Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Neoadjuvant management of locally advanced pancreatic ductal adenocarcinoma - Heading towards a promising change in treatment paradigm.

Traditional chemotherapy-based adjuvant therapies for locally advanced pancreatic ductal adenocarcinoma (PDAC) have been associated with poor clinical outcomes driven partly by its complex anatomy and molecular heterogeneity. Treatment for PDAC is challenged by presence of a dense tumour microenvironment involving an interplay of multiple tumoural and stromal components which promote metastatic oncogenic behaviour. PDAC also involves aberrations in multiple signalling pathways with paucity of treatment options against the most common mutations including KRAS, TP53, CDKN2A andSMAD4. However, recent discovery of new mechanisms implicated in pancreatic carcinogenesis have led to identification of promising mechanistic therapeutic targets such as NET1 and ULK1. Early evidence also suggests the utility of targeting multiple DNA repair processes, modulators of DNA replication and major DNA damage response regulators. We explore the clinical rationale behind a neoadjuvant therapeutic strategy and emerging predictors of survival benefit associated with this approach. We also discuss challenges and opportunities originating from recent clinical trials evaluating neoadjuvant treatments composed of various combinations of radiotherapy, chemotherapy and immunotherapeutic regimens that have aimed to address some of these biological challenges. Selective treatment of patients harbouring specific genomic aberrations with targeted agents and immunotherapy can translate into optimum survival outcomes in PDAC. We also share perspectives on emerging prospective clinical evidence regarding stromal modifying agents, such as Tumour Growth Factor-Beta and Connective Tissue Growth Factor inhibitors along with novel vaccination-based approaches in improving PDAC outcomes.

Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer.

PURPOSE: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. EXPERIMENTAL DESIGN: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib.

Comprehensive Examination of Cholangiocarcinoma Patients Treated with Novel Targeted Therapies after Extended Molecular Profiling on Liquid Biopsies.

BACKGROUND: Cholangiocarcinoma (CCA) is associated with poor outcomes and limited treatment options, leading to increased use of targeted therapies for its management. Here, we performed one of the largest single-centre reviews evaluating outcomes following personalised targeted agents in CCA patients. METHODS: All consecutive CCA patients receiving systemic therapy between January 2010 and April 2023 at UCLH were included. The primary objective of this study was to evaluate treatment response, survival outcomes and predictors of clinical benefit in CCA patients treated with molecularly guided therapies. Patient demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan-Meier method and Cox proportional-hazards models. RESULTS: Of the 227 consecutive CCA patients, 162 (71%) had molecular profiling, of whom 56 (35%) were eligible and 55 received molecular-targeted treatment. CCA histological classifications comprised intrahepatic (N = 32), extrahepatic (N = 11), hilar (N = 4) and unknown (N = 9) subtypes. Most patients received targeted agents based on genomic profiling in a second treatment line setting (N = 34). Frequently observed genomic alterations occurred in the FGFR2 (N = 21), IDH1 (N = 7) and BRCA2 (N = 6) genes. Median progression-free survival (PFS) following first-, second- and third-line systemic therapy and overall survival (OS) were 8.44 (95% CI, 7.49-12.78), 5.65 (95% CI, 3.71-7.13), 5.55 (2.79-12.58) and 29.01 (24.21-42.91) months, respectively. CCA subtype and FGFR/BRCA molecular aberration status were not associated with PFS or OS. However, a prior CCA-related surgical history was predictive of OS (p = 0.02). Stratification by best overall response to second-line targeted agents demonstrated an association with PFS (p = 0.002) and OS (p = 0.02). Duration of treatment with second-line targeted therapy was associated with OS (p < 0.001). CONCLUSIONS: Patients receiving targeted therapeutics achieved promising outcomes, especially those attaining a favourable treatment response and those receiving targeted agents for longer periods. Liquid biopsies can reliably provide information on extended molecular profiling to aid patient selection for personalised therapies.

The immunomodulatory role of IDO1-Kynurenine-NAD+ pathway in switching cold tumor microenvironment in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is the most common exocrine tumor of the pancreas characterized by late diagnosis, adverse overall 5-year survival, a higher propensity for metastatic disease, and lack of efficacy of systemic therapy options. These adverse outcomes can be partly attributed to complex tumor microenvironment (TME). Over the past decade, immunotherapy has revolutionized the management of certain cancers; thus far, the immunologically 'non-inflamed' tumor microenvironment in PDACs has proven to be challenging. Indolamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the catabolic pathway of L-Tryptophan, an essential amino acid, that gives rise to the immunosuppressive metabolite Kynurenine. IDO1, Indolamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3-dioxygenase (TDO) are the key enzymes in the tryptophan catabolic pathway but we focus on the role of the predominant enzyme form IDO1 in this review. Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD+ as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.

An International Comparison of Presentation, Outcomes and CORONET Predictive Score Performance in Patients with Cancer Presenting with COVID-19 across Different Pandemic Waves.

Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

Establishing a colorectal cancer research database from routinely collected health data: the process and potential from a pilot study.

OBJECTIVE: Colorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source. METHODS: Clinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically. RESULTS: Three pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed. DISCUSSION: Algorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer. CONCLUSION: The data set has great potential to facilitate research into colorectal cancer.

Establishment of CORONET, COVID-19 Risk in Oncology Evaluation Tool, to Identify Patients With Cancer at Low Versus High Risk of Severe Complications of COVID-19 Disease On Presentation to Hospital.

PURPOSE: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET). METHODS: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O2) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort. RESULTS: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation. CONCLUSION: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer.

The role of PARP inhibitors in gastrointestinal cancers.

The use of BReast CAncer (BRCA) mutations as biomarkers for sensitivity to DNA damage response (DDR) targeted drugs and platinum agents is well documented in breast and gynaecological cancers. More recently the successful use DDR targeted therapies including poly (ADP-ribose) polymerases (PARP) inhibitors has been shown to extend to other germline and somatic deficiencies within the homologous recombination (HR) pathway (Farmer et al., 2005; Turner et al., 2019; Li and Heyer, 2008). Gastrointestinal (GI) cancers are lagging behind other tumour types when it comes to personalising treatment with targeted therapies. Current methods of identifying PARP-inhibitor sensitivity in gastrointestinal cancers are based on analogies from other cancer types despite there being a lack of uniformity in determining HR status between tumour types. There is an urgent clinical need to better understand the treatment implications of DDR alterations in gastrointestinal cancers. We have reviewed PARP-inhibitor use in pancreatic, gastroesophageal, hepatobiliary and colorectal cancers and explored HRD as a biomarker for sensitivity to PARP-inhibitors.

DCE-MRI is more sensitive than IVIM-DWI for assessing anti-angiogenic treatment-induced changes in colorectal liver metastases.

BACKGROUND: Diffusion weighted imaging (DWI) with intravoxel incoherent motion (IVIM) modelling can inform on tissue perfusion without exogenous contrast administration. Dynamic-contrast-enhanced (DCE) MRI can also characterise tissue perfusion, but requires a bolus injection of a Gadolinium-based contrast agent. This study compares the use of DCE-MRI and IVIM-DWI methods in assessing response to anti-angiogenic treatment in patients with colorectal liver metastases in a cohort with confirmed treatment response. METHODS: This prospective imaging study enrolled 25 participants with colorectal liver metastases to receive Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using slice-matched IVIM-DWI and DCE-MRI protocols. MRI data were motion-corrected and tumour volumes of interest drawn on b=900 s/mm2 diffusion-weighted images were transferred to DCE-MRI data for further analysis. The median value of four IVIM-DWI parameters [diffusion coefficient D (10-3 mm2/s), perfusion fraction f (ml/ml), pseudodiffusion coefficient D* (10-3 mm2/s), and their product fD* (mm2/s)] and three DCE-MRI parameters [volume transfer constant Ktrans (min-1), enhancement fraction EF (%), and their product KEF (min-1)] were recorded at each visit, before and after treatment. Changes in pre- and post-treatment measurements of all MR parameters were assessed using Wilcoxon signed-rank tests (P<0.05 was considered significant). DCE-MRI and IVIM-DWI parameter correlations were evaluated with Spearman rank tests. Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations. RESULTS: Significant treatment-induced reductions of DCE-MRI parameters across the cohort were observed for EF (91.2 to 50.8%, P<0.001), KEF (0.095 to 0.045 min-1, P<0.001) and Ktrans (0.109 to 0.078 min-1, P=0.002). For IVIM-DWI, only D (a non-perfusion parameter) increased significantly post treatment (0.83 to 0.97 × 10-3 mm2/s, P<0.001), while perfusion-related parameters showed no change. No strong correlations were found between DCE-MRI and IVIM-DWI parameters. A moderate correlation was found, after treatment, between Ktrans and D* (r=0.60; P=0.002) and fD* (r=0.67; P<0.001). When compared to RECIST v.1.1 evaluations, KEF and D correctly identified most clinical responders, whilst non-responders were incorrectly identified. CONCLUSION: IVIM-DWI perfusion-related parameters showed limited sensitivity to the anti-angiogenic effects of Regorafenib treatment in colorectal liver metastases and showed low correlation with DCE-MRI parameters, despite profound and significant post-treatment reductions in DCE-MRI measurements. TRIAL REGISTRATION: NCT03010722 clinicaltrials.gov; registration date 6th January 2015.

A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors.

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).

COVID-19 and Its Impact on Upper Gastrointestinal (GI) Cancer Management.

Coronavirus disease 2019 (COVID-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has left dramatic footprints on human health and economy. Cancer, whilst not an infective disease, is prevalent in epidemic proportions and cannot be pretermitted due to the impact of COVID-19. As we emanate from the second national lockdown in the UK with mixed feelings of hope and despair-due to vaccination and new COVID-19 variant, respectively-we reflect on the impact of the first wave on the provision on diagnosis and management of with upper gastrointestinal (UGI) cancers. This review provides a critical analysis of available literature on COVID-19 and its impact on cancer management in general and that of UGI cancers in particular.

Multimodal Treatment in Metastatic Colorectal Cancer (mCRC) Improves Outcomes-The University College London Hospital (UCLH) Experience.

BACKGROUND: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of individuals with mCRC are considered potentially suitable for primary or metastasis-directed multimodal therapy, including surgical resection, ablative techniques, or stereotactic radiotherapy (RT), with the aim of improving survival outcomes. We reviewed the potential benefits of multimodal therapy on the survival of patients with mCRC treated at the UCLH. METHODS: Clinical data on baseline characteristics, multimodal treatments, and survival outcomes were retrospectively collected from all patients with mCRC receiving systemic chemotherapy between January 2013 and April 2017. Primary outcome was the impact of multimodal therapy on overall survival, compared to systemic therapy alone, and the effect of different types of multimodal therapy on survival outcome, and was assessed using the Kaplan-Meier approach. All analyses were adjusted for age, gender, and side of primary tumour. RESULTS: One-hundred and twenty-five patients with mCRC were treated during the study period (median age: 62 years (range 19-89). The liver was the most frequent metastatic site (78%; 97/125). A total of 52% (65/125) had ≥2 lines of systemic chemotherapy. Of the 125 patients having systemic chemotherapy, 74 (59%) underwent multimodal treatment to the primary tumour or metastasis. Median overall survival (OS) was 25.7 months [95% Confidence Interval (CI) 21.5-29.0], and 3-year survival, 26%. Univariate analysis demonstrated that patients who had additional procedures (surgery/ablation/RT) were significantly less likely to die (Hazard Ratio (HR) 0.18, 95% CI 0.12-0.29, p < 0.0001) compared to those receiving systemic chemotherapy alone. Increasing number of multimodal procedures was associated with an incremental increase in survival-with median OS 28.4 m, 35.7 m, and 64.8 m, respectively, for 1, 2, or ≥3 procedures (log-rank p < 0.0001). After exclusion of those who received systemic chemotherapy only (n = 51), metastatic resections were associated with improved survival (adjusted HR 0.36, 95% CI 0.20-0.63, p < 0.0001), confirmed in multivariate analysis. Multiple single-organ procedures did not improve survival. CONCLUSION: Multimodal therapy for metastatic bowel cancer is associated with significant survival benefit. Resection/radical RT of the primary and resection of metastatic disease should be considered to improve survival outcomes following multidisciplinary team (MDT) discussion and individual assessment of fitness.

COVID-19 in cancer patients on systemic anti-cancer therapies: outcomes from the CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London) cohort study.

BACKGROUND: Patients with cancer are hypothesised to be at increased risk of contracting COVID-19, leading to changes in treatment pathways in those treated with systemic anti-cancer treatments (SACT). This study investigated the outcomes of patients receiving SACT to assess whether they were at greater risk of contracting COVID-19 or having more severe outcomes. METHODS: Data was collected from all patients receiving SACT in two cancer centres as part of CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London). The primary outcome was the effect of clinical characteristics on the incidence and severity of COVID-19 infection in patients on SACT. We used univariable and multivariable models to analyse outcomes, adjusting for age, gender and comorbidities. RESULTS: A total of 2871 patients receiving SACT from 2 March to 31 May 2020 were analysed; 68 (2.4%) were diagnosed with COVID-19. Cancer patients receiving SACT were more likely to die if they contracted COVID-19 than those who did not [adjusted (adj.) odds ratio (OR) 9.84; 95% confidence interval (CI) 5.73-16.9]. Receiving chemotherapy increased the risk of developing COVID-19 (adj. OR 2.99; 95% CI = 1.72-5.21), with high dose chemotherapy significantly increasing risk (adj. OR 2.36, 95% CI 1.35-6.48), as did the presence of comorbidities (adj. OR 2.29; 95% CI 1.19-4.38), and having a respiratory or intrathoracic neoplasm (adj. OR 2.12; 95% CI 1.04-4.36). Receiving targeted treatment had a protective effect (adj. OR 0.53; 95% CI 0.30-0.95). Treatment intent (curative versus palliative), hormonal- or immunotherapy and solid versus haematological cancers had no significant effect on risk. CONCLUSION: Patients on SACT are more likely to die if they contract COVID-19. Those on chemotherapy, particularly high dose chemotherapy, are more likely to contract COVID-19, while targeted treatment appears to be protective.

Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data.

BACKGROUND: Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses. PATIENTS AND METHODS: All consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In the next step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and PROSPECT-R) were assessed for the DNA yield from biopsies assessed for complex genomic analysis. RESULTS: A total of 522 plugged core biopsies were performed in 457 patients [men, 52%; median age, 63 years (range, 17-93)]. Histological diagnosis was achieved in 501 of 522 (96%) performed biopsies. Age, gender, modality, metastatic site, and seniority of the interventionist were not found to be significant factors associated with odds of failure on a logistic regression. Seventeen (3.3%) were admitted due to biopsy-related complications; nine, three, two, one, one, and one were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, hematuria, and deranged liver functions, respectively; two patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular hematoma requiring conservative treatment. One patient (0.2%) developed grade III hemorrhage following biopsy of a gastric gastrointestinal stromal tumor (GIST). Overall molecular analysis was successful in 89% (197/222 biopsies). Prospective validation in 62 biopsies gave success rates of 92.06 and 79.03% for DNA extraction of >1 µm and tmour content of >20%, respectively. CONCLUSION: The probability of diagnostic success for complex molecular analysis is increased with plugged large coaxial needle biopsy technique, which also minimizes complications and reduces hospital stay. High-yield DNA acquisition allows genomic molecular characterization for personalized medicine.

Outcomes of the 2019 novel coronavirus in patients with or without a history of cancer: a multi-centre North London experience.

BACKGROUND: This study aims to compare the outcomes of COVID-19-positive disease in patients with a history of cancer to those without. METHODS: We retrospectively collected clinical data and outcomes of COVID-19 positive cancer patients treated consecutively in five North London hospitals (cohort A). Outcomes recorded included time interval between most recent anti-cancer treatment and admission, severe outcome [a composite endpoint of intensive care unit (ITU) admission, ventilation and/or death] and mortality. Outcomes were compared with consecutively admitted COVID-19 positive patients, without a history of cancer (cohort B), treated at the primary centre during the same time period (1 March-30 April 2020). Patients were matched for age, gender and comorbidity. RESULTS: The median age in both cohorts was 74 years, with 67% male, and comprised of 30 patients with cancer, and 90 without (1:3 ratio). For cohort B, 579 patients without a history of cancer and consecutively admitted were screened from the primary London hospital, 105 were COVID-19 positive and 90 were matched and included. Excluding cancer, both cohorts had a median of two comorbidities. The odds ratio (OR) for mortality, comparing patients with cancer to those without, was 1.05 [95% confidence interval (CI) 0.4-2.5], and severe outcome (OR 0.89, 95% CI 0.4-2.0) suggesting no increased risk of death or a severe outcome in patients with cancer. Cancer patients who received systemic treatment within 28 days had an OR for mortality of 4.05 (95% CI 0.68-23.95), p = 0.12. On presentation anaemia, hypokalaemia, hypoalbuminaemia and hypoproteinaemia were identified predominantly in cohort A. Median duration of admission was 8 days for cancer patients and 7 days for non-cancer. CONCLUSION: A diagnosis of cancer does not appear to increase the risk of death or a severe outcome in COVID-19 patients with cancer compared with those without cancer. If a second spike of virus strikes, rational decision making is required to ensure optimal cancer care.

Immunotherapy in gastrointestinal cancer: The current scenario and future perspectives.

Gastrointestinal cancers include colorectal, gastric, oesophageal, pancreatic and liver cancers. They continue to be a significant cause of mortality and morbidity worldwide. Current treatment strategies include chemotherapy, surgery, radiotherapy and targeted therapies. Immunotherapy has recently been incorporated in treatment regimens for some gastrointestinal malignancies and research into different immune modifying treatments is being carried out in this context. Approaches to immune modulation such as vaccination, adoptive cell therapy and checkpoint inhibition have shown varying clinical benefit, with most of the benefit seen in checkpoint inhibition. This review summarises recent advances and future direction of immunotherapy in patients with gastrointestinal malignancies.

Imaging and clinical correlates with regorafenib in metastatic colorectal cancer.

In colorectal cancer (CRC), imaging is important in determining tumor stage, selecting treatment strategies, and in assessing response to therapy. However, some challenges remain with established imaging techniques, such as computed tomography, and with some commonly used response criteria, such as Response Evaluation Criteria in Solid Tumors, which measures change in size of several target lesions instead of change in tumor morphology or metabolic function. In addition, these assessments are not typically conducted until after 8 weeks of treatment, meaning that potential non-responders are often not identified in a timely manner. Regorafenib, an oral tyrosine kinase inhibitor indicated for the treatment of metastatic CRC, blocks the activity of several protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity. Timely differentiation of regorafenib responders from non-responders using appropriate imaging techniques that recognize not only changes in tumor size but also changes in tumor density or vasculature, may reduce unnecessary drug-related toxicity in patients who are unlikely to respond to treatment. This review discusses the latest developments in computed tomography, magnetic resonance imaging, and positron emission tomography tumor imaging modalities, and how these aid in identifying patients with metastatic CRC who are responders or non-responders to regorafenib treatment.