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Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms.

Indications for immune checkpoint inhibitor therapy are increasing. As the population ages, many patients receiving such drugs will be older adults. Such patients are under-represented in clinical trials, and therefore the safety of immune checkpoint inhibitors in this population has not been adequately assessed. A retrospective multicenter analysis of toxicities was performed in patients with advanced or metastatic solid cancers receiving anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies across three age cohorts (<65 years, 65–74 years and ≥75 years) using univariable and multivariable analyzes. Eligible patients (n=448) were divided into age cohorts: <65 years (n=185), 65–74 years (n=154) and ≥75 years (n=109). Fewer patients in the oldest cohort (7.3%) received an anti-CTLA4 antibody containing regimen compared with the younger cohorts (21.1% and 17.5%). There was no significant difference overall in all grade or ≥G3 toxicities between age cohorts. Significantly fewer patients in the older (65–74 years and ≥75 years) age cohorts discontinued treatment because of toxicity (10.1% and 7.4%) compared with in the <65 years cohort (20.5%; p=0.006). Using logistic regression, only treatment type (ipilimumab containing) was significantly associated with all grade toxicity. However, there was a significantly lower incidence of all-grade endocrine toxicity in the oldest cohort (11.0%) compared with the youngest cohort (22.7%, p=0.02; OR 0.43, 95% CI 0.21 to 0.87), while all-grade dermatological toxicity showed the reverse trend (28.4% vs 18.9%; OR 1.85, 95% CI 1.04 to 3.30). Results were corroborated in the sensitivity analysis using only data from patients who received PD-1 inhibitor monotherapy. This multicenter, real-world cohort demonstrates that immune checkpoint inhibitor therapy is safe and well tolerated regardless of age, with no appreciable increase in adverse events in older adult patients.

Background: The impact of nonalcoholic fatty liver disease (NAFLD) on overall survival (OS), treatment response and toxicity in patients with hepatocellular carcinoma (HCC) treated with sorafenib is unknown. We examined the impact of NAFLD on survival and toxicity in an international cohort of patients receiving sorafenib. Methods: Clinical and demographic data were collected from patients consecutively treated at specialist centres in Europe and North America. The impact of NAFLD on OS, sorafenib-specific survival and toxicity compared with other aetiologies of liver disease using multivariable Cox-proportional hazards and logistic regression modelling was assessed. Results: A total of 5201 patients received sorafenib; 183 (3.6%) had NAFLD-associated HCC. NAFLD-associated HCC patients were more likely to be older women (median age 65.8 versus 63.0 years, p < 0.01 and 10.4% versus 2.3%, < 0.01), with a median body mass index (BMI) of 29.4. After controlling for known prognostic factors, no difference in OS in patients with or without NAFLD was observed [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.84–1.18, p = 0.98]. NAFLD-associated patients had more advanced stage HCC when they commenced sorafenib [Barcelona Clinic Liver Class (BCLC) C/D 70.9% versus 58.9%, p < 0.01] and were more likely to be commenced on a lower starting dose of sorafenib (51.4 versus 36.4%, p < 0.01). There was no difference in sorafenib-specific survival between NAFLD and other aetiologies (HR: 0.96, 95% CI: 0.79–1.17, p = 0.96). Adverse events were similar between NAFLD and non-NAFLD HCC groups, including rates of greater than grade 2 hypertension (6.3% versus 5.8%, p = 1.00). Conclusion: Survival in HCC does not appear to be influenced by the presence of NAFLD. NAFLD-associated HCC derive similar clinical benefit from sorafenib compared with other aetiologies.

Electronic health records (EHRs) are a cornerstone of modern health care delivery, but their current configuration often fragments information across systems, impeding timely and effective clinical decision-making. In gynecological oncology, where care involves complex, multidisciplinary coordination, these limitations can significantly impact the quality and efficiency of patient management. Few studies have examined how EHR systems support clinical decision-making from the perspective of end users. This study aimed to explore multiprofessional experiences of EHR use in gynecological oncology and to develop a co-designed informatics platform to improve decision-making for ovarian cancer care. This study aims to evaluate the perspectives of health care professionals on retrieving routine clinical data from EHRs in the management of ovarian cancer and to design an integrated informatics platform that supports clinical decision-making. We conducted a national cross-sectional survey of 92 UK-based professionals working in gynecological oncology, including oncologists, nurses, radiologists, and other specialists in ovarian cancer. The web-based questionnaire, combining quantitative and free-text responses, assessed their experiences with EHR use, focusing on information retrieval, usability challenges, perceived risks, and benefits. In parallel, a human-centered design approach involving health care professionals, data engineers, and informatics experts codeveloped a digital informatics platform that integrates structured and unstructured data from multiple clinical systems into a unified patient summary view for clinical decision-making. Natural language processing was applied to extract genomic and surgical information from free-text records, with data pipelines validated by clinicians against original clinical system sources. Among 92 respondents, 84 out of 91 (92%) routinely accessed multiple EHR systems, with 26 out of 91 (29%) using 5 or more. Notably, 16 out of 92 respondents (17%) reported spending more than 50% of their clinical time searching for patient information. Key challenges included lack of interoperability (35/141 reported challenges, 24.8%), difficulty locating critical data such as genetic results (57/85 respondents, 67%), and poor organization of information. Only 10 out of 92 professionals (11%) strongly agreed that their systems provided well-organized data for clinical use. While ease of access to patient data was a key benefit, 54 out of 90 respondents (60%) reported lacking access to comprehensive patient summaries. To address these issues, our co-designed informatics platform consolidates disparate patients' data from different EHR systems into a single visual display to support clinical decision-making and audit. Current EHR systems are suboptimal for supporting complex gynecological oncology care. Our findings highlight the urgent need for integrated, user-centered clinical decision tools. Fragmentation and lack of interoperability hinder information retrieval and may compromise patient care. Our co-designed ovarian cancer informatics platform is a potential real-world solution to improve data visibility, clinical efficiency, and ultimately the quality of ovarian cancer care.

BackgroundNon-vitamin K antagonist oral anticoagulants provide a valuable alternative option to warfarin for thromboprophylaxis for non-valvular atrial fibrillation. NICE has recently released a national consensus statement which will guide local protocol/guideline development. Currently, their use is often governed by physician preference combined with patient factors. We explored the pattern of prescribing in the pre-guideline era.MethodRetrospective analysis of admissions from June–October 2014. Student T-test and Fischer's exact test with Bonferroni corrections were used to compare demographics between groups. A creatinine clearance of <60 umol/L defined renal impairment.Results61 patients, 37 female, mean age 80.8 years were audited. 35 were prescribed rivoroxaban 20 mg, 7 rivoroxaban 15 mg, 11 apixaban 5 mg and 8 apixaban 2.5 mg. None were prescribed dabigatran. Age, CHADS2 and HAS-BLED scores did not show statistically significant variability between subgroups. Renal impairment was signficantly commoner in the apixaban 2.5 mg group compared to the 5mg group (p<0.001) and the rivoroxaban 15mg compared to the 20mg group (P<0.01). There was no difference between the rivoroxaban and apixaban groups.ConclusionCurrently, renal impairment is the main determinant for thromboprophylaxis choice. Local guidelines have been created with physician education underway and re-audit planned in 3 months. The authors will present the full data.

Cerebrospinal fluid (CSF) examination showed a protein level of 0.74 g/L with a glucose of 3.2 mmol/L (serum 5.5 mmol/L), <1 white blood cell per millilitre and negative oligoclonal bands. A case study in 1999 coined the term 'lymphomatosis cerebri' to describe an exceedingly rare variant of PCNSL characterised by diffuse parenchymal infiltration of lymphomatous cells. 2 Previous presentations include gait disturbance (mainly ataxic), personality change, memory deficits and weight loss. 3 White matter abnormalities in LC have been described affecting all regions of the brain; however, serial MRI has rarely been performed.

BackgroundImmune check point inhibitors (ICPis) have transformed the treatment landscape for several cancers, but at the cost of triggering ICPi-induced colitis which resembles some aspects of IBD. Diagnosis is often made by symptoms, or by identifying endoscopic features of colitis. Little is known about histological findings in the absence of macroscopic disease. Furthermore, first-line management strategies beyond the use of systemic corticosteroids have not been explored. Our aim was to assess the incidence of microscopic inflammation in patients with ICPi-diarrhoea, and report our experience of treating two such patients with beclomethasone diproprionate (Clipper).MethodsElectronic records of patients with advanced melanoma and ICPi- diarrhoea/colitis at the Royal Marsden Hospital (RMH) and Guy’s and St Thomas’ Hospital (GSTT) between 2011–2016, were retrospectively reviewed. Endoscopic, histological and clinical outcome data was recorded for patients who underwent flexible sigmoidoscopy and had colonic biopsies taken regardless of macroscopic findings.Two symptomatic patients (one treated with anti-PD-1, and another on combination -anti-PD-1/anti-CTLA-4 therapy) with isolated microscopic disease were managed with 5 mg Clipper, once a day, for 4 weeks. Endoscopic, histological and clinical outcomes were recorded 6 weeks after completion of therapy.ResultsA total of 63 flexible sigmoidoscopies were performed in 59 patients with ICPi diarrhoea/colitis. Microscopic inflammation with normal macroscopic appearances were recorded in 22% of cases. 6 patients were prescribed anti-CTLA-4, 4 anti-PD-1, and 4 combination therapy. Histological features that were distinct from conventional microscopic colitis were recorded in the majority of patients (10/14), which included acute and chronic inflammation, architectural distortion, crypt abscess formation and neutrophil infiltration. Four patients had changes consistent with conventional microscopic colitis (2 lymphocytic colitis, 2 collagenous colitis). Clipper induced clinical remission within 7 days, and histological remission by week 6 in both patients with ICPi-induced microscopic inflammation. There was no treatment associated adverse events.ConclusionMicroscopic inflammation in the absence of macroscopic features of colitis is a common finding in ICPi-induced diarrhoea, justifying the routine practice of performing colonic biopsies even when endoscopy is normal. Our favourable clinical experience of using Clipper in 2 patients with microscopic inflammation merit further investigation in appropriately controlled clinical trials.

We describe a case of lymphomatosis cerebri (LC), an extremely rare variant of Primary Central Nervous System Lymphoma (PCNSL) characterised by diffuse infiltration of brain parenchyma by a non-cohesive mass of malignant lymphocytes.A 50 year-old lady presented with rapidly progressive cognitive decline. Neuropsychometric testing showed global cognitive deficits with magnetic resonance imaging of the brain showing diffuse T2-weighted white matter hyperintensity. Initial impression included metachromatic leukodystrophy however after a series of normal investigations, and clinicoradiological deterioration, a decision was made to proceed to brain biopsy which showed LC. Following chemoradiotherapy she regained the ability to ambulate independently and her cognitive state improved.PCNSL typically presents as discrete gadolinium-enhancing T2 hyperintense lesions. Very rarely it presents as LC, usually manifest as rapidly progressive cognitive decline and leukoencepahlopathy. Complete remission of LC has been achieved with steroid use followed by radiotherapy, cisplatin or methotrexate. Although there are many causes of rapidly progressive leukoencephalopathy, rapid progression of structural change, perhaps combined with new foci of enhancement, should prompt thoughts of an underlying neoplastic process and the need for biopsy. This case highlights the diagnostic (and potential therapeutic) importance of early consideration of brain biopsy in patients with rapidly progressive atypical neurological syndromes

BackgroundImmune checkpoint inhibitors (ICIs) including anti-CLTA-4 (e.g. ipilimumab (ipi)) and anti-PD-1 antibodies (e.g. nivolumab (nivo)) have improved outcomes in many cancers. However their use is complicated by ICI-related diarrhoea/colitis (irD/C), a common cause of morbidity and ICI discontinuation. The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) has been used to grade irD/C according to frequency of bowel movements over baseline. Grade 1–2 represents mild-moderate disease, grade 3–4 severe disease and grade 5 represents death. In clinical trials diarrhoea/colitis is more common in regimes using anti-CTLA-4 agents.1 There are few real world data reported in the UK.MethodsElectronic medical records were reviewed for melanoma patients (pts) at The Royal Marsden Hospital (RMH) and melanoma, renal and lung cancer pts Guy’s and St Thomas’ Hospital (GSTT), receiving at least one ICI dose between 2011–2016. Clinical outcome data included class of ICI therapy and CTCAE grade of diarrhoea.Results651 ICI treatment courses were administered mostly for melanoma (100% RMH, 53% GSTT). 285 (44%) received anti-CTLA-4 monotherapy, 288 (44%) anti-PD-1 monotherapy, and 77 (12%) combination ipi +nivo. The incidence of all-grade irD/C was 27% for anti-CTLA-4 therapy, 12% for anti-PD-1%–34% for ipi +nivo. The incidence of severe irD/C (grade 3–5) was 12% in anti-CTLA-4 monotherapy, 4% in anti-PD-1 therapy and 26% in combination therapy (figure 1). There was one only death reported in a pt who developed colitis following treatment with anti-CTLA-4 monotherapy.Abstract PTU-006 Figure 1ConclusionThis is the largest cohort of data reporting the incidence of irD/C involving real-world patients. Compared to trial data, the incidence of all-grade diarrhoea was slightly lower but the incidence of severe disease was higher in all treatment groups, particularly with ipi +nivo. Given the expansion of ICIs in other cancer types and use as an adjuvant therapy, there is an urgent need to engage gastroenterology services and to develop evidence-based management algorithms for treatment of irD/C.Reference. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev2016;44:51–60.

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community. Genome-wide association and Mendelian randomization analyses in the UK Biobank identify genetic variants associated with leukocyte telomere length and highlight putative causal links between telomere length and biomedical phenotypes.