Predictive significance of circulating histones in hepatocellular carcinoma patients treated with sorafenib

Background: Predictive biomarkers for advanced hepatocellular carcinoma are lacking. EZH2 drives sorafenib resistance through H3K27me3 and is counteracted by SETD2, which catalyzes H3K36me3. The authors tested the predictive power of circulating H3K27me3 and H3K36me3 in advanced hepatocellular carcinoma patients treated with sorafenib. Methods: A total of 80 plasma samples were tested for histone variants by ELISA. Changes from baseline to best response or progressive disease were correlated with patient survival. Results: A higher EZH2/SETD2 ratio predicted worse prognosis in this setting. H3K27me3 and H3K36me3 decreased from baseline to best response. The H3K27me3/H3K36me3 ratio increased from baseline to progressive disease. Higher ratios at best response were associated with shorter progression-free survival. Conclusion: The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced hepatocellular carcinoma

DYNAMICS OF TUMOUR MICROENVIRONMENT IN GASTRIC CANCER PATIENTS RECEIVING PERIOPERATIVE FLOT: IMMUNE PROFILING OF PRE- AND POST-TREATMENT TISSUES

Background. Gastric cancer (GC) represents the fifth most frequently diagnosed tumour and the third leading cause of cancer-related death worldwide. In the last decades, a compelling body of evidence has progressively provided new insights into the definition of new epidemiological, clinical, pathologic and molecular features, new emerging biomarkers and different treatment options in all settings of GC disease. In the setting of locally advanced resectable GC/ gastroesophageal junction carcinoma (GEJC), perioperative FLOT (fluorouracil, oxaliplatin, docetaxel) recently became the new standard of care, revealing a significant improvement in survival. Moreover, moving from the first signals of immunotherapy potential efficacy in advanced disease and from new molecular insights, many efforts have been focused on optimising the preoperative treatment strategies, as combining immunotherapies with chemotherapies. Taking into account the complexity and heterogeneity of GC, in order to choose the best therapeutic strategy, the best timing and the selected patient, we cannot avoid a more profound knowledge of tumour microenvironment (TME) and of its modifications. Indeed, TME is a niche of stromal, immune and tumoural cells and extracellular matrix components in which cells cross talk through a huge reciprocal exchange of molecular information, above all in GC, and it influences the tumour behaviour and the treatment response. Aim. Accordingly, our aim is to analyse the TME of pre and post treatment samples of patients treated with perioperative FLOT and to study both its baseline characteristics and its modifications after neoadjuvant therapy, in order to unravel new potential strategies to enhance the efficacy of chemotherapy. Materials and methods. We prospectively analysed both diagnostic biopsies (PRE) and surgical samples (POST) from patients treated with perioperative FLOT at our centre. We collected clinicopathologic data (age, gender, clinical TNM, tumour location, pathological TNM, histotype, grading, tumour regression grade) and molecular data (HER2, MSI and EBV evaluation). Using RNA extracted from TME of the paired samples, we performed gene expression profile using NanoString nCounter® PanCancer Panel, a computational advanced analysis that allows to measure the expression of 730 immune-related genes (and 40 housekeeping genes), corresponding to 14 immune cell types and 22 immune functions. Results. We enrolled a total of 25 consecutive patients eligible for the study, 22 male and 3 female, with a median age of 63 years. Clinical T stage was cT3-4 in the majority of cases (88%) and N-positive status in all cases. According to Lauren’s histotype, 8 cases were diffuse, 7 intestinal, 2 mixed and 8 were not detailed. Three cases were HER2 positive, only 1 was MSI high and all cases were EBV negative. After a median follow-up of 29.8 months, 9 patients (36.0%) had progressed and 6 (24.0%) had died. The estimated survival rate was 81% at 1 year and 64% at 2 years. The number of events were not enough to obtain median disease free and overall survival estimations and to provide survival correlations. T-regression, considered as the reduction from a baseline cT3-4 to an ypT0-2, was achieved in 5 patients (20%), while 4 patients (16.0%) reported an ypN0 stage (N-clearance). At a first unsupervised hierarchical method analysis performed with Nanostring panel, all samples were considered jointly: even though analysed without any descriptors, the method recognized similarities and almost exactly distinguished PRE and POST samples, demonstrating that chemotherapy could have an impact on TME changing its immune profile. Looking at the differential gene expressions, when POST were compared with the PRE samples, the main features of the differential expression were traced in hyper expressed genes from gene sets related to cytotoxicity, T cell functions, complement system, TNF superfamily, cell cycle and regulation. Among post samples, the main modifications in immune gene sets resulted related to T regression covariate, which we went to look more in detail. Cases with pre-treatment activation were the ones that preferentially reported tumour regression, with a baseline activation of cytotoxicity system and T cell functions carrying higher expression of granzyme, perforin and grunulysin. After treatment, these cases remained activated and also other samples revealed FLOT-induced changes, globally showing a hyper activation of T cell functions, B cell functions, antigen processing and cytotoxicity that seemed to be involve in treatment response. If we consider patients with consequently tumour regression compared with patients who didn’t achieve it, their pre-treatment samples showed a high percentage of all immune cells, exception made for neutrophils; similarly, their post-treatment samples presented a markedly higher percentage of B cells, T cells, NK cells, CD8+ T cells, while neutrophils and above all mast cells appeared to be reduced. Conclusions. Our analysis suggested that FLOT regimen could have an impact on immune TME of GC/GEJC patients and may help to convert immune “cold” cancers to immune “hot” ones. The presence of activated cytotoxic T cells with granulysin, perforin, granzymes expression were important for achieving treatment response with chemotherapy, either if already presented at baseline or if induced by chemotherapy. The upregulation of B cells, T cell, CD8+ T cells were associated with better response to chemotherapy, together with a downregulation of mast cells and neutrophils. Further analyses and longer follow up were ongoing, in order These findings needed to be were consistent with the anti-tumour immunity role of T cells and CD8+ T cells and with the pro-angiogenic and pro-tumorigenic role of mast cells, as well as their relationship with neutrophils. This immune phenotype could be exploited to potentiate a treatment response or probably to gain efficacy in non-responders, also in chemo-immunotherapy combinations in which FLOT could be a valid chemotherapy backbone. Considering the small samples size, the preliminary results and the relevance of the issue, additional evaluations should be integrated in order to put our data in context and further analyses are still needed

Management of Infectious Lymphadenitis in Children

Lymphadenopathy is an irregularity in the size and texture of the lymph nodes, which is quite common in childhood. When the enlargement of lymph nodes is caused by inflammatory and infectious processes, it is called lymphadenitis. The main objective of this manuscript is to summarize the common infectious etiologies and presentations of lymphadenitis in children providing a management guide for clinical practice. PubMed was used to search for all of the studies published up to April 2021 using keywords such as “lymphadenitis” and “children”. Literature analysis showed that the differential diagnosis for lymphadenitis in pediatrics is broad. Although lymph node enlargement in children is usually benign and self-limited, it is important to exclude malignant etiology. In most cases, history and physical examination allow to identify the correct diagnosis and start a proper treatment with a prompt resolution of the lymphadenopathy. However, particularly in the case of persistent lymphadenitis, determining the cause of lymph node enlargement may be difficult, and the exact etiology may not be identified despite extensive investigations. Further studies should develop and validate an algorithm to assist pediatricians in the diagnosis and timely treatment of lymphadenitis, suggesting situations in which a watchful waiting may be considered a safe approach, those in which empiric antibiotic therapy should be administered, and those requiring a timely diagnostic work-up

Analysis of irradiated Argentinean fetal bovine serum for adventitious agents

Fetal bovine serum (FBS) used in cell culture may be contaminated with adventitious agents, which can affect the production of biologicals and the results of clinical laboratory tests. We carried out a retrospective study to determine the incidence of adventitious agent contamination of Argentinean irradiated FBS dating from 2015 to 2019. We analyzed FBS batches for mycoplasma and adventitious viruses (bovine pestiviruses, bovine adenovirus, bluetongue virus, bovine parainfluenza virus 3, rabies virus, bovine parvovirus, bovine herpesvirus 1, bovine respiratory syncytial virus, and reovirus). Cell passages followed by direct immunofluorescence were carried out to check viability of the mentioned adventitious agents. Also, molecular detection of mycoplasma and pestiviruses was performed on the FBS samples. The presence of neutralizing antibodies against pestiviruses was determined. Molecular analyses indicated that frequencies of mycoplasma and pestiviruses in FBS were 14% and 84%, respectively. All of the batches were seronegative for pestiviral antibodies. After cell passages, all FBS samples were negative for hemadsorbent agents and by immunofluorescence for all of the viral species analyzed; PCR assays were negative for mycoplasma and pestiviruses. Our results demonstrate that, of all adventitious agents tested, local FBS batches only had traces of mycoplasma and pestiviruses; gamma irradiation was effective in inactivating them.Instituto de VirologíaFil: Pecora, Andrea. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Perez Lopez, Jorgelina. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Jordan, Maximiliano Jesus. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Franco, Lautaro Nahuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Politzki, Romina Paula. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Ruiz, Vanesa. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Tecnológicas; ArgentinaFil: Alvarez, Irene. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Tecnológicas; Argentin

Role of Baseline Computed-Tomography-Evaluated Body Composition in Predicting Outcome and Toxicity from First-Line Therapy in Advanced Gastric Cancer Patients

Sarcopenia is recognised as a predictor of toxicity and survival in localised and locally advanced gastric cancer (GC). Its prognostication power in advanced unresectable or metastatic GC (aGC) is debated. The survival impact of visceral and subcutaneous fat distribution (visceral fat area (VFA)/subcutaneous fat area (SFA)) is ambiguous. Our aim was to determine the influence of body composition parameters (BCp) on toxicity and survival in aGC patients undergoing palliative treatment. BCp were retrospectively assessed by baseline computed tomography for 78 aGC patients who received first-line chemotherapy from March 2010 to January 2017. Correlations between BCp and toxicity and survival were calculated by chi(2)-test and by log-rank-test and Cox-model, respectively. Sarcopenia fails to show association with progression-free survival (PFS) (p = 0.44) and overall survival (OS) (p = 0.88). However, sarcopenia influences the development of high-grade neutropenia (p = 0.048) and mucositis (p = 0.054). VFA/SFA (high vs. all the rest) results as a strong predictor of objective response (p = 0.02) and outcome (PFS, p = 0.001; OS, p = 0.02). At multivariate analysis for PFS, prognostic factors are VFA/SFA (p = 0.03) and a neutrophil-lymphocyte ratio >3. The same factors remain significant for OS (each p = 0.03) along with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008) and number of metastatic sites >= 2 (p < 0.001). In our cohort of aGC, VFA/SFA exhibit a robust impact on survival, with a higher sensitivity than sarcopenia

HER2 overexpression as a poor prognostic determinant in resected biliary tract cancer

HER2 overexpression has been investigated as a potential biomarker and therapeutic target in biliary tract cancer (BTC), but a prognostic role of such alteration has not been demonstrated yet

Early Tumor Shrinkage and Depth of Response Evaluation in Metastatic Pancreatic Cancer Treated with First Line Chemotherapy: An Observational Retrospective Cohort Study

Early tumor shrinkage (ETS) and depth of response (DoR) predict favorable outcomes in metastatic colorectal cancer. We aim to evaluate their prognostic role in metastatic pancreatic cancer (PC) patients treated with first-line modified-FOLFIRINOX (FOLFOXIRI) or Gemcitabine + Nab-paclitaxel (GemNab). Hence, 138 patients were tested for ETS, defined as a ≥20% reduction in the sum of target lesions’ longest diameters (SLD) after 6–8 weeks from baseline, and DoR, i.e., the maximum percentage shrinkage in the SLD from baseline. Association of ETS and DoR with progression-free survival (PFS) and overall survival (OS) was assessed. ETS was reached in 49 patients (39.5% in the FOLFOXIRI, 29.8% in the GemNab group; p = 0.280). In the overall population, ETS was significantly associated with better PFS (8.0 vs. 4.8 months, p < 0.001) and OS (13.2 vs. 9.7 months, p = 0.001). Median DoR was −27.5% (−29.4% with FOLFOXIRI and −21.4% with GemNab, p = 0.016): DoR was significantly associated with better PFS (9.0 vs. 6.7 months, p < 0.001) and OS (14.3 vs. 11.1 months, p = 0.031). Multivariate analysis confirmed both ETS and DoR are independently associated with PFS and OS. In conclusion, our study added evidence on the role of ETS and DoR in the prediction of outcome of PC patients treated with first-line combination chemotherapy

Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience

Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS)