Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage.

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)-dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.

Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures, and fibrosis. hBECs are expandable and phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.

Analysis of the interactions between small pulmonary nodules, clinical factors and the risk of malignancy in the chest following diagnosis of head and neck cancer.

BACKGROUND: This study aims to investigate radiological and clinical factors which predict malignancy in indeterminate pulmonary nodules in patients with head and neck cancer (HNC). METHODS: Prospective data were collected in 424 patients who were reviewed in the NHS Lothian HNC multidisciplinary meeting from May 2016 to May 2018. Staging and follow-up CT chest imaging were reviewed to identify and assess pulmonary nodules in all patients. RESULTS: About 61.8% of patients had at least one pulmonary nodule at staging CT. In total, 25 patients developed malignancy in the chest. Metastatic disease in the chest was significantly associated with unknown or negative p16 status (p < .0005). Pleural indentation and spiculation were associated with indeterminate nodules, subsequently being shown to represent metastatic disease (p > .0005 and p = .046, respectively). CONCLUSION: Negative or unknown p16 status was associated with an increased propensity to develop metastatic disease in the chest in patients with HNC.

Cell therapy for advanced liver diseases: Repair or rebuild.

Advanced liver disease presents a significant worldwide health and economic burden and accounts for 3.5% of global mortality. When liver disease progresses to organ failure the only effective treatment is liver transplantation, which necessitates lifelong immunosuppression and carries associated risks. Furthermore, the shortage of suitable donor organs means patients may die waiting for a suitable transplant organ. Cell therapies have made their way from animal studies to a small number of early clinical trials. Herein, we review the current state of cell therapies for liver disease and the mechanisms underpinning their actions (to repair liver tissue or rebuild functional parenchyma). We also discuss cellular therapies that are on the clinical horizon and challenges that must be overcome before routine clinical use is a possibility.

Diaphragmatic hernia: a rare complication of hepatic ablation.

INTRODUCTION: Ablation has become an effective treatment for small hepatocellular carcinomas (HCC). Whilst ablation is a safe and effective technique, diaphragmatic injury is a rarely associated but significant complication.Case presentation: We present a case of a 67 year old patient who developed a diaphragmatic defect following microwave ablation (MWA) for HCC. The diaphragmatic defect progressed to herniation which was complicated by perforation of intrahernial large bowel. The patient was treated by emergency laparotomy and an extended right hemi-colectomy was performed. CONCLUSION: Our report adds to the current available knowledge on diaphragmatic injury following hepatic ablation and demonstrates the potential for life threatening consequences associated with this complication.

Incidental Non-cardiac Findings in Cardiovascular Imaging.

Improvements in imaging techniques have led to an expansion in the number of cross-sectional cardiac studies being performed. This means that incidental non-cardiac findings (INCF) identified on cardiac imaging have become an important clinical concern. The majority of INCF are not clinically significant. However, some INCF will require follow-up or changes in management. Differentiating clinically significant from non-significant INCF can be challenging, particularly given the breadth of potential findings and the range of organ systems involved. Following up INCF also has economic implications. Recent changes to the lung nodule follow-up guidelines will reduce the cost of following up incidental lung nodules. In this manuscript, we discuss the common and important INCF which may be identified in cardiovascular imaging and explore potential implications of these findings.

Impact of noncardiac findings in patients undergoing CT coronary angiography: a substudy of the Scottish computed tomography of the heart (SCOT-HEART) trial.

OBJECTIVES: Noncardiac findings are common on coronary computed tomography angiography (CCTA). We assessed the clinical impact of noncardiac findings, and potential changes to surveillance scans with the application of new lung nodule guidelines. METHODS: This substudy of the SCOT-HEART randomized controlled trial assessed noncardiac findings identified on CCTA. Clinically significant noncardiac findings were those causing symptoms or requiring further investigation, follow-up or treatment. Lung nodule follow-up was undertaken following the 2005 Fleischner guidelines. The potential impact of the 2015 British Thoracic Society (BTS) and the 2017 Fleischner guidelines was assessed. RESULTS: CCTA was performed in 1,778 patients and noncardiac findings were identified in 677 (38%). In 173 patients (10%) the abnormal findings were clinically significant and in 55 patients (3%) the findings were the cause of symptoms. Follow-up imaging was recommended in 136 patients (7.6%) and additional clinic consultations were organized in 46 patients (2.6%). Malignancy was diagnosed in 7 patients (0.4%). Application of the new lung nodule guidelines would have reduced the number of patients undergoing a follow-up CT scan: 68 fewer with the 2015 BTS guidelines and 78 fewer with the 2017 Fleischner guidelines; none of these patients subsequently developed malignancy. CONCLUSIONS: Clinically significant noncardiac findings are identified in 10% of patients undergoing CCTA. Application of new lung nodule guidelines will reduce the cost of surveillance, without the risk of missing malignancy. KEY POINTS: • Clinically significant noncardiac findings occur in 10% of patients undergoing CCTA. • Noncardiac findings may be an important treatable cause of chest pain • Further imaging investigations for noncardiac findings were recommended in 8% of patients after CCTA. • New lung nodule follow-up guidelines will result in cost savings.

Analysis of the incidence and factors predictive of outcome in patients with head and neck cancer with pulmonary nodules.

BACKGROUND: The management of pulmonary nodules is challenging; unfortunately, little is known about the incidence and significance of pulmonary nodules in patients with head and neck cancer. METHODS: A review was conducted of 400 consecutive patients with head and neck cancer. Imaging was reviewed to identify the incidence of nodules and patient, tumor, and radiological factors associated with the risk of malignancy. RESULTS: Nodules were found in 58% of patients, with a malignant rate of 6%. Age was the only predictor of having a nodule and advanced-stage III + IV was a predictor of malignancy (P = .023; odds ratio [OR] 10.64; confidence interval 1.33-84.98). CONCLUSION: Patients presenting with head and neck cancer have a higher incidence of pulmonary nodules and a higher risk of malignancy. In contrast to the British Thoracic Society (BTS) guidelines, which use size to guide the need for serial scans, we would recommend follow-up imaging in all patients with head and neck cancer with nodules, irrespective of size.

The relationships between body composition and the systemic inflammatory response in patients with primary operable colorectal cancer.

BACKGROUND: Weight loss is recognised as a marker of poor prognosis in patients with cancer but the aetiology of cancer cachexia remains unclear. The aim of the present study was to examine the relationships between CT measured parameters of body composition and the systemic inflammatory response in patients with primary operable colorectal cancer. PATIENT AND METHODS: 174 patients with primary operable colorectal cancer who underwent resection with curative intent (2003-2010). Image analysis of CT scans was used to measure total fat index (cm(2)/m(2)), subcutaneous fat index (cm(2)/m(2)), visceral fat index (cm(2)/m(2)) and skeletal muscle index (cm(2)/m(2)). Systemic inflammatory response was measured by serum white cell count (WCC), neutrophil:lymphocyte ratio (NLR) and the Glasgow Prognostic Score (mGPS). RESULTS: There were no relationships between any parameter of body composition and serum WCC or NLR. There was a significant relationship between low skeletal muscle index and an elevated systemic inflammatory response, as measured by the mGPS (p = 0.001). This was confirmed by linear relationships between skeletal muscle index and both C-reactive protein (r = -0.21, p = 0.005) and albumin (r = 0.31, p<0.001). There was no association between skeletal muscle index and tumour stage. CONCLUSIONS: The present study highlights a direct relationship between low levels of skeletal muscle and the presence of a systemic inflammatory response in patients with primary operable colorectal cancer.