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Fundus images are crucial for the detection and monitoring of retinal diseases such as diabetic retinopathy (DR). However, issues such as uneven illumination, low contrast, and noise often degrade image quality, impacting the accuracy of automated grading systems. This study introduces three novel preprocessing techniques Adaptive Sigmoid Enhancement, LAB-ACE Image Enhancement, and Multi-channel Image Enhancement designed to address these challenges. Adaptive Sigmoid Enhancement adaptively adjusts local contrast to highlight subtle lesions, LAB-ACE operates in the LAB color space to selectively enhance the lightness channel while preserving color fidelity, and Multi-channel Image Enhancement applies targeted green-channel optimization combined with contrast stretching and channel recombination. These methods extend beyond conventional contrast enhancement and normalization by integrating multi-stage adaptive processing and color-channel-specific optimization to improve lesion visibility and vessel delineation while minimizing background noise. Following pre-processing, handcrafted features (LBP, GLCM) and deep features from a pre-trained ResNet-50 are fused in a multi-modal framework and evaluated using multiple classifiers, including SVM, KNN, Random Forest, and XGBoost. Results demonstrate that XGBoost with fused features and Adaptive Sigmoid Enhancement achieves the highest accuracy (96.39%), outperforming other combinations. The findings highlight the effectiveness of the proposed pre-processing strategies in enhancing DR grading performance, paving the way for improved computer-aided diagnosis systems.

The triple chemotherapy with epirubicin plus cisplatin and fluorouracil is standard for advanced esophagogastric cancer. The fluorouracil must be infused through an ambulatory infusion pump, which impairs the quality of life; cisplatin, which is nephrotoxic, requires intravenous hydration. In this randomized trial, capecitabine, an oral fluoropyrimidine, plus oxaliplatin, a platinum compound that does not require hydration, was as effective in prolonging overall survival as was fluorouracil plus cisplatin. Capecitabine, an oral fluoropyrimidine, plus oxaliplatin, a platinum compound that does not require hydration, was as effective in prolonging overall survival as was fluorouracil plus cisplatin. Gastric and esophageal cancers are the second and sixth most common causes of cancer-related deaths worldwide, respectively. 1 Most patients present with advanced, inoperable, or metastatic disease, and 5-year survival rates are approximately 10 to 15%. Palliative chemotherapy for advanced disease improves survival, as compared with the best supportive care. 2 – 4 There is no single, global standard regimen for the first-line treatment of advanced disease. Of the available regimens, the regimen containing epirubicin, cisplatin, and infused fluorouracil (ECF) is widely used in Europe, particularly in the United Kingdom, on the basis of the results of two randomized studies 5 , 6 and a . . .

Background Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. Methods Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A ( DPYD *2A), c.2846A>T ( DPYD rs67376798), c.1679T>G ( DPYD *13), c.1236G>A ( DPYD rs56038477), c.1601G>A ( DPYD *4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. Results Between 1 st December 2018 and 31 st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine ( n  = 236, 63.8%) or 5FU ( n  = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A ( n  = 16) and c.1236G > A ( n  = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) for DPYD heterozygous carriers and 93.2% (42.9–100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P  = 0.0924). Conclusions Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

ObjectivesPercutaneous liver biopsy (PLB) poses specific challenges in oncological patients such as bleeding and tumour seeding. This study’s aim was to compare a coaxial (C-PLB) and non-coaxial (NC-PLB) biopsy technique in terms of diagnostic yield, safety and seeding risk of image-guided PLB techniques in an oncological setting.MethodsLocal research committee approval was obtained for this single-site retrospective study. Patients who underwent a PLB between November 2011 and December 2017 were consecutively included. Medical records were reviewed to determine diagnostic yield and complications. Follow-up imaging was re-reviewed for seeding, defined as visible tumour deposits along the PLB track. Mann-Whitney U and chi-squared tests were performed to investigate differences between biopsy techniques in sample number, complications and seeding rate.ResultsIn total, 741 patients (62 ± 13 years, 378 women) underwent 932 PLB (C-PLB 72.9% (679/932); NC-PLB 27.1% (253/932)). More tissue cores (p < 0.001) were obtained with C-PLB (median 4 cores; range 1–12) compared with NC-PLB (2 cores; range 1–4) and diagnostic yield was similar for both techniques (C-PLB 92.6% (629/679); NC-PLB 92.5% (234/253); p = 0.940). Complication rate (9.3%; 87/932) using C-PLB (8.2% (56/679)) was lower compared with NC-PLB (12.3% (31/253); p = 0.024). Major complications were uncommon (C-PLB 2.7% (18/679); NC-PLB 2.8% (7/253)); bleeding developed in 1.2% (11/932; C-PLB 1.2% (8/679); NC-PLB 1.2% (3/253)). Seeding was a rare event, occurring significantly less in C-PLB cases (C-PLB 1.3% (7/544); NC-PLB 3.1% (6/197); p = 0.021).ConclusionsC-PLB allows for high diagnostic tissue yield with a lower complication and seeding rate than a NC-PLB and should be the preferred method in an oncological setting.Key Points• A coaxial percutaneous liver biopsy achieves a significant higher number of cores and fewer complications than a non-coaxial biopsy technique.• The risk of tumour seeding is very low and is significantly lower using the coaxial biopsy technique.• In this study, a larger number of cores (median = 4) could be safely acquired using the coaxial technique, providing sufficient material for advanced molecular analysis.

ObjectiveRegorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.DesignPatients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.ResultsTwenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

BackgroundPatient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment.MethodsFour microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS.ResultsWe identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment.ConclusionsOnly 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.

Background Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a ‘good’ mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a ‘poor response’ identifies an adverse prognostic group which may benefit from additional pre-operative therapy. Methods/design TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. Discussion The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. Trial registration ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.

Background The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity. Methods We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells. Results PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA hi ( n  = 3), CEA lo ( n  = 1) and CEA mixed PDOs ( n  = 4), that stably maintained populations of CEA hi and CEA lo cells, which has not previously been described in CRC cell lines. CEA hi PDOs were sensitive whereas CEA lo PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA lo cells maintain cancer cell growth. Culture of FACS-sorted CEA hi and CEA lo cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA lo cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway. Conclusions Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.

IntroductionThe incidence of anal carcinoma is increasing, with the current gold standard treatment being chemoradiotherapy. There is currently a wide range in the radiotherapy dose used internationally which may lead to overtreatment of early-stage disease and potential undertreatment of locally advanced disease.PLATO is an integrated umbrella trial protocol which consists of three trials focused on assessing risk-adapted use of adjuvant low-dose chemoradiotherapy in anal margin tumours (ACT3), reduced-dose chemoradiotherapy in early anal carcinoma (ACT4) and dose-escalated chemoradiotherapy in locally advanced anal carcinoma (ACT5), given with standard concurrent chemotherapy.Methods and analysisThe primary endpoints of PLATO are locoregional failure (LRF)-free rate for ACT3 and ACT4 and LRF-free survival for ACT5. Secondary objectives include acute and late toxicities, colostomy-free survival and patient-reported outcome measures. ACT3 will recruit 90 participants: participants with removed anal tumours with margins ≤1 mm will receive lower dose chemoradiotherapy, while participants with anal tumours with margins >1 mm will be observed. ACT4 will recruit 162 participants, randomised on a 1:2 basis to receive either standard-dose intensity modulated radiotherapy (IMRT) in combination with chemotherapy or reduced-dose IMRT in combination with chemotherapy. ACT5 will recruit 459 participants, randomised on a 1:1:1 basis to receive either standard-dose IMRT in combination with chemotherapy, or one of two increased-dose experimental arms of IMRT with synchronous integrated boost in combination with chemotherapy.Ethics and disseminationThis study has been approved by Yorkshire & The Humber – Bradford Leeds Research Ethics Committee (ref: 16/YH/0157, IRAS: 204585), July 2016. Results will be disseminated via national and international conferences, peer-reviewed journal articles and social media. A plain English report will be shared with the study participants, patients’ organisations and media.Trial registration numberISRCTN88455282.

Background Oesophageal and gastric adenocarcinoma (OGA) treatment remains challenging. Improvements in early diagnosis, staging and management might have contributed to survival prolongation. To examine this hypothesis, we assessed outcomes of resected OGA patients in our institution over 10 years, comparing two time periods, 2001–2005 and 2006–2010. Methods Records from patients who had undergone surgery with radical intent and follow-up for OGA were retrospectively reviewed. Patients followed up at hospitals other than the Royal Marsden Hospital were excluded. Two different cohorts were identified: patients with oesophageal and type I or type II oesophagogastric junction (OGJ) tumours, and patients with gastric and type III OGJ tumours. Results We identified 360 patients: 147 from 2001–2005 and 213 from 2006–2010. The characteristics were comparable across the two time periods. Between 2001–2005 and 2006–2010, the percentage of R0 resections increased (from 67.1 to 81.1 % for proximal tumours and from 76.3 to 95.9 % for gastric and type III OGJ tumours). The mean number of lymph nodes retrieved increased over time. The 5-year overall survival rate increased significantly from 42.3 to 56.6 % for proximal tumours and from 38.8 to 55.3 % for gastric and type III OGJ tumours. Similarly, the disease-free survival rate significantly increased from 34.6 to 53.5 % for proximal tumours and from 35.9 to 51.1 % for gastric and type III OGJ tumours. Conclusion This study comprehensively describes the improvement in survival outcomes in a major UK referral centre over a 10-year period, identifying potentially relevant factors such as increased number of R0 resections and higher lymph node yield.