International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

BACKGROUND: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies

Assembly of Linked Nanocrystal Colloids by Reversible Covalent Bonds

The use of dynamically bonding molecules designed to reversibly link solvent-dispersed nanocrystals (NCs) is a promising strategy to form colloidal assemblies with controlled structure and macroscopic properties. In this work, tin-doped indium oxide NCs are functionalized with ligands that form reversible covalent bonds with linking molecules to drive assembly of NC gels. We monitor gelation using small angle X-ray scattering and characterize how changes in the gel structure affect infrared optical properties arising from the localized surface plasmon resonance of the NCs. The assembly is reversible because of the designed linking chemistry, and we disassemble the gels using two strategies: addition of excess NCs to change the ratio of linking molecules to NCs and addition of a capping molecule that displaces the linking molecules. The assembly behavior is rationalized using a thermodynamic perturbation theory to compute the phase diagram of the NC–linking molecule mixture. Coarse-grained molecular dynamics simulations reveal the competition between loop and bridge linking motifs essential for understanding NC gelation. This combined experimental, computational, and theoretical work provides a platform for controlling and designing the properties of reversible colloidal assemblies that incorporate NC and solvent compositions beyond those compatible with other contemporary (e.g, DNA-based) linking strategies.We would like to acknowledge the UT Mass Spectrometry Facility for their instrumental help and the UT NMR facilities for equipment use and assistance: NIH Grant Number 1 S10 OD021508-01. This work was primarily supported by the National Science Foundation through the Center for Dynamics and Control of Materials: an NSF Materials Research Science and Engineering Center (NSF MRSEC) under Cooperative Agreement DMR-1720595. This work was also supported by NSF Graduate Research Fellowships DGE-1610403 (M.N.D. and S.V.), an Arnold O. Beckman Postdoctoral Fellowship (Z.M.S.), NSF (CHE- 1905263), and the Welch Foundation (F-1848 and F-1696). E.V.A. acknowledges support from the Welch Regents Chair (F-0046). We acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing HPC resources.Center for Dynamics and Control of Material

Increased arterial stiffness in young adults with end-stage renal disease since childhood

Increased arterial stiffness is a risk factor for mortality in adults over 40 yr of age with end-stage renal disease (ESRD). As no data exist on vascular changes in young adults with ESRD since childhood, a long-term outcome study was performed. All living Dutch adult patients with onset of ESRD between 1972 and 1992 at age 0 to 14 yr were invited for carotid artery and cardiac ultrasound and BP measurements. Data on clinical characteristics were collected by review of all medical charts. Carotid ultrasound data were compared with those of 48 age-matched and gender-matched healthy controls. Carotid artery and cardiac ultrasound was performed in 130 out of 187 eligible patients. Mean age was 29.0 (20.7 to 40.6) yr. Compared with controls, patients had a similar intima media thickness but a reduced mean arterial wall distensibility DC (40.0 versus 45.0 kPa(-1). 10(-3); 95% CI, -9.1 to -0.8; P <0.001), an increased stiffness parameter beta (4.2 versus 3.8; 95% CI, 0.05 to 0.68; P = 0.02), an increased elastic incremental modulus E-inc (0.35 versus 0.27 kPa . 10(3); 95% CI, 0.02 to 0.12; P <0.001). Multiple regression analyses in all subjects revealed that ESRD was associated with an increase in 0 and Einc. Arterial wall properties of patients currently on dialysis and transplanted patients were comparable. In all patients, current systolic hypertension was associated with increased E-inc and decreased DC. In conclusion, carotid arterial wall stiffness is increased in young adult patients with pediatric ESRD. Hypertension is a main determinant and might be a target for treatment of these potentially lethal arterial wall change

Does portal vein embolization prior to liver resection influence the oncological outcomes - A propensity score matched comparison

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Maternal nutrition during gestation and carotid arterial compliance in the adult offspring: the Dutch famine birth cohort

OBJECTIVE: Experimental evidence indicates that maternal undernutrition during gestation may program hypertension in the offspring. We investigated whether maternal undernutrition leads to increased arterial stiffness. METHODS: We measured carotid artery lumen diameter (LD), distensibility (DC), stiffness (beta), and compliance (CC) by M-mode ultrasound in 673 individuals, aged 56-61 years, who had been born as term singletons around the time of the 1944-45 Dutch famine. RESULTS: Maternal famine exposure had no effect on any of the measures of carotid size or stiffness in the offspring. Low maternal weight at the end of pregnancy and low birth weight were associated with decreased LD (0.01 mm/kg maternal weight, sex-adjusted P < 0.001; 0.1 mm/kg birth weight, sex-adjusted P = 0.08) and CC (0.002 mm2/kPa per kg maternal weight, sex-adjusted P = 0.001; 0.03 mm2/kPa per kg birth weight, sex-adjusted P = 0.03), but neither was associated with increased beta, or decreased DC. These effects were not attenuated by adjusting for maternal protein/carbohydrate ratio in the third trimester. The association of low birth weight with increased CC diminished after adjusting for maternal weight. The association of maternal weight with CC was smaller when adjusted for LD. CONCLUSION: Our findings suggest that small maternal size, not poor maternal diet, in late gestation programs decreased arterial compliance in the adult offspring by affecting vessel size rather than vessel wall stiffnes

Maternal nutrition during gestation and carotid arterial compliance in the adult offspring: the Dutch famine birth cohort

OBJECTIVE: Experimental evidence indicates that maternal undernutrition during gestation may program hypertension in the offspring. We investigated whether maternal undernutrition leads to increased arterial stiffness. METHODS: We measured carotid artery lumen diameter (LD), distensibility (DC), stiffness (beta), and compliance (CC) by M-mode ultrasound in 673 individuals, aged 56-61 years, who had been born as term singletons around the time of the 1944-45 Dutch famine. RESULTS: Maternal famine exposure had no effect on any of the measures of carotid size or stiffness in the offspring. Low maternal weight at the end of pregnancy and low birth weight were associated with decreased LD (0.01 mm/kg maternal weight, sex-adjusted P &lt; 0.001; 0.1 mm/kg birth weight, sex-adjusted P = 0.08) and CC (0.002 mm/kPa per kg maternal weight, sex-adjusted P = 0.001; 0.03 mm/kPa per kg birth weight, sex-adjusted P = 0.03), but neither was associated with increased beta, or decreased DC. These effects were not attenuated by adjusting for maternal protein/carbohydrate ratio in the third trimester. The association of low birth weight with increased CC diminished after adjusting for maternal weight. The association of maternal weight with CC was smaller when adjusted for LD. CONCLUSION: Our findings suggest that small maternal size, not poor maternal diet, in late gestation programs decreased arterial compliance in the adult offspring by affecting vessel size rather than vessel wall stiffness

Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases

BACKGROUND: In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy. METHODS: All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver. RESULTS: In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen. CONCLUSIONS: The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials

The impact of hepatic arterial infusion pump chemotherapy on hepatic recurrences and survival in patients with resected colorectal liver metastases

BACKGROUND: The objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM). METHODS: Recurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses. RESULTS: 2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60-0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57-0.78,p < 0.001). CONCLUSION: Adjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM