Neurological monitoring and management for adult extracorporeal membrane oxygenation patients: Extracorporeal Life Support Organization consensus guidelines.

BACKGROUND: Critical care of patients on extracorporeal membrane oxygenation (ECMO) with acute brain injury (ABI) is notable for a lack of high-quality clinical evidence. Here, we offer guidelines for neurological care (neurological monitoring and management) of adults during and after ECMO support. METHODS: These guidelines are based on clinical practice consensus recommendations and scientific statements. We convened an international multidisciplinary consensus panel including 30 clinician-scientists with expertise in ECMO from all chapters of the Extracorporeal Life Support Organization (ELSO). We used a modified Delphi process with three rounds of voting and asked panelists to assess the recommendation levels. RESULTS: We identified five key clinical areas needing guidance: (1) neurological monitoring, (2) post-cannulation early physiological targets and ABI, (3) neurological therapy including medical and surgical intervention, (4) neurological prognostication, and (5) neurological follow-up and outcomes. The consensus produced 30 statements and recommendations regarding key clinical areas. We identified several knowledge gaps to shape future research efforts. CONCLUSIONS: The impact of ABI on morbidity and mortality in ECMO patients is significant. Particularly, early detection and timely intervention are crucial for improving outcomes. These consensus recommendations and scientific statements serve to guide the neurological monitoring and prevention of ABI, and management strategy of ECMO-associated ABI.

Application of Comprehensive Genomic Profiling-Based Next-Generation Sequencing Assay to Improve Cancer Care in a Developing Country.

PURPOSE: Identifying actionable oncogenic mutations have changed the therapeutic landscape in different types of tumors. This study investigated the utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) assay, in clinical practice in a developing country. METHODS: In this retrospective cohort study, CGP was performed on clinical samples from patients with different solid tumors recruited between December 2016 and November 2020, using hybrid capture-based genomic profiling, at the individual treating physicians' request in the clinical care for therapy decisions. Kaplan-Meier survival curves were estimated to characterize the time-to-event variables. RESULTS: Patients median age was 61 years (range: 14-87 years), and 64.7% were female. The most common histological diagnosis was lung primary tumors, with 90 patients corresponding to 52.9% of the samples (95% CI 45.4-60.4%). Actionable mutations with FDA-approved medications for specific alterations correspondent to tumoral histology were identified in 58 cases (46.4%), whereas other alterations were detected in 47 different samples (37.6%). The median overall survival was 15.5 months (95% CI 11.7 months-NR). Patients who were subjected to genomic evaluation at diagnosis reached a median overall survival of 18.3 months (95% CI 14.9 months-NR) compared to 14.1 months (95% CI 11.1 months-NR) in patients who obtained genomic evaluation after tumor progression and during standard treatment (P = .7). CONCLUSION: CGP of different types of tumors identifies clinically relevant genomic alterations that have benefited from targeted therapy and improve cancer care in a developing country to guide personalized treatment to beneficial outcomes of cancer patients.

Cost-utility analysis of genomic profiling in early breast cancer in Colombia.

BACKGROUND: In Colombia, the best strategy to establish indication for adjuvant chemotherapy in early breast cancer (EBC) remains unknown. This study aimed to identify the cost-utility of Oncotype DX™ (ODX) or Mammaprint™ (MMP) tests to establish the necessity of adjuvant chemotherapy. METHODS: This study used an adapted decision-analytic model to compare cost and outcomes of care between ODX or MMP tests and routine care without ODX or MMP tests (adjuvant chemotherapy for all patients) over a 5-year time horizon from the perspective of the Colombian National Health System (NHS; payer). Inputs were obtained from national unit cost tariffs, published literature, and clinical trial database. The study population comprised women with hormone-receptor-positive (HR +), HER2-negative, lymph-node-negative (LN0) EBC with high-risk clinical criteria for recurrence. The outcome measures were discounted incremental cost-utility ratio (ICUR; 2021 United States dollar per quality-adjusted life-year [QALY] gained) and net monetary benefit (NMB). Probabilistic (PSA) and deterministic sensitivity analysis (DSA) were performed. RESULTS: ODX increases QALYs by 0.05 and MMP by 0.03 with savings of $2374 and $554 compared with the standard strategy, respectively, and were cost-saving in cost-utility plane. NMB for ODX was $2203 and for MMP was $416. Both tests dominate the standard strategy. Sensitivity analysis revealed that with a threshold of 1 gross domestic product per capita, ODX will be cost-effective in 95.5% of the cases compared with 70.2% cases involving MMP.DSA showed that the variable with significant influence was the monthly cost of adjuvant chemotherapy. PSA revealed that ODX was a consistently superior strategy. CONCLUSIONS: Genomic profiling using ODX or MMP tests to define the need of adjuvant chemotherapy treatment in patients with HR + and HER2 -EBC is a cost-effective strategy that allows Colombian NHS to maintain budget.

Maternal-Fetal Results of COVID-19-Infected Pregnant Women Treated with Extracorporeal Membrane Oxygenation: A Descriptive Report.

OBJECTIVE: COVID-19 infection may produce severe pneumonia, mainly in the adult population. Pregnant women with severe pneumonia are at high risk of developing complications, and conventional therapy sometimes fails to reverse hypoxemia. Therefore, extracorporeal membrane oxygenation (ECMO) is an option in cases with refractory hypoxemic respiratory failure. This study aims to evaluate the maternal-fetal risk factors, clinical characteristics, complications, and outcomes of 11 pregnant or peripartum patients with COVID-19 treated with ECMO. STUDY DESIGN: This is a retrospective descriptive study of 11 pregnant women undergoing ECMO therapy during the COVID-19 pandemic. RESULTS: In our cohort, four patients underwent ECMO during pregnancy (36.3%) and 7 during the postpartum period. Initially, they started on venovenous ECMO, and three patients were required to change modality due to clinical conditions. In total, 4/11 pregnant women (36.3%) died. We established two periods that differed in the implementation of a standardized care model for reducing associated morbidities and mortality. Neurological complications were responsible for most deaths. Regarding fetal outcomes at early-stage pregnancies on ECMO (4), we report three stillbirths (75%), and one newborn (twin pregnancy) survived and had a favorable evolution. CONCLUSION: At later-stage pregnancies, all newborns survived, and we did not identify any vertical infection. ECMO therapy is an alternative for pregnant women with severe hypoxemic respiratory failure due to COVID-19, and may improve maternal and neonatal results. Regarding fetal outcomes, the gestational age played a definitive role. However, the main complications reported in our series and others are neurological. It is essential to develop novel, future interventions to prevent these complications.

Applications of Single-Molecule Vibrational Spectroscopic Techniques for the Structural Investigation of Amyloid Oligomers.

Amyloid oligomeric species, formed during misfolding processes, are believed to play a major role in neurodegenerative and metabolic diseases. Deepening the knowledge about the structure of amyloid intermediates and their aggregation pathways is essential in understanding the underlying mechanisms of misfolding and cytotoxicity. However, structural investigations are challenging due to the low abundance and heterogeneity of those metastable intermediate species. Single-molecule techniques have the potential to overcome these difficulties. This review aims to report some of the recent advances and applications of vibrational spectroscopic techniques for the structural analysis of amyloid oligomers, with special focus on single-molecule studies.

Time-Evolved SERS Signatures of DEP-Trapped Aß and Zn2+Aß Peptides Revealed by a Sub-10 nm Electrode Nanogap.

Alzheimer's disease (AD) has become highly relevant in aging societies, yet the fundamental molecular basis for AD is still poorly understood. New tools to study the undergoing structural conformation changes of amyloid beta (Aß) peptides, the pathogenic hallmark of AD, could play a crucial role in the understanding of the underlying mechanisms of misfolding and cytotoxicity of this peptide. It has been recently reported that Zn2+ interacts with Aß and changes its aggregation pathway away from less harmful fibrillar forms to more toxic species. Here, we present a versatile platform based on a set of sub-10 nm nanogap electrodes for the manipulation and sensing of biomolecules in the physiological condition at a low copy number, where molecules are trapped via dielectrophoresis (DEP) across the nanogap, which also serves as a surface-enhanced Raman spectroscopy hotspot. In this study, we demonstrate that our electrode nanogap platform can be used to study the structural difference between Aß40 and ZnAß40 peptides at different aggregation stages in the physiologically relevant concentration and in solution phase. The Raman spectroscopic signatures of the DEP-captured neuropeptides prove the device to be attractive as a label-free bioanalytical tool.

Cell-Free Circulating Tumor DNA Improves Standard Genotyping of Non-Small-Cell Lung Cancer and Increases Detection of Targetable Alterations in a Selected Hispanic Cohort.

BACKGROUND: Several studies have shown that the non-small-cell lung cancer (NSCLC) genomic background among Hispanics differs from other populations. The finding of low-frequency genomic alterations in cell-free DNA (cfDNA) can increase diagnostic accuracy and could improve treatment in NSCLC. METHODS: Data from 54 Hispanic patients with advanced NSCLC with high clinical suspicion for ALK, EGFR, and ROS1 mutations were collected (including young age, female sex, and non-smokers). cfDNA was extracted from plasma and analyzed using a commercial next-generation sequencing test (Guardant360) which detects genomic alterations in 74 genes. RESULTS: The median age was 56 years (range 31-83). Most patients were female (661.1%) and never smokers (72.3%). Among the patients included, 96% (52/54) had cfDNA detectable alterations with a mean number of 3.37 cfDNA alterations per test (range 1-10). cfDNA was able to detect some genomic alterations previously undetected by tissue biopsy. Among patients with insufficient or unavailable tissue to perform testing, mutations in EGFR and ALK which led to a change in therapy were determined using cfDNA in 28.8 and 3.8% of cases, respectively. Among patients with cfDNA alterations, 46.1% (n = 24) were switched to a targeted therapy with a median progression-free survival of 11.1 months (95% CI 7.6-14.6) and an overall survival of 40.3 months (95% CI 27.1-53.6). Concurrent genetic mutations with TP53 and KRAS negatively impacted the prognosis. CONCLUSIONS: In a selected population of NSCLC Hispanic patients, comprehensive cfDNA analysis allowed a treatment change in 46.1% of the cases. Guardant360 allows the identification of genomic alterations to improve treatment selection and increase prognosis.

Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation.

BACKGROUND: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer. METHODS: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy. RESULTS: There were ten males (66.7%), and the median patient's age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR. CONCLUSIONS: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Molecular Epidemiology of ALK Rearrangements in Advanced Lung Adenocarcinoma in Latin America.

OBJECTIVE: Latin American countries are heterogeneous in terms of lung cancer incidence and exposure to potential carcinogens. We evaluated the frequency and clinical characteristics of ALK rearrangements (ALKr) in Latin America. METHODS: A total of 5,130 lung cancer patients from 10 Latin American countries were screened for inclusion. ALKr detection was performed by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to assess method variability. Demographic and clinicopathologic characteristics were analyzed. RESULTS: Among the 5,130 patients screened, 8.4% (n = 433) had nonevaluable FISH tests. Evaluable FISH analyses revealed positive ALKr in 6.8% (320/4,697) of the study population, which included patients from 9 countries. ALKr distribution for each country was: Mexico 7.6% (79/1,034), Colombia 4.1% (10/242), Argentina 6.0% (153/2,534), Costa Rica 9.5% (13/137), Panama 4.4% (5/114), Uruguay 5.4% (2/37), Chile 8.6% (16/185), Venezuela 8.9% (13/146), and Peru 10.8% (29/268). RT-PCR showed high positive (83.6%) and negative (99.7%) predictive values when compared to the gold standard FISH. In contrast, IHC only showed a high negative predictive value (94.6%). CONCLUSIONS: Although there is a clear country and continental variability in terms of ALKr frequency, this difference is not significant and the overall incidence of ALKr in Latin America does not differ from the rest of the world.

Real-World Treatment Patterns, Survival, and Prediction of CNS Progression in ALK-Positive Non-Small-Cell Lung Cancer Patients Treated with First-Line Crizotinib in Latin America Oncology Practices.

OBJECTIVE: This study describes the real-world characteristics, treatment sequencing, and outcomes among Hispanic patients with locally advanced/metastatic ALK-positive non-small-cell lung cancer (NSCLC) treated with crizotinib. METHODS: A retrospective patient review was conducted for several centers in Latin America. Clinicians identified ALK-positive NSCLC patients who received crizotinib and reported their clinical characteristics, treatments, and survival. Overall survival and progression-free survival (PFS) were described. A Random Forest Tree (RFT) model was constructed to predict brain progression. RESULTS: A total of 73 patients were included; median age at diagnosis was 58 years, 60.3% were female, and 93.2% had adenocarcinoma. Eighty-nine percent of patients were never smokers/former smokers, 71.1% had ≥2 sites of metastasis, and 20.5% had brain metastases at diagnosis. The median PFS on first-line crizotinib was 7.07 months (95% CI 3.77-12.37) and the overall response rate was 52%. Of those who discontinued crizotinib, 55.9% progressed in the central nervous system (CNS). The RFT model reached a sensitivity of 100% and a specificity of 88% for prediction of CNS progression. CONCLUSIONS: The overall response rate and the PFS observed in Hispanic patients with ALK-positive NSCLC treated with first-line crizotinib were similar to those in previous reports. An RFT model is helpful in predicting CNS progression and can help clinicians tailor treatments in a resource-limited practice.

Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma.

Epilepsy is a common symptom in patients with glioblastoma (GB). 213 patients with GB from RedLANO follow-up registry were included. All patients underwent surgery, if feasible, followed by chemoradiation based on temozolomide (Stupp platform). Information was recorded regarding demographics, seizure timing, anti-epileptic drugs (AEDs), dosage, time to next seizure, total seizures in 6 months, and main side effects of AEDs. The relationship between epilepsy treatment and overall survival (OS) was evaluated. Mean age was 53 years old and 56.8% were male. Seventy-eight patients (37%) were treated with levetiracetam (LEV), 27% were given another AED and 36% did not require any AED. Choice of AED was not associated with age (p = 0.67), performance status (p = 0.24) or anatomic tumor site (p = 0.34). Seizures and AED requirement were greater in those having primary GB (p = 0.04). After starting an AED, the mean time until next crisis was 9.9 days (SD ± 6.3), which was shorter in those receiving LEV (p = 0.03); mean number of seizures during the first 3 and 6 months were 2.9 and 4, respectively. Most patients treated with LEV (n = 46) required less than two medication adjustments compared to those treated with other AEDs (p = 0.02). Likewise, less patients exposed to LEV required a coadjuvant drug (p = 0.04). Additionally, patients receiving LEV had significantly less adverse effects compared to patients treated with another AED. OS was significantly higher in the group treated with LEV compared to other AEDs (25.5 vs. 17.9 months; p = 0.047). Patients treated with LEV had better seizure control and longer OS compared to other AEDs.

Pristine but metal-rich Río Sucio (Dirty River) is dominated by Gallionella and other iron-sulfur oxidizing microbes.

Whether the extreme conditions of acidity and heavy metal pollution of streams and rivers originating in pyritic formations are caused primarily by mining activities or by natural activities of metal-oxidizing microbes living within the geological formations is a subject of considerable controversy. Most microbiological studies of such waters have so far focused on acid mine drainage sites, which are heavily human-impacted environments, so it has been problematic to eliminate the human factor in the question of the origin of the key metal compounds. We have studied the physico-chemistry and microbiology of the Río Sucio in the Braulio Carrillo National Park of Costa Rica, 22 km from its volcanic rock origin. Neither the remote origin, nor the length of the river to the sampling site, have experienced human activity and are thus pristine. The river water had a characteristic brownish-yellow color due to high iron-dominated minerals, was slightly acidic, and rich in chemolithoautotrophic iron- and sulfur-oxidizing bacteria, dominated by Gallionella spp. Río Sucio is thus a natural acid-rock drainage system whose metal-containing components are derived primarily from microbial activities.

Low-copy number protein detection by electrode nanogap-enabled dielectrophoretic trapping for surface-enhanced Raman spectroscopy and electronic measurements.

We report a versatile analysis platform, based on a set of nanogap electrodes, for the manipulation and sensing of biomolecules, as demonstrated here for low-copy number protein detection. An array of Ti nanogap electrode with sub-10 nm gap size function as templates for alternating current dielectrophoresis-based molecular trapping, hot spots for surface-enhanced Raman spectroscopy as well as electronic measurements, and fluorescence imaging. During molecular trapping, recorded Raman spectra, conductance measurements across the nanogaps, and fluorescence imaging show unambiguously the presence and characteristics of the trapped proteins. Our platform opens up a simple way for multifunctional low-concentration heterogeneous sample analysis without the need for target preconcentration.

Genomic ancestry and cancer among Latin Americans.

Latin American populations, characterized by intricate admixture patterns resulting from the intermingling of ancestries from European, Native American (NA) Asian, and African ancestries which result in a vast and complex genetic landscape, harboring unique combinations of novel variants. This genetic diversity not only poses challenges in traditional population genetics methods but also opens avenues for a deeper understanding of its implications in health. In cancer, the interplay between genetic ancestry, lifestyle factors, and healthcare disparities adds a layer of complexity to the varying incidence and mortality rates observed across different Latin American subpopulations. This complex interdependence has been unveiled through numerous studies, whether conducted on Latin American patients residing on the continent or abroad, revealing discernible differences in germline composition that influence divergent disease phenotypes such as higher incidence of Luminal B and Her2 breast tumors, EGFR and KRAS mutated lung adenocarcinomas in addition to an enrichment in BRCA1/2 pathogenic variants and a higher than expected prevalence of variants in colorectal cancer associated genes such as APC and MLH1. In prostate cancer novel risk variants have also been solely identified in Latin American populations. Due to the complexity of genetic divergence, inputs from each individual ancestry seem to carry independent contributions that interplay in the development of these complex disease phenotypes. By understanding these unique population characteristics, genomic ancestries hold a promising avenue for tailoring prognostic assessments and optimizing responses to oncological interventions.

Molecular Tumor Board Improves Outcomes for Hispanic Patients With Advanced Solid Tumors.

PURPOSE: Multidisciplinary molecular tumor boards (MTBs) decode complex genomic data into clinical recommendations. Although MTBs are well-established in the oncology practice in developed countries, this strategy needs to be better explored in developing countries. Herein, we describe the possible benefits and limitations of the first MTB established in Colombia. METHODS: Demographic, clinical, and genomic information was collected between August 2020 and November 2021. By mid-2020, an MTB strategy was created to discuss clinical cases with one or more genomic alterations identified by next-generation sequencing using an open-access virtual platform. We characterized the patient population as benefiting from the recommended treatment option. We assessed the benefits and access to available targeted therapies that have the potential to change clinical management by making recommendations to treating oncologists on the basis of genomic profiling. However, we did not assess the treatment oncologists' compliance with MTB recommendations because they were not intended to replace clinical judgment/standard of care. RESULTS: A total of 146 patients were included in the discussions of the MTB. The median age was 59 years, and 59.6% were women. Genomic results prompting a change in therapeutic decisions were obtained in 53.1% of patients (95% CI, 44.9 to 61.3). The most prevalent malignancy was non-small-cell lung cancer (51%). Other malignancies represented 60%, 50%, and 30% of patients with soft-tissue sarcomas, brain tumors, and breast cancer, respectively. CONCLUSION: Using an open-access virtual platform, MTBs were feasible in low- and middle-income countries on the basis of the capability to provide the benefits and access to available targeted therapies that are not standard of care. Furthermore, MTB recommendations were made available to the treating oncologist in different locations across Colombia, providing the option to modify clinical management in most of these patients.

Venopulmonary Artery Extracorporeal Life Support (VPa ECMO): A Novel Strategy for Refractory Hypoxemia Complicating VV ECMO.

Refractory hypoxemia (RH) during venovenous extracorporeal membrane oxygenation (VV ECMO) support is a complex problem that limits the benefit of this therapy. The need for sustained deep sedation and delays in active rehabilitation are considered as a direct consequence of RH. Changing from VV ECMO to a configuration that returns the flow to pulmonary artery, such as venopulmonary extracorporeal membrane oxygenation (VPa ECMO) may decrease recirculation and improve systemic oxygen delivery. We present a retrospective report that describes the impact of VPa ECMO on oxygenation during sedation withdrawal in 41 patients who received VV ECMO for coronavirus disease 2019 (COVID-19). We evidenced that arterial oxygen pressure (PaO 2 ) increased from 68 to 112.3 mm Hg ( p = 0.001) with a reduction of ECMO flow (5.7-4.8 L/m; p = 0.001). Other findings included lower rates of depth sedation (Richmond Agitation Sedation Scale [RASS] ≤3, 37-63%; p = 0.007) and lower requirement inotropic support assessed by LVIS score (4.7-1.1; p = 0.005). Discharge survival was 54% with a sustained benefit until day 79. This cannulation strategy improved effectively PaO 2 in this cohort, it may be an alternative in patients with RH in VV ECMO.

Microfluidic Blood Separation: Key Technologies and Critical Figures of Merit.

Blood is a complex sample comprised mostly of plasma, red blood cells (RBCs), and other cells whose concentrations correlate to physiological or pathological health conditions. There are also many blood-circulating biomarkers, such as circulating tumor cells (CTCs) and various pathogens, that can be used as measurands to diagnose certain diseases. Microfluidic devices are attractive analytical tools for separating blood components in point-of-care (POC) applications. These platforms have the potential advantage of, among other features, being compact and portable. These features can eventually be exploited in clinics and rapid tests performed in households and low-income scenarios. Microfluidic systems have the added benefit of only needing small volumes of blood drawn from patients (from nanoliters to milliliters) while integrating (within the devices) the steps required before detecting analytes. Hence, these systems will reduce the associated costs of purifying blood components of interest (e.g., specific groups of cells or blood biomarkers) for studying and quantifying collected blood fractions. The microfluidic blood separation field has grown since the 2000s, and important advances have been reported in the last few years. Nonetheless, real POC microfluidic blood separation platforms are still elusive. A widespread consensus on what key figures of merit should be reported to assess the quality and yield of these platforms has not been achieved. Knowing what parameters should be reported for microfluidic blood separations will help achieve that consensus and establish a clear road map to promote further commercialization of these devices and attain real POC applications. This review provides an overview of the separation techniques currently used to separate blood components for higher throughput separations (number of cells or particles per minute). We present a summary of the critical parameters that should be considered when designing such devices and the figures of merit that should be explicitly reported when presenting a device's separation capabilities. Ultimately, reporting the relevant figures of merit will benefit this growing community and help pave the road toward commercialization of these microfluidic systems.

DICER1-associated central nervous system sarcoma: A comprehensive clinical and genomic characterization of case series of young adult patients.

Background: DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described "primary DICER1-associated CNS sarcoma" (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy. Methods: We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed. Results: Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months. Conclusions: DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.

Genomic Landscape of Primary Resistance to Osimertinib Among Hispanic Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC): Results of an Observational Longitudinal Cohort Study.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations (EGFRm) represent one of the most common genomic alterations identified among patients with non-small cell lung cancer (NSCLC). Several targeted agents for patients with EGFRm have been proven safe and effective, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib. Nonetheless, some patients will present with or develop EGFR-TKI resistance mechanisms. OBJECTIVE: We characterized the genomic landscape of primary resistance to osimertinib among Hispanic patients with EGFR-mutant NSCLC. METHODS: An observational longitudinal cohort study was conducted with two groups of patients, those with intrinsic resistance (cohort A) and those with long-term survival (cohort B). All patients were treated and followed between January 2018 and May 2022. All patients were assessed for Programmed Cell Death Ligand 1 (PD-L1) expression and Bcl-2-like protein 11 (BIM)/AXL mRNA expression before starting TKI. After 8 weeks of treatment, a liquid biopsy was performed to determine the presence of circulating free DNA (cfDNA), and next-generation sequencing (NGS) was used to identify mutations at the time of progression. In both cohorts, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: We found a homogeneous distribution of EGFR-sensitizing mutations in both cohorts. For cohort A, exon 21 mutations were more common than exon 19 deletions (ex19dels) for cohort B (P = 0.0001). The reported ORR for osimertinib was 6.3% and 100% for cohorts A and B, respectively (P = 0.0001). PFS was significantly higher in cohort B (27.4 months vs. 3.1 months; P = 0.0001) and ex19del patients versus L858R (24.5 months, 95% confidence interval [CI] 18.2-NR), vs. 7.6 months, 95% CI 4.8-21.1; P = 0.001). OS was considerably lower for cohort A (20.1 months vs. 36.0 months; P = 0.0001) and was better for patients with ex19del, no brain metastasis, and low tumor mutation burden. At the time of progression, more mutations were found in cohort A, identifying off-target alterations more frequently, including TP53, RAS, and RB1. CONCLUSION: EGFR-independent alterations are common among patients with primary resistance to osimertinib and significantly impact PFS and OS. Our results suggest that among Hispanic patients, other variables associated with intrinsic resistance include the number of commutations, high levels AXL mRNA, and low levels of BIM mRNA, T790M de novo, EGFR p.L858R presence, and a high tumoral mutational burden.

KRAS and MET in non-small-cell lung cancer: two of the new kids on the 'drivers' block.

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced to identify various critical oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalized treatment based on the tumor's molecular genomics. This review presents a comprehensive review of the biology, new therapeutic interventions, and resistance patterns of two well-defined subgroups, tumors with KRAS and MET alterations. We also discuss the status of molecular testing practices for these two key oncogenic drivers, considering the progressive introduction of next-generation sequencing (NGS) and RNA sequencing in regular clinical practice.