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"Klein, A."
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Cancer progression and the invisible phase of metastatic colonization
Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.Metastatic dissemination can occur early during cancer progression, yet clinically overt metastases are often not detected for many years after surgical removal of the primary tumour. In this Perspective, Klein argues that understanding the ‘invisible’ phase of metastatic colonization is necessary to explain this phenomenon and develop better therapies to prevent metastasis.
Journal Article
Selection and adaptation during metastatic cancer progression
Cancer is often regarded as a process of asexual evolution driven by genomic and genetic instability. Mutation, selection and adaptation are by convention thought to occur primarily within, and to a lesser degree outside, the primary tumour. However, disseminated cancer cells that remain after 'curative' surgery exhibit extreme genomic heterogeneity before the manifestation of metastasis. This heterogeneity is later reduced by selected clonal expansion, suggesting that the disseminated cells had yet to acquire key traits of fully malignant cells. Abrogation of the cells' progression outside the primary tumour implies new challenges and opportunities for diagnosis and adjuvant therapies.
Journal Article
Tumor Cell Invasion in Glioblastoma
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.
Journal Article
High-flow nasal oxygen vs. standard oxygen therapy for patients undergoing transcatheter aortic valve replacement with conscious sedation: a randomised controlled trial
Background
Minimally invasive surgery is becoming more common and transfemoral transcatheter aortic valve replacement is offered to older patients with multiple comorbidities. Sternotomy is not required but patients must lie flat and still for up to 2–3 h. This procedure is increasingly being performed under conscious sedation with supplementary oxygen, but hypoxia and agitation are commonly observed.
Methods
In this randomised controlled trial, we hypothesised that high-flow nasal oxygen would provide superior oxygenation as compared with our standard practice, 2 l min
−1
oxygen by dry nasal specs. This was administered using the Optiflow THRIVE Nasal High Flow delivery system (Fisher and Paykel, Auckland, New Zealand) at a flow rate of 50 l min
−1
and FiO
2
0.3. The primary endpoint was the change in arterial partial pressure of oxygen (pO
2
) during the procedure. Secondary outcomes included the incidence of oxygen desaturation, airway interventions, the number of times the patient reached for the oxygen delivery device, incidence of cerebral desaturation, peri-operative oxygen therapy duration, hospital length of stay and patient satisfaction scores.
Results
A total of 72 patients were recruited. There was no difference in change in pO
2
from baseline using high-flow compared with standard oxygen therapy: median [IQR] increase from 12.10 (10.05–15.22 [7.2–29.8]) to 13.69 (10.85–18.38 [8.5–32.3]) kPa vs. decrease from 15.45 (12.17–19.33 [9.2–22.8]) to 14.20 (11.80–19.40 [9.7–35.1]) kPa, respectively. The percentage change in pO2 after 30 min was also not significantly different between the two groups (
p
= 0.171). There was a lower incidence of oxygen desaturation in the high-flow group (
p
= 0.027). Patients in the high-flow group assigned a significantly higher comfort score to their treatment (
p
≤ 0.001).
Conclusion
This study has demonstrated that high flow, compared with standard oxygen therapy, does not improve arterial oxygenation over the course of the procedure. There are suggestions that it may improve the secondary outcomes studied.
Trial registration
International Standard Randomised Controlled Trial Number (ISRCTN) 13,804,861. Registered on 15 April 2019.
https://doi.org/10.1186/ISRCTN13804861
Journal Article
Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study
Multicancer early detection (MCED) blood tests can detect a cancer signal from circulating cell-free DNA (cfDNA). PATHFINDER was a prospective cohort study investigating the feasibility of MCED testing for cancer screening.
In this prospective cohort study done in oncology and primary care outpatient clinics at seven US health networks, a convenience sample of adults aged 50 years or older without signs or symptoms of cancer consented to MCED testing. We collected blood, analysed cfDNA, and returned results to participants’ doctors. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was time to, and extent of, diagnostic testing required to confirm the presence or absence of cancer. This trial is registered at ClinicalTrials.gov, NCT04241796, and is completed.
Between Dec 12, 2019, and Dec 4, 2020, we recruited 6662 participants. 4204 (63·5%) of 6621 participants with analysable results were women, 2417 (36·5%) were men, and 6071 (91·7%) were White. A cancer signal was detected in 92 (1·4%) of 6621 participants with analysable results. 35 (38%) participants were diagnosed with cancer (true positives) and 57 (62%) had no cancer diagnosis (false positives). Excluding two participants whose diagnostic assessments began before MCED test results were reported, median time to diagnostic resolution was 79 days (IQR 37–219): 57 days (33–143) in true-positive and 162 days (44–248) in false-positive participants. Most participants had both laboratory tests (26 [79%] of 33 with true-positive results and 50 [88%] of 57 with false-positive results) and imaging (30 [91%] of 33 with true-positive results and 53 [93%] of 57 with false-positive results). Fewer procedures were done in participants with false-positive results (17 [30%] of 57) than true-positive results (27 [82%] of 33) and few had surgery (one with a false-positive result and three with a true-positive result).
This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility.
GRAIL.
Journal Article