Chemobrain: revisión de estudios que evalúan el deterioro cognitivo de supervivientes de cáncer tratados con quimioterapia

The problem: Some cancer patients have expressed attention, concentration and memory problems, during and after their treatment with chemotherapy, also called chemobrain. Following these complains, in recent decades, studies about this adverse effect had increased. Development of the topic: this work aims to review and analyze the latest scientific studies investigating the nature and severity of cognitive impairment associated with chemotherapy treatments. Works discussed are drowned from different bibliographical sources, mainly from the PubMed database. Results show that, in recent years, longitudinal studies have increased, chemobrain is being studied above all in samples from women with breast cancer, research in other types of cancer is insufficient. Also, the works include new assessment tools, such as MRI and EEG. Advances are done with animal experiments, in vivo and in vitro. Finally, we found studies on drugs and effective strategies for coping of cognitive impairment. The development of guidelines for its systematic study and recommendations for its approach are still pending. Conclusion: There is not conclusive data on the chemobrain, longitudinal studies should be encouraged, as well as assessing the cognitive impact of certain chemotherapeutic agents in different cancers. The works on cognitive impairment´s coping, psychological and drug, should continue.Planteamiento del problema: Algunos pacientes oncológicos han expresado problemas de atención, concentración y memoria durante y después de los tratamientos con quimioterapia, a los que se ha llamado chemobrain. Como consecuencia de estas manifestaciones, en las últimas décadas los estudios dedicados a indagar este posible efecto adverso se han incrementado. Desarrollo del tema: Este trabajo pretende revisar y analizar los estudios científicos más recientes que investigan la naturaleza y alcance del daño cognitivo asociado a los tratamientos quimioterapéuticos. Los artículos analizados se han extraído de diferentes fuentes bibliográficas, principalmente de la base de datos PubMed. Como resultado de la búsqueda se aprecia que, en los últimos años, se han incremento los estudios de diseño longitudinal; este posible efecto adverso se sigue estudiando sobre todo en muestras de mujeres con cáncer de mama, las investigaciones en otros tipos de cánceres son insuficientes; así mismo, destaca la inclusión de nuevas herramientas de evaluación, como la resonancia magnética y el electroencefalograma, junto con nuevos experimentos realizados con animales, in vivo e in vitro, finalmente se constata la inclusión de algunos estudios sobre fármacos y estrategias eficaces para su afrontamiento. La elaboración de guías para el estudio sistemático y las recomendaciones para su abordaje aún quedan pendientes. Conclusiones: no existen datos concluyentes sobre el chemobrain, los estudios longitudinales deberán incentivarse, así como la valoración del impacto cognitivo de determinados esquemas quimioterapéuticos en diferentes cánceres. Los trabajos sobre el afrontamiento, psicológico y/o farmacológico, de este problema deben continuar

Variables asociadas al deterioro cognitivo en pacientes de cáncer de colon

Objective: Identify predictors of lower cognitive performance in colon cancer patients treated with surgery before undergoing chemotherapy. Methods: In a sample of 89 colon cancer patients, we evaluated the relation between their cognitive performance in three cognitive domains (executive function, verbal memory and psychomotor skill) and the following variables: Age, sex, years of study, stage, medical prognosis, comorbidity, haemoglobin, anxiety, depression, fatigue, quality of life, physical and psychosocial problems. Results: They are a predominantly male sample (61.8%), over 65 years (mean 66.9) without neuropsychological illness history (89.9%). But, data show correlational relationships between some cognitive performance test and certain variables assessed. There are remarkable negative correlations with age, respiratory problems and social perception of the quality of life, with lower cognitive performance on tests of verbal memory, executive function and psychomotor ability (p <0.05). Also, patients with stage III colon cancer performed worse than those with stage II disease and those with less than five years of study differ from most studies in the three cognitive domains (p < 0.05). Conclusions: The profile of patients with colon cancer at high risk of cognitive deficit is: Old age, with stage III disease, little formal education, breathing problems and a good perception of their quality of social life.Objetivo: Identificar las variables predictoras de menor rendimiento cognitivo en pacientes de cáncer de colon tratados con cirugía que esperan recibir quimioterapia. Método: En una muestra de 89 pacientes de cáncer de colon se valoró la relación entre su rendimiento en tres dominios cognitivos (función ejecutiva, memoria verbal y habilidad psicomotora) y las siguientes variables: edad, sexo, años de escolaridad, estadio, pronóstico médico, comorbilidad, hemoglobina, ansiedad, depresión, astenia, calidad de vida, problemas físicos y psicosociales. Resultados: En la muestra predominan los varones (61,8%), mayores de 65 años (media 66,9), sin antecedentes neuropsicológicos (89,9%). Los datos correlacionales ponen de manifiesto relaciones selectivas entre alguna prueba de rendimiento cognitivo y ciertas variables evaluadas. Se destaca la existencia de correlaciones negativas de la edad, los problemas respiratorios y la percepción social de la calidad de vida con el rendimiento cognitivo en pruebas de memoria verbal, función ejecutiva y habilidad psicomotora (p < 0,05). Así mismo, los pacientes en estadio III del cáncer de colon rinden peor que aquellos con la enfermedad en estadio II y quienes tienen menos de cinco años de estudios difieren de los de más estudios en los tres dominios cognitivos (p < 0,05) Conclusiones: el perfil detectado de los enfermos de cáncer de colon de alto riesgo de déficit cognitivo es: paciente mayor, con enfermedad en estadio III, de escasa formación escolar, que tiene problemas respiratorios y una buena percepción de su calidad de vida social

Clinico-pathological features, outcomes and impacts of COVID-19 pandemic on patients with early-onset colorectal cancer: A single-Institution Experience

The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic. Methods: We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old. Results: A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%). Conclusions: EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determinedThe work in the authors’ laboratory is funded by the Instituto de Salud Carlos III (ISCIII) and the Fondo Europeo de Desarrollo Regional (FEDER) (ICI20/00057, CIBERONC/CB16/12/00273, and CIBERONC/CB16/12/00398), as well as the Comunidad de Madrid (S2022/BMD-7212

Clinical nutrition as part of the treatment pathway of pancreatic cancer patients: an expert consensus

Purpose: Malnutrition is a common problem among pancreatic cancer (PC) patients that negatively impacts on their quality of life (QoL) and clinical outcomes. The main objective of this consensus is to address the role of Medical Nutrition Therapy (MNT) into the comprehensive therapeutic management of PC patients. Methods: A Spanish multidisciplinary group of specialists from the areas of Medical Oncology; Radiation Oncology; Endocrinology and Nutrition; and General Surgery agreed to assess the role of MNT as part of the best therapeutic management of PC patients. Results: The panel established different recommendations focused on nutritional screening and nutritional screening tools, MNT strategies according to PC status, and MNT in palliative treatment. Conclusions: There is an unmet need to integrate nutritional therapy as a crucial part of the multimodal care process in PC patients. Health authorities, health care professionals, cancer patients, and their families should be aware of the relevance of nutritional status and MNT on clinical outcomes and QoL of PC patientsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Logistics of the meetings and the assistance with the medical writing have been provided by unrestricted Grant from Baxter Laboratorie

Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer

CDC42 is an oncogenic Rho GTPase overexpressed in colorectal cancer (CRC). Although CDC42 has been shown to regulate gene transcription, the specific molecular mechanisms regulating the oncogenic ability of CDC42 remain unknown. Here, we have characterized the transcriptional networks governed by CDC42 in the CRC SW620 cell line using gene expression analysis. Our results establish that several cancer-related signaling pathways, including cell migration and cell proliferation, are regulated by CDC42. This transcriptional signature was validated in two large cohorts of CRC patients and its clinical relevance was also studied. We demonstrate that three CDC42-regulated genes offered a better prognostic value when combined with CDC42 compared to CDC42 alone. In particular, the concordant overexpression of CDC42 and silencing of the putative tumor suppressor gene CACNA2D2 dramatically improved the prognostic value. The CACNA2D2/CDC42 prognostic classifier was further validated in a third CRC cohort as well as in vitro and in vivo CRC models. Altogether, we show that CDC42 has an active oncogenic role in CRC via the transcriptional regulation of multiple cancer-related pathways and that CDC42-mediated silencing of CACNA2D2 is clinically relevant. Our results further support the use of CDC42 specific inhibitors for the treatment of the most aggressive types of CRCThis work has been supported by grants to JCL from Ministerio de Ciencia e Innovación (SAF2008- 03750, RD06-0020-0016 and RD12/0036/0019) and to DGO Cancer Institute New South Wales (2017/CDF625). FVM is a National Breast Cancer Foundation/Cure Cancer Australia Foundation Postdoctoral Training Fellow

A novel molecular analysis approach in colorectal cancer suggests new treatment opportunities

Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on clinical practice. The purpose of this study is to deepen the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means–consensus cluster layer analyses, was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then sparse k-means–consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Three different layers based on biological features were identified: adhesion, immune, and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immunelow groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, the Wnt signaling pathway, and extracellular functions. Immune-high patients, with higher expression of immune-related genes and genes involved in the viral mimicry response, may benefit from immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful in searching for new therapeutic targets and specific therapeutic strategies in CRC diseas

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

BACKGROUND: Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. METHODS: To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. RESULTS: SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. CONCLUSIONS: This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p <.0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7–24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p =.02, HR = 3.6; 95% CI, 1.1–5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. Plain Language Summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacyIdiPAZ, Grant/Award Number: Jesús Antolín Garciarena Fellowship; European Proteomics Infrastructure Consortium, Grant/Award Number: 823839, Horizon 2020 Programm