Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers

Biomarkers; Liver metastases; NeoadjuvantBiomarcadors; Metàstasis hepàtiques; NeoadjuvantBiomarcadores; Metástasis hepáticas; NeoadyuvanteMicrosatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including B2M and JAK1/2 mutations, TMB, WNT pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases

Caracterización gravimétrica y magnética de controles estructurales en depósitos de Sn-W. Ejemplo del yacimiento de San Finx (A Coruña)

Critical raw materials are essential for the development of our society. However, most shallow ores have already been exploited and only deep targets remain unexplored. This work aims to apply indi-rect geophysical techniques to the San Finx Sn-W deposit (A Coruña) in order to get further constrains of its deep structure and geometry. Accordingly, a magnetic and a gravity survey have been carried out in the area (SE of Noia, A Coruña), at the southern part of the Mal-pica-Tui Complex. The resulting absolute magnetic anomaly and the relative gravity anomaly have been studied analytically and through 2-2.75D forward modeling. Results indicate that, the sampling inter-val (~1 km) is too high to characterize the anomalies related to the Sn-W mineralization. Contrarily, they show the potential field imprint of the regional Variscan tectonics. To better assess the relationship between the regional Variscan tectonics and the mineralization, a higher resolution survey should be acquired to detect this depositLas materias primas críticas son fundamentales para el desarro-llo de nuestra sociedad. Sin embargo, la mayoría de los yacimientos poco profundos ya han sido explotados, quedando únicamente sin explorar los objetivos profundos. En este trabajo se presentan los re-sultados de la aplicación de técnicas geofísicas indirectas al estudio del yacimiento de Sn-W de San Finx (A Coruña). Su objetivo es cons-treñir la geometría y estructura del yacimiento en profundidad. En este sentido, se ha realizado una campaña de adquisición de datos magnéticos y gravimétricos en dicha zona (SE de Noia, A Coruña) en la parte sur del Complejo Malpica-Tui. La anomalía magnética absoluta y la anomalía gravimétrica relativa resultante se han estu-diado analíticamente y mediante modelización directa 2-2,75D. Los resultados indican que el intervalo de muestreo usado (~1 km) es muy alto para individualizar la respuesta magnética y gravimétrica del yacimiento. Sin embargo, los mapas obtenidos muestran que la signatura de campos potenciales está ligada a la tectónica Varisca a gran escala. Encontrar la relación entre esta última y la mineraliza-ción y hacer un muestreo geofísico de alta resolución en la zona son la clave para entender este depósit

3D Modelling of archaeoseismic damage in the Roman site of Baelo Claudia (Gibraltar Arc, south Spain)

This study deals with the morphometric characterization and quantification of earthquake damage in the ancient Roman city of Baelo Claudia in South Spain (Gibraltar Arc) by means of the use of 3D modelling from drone imagery. Baelo Claudia is a world-renowned archaeological site recording recurrent earthquake destruction during the first and third centuries AD. The first earthquake destroyed the lower littoral zone of the city, allowing its reconstruction from the year c. 60–70 CE, but the second earthquake in 365–390 CE led to the complete destruction of the renewed city and its eventual abandonment. This second earthquake imprinted important deformations in the main monumental zone of the city, including the basilica temples, macellum, city walls, aqueducts and funerary monuments, as well as in the main paved zones of the city. This is the case for the Forum, Decumanus and Cardos, which show a variety of folds, pop-up structures, conjugate fractures and impact marks susceptible to be measured in a 3D format. The current study presents detailed (up to 3 mm/pixel) surface models of iconic monuments within the city. The 3D models were obtained by means of serial orthophotos taken with a UAV Mavic Pro 2 (DJI) Drone device equipped with a 20 mpx camera and a 1” CMOS sensor. Each individual image was captured in a geo-referenced jpg format and processed with the Agisoft Metashape Professional software®. Depending on the measured monument, the final images consisted of 250 to 700 photographs clustered by 50,000 to 150,000 tie points. In all studied items (Decumanus, city walls and bath dish), we follow the same workflow of analysis: (1) alignment of photos with support points; (2) building a dense cloud of points; (3) creation of the surface texture; (4) creation of the Digital Elevation Model (DEM); (5) creation of the orthomosaic; and finally, (6) the building of the high-quality 3D tiled surface models. The obtained models allow the geometric quantification of earthquake deformations (displacements, amplitudes, orientation, etc.) in a GIS-based 3D environment suitable to quantify oriented damage of seismic origin. In a complementary way, these 3D models deserve to be considered for their potential role as digital seismoscopes of ancient archaeological sites and/or heritage building

Inland Record of the Last Interglacial Maximum in the Western Mediterranean: Revealing the Aljezares Pleistocene Basin (Alicante, SE-Spain)

The search for a continuous continental record of interglacial periods in semi-arid regions is problematic due to the absence of stable and continuous sedimentary systems over time in this type of climate. In this work, a relatively stable basin is described and analyzed during the last interglacial period in a semi-arid region of the western Mediterranean. For this purpose, a geomorphological, stratigraphic and sedimentological study has been carried out, with dating through 230Th. A semi-endorheic Pleistocene section has been identified, with two units that correspond to a fluvial-lacustrine system (unit P1) and an alluvial system (unit P2). Unit P1 has been dated to the MIS 5e interglacial episode. A framework for future studies is described, in which the Aljezares Pleistocene basin can be considered as a possible source of paleoenvironmental and paleoclimatic information in semi-arid regions from the last interglacial period.The research has been funded through the following Spanish research projects: I+D+i PID2021-122308NA-I00 (NESUBSTRA-UV) and I+D+i PID2021-123510OB-I00 (QTECTIBERIA-USAL) by the MICIN

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer

Neoplàsies gastrointestinals; Immunoteràpia; Biomarcadors tumoralsNeoplasias gastrointestinales; Inmunoterapia; Biomarcadores tumoralesGastrointestinal neoplasms; Immunotherapy; Tumor biomarkersBackground Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs. Methods We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models. Results Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS. Conclusions Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response

Reappraisal of the 1863 huércal‐overa earthquake (Betic cordillera, se spain) by the analysis of esi‐07 environmental effects and building oriented damage

This work reviews the 1863 Huércal‐Overa earthquake (VI‐VII EMS) based on the environmental seismic intensity scale (ESI‐07) and oriented archaeoseismological building damage. The performed analysis identifies 23 environmental effects (EEEs) and 11 archaeoseismological effects (EAEs), completing a total of 34 intensity data‐points within the intensity zone ≥ VI EMS. The new ESI intensity data quintuplicate the previous intensity data‐points ≥ VI EMS (five localities) for this event. Sixteen of the identified EEEs indicate the occurrence of intensity VII‐VIII within the Almanzora valley, south of Huércal‐Overa, over an area of ca. 12–15 km2. Anomalies in water bodies, slope movements, hydrogeological anomalies, ground cracking, and other effects (gas emissions, tree shaking) are the more diagnostic EEEs—with one of them indicating a local maximum intensity of VIII‐IX ESI‐07 (Alboraija lake). Environmental earthquake damage of intensity ≥ VI covers an area of c. 100 km2, compatible with a VIII ESI intensity event. The spatial distribution of EEEs and EAEs indicates that the zone of Almanzora River Gorge, which was depopulated during the earthquake epoch, was the epicentral area, and compatible with seismotectonic data from active shallow blind thrusting beneath the Almagro Range. The use of ESI data in nearly unpopulated areas help to fill gaps between damaged localities (EMS data) multiplying intensity data‐points, providing a better definition of the intensity zones and offering a geological basis to look for suspect seismic sourcesCGL2015-67169-

Nomogram to predict the outcomes of patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors

Neoplasias gastrointestinales; InmunoterapiaNeoplàsies gastrointestinals; ImmunoteràpiaGastrointestinal neoplasms; ImmunotherapyBackground The efficacy of immune checkpoint inhibitors (ICIs) in patients with microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC) is unprecedented. A relevant proportion of subjects achieving durable disease control may be considered potentially ‘cured’, as opposed to patients experiencing primary ICI refractoriness or short-term clinical benefit. We developed and externally validated a nomogram to estimate the progression-free survival (PFS) and the time-independent event-free probability (EFP) in patients with MSI-high mCRC receiving ICIs. Methods The PFS and EFP were estimated using a cure model fitted on a developing set of 163 patients and validated on a set of 146 patients with MSI-high mCRC receiving anti-programmed death (ligand)1 (PD-(L)1) ± anticytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. A total of 23 putative prognostic factors were chosen and then selected using a random survival forest (RSF). The model performance in estimating PFS probability was evaluated by assessing calibration (internally—developing set and externally—validating set) and quantifying the discriminative ability (Harrell C index). Results RFS selected five variables: ICI type (anti-PD-(L)1 monotherapy vs anti-CTLA-4 combo), ECOG PS (0 vs >0), neutrophil-to-lymphocyte ratio (≤3 vs >3), platelet count, and prior treatment lines. As both in the developing and validation series most PFS events occurred within 12 months, this was chosen as cut-point for PFS prediction. The combination of the selected variables allowed estimation of the 12-month PFS (focused on patients with low chance of being cured) and the EFP (focused on patients likely to be event-free at a certain point of their follow-up). ICI type was significantly associated with disease control, as patients receiving the anti-CTLA-4-combination experienced the best outcomes. The calibration of PFS predictions was good both in the developing and validating sets. The median value of the EFP (46%) allowed segregation of two prognostic groups in both the developing (PFS HR=3.73, 95% CI 2.25 to 6.18; p<0.0001) and validating (PFS HR=1.86, 95% CI 1.07 to 3.23; p=0.0269) sets. Conclusions A nomogram based on five easily assessable variables including ICI treatment was built to estimate the outcomes of patients with MSI-high mCRC, with the potential to assist clinicians in their clinical practice. The web-based system ‘MSI mCRC Cure’ was released.The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors

Liver transplantation in metastatic colorectal cancer: are we ready for it?

Liver transplantation; Metastatic colorectal cancerTrasplantament de fetge; Càncer colorectal metastàticTrasplante de hígado; Cáncer colorrectal metastásicoColorectal 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

Encorafenib plus cetuximab for the treatment of BRAF-V600E-mutated metastatic colorectal cancer

BRAF mutation; Cetuximab; Colorectal cancerMutación BRAF; Cetuximab; Cáncer colorrectalMutació BRAF; Cetuximab; Càncer colorectalB-type RAF (BRAF)-V600E mutations in metastatic colorectal cancer (mCRC) have been described in up to 12% of the patients. This mutation confers a bad prognostic and poor response with standard chemotherapy. Unlike the scenario for BRAF mutant melanoma, successful BRAF blockade in mCRC has emerged as a complex path, primarily due to the complex underlying biology of mCRC. The BEACON trial has reshaped the therapeutic landscape of BRAF mCRC demonstrating the benefit of the BRAF inhibitor encorafenib in combination with the anti-epidermal growth factor receptor cetuximab. This paper aims to review the main features of BRAF mCRC as well as to review the development of targeted therapy and biomarkers in this specific population. Finally, a deep insight into the underlying biology and molecular classification of BRAF-V600E mCRC has also been performed. The words ‘BRAF-V600E mutation’, ‘colorectal cancer’, ‘BRAF inhibitors’, ‘consensus molecular subtypes’, ‘encorafenib’, and ‘cetuximab’ were used to identify the clinical trials from phase I to phase III related to the development of BRAF inhibitors in this population. A deep search among international meetings (American Society of Clinical Oncology and European Society of Medical Oncology) has been performed to incorporate the last trials presented. BRAF-V600E mCRC is a challenging disease, mostly because of its molecular biology. The BEACON trial has been the most important therapeutic change in the last decade. Nevertheless, new information regarding biomarkers or novel combinations including BRAF inhibitors plus immune checkpoint inhibitors are also promising

Biomarker-Guided Anti-Egfr Rechallenge Therapy in Metastatic Colorectal Cancer

Anticossos monoclonals anti-EGFR; Càncer colorectal metastàticAnticuerpos monoclonales anti-EGFR; Cáncer colorrectal metastásicoAnti-EGFR monoclonal antibodies; Metastatic colorectal cancerThe prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.Regione Campania (I-Cure Research Project, Grant number: Cup 21C17000030007), Gruppo Oncologico dell’Italia Meridionale (GOIM)