The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of localised colon cancer was published in 2020. It ...was decided by both the ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special virtual guidelines meeting in March 2021 to adapt the ESMO 2020 guidelines to take into account the ethnic differences associated with the treatment of localised colon cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with localised colon cancer representing the oncological societies of Japan (JSMO), China (CSCO), India (ISMPO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug availability and reimbursement situations in the different Asian countries.
•This article provides ESMO expert recommendations adapted for the treatment of localised colon cancer in Asian patients.•The aim was to provide guidance for the optimisation of the management of such patients across Asia.•The availability and applicability of certain procedures as they relate to certain of the recommendations are discussed.
The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a ...new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.
RAS mutation is considered one of the most relevant oncogenic drivers in human cancers. Unfortunately, for more than three decades, RAS has been considered an undruggable target. Recently, the ...discovery of selective and potent KRASG12C inhibitors represented a light at the end of the tunnel. Indeed, sotorasib and adagrasib proved clinical activity in patients with refractory metastatic colorectal cancer harboring KRASG12C mutation; however, responses are lower than expected, suggesting the presence of intrinsic resistance. Consequently, novel combinatory strategies to disrupt the RAS signaling pathways are under clinical investigation. This review aims to discuss the current knowledge and novel routes of KRASG12C inhibition in metastatic colorectal cancer.
•KRASG12C mutation occurs in 2%-4% of metastatic colorectal cancer (mCRC).•The presence of KRASG12C mutation is correlated with a dismal response to chemotherapy and poor prognosis.•Selective KRASG12C inhibitors, including sotorasib and adagrasib, showed signals of antitumor activity in mCRC.•Different combinatory strategies are under clinical investigation.
The purpose of this study was to compare short term in vitro and in vivo biodegradation studies with low purity Mg (> 99.94 %), Mg-10Gd and Mg-2Ag designed for biodegradable implant applications. ...Three in vitro testing conditions were applied, using (i) phosphate buffered saline (PBS), (ii) Hank's balanced salt solution (HBSS) and (iii) Dulbecco's modified eagle medium (DMEM) in 5 % CO2 under sterile conditions. Gas evolution and mass loss (ML) were assessed, as well as the degradation layer, by elemental mapping and scanning electron microscopy (SEM). In vivo, implantations were performed on male Sprague-Dawley rats evaluating both, gas cavity volume and implant volume reduction by micro-computed tomography (µCT), 7 d after implantation. Samples were produced by casting, solution heat treatment and extrusion in disc and pin shape for the in vitro and in vivo experiments, respectively. Results showed that when the processing of the Mg sample varied, differences were found not only in the alloy impurity content and the grain size, but also in the corrosion behaviour. An increase of Fe and Ni or a large grain size seemed to play a major role in the degradation process, while the influence of alloying elements, such as Gd and Ag, played a secondary role. Results also indicated that cell culture conditions induced degradation rates and degradation layer elemental composition comparable to in vivo conditions. These in vitro and in vivo degradation layers consisted of Mg hydroxide, Mg-Ca carbonate and Ca phosphate.
Burnout in health care professionals could have serious negative consequences on quality of patient care, professional satisfaction and personal life. Our aim was to investigate the burnout ...prevalence, work and lifestyle factors potentially affecting burnout amongst European oncologists≤40 (YOs).
A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/lifestyle factors. Statistical analyses were carried out to identify factors associated with burnout.
Total of 737 surveys (all ages) were collected from 41 European countries. Countries were divided into six regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). Seventy-one percent of YOs showed evidence of burnout (burnout subdomains: depersonalization 50%; emotional exhaustion 45; low accomplishment 35%). Twenty-two percent requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (P<0.0001). Burnout was highest in central European (84%) and lowest in Northern Europe (52%). Depersonalization scores were higher in men compared with women (60% versus 45% P=0.0001) and low accomplishment was highest in the 26–30 age group (P<0.01). In multivariable linear regression analyses, European region, work/life balance, access to support services, living alone and inadequate vacation time remained independent burnout factors (P<0.05).
This is the largest burnout survey in European Young Oncologists. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance, access to support services and adequate vacation time may reduce burnout levels. Raising awareness, support and interventional research are needed.
Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in ...patients treated with first-line anti-EGFR monoclonal antibody-based therapy.
In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing.
A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis.
This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.
Abstract
The heat generated during early age cement hydration causes a semi-adiabatic temperature rise of hardening concrete, while starting to develop its physical and mechanical properties. As a ...matter of principle, the heat generated by the hardening mixture depends on the cement properties and its hardening conditions like for instance the type of binders, quality of aggregates, water-to-cement ratio and type of formwork. A simple 1D numerical model can be formulated for simulating the evolution in time of this reaction, in order to identify the so called degree of hydration. The present paper proposes a detailed description of a theoretical approach which allow to assess the temperature development occurring in concrete elements at the early-age when the produced mixture is cured in semi-adiabatic boundary conditions. In this numerical procedure, the differential heat equation takes into account the heat that liberates to the environment through the formwork or concrete’s surface. This is done by considering the Arrhenius Principle and assuming a pre-defined shape of the adiabatic hydration curve of the concrete mixture. Hence, an indirect identification procedure of the aforementioned adiabatic curve is ideally carried out, as the simulated temperature evolution in semi-adiabatic conditions is brought to match the temperature measurements on a hardening concrete sample. This modelling procedure, enabling various boundary conditions, ranging from semi-adiabatic to isothermal, can be used to calculate the degree of hydration of a real in-situ cast concrete. Specifically, considering the variation of concrete strength class and element size some possible applications are proposed: this represents a simplified approach for the prediction of the temperature time-evolution in the concrete elements at early-age which may be also used as a practical tool for mitigating the risk of premature cracking.
Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal ...cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations.
A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi–anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n= 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations.
Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001 and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01).
Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF-V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies.
•Plasmatic BRAF AF has a prognostic role for survival in mCRC treated with BRAF inhibitors.•ddPCR, applied in a cohort including a real-world population, mirrored those of the BEACON clinical trial using next-generation sequencing (NGS).•ddPCR detects BRAF AF in circulating tumor DNA (ctDNA) with high reproducibility and sensitivity, offering a validated alternative to NGS.•Identifying prognostic factors in BRAF-mutant mCRC is crucial to stratify patients and guide treatment strategies.
Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK ...pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance.
We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance.
The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models.
These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
We describe a novel method to achieve a universal, massive, and fully automated analysis of cell motility behaviours, starting from time-lapse microscopy images. The approach was inspired by the ...recent successes in application of machine learning for style recognition in paintings and artistic style transfer. The originality of the method relies i) on the generation of atlas from the collection of single-cell trajectories in order to visually encode the multiple descriptors of cell motility, and ii) on the application of pre-trained Deep Learning Convolutional Neural Network architecture in order to extract relevant features to be used for classification tasks from this visual atlas. Validation tests were conducted on two different cell motility scenarios: 1) a 3D biomimetic gels of immune cells, co-cultured with breast cancer cells in organ-on-chip devices, upon treatment with an immunotherapy drug; 2) Petri dishes of clustered prostate cancer cells, upon treatment with a chemotherapy drug. For each scenario, single-cell trajectories are very accurately classified according to the presence or not of the drugs. This original approach demonstrates the existence of universal features in cell motility (a so called "motility style") which are identified by the DL approach in the rationale of discovering the unknown message in cell trajectories.
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