Search

Liver transplantation; Metastatic colorectal cancer Trasplantament de fetge; Càncer colorectal metastàtic Trasplante de hígado; Cáncer colorrectal metastásico Colorectal cancer (CRC) is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Five-year overall survival remains modest among patients with metastatic CRC (mCRC) treated with conventional therapies however, liver transplantation in a highly selected population can improve clinical outcomes with an impressive 5-year overall survival of 83%. Despite liver transplantation appearing to be a promising therapeutical option for well-selected patients with mCRC with the liver-limited disease, these data come from small monocentric trials which included a heterogeneous population. Currently, several clinical trials are evaluating liver transplantation in this scenario, aiming for a more accurate patient selection by integrating liquid biopsy, tissue profiling, and nuclear medicine to the already known clinical biomarkers that eventually may lead to a survival improvement. In this paper, the clinical outcomes and inclusion criteria from the most relevant clinical trials and clinical series involving liver transplantation in patients with liver-limited disease colorectal cancer are reviewed as well as the trials currently recruiting.

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Resumen La hidatidosis es una zoonosis causada por la larva del cestodo Echinococcus granulosus. La afectacion cerebral en el ser humano es inusual, solo en el 1-2% de los casos se observa compromiso encefalico. Este cuadro se presenta fundamentalmente en poblacion pediatrica y se caracteriza por la presencia de quistes unicos y uniloculares. A continuacion, se presenta el caso de una paciente de 29 anos que acude a urgencias por una cefalea invalidante de varias semanas de evolucion. El estudio cerebral mediante imagen, revela la presencia de una masa de origen desconocido, siendo el diagnostico final de quiste hidatidico bilobulado. A proposito de este caso, se revisaran los aspectos clinico-epidemiologicos, los diagnosticos y los tratamientos de la hidatidosis cerebral.

El ictus isquémico ha sido reportado en los pacientes con infección por SARS-CoV-2. No está claro si el COVID-19 es causal o simplemente coexiste o desencadena la aparición del ictus. El ictus es relativamente infrecuente en contexto de COVID-19 y en su mayor parte ocurre en ancianos con factores de riesgo vascular. El mecanismo subyacente del ictus es múltiple. Presentamos un varón de 84 años con ictus por oclusión de grandes vasos coincidente con infección grave por COVID-19 que, a pesar de una trombectomía mecánica exitosa inicial, tuvo un desenlace fatal debido a complicaciones respiratorias y a un infarto cerebral masivo contralateral por recurrencia temprana. En consecuencia, la vigilancia en este tipo de pacientes debe ser extrema ya que el ictus isquémico con infección activa por SARS-CoV-2 puede ser de mal pronóstico.

Immune checkpoint inhibitors yielded unprecedented outcomes in patients with mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), but clinical decision-making in this rapidly evolving treatment landscape is challenging. Since performance status (PS) represents a well-established prognostic factor in clinical practice, we investigated whether worse PS, overall or related to either patients' frailty or high tumour burden, could affect the outcomes in this whole patients' population and according to immune checkpoint inhibitor treatment type.We conducted a global study at Tertiary Cancer Centres and collected data of patients with dMMR/MSI-H mCRC treated with anti- programmed-death (ligand)-1 (PD(L)-1) monotherapy or anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination.The cohort included 502 patients. At a median follow-up of 31.2 months, worse PFS and OS were reported in patients with patient-related PS ≥ 1 (adjusted-HRs: 1.73, 95%CI: 1.06-2.83, p = 0.004 and 2.06, 95%CI: 1.13-3.74, p = 0.001, respectively) and cancer-related PS ≥ 1 (adjusted-HRs: 1.61, 95%CI: 1.19-2.17, p = 0.004 and 1.87, 95%CI: 1.32-2.66, p = 0.001, respectively). Anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination did not provide significantly better survival compared to anti-PD(L)-1 monotherapy in PS 0 subgroup (PFS HR = 0.62, 95%CI: 0.37-1.02, p = 0.059; OS HR = 0.59, 95%CI: 0.32-1.11, p = 0.100) and in patient-related PS ≥ 1 (PFS HR 0.93, 95%CI: 0.31-2.83, p = 0.899; OS HR 1.22, 95%CI: 0.34-4.37, p = 0.760), but the difference was significant and clinically meaningful in the subgroup with cancer-related PS ≥ 1 (PFS HR = 0.32, 95%CI: 0.19-0.53, p lt; 0.001; OS HR = 0.26, 95%CI: 0.14-0.48, p lt; 0.001).In patients with dMMR/MSI-H mCRC, an extensive evaluation of clinical variables including PS may be implemented in the therapy decision-making.

This case report concerns a 63-year-old man affected by metastatic undifferentiated liposarcoma. After receiving pembrolizumab as a second-line treatment in a clinical trial, the patient experienced an immune-mediated myocarditis, myositis and myasteniform syndrome. The last two adverse events showed significant clinical relevance in terms of severity, duration and the required specific treatment.Initial treatment approach consisted in pulses of 1 g of methylprednisolone, followed by 2 mg/kg/day, with clinical improvement. After 12 days, the immune-mediated myasteniform syndrome worsened, with dysphagia, dysphonia, bilateral palpebral ptosis and respiratory difficulty. Due to the refractoriness to glucocorticoid treatment, it was decided to initiate intravenous immunoglobulin at 2 g/kg, followed by 2 mg/kg every 4 weeks once discharged and mycophenolate 500 mg/12 hours, in order to reduce the dose of glucocorticoids.After 2 months, the patient presented an optimal clinical evolution, without muscular weakness and referred to an improvement in dysphagia and speech.

Between 8% and 12% of patients with metastatic colorectal cancer (mCRC) harbor a BRAF-V600E mutation in their tumors, which is associated with a poor response to standard chemotherapy and short overall survival. Moreover, nearly 30% of BRAF-V600E mCRC tumors also have microsatellite instability. Transcriptomic signatures suggest a strong immunogenic biologic background for most of these tumors. In contrast to the melanoma context, single-agent BRAF inhibition does not achieve clinical benefit in BRAF-V600E mCRC. Different preclinical/translational studies have elucidated that, in this context, upon BRAF inhibition, there is immediate signal upregulation via the EGFR, and therefore an anti-EGFR treatment should be added to the BRAF inhibitor. Several phase II studies have confirmed the activity of BRAF inhibitors combined with EGFR-directed monoclonal antibodies in patients with BRAF-V600E mCRC. The role of other mitogen-activated protein kinase inhibitors, such as mitogen-activated protein kinase kinase or PI3K inhibitors, remains unclear. The phase III BEACON clinical trial confirmed the BRAF/EGFR inhibitor combination of encorafenib/cetuximab as the new standard of care for BRAF-V600E mCRC after at least one previous line of systemic therapy. Novel approaches for managing BRAF-V600E mCRC include, among others, triple combinations of BRAF inhibitors and anti-EGFR antibodies combined with immune checkpoint inhibitors in the microsatellite instability population and evaluation of the encorafenib/cetuximab treatment in combination with standard chemotherapy with bevacizumab in the first-line setting.

Supplementary Figures S1-S4 and Supplementary Tables S1-S4

Figure S1. Flowchart of study selection process with ICIs treatment. Figure S2. Flowchart of study selection process with TAs treatment. Figure S3. Overall Survival comparing HPD with non-HPD in patients with progression disease as best response in the ICIs and TAs cohorts ( RECIST 1.1 progression disease Landmark Analysis). Figure S4. Overall Survival in second line (a) and third (b) setting HPD vs non-HPD progressors by RECIST criteria in ICIs cohort. Figure S5. Concordance between RECIST and TGR criteria in ICIs cohort. Table S1. Computed tomography (CT) acquisition protocol parameters. Table S2. Clinical variables in patients treated with TAs. Table S3. Multivariate model in patients with progression disease as best response in ICIs group (using TGR).

Purpose:Most hyperprogression disease (HPD) definitions are based on tumor growth rate (TGR). However, there is still no consensus on how to evaluate this phenomenon.Patients and Methods:We investigated two independent cohorts of patients with advanced solid tumors treated in phase I trials with (i) programmed cell death 1 (PD-1)/PD-L1 antibodies in monotherapy or combination and (ii) targeted agents (TA) in unapproved indications. A Response Evaluation Criteria in Solid Tumors (RECIST) 1.1–based definition of hyperprogression was developed. The primary endpoint was the assessment of the rate of HPD in patients treated with ICIs or TAs using both criteria (RECIST and TGR) and the impact on overall survival (OS) in patients who achieved PD as best response.Results:Among 270 evaluable patients treated with PD-1/PD-L1 inhibitors, 29 PD-1/PD-L1–treated patients (10.7%) had HPD by RECIST definition. This group had a significantly lower OS (median of 5.23 months; 95% CI, 3.97–6.45) when compared with the non-HPD progressor group (median, 7.33 months; 95% CI, 4.53–10.12; HR = 1.73, 95% CI, 1.05–2.85; P = 0.04). In a subset of 221 evaluable patients, 14 (6.3%) were categorized as HPD using TGR criteria, differences in median OS (mOS) between this group (mOS 4.2 months; 95% IC, 2.07–6.33) and non-HPD progressors (n = 44) by TGR criteria (mOS 6.27 months; 95% CI, 3.88–8.67) were not statistically significant (HR 1.4, 95% IC, 0.70–2.77; P = 0.346). Among 239 evaluable patients treated with TAs, 26 (10.9%) were classified as having HPD by RECIST and 14 using TGR criteria in a subset of patients. No differences in OS were observed between HPD and non-HPD progressors treated with TAs.Conclusions:HPD measured by TGR or by RECIST was observed in both cohorts of patients; however, in our series, there was an impact on survival only in the immune-checkpoint inhibitor cohort when evaluated by RECIST. We propose a new way to capture HPD using RECIST criteria that is intuitive and easy to use in daily clinical practice.

Purpose:OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site.Experimental Design:Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden.Results:Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%–95%), 88% (68%–97%), and 64% (49%–78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10.Conclusions:Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.

Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing forPreclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, all clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented.The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide CRC patients' treatment has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low; however, the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.

The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population.This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab. Efficacy and mechanism of action of bispecific antibodies are also covered.mCRC is a heterogeneous disease and the optimal selection and sequence of treatments is challenging. Monoclonal antibodies have complex pharmacokinetics and pharmacodynamics, with important interactions between them. The arrival of bioequivalent molecules to the market increases the need for the characterization of pharmacokinetics and pharmacodynamics of classic monoclonal antibodies to reach bioequivalent novel molecules.

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICI) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM, and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (7 ICI-myositis, 4 DM, 3 AS, 6 IMNM, and 2 IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1, and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed co-existing myocarditis. ICI-MYO2 was composed of patients with predominant necrotizing pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICIDM and ICI-MYO1, and only ICI-MYO1 patients developed myocarditis.

El presente artículo indaga algunos de los elementos sociales que tras el confinamiento debido a la pandemia de covid-19 han aflorado y consolidado en un nuevo escenario social, así como las líneas maestras que desde la identidad católica se hacen imprescindibles para abrir vías hacia una sociedad donde lo humano pueda desarrollarse en todos los ámbitos. La enfermedad, la impredecibilidad y la vulnerabilidad se han abierto paso al tiempo que el Estado y las redes tecnológicas globales buscan afianzarse como pretendidos y únicos garantes de las relaciones sociales. Frente a ello, la Iglesia católica es capaz de aportar su sabiduría de origen trascendente aquilatada en siglos de experiencia pues siendo fiel al mensaje evangélico recibido, es capaz de erigirse en referente moral que nos permita repensar los nuevos escenarios sociales desde una fe, una esperanza y una caridad encarnadas en actitudes personales. Actitudes personales que, fraguadas en la comunidad cristiana bajo el modelo de las denominadas minorías creativas, trascienden la autorreferencialidad y permean el tejido societario haciendo frente a los paradigmas tanto individualistas como colectivistas siempre enemigos de la verdad del hombre y de sus relaciones.

Colorectal cancer; Predictive markers; Tumour biomarkers Cáncer colorrectal; Marcadores predictivos; Biomarcadores tumorales Càncer colorrectal; Marcadors predictius; Biomarcadors tumorals Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support, the Consorcio Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00259) from the Institute of Health Carlos III (ISCIII), Ministry of Science and Innovation, and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 and SLT008/18/00205) for their support on this research. Authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S / AEI / 10.13039 /501100011033). This research is funded by the SCITRON program; Novartis funded the genomics characterization by WES of samples from 28 patients from the discovery cohort and had no influence on data analysis/interpretation or writing of the paper (3003145512 to R.A.T.). S.Li. is financially supported by a Chinese Scholarship Council PhD fellowship (201909370083 to S. Li). R.P.-L. is supported by a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395 and PI21/01019 to R.P.-L.) and the Prostate Cancer Foundation (Young Investigator Award). This work was supported by the Miguel Servet-I Research Award from ISCIII of the Ministry of Economy (CP17/00199 to R.A.T.), the Olga Torres Foundation Award to emerging researchers (2601 to R.A.T.), the ISCIII-FEDER (PI17/00947 and PI20/00968 to E.E.), and the Fundación AECC (CLSEN19001ELEZ to E.E.) and Ministry of Science and Innovation (Europa Redes y Gestores, ECT2020-000827 to E.E.).

Introduction: Colorectal cancer (CRC) is a major public health problem. Despite major progress understanding the biological basis of this tumor added to the incorporation of optimized diagnostic an...

Recensión de la última obra de José Pérez Adán.

Cancer-associated myositis (CAM) is defined as when cancer appears within 3 years of myositis onset. Dermatomyositis and seronegative immune-mediated necrotizing myopathy are the phenotypes mostly related to cancer. In general, treatment principles in myositis patients with and without CAM are similar. However, some aspects of myositis management are particular to CAM, including (a) the need for a multidisciplinary approach and a close relationship with the oncologist, (b) the presence of immunosuppressive and antineoplastic drug interactions, and (c) the role of the long-term immunosuppressive therapy as a risk factor for cancer relapse or development of a second neoplasm. In this review, we will also discuss immunotherapy in patients treated with checkpoint inhibitors as a treatment for their cancer.Studies on cancer risk in patients treated with long-term immunosuppressive drugs, in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis, and in solid organ transplant recipients have shed some light on this topic. Immunotherapy, which has been a great advance for the treatment of some types of malignancy, may be also of interest in CAM, given the special relationship between both disorders.Management of CAM is a challenge. In this complex scenario, therapeutic decisions must consider both diseases simultaneously.The online version contains supplementary material available at 10.1007/s40674-022-00197-2.

Model selection methods are used in different scientific contexts to represent a characteristic data set in terms of a reduced number of parameters. Apparently, these methods have not found their way in the multibody systems dynamics literature. Multibody models can be considered parametric models in terms of their dynamic parameters and model selection techniques can then be used to express these models in terms of a reduced number of parameters. These parameter-reduced models are expected to have a computational complexity smaller than the original one, and still preserve the desired level of accuracy. They are also known to be good candidates for parameter estimation purposes. In this work, simulations of the actual model are used to define a data set representative of the standard working conditions of the system. A parameter-reduced model is chosen and its parameter values estimated so that they minimize a prediction error on these data. To that end, model selection heuristics as well as normalized error measures are proposed. Using this methodology two multibody systems with very different characteristic mobility are analyzed. Very important reductions in the number of parameters and in the computational cost are obtained without compromising too much on the reduced model accuracy. As an aside result, a generalization of the base parameter concept to the context of parameter-reduced models is proposed.

Introduction: Metastasis involves a set of complex events that finally result in malignant cells from primary tumors invading distant tissues by the pass of circulant tumor cells (CTC) through the blood circulation. To authentically comprehend the complex chain of events and even enable new therapeutic approaches in mCRC patients, ex-vivo functional models are an unmet research need. Experimental Plan: PROMISE project is combining bioengineering solutions such as bioprinting biomaterials and microfluidics to mimic the tumor microenvironment (TME) of metastatic sites in mCRC. In this project, we are developing a bioprinted hydrogel-based microfluidic device that recapitulates this TME. Then, CTCs are isolated from mCRC patients, cultured, and characterized by microdroplet technology. Those CTCs are then infused on the biodegradable polymer that mimics vascular channels and surrounding stromal cells, through microfluidic connection, in order to mimic CTC-endothelial interactions, study the procedures of extravasation (the invasiveness potential of extravasated patient-derived CTCs into TME) and intravasation (the process of CTCs-derived and biopsy-derived tumor spheroids from the TME to the vascular channel). The photopolymerizable hydrogel mimics vascular structures, supporting the growth of HUVEC cells, and is printed in a cost-effective manner (30 minutes) using a semi-direct printing method with visible light. The CROSS chip is used for fast and efficient isolation of CTCs from unprocessed blood of mCRC patients. In parallel, multi-omics of mCRC are done in circulant tumor DNA (ctDNA) and tumor biopsy of mCRC, therefore correlating the phenotypic and genetic profile of the patient cohorts studied. A first pilot test has been carried out successfully obtaining blood from mCRc refractory patients, and excellent coordination between the multidisciplinary consortium has been achieved to draw blood from the patient, isolate CTCs and infuse them into the hydrogel. Extravasation and intravasation studies are ongoing. Conclusion: This multidisciplinary project, which brings together bioengineering, microfluidic, and oncology experts’ teams, is developing a successful ex-vivo, in vitro, and dynamic model that will permit a better study and understanding of the metastatic process in mCRC, from the process of intravasation to extravasation of CTCs, passing thought the better multi-omic characterization of CTCs and ctDNA. Citation Format: Nadia Saoudi González, Francesc Salvà Ballabrera, Ariadna García, Javier Gonzalo-Ruiz, Iosune Baraibar, Javier Ros, Marta Rodriguez, María García Díaz, Marta Falcó Fusté, Melika Parchehbaf Kashani, Carlos Honrado, Alar Ainla, Josep Tabernero, Lorena Diéguez, Elena Martínez Fraiz, Elena Élez. An innovative platform to mimic the tumoral vascular microenvironment (TME) of patients with metastatic colorectal cancer (mCRC) using bioprinted hydrogel microfluidics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4577.

Purpose: OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site. Experimental Design: Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden. Results: Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%–95%), 88% (68%–97%), and 64% (49%–78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10. Conclusions: Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.

Currently, clinicopathologic characteristics of colon cancer tumors guide the selection of patients suitable for adjuvant therapy. Circulating tumor DNA (ctDNA) analysis after surgery has a strong correlation with prognosis, and positive ctDNA status defines a subset of patients with high risk of recurrence. Ongoing interventional adjuvant trials in colon cancer including ctDNA analyses will determine the predictive value of ctDNA in the adjuvant setting. For patients with stage III colon cancer, noninferiority of 3 months of adjuvant therapy compared with 6 months has not been demonstrated. However, for selected subgroups, the shorter duration of therapy may limit toxic effects without impairing clinical outcomes.

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFsupV600E/supcolorectal cancer (mCRCsupBRAF-V600E/sup). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCsupBRAF-V600E/suptreated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43supmutated/supversus MSS-RNF43supwild-type/suptumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCsupBRAF-V600E/suptumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

Thyroid cancer is the most common endocrine malignancy and it accounts for 1% of all newly diagnosed tumors. Approximately 10% of patients with differentiated thyroid carcinomas (DTC) and 30% with medullary thyroid carcinoma (MTC) could not be cured with locoregional treatment and could develop metastatic disease. In addition, one of the most aggressive solid tumors can arise from the thyroid gland, the anaplastic thyroid carcinoma, with a median overall survival of less than 6 months. Currently, only four drugs are approved for the treatment of DTC and MTC and several unmet needs are focusing the scientific discussions, including the resistant setting, the off-target side effects that may reduce the efficacy and the molecular knowledge-based combinations. In this review, we aimed to discuss the current molecular landscape and treatment of thyroid cancers, and the ongoing clinical and translational research lines focusing on new drugs and drug combinations to improve the inhibition of driver mutations, such as BRAF and RET, and how systemic therapies that improved outcomes of other cancer types, like immunotherapy and peptide receptor radionuclide therapy, may play a role in the future management of advanced thyroid cancers.

Metastatic melanoma has been historically associated with a poor prognosis; however, the therapeutic landscape has experimented and impressive change in the last years due to rapid advances in the immunotherapy field. The first immunotherapy treatment for metastatic melanoma was ipilimumab (anti-CTLA-4), which showed a significant improvement of overall survival compared to chemotherapy. However, in 2015 anti-PD-1 pembrolizumab shown an improved overall survival, progression-free survival and response rate compared to ipilimumab with either a better toxicity profile. Moreover, other immunotherapy combinations and target therapies, such as BRAF and MEK inhibitors combinations, have shown better outcomes than ipilimumab. Thus, ipilimumab seems to have no role in frontline metastatic melanoma treatment and even their role in second line is being less frequent due to clinical efficacy of those other treatments. Actually, the role of ipilimumab in second line after anti-PD-1 progression is not clear although there is clinical evidence for its use. Here, we report two cases of treatment response with ipilimumab in second line setting after receiving anti-PD-1 combination. So that, ipilimumab may have a role after progression to an anti-PD-1 treatment.

La parálisis cerebral (PC) es un grupo de trastornos que afectan el movimiento y el tono muscular o la postura. Es causada por un daño que se produce en el cerebro inmaduro a medida que se desarrolla, con mayor frecuencia antes del nacimiento. Aunque existen pocos estudios en la literatura, se ha visto que el riesgo de ictus está incrementado en este tipo de pacientes. Se presenta el caso de un joven adulto con ictus reciente y portador de PC. Fue encontrado el genotipo MTHFR variante C677T homocigótica, disminución de ácido fólico y vitamina D. El ictus en contexto de PC es un reto para el clínico. Por consiguiente, pensamos que se debe contemplar la posibilidad de ictus en todo paciente con PC, sugiriendo medidas de prevención primaria en todo paciente con PC.