5728 research outputs found
Sort by
Space Oncology: A Comprehensive Scoping Review.
No full textSpace exploration exposes astronauts to unique conditions such as microgravity and space radiation, potentially influencing gene expression and triggering carcinogenesis. Paradoxically, these extreme environments could uncover other pro-treatment aspects of cancer biology. Despite numerous reviews addressing these aspects in isolation, a comprehensive synthesis of the effects of space stressors on cancer development is incomplete. This scoping review aims to provide a holistic perspective on the influence of spaceflight and associated stressors-including gravitation (hyper- and microgravity), radiation, and vibration-on the potential for cancer development and altered cellular mechanisms. We adhered to the PRISMA-ScR checklist for our review. A multitiered search strategy was employed in English, starting with a preliminary keyword identification in Google Scholar and PubMed. Subsequently, the main search was conducted across five databases-Cochrane, Embase, PubMed, Scopus, and Web of Science-until 22 February 2024. All included studies were thoroughly assessed by two independent reviewers. Of the 15,553 identified articles, 158 were deemed eligible. The majority (92%) were experimental studies, predominantly cell-based (74.17%). Breast (15.19%), thyroid (13.92%), and hematopoietic (11.40%) cancers were the most frequently examined. Spaceflight stressors could affect different biological systems variably, with microgravity impacting spatial growth and metastasis, and cosmic radiation exerting both tumor-suppressive and mutagenic effects. Our findings highlight the need for large-scale, prolonged analog studies mimicking space conditions to enhance mission safety and shed light on the nuanced effects of space stressors on cancer. Additionally, further extensive studies need to be performed in the true weightlessness of spaceflight, both animal-based and on human tissue (cell cultures and potentially whole perfusion organ models), in addition to crew pre/intra/post-flight long-duration evaluations. Furthermore, this unique research avenue may reveal cancer cell sensitivities to these stressors, opening new pathways for innovative therapeutic strategies in cancer treatment
Real-world data on immune checkpoint inhibitors in advanced sarcomas across multiple European institutions.
No full textBACKGROUND: Following the success of immune checkpoint inhibitors (ICI) in other cancer types, their role is being evaluated in sarcomas. They have been assessed as monotherapy, or in combination with other ICI, chemotherapeutic drugs and tyrosine kinase inhibitors (TKI) in several clinical trials. So far the results have been limited to non-selected sarcoma populations. Further work is required to select patients who will benefit from immunotherapy. PATIENTS AND METHODS: We conducted a pooled retrospective analysis of the use of ICI in patients with advanced sarcomas in multiple European institutions. ICI-based treatments included ICI monotherapy (n = 43, 59.7%), double ICI (n = 5, 6.9%), ICI plus TKI (n = 21, 29.2%) and ICI plus chemotherapy (n = 3, 4.2%). RESULTS: Seventy-two patients from 10 European institutions, with metastatic (87.5%) or locally advanced (12.5%) disease were included. The most common subtype was undifferentiated pleomorphic sarcoma (16.7%), followed by leiomyosarcoma (12%), liposarcoma (10%) and angiosarcoma (9.7%). The median number of prior lines of systemic therapy was 2 (0-8). The objective response rate was 34.4% and was higher in combination regimens versus ICI monotherapy. With a median follow-up of 20.7 months, median progression-free survival (PFS) was 4.6 and median overall survival (OS) 18.8 months. Line of therapy (1st/2nd vs. ≥ 3rd line) and best response to ICI was significantly associated with PFS and OS. Histological subtype was significantly associated with OS. Toxicity was in general manageable; only six (8.3%) patients discontinued therapy for AE. INTERPRETATION: Our study provided additional real-world data on the outcome of ICI in patients with advanced sarcomas
Inherited chromosomally integrated human herpesvirus 6: regional variation in prevalence, association with angina, and identification of ancestral viral lineages in two large UK studies.
No full textTens of millions of people worldwide have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), yet we know little about the consequences. iciHHV-6-positive individuals inherit the genome of HHV-6A or HHV-6B in the germline, and viral genomes are therefore present in every nucleated cell. To investigate the epidemiology of iciHHV-6 in the UK, almost 32,000 individuals were screened from two volunteer research studies: the family-based Generation Scotland: Scottish Family Health Study (GS:SFHS) and the Breakthrough Generations Study (BGS). iciHHV-6 prevalence in GS:SFHS was, to our knowledge, higher than that in other large studies at 2.74% (647/23,637), with an iciHHV-6B prevalence of 2.55%. Scottish participants were more likely to be iciHHV-6B-positive than English (P < 0.001), and the BGS results suggested a north-south gradient of iciHHV-6B prevalence in mainland Britain. Disease association analysis confirmed the previously reported association with angina, with an odds ratio of 1.91 (95% confidence interval, 1.29, 2.82) following adjustment for known risk factors, providing compelling evidence that iciHHV-6 contributes to the risk of a common symptom. De novo integrations were not detected within GS:SFHS pedigrees; rather, our findings indicated that three viral lineages accounted for over 95% of iciHHV-6A-positive samples, and six viral lineages accounted for 90% of iciHHV-6B-positive samples in GS:SFHS. This study demonstrates that iciHHV-6 is common in the UK, shows significant regional heterogeneity in prevalence, is not entirely harmless, and is largely derived from a relatively small number of ancestral viral lineages.IMPORTANCEHuman herpesvirus 6 (HHV-6) has the unusual ability to integrate into the host chromosome telomeres. Most of the world's population is infected by HHV-6 in early childhood, but around 1% inherit the virus as a chromosomally integrated viral genome-referred to as inherited chromosomally integrated HHV-6 (iciHHV-6). Little is known about the consequences of iciHHV-6, which has the potential to cause disease through various mechanisms. Here, we have used large cohorts to study iciHHV-6 prevalence, lineages, and phenotypic associations. We replicate a previously reported association between iciHHV-6 and angina, suggesting that iciHHV-6 is not entirely benign. We show significant variation in iciHHV-6 prevalence within the UK with almost 3% of Scottish people carrying iciHHV-6. In the first detailed analysis of viral lineages at the population level, we show that 90% of iciHHV-6 is explained by nine ancestral viral lineages. These results have important implications for future disease association analyses
AI-driven software for automated quantification of skeletal metastases and treatment response evaluation using whole-body diffusion-weighted MRI (WB-DWI) in advanced prostate cancer.
No full textObjective. Quantitative assessment of treatment response in advanced prostate cancer (APC) with bone metastases remains an unmet clinical need. Whole-body diffusion-weighted MRI (WB-DWI) provides two response biomarkers: total diffusion volume (TDV) and global apparent diffusion coefficient (gADC). However, tracking post-treatment changes of TDV and gADC from manually delineated lesions is cumbersome and increases inter-reader variability. We developed a software to automate this process.Approach. Core technologies include: (i) a weakly-supervised Residual U-Net model generating a skeleton probability map to isolate bone; (ii) a statistical framework for WB-DWI intensity normalisation, obtaining a signal-normalisedb= 900 s mm-2(b900) image; and (iii) a shallow convolutional neural network that processes outputs from (i) and (ii) to generate a mask of suspected bone lesions, characterised by higher b900 signal intensity due to restricted water diffusion. This mask is applied to the gADC map to extract TDV and gADC statistics. We tested the tool using expert-defined metastatic bone disease delineations on 66 datasets, assessed repeatability of imaging biomarkers (N= 10), and compared software-based response assessment with aconstruct reference standard, defined as multidisciplinary consensus based on ⩾12 months of imaging, clinical, and laboratory follow-up (N= 118).Main results. Average dice score between manual and automated delineations was 0.6 for lesions within pelvis and spine, with an average surface distance of 2 mm. Relative differences for log-transformed TDV (log-TDV) and median gADC were 8.8% and 5%, respectively. Repeatability analysis showed coefficients of variation of 4.6% for log-TDV and 3.5% for median gADC, with intraclass correlation coefficients of 0.94 or higher. The software achieved 80.5% accuracy, 84.3% sensitivity, and 85.7% specificity in assessing response to treatment. Average computation time was 90 s per scan.Significance. Our software enables reproducible TDV and gADC quantification from WB-DWI scans for monitoring metastatic bone disease response, thus providing potentially useful measurements for clinical decision-making in APC patients
Long-Term Efficacy and Safety of Lifileucel Tumor-Infiltrating Lymphocyte Cell Therapy in Patients With Advanced Melanoma: A 5-Year Analysis of the C-144-01 Study.
No full textPatients with advanced melanoma resistant to immune checkpoint or BRAF/MEK inhibitors have treatment options with relatively low efficacy. Lifileucel, a one-time autologous tumor-infiltrating lymphocyte cell therapy, was approved in the United States on the basis of the pivotal C-144-01 study. A 5-year follow-up of the C-144-01 trial assessed the long-term efficacy and safety of lifileucel. At the cutoff date (November 20, 2024), the objective response rate was 31.4% (complete response [CR], 5.9%; partial response [PR], 25.5%). Overall, 79.3% of patients had tumor burden reduction; 16 had deepened responses with four converting from PR to CR > 1 year after lifileucel infusion; 31.3% of responders completed the 5-year assessment with ongoing responses. The median duration of response was 36.5 months. Responders (n = 48) had lower tumor burden and fewer liver or brain metastases than the overall population. The median overall survival (OS) was 13.9 months, with a 5-year OS of 19.7%. Adverse events were consistent with nonmyeloablative lymphodepletion and interleukin-2 safety profiles and declined rapidly within 2 weeks after lifileucel infusion. Most grade 3/4 cytopenias resolved to grade ≤2 by day 30. This 5-year analysis demonstrated long-term benefit and meaningful OS with one-time lifileucel therapy, with no additional long-term safety concerns
Adaptation of a small animal radiation research platform for pre-clinical microbeam irradiations.
No full textBACKGROUND: Microbeam radiotherapy (MRT) was introduced as a method to widen the therapeutic window compared to standard radiotherapy treatments. Studies have shown the normal tissue sparing effects of MRT, whilst maintaining the tumor control of standard broad beam radiotherapy. PURPOSE: To create and test a microbeam (MB) delivery system compatible with a small animal radiation research platform (SARRP, Xstrahl), which would allow the machine to be easily adapted to deliver MB irradiations without making any permanent changes to the system. METHODS: A MB collimator was designed, that fits in with the existing SARRP infrastructure and can easily be removed to revert the machine back to a normal broad beam delivery system. A translatable mousebed was developed to reduce the source-to-surface distance (SSD) for MB delivery, allowing the target position to be moved between imaging and treatment. Gafchromic film was used to test the accuracy of the positioning, and to determine the dose rates achievable in a solid water phantom. RESULTS: At 1 mm depth in solid water, a peak-to-valley dose ratio (PVDR) of 46 was achieved when the target was placed directly under the collimator, whilst a PVDR of 29 was reached when a 10.5 mm air gap was introduced between the collimator and target. Integral dose rates at 1 mm depth for these setups were 0.93 ± 0.04 and 0.94 ± 0.01 Gy/min, respectively. Conversion between broad beam and microbeam setup was found to take less than 5 min. CONCLUSIONS: Our adaptations enable any SARRP machine to be converted into a MB delivery system, with feasibility studies confirming MB delivery in a solid water phantom. The system is now routinely used to deliver MBs for in vivo studies
The CIP2A-TOPBP1 axis facilitates mitotic DNA repair via MiDAS and MMEJ.
No full textMitotic DNA double-strand breaks (DSBs) accumulate in response to replication stress or BRCA1/2 deficiency posing a significant threat to genome stability as repair by non-homologous end-joining (NHEJ) and homologous recombination (HR) is largely inactivated in mitosis. Instead, mitotic cells rely on alternative repair processes such as microhomology-mediated end-joining (MMEJ) and mitotic DNA synthesis (MiDAS). How these mitotic DNA repair pathways are functionally regulated remains unclear. Here we reveal that the CIP2A-TOPBP1 complex plays an essential regulatory role by facilitating the mitotic recruitment of both SMX complex components and Polθ to mitotic chromatin. Recruitment of the SMX complex components is driven by CDK1-dependent phosphorylation of SLX4 at Thr1260, enabling its interaction with TOPBP1 BRCT domains 1/2, thereby promoting MiDAS. Concurrently, CIP2A promotes efficient mitotic localisation of Polθ to facilitate MMEJ. The simultaneous functional disruption of both MiDAS and MMEJ pathways upon CIP2A loss provides rationale for the synthetic lethality observed in BRCA1 or 2-deficient cells. These findings position the CIP2A-TOPBP1 axis as a central regulatory hub for mitotic DNA repair, highlighting therapeutic opportunities in tumours characterised by HR deficiency or elevated replication stress
Quantitative Prostate MRI, From the AJR Special Series on Quantitative Imaging.
No full textProstate MRI has traditionally relied on qualitative interpretation. However, quantitative components hold the potential to markedly improve performance. The ADC from DWI is probably the most widely recognized quantitative MRI biomarker and has shown strong discriminatory value for clinically significant prostate cancer as well as for recurrent cancer after treatment. Advanced diffusion techniques, including intravoxel incoherent motion imaging, diffusion kurtosis imaging, diffusion-tensor imaging, and specific implementations such as restriction spectrum imaging, purport even better discrimination but are more technically challenging. The inherent T1 and T2 of tissue also provide diagnostic value, with more advanced techniques deriving luminal water fraction and hybrid multidimensional MRI metrics. Dynamic contrast-enhanced imaging, primarily using a modified Tofts model, also shows independent discriminatory value. Finally, quantitative lesion size and shape features can be combined with the aforementioned techniques and can be further refined using radiomics, texture analysis, and artificial intelligence. Which technique will ultimately find widespread clinical use will depend on validation across a myriad of platforms and use cases
Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models.
No full textBACKGROUND AND OBJECTIVE: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and over half of its high estimated heritability is unexplained. Our objective was to identify rare pathogenic germline variation driving TGCT susceptibility. METHODS: This study is a case-control meta-analysis of whole-exome sequencing data from three datasets (Institute of Cancer Research, The Cancer Genome Atlas, and UK Biobank). We retained unrelated male individuals of European ancestry comprising 1435 TGCT cases and 18 284 cancer-free controls. We performed gene-level association testing of protein-truncating variants and nonsynonymous disruptive variants across six candidate gene sets (733 genes) potentially biologically related to TGCT. We then analysed exome wide (19 355 genes) under dominant and recessive models, including X-linked genes. KEY FINDINGS AND LIMITATIONS: No individual gene-disease association was identified following multiple testing corrections. However, functional gene-set analyses identified an excess of associations with genes involved in microtubular/ciliary pathways (p = 1.69 × 10-8). Our study was well powered to detect rare variation of moderate/high effect sizes (odds ratio [OR] ≥5), but power diminished for modest effect sizes (OR <5). CONCLUSIONS AND CLINICAL IMPLICATIONS: Although this is the largest whole-exome analysis of TGCT to date and first exome-wide examination for recessively acting gene associations, larger studies are required to identify robust associations for individual genes. PATIENT SUMMARY: We investigated samples from 1435 men with testicular cancer and 18 284 men without cancer to compare the rate of disruptive mutations in 19 355 genes. No evidence of specific genes associated with testicular cancer was discovered, although one gene group showed a strong association. Larger studies are needed to identify individual genes associated with causing testicular cancer
