpretação. O teste t de Student e o coeficiente de correlação kappa foram empregados para comparar a classificação dos termos. Os itens relacionados aos estadiamentos T e N foram analisados pelo teste exato de Fisher. O nível de confança foi fixado em 97% (p < 0,03). Resultados: A concordância geral entre radiologistas e médicos assistentes na classificação hierárquica dos termos foi baixa (kappa = 0,10-0,35), porém, os valores médios e medianos dos dois grupos foram semelhantes. A maioria dos médicos (86%) e radiologistas (67%) foi receptiva à introdução de um léxico padronizado. Uma proposta de léxico foi elaborada com base nas respostas dos participantes e representada graficamente. Em relação aos descritores do sistema TNM, diferenças estatisticamente significativas foram observadas nos seguintes itens: forma de relatar o número de linfonodos; menção a características indicativas de ruptura capsular nodal; menção de irregularidades nas paredes vasculares; e preferência por descrições sucintas para comprometimento de estruturas vasculares. Conclusão: Falhas de comunicação e diferenças na interpretação de laudos entre radiologistas e médicos assistentes ainda são prevalentes em radiologia e oncologia. Esforços para melhor compreendê-los podem melhorar a objetividade do laudo radiológico e a qualidade do atendimento médico.

BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia.

The constitutively active BCR-ABL1 tyrosine kinase, found in t(9;22)(q34;q11) chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies.

A review of Cochrane reviews on pharmacological treatment for attention deficit hyperactivity disorder / Revisão de revisões Cochrane sobre o tratamento farmacológico para transtorno do déficit de atenção e hiperatividade

ABSTRACT. Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems. Objective: The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD. Methods: The search was performed in the Cochrane Database of Systematic Reviews (via Wiley) in July 2020. Results: The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids. Conclusions: The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.

RESUMO. Déficit de atenção e hiperatividade (TDAH) é uma das mais frequentes condições psiquiátricas da infância. Objetivo: O objetivo deste artigo foi identificar, sintetizar os resultados e avaliar criticamente todas as revisões sistemáticas (RS) da Cochrane sobre as intervenções farmacológicas para crianças e adolescentes (até 18 anos de idade) diagnosticados com transtorno do déficit de atenção com hiperatividade. Métodos: A pesquisa foi realizada na base de dados Cochrane de Revisões Sistemáticas — CDSR (via Wiley) em julho de 2020. Resultados: A estratégia de busca resultou em quatro RS de alta qualidade metodológica, que analisavam 51 ensaios clínicos randomizados (9.013 participantes). Comparado ao placebo, o tratamento com antidepressivos tricíclicos (desipramina), anfetamina e metilfenidato apresentou melhora nos sintomas, como dificuldade de concentração, impulsividade e hiperatividade no curto prazo (até seis meses). Houve aumento na ocorr≖ncia de eventos adversos, como redução do apetite, dificuldade para dormir e dor abdominal. Foram encontradas evid≖ncias insuficientes para apoiar os efeitos da suplementação com ácidos graxos poli-insaturados. Conclusões: Com base nos resultados de revisões sistemáticas Cochrane, o uso de antidepressivos tricíclicos, anfetamina e metilfenidato em crianças e adolescentes com TDAH parece apresentar efeitos positivos e taxas mais elevadas de eventos adversos menores quando comparado ao placebo. Dado o alto risco de viés nos estudos primários incluídos nessas RS, ainda são necessários novos ensaios clínicos randomizados com rigor metodológico para apoiar esses achados.

Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer.

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-ß receptor I (TGF-ßRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS- was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-ßRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

Absence of Bim sensitizes mice to experimental Trypanosoma cruzi infection.

Chagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/-, Bim-/- mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim-/- mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/- mice. At the peak of parasitemia, peritoneal macrophages of Bim-/- mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim-/- splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim-/- mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim-/- mice and place Bim as an important protein in the control of T. cruzi infections.

Quantification of 6-nitrodopamine in Krebs-Henseleit's solution by LC-MS/MS for the assessment of its basal release from Chelonoidis carbonaria aortae in vitro.

In this study, the development and validation of a method for quantification of 6-nitrodopamine in Krebs-Henseleit's solution by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with positive ion electrospray ionization is described. Aortic rings taken from tortoise were either denuded or left with endothelium intact (15 mm, N = 6) and were incubated for 30 min in 5 mL Krebs-Henseleit's solution in an organ bath. Solid phase extraction (SPE) was performed for aliquots of 1 mL of the supernatant. The separation of 6-nitrodopamine was obtained on a 150 mm × 3 mm Shim-pack GIST-HP C18 column, using 75% of mobile phase A consisted of deionized water with 0.1% formic acid (v/v) and 25% of mobile phase B consisted of acetonitrile/deionized water (50/50, v/v) + 0.1% formic acid at a flow rate of 350 µL/min in an isocratic mode. The method was linear over the concentration range of 0.1-20 ng/mL. The method was sensitive, precise and accurate for the assessment of the basal release of 6-nitrodopamine from Chelonoidis carbonaria aortae in vitro. The mean ± SEM concentrations of 6-nitrodopamine released from endothelium-intact and endothelium-denuded aortae were 0.44 ± 0.06 ng/mL and 0.18 ± 0.05 ng/mL, respectively. These results indicate that tortoise's aortae display a basal endothelium-derived 6-nitrodopamine release.

DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells.

We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8+ T cells. In vivo HMA treatment promotes CD8+ T cell tumor infiltration and suppresses tumor growth via CD8+ T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8+ T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8+ T cell subpopulations, increasing both the number and abundance of a granzyme Bhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.

Cardiac tumors: three decades of experience from a tertiary center: are we changing diagnostic work-up with new imaging tools?

BACKGROUND: Primary cardiac tumours are relatively rare. Cardiac myxomas are the most prevalent and in a significant proportion of cases they are accidentally discovered in asymptomatic patients. Noninvasive definitive diagnosis remains challenging despite improvements provided by newer imaging tools. Our aim was to describe the long-term experience of a tertiary cardiac center managing cardiac tumours. METHODS: We analyzed 154 consecutive patients admitted to a single-tertiary center with the diagnosis of a cardiac mass or tumor between 1990 and 2018. Data files including clinical presentation, noninvasive investigations, presumptive diagnosis and histopathology were collected. The follow-up was obtained from clinical records or telephone contact. RESULTS: In 154 patients with a median age at diagnosis of 61 (51-71) years, 62% were females. Anatomopathology studywas obtained in 144 cases, from which 81% were benign tumours (106 myxomas; 11 papillary fibroelastomas). In comparison with malignant lesions, patients with benign tumours were older (62 versus 48 years) and more often women (65% versus 27%, P = .021). Incidental diagnosis of a benign tumor occurred in 36% of the cases. Transthoracic echocardiography was the initial technique for diagnostic suspicion in the great majority of patients. Both cardiac computed tomography and magnetic resonance were rarely performed before excision. Imaging based (mostly echocardiography) pre-operative presumptive diagnosis was discordant with histopathologic findings in 21% of the benign and in 55% of malignant lesions (previously considered as benign). Uncommon histologic findings were found in 18% of myxomas. During the follow-up period of 11 ± 12 years there were 12 recurrences. CONCLUSION: Among surgically excised cardiac tumours benign cardiac tumors are far more common than both primary and secondary malignancies. In this series of patients, there was a significant proportion of asymptomatic lesions. Preoperative misdiagnosis could be related to the scarce use of adjunctive noninvasive imaging tools beyond echocardiography. Preoperative noninvasive investigation should be expanded to improve diagnostic presumption and better plan the best therapeutic approach.

RIPK3 and Caspase-1/11 Are Necessary for Optimal Antigen-Specific CD8 T Cell Response Elicited by Genetically Modified Listeria monocytogenes.

Efficient induction of effector and long-term protective antigen-specific CD8+ T memory response by vaccination is essential to eliminate malignant and pathogen-infected cells. Intracellular infectious bacteria, including Listeria monocytogenes, have been considered potent vectors to carry multiple therapeutic proteins and generate antigen-specific CD8+ T cell responses. Although the role of molecules involved in inflammatory cell death pathways, such as necroptosis (RIPK3-mediated) and pyroptosis (Caspase-1/11-mediated), as effectors of immune response against intracellular bacteria are relatively well understood, their contribution to the adjuvant effect of recombinant bacterial vectors in the context of antigen-specific CD8+ T cell response remained obscure. Therefore, we evaluated the impact of RIPK3 and Caspase-1/11 (Casp-1/11) individual and combined deficiencies on the modulation of antigen-specific CD8+ T cell response during vaccination of mice with ovalbumin-expressing L. monocytogenes (LM-OVA). We observed that Casp-1/11 but not RIPK3 deficiency negatively impacts the capacity of mice to clear LM-OVA. Importantly, both RIPK3 and Casp-1/11 are necessary for optimal LM-OVA-mediated antigen-specific CD8+ T cell response, as measured by in vivo antigen-specific CD8+ T cell proliferation, target cell elimination, and cytokine production. Furthermore, Casp-1/11 and Casp-1/11/RIPK3 combined deficiencies restrict the early initiation of antigen-specific CD8+ T cell memory response. Taken together, our findings demonstrate that RIPK3 and Casp-1/11 influence the quality of CD8+ T cell responses induced by recombinant L. monocytogenes vectors.

Diagnostic accuracy of computed tomography angiography for the exclusion of coronary artery disease in candidates for transcatheter aortic valve implantation.

Coronary CT angiography (CTA) is currently considered a reliable method to exclude obstructive coronary artery disease (CAD) before valvular heart surgery in patients with low pretest probability. However, its role in excluding obstructive CAD before transcatheter aortic valve implantation (TAVI) is less well established. Single-center retrospective study where patients with severe symptomatic aortic stenosis underwent both CTA and invasive coronary angiography (ICA) as part of TAVI planning. CTA exams were conducted on a 64-slice dual source scanner, with a median interval of 45 days to ICA (IQR 25-75 [13-82]). In both tests, obstructive CAD was defined as a ≥50% stenosis in an epicardial vessel ≥2 mm diameter. Per-patient, per-vessel and per-proximal segment analyses were conducted, excluding and including non-evaluable segments. The study included 200 patients (120 women, mean age 83 ± 6 years). The prevalence of obstructive CAD on ICA was 35.5% (n = 71). On a per-patient analysis (assuming non-evaluable segments as stenotic), CTA showed sensitivity of 100% (95% CI, 95-100%), specificity of 42% (95% CI, 33-51%), and positive and negative predictive values of 48% (95% CI, 44-51%) and 100% (95% CI, 92-100%), respectively. CTA was able to exclude obstructive CAD in 54 patients (27%), in whom ICA could have been safely withheld. Despite the high rate of inconclusive tests, pre-procedural CTA is able to safely exclude obstructive CAD in a significant proportion of patients undergoing TAVI, possibly avoiding the need for ICA in roughly one quarter of the cases.

Molecular and Kinetic Analyses of Circulating Tumor Cells as Predictive Markers of Treatment Response in Locally Advanced Rectal Cancer Patients.

Neoadjuvant chemoradiation (NCRT) followed by total mesorectal excision is the standard treatment for locally advanced rectal cancer (LARC). To justify a non-surgical approach, identification of pathologic complete response (pCR) is required. Analysis of circulating tumor cells (CTCs) can be used to evaluate pCR. We hypothesize that monitoring of thymidylate synthase (TYMS) and excision repair protein, RAD23 homolog B (RAD23B), can be used to predict resistance to chemotherapy/radiotherapy. Therefore, the aims of this study were to analyze CTCs from patients with LARC who underwent NCRT plus surgery for expression of TYMS/RAD23B and to evaluate their predictive value. Blood samples from 30 patients were collected prior to NCRT (S1) and prior to surgery (S2). CTCs were isolated and quantified by ISET®, proteins were analyzed by immunocytochemistry, and TYMS mRNA was detected by chromogenic in situ hybridization. CTC counts decreased between S1 and S2 in patients exhibiting pCR (p = 0.02) or partial response (p = 0.01). Regarding protein expression, TYMS was absent in 100% of CTCs from patients with pCR (p = 0.001) yet was expressed in 83% of non-responders at S2 (p < 0.001). Meanwhile, RAD23B was expressed in CTCs from 75% of non-responders at S1 (p = 0.01) and in 100% of non-responders at S2 (p = 0.001). Surprisingly, 100% of non-responders expressed TYMS mRNA at both timepoints (p = 0.001). In addition, TYMS/RAD23B was not detected in the CTCs of patients exhibiting pCR (p = 0.001). We found 83.3% of sensitivity for TYMS mRNA at S1 (p = 0.001) and 100% for TYMS (p = 0.064) and RAD23B (p = 0.01) protein expression at S2. Thus, TYMS mRNA and/or TYMS/RAD23B expression in CTCs, as well as CTC kinetics, have the potential to predict non-response to NCRT and avoid unnecessary radical surgery for LARC patients with pCR.

Randomized, double-blind, phase III clinical study of a novel nanotechnological topical anesthetic formulation containing lidocaine 25 mg/g and prilocaine 25 mg/g (nanorap) in skin phototypes I-III patients with ablative fractional CO2 laser treatment indication in the forehead.

BACKGROUND AND OBJECTIVES: Nanotechnology may increase the speed of penetration into the skin. This study evaluated the efficacy, safety, and pharmacokinetics of a novel topical anesthetic nanocapsule formulation (2 g) containing 2.5% lidocaine and 2.5% prilocaine (nanorap-test formulation) compared to placebo (control formulation) in skin types I-III patients of both sexes submitted to the ablative fractional CO2 laser treatment. METHODS: The patients (n = 120) included in this double-blind, single-center, randomized trial, received topical application of 2 g of the test formulation (50 mg lidocaine + 50 mg prilocaine) and placebo on the forehead region. Efficacy was assessed as pain sensation in four quadrants of each side of the forehead using a visual analogue scale immediately (0 min) and at 30, 60, and 90 minutes after laser application compared to placebo. The safety and tolerability of the test product were evaluated based on the occurrence of systemic adverse events as well as the occurrence of immediate and late skin reactions. Pharmacokinetic evaluation was performed in plasma of eight patients using a validated LC-MS/MS method for drugs quantification. RESULTS: Nanorap induced a clinically significant reduction in the pain assessment at all evaluated times (57.2%, 41.6%, 38.6%, and 37.3% at 0, 30, 60, and 90 minutes after drug application, respectively. Mean values of Cmax were 14.20 and 5.36 ng/ml and tmax were 3.5 and 1.8 hour for lidocaine and prilocaine, respectively. No systemic adverse events were observed. CONCLUSION: The nanorap formulation demonstrated a clinically and statistically significant efficacy providing analgesia after the ablative fractional CO2 laser therapy in the investigated patients, when compared to placebo. The product also presented good safety and tolerability. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Impact of Bariatric Surgery on the Pharmacokinetics Parameters of Amoxicillin.

BACKGROUND: Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs, such as antibiotics. The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass (RYGB) surgery is unknown. OBJECTIVES: The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of amoxicillin. METHODS: This study was performed as a randomized, open-label, single-dose clinical trial, with two periods of treatment, in which obese subjects (n = 8) received an amoxicillin 500 mg capsule orally before and 2 months after the RYGB surgery. The amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: After the surgery, the mean weight loss was 17.03 ± 5.51 kg, and mean body mass index (BMI) decreased from 46.21 ± 2.82 to 38.82 ± 3.32 kg/m2. The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration (AUC0-tlast) increased significantly (3.5-fold); the maximum plasma concentration (Cmax) increased 2.8-fold after the bariatric surgery. No correlation was found between amoxicillin absorption, BMI, and weight loss percentage. CONCLUSION: The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery. However, despite this increase, its exposure was lower than the values reported for non-obese volunteers. TRIAL REGISTRATION: Identifiers: NCT03588273.

ZAP-70 expression is associated with increased CD4 central memory T cells in chronic lymphocytic leukemia: cross-sectional study.

BACKGROUND: Although chronic lymphocytic leukemia is basically a B cell disease, its pathophysiology and evolution are thought to be significantly influenced by T cells, as these are probably the most important interaction partner of neoplastic B cells, participating in their expansion, differentiation and survival. Chronic lymphocytic leukemia B cells may also drive functional and phenotypic changes of non-malignant T cells. There are few data about the association between memory T cells and prognosis, especially related to ZAP-70, a common reliable surrogate of the gold standard chronic lymphocytic leukemia prognostic markers. OBJECTIVE: The aim of this study was to investigate whether the expression of ZAP-70 in chronic lymphocytic leukemia patients is associated with abnormal patterns of the distribution of naïve and memory T cells related to crosstalk between these cells. METHODS: In this cross-sectional, controlled study, patients with chronic lymphocytic leukemia were compared with healthy blood donors regarding the expression of ZAP-70 and the distribution of naïve and memory T cell subsets in peripheral blood as measured by flow cytometry. RESULTS: ZAP-70 positive patients presented an increased frequency and absolute number of central memory CD4+ T cells, but not CD8+ T cells, compared to ZAP-70 negative patients and age-matched apparently healthy donors. CONCLUSIONS: Because central memory CD4+ T cells are located in lymph nodes and express CD40L, we consider that malignant ZAP-70-positive B cells may receive beneficial signals from central memory CD4+ T cells as they accumulate, which could contribute to more aggressive disease.