Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma.

BACKGROUND: There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. METHODS: Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. RESULTS: RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. CONCLUSIONS: Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.

Still elusive: Developments in the accurate diagnosis of indeterminate biliary strictures.

Indeterminate biliary strictures pose a significant diagnostic dilemma for gastroenterologists. Despite advances in endoscopic techniques and instruments, it is difficult to differentiate between benign and malignant pathology. A positive histological diagnosis is always preferred prior to high risk hepatobiliary surgery, or to inform other types of therapy. Endoscopic retrograde cholangiopancreatography with brushings has low sensitivity and despite significant improvements in instruments there is still an unacceptably high false negative rate. Other methods such as endoscopic ultrasound and cholangioscopy have improved diagnostic quality. In this review we explore the techniques available to aid accurate diagnosis of indeterminate biliary strictures and obtain accurate histology to facilitate clinical management.

Challenge of achieving truly individualised informed consent in therapeutic endoscopy.

Objective: Guidance covering informed consent in endoscopy has been refined in the UK following the obstetric case of Nadine Montgomery, and in light of updated General Medical Council guidance. All risks likely to be material to the patient must be explored, as well as alternatives to the procedure. Despite this, departments and endoscopists still struggle to meet the current standards. In this article, we explore the challenges encountered in achieving individualised consent in therapeutic endoscopy through real-life scenarios. Methods: Five realistic therapeutic endoscopy (hepatobiliary) scenarios are described, followed by presentation of possible or ideal approaches, with references related to existing literature in this field. Results: The vignettes allow consideration of how to approach difficult consent challenges, including anxiety and information overload, urgency during acute illness, failure to disclose the risk of death, the role of trainees and intraprocedural distress under conscious sedation. Conclusions: The authors conclude that a high degree of transparency is required while obtaining consent for therapeutic endoscopy accompanied by full documentation, involvement of relatives in nearly all cases, and clarity around the presence of trainees who may handle the scope. A greater focus on upskilling trainees in the consent process for therapeutic endoscopy is required.

Achieving Improving Quality in Liver Services (IQILS) accreditation - lessons learned from one unit's experience.

In 2017 the Royal College of Physicians launched a voluntary accreditation process supported by British Association for the Study of the Liver (BASL) and the British Society of Gastroenterologists (BSG) to improve the quality and consistency of liver services across the UK and Ireland. This article describes the approach that we took and the challenges that we met on the way to achieving accreditation.

Improving compliance with the duty of candour: 5-year experience within an endoscopy department.

BACKGROUND AND AIMS: Duty of candour (DoC) is the requirement for timely and transparent disclosure after significant healthcare-related harm. We describe the experience of DoC following patient safety incidents (PSI) related to endoscopy, and offer reflections on improving compliance across other areas of clinical medicine. METHODS: PSI notified on an electronic reporting system (DATIX) from January 2015 to June 2021 were identified. Details of the procedure, level of harm and evidence of both verbal and written DoC were collected and analysed. RESULTS: 33 PSI were notified on DATIX. A verbal apology was documented in 23 cases (70%) and a written notification was offered or sent to in 20 (61%). Verbal apologies were timely, while written DoC was delayed. PSI reporting and verbal DoC increased over this period. Patients or families were invited to present questions for investigation in all 20 with written DoC. There were two claims for compensation during this period. CONCLUSION: DoC remains challenging for clinicians and patient safety teams 8 years after its inception. Improved compliance requires promotion by clinical leaders and high levels of awareness among clinical and nursing staff, a culture of openness and importantly, sustained administrative support to ensure that downstream actions are not overlooked.

Luetic (syphilitic) hepatitis: the great imitator persists in the 21st century.

A male patient in his 20s was referred to the hepatology team with jaundice, pruritus and drenching night sweats. Investigations revealed an acute hepatitis with negative autoimmune and viral serology. Liver biopsy demonstrated severe pan-lobular hepatitis, and an extended diagnostic screen included a positive treponemal antibody test, with an RPR titre of 64, indicating active syphilis infection. He was treated with 2.4 million units of intramuscular benzathine penicillin as a single dose which led to complete resolution of the abnormal liver tests and symptoms. Diagnostic and management challenges, including the role of good history taking, appropriate investigations and role of multidisciplinary team, are discussed.

Immune checkpoint inhibitor-related cholangiopathy: Novel clinicopathological description of a multi-centre cohort.

BACKGROUND AND AIMS: Cholestatic liver dysfunction is common in immune-related hepatitis (irH) during treatment with immune checkpoint inhibitors (CPI) for malignancy. We investigated the spectrum of bile duct injury and associated natural history in this cohort. METHOD: Clinical, laboratory, radiological and histopathological data in patients with evidence of bile duct injury during CPI treatment from 2018 to 2020 was collected in three tertiary hospitals. RESULTS: In this study, ten patients with confirmed bile duct disease were identified. Pembrolizumab was most commonly implicated (8/10). Median CPI cycles prior to bile duct injury was 6. Median alanine aminotransferase and alkaline phosphatase were 225 U/L and 1549 U/L respectively. Clinical jaundice was seen in 6/10 and radiological evidence of bile duct pathology in 8/10. Of five patients, who had liver biopsy, three cases (including two cases with normal MRCP) showed primary sclerosing cholangitis (PSC) like changes with periductal fibrosis. All patients were treated first-line with prednisolone following cessation of CPI, three with mycophenolate mofetil and one with tacrolimus, with clinical response in four patients. Five patients died after a mean follow-up of 27 weeks; cause of death was primarily related to progression of malignancy. CONCLUSION: Within this heterogeneous cohort, we identified that CPI-related cholangiopathy responded poorly to immunosuppression and potentially progressed to bile duct loss. Thorough radiological and histological assessment is recommended, as identification of the cholangiopathy-associated phenotype may permit more informed advice regarding prognosis. Further data is required to determine detailed immunological characterisation in order to identify individuals at an increased risk of developing cholangiopathy.

Diagnostic, therapeutic and prognostic challenges in a jaundiced patient treated with a checkpoint inhibitor.

Immune check point inhibitors (CPI) are now standard treatment for numerous metastatic malignancies. They are associated with hepatological adverse reactions, the most common of which is immune related hepatitis (irH). Bile duct injury is rarely described. We present the case of a 42 year old male with metastatic non-small cell lung cancer (NSCLC) treated with atezolizumab who developed severe liver dysfunction with biochemical and radiological features of a cholangiopathy. Establishing the final diagnosis proved exceptionally difficult due to multiple potential aetiologies. In this article the diagnostic, prognostic and management challenges including the role of liver biopsy, biliary drainage and immune suppression are explored. Cholangiopathy related to CPI is an emerging clinical entity that requires coordinated, expert care and further research.