Prediction of survival in patients with colorectal liver metastases- development and validation of a prognostic score model.

BACKGROUND: Metastatic spread of colorectal cancer to the liver impacts prognosis. Advances in chemotherapy have resulted in increased resectability rates and thereby improved survival in patients with colorectal liver metastases (CRLM). However, criteria are needed to ensure that patients selected for hepatic resection benefit from the invasive therapy. The study aimed to construct a predictive model for overall survival (OS) in patients with CRLM, based on preoperatively available information. METHODS: The retrospective cohort study reviewed all patients with CRLM discussed at multidisciplinary team conference at Karolinska University Hospital, Stockholm, Sweden, 2013-2018. Independent prognostic factors for OS were identified, based on which a score model was generated. The model was validated on patients treated for CRLM at Hôpital Universitaire Paul Brousse, Villejuif, France, 2007-2018. Calibration and discrimination methods were used for internal and external validation. RESULTS: The Swedish development cohort included 1013 patients, the French validation cohort 391 patients. Poor OS was significantly associated with age>60years (hazard ratio (HR) 3.57 (95%CI 2.18-9.94)), number of CRLM (HR 4.59 (2.83-12.20)), diameter of largest CRLM>5 cm (HR 2.59 (1.74-5.03)), right-sided primary tumour (HR 2.98 (2.00-5.80)), extrahepatic disease (HR 4.14 (2.38-15.87)) and non-resectability (HR 0.77 (0.66-0.90)). The C-statistic for prediction of OS was .74, in the development cohort and 0.69 in the validation cohort. CONCLUSION: The presented predictive score model can adequately predict OS for patients at the initial diagnosis of CRLM. The prognostic model could be of clinical value in the management of all patients with CRLM, by predicting individualized survival and thereby facilitating treatment recommendations.

Blockade of HMGB1 Attenuates Diabetic Nephropathy in Mice.

Activation of TLR2 or TLR4 by endogenous ligands such as high mobility group box 1 (HMGB1) may mediate inflammation causing diabetic kidney injury. We determined whether blockade of HMGB1 signaling by: (1) supra-physiological production of endogenous secretory Receptor for Advanced Glycation End-products (esRAGE), a receptor for HMGB1; (2) administration of HMGB1 A Box, a specific competitive antagonist, would inhibit development of streptozotocin induced diabetic nephropathy (DN). Wild-type diabetic mice developed albuminuria, glomerular injuries, interstitial fibrosis and renal inflammation. Using an adeno-associated virus vector, systemic over-expression of esRAGE afforded significant protection from all parameters. No protection was achieved by a control vector which expressed human serum albumin. Administration of A Box was similarly protective against development of DN. To determine the mechanism(s) of protection, we found that whilst deficiency of TLR2, TLR4 or RAGE afforded partial protection from development of DN, over-expression of esRAGE provided additional protection in TLR2-/-, modest protection against podocyte damage only in TLR4-/- and no protection in RAGE-/- diabetic mice, suggesting the protection provided by esRAGE was primarily through interruption of RAGE and TLR4 pathways. We conclude that strategies to block the interaction between HMGB1 and its receptors may be effective in preventing the development of DN.

Contralateral neck failure in lateralized oral squamous cell carcinoma.

BACKGROUND: Elective treatment of the contralateral clinically node-negative (cN0) neck is not routinely recommended for lateralized oral cavity squamous cell carcinoma (SCC). We sought to determine the failure rate in the untreated contralateral neck in patients with lateralized oral SCC undergoing treatment of the primary and ipsilateral neck and to identify any features placing patients at sufficient risk of contralateral regional failure to justify elective treatment. METHODS: We identified 688 patients with oral SCC undergoing curative surgery ± adjuvant therapy between 1985 and 2012 from a prospectively collected database. Patients with midline primaries and those undergoing bilateral neck treatment were excluded. The primary endpoint was isolated contralateral neck failure. RESULTS: Of 481 patients, 14 (2.9%) developed isolated contralateral neck recurrence, with median time to recurrence of 8 months. Patients with poorly differentiated tumours or pathologically proven ipsilateral nodal metastases were at significantly higher risk of contralateral failure (hazard ratio (HR) 3.6, 95% confidence interval (CI) 1.1-11.9, P = 0.037 and HR 4.6, 95% CI 1.5-13.8, P = 0.006 respectively). Presence of both of these factors conferred a 10% risk of contralateral failure. CONCLUSION: Patients with lateralized oral SCC undergoing treatment of the primary tumour and ipsilateral neck have a low rate of isolated contralateral neck failure. Although poorly differentiated primaries and ipsilateral nodal metastases were predictors of contralateral recurrence, the risk remains relatively modest in this subset of patients suggesting close observation may be more appropriate than elective treatment. Our results support current recommendations for observation of the cN0 contralateral neck in lateralized oral SCC.

ACE2 Therapy Using Adeno-associated Viral Vector Inhibits Liver Fibrosis in Mice.

Angiotensin converting enzyme 2 (ACE2) which breaks down profibrotic peptide angiotensin II to antifibrotic peptide angiotensin-(1-7) is a potential therapeutic target in liver fibrosis. We therefore investigated the long-term therapeutic effect of recombinant ACE2 using a liver-specific adeno-associated viral genome 2 serotype 8 vector (rAAV2/8-ACE2) with a liver-specific promoter in three murine models of chronic liver disease, including carbon tetrachloride-induced toxic injury, bile duct ligation-induced cholestatic injury, and methionine- and choline-deficient diet-induced steatotic injury. A single injection of rAAV2/8-ACE2 was administered after liver disease has established. Hepatic fibrosis, gene and protein expression, and the mechanisms that rAAV2/8-ACE2 therapy associated reduction in liver fibrosis were analyzed. Compared with control group, rAAV2/8-ACE2 therapy produced rapid and sustained upregulation of hepatic ACE2, resulting in a profound reduction in fibrosis and profibrotic markers in all diseased models. These changes were accompanied by reduction in hepatic angiotensin II levels with concomitant increases in hepatic angiotensin-(1-7) levels, resulting in significant reductions of NADPH oxidase assembly, oxidative stress and ERK1/2 and p38 phosphorylation. Moreover, rAAV2/8-ACE2 therapy normalized increased intrahepatic vascular tone in fibrotic livers. We conclude that rAAV2/8-ACE2 is an effective liver-targeted, long-term therapy for liver fibrosis and its complications without producing unwanted systemic effects.

Evidence-based and clinical outcome scores to facilitate audit and feedback for colorectal cancer care.

PURPOSE: To describe a methodology for surgical audit and feedback based on hospital-level indicators of the quality of colorectal cancer care. METHODS: Process and outcome indicators were identified from a population-based database (N = 3095 patients treated by 258 surgeons at 130 hospitals across New South Wales between February 1, 2000 and January 31, 2001). Hospitals were ranked on each indicator, with those in the lowest 20th percentile receiving a score of 0 and the remainder receiving a score of 1. Scores for individual indicators were then summed for each hospital and divided by the number of relevant indicators to provide an evidence-based score (EBS) and a clinical outcome score. RESULTS: Ten process and six clinical outcome indicators were identified. Hospital-level summary scores ranged from 0.14 to 1.0 for evidence-based processes and from 0.17 to 1.0 for clinical outcomes. Evidence-based score and clinical outcome score were independent (r = 0.12, P = 0.32). There was a small positive association between evidence-based score and caseload (r = 0.33, P = 0.005) but clinical outcome score and caseload were unrelated (r = 0.11, P = 0.36). CONCLUSIONS: Evidence-based score and clinical outcome score address different aspects of quality of care. The wide variability of hospitals' outcome scores and an association of evidence-based score and caseload indicate that simple scores may be useful in audit and feedback.