Publications by authors named "Javier de Castro"

80 Publications

Targeted therapy moves to earlier stages of non-small-cell lung cancer: emerging evidence, controversies and future challenges.

Future Oncol 2021 Aug 2. Epub 2021 Aug 2.

Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Madrid 28223, Spain.

Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field. In recent years, there has been a decrease in mortality from lung cancer coinciding with the approval times of targeted therapy. To date, targeted therapy has been used in the context of advanced disease in clinical practice, with great benefits in survival and quality of life. The next step will be to incorporate targeted therapy into the treatment of earlier stages of non-small-cell lung cancer, and there is already a randomized trial showing a disease-free survival benefit. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of targeted therapies in nonmetastatic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-1255DOI Listing
August 2021

[Pulmonary adenocarcinoma with double mutation EGFR: L858R and G719X].

Rev Esp Patol 2021 Jul-Sep;54(3):211-214. Epub 2020 May 13.

Servicio de Oncología Medica, Hospital Universitario La Paz, Madrid, España.

Lung cancer with EGFR mutation is rare in our country, with an estimated incidence of 7-10%. It is well known that, in this type of disease, specific inhibitors should be used, as they increase patient survival and therefore prognosis. So-called tumour heterogeneity, the possibility of various mutations concurring in the same tumour, is currently being debated. We present a case of a double mutation of EGFR and discuss treatment, management and possible implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.patol.2019.11.003DOI Listing
May 2020

Clinical validation of a novel quantitative assay for the detection of MGMT methylation in glioblastoma patients.

Clin Epigenetics 2021 03 9;13(1):52. Epub 2021 Mar 9.

Epigenetics Laboratory. INGEMM, Paseo La Castellana 261. Edificio Bloque Quirúrgico Planta -2. University Hospital La Paz, 28046, Madrid, Spain.

Background: The promoter hypermethylation of the methylguanine-DNA methyltransferase gene is a frequently used biomarker in daily clinical practice as it is associated with a favorable prognosis in glioblastoma patients treated with temozolamide. Due to the absence of adequately standardized techniques, international harmonization of the MGMT methylation biomarker is still an unmet clinical need for the diagnosis and treatment of glioblastoma patients.

Results: In this study we carried out a clinical validation of a quantitative assay for MGMT methylation detection by comparing a novel quantitative MSP using double-probe (dp_qMSP) with the conventional MSP in 100 FFPE glioblastoma samples. We performed both technologies and established the best cutoff for the identification of positive-methylated samples using the quantitative data obtained from dp_qMSP. Kaplan-Meier curves and ROC time dependent curves were employed for the comparison of both methodologies.

Conclusions: We obtained similar results using both assays in the same cohort of patients, in terms of progression free survival and overall survival according to Kaplan-Meier curves. In addition, the results of ROC(t) curves showed that dp_qMSP increases the area under curve time-dependent in comparison with MSP for predicting progression free survival and overall survival over time. We concluded that dp_qMSP is an alternative methodology compatible with the results obtained with the conventional MSP. Our assay will improve the therapeutic management of glioblastoma patients, being a more sensitive and competitive alternative methodology that ensures the standardization of the MGMT-biomarker making it reliable and suitable for clinical use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-021-01044-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941980PMC
March 2021

[Retrospective study of lung carcinoid: experience in a third level Spanish hospital].

Rev Esp Patol 2021 Apr-Jun;54(2):85-91. Epub 2020 Oct 29.

Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, España.

Introduction: Pulmonary carcinoids are relatively rare neuroendocrine neoplasms, accounting for only 1-2% of malignant thoracic tumours. We describe our experience in the management and follow-up of such an infrequent tumour, with special emphasis on possible problems that might arise.

Patients And Methods: We present a descriptive retrospective study of all patients diagnosed with carcinoid tumour between January 2013 and January 2018. Demographic, histological and clinical data were collected and analyzed. Survival was recorded. SPSS version 21 was used for the statistical analysis.

Results: 42 patients with an average age of 66.26 years were included. The mean period of follow-up was 60 months and the average survival 59.12 months. The only statistically significant factor related to an improved survival time was tumour stage at diagnosis.

Conclusion: Carcinoid tumours are infrequent, which makes the objective collecting of data difficult. For this reason, we hope that the present study will contribute to a better understanding of their evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.patol.2020.04.004DOI Listing
October 2020

Novel SLC12A2-ROS1 Fusion in Non-Small Cell Lung Cancer with a Significant Response to Crizotinib: The Importance of Choosing the Appropriate Next-Generation Sequencing Assay.

Oncologist 2021 06 26;26(6):e908-e912. Epub 2021 Mar 26.

Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain.

Identifying the druggable target is crucial for patients with nonsquamous advanced non-small cell lung cancer (NSCLC). This article adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2-ROS1 rearrangement that has not been previously reported in other cancers: a fusion that has clinical and radiological sensitivity to crizotinib. Fluorescence in situ hybridization detected the SLC12A2-ROS1 fusion and it was confirmed through hybrid capture-based next-generation sequencing (NGS); however, the fusion could not be detected by amplicon-based assay. The success of implementing NGS into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results. Given this patient's response to crizotinib, identifying patients with undescribed ROS1 fusions has important therapeutic implications. KEY POINTS: This is the first known description of an SLC12A2-ROS1 fusion. Considering the patient's clinical features and tumor response observed after crizotinib therapy, the authors confirm that this new rearrangement has relevant clinical impact for patients with non-small cell lung cancer. The success of implementing next-generation sequencing (NGS) into routine clinical practice depends on the accuracy of the testing. Different assays and NGS platforms can achieve differing results. Each assay's limitations need to be considered to ensure the quality of precision medicine in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176992PMC
June 2021

Low-Dose Radiation Therapy in the Management of Coronavirus Disease 2019 (COVID-19) Pneumonia (LOWRAD-Cov19): Preliminary Report.

Int J Radiat Oncol Biol Phys 2021 03 26;109(4):880-885. Epub 2020 Nov 26.

Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain; Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.

Purpose: Low-dose radiation therapy (LD-RT) has been shown to have an anti-inflammatory effect, and preliminary results suggest it is feasible to treat patients with coronavirus disease 2019 (COVID-19) pneumonia.

Materials And Methods: We conducted a prospective, single-arm, phase 1/2 clinical trial enrolling patients aged ≥50 years, who were coronavirus disease 2019 (COVID-19) positive, at phase 2 or 3 with lung involvement at imaging study and oxygen requirement. Patients received 100 cGy to total lungs in a single fraction. Primary outcome was radiologic response using severity and extension score on baseline computed tomography (CT), at days 3 and 7 after LD-RT. Secondary outcomes were toxicity using Common Terminology Criteria for Adverse Events v.5.0, duration of hospitalization, blood work evolution, and oxygen requirements using SatO2/FiO2 index (SAFI), at days 3 and 7 after LD-RT.

Results: Nine patients were included. Median age was 66 (interquartile range, 57-77). Severity score was stable or decreased in the third CT but was not statistically significant (P = .28); however, there were statistically significant changes in the extension score (P = .03). SAFI index significantly improved 72 hours and 1 week after LD-RT (P = .01). Inflammatory blood parameters decreased 1 week after RT compared with baseline; only lactate dehydrogenase decreased significantly (P = .04). Two patients presented grade 2 lymphopenia after RT and another (with baseline grade 3) worsened to grade 4. Overall, the median number of days of hospitalization was 59 (range, 26-151). After RT the median number of days in the hospital was 13 (range, 4-77). With a median follow-up after RT of 112 days (range, 105-150), 7 patients were discharged and 2 patients died, 1 due to sepsis and the other with severe baseline chronic obstructive pulmonary disease from COVID-19 pneumonia.

Conclusions: Our preliminary results show that LD-RT was a feasible and well-tolerated treatment, with potential clinical improvement. Randomized trials are needed to establish whether LD-RT improves severe pneumonia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2020.11.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690272PMC
March 2021

Immunotherapy Moves to the Early-Stage Setting in Non-Small Cell Lung Cancer: Emerging Evidence and the Role of Biomarkers.

Cancers (Basel) 2020 Nov 20;12(11). Epub 2020 Nov 20.

Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, 28223 Madrid, Spain.

Despite numerous advances in targeted therapy and immunotherapy in the last decade, lung cancer continues to present the highest mortality rate of all cancers. Targeted therapy based on specific genomic alterations, together with PD-1 and CTLA-4 axis blocking-based immunotherapy, have significantly improved survival in advanced non-small cell lung cancer (NSCLC) and both therapies are now well-established in this clinical setting. However, it is time for immunotherapy to be applied in patients with early-stage disease, which would be an important qualitative leap in the treatment of lung cancer patients with curative intent. Preliminary data from a multitude of studies are highly promising, but therapeutic decision-making should be guided by an understanding of the molecular features of the tumour and host. In the present review, we discuss the most recently published studies and ongoing clinical trials, controversies, future challenges and the role of biomarkers in the selection of best therapeutic options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699975PMC
November 2020

Assessment of the psychosocial and economic impact according to sex in non-small cell lung cancer patients: an exploratory longitudinal study.

BMC Psychol 2020 Nov 23;8(1):123. Epub 2020 Nov 23.

Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.

Background: Little is known about the impact of sex on lung cancer patients from the psychological, economic and social perspectives. This study was designed to explore the psychosocial and economic impact according to sex of metastatic non-small cell lung cancer (mNSCLC) in patients and caregivers.

Methods: Exploratory study of two cohorts of patients starting first-line treatment for mNSCLC. The following questionnaires were administered at baseline, 4 months later and following the first and second disease progression: APGAR, relationship impact scale, DUKE-UNC scale, economic impact in patients and caregiver, and Zarit scale. It was planned to include 1250 patients to get an 80% possibility of detecting as significant (p < 0.05) effect sizes less than 0.19 between men and women. Univariate comparisons were made between the tests applied to men and women. Overall survival was estimated with Kaplan-Meier method. Cox analyses were done to estimate hazard ratios (HRs) with 95% CI.

Results: 333 patients were included. Most families reported to continue being functional despite the lung cancer diagnosis. Regardless of sex, they did not perceive changes in their partner relationship. Most patients felt their social support was normal. Roughly 25% of people reported a worsening in their economic situation, without remarkable differences by sex. Statistically significant differences were found between both groups regarding the caregiver's relationship to the patient (more parents were the caregiver in females than in males, p < 0.0001) and the caregiver's employment situation (more employed caregivers in females) (p < 0.0001). Most caregivers of both sexes considered that taking care of their relative did not pose a significant burden.

Conclusions: This study provides a preliminary insight into sex-related characteristics in the management of advanced NSCLC and its impact on the emotional, social and economic burden of patients and their caregivers, and recall the high priority of researching in cancer from a sex perspective. Nevertheless, due to the low recruitment rate and the relevant loss of patients during the follow-up, it was difficult to find differences by sex.

Trial Registration: ClinicalTrials.gov identifier: NCT02336061.

Ethics Committee: Comité Ético de Investigación Clínica del Hospital Clínic de Barcelona, Spain. Reference number: HCB/2014/0705.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40359-020-00489-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685640PMC
November 2020

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells.

Oncoimmunology 2020 06 16;9(1):1773204. Epub 2020 Jun 16.

The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36CD14PANK allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1773204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458638PMC
June 2020

Lung Adenocarcinoma during Pregnancy: 11-Year Follow-Up.

Case Rep Oncol 2020 May-Aug;13(2):892-895. Epub 2020 Jul 29.

Department of Medical Oncology, Hospital Universitario Madrid Sanchinarro-CIOCC, Madrid, Spain.

The incidence of lung cancer during pregnancy is rising due to the high rate of smokers in young women and the late mean age of pregnancy; in addition, considering that the patients are young women with a higher incidence of molecular alterations, molecular testing in lung adenocarcinoma should always be performed, even in pregnancy. Here, we report the case of a lung adenocarcinoma diagnosed during pregnancy with a long survival who benefitted from brain radiotherapy, conventional chemotherapy, and ALK TKI-targeted treatment. It reveals the safety of whole brain radiotherapy during pregnancy and consideration of other brain radiation techniques even in palliative cases, which should be personalized and managed by a multidisciplinary team. However, upfront management of brain metastasis in ALK-positive patients remains unresolved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000508360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443663PMC
July 2020

[Updated guidelines for predictive biomarker testing in advanced non-small-cell lung cancer: A National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology].

Rev Esp Patol 2020 Jul - Sep;53(3):167-181. Epub 2020 Jun 16.

Departamento de Oncología Médica, Hospital Universitario Ramón y Cajal, Universidad Alcalá, IRYCIS, CIBERONC, Madrid, España.

In 2011, the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) initiated a joint project to establish guidelines for biomarker testing in patients with advanced non-small-cell lung cancer based on the information available at the time. As this field is constantly evolving, these guidelines were updated in 2012 and 2015 and now in 2019. Current evidence suggests it should be mandatory to test all patients with this kind of advanced lung cancer for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). However, the coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remain a challenge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.patol.2019.11.004DOI Listing
June 2020

Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy.

Br J Cancer 2020 09 22;123(5):694-697. Epub 2020 Jun 22.

Mayo Clinic, Rochester, MN, USA.

Three cardinal manifestations of neoplasia, namely inflammation, immune dysfunction, and coagulopathy are also seen in patients with severe SARS-CoV-2 infection, providing a biological rationale for testing selected anticancer drugs for their ability to control the symptoms and/or modify the course of COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-020-0948-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307309PMC
September 2020

Breakthrough cancer pain treatment in Spain: physicians' perception of current opioids utilization and prescription.

Curr Med Res Opin 2020 08 11;36(8):1383-1391. Epub 2020 Jun 11.

Medical Department, Mylan, Madrid, Spain.

Multiple reasons for suboptimal treatment of breakthrough cancer pain (BTcP) have been reported in the literature. We aimed to ascertain the perception of physicians on the potential inappropriate use and prescription of rapid-onset opioids (ROOs) for breakthrough cancer pain (BTcP) and the causes thereof. Observational study based on an online survey addressed to doctors from different specialties (radiation oncology, medical oncology, anesthesia, palliative care and general practitioners) with experience in the management of BTcP in the Spanish public health setting. A total of 114 eligible specialists mainly from radiation oncology (37.7%), medical oncology (24.6%) and pain units (18.4%) participated in the study. Most agreed on important aspects of BTcP management, such as their preference for ROOs or the need for early follow-up after treatment initiation. However, their answers revealed a lack of standardization of BTcP diagnosis. Half of respondents believed that their BTcP patients might misuse ROOs. Physicians polled believed that lack of training in pain management (71.9%) and inadequate BTcP diagnosis and evaluation (66.7%) were the greatest obstacles for prescribing opioids. Specialists also thought that they do not provide the necessary information to patients (51.8%) and caregivers (57.9%) to guarantee the correct use of these drugs. These results are of utmost importance as they highlight the need to increase physicians' awareness of BTcP and its management and the need to improve communication with patients and their caregivers. Our findings also indicate the need for future research on the possible misuse of opioids in BTcP patients and its causes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/03007995.2020.1775073DOI Listing
August 2020

Assessment of the Feasibility and Safety of Durvalumab for Treatment of Solid Tumors in Patients With HIV-1 Infection: The Phase 2 DURVAST Study.

JAMA Oncol 2020 07;6(7):1063-1067

Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain.

Importance: Therapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1-infected individuals have led to the exclusion of these patients from clinical trials on cancer immunotherapies.

Objective: To evaluate the feasibility and safety of durvalumab treatment in patients with advanced cancer and virologically controlled HIV-1 infection.

Design, Setting, And Participants: The DURVAST study was a nonrandomized, open-label, phase 2 clinical trial in patients with any solid tumor type in which anti-PD-1 or anti-PD-L1 antibodies have approved indications or for which there are data of antitumoral activity with no other available curative therapy. All patients had basal undetectable plasma viremia while undergoing combination antiretroviral therapy.

Interventions: Treatment consisted of intravenous infusion of durvalumab (1500 mg every 4 weeks) until disease progression or unacceptable toxic effects.

Main Outcomes And Measures: Adverse events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1.

Results: A total of 20 HIV-1-infected patients with advanced cancer were enrolled; 16 (80%) were male, the median (range) age was 54 (30-73) years, and 12 (60%) had progressed with previous cancer treatment lines. A median (range) of 4 (1-16) cycles of durvalumab were administered. Drug-related adverse events were observed in 50% of patients, and all were grade 1 and 2 (mainly diarrhea, asthenia, and arthromyalgia). Four of 16 response-evaluable patients (25%) had a partial response. Five patients (31%) had stable disease, including 4 with durable stable disease (disease control rate of 50%). CD4+ and CD8+ T-cell counts and plasma HIV-1 viremia remained stable throughout the study.

Conclusions And Relevance: Durvalumab treatment was feasible and safe in HIV-1-infected patients with cancer receiving combination antiretroviral therapy. HIV-1-infected patients on suppressive antiretroviral therapy with advanced cancer should have access to cancer immunotherapy treatments.

Trial Registration: ClinicalTrials.gov Identifier: NCT03094286.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.0465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146525PMC
July 2020

A Novel Role for the Tumor Suppressor Gene in Tumorigenesis and Chemotherapy Response.

Cancers (Basel) 2020 03 26;12(4). Epub 2020 Mar 26.

Epigenetics Laboratory, INGEMM, Hospital La PAZ, 28046 Madrid, Spain.

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyzed and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million microarray-based comparative genomic hybridization (array-CGH) and qRT-PCR methodologies. RNA-sequencing, functional transfection assays, and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. The results were further explored in 55 lung and ovarian primary tumors and control samples, and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of gene. Its expression re-sensitized tumor cells to platinum and recovered the levels of Wnt/β-catenin transcriptional activity. expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between and expression, revealing that Non-small cell lung cancer (NSCLC) patients with lower expression of had a better overall survival rate. We defined the implication of as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of and as novel therapeutic targets for platinum resistant tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12040786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226299PMC
March 2020

[Protein expression of PD-L1 and clinico-pathological data in a cohort of 53 patients with resectable non small cell lung cancer (NSCLC). Concordance between clones (22C3 and 28-8) and observers. Correlation and prognostic value of clinico-pathological data].

Rev Esp Patol 2020 Jan - Mar;53(1):10-18. Epub 2019 Jul 2.

Servicio de Oncología, Hospital Universitario La Paz, Madrid, España; Grupo de Terapias Experimentales y Biomarcadores en Cáncer, IdiPAZ, Madrid, España.

Introduction: 85% of lung cancers are non-small cell carcinomas (NSCLC), the majority of which are diagnosed in an advanced stage. Immunotherapy has changed the treatment pattern for these tumors and created the need to find a marker for patient selection. Although not ideal, PD-L1 is the biomarker currently used in clinical practice.

Material And Methods: Retrospective review by two pathologists of 53 cases of NSCLC from 2005 to 2007 in Hospital Universitario La Paz, using the WHO 2015 classification studying PD-L1 with clones 22C3 and 28-8. The consistency between observers and clones was assessed and all data studied were correlated with survival rates.

Results: We found a prevalence of PD-L1 expression in tumor cells (TC) similar to that previously reported in the literature and a very good consistency between clones in the evaluation of TC and immune cells (ICC 0.99-0.93, p<.001). Interobserver concordance was very good in the evaluation of TC (ICC 0.902, 95% CI: 0.836-0.942, p<.001 for clone 22C3 and ICC 0.927, 95% CI: 0.877-0.957, p<.001 for clone 28-8) and poor for immune cells (ICC of 0.413, 95% CI: 0.163-0.613, p=.001 with clone 22C3 and ICC of 0.313, 95% CI: 0.053-0.534, p=.010 with clone 28-8). Subtype and histological grade were the only variables related to prognosis.

Conclusions: The clones of PD-L1 22C3 and 28-8 are equivalent and there is good interobserver consistency in the evaluation of TC but not in immune cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.patol.2019.04.003DOI Listing
March 2021

Hypermethylation of Anti-oncogenic MicroRNA 7 is Increased in Emphysema Patients.

Arch Bronconeumol (Engl Ed) 2020 Aug 25;56(8):506-513. Epub 2019 Nov 25.

Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, Madrid, Spain; Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, Madrid, Spain.

Introduction: MicroRNA-7 (miR-7) has a suppressive role in lung cancer and alterations in its DNA methylation may contribute to tumorigenesis. As COPD patients with emphysema have a higher risk of lung cancer than other COPD phenotypes, we compared the miR-7 methylation status among smoker subjects and patients with various COPD phenotypes to identify its main determinants.

Methods: 30 smoker subjects without airflow limitation and 136 COPD patients without evidence of cancer were recruited in a prospective study. Clinical and functional characteristics were assessed and patients were classified into: frequent exacerbator, emphysema, chronic bronchitis and asthma COPD overlap (ACO). DNA collected from buccal epithelial samples was isolated and bisulfite modified. miR-7 methylation status was evaluated by quantitative methylation-specific polymerase chain reaction (qMSP).

Results: miR-7 Methylated levels were higher in COPD patients than in smokers without airflow limitation (23.7±12.4 vs. 18.5±8.8%, p=0.018). Among COPD patients, those with emphysema had higher values of methylated miR-7 (27.1±10.2%) than those with exacerbator (19.4±9.9%, p=0.004), chronic bronchitis (17.3±9.0%, p=0.002) or ACO phenotypes (16.0±7.2%, p=0.010). After adjusting for clinical parameters, differences between emphysematous patients and those with other phenotypes were retained. In COPD patients, advanced age, mild-moderate airflow limitation, reduced diffusing capacity and increased functional residual capacity were identified as independent predictors of methylated miR-7 levels.

Conclusion: The increase of miR-7 methylation levels experienced by COPD patients occurs mainly at the expense of the emphysema phenotype, which might contribute to explain the higher incidence of lung cancer in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arbres.2019.10.017DOI Listing
August 2020

miR-7 methylation as a biomarker to predict poor survival in early-stage non-small cell lung cancer patients.

Cell Biosci 2019 7;9:63. Epub 2019 Aug 7.

1Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, Madrid, Spain.

Non-small-cell lung cancer (NSCLC) is the most common malignancy worldwide. Platinum-based chemotherapy is the standard of care for these patients. Recent research showed that miR-7 methylation status is a biomarker of cisplatin resistance in lung and ovarian cancer cells, which is one of the major limitations associated with their clinical management. The aim of the present study is to provide clinical insights associated with this novel potential biomarker in NSCLC patients by comparing the miR-7 methylation status with the cisplatin treatment response. Our results analyzed in 81 samples show that miR-7 methylation is a common event in tumor tissue and it is more frequent as the stage of the disease advances, remaining in 75% of metastatic patients. Tumor miR-7 unmethylation trend to a better PFS in early stages, and when our data was validated in an extended in silico" cohort of 969 patients we obtained a significant increment in PFS and OS in those patients harboring miR-7 unmethylated (p = 0.010 and p = 0.007 respectively). When we select those early-stages patients harbouring miR-7 methylation, we observed that adenocarcinoma patients present a dramatic decrease in PFS compared with squamous cell carcinoma patients (median 18.9 versus 59.7 months, p = 0.002). In conclusion, our results show that presence of miR-7 methylation in early-stage NSCLC is suggestive of aggressive behavior, especially for adenocarcinoma patients. One major challenge in early diagnosis in NSCLC is identify the subgroup of patients that could benefit for adjuvant therapy, our data establish the basis for epigenetic classification on early-stage NSCLC that could influence treatment decisions in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13578-019-0326-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686393PMC
August 2019

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

J Thorac Oncol 2019 12 23;14(12):2120-2132. Epub 2019 Jul 23.

Alvaro Cunqueiro Hospital, Vigo, Spain.

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data.

Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific).

Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively).

Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.07.005DOI Listing
December 2019

Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance.

Lung Cancer 2019 08 30;134:72-78. Epub 2019 May 30.

CIBERONC, Spain; Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Universidad Alcalá, Madrid, Spain. Electronic address:

Objectives: Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance.

Materials And Methods: We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1-altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay).

Results: We included 53 patients separated in 3 cohorts: 31 EGFR-mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790M + NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1-rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (n = 9, 17%), or plasma NGS and tissue sequencing (n = 2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790 M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790 M by Guardant360 but were T790M + by tissue and BEAMing digital PCR respectively, and also received osimertinib.

Conclusion: NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2019.05.032DOI Listing
August 2019

Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer.

Int J Mol Sci 2019 Apr 25;20(8). Epub 2019 Apr 25.

Department of Experimental Models of Human Diseases, Instituto de Investigaciones Biomédicas C.S.I.C./U.A.M, 28029 Madrid, Spain.

DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of . In agreement with these data, here we show that plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in epithelial to mesenchymal transition (EMT) in NSCLC- depleted cells. Data obtained in RNA-seq studies carried out in depleted cells identified EGFR, TGF-β and WNT signaling pathways and several genes such as whose expression is upregulated in these cells and therefore affecting cellular functions such as integrin mediated cell adhesion, focal adhesion and motility. Furthermore, EGF signaling pathway is activated via ERK5 and not ERK1/2 and TGF-β via SMAD2/3 in depleted cells. In summary is a tumor suppressor in NSCLC and re-establishment of its expression may be a potential strategy to revert poor outcome in NSCLC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20082036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514584PMC
April 2019

Patterns of Progression and Feasibility of Re-biopsy After First-line Erlotinib for Advanced Mutation-positive Non-small-cell Lung Cancer.

Anticancer Res 2019 Mar;39(3):1317-1328

Virgen de la Victoria University Hospital, IBIMA, Campus de Teatinos, Málaga, Spain

Aim: To assess the patterns of disease progression in advanced/metastatic epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) on first-line treatment with erlotinib and identify potential prognostic factors for progression-free survival (PFS).

Patients And Methods: Patients with stage IIIB/IV EGFR-mutation-positive NSCLC receiving first-line erlotinib were followed-up until 24 months after the last patient was enrolled or until premature withdrawal for any cause.

Results: A total of 127 evaluable patients were enrolled. The median PFS and overall survival were 8.8 and 19.1 months, respectively. Disease progression was asymptomatic in 57.6% of patients and 53.3% developed new sites of metastasis. The presence of liver metastasis was identified as an independent prognostic factor for poor PFS.

Conclusion: Metastatic progression with asymptomatic disease seems to be the predominant pattern of disease progression on first-line erlotinib in real-life practice in patients with advanced/metastatic EGFR-mutant NSCLC. Additionally, the presence of liver metastases may negatively affect PFS in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.13244DOI Listing
March 2019

Molecular testing and treatment patterns for patients with advanced non-small cell lung cancer: PIvOTAL observational study.

PLoS One 2018 27;13(8):e0202865. Epub 2018 Aug 27.

Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.

Background: The goals of this multinational retrospective study were to describe treatment patterns and survival outcomes by receipt of molecular testing and molecular status of patients with advanced non-small cell lung cancer (NSCLC).

Methods: This chart review study, conducted in Italy, Spain, Germany, Australia, Japan, Korea, Taiwan, and Brazil, included 1440 patients with newly diagnosed advanced (stage IIIB/IV) NSCLC initiating systemic therapy from January 2011 through June 2013, with follow-up until July 2016. We evaluated treatment patterns and survival by histology, line of therapy, molecular testing, and test results for epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase (ALK) rearrangement. Country-specific data were analyzed descriptively and presented as ranges (lowest to highest country). Overall survival (OS) was estimated using Kaplan-Meier method.

Results: Patients with ≥1 molecular test varied from 43% (Brazil) to 85% (Taiwan). Numerically greater proportions of patients who were female, Asian, or never/former-smokers, and those with nonsquamous histology or stage-IV NSCLC, received a test. Testing was common for nonsquamous NSCLC (54%, Brazil, to 91%, Taiwan), with positive EGFR and ALK tests from 17% (Brazil and Spain) to 67% (Taiwan) and from 0% (Brazil) to 60% (Taiwan), respectively. First-line treatment regimens for nonsquamous NSCLC with positive EGFR/ALK tests included targeted therapy for 30% (Germany) to 89% (Japan); with negative/inconclusive test results, platinum-based combinations for 88% (Japan) to 98% (Brazil); and if not tested, platinum-based combinations for 80% (Australia) to 95% (Japan), except in Taiwan, where 44% received single agents. Median OS from first-line therapy initiation was 10.0 (Japan) to 26.7 (Taiwan) months for those tested and 7.6 (Australia/Brazil) to 19.3 (Taiwan) months for those not tested.

Conclusions: We observed substantial variation among countries in testing percentages, treatment patterns, and survival outcomes. Efforts to optimize molecular testing rates should be implemented in the context of each country's health care scenario.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202865PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110501PMC
February 2019

MAFG is a potential therapeutic target to restore chemosensitivity in cisplatin-resistant cancer cells by increasing reactive oxygen species.

Transl Res 2018 10 30;200:1-17. Epub 2018 Jun 30.

Cancer Epigenetics Laboratory, INGEMM, La Paz University Hospital, Madrid, Spain; Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, Madrid, Spain. Electronic address:

Adjuvant chemotherapy for solid tumors based on platinum-derived compounds such as cisplatin is the treatment of choice in most cases. Cisplatin triggers signaling pathways that lead to cell death, but it also induces changes in tumor cells that modify the therapeutic response, thereby leading to cisplatin resistance. We have recently reported that microRNA-7 is silenced by DNA methylation and is involved in the resistance to platinum in cancer cells through the action of the musculoaponeurotic fibrosarcoma oncogene family, protein G (MAFG). In the present study, we first confirm the miR-7 epigenetic regulation of MAFG in 44 normal- and/or tumor-paired samples in non-small-cell lung cancer (NSCLC). We also provide translational evidence of the role of MAFG and the clinical outcome in NSCLC by the interrogation of two extensive in silico databases of 2019 patients. Moreover, we propose that MAFG-mediated resistance could be conferred due to lower reactive oxygen species production after cisplatin exposure. We developed specifically selected aptamers against MAFG, with high sensitivity to detect the protein at a nuclear level probed by aptacytochemistry and histochemistry analyses. The inhibition of MAFG activity through the action of the specific aptamer apMAFG6F increased the levels of reactive oxygen species production and the sensitivity to cisplatin. We report first the specific nuclear identification of MAFG as a novel detection method for diagnosis in NSCLC, and then we report that MAFG modulates the redox response and confers cell protection against free radicals generated after platinum administration, thus also being a promising therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trsl.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787305PMC
October 2018

A survey of perceptions, attitudes, knowledge and practices of medical oncologists about cancer pain management in Spain.

Clin Transl Oncol 2018 Aug 2;20(8):1061-1071. Epub 2018 May 2.

Hospital Universitario de Salamanca-Universidad de Salamanca (USAL), Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.

Purpose: To monitor oncologists' perspective on cancer pain management.

Methods: An anonymized survey was conducted in two waves. First, over a convenience sample of oncologists known to be particularly concerned with the management of pain. Second, using a random sample of oncologists.

Results: In total, 73 and 82 oncologists participated in the first and second wave, respectively. Many oncologists reported to have good knowledge of analgesic drugs (95.9%), the mechanism of action of opioids (79.5%), and good skills to manage opioid-related bowel dysfunction (76.7%). Appropriate adjustment of background medication to manage breakthrough pain was reported by 95.5% of oncologists. Additionally, 87.7% (68.3% in the second wave, p = 0.035) of oncologists reported suitable opioid titration practices, and 90.4% reported to use co-adjuvant medications for neuropathic pain confidently. On the other hand, just 9.6% of oncologists participated in multidisciplinary pain management teams, and merely 30.3 and 27.1% reported to routinely collaborate with the Pain Clinics or involve other staff, respectively. Only 26.4% of the oncologists of the second wave gave priority to pain pathophysiology to decide therapies, and up to 75.6% reported difficulties in treating neuropathic pain. Significantly less oncologists of the second wave (82.9 vs. 94.5%, p = 0.001) used opioid rotation routinely.

Conclusions: Unlike in previous surveys, medical oncologists reported in general good knowledge and few perceived limitations and barriers for pain management. However, multi-disciplinary management and collaboration with other specialists are still uncommon. Oncologists' commitment to optimize pain management seems important to improve and maintain good practices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12094-017-1826-8DOI Listing
August 2018

Small Cell Breast Cancer with Lung Metastases.

Arch Bronconeumol (Engl Ed) 2018 Nov 9;54(11):586-587. Epub 2018 Apr 9.

Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, España.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arbres.2018.02.014DOI Listing
November 2018

Health care resource use among patients with advanced non-small cell lung cancer: the PIvOTAL retrospective observational study.

BMC Health Serv Res 2018 03 1;18(1):147. Epub 2018 Mar 1.

Medical Oncology Service, Hospital Universitario La Paz (IDIPAZ), Madrid, Spain.

Background: Data are scarce regarding real-world health care resource use (HCRU) for non-small cell lung cancer (NSCLC). An understanding of current clinical practices and HCRU is needed to provide a benchmark for rapidly evolving NSCLC management recommendations and therapeutic options. The objective of this study was to describe real-world HCRU for patients with advanced NSCLC.

Methods: This multinational, retrospective chart review study was conducted at academic and community oncology sites in Italy, Spain, Germany, Australia, Japan, South Korea, Taiwan, and Brazil. Deidentified data were drawn from medical records of 1440 adults (≥18 years old) who initiated systemic therapy (2011 to mid-2013) for a new, confirmed diagnosis of advanced or metastatic (stage IIIB or IV) NSCLC. We summarized HCRU associated with first and subsequent lines of systemic therapy for advanced/metastatic NSCLC.

Results: The proportion of patients who were hospitalized at least once varied by country from 24% in Italy to 81% in Japan during first-line therapy and from 22% in Italy to 84% in Japan during second-line therapy; overall hospitalization frequency was 2.5-11.1 per 100 patient-weeks, depending on country. Emergency visit frequency also varied among countries (overall from 0.3-5.9 per 100 patient-weeks), increasing consistently from first- through third-line therapy in each country. The outpatient setting was the most common setting of resource use. Most patients in the study had multiple outpatient visits in association with each line of therapy (overall from 21.1 to 59.0 outpatient visits per 100 patient-weeks, depending on country). The use of health care resources showed no regular pattern associated with results of tests for activating mutations of the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements.

Conclusions: HCRU varied across countries. These findings suggest differing approaches to the clinical management of advanced NSCLC among the eight countries. Comparative findings and an understanding of country-specific clinical practices can help to identify areas of need and guide future resource allocation for patients with advanced NSCLC. Further studies evaluating the costs associated with resource use are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12913-018-2946-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831211PMC
March 2018

An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells.

Epigenetics 2018 2;13(3):251-263. Epub 2018 Apr 2.

a Cancer Epigenetics Laboratory, INGEMM , La Paz University Hospital , Madrid , Spain.

Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer. The potential role of lncRNAs and their epigenetic regulation in response to platinum treatment are largely unknown. We analyzed four paired cisplatin-sensitive/resistant non-small cell lung cancer and ovarian cancer cell lines. The epigenetic landscape of overlapping and cis-acting lncRNAs was determined by combining human microarray data on 30,586 lncRNAs and 20,109 protein coding mRNAs with whole-genome bisulfite sequencing. Selected candidate lncRNAs were further characterized by PCR, gene-ontology analysis, and targeted bisulfite sequencing. Differential expression in response to therapy was observed more frequently in cis-acting than in overlapping lncRNAs (78% vs. 22%, fold change ≥1.5), while significantly altered methylation profiles were more commonly associated with overlapping lncRNAs (29% vs. 8%; P value <0.001). Moreover, overlapping lncRNAs contain more CpG islands (CGIs) (25% vs. 17%) and the majority of CGI-containing overlapping lncRNAs share these CGIs with their associated coding genes (84%). The differences in expression between sensitive and resistant cell lines were replicated in 87% of the selected candidates (P<0.05), while our bioinformatics approach identifying differential methylation was confirmed in all of the selected lncRNAs (100%). Five lncRNAs under epigenetic regulation appear to be involved in cisplatin resistance (AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, and AF198444). These novel findings provide new insights into epigenetic mechanisms and acquired resistance to cisplatin that highlight specific lncRNAs, some with unknown function, that may signal strategies in epigenetic therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15592294.2018.1436364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997141PMC
February 2019
-->