The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several ...cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.
Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression ...of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy.
Phase 1 dose-escalation trials are crucial to drug development by providing a framework to assess the toxicity of novel agents in a stepwise and monitored fashion. Despite widely adopted, rule-based ...dose-escalation methods (such as 3 + 3) are limited in finding the maximum tolerated dose (MTD) and tend to treat a significant number of patients at subtherapeutic doses. Newer methods of dose escalation, such as model-based and model-assisted designs, have emerged and are more accurate in finding MTD. However, these designs have not yet been broadly embraced by investigators. In this review, we summarise the advantages and disadvantages of contemporary dose-escalation methods, with emphasis on model-assisted designs, including time-to-event designs and hybrid methods involving optimal biological dose (OBD). The methods reviewed include mTPI, keyboard, BOIN, and their variations. In addition, the challenges of drug development (and dose-escalation) in the era of immunotherapeutics are discussed, where many of these agents typically have a wide therapeutic window. Fictional examples of how the dose-escalation method chosen can alter the outcomes of a phase 1 study are described, including the number of patients enrolled, the trial’s timeframe, and the dose level chosen as MTD. Finally, the recent trends in dose-escalation methods applied in phase 1 trials in the immunotherapeutics era are reviewed. Among 856 phase I trials from 2014 to 2019, a trend towards the increased use of model-based and model-assisted designs over time (OR = 1.24) was detected. However, only 8% of the studies used non-rule-based dose-escalation methods. Increasing familiarity with such dose-escalation methods will likely facilitate their uptake in clinical trials.
•Model-based/assisted methods have not been broadly adopted despite favourable features.•Model-assisted methods combine features of both model-based and rule-based designs.•Dose-escalation methods can affect the duration and sample size of phase I trials.•From 2014 to 2019, only 8% of phase I trials used non-ruled based methods.•IO agents should be risk stratified based on therapeutic range and toxicity potential.
Abstract
February 2020 was anomalously warm in the Antarctic Peninsula region and registered one of the most intense heatwaves ever recorded in Western Antarctica. The event featured unprecedented ...regional mean temperature anomalies (+4.5 °C) over the Antarctic Peninsula between 6 and 11 February 2020 and the highest local temperature of the continental Antarctic region. Taking flow analogs of the event from past (1950–1984) and recent (1985–2019) periods of the ERA5 reanalysis, here we quantify the role of recent climate change in the magnitude of this 6-day regional heatwave. Results show that 2020-like heatwaves over the Antarctic Peninsula are now at least ~0.4 °C warmer than in the past period, which represents a ~25% increase in magnitude. Given the observed atmospheric circulation conditions, the probability of experiencing 6-day regional mean anomalies above ~2 °C has increased ten times since 1950–1984. The aggravated severity of the event can be largely ascribed to long-term summer warming of the Antarctic Peninsula rather than recent atmospheric circulation trends.
The main objective of this research is to improve knowledge of the deglaciation stages in Sierra Nevada (southern Spain) by applying 36Cl cosmogenic exposure dating to 28 samples from moraine and ...fossil rock glacier boulders and glacial polished surfaces, in 5 glaciated valleys around Veleta Peak (3396 m asl; 37°03′02″N 3°20′54″W). The results show that shortly before the Last Glacial Maximum (LGM) and during the LGM, the heads of the glacial valleys were occupied by ice tongues, with possible glacial transfluence between the valleys. After 19 ka, a major glacial regression started, but glaciers during the Oldest Dryas (OD) expanded again and refilled the valley bottoms. The glacial advances of the pre-LGM, LGM and OD formed polygenic moraine systems. During the Bølling-Allerød the glaciers receded and probably disappeared. Thereafter, the valley bottoms remained ice-free. During the Younger Dryas (YD) small glaciers developed again, but only in cirques shaped on east-facing slopes. Subsequently, these glaciers started retreating towards their valley heads and finally disappeared completely. With the onset of the Holocene, rock glaciers developed inside the deglaciated cirques on the eastern slopes of some valleys, but only under the most active and protected headwalls did large complex rock glaciers develop and remained active until the mid-Holocene.
•Deglaciation stages in Sierra Nevada (southern Spain) by applying 36Cl cosmogenic exposure dating to 28 samples.•Shortly before the Last Glacial Maximum, the glacier occupied the valleys, with transfluences between them until 19 ka.•The glaciers expanded again during the Oldest Dryas and refilled the valleys by the last time.•During the Younger Dryas small glaciers developed only in cirques shaped on east-facing slopes.•With the onset of the Holocene, rock glaciers developed inside the deglaciated cirques on some valleys.
Tumor-Associated Microbiome: Where Do We Stand? Oliva, Marc; Mulet-Margalef, Nuria; Ochoa-De-Olza, Maria ...
International journal of molecular sciences,
02/2021, Letnik:
22, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of studies investigating ...associations of microbiome and cancer, from oncogenesis and cancer progression to resistance or sensitivity to specific anticancer therapies. The gut microbiome is now known to play a significant role in antitumor immune responses and in predicting the efficacy of immune-checkpoint inhibitors in cancer patients. Beyond the gut, the tumor-associated microbiome-microbe communities located either in the tumor or within its body compartment-seems to interact with the local microenvironment and the tumor immune contexture, ultimately impacting cancer progression and treatment outcome. However, pre-clinical research focusing on causality and mechanistic pathways as well as proof-of-concept studies are still needed to fully understand the potential clinical utility of microbiome in cancer patients. Moreover, there is a need for the standardization of methodology and the implementation of quality control across microbiome studies to allow for a better interpretation and greater comparability of the results reported between them. This review summarizes the accumulating evidence in the field and discusses the current and upcoming challenges of microbiome studies.
Abstract Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain ...unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
La dinámica geomorfológica glaciar y periglaciar modeló intensamente el relieve de las montañas de las sierras de Guadarrama y Gredos durante el Pleistoceno, dando lugar a los principales sistemas ...lagunares de alta montaña del sistema Central ibérico en España. Aunque estas lagunas comparten un origen glaciar común, presentan características morfogenéticas diferentes en función de la acción de los hielos y su edad de deglaciación. En este trabajo se realiza por primera vez una clasificación tipológica individualizada de la morfogénesis glaciar de las cubetas de los sistemas lacustres del sistema Central ibérico. Para la caracterización y definición de los tipos se han utilizado variables morfométricas de las cubetas lacustres y topográficas del entorno, datos geomorfológicos de trabajos previos de otros autores y clasificaciones tipológicas de lagos de origen glaciar establecidas en otros ámbitos con diferentes escalas geográficas. Sobre un conjunto de 26 lagunas, en su mayoría con superficies > 0,5 ha y profundidades máximas > 0,5 m, repartidas en la sierra de Guadarrama (macizo de Peñalara) y en la sierra de Gredos (macizo Central de Gredos, sierra del Barco y sierra de Béjar) se han definido 9 tipos morfogenéticos que representan la diversidad geomorfológica de su origen glaciar. Se han clasificado en dos grupos genéticos por su origen común: de hoya, generados por la acción directa de sobreexcavación de los hielos, y morrénicas, formados por el represamiento de las aguas producido por los materiales erosionados, transportados y depositados por los glaciares. El primero comprende 7 tipos: hoya-circo sensu estricto (s.s.), hoya-circo con morrena, hoya-valle s.s., hoya-valle en rosario, hoya-valle lateral, hoya-ombligo y hoya-fluvial. El segundo incluye 2 tipos: morrénica s.s. e intermorrénica. La ubicación en nichos colgados o circos en las cabeceras, zonas bajas, depresiones laterales o ejes fluviales de los valles, la presencia de umbrales y estrechamientos rocosos del terreno, las pendientes y orientaciones del entorno, o la existencia de cordones morrénicos únicos o múltiples, son algunas de las variables principales que diferencian los tipos establecidos. Algunas lagunas han perdido su condición natural al haber sido represadas para usos hidroeléctricos y de regadío, en especial, las de tipología genética de hoya-valle.
The caldera collapse of Deception Island Volcano, Antarctica, was comparable in scale to some of the largest eruptions on Earth over the last several millennia. Despite its magnitude and potential ...for far-reaching environmental effects, the age of this event has never been established, with estimates ranging from the late Pleistocene to 3370 years before present. Here we analyse nearby lake sediments in which we identify a singular event produced by Deception Island's caldera collapse that occurred 3980 ± 125 calibrated years before present. The erupted tephra record the distinct geochemical composition of ejecta from the caldera-forming eruption, whilst an extreme seismic episode is recorded by lake sediments immediately overlying the collapse tephra. The newly constrained caldera collapse is now the largest volcanic eruption confirmed in Antarctica during the Holocene. An examination of palaeorecords reveals evidence in marine and lacustrine sediments for contemporaneous seismicity around the Antarctic Peninsula; synchronous glaciochemical volcanic signatures also record the eruption in ice cores spread around Antarctica, reaching >4600 km from source. The widespread footprint suggests that this eruption would have had significant climatic and ecological effects across a vast area of the south polar region.
Tephrochronology uses recognizable volcanic ash layers (from airborne pyroclastic deposits, or tephras) in geological strata to set unique time references for paleoenvironmental events across wide ...geographic areas. This involves the detection of tephra layers which sometimes are not evident to the naked eye, including the so-called cryptotephras. Tests that are expensive, time-consuming, and/or destructive are often required. Destructive testing for tephra layers of cores from difficult regions, such as Antarctica, which are useful sources of other kinds of information beyond tephras, is always undesirable. Here we propose hyperspectral imaging of cores, Self-Organizing Map (SOM) clustering of the preprocessed spectral signatures, and spatial analysis of the classified images as a convenient, fast, non-destructive method for tephra detection. We test the method in five sediment cores from three Antarctic lakes, and show its potential for detection of tephras and cryptotephras.
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