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18 pages, 4354 KiB

Open AccessArticle

PCR-Based Strategy for Introducing CRISPR/Cas9 Machinery into Hematopoietic Cell Lines

by Elisa González-Romero, Cristina Martínez-Valiente, Gema García-García, Antonio Rosal-Vela, José María Millán, Miguel Ángel Sanz, Guillermo Sanz, Alessandro Liquori, José Vicente Cervera and Rafael P. Vázquez-Manrique

Cancers 2023, 15(17), 4263; https://doi.org/10.3390/cancers15174263 - 25 Aug 2023

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Abstract

Acute myeloid leukemia is a complex heterogeneous disease characterized by the clonal expansion of undifferentiated myeloid precursors. Due to the difficulty in the transfection of blood cells, several hematological models have recently been developed with CRISPR/Cas9, using viral vectors. In this study, we [...] Read more.

Acute myeloid leukemia is a complex heterogeneous disease characterized by the clonal expansion of undifferentiated myeloid precursors. Due to the difficulty in the transfection of blood cells, several hematological models have recently been developed with CRISPR/Cas9, using viral vectors. In this study, we developed an alternative strategy in order to generate CRISPR constructs by fusion PCR, which any lab equipped with basic equipment can implement. Our PCR-generated constructs were easily introduced into hard-to-transfect leukemic cells, and their function was dually validated with the addition of MYBL2 and IDH2 genes into HEK293 cells. We then successfully modified the MYBL2 gene and introduced the R172 mutation into the IDH2 gene within NB4 and HL60 cells that constitutively expressed the Cas9 nuclease. The efficiency of mutation introduction with our methodology was similar to that of ribonucleoprotein strategies, and no off-target events were detected. Overall, our strategy represents a valid and intuitive alternative for introducing desired mutations into hard-to-transfect leukemic cells without viral transduction. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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11 pages, 1476 KiB

Open AccessArticle

An Integrated CT and MRI Imaging Model to Differentiate between Adrenal Adenomas and Pheochromocytomas

by Marta Araujo-Castro, Iñigo García Sanz, César Mínguez Ojeda, María Calatayud, Felicia A. Hanzu, Mireia Mora, Almudena Vicente Delgado, Concepción Blanco Carrera, Paz de Miguel Novoa, María del Carmen López García, Laura Manjón-Miguélez, Pablo Rodríguez de Vera Gómez, María del Castillo Tous, Rebeca Barahona San Millán, Mónica Recansens, Mariana Tomé Fernández-Ladreda, Nuria Valdés, Paola Gracia Gimeno, Cristina Robles Lazaro, Theodora Michalopoulou, Victoria Gómez Dos Santos, Cristina Alvarez-Escola, Rogelio García Centeno, Cristina Lamas and Aura Herrera-Martínez Show full author list Hide full author list

Cancers 2023, 15(14), 3736; https://doi.org/10.3390/cancers15143736 - 23 Jul 2023

Cited by 1 | Viewed by 1028

Abstract

Purpose: to perform an external validation of our predictive model to rule out pheochromocytoma (PHEO) based on unenhanced CT in a cohort of patients with PHEOs and adenomas who underwent adrenalectomy. Methods: The predictive model was previously developed in a retrospective cohort of [...] Read more.

Purpose: to perform an external validation of our predictive model to rule out pheochromocytoma (PHEO) based on unenhanced CT in a cohort of patients with PHEOs and adenomas who underwent adrenalectomy. Methods: The predictive model was previously developed in a retrospective cohort of 1131 patients presenting with adrenal lesions. In the present study, we performed an external validation of the model in another cohort of 214 patients with available histopathological results. Results: For the external validation, 115 patients with PHEOs and 99 with adenomas were included. Our previously described predictive model combining the variables of high lipid content and tumor size in unenhanced CT (AUC-ROC: 0.961) had a lower diagnostic accuracy in our current study population for the prediction of PHEO (AUC: 0.750). However, when we excluded atypical adenomas (with Hounsfield units (HU) > 10, n = 39), the diagnostic accuracy increased to 87.4%. In addition, in the whole cohort (including atypical adenomas), when MRI information was included in the model, the diagnostic accuracy increased to up to 85% when the variables tumor size, high lipid content in an unenhanced CT scan, and hyperintensity in the T2 sequence in MRI were included. The probability of PHEO was <0.3% for adrenal lesions <20 mm with >10 HU and without hyperintensity in T2. Conclusion: Our study confirms that our predictive model combining tumor size and lipid content has high reliability for the prediction of PHEO when atypical adrenal lesions are excluded. However, for atypical adrenal lesions with >10 HU in an unenhanced CT scan, MRI information is necessary for a proper exclusion of the PHEO diagnosis. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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17 pages, 2827 KiB

Open AccessArticle

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients

by Susana Cedres, Garazi Serna, Alberto Gonzalez-Medina, Augusto Valdivia, Juan David Assaf-Pastrana, Patricia Iranzo, Ana Callejo, Nuria Pardo, Alejandro Navarro, Alex Martinez-Marti, Ilaria Priano, Roberta Fasani, Xavier Guardia, Javier Gonzalo, Caterina Carbonell, Joan Frigola, Ramon Amat, Victor Navarro, Rodrigo Dienstmann, Ana Vivancos, Paolo Nuciforo and Enriqueta Felip Show full author list Hide full author list

Cancers 2023, 15(14), 3611; https://doi.org/10.3390/cancers15143611 - 14 Jul 2023

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Abstract

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of [...] Read more.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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15 pages, 2519 KiB

Open AccessArticle

The Scarface Score: Deciphering Response to DNA Damage Agents in High-Grade Serous Ovarian Cancer—A GEICO Study

by Antonio Fernández-Serra, Raquel López-Reig, Raúl Márquez, Alejandro Gallego, Luís Miguel de Sande, Alfonso Yubero, Cristina Pérez-Segura, Avinash Ramchandani-Vaswani, María Pilar Barretina-Ginesta, Elsa Mendizábal, Carmen Esteban, Fernando Gálvez, Ana Beatriz Sánchez-Heras, Eva María Guerra-Alía, Lydia Gaba, María Quindós, Isabel Palacio, Jesús Alarcón, Ana Oaknin, Jessica Aliaga, Marta Ramírez-Calvo, Zaida García-Casado, Ignacio Romero and José Antonio López-Guerrero Show full author list Hide full author list

Cancers 2023, 15(11), 3030; https://doi.org/10.3390/cancers15113030 - 01 Jun 2023

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Abstract

Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely [...] Read more.

Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87–159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p < 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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13 pages, 1558 KiB

Open AccessArticle

Impact of the COVID-19 Pandemic on Cancer Diagnosis in Madrid (Spain) Based on the RTMAD Tumor Registry (2019–2021)

by Gregorio Garrido-Cantero, Federico Longo, Javier Hernández-González, Ángel Pueyo, Tomás Fernández-Aparicio, Juan F. Dorado, Javier C. Angulo and on behalf of the Madrid Cancer Registry (RTMAD) Investigators

Cancers 2023, 15(6), 1753; https://doi.org/10.3390/cancers15061753 - 14 Mar 2023

Cited by 4 | Viewed by 1609

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant disruption to cancer diagnosis, treatment and prevention worldwide that could have serious consequences in the near future. We intend to evaluate the weight of this backlog on a community-wide scale in Madrid during [...] Read more.

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant disruption to cancer diagnosis, treatment and prevention worldwide that could have serious consequences in the near future. We intend to evaluate the weight of this backlog on a community-wide scale in Madrid during the period 2020–2021, and whether a stage shift towards the advanced stage has occurred. Cancer diagnoses in the Madrid tumor registry (RTMAD) from 2019–2021 were evaluated. Absolute and percentage differences in annual volume and observed-to-expected (O/E) volume ratios were calculated. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated using the O/E ratio. The SIR for 2020–2021 compared to 2019 was 94.5% (95% CI 93.8–95.3), with unequal gender-specific cancer diagnosis recovery (88.5% for males and 102.1% for females). Most cancer types were underdiagnosed in 2020. The tendency worsened in 2021 for colorectal and prostate cancers (87.8%), but lung cancer recovered (102.1%) and breast cancer was over-diagnosed (114.4%) compared with reference pre-COVID-19 data. These changes have modified the ranking of the most frequent malignancies diagnosed in Madrid. Breast cancer has overtaken colorectal and prostate cancers, displaced to second and third position, respectively. Not only was colorectal cancer diagnosis affected more as a consequence of the COVID-19 pandemic but diagnosis of this malignancy at the advance stage also increased by 3.6% in 2020 and 4.2% in 2021 compared to the reference period of 2019. In summary, there is a large volume of undetected cancer in Madrid caused by the reduced access to care secondary to the COVID-19 pandemic, especially regarding colorectal and prostate cancer. Strategies are needed to recover the backlog of diagnoses and effectively treat these cases in the future and solve the negative impact that will be caused by the diagnostic delay. Analyzing the impact of new diagnoses suffered by each different malignancy and their recovery will help to understand how the future allocation of resources should look. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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15 pages, 2631 KiB

Open AccessArticle

Impact of Molecular Testing Using Next-Generation Sequencing in the Clinical Management of Patients with Non-Small Cell Lung Cancer in a Public Healthcare Hospital

by Javier Simarro, Gema Pérez-Simó, Nuria Mancheño, Emilio Ansotegui, Carlos Francisco Muñoz-Núñez, José Gómez-Codina, Óscar Juan and Sarai Palanca

Cancers 2023, 15(6), 1705; https://doi.org/10.3390/cancers15061705 - 10 Mar 2023

Cited by 4 | Viewed by 2063

Abstract

Next-generation sequencing (NGS) is a molecular approach able to provide a comprehensive molecular profile of non-small cell lung cancer (NSCLC). The broad spectrum of biomarker-guided therapies has positioned molecular diagnostic laboratories as a central component of patient clinical management. Here, we show the [...] Read more.

Next-generation sequencing (NGS) is a molecular approach able to provide a comprehensive molecular profile of non-small cell lung cancer (NSCLC). The broad spectrum of biomarker-guided therapies has positioned molecular diagnostic laboratories as a central component of patient clinical management. Here, we show the results of an UNE-EN ISO 15189:2022 NGS-accredited assay in a cohort of 350 patients. TP53 (51.0%), KRAS (26.6%) and EGFR (12.9%) were the most frequently mutated genes. Furthermore, we detected co-occurring and mutually exclusive alterations, as well as distinct molecular profiles according to sex and smoking habits. Actionable genetic alterations were significantly more frequent in female patients (80.5%, p < 0.001) and in never-smoker patients (87.7%, p < 0.001). When NGS was established as the main molecular testing strategy, 36.4% of patients received at least one line of targeted treatment. Among 200 patients with stage IV NSCLC, first-line treatment with targeted therapies was associated with a longer progression-free survival (PFS) (13.4 months (95% CI, 10.2–16.6) (p = 0.001)). Similarly, the overall survival (OS) of patients receiving at least one targeted drug was significantly longer (26.2 months (95% CI, 11.8–40.5) (p < 0.001)). Our results show that the implementation of NGS in the public healthcare system has provided a broader application of precision medicine. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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13 pages, 1858 KiB

Open AccessArticle

Independent Validation of a Deep Learning nnU-Net Tool for Neuroblastoma Detection and Segmentation in MR Images

by Diana Veiga-Canuto, Leonor Cerdà-Alberich, Ana Jiménez-Pastor, José Miguel Carot Sierra, Armando Gomis-Maya, Cinta Sangüesa-Nebot, Matías Fernández-Patón, Blanca Martínez de las Heras, Sabine Taschner-Mandl, Vanessa Düster, Ulrike Pötschger, Thorsten Simon, Emanuele Neri, Ángel Alberich-Bayarri, Adela Cañete, Barbara Hero, Ruth Ladenstein and Luis Martí-Bonmatí

Cancers 2023, 15(5), 1622; https://doi.org/10.3390/cancers15051622 - 06 Mar 2023

Cited by 5 | Viewed by 2595

Abstract

Objectives. To externally validate and assess the accuracy of a previously trained fully automatic nnU-Net CNN algorithm to identify and segment primary neuroblastoma tumors in MR images in a large children cohort. Methods. An international multicenter, multivendor imaging repository of patients with neuroblastic [...] Read more.

Objectives. To externally validate and assess the accuracy of a previously trained fully automatic nnU-Net CNN algorithm to identify and segment primary neuroblastoma tumors in MR images in a large children cohort. Methods. An international multicenter, multivendor imaging repository of patients with neuroblastic tumors was used to validate the performance of a trained Machine Learning (ML) tool to identify and delineate primary neuroblastoma tumors. The dataset was heterogeneous and completely independent from the one used to train and tune the model, consisting of 300 children with neuroblastic tumors having 535 MR T2-weighted sequences (486 sequences at diagnosis and 49 after finalization of the first phase of chemotherapy). The automatic segmentation algorithm was based on a nnU-Net architecture developed within the PRIMAGE project. For comparison, the segmentation masks were manually edited by an expert radiologist, and the time for the manual editing was recorded. Different overlaps and spatial metrics were calculated to compare both masks. Results. The median Dice Similarity Coefficient (DSC) was high 0.997; 0.944–1.000 (median; Q1–Q3). In 18 MR sequences (6%), the net was not able neither to identify nor segment the tumor. No differences were found regarding the MR magnetic field, type of T2 sequence, or tumor location. No significant differences in the performance of the net were found in patients with an MR performed after chemotherapy. The time for visual inspection of the generated masks was 7.9 ± 7.5 (mean ± Standard Deviation (SD)) seconds. Those cases where manual editing was needed (136 masks) required 124 ± 120 s. Conclusions. The automatic CNN was able to locate and segment the primary tumor on the T2-weighted images in 94% of cases. There was an extremely high agreement between the automatic tool and the manually edited masks. This is the first study to validate an automatic segmentation model for neuroblastic tumor identification and segmentation with body MR images. The semi-automatic approach with minor manual editing of the deep learning segmentation increases the radiologist’s confidence in the solution with a minor workload for the radiologist. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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28 pages, 3864 KiB

Open AccessArticle

Artificial Diets with Selective Restriction of Amino Acids and Very Low Levels of Lipids Induce Anticancer Activity in Mice with Metastatic Triple-Negative Breast Cancer

by Emilio Guillén-Mancina, Julio José Jiménez-Alonso, José Manuel Calderón-Montaño, Víctor Jiménez-González, Patricia Díaz-Ortega, Estefanía Burgos-Morón and Miguel López-Lázaro

Cancers 2023, 15(5), 1540; https://doi.org/10.3390/cancers15051540 - 28 Feb 2023

Cited by 3 | Viewed by 2035

Abstract

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by [...] Read more.

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were also tested in this model. AA manipulation led to modest improvements in mice survival when the levels of lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Some mice fed the artificial diets as monotherapy lived much longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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16 pages, 5846 KiB

Open AccessArticle

Direct Cell Death Induced by CD20 Monoclonal Antibodies on B Cell Lymphoma Cells Revealed by New Protocols of Analysis

by Michael Constantinides, Alexis Fayd’herbe De Maudave, Marie Potier-Cartereau, Mauricio Campos-Mora, Guillaume Cartron and Martin Villalba

Cancers 2023, 15(4), 1109; https://doi.org/10.3390/cancers15041109 - 09 Feb 2023

Cited by 3 | Viewed by 2028

Abstract

CD20 monoclonal antibodies (mAbs) eliminate B cells in several clinical contexts. At least two of these Abs, obinutuzumab (OBI) and rituximab (RTX), induce quick elimination of targets and put cancer patients at risk of tumor lysis syndrome (TLS) within 12–24 h of the [...] Read more.

CD20 monoclonal antibodies (mAbs) eliminate B cells in several clinical contexts. At least two of these Abs, obinutuzumab (OBI) and rituximab (RTX), induce quick elimination of targets and put cancer patients at risk of tumor lysis syndrome (TLS) within 12–24 h of the first dose. The mechanisms of killing can require the recruiting of effector mechanisms from the patient’s immune system, but they can induce direct killing as well. This can be more rapid than recruiting cellular effectors and/or complement. We showed here that OBI and RTX induce quick (<1 h) and high (up to 60% for OBI) killing of two different B cell lines. This was unveiled by using two different techniques that circumvent cell centrifugation steps: a Muse^® Cell Analyzer-based approach and a direct examination of the cells’ physical properties by using forward scatter (FS) area and side scatter (SS) area by flow cytometry. These results excluded the presence of aggregates and were also confirmed by developing a normalized survival ratio based on the co-incubation of RTX- and OBI-sensitive cells with MOLM-13, an insensitive cell line. Finally, this normalized survival ratio protocol confirmed the RTX- and OBI-direct killing on primary tumor B cells from B cell chronic lymphocytic leukemia (B-CLL) and Non-Hodgkin’s lymphoma (NHL) patients. Moreover, we unveiled that direct killing is higher than previously expected and absent in patients’ samples at relapse. We also observed that these mAbs, prior to increasing intracellular calcium levels, decrease calcium entry, although manipulating calcium levels did not affect their cytotoxicity. Altogether, our results show that direct killing is a major mechanism to induce cell death by RTX and OBI mAbs. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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12 pages, 1672 KiB

Open AccessArticle

An Optimized Single Nucleotide Polymorphism-Based Detection Method Suggests That Allelic Variants in the 3’ Untranslated Region of RRAS2 Correlate with Treatment Response in Chronic Lymphocytic Leukemia Patients

by Alejandro Hortal, Marta Lacuna, Claudia Cifuentes, Miguel Alcoceba, Xosé R. Bustelo, Marcos González and Balbino Alarcón

Cancers 2023, 15(3), 644; https://doi.org/10.3390/cancers15030644 - 19 Jan 2023

Cited by 1 | Viewed by 1775

Abstract

Unlike classical RAS genes, oncogenic mutations on RRAS2 are seldomly found in human cancer. By contrast, RRAS2 is frequently found overexpressed in a number of human tumors, including B and T cell lymphomas, breast, gastric, head and neck cancers. In this regard, we [...] Read more.

Unlike classical RAS genes, oncogenic mutations on RRAS2 are seldomly found in human cancer. By contrast, RRAS2 is frequently found overexpressed in a number of human tumors, including B and T cell lymphomas, breast, gastric, head and neck cancers. In this regard, we have recently shown that overexpression of wild-type RRAS2 drives the formation of both chronic lymphocytic leukemia (CLL) and breast cancer in mice. In support for the relevance of overexpression of wild type RRAS2 in human cancer, we have found that RRAS2 expression is influenced by the presence of a specific single nucleotide polymorphism (SNP) located in the 3’-untranslated region (UTR) of the RRAS2 mRNA. Perhaps more importantly, the presence of the alternate C, rather than the G allele, at the RRAS2 SNP designated as rs8570 is also associated with worse patient prognosis in CLL. This indicates that the detection of this SNP allelic variants can be informative to predict RRAS2 expression levels and disease long-term evolution in patients. Here, we describe a polymerase chain reaction (PCR)-based method that facilitates the rapid and easy determination of G and C allelic variants of the SNP. Using this approach, we confirm that the C allelic variant is associated with higher expression levels of RRAS2 transcripts and poor patient prognosis. However, we have also found that expression of the C allelic variants correlates with better response to ibrutinib, a Bruton kinase inhibitor commonly used in CLL treatments. This suggests that this method for detecting the RRAS2 rs8570 SNP might be a useful as a tool to predict both patient prognosis and response to targeted therapy in CLL. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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19 pages, 1914 KiB

Open AccessArticle

A Subset of PD-1-Expressing CD56^bright NK Cells Identifies Patients with Good Response to Immune Checkpoint Inhibitors in Lung Cancer

by Marta Gascón-Ruiz, Ariel Ramírez-Labrada, Rodrigo Lastra, Luis Martínez-Lostao, J. Ramón Paño-Pardo, Andrea Sesma, María Zapata-García, Alba Moratiel, Elisa Quílez, Irene Torres-Ramón, Alfonso Yubero, María Pilar Domingo, Patricia Esteban, Eva M. Gálvez, Julián Pardo and Dolores Isla

Cancers 2023, 15(2), 329; https://doi.org/10.3390/cancers15020329 - 04 Jan 2023

Cited by 7 | Viewed by 2318

Abstract

(1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a [...] Read more.

(1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3−CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3−CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56^bright NK cell subpopulation (CD56+CD3−CD16−PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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11 pages, 891 KiB

Open AccessArticle

Telomere Length and Telomerase Activity in Subcutaneous and Visceral Adipose Tissues from Obese and Non-Obese Patients with and without Colorectal Cancer

by Sergio García-Martínez, Daniel González-Gamo, Sofía Elena Tesolato, Ana Barabash, Sofía Cristina de la Serna, Inmaculada Domínguez-Serrano, Jana Dziakova, Daniel Rivera, Antonio José Torres and Pilar Iniesta

Cancers 2023, 15(1), 273; https://doi.org/10.3390/cancers15010273 - 31 Dec 2022

Cited by 1 | Viewed by 1433

Abstract

To investigate the molecular mechanisms that link obesity and colorectal cancer (CRC), we analyzed parameters related to telomere function in subcutaneous and visceral adipose tissues (SAT and VAT), including subjects with and without CRC, who were classified according to their body mass index [...] Read more.

To investigate the molecular mechanisms that link obesity and colorectal cancer (CRC), we analyzed parameters related to telomere function in subcutaneous and visceral adipose tissues (SAT and VAT), including subjects with and without CRC, who were classified according to their body mass index (BMI). Adipose tissues were obtained from 147 patients who had undergone surgery. A total of 66 cases corresponded to CRC patients, and 81 subjects were not affected by cancer. Relative telomere length was established by qPCR, and telomerase activity was determined by a method based on the telomeric repeat amplification protocol. Our results indicated longer telomeres in patients affected by CRC, both in SAT and VAT, when compared to the group of subjects without CRC. Tumor local invasion was associated with telomere length (TL) in SAT. Considering the BMI values, significant differences were found in the TL of both adipose tissues between subjects affected by CRC and those without cancer. Overweight subjects showed the greatest differences, with longer telomeres in the group of CRC patients, and a higher number of cases with telomerase reactivation in the VAT of subjects without cancer. In conclusion, parameters related to telomere function in adipose tissue could be considered as potential biomarkers in the evaluation of CRC and obesity. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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Review

Jump to: Research

63 pages, 12139 KiB

Open AccessReview

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

by Manuel Lisardo Sánchez, Francisco D. Rodríguez and Rafael Coveñas

Cancers 2023, 15(6), 1694; https://doi.org/10.3390/cancers15061694 - 09 Mar 2023

Cited by 4 | Viewed by 2929

Abstract

The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, [...] Read more.

The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, and CGRP receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis. Several antitumor therapeutic strategies, including peptide receptor antagonists, are discussed. The main research lines to be developed in the future are mentioned. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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12 pages, 801 KiB

Open AccessReview

The Secondary Myelodysplastic Neoplasms (MDS) Jigsaw

by Oriol Calvete, Julia Mestre, Andrés Jerez and Francesc Solé

Cancers 2023, 15(5), 1483; https://doi.org/10.3390/cancers15051483 - 26 Feb 2023

Cited by 2 | Viewed by 1715

Abstract

There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive [...] Read more.

There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive for secondary MDSs and there are multiple overlapping scenarios, a comprehensive and definitive classification is yet to come. In addition, a sporadic MDS might arise after a primary tumor fulfills the diagnostic criteria of MDS-pCT without a causative cytotoxicity. In this review, we describe the triggering pieces of a secondary MDS jigsaw: previous cytotoxic therapy, germline predisposition and clonal hematopoiesis. Epidemiological and translational efforts are needed to put these pieces together and ascertain the real weight of each of these pieces in each MDS patient. Future classifications must contribute to understanding the role of secondary MDS jigsaw pieces in different concomitant or independent clinical scenarios associated with the primary tumor. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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Challenges in the Early Diagnosis of Oral Cancer, Evidence Gaps and Strategies for Improvement: A Scoping Review of Systematic Reviews

by Miguel Ángel González-Moles, Manuel Aguilar-Ruiz and Pablo Ramos-García

Cancers 2022, 14(19), 4967; https://doi.org/10.3390/cancers14194967 - 10 Oct 2022

Cited by 25 | Viewed by 6164

Abstract

Oral cancer is a growing problem, accounting for 377,713 worldwide new cases per year, and 177,757 deaths annually and representing a 5-year mortality rate close to 50%, which is a considerable mortality that has not decreased substantially in the last 40 years. The [...] Read more.

Oral cancer is a growing problem, accounting for 377,713 worldwide new cases per year, and 177,757 deaths annually and representing a 5-year mortality rate close to 50%, which is a considerable mortality that has not decreased substantially in the last 40 years. The main cause of this high mortality is related to the diagnosis of a high percentage of oral cancers in advanced stages (stages III and IV) in which treatment is complex, mutilating or disabling, and ineffective. The essential cause of a cancer diagnosis at a late stage is the delay in diagnosis, therefore, the achievement of the objective of improving the prognosis of oral cancer involves reducing the delay in its diagnosis. The reasons for the delay in the diagnosis of oral cancer are complex and involve several actors and circumstances—patients, health care providers, and health services. In this paper, we present the results of a scoping review of systematic reviews on the diagnostic delay in oral cancer with the aim to better understand, based on the evidence, and discuss in depth, the reasons for this fact, and to identify evidence gaps and formulate strategies for improvement. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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