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Surgical Lymph Node Staging in Extremity Rhabdomyosarcoma: The EpSSG RMS 2005 Trial Experience.
No full textBACKGROUND: The European pediatric soft tissue Sarcoma Study Group (EpSSG) RMS 2005 study recommends a lymph node biopsy for extremity rhabdomyosarcoma (RMS). The aim of our study was to analyze the results of the lymph node sampling strategies used, such as sentinel node biopsy (SNB) and nodal sampling (NS), and compare the outcome of patients undergoing different nodal staging techniques. METHODS: All non-metastatic (M0) patients registered in the EpSSG RMS 2005 study with an RMS of the extremity, presenting between 2005 and 2016, were included for analysis of the lymph node sampling techniques used. The secondary objective was to compare the results and outcome for the different sampling procedures. RESULTS: Of 198 patients, 144 had clinically/radiologically negative nodes (cN0), and 72/144 underwent a biopsy (26 SNB/46 NS). Final nodal status was upstaged to pN1 in 11/72 (15.3%) patients-6 after SNB and 5 after NS. In 54 radiologically malignant/suspicious-appearing nodes, 34 NS biopsies were performed, resulting in downstaging to N0 in 9/34 (26.5%) patients. 5-years overall survival (OS) of N0 patients versus N1 patients was 82.5% (95% confidence interval CI 74.7-88.0) versus 46.5% (95% CI 32.2-59.7). 5-years OS in N0 patients was not significantly different in biopsied and non-biopsied patients (p = 0.88). However, in N1 patients, survival was significantly better in biopsied compared with non-biopsied patients (p = 0.006). CONCLUSION: Lymph node staging plays a crucial role in determining appropriate treatment strategies. Pathology of sampled lymph nodes can upstage or downstage the lymph node status, guiding treatment decisions based on the stage
Two-year toxicity outcomes from PACE-C: Stereotactic Body Radiotherapy (SBRT) versus moderate hypofractionated radiotherapy (MHRT)
No full textContribution of Prediagnostic Host Factors to Shaping the Stromal Microenvironment of Breast Cancer among Sub-Saharan African Women.
No full textBACKGROUND: The stromal microenvironment (SME) is integral to breast cancer biology, impacting metastatic proclivity and treatment response. Emerging data indicate that host factors may impact the SME, but the relationship between prediagnostic host factors and SME phenotype remains poorly characterized, particularly among women of African ancestry. METHODS: We conducted a case-only analysis involving 792 patients with breast cancer (17-84 years) from the Ghana Breast Health Study. High-accuracy machine-learning algorithms were applied to standard H&E-stained images to characterize SME phenotypes [including percent tumor-associated connective tissue stroma, Ta-CTS (%); tumor-associated stromal cellular density, Ta-SCD (%)]. Associations between prediagnostic host factors and SME phenotypes were assessed in multivariable linear regression models. RESULTS: Decreasing Ta-CTS and increasing Ta-SCD were associated with aggressive, mostly high-grade tumors (P-value < 0.001). Several prediagnostic host factors were associated with Ta-SCD independently of tumor characteristics. Compared with nulliparous women, parous women had higher levels of Ta-SCD [mean (standard deviation, SD) = 31.3% (7.6%) vs. 28.9% (7.1%); P-value = 0.01]. Similarly, women with a positive family history of breast cancer had higher levels of Ta-SCD than those without family history [mean (SD) = 33.0% (7.5%)] vs. 30.9% (7.6%); P-value = 0.03]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (SD) = 31.6% (7.4%), 31.4% (7.3%), and 30.1% (8.0%) for slight, average, and large body sizes, respectively; P-value = 0.005]. CONCLUSIONS: Epidemiological risk factors were associated with varying degrees of stromal cellularity in tumors, independently of clinicopathological characteristics. IMPACT: The findings raise the possibility that epidemiological risk factors may partly influence tumor biology via the stromal microenvironment. See related In the Spotlight, p. 459
Unraveling complexity and leveraging opportunities in uncommon breast cancer subtypes.
No full textSpecial histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases. Uncommon BC presentations like male, inflammatory and pregnancy-related BC pose challenges. Emerging therapeutic strategies targeting genetic alterations or immune microenvironment are being explored
Whole Slide Image Classification Using Deep Learning.
No full textThe digital transformation of histopathological assessment through Whole Slide Imaging (WSI) has
sparked a revolution in digital pathology, primarily propelled by advancements in artificial
intelligence (AI) and deep learning (DL). This thesis seeks to the contribute to this ongoing
technological evolution by developing, and evaluating methods that broaden the current capabilities
of pathological diagnostics. Specifically, we focus on WSI classification tasks, using solely the
visual information present in the histology images, without incorporating any other data
modalities.
However, WSI classification models struggle to generalise on new, unseen data due to the limited
availability of diverse and standardized histopathology datasets. In the first part of our thesis,
we introduce a new a diverse soft tissue sarcoma (STS) dataset. The STS dataset comprises 1163 WSIs
from 303 patients collected from the Royal Marsden Hospital (RMH). This dataset, spanning over 12
subtypes, is intended to be publicly accessible, fostering further studies in the field of WSI
analysis and contributing to the development of models with enhanced generalizability.
A recent trend emerging in WSI classification is adopting graph-based approaches, where every tile
within a WSI represents the central node of a graph and its spatially closest neighbouring tiles
constitute the surrounding nodes. Many WSI approaches commonly use a fixed number of neighbours for
constructing the graphs. In the second part of our thesis, we explore whether the contextual
information provided by neighbouring tiles enhances or hinders the network's performance in
identifying patterns and features relevant to the performance of the WSI classification models.
Through systematic variations in the content and arrangement of neighbouring tiles, we explore this
aspect using two histopathology datasets.
In the third part of our thesis, we present Context-aware Multiple Instance Learning. (CAMIL)
addresses the complex challenges of intra- and intertumoral heterogeneity by leveraging
dependencies among tiles within WSIs. Our findings, validated on two widely used histopathology
datasets, namely camelyon16 and TCGA- NLSC, demonstrate substantial enhancements in classification
performance.
In the fourth part our thesis, we introduce an instance-based loss inspired by semi-supervised
anomaly detection (AD). Leveraging the available slide-level labels, the AD-loss plays a crucial
role in discerning between normal and anomalous tiles in WSIs. When dealing with normal slides, the
AD-loss exerts a pull effect, drawing feature representations towards a predefined central point.
Conversely, for disease-positive bags that are primarily composed of negative tiles occasionally
interspersed with positive ones, the AD-loss initiates a push-pull effect. Results on two
histopathology datasets showcase our model's ability to boost classification performance by
minimising false negatives
Proteogenomic discovery of RB1-defective phenocopy in cancer predicts disease outcome, response to treatment, and therapeutic targets.
No full textGenomic defects caused by truncating mutations or deletions in the Retinoblastoma tumor suppressor gene (RB1) are frequently observed in many cancer types leading to dysregulation of the RB pathway. Here, we propose an integrative proteogenomic approach that predicts cancers with dysregulation in the RB pathway. A subset of these cancers, which we term as "RBness," lack RB1 genomic defects and yet phenocopy the transcriptional profile of RB1-defective cancers. We report RBness as a pan-cancer phenomenon, associated with patient outcome and chemotherapy response in multiple cancer types, and predictive of CDK4/6 inhibitor response in estrogen-positive breast cancer. Using RNA interference and a CRISPR-Cas9 screen in isogenic models, we find that RBness cancers also phenocopy synthetic lethal vulnerabilities of cells with RB1 genomic defects. In summary, our findings suggest that dysregulation of the RB pathway in cancers lacking RB1 genomic defects provides a molecular rationale for how these cancers could be treated
Functional characterisation and target discovery in DNA damage response-altered endometrial cancer
No full textDNA damage response (DDR) genes are frequently altered in cancer, which can lead to protein loss-of-function (LoF) and DDR defects that can be therapeutically targeted using synthetic lethality (SL). Endometrial cancer (EC), a gynaecologic malignancy with rising incidence and mortality and an urgent need for novel treatment options, is characterised by a high prevalence of DDR alterations. Here, two complementary approaches were used for SL target-biomarker discovery in EC. The first hypothesis-driven approach focused on alterations in the ataxia-telangiectasia mutated (ATM) DDR kinase, which is frequently mutated in EC, but the functional impact of most variants is unknown. It was hypothesised that ATM mutations in EC were LoF drivers that could be targeted using DDR inhibitors (DDRis). However, functional characterisation of ATM mutations in EC cells revealed no clear correlation between mutation status, protein expression, pathway activation, and sensitivity to DDRis. Although reduced or partially aberrant ATM function was observed in some ATM-mutant EC cells, ATM mutations retained kinase function and no targetable ATM deficiency was identified. In the second approach, The Institute of Cancer Research-developed Target/Biomarker/Lineage (TBL) bioinformatic pipeline was refined and optimised to identify novel SL targets specific to DDR LoF alterations in EC. Downstream refinement of significant hits, following pipeline SL analysis based on Cancer Dependency Map datasets, identified four target-biomarker gene pairs for experimental validation. Initial experiments in EC cell lines with altered or wild-type biomarker status provided positive evidence for TYMS/MSH2 and CAD/TRRAP, but were inconclusive for MECOM/SLX4 and ASH1L/SLX4. Taken together, these studies show the power of informatics approaches in discovering novel SL interactions, highlight the complexity of SL target-biomarker discovery in EC, and provide a starting point for novel SL target drug discovery for treatment of DDR-altered EC patients
BRCA1/2 and Other Predisposition Genes in High-Risk Hormone Receptor+/Human Epidermal Growth Factor Receptor 2- Breast Cancer Treated With Endocrine Therapy With or Without Palbociclib: A Secondary PENELOPE-B Study Analysis.
No full textPURPOSE: The PENELOPE-B trial (ClinicalTrials.gov identifier: NCT01864746) recruited patients with hormone receptor+/human epidermal growth factor receptor 2- early breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at a high risk of relapse. Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET). PENELOPE-B did not show improved invasive disease-free survival (iDFS) after adding palbociclib to ET. This retrospective analysis investigated the impact of germline pathogenic variant (PV) status of BRCA1/2 and non-BRCA1/2 cancer predisposition genes on the outcomes of PENELOPE-B trial patients. METHODS: In total, 445 patients were sampled following a case-cohort design and 442 were analyzed for germline PVs. Statistical analyses were performed for time-to-event end points (iDFS, distant disease-free survival [DDFS], and overall survival [OS]). RESULTS: Of the 442 patients, 42 carried PVs in any cancer predisposition gene; 15 carried BRCA1/2 PVs. Irrespective of the treatment arms, PV status was not a prognostic factor. Regarding the treatment arms in BRCA1/2 PV carriers, numerically better 3-year outcomes were observed in the palbociclib arm (iDFS, 95%; DDFS, 95%; OS, 100%) than in the placebo arm (iDFS, 72.8%; DDFS, 72.8%; OS, 87.5%; hazard ratios palbociclib v placebo 0.349 [iDFS] and 0.562 [DDFS], not calculated for OS, too few events). In patients without BRCA1/2 PVs, the differences in 3-year outcomes were negligible. PVs in non-BRCA1/2 cancer predisposition genes did not influence the efficacy of palbociclib, although gene-specific effects could not be excluded. CONCLUSION: Patients with BRCA1/2 PVs had numerically better outcomes after palbociclib. However, the number of BRCA1/2 carriers was small. Larger randomized clinical trials should consider the PV status to further evaluate whether BRCA1/2 PV carriers benefit from cyclin-dependent kinase 4 and 6 inhibitor treatment
Digital innovation in healthcare: quantifying the impact of digital sepsis screening tools on patient outcomes-a multi-site natural experiment.
No full textINTRODUCTION: The National Health Service (NHS) 'move to digital' incorporating electronic patient record systems (EPR) facilitates the translation of paper-based screening tools into digital systems, including digital sepsis alerts. We evaluated the impact of sepsis screening tools on in-patient 30-day mortality across four multi-hospital NHS Trusts, each using a different algorithm for early detection of sepsis. METHODS: Using quasi-experimental methods, we investigated the impact of the screening tools. Individual-level EPR data for 718 000 patients between 2010 and 2020 were extracted to assess the impact on a target cohort and control cohort using interrupted time series analysis, based on a binomial regression model. We included one Trust which uses a paper-based screening tool to compare the impact of digital and paper-based interventions, and one Trust which did not introduce a sepsis screening tool, but did introduce an EPR. RESULTS: All Trusts had lower odds of mortality, between 5% and 12%, after the introduction of the sepsis screening tool, before adjustment for pre-existing trends or patient casemix. After adjustment for existing trends, there was a significant reduction in mortality in two of the three Trusts which introduced sepsis screening tools. We also observed age-specific effects across Trusts. CONCLUSION: Our findings confirm that patients with similar profiles have a lower mortality risk, consistent with our previous work. This study, conducted across multiple NHS Trusts, suggests that alerts could be tailored to specific patient groups based on age-related effects. Different Trusts may require unique indicators, thresholds, actions and treatments. Including additional EPR information could further enhance personalised care
Enhancement of colorectal cancer liver metastases with gadoxetate-enhanced MRI at multiple time points is associated with disease-free survival following hepatectomy.
No full textOBJECTIVES: To investigate signal intensity of colorectal cancer liver metastases (CRLM) at hepatobiliary phase (HBP) gadoxetate-enhanced MRI at 2 time points pre- (TP1) and post- chemotherapy (TP2) and association with disease-free survival (DFS) in patients undergoing curative liver resection. METHODS: Retrospective study was conducted. Single largest tumours were outlined and HBP T1 signal intensity was measured and normalized to skeletal muscle at TP1 and TP2. Enhancement thresholds were defined and risk groups at each TP and Kaplan-Meier survival curves were compared using the log-rank test. Univariate and multivariate association of enhancement and 8 clinical features with risk of recurrence were calculated using Cox proportional hazards. RESULTS: 82 patients (48 male, mean age 59 years) underwent 135 imaging studies, 58 at TP1, 77 at TP2, and 53 patients at TP1 + 2. Of 82 patients, 58 recurred with a median time to recurrence of 11.7 months. Enhancement of ≥135 and ≥15 at TP1 and TP2, respectively, were predictive of reduced risk of recurrence (P .05). Change in enhancement between TP was not associated with risk of recurrence; however, tumours that consistently exhibited low enhancement were 9 times more likely to recur. CONCLUSIONS: Increased CRLM enhancement in the HBP following gadoxetic acid at 2 TPs is associated with improved DFS in patients undergoing liver resection. This initial observation warrants further investigation of serial enhancement measurements as prognostic biomarkers. ADVANCES IN KNOWLEDGE: Dual-time point signal assessment may be informative for clinical outcomes in CRLM undergoing resection