Evaluating trifluridine + tipiracil hydrochloride in a fixed combination (TAS-102) for the treatment of colorectal cancer

Introduction: Despite major progress in treating advanced colorectal cancer (CRC), prognosis in this population after progression on standard treatment remains dismal and the development of new drugs represents an unmet need. Historically, fluoropyrimidines have played a major role in the treatment of metastatic CRC. TAS-102, a novel combination of trifluridine and tipiracil hydrochloride, has demonstrated improvement in overall survival in the refractory CRC setting, with a safe toxicity profile. Areas covered: A literature review of published clinical studies was performed. Herein, the authors review the pharmacological and clinical data of TAS-102 when used in metastatic CRC, both as a single agent as well as in novel combinations under investigation. Expert opinion: The addition of TAS-102 to the therapeutic armamentarium of metastatic CRC is an encouraging breakthrough considering the demonstrated survival benefit and favorable tolerability profile. Combinations with other agents are under clinical investigation in different settings in an attempt to widen its use. To optimize treatment in today’s era of molecular oncology, efforts should be focused on understanding primary and secondary resistance mechanisms, along with the identification of potential biomarkers of response

Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

Aflibercept; Càncer colorectal; Perfil del pacientAflibercept; Cáncer colorrectal; Perfil del pacienteAflibercept; Colorectal cancer; Patient profileColorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient’s profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment

The Medical Oncology resident mentor: situation and workload

Purpose: The Spanish Society for Medical Oncology (SEOM, for its acronym in Spanish) and the National Commission for the Specialty of Medical Oncology seek to highlight the important workload and unrecognized dedication entailed in working as a Medical Oncology (MO) resident mentor, as well as its relevance for the quality of teaching units and the future of the specialty. Materials and methods: The current situation and opinion regarding the activity of MO resident mentors was analyzed by reviewing the standing national and autonomic community regulations and via an online survey targeting mentors, residents, and physicians who are not MO mentors. The project was supervised by a specially designated group that agreed on a proposal containing recommendations for improvement. Results: Of the MO mentors, 90% stated that they did not have enough time to perform their mentoring duties. An estimated 172 h/year on average was dedicated to mentoring, which represents 10.1% of the total time. MO mentors dedicate an average of 6.9 h/month to these duties outside their workday. Forty-five percent of the mentors feel that their role is scantly recognized, if at all. Conclusions: The study reveals the substantial dedication and growing complexity of MO resident mentoring. A series of recommendations are issued to improve the conditions in which it is carried out, including the design of systems that adapt to the professional activity in those departments that have time set aside for mentoring tasks

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Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study

PURPOSE: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data. METHODS: In this open-label, phase III trial, 665 patients with BRAF V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients. RESULTS: Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively. CONCLUSION: In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC

Análisis arqueosismológico del conjunto arqueológico romano de Mulva- Munigua (Sevilla, España). Resultados preliminares

El conjunto arqueológico romano de Mulva-Munigua (Sevilla, España) presenta daños en las edificaciones que pueden ser interpretadas como resultado de la ocurrencia de un evento sísmico (Efectos Arqueológicos de los Terremotos: EAEs) a finales del siglo III A.D., fecha coincidente con el inicio del periodo de declive económico de este asentamiento romano. Para intentar establecer el posible origen sísmico de las deformaciones, se ha procedido al inventario y análisis de las estructuras deformadas presentes en el yacimiento. No obstante, algunas de estas deformaciones también se pueden interpretar como resultado de procesos gravitaciones asociados a la ladera Este de la colina sobre la que se sitúa parte del yacimiento. Las direcciones de máxima deformación (ey) obtenidas del análisis de EAEs indica dos direcciones preferentes de la deformación (o movimiento preferente del terreno): NNO-SSE y ENEOSO. Aunque los datos presentan una dispersión importante, se puede establecer que la orientación principal NNO-SSE es compatible con un evento sísmico situado en el borde norte del Valle del Guadalquivir. La orientación ENE-OSO podría relacionarse con un evento posterior, o más seguramente con procesos de ladera de carácter cosísmico o no.The Roman archaeological site of Mulva-Munigua (Sevilla, Spain) displays building damage features suggesting a seismic origin (Earthquake Archaeological Effects: EAEs). The proposed seismic event could be tentatively dated in the late 3rd century AD, coinciding with the beginning of the economic fall of the Roman Empire at Iberia. However, some of the recorded EAEs can be also interpreted as a result of intervening slope movements in the eastern hillslope of this roman site. The inventory and analysis of the proposed EAEs make possible to discern between seismic oriented damage and other causes. In spite of the data show a significant dispersion, their analysis result in two different orientations of maximum deformation (ey) or preferential ground movement: NNW-SSE and ENE-WSW. The main ey orientation (NNW-SSE) can be tentatively related to a seismic event occurred in the environs of the northern border of the Guadalquivir Depression. The secondary orientation (ENE-WSW) can be interpreted as a consequence of latter slope movements triggered (or not) by other ancient earthquakes

Escherichia coli YafP protein modulates DNA damaging property of the nitroaromatic compounds

Escherichia coli SOS functions constitute a multifaceted response to DNA damage. We undertook to study the role of yafP, a SOS gene with unknown function. yafP is part of an operon also containing the dinB gene coding for DNA Polymerase IV (PolIV). Our phylogenetic analysis showed that the gene content of this operon is variable but that the dinB and the yafP genes are conserved in the majority of E. coli natural isolates. Therefore, we studied if these proteins are functionally linked. Using a murine septicaemia model, we showed that YafP activity reduced the bacterial fitness in the absence of PolIV. Similarly, YafP increased cytotoxicity of two DNA damaging nitroaromatic compounds, 4-nitroquinoline-1-oxide (NQO) and nitrofurazone, in the absence of PolIV. The fact that PolIV counterbalances YafP-induced cytotoxicity could explain why these two genes are transcriptionally linked. We also studied the involvement of YafP in genotoxic-stress induced mutagenesis and found that PolIV and YafP reduced NQO-induced mutagenicity. The YafP antimutator activity was independent of the PolIV activity. Given that YafP was annotated as a putative acetyltransferase, it could be that YafP participates in the metabolic transformation of genotoxic compounds, hence modulating the balance between their mutagenicity and cytotoxicity

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08–4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.This clinical trial was approved and supported by Merck S.L., an affiliate of Merck KGaA, Darmstadt. Germany [research project number 2010-023580-18, date: 05-06-2014

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E–mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224. opens in new tab; EudraCT number, 2015-005805-35. opens in new tab.

Impacto de un evento de inundación en la comunidad bacteriana de un ecosistema subterráneo somero (Cueva del Pindal, Asturias)

14 páginas.- 4 figuras.- 3 tablas.- 12 referencias.- Comunicación oral presentada en el VIII Congreso Español sobre Cuevas y Minas Turísticas "Minas y Cuevas: Patrimonio Geológico y Turístico". J.M. Calaforra y J.J. Durán Valsero (eds.), Pulpí (Almería) 19-22 octubre 2022.- Enlace al libro de Actas completo https://www.cuevasturisticas.es/actas-cuevatur-2022La Cueva del Pindal (Ribadedeva, Asturias) y su arte rupestre paleolítico forman parte de la Lista del Patrimonio Mundial de la UNESCO desde 2008. Actualmente está abierta al público con visitas limitadas y en ella se desarrolla un proyecto de investigación sobre actividad microbiana en ecosistemas naturales subterráneos y su aplicación al diseño de estrategias de conservación. El sistema kárstico del Pindal se desarrolla en un macizo calcáreo modelado en forma de terrazas marinas (rasas), situadas entre 30 y 68 metros s.n.m que constituyen el área de captación hídrica preferente y en las que se observan numerosas estructuras exokársticas tipo dolina y poljé. Sobre una de las dolinas, situada casi en la vertical de la cavidad, se instaló una explotación ganadera en 1995. El 23 de octubre de 2019 tras un episodio extremo de precipitaciones (209 l/m2) se produjo una fuerte acumulación de agua en la dolina y una entrada masiva de agua y sedimentos en la cueva. El 31 de octubre se realizó un muestreo específico para conocer los cambios provocados en el ecosistema subterráneo. La inundación provocó un fuerte incremento de materia orgánica, nitrógeno, fósforo y potasio disponibles en los sedimentos y modificaciones muy significativas en la composición de las comunidades microbianas presentes en los sedimentos: aparición de nuevos filos bacterianos (Firmicutes y Bacteroidetes), incluyendo grupos de bacterias patógenas oportunistas (Corynebacterium, Thauera, Clostridiales) y la casi total desaparición de otros (Rokubacteria y Nitrospirae). Los resultados confirman que el agua y sedimentos arrastrados al interior de la cueva en la inundación fueron acompañados de residuos procedentes de la explotación ganadera, demostrando el alto grado de vulnerabilidad de este tipo de ambientes. Tras el estudio e informe correspondiente, la actividad ganadera cesó en 2021 y continúa el estudio de las poblaciones microbianas para conocer su evolución a medio-largo plazo.Este trabajo ha contado con la financiación de la Consejería de Cultura, Política Lingüística y Turismo del Principado de Asturias para la realización de los análisis de las muestras de octubre de 2019 y con el soporte del proyecto PID2019-110603RB-I00, MCIN/AEI/FEDER UE/10.13039/501100011033 para el resto de la investigación. Cuenta con el apoyo de la Plataforma Temática Interdisciplinar CSIC Patrimonio Abierto: Investigación y Sociedad (PTI-PAIS).N