Tackling hurdles in front of young clinical investigators in oncology - Results from an international survey.

INTRODUCTION: Cancer is a leading cause of morbidity and mortality worldwide, and coordinated research efforts are vital to improve global outcomes. Clinical or translational research is usually planned, coordinated and executed by clinical researchers. With this survey we aimed to identify the main hurdles in front of young clinical investigators in oncology. METHODS AND MATERIALS: An anonymized survey was distributed using social media between April and November 2022. Target population were health-care professionals in the field of oncology - physicians, nurses and researchers. We divided participants according to working experience (<40 vs. >40 years of age) and country of practice (Europeans vs. non-Europeans). RESULTS: We received 121 responses from participants practicing in 36 countries. Eighty-seven (72%) of the participants were under 40 years. Eighty-nine (74%) were from European countries and thirty-two (26%) were from non-European. Experienced and European professionals were more likely to be involved in all different aspects of clinical trials. The main source of funding - independently of geographic location - were industry grants. Investigators out of Europe have less participation in international grants. Over 50% of participants dedicate time for clinical research from their personal time and are not paid for it. Almost 50% of investigators don't have access to an experienced mentor in their institution. CONCLUSION: The majority of respondents to our survey are active clinical researchers. Our data indicate that access to education and training as well as possibilities for appropriate networking, and specifically lack of mentorship, are key limiting factors in developing clinical research by healthcare professionals.

APOL1 Gene Variants and Risk for Cardiovascular Disease.

INTRODUCTION: The association of APOL1 risk variants with cardiovascular risk and cardiovascular disease (CVD) in observational and clinical trials has had inconsistent results. We aim to assess the relationship between the presence of APOL1 risk variants and the CVD risk in Afro-descendant patients with end-stage renal disease (ESRD). METHODS: We performed an observational, cross-sectional study of Afro-descendant adult patients with ESRD who were on the waitlist for a kidney transplant. Associations of APOL1 genotypes (high-risk [HR] = 2 alleles; low-risk [LR] = 0 or 1 allele) with cardiovascular risk were the primary clinical endpoint. The relation was evaluated using univariate and multivariate analysis. RESULTS: We enrolled a total of 102 patients with ESRD; 37% (38 patients) had APOL1 HR status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form and 63% (64 patients) had APOL1 LR status. No significant association was found between HR APOL1 genotypes and high cardiovascular risk (in adjusted Colombia Framingham Risk Score). APOL1 HR versus LR variants were not independently associated with left ventricular hypertrophy or systolic dysfunction. No cardiovascular deaths occurred during the follow-up. CONCLUSION: In Afro-descendent patients with ESRD, APOL1 HR status is not associated with the increase in cardiovascular risk profile and metabolic disturbances.

COVID-19 en receptores de trasplante renal: la experiencia inicial en Colombia

Contexto: los pacientes con trasplante de riñón parecen tener un riesgo particularmente alto de enfermedad grave por COVID-19 debido a la inmunosupresión y la presencia de comorbilidades. Objetivo: describir las características clínicas, paraclínicas y desenlaces de los pacientes trasplantados renales que presentan infección por SARS-COV-2 en un hospital de cuarto nivel en Cali, Colombia. Metodología: realizamos un estudio observacional de receptores de trasplante renal con infección por SARS-CoV-2 ingresados ​​en la Fundación Valle del Lili, de junio a diciembre del 2020. Para ser elegibles en el estudio, los pacientes debían presentar síntomas compatibles, RT-PCR positiva y manejo hospitalario. Se excluyó a los pacientes asintomáticos. Resultados: inscribimos a un total de 50 pacientes, donde el 64 % eran hombres y la edad media fue de 53,5 años (rango 46-60). Las comorbilidades fueron: 36 (70 %) con hipertensión, 16 (32 %) con diabetes mellitus y 5 (10 %) con obesidad y los regímenes inmunosupresores más comunes fueron: tacrolimus, micofenolato y prednisona. La mediana de tiempo desde el inicio de los síntomas hasta la RT-PCR positiva fue de siete días. Los síntomas iniciales más comunes fueron fiebre (64 %), fatiga (58%), tos (44%) y disnea (36%). Los niveles basales de proteína C reactiva (PCR) fueron de 6,43 mg/dl (3,25-11,22), la mediana del recuento de linfocitos fue de 785 mm3/uL (550-1230), el dímero D basal fue de 0,767 ug/ml (0,484-1153,5) y el nivel medio de ferritina fue de 1011 ng/ml (670-2145). El 40 % desarrolló lesión renal aguda (20 pacientes), de los cuales 11 pacientes necesitaron terapia de remplazo renal, 6 de los pacientes fallecieron (12 %), 4/6 por insuficiencia multiorgánica relacionada con la sepsis y 2/6 por el síndrome de dificultad respiratoria agudo (SDRA). Conclusiones: las complicaciones mayores como la lesión renal aguda, el síndrome de dificultad respiratoria aguda y la mortalidad relacionada con la infección por COVID-19 observadas en nuestro estudio son significativas, pero menos frecuentes que las reportadas en otros países.

Background: Patients with kidney transplants seem to be at particularly high risk for severe COVID19 disease due to their impaired immune responses and comorbidities. Purpose: This study aims to describe kidney transplant patients' clinical characteristics and outcomes with SARSCOV-2 infection in a fourth-level hospital in Cali, Colombia. Methodology: We performed an observational study of kidney transplant recipients with SARS-CoV2 infection admitted at Fundación Valle del Lili from June to December 2020. To be eligible for this study, patients have symptoms compatible, a positive RT-PCR and inpatient management. Asymptomatic patients were excluded. Results: We enrolled a total of 50 patients. 64% were male, and the median age was 53.5 years (range 46-60). The comorbidities were 36 (70%) hypertension, 16 (32%) diabetes mellitus, 5 (10%) obesity. The most common immunosuppressive regimen was tacrolimus, mycophenolate and prednisone. The median time from symptoms onset to the positive RT-PCR was 7 days. The most common initial symptom was fever (64%), and fatigue (58%), cough (44%) and dyspnea (36%). Baseline levels of CRP was 6.43 mg/dL (3.25-11.22). The median lymphocyte count was 785 mm3/uL (550-1230). Baseline D-Dimer was 0.767 ug/ml (0.484-1153.5), ferritin median level was 1011ng/ml (670-2145). Six of the patients died (12%), 4/6 were by sepsis-related multi-organ failure and 2/6 were by ARDS. Conclusions: Major complications such as acute kidney injury, acute respiratory distress syndrome and mortality related to COVID-19 infection observed in our study are lower than those reported in other countries.

Amigdalitis prolongada con pobre respuesta al manejo, raro caso de tuberculosis extrapulmonar / Prolonged tonsilitis with poor response to therapy: a rare case of extrapulmonary tuberculosis

La tuberculosis es la primera causa de mortalidad infectocontagiosa a nivel mundial. La tuberculosis pulmonar corresponde a la presentación más frecuente, sin embargo, el 15 % de los casos cursan con infección extrapulmonar, siendo raro el compromiso amigdalino. Este reporte de caso describe a un paciente de 39 años con odinofagia recurrente secundaria a amigdalitis por Mycobacterium tuberculosis, un raro caso de tuberculosis extrapulmonar. La amigdalitis es una infección leve y frecuente de la vía aérea superior, que responde adecuadamente al manejo antibiótico; sin embargo, cuadros recurrentes y prolongados, manifestaciones atípicas o pobre respuesta a la antibioticoterapia son características que obligan a la búsqueda de diagnósticos diferenciales, lo que lleva a considerar la presencia de Mycobacterium tuberculosis como agente etiológico, especialmente en países con alto índice de tuberculosis como Colombia

Tuberculosis is the leading cause of infectious mortality worldwide. The pulmonary one corresponds to the most frequent presentation, however up to 15% of tuberculosis cases present extrapulmonary involvement, tonsillar tuberculosis being rare. The following is a case report of a 39-year-old patient with recurrent odynophagia secondary to Mycobacterium tuberculosis tonsillitis, a rare form of extrapulmonary tuberculosis. Tonsillitis is a benign and extremely common infection of the upper airway. Such patients benefit from systemic antibiotics, although, recurrent episodes, prolonged odynophagia, atypical manifestations, or poor response to antimicrobial therapy forces consideration of diagnostic possibilities other than the obvious, including Mycobacterium tuberculosis as the etiological agent, especially in countries with the highest rates of tuberculosis.

Efectos de la rehabilitación cardiaca en el paciente cardiovascular con ansiedad y depresión / Effects of cardiac rehabilitation on the cardiovascular patient with anxiety

Resumen Objetivo: determinar el efecto de un programa de rehabilitación en los puntajes de ansiedad y depresión de pacientes con enfermedad cardiovascular. Materiales y métodos: se analizó la información de una cohorte retrospectiva de pacientes con enfermedad cardiovascular, admitidos a un programa de rehabilitación cardiaca. La ansiedad y depresión fueron medidas con la escala HADS (Hospital Anxiety and Depression Scale) y se categorizaron según el tratamiento de base recibido (médico o quirúrgico). Se comparó el cambio en los puntajes de ansiedad y depresión al ingreso y al final de la rehabilitación cardiaca mediante la prueba de Wilcoxon para muestras pareadas y la prueba de McNemar para evaluar el cambio de los porcentajes en cada subescala. Resultados: se incluyeron 1.221 pacientes. La mediana de edad fue 61 años, 68,30% eran hombres. Al ingreso, la mediana del puntaje de ansiedad y depresión fue 3, de los cuales 141 pacientes presentaron un trastorno de ansiedad (11,55%) y 67 un trastorno depresivo (5,49%). Al final de la rehabilitación cardiaca se obtuvo una mejoría en los puntajes de ansiedad y depresión tanto en pacientes en tratamiento médico (promedio -1,87 puntos 95% IC -2,14 a -1,60 p<0,01 y -1,46 puntos 95% IC -1,72 a -1,21 p<0,01 respectivamente) como quirúrgico (promedio -1,48 puntos 95% IC -1,78 a -1,18 p<0,01 y -1,83 puntos 95% IC -2,12 a -1,57 p<0,01). Conclusiones: los puntajes de ansiedad y depresión, en pacientes con enfermedad cardiovascular en tratamiento médico o quirúrgico, mejoraron luego de un programa integral de rehabilitación cardíaca.

Abstract Objective: To determine the effects of a rehabilitation program on the anxiety and depression scores of patients with cardiovascular disease. Materials and methods: An analysis was performed on the information collected from a retrospective cohort of patients with cardiovascular disease, admitted to a cardiac rehabilitation program. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS), and were classified according to the baseline treatment (medical or surgical) received. A comparison was made between the anxiety and depression scores on admission and at the end of the cardiac rehabilitation program using Wilcoxon test for paired samples and the McNemar test to evaluate the change in the percentages in each sub-scale. Results: A total of 1,221 patients were included. The median age was 61 years, and 68.3% were males. On admission, the median score was 3 on the anxiety and depression scale, with 141 (11.55%) patients having an anxiety disorder, and 67 (5.49%) with depressive disorder. An improvement was observed in the anxiety and depression scores at the end of the end of the cardiac rehabilitation, both in patients on medical treatment (mean difference minus 1.87 points, 95% CI; -2.14 to -1.60: P<.01, and -1.46 points, 95% CI; -1.72 to -1.21: P<.01, for anxiety and depression, respectively) and on surgical treatment (mean difference -1.48 points, 95% CI; -1.78 to -1.18, P<.01 and -1.83 points, 95% CI -2.12 to -1.57, P<.01, respectively). Conclusions: The anxiety and depression scores in patients with cardiovascular disease on medical or surgical treatment improved after an integrated cardiac rehabilitation program.

Seroprevalence and Risk Factors Possibly Associated with Emerging Zoonotic Vaccinia Virus in a Farming Community, Colombia.

In 2014, vaccinia virus (VACV) infections were identified among farmworkers in Caquetá Department, Colombia; additional cases were identified in Cundinamarca Department in 2015. VACV, an orthopoxvirus (OPXV) used in the smallpox vaccine, has caused sporadic bovine and human outbreaks in countries such as Brazil and India. In response to the emergence of this disease in Colombia, we surveyed and collected blood from 134 farmworkers and household members from 56 farms in Cundinamarca Department. We tested serum samples for OPXV antibodies and correlated risk factors with seropositivity by using multivariate analyses. Fifty-two percent of farmworkers had OPXV antibodies; this percentage decreased to 31% when we excluded persons who would have been eligible for smallpox vaccination. The major risk factors for seropositivity were municipality, age, smallpox vaccination scar, duration of time working on a farm, and animals having vaccinia-like lesions. This investigation provides evidence for possible emergence of VACV as a zoonosis in South America.

An endothelial growth factor receptor compound mutation of T790M substitution with exon 19 deletion in a previously untreated patient: a case report.

BACKGROUND: Endothelial growth factor receptor (EGFR) mutations are an essential driver of personalized therapy for patients with lung cancer and are detected in approximately 15% of Caucasian and 50% of Asian patients. EGFR tyrosine kinase inhibitors have been developed and used for this set of patients. T790M mutation in exon 20 is usually associated with secondary resistance to EGFR tyrosine kinase inhibitors therapy but is also present in treatment-naïve patients. The frequency for baseline T790M mutation varies from 4 to 35% according to the detection method used. Newer techniques have yielded higher rates, but concerns about false-positive results have been raised. Compound mutations account for 4-14% of all EGFR-mutated tumors, with no studies yet to provide a frequency rate for T790M + 19 deletion association due to the small number of cases. However, there are reports that pretreatment T790M + L858R association is significantly more frequent compared to T790M + exon 19 deletion mutations. Diagnostic challenges, current knowledge on the subject, and therapeutic decisions are discussed. CASE PRESENTATION: We present the case of a 43-year-old Hispanic woman, a treatment-naïve patient, with metastasized lung cancer adenocarcinoma harboring a T790M deletion along with the classic 19 mutation. The initial symptoms were monoparesis of her left leg, associated with hyperreflexia, and hypoesthesia. In the absence of third-generation tyrosine kinase inhibitors, a platinum-based therapy was initiated with no response and she died 4 months after diagnosis. CONCLUSIONS: Osimertinib seems to be a suitable therapy for treatment-naïve patients with sensitizing and resistant compound EGFR mutations. More studies regarding the clinical characteristics of these patients and the appropriate management of this condition are needed to provide the highest standard of care.

Development of a gene panel for next-generation sequencing of clinically relevant mutations in cell-free DNA from cancer patients.

BACKGROUND: When tumour tissue is unavailable, cell-free DNA (cfDNA)can serve as a surrogate for genetic analyses. Because mutated alleles in cfDNA are usually below 1%, next-generation sequencing (NGS)must be narrowed to target only clinically relevant genes. In this proof-of-concept study, we developed a panel to use in ultra-deep sequencing to identify such mutations in cfDNA. METHODS: Our panel ('SiRe') covers 568 mutations in six genes (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα)involved in non-small-cell lung cancer (NSCLC), gastrointestinal stromal tumour, colorectal carcinoma and melanoma. We evaluated the panel performance in three steps. First, we analysed its analytical sensitivity on cell line DNA and by using an artificial reference standard with multiple mutations in different genes. Second, we analysed cfDNA from cancer patients at presentation (n=42), treatment response (n=12) and tumour progression (n=11); all patients had paired tumour tissue and cfDNA previously genotyped with a Taqman-derived assay (TDA). Third, we tested blood samples prospectively collected from NSCLC patients (n=79) to assess the performance of SiRe in clinical practice. RESULTS: SiRe had a high analytical performance and a 0.01% lower limit of detection. In the retrospective series, SiRe detected 40 EGFR, 11 KRAS, 1 NRAS and 5 BRAF mutations (96.8% concordance with TDA). In the baseline samples, SiRe had 100% specificity and 79% sensitivity relative to tumour tissue. Finally, in the prospective series, SiRe detected 8.7% (4/46) of EGFR mutations at baseline and 42.9% (9/21) of EGFR p.T790M in patients at tumour progression. CONCLUSIONS: SiRe is a feasible NGS panel for cfDNA analysis in clinical practice.

KRAS mutations in the circulating free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients.

Circulating free DNA (cfDNA) is obtained from serum or plasma by non-invasive methods such as a simple blood draw, a technique known as "liquid biopsy". Genetic analyses of driver alterations in cfDNA have proved very effective to predict survival and treatment response of cancer patients according to tumoral cfDNA burden in blood. Non-small cell lung cancer (NSCLC) patients with higher concentration of tumoral cfDNA in blood have, on average, shorter progression-free survival (PFS) and overall survival (OS). Regarding specific genetic alterations, KRAS proto-oncogene, GTPase (KRAS) is one of the main genes involved in NSCLC and several studies have been performed to determine its value as a predictive and prognostic biomarker in liquid biopsy. Unfortunately, to date no strong conclusions can be drawn since they have yielded contradictory results. Therefore, further investigations are necessary to establish the value of KRAS testing in liquid biopsy as prognostic or predictive factor in NSCLC. Herein, we review the current knowledge on the importance of KRAS as prognostic and predictive biomarker using non-invasive approaches and the scientific data available regarding its application in clinical practice for treatment of NSCLC.

Fusion gene and splice variant analyses in liquid biopsies of lung cancer patients.

Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance. In contrast, a blood extraction is safe, can be performed at many time points during the course disease and encourages appropriate therapy modifications, potentially improving the patient's clinical outcome and quality of life. Fusion of the tyrosine kinase genes anaplastic lymphoma kinase (ALK), C-ROS oncogen 1 (ROS 1), rearranged during transfection (RET) and neurotrophic tyrosine kinase 1 (NTRK1) occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors. In addition, a MET splicing variant of exon 14, has been reported in 2-4% of lung adenocarcinoma and recent studies suggests that targeted therapies inhibiting MET signaling would be beneficial for patients with this alteration. In this review, we will summarize the new techniques recently developed to detect ALK, RET, ROS and NTRK1 fusions and MET exon 14 splicing variant in liquid biopsy using plasma, serum, circulating tumor cells (CTCs), platelets and exosomes as starting material.

Usefulness of circulating free DNA for monitoring epidermal growth factor receptor mutations in advanced non-small cell lung cancer patients: a case report.

Genomic analysis of circulating tumor DNA (ctDNA) released from cancer cells into the bloodstream has been proposed as a useful method to capture dynamic changes during the course of the disease. In particular, the ability to monitor epidermal growth factor receptor (EGFR) mutation status in cell-free circulating DNA (cfDNA) isolated from advanced non-small cell lung cancer (NSCLC) patients EGFR can help to the correct management of the disease and overcome the challenges associated with tumor heterogeneity and insufficient biopsied material to perform key molecular diagnosis. Here, we report a case of long term monitorization of EGFR mutation status in cfDNA from peripheral blood in an NSCLC patient in, with excellent correlation with clinical evolution.

Treatment for small cell lung cancer, where are we now?-a review.

Small cell lung cancer (SCLC) represents between 13% and 15% of all diagnosed lung cancers worldwide. It is an aggressive neoplasia, with a 5-year mortality of 90% or more. It has historically been classified as limited disease (LD) and extensive disease (ED) in most study protocols. The cornerstone of treatment for any stage of SCLC is etoposide-platinum based chemotherapy; in limited stage (LS), concomitant radiotherapy to thorax and mediastinum. Prophylactic radiotherapy to the central nervous system (CNS) [prophylactic cerebral irradiation (PCI)] has diminished the incidence of brain metastasis as the site for relapse in LD and ED patients, therefore it should be offered to patients with complete response to induction first-line treatment. Regarding second-line treatment, results are more modest and topotecan is accepted as treatment for this scenario offering a modest benefit.

Liquid Biopsy in Non-Small Cell Lung Cancer.

Liquid biopsy analyses are already incorporated in the routine clinical practice in many hospitals and oncology departments worldwide, improving the selection of treatments and monitoring of lung cancer patients. Although they have not yet reached its full potential, liquid biopsy-based tests will soon be as widespread as "standard" biopsies and imaging techniques, offering invaluable diagnostic, prognostic, and predictive information. This review summarizes the techniques available for the isolation and analysis of circulating free DNA and RNA, exosomes, tumor-educated platelets, and circulating tumor cells from the blood of cancer patients, presents the methodological challenges associated with each of these materials, and discusses the clinical applications of liquid biopsy testing in lung cancer.

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.

BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.

Melanoma: oncogenic drivers and the immune system.

Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches.

Pharmacogenomics in the treatment of lung cancer: an update.

Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies.

Erratum to Assays for predicting and monitoring responses to lung cancer immunotherapy.

[This corrects the article on p. 87 in vol. 12, PMID: 26175924.].

Assays for predicting and monitoring responses to lung cancer immunotherapy.

Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway.