Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11).

BACKGROUND: Few prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. MATERIALS AND METHODS: A total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. RESULTS: There were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046). CONCLUSIONS: Our biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.

[Gossypibomas in neurosurgery]. / Gossypibomas en neurocirugía.

INTRODUCTION: The term «gossypiboma¼ comes from the Latin gossypium, which refers to a genus of cotton plants, and from the Swahili word boma, which translates as «place of concealment¼. It may be mistaken for tumorous lesions or abscesses due to the way it is encapsulated, as evidenced in imaging examinations, and its variable and non-specific clinical features, which give rise to difficulty in its diagnosis and significant morbidity. AIM: To synthesise the available evidence on the presence of gossypibomas during neurosurgical procedures. DEVELOPMENT: A review was performed that included a search for articles in English and Spanish published in the last 15 years in PubMed, Ebsco Host, Embase, Mediclatina, Cochrane, Lilacs and Scopus, between January and June 2019, using the keywords «gossypiboma¼, «textiloma¼, «neurosurgery¼ and «neurosurgical procedures¼. In all, a total of 630 articles were found in the search, although, after selecting them by title and abstract, 22 case report articles were included for this review process. Altogether 36 individuals were identified, of whom 21 (58.3%) were women, and whose mean age was 56.1 years. Surgical sponges were observed as gossypibomas in 20 cases (55.6%). CONCLUSIONS: Gossypiboma is a complication secondary to surgical procedures that presents fairly unspecific signs and symptoms. The time that elapses before it appears usually ranges from a few days to several years after surgery and is correlated with multiple medical and legal implications.

TITLE: Gossypibomas en neurocirugía.Introducción. El término «gossypiboma¼ proviene del latín gossypium, que hace referencia a un género de plantas de algodón, y de la palabra kiswahili boma, que se traduce como «lugar de escondite¼. Puede confundirse con lesiones tumorales o abscesos debido a la forma de encapsulación evidenciada en los exámenes imaginológicos y su clínica variable e inespecífica, situación que genera dificultad para el diagnóstico y una morbilidad importante. Objetivo. Sintetizar la evidencia disponible sobre la presencia de gossypibomas durante la realización de procedimientos quirúrgicos en neurocirugía. Desarrollo. Se realizó una revisión en la cual se incluyó una búsqueda de artículos en inglés y castellano publicados en los últimos 15 años en PubMed, Ebsco Host, Embase, Mediclatina, Cochrane, Lilacs y Scopus, entre enero y junio de 2019, utilizando las palabras clave «gossypiboma¼, «textiloma¼, «neurosurgery¼ y «neurosurgical procedures¼. El total de artículos encontrados en la búsqueda fue de 630; sin embargo, tras la selección por título y resumen fueron 22 los artículos de informe de caso que se incluyeron. Se identificó a un total de 36 individuos, de los cuales 21 (58,3%) eran mujeres, y cuya edad media era de 56,1 años. En 20 casos (55,6%) se observaron esponjas quirúrgicas como gossypibomas. Conclusiones. El gossypiboma es una complicación secundaria a procedimientos quirúrgicos, con signos y síntomas bastante inespecíficos. Su tiempo de aparición suele oscilar entre unos cuantos días hasta varios años después de realizada la cirugía y se correlaciona con múltiples implicaciones médicas y legales.

Semaphorin 7A inhibits platelet production from CD34+ progenitor cells.

BACKGROUND: The multifunctional protein semaphorin 7A (Sema7A) may have regulatory effects on blood cell differentiation via its receptors ß1-integrin and plexin C1. As thrombocytopenia can be treated with transfusion of ex vivo CD34(+) cell-derived megakaryocytes, we investigated the effect of Sema7A on differentiation of CD34(+) progenitor cells into megakaryocytes and platelets. METHODS: Megakaryocytes and platelets were differentiated with a specific cytokine cocktail (CC) from CD34(+) progenitor cells in the presence or absence of Sema7A. Expression of cell markers CD41, CD42a and CD61 or detection of the activation of the signal mediator focal adhesion kinase (FAK) was performed by flow cytometry, cytokine secretion by Luminex technology, and megakaryocyte cell density and morphology by microscopic studies. Sema7A levels in vivo were assessed by real-time PCR and ELISA in hematological patients undergoing chemotherapy. RESULTS: CD34(+) progenitor cells expressed the receptors for Sema7A. Expression of CD41, CD42a and CD61 was markedly reduced in the presence of Sema7A, after CC-dependent platelet production from CD34(+) progenitor cells. As revealed by microscopic analysis, megakaryocyte cell density was significantly lower in the presence of Sema7A as compared with controls. Blocking of CD29 abrogated the Sema7A-mediated inhibition. Sema7A activated FAK in CD34(+) progenitor cells and significantly increased secretion of the proinflammatory cytokines IL-6, IL-8 and GM-CSF. Finally, Sema7A levels were up-regulated in 50% of patients after chemotherapy. CONCLUSIONS: Sema7A markedly reduces the production rates of megakaryocytes and platelets from CD34(+) progenitor cells. Hence, up-regulation of Sema7A may be a major risk factor for a reduced platelet repopulation after hematopoietic stem cell transplantation.

Regulation of HLA class II expression prevents allogeneic T-cell responses.

Human leukocyte antigen (HLA) class II molecules are polymorphic heterodimers that present peptides to CD4+ T-cells. The HLA-DM molecule contributes to assemble HLA class II-peptide complexes. We investigated the effect of silencing either HLA-DR or HLA-DM expression in the allogeneic T-cell responses. The delivery of HLA-DR- or HLA-DM-specific short hairpin RNAs (shRNAs) in a monocytic cell line caused a decrease by up to 85% and 75% at the respective mRNA level. Allogeneic T-cells stimulated with HLA-DM-silenced monocytes decreased to 30% granzyme B mRNA and interferon gamma (IFN-γ) production in comparison with T-cells stimulated with monocytes expressing a non-specific shRNA. By contrast, HLA-DR-silenced monocytes did not induce proliferation, up-regulation of granzyme B mRNA levels or high IFN-γ secretion by allogeneic T-cells vs HLA-DR expressing cells. Direct targeting of HLA-DR expression prevented more efficiently an allogeneic T-cell response in comparison with the knockdown of the expression of HLA-DM molecules. Silencing the expression of HLA-DR molecules might contribute to the development of new allogeneic cell-based therapeutic approaches.

The new HLA-Cw*0524 allele increase the variability of position 49 in HLA-C.

The identification of the novel human leukocyte antigen (HLA)-Cw*0524, which was found in a potential stem cell donor, is described. The sequence of the new allele differs from HLA-Cw*0501 and HLA-Cw*0503 by a nonsynonymous amino acid (AA) exchanges at position 49.