Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report

Background

Following failure of standard systemic chemotherapy, the role of hepatic transarterial therapy for colorectal hepatic metastasis continues to evolve as the experience with this technique matures. The aim of this study to gain a better understanding of the value of drug eluting bead therapy when administered to patients with unresectable colorectal hepatic metastasis.

Methods

This was an open-label, multi-center, single arm study, of unresectable colorectal hepatic metastasis patients who had failed standard therapy from 10/2006-10/2008. Patients received repeat embolizations with Irinotecan loaded beads(max 100 mg per embolization) per treating physician's discretion.

Results

Fifty-five patients underwent 99 treatments using Irinotecan drug eluting beads. The median number of total treatments per patient was 2(range of 1-5). Median length of hospital stay was 23 hours(range 23 hours - 10 days). There were 30(30%) sessions associated with adverse reactions during or after the treatment. The median disease free and overall survival from the time of first treatment was 247 days and 343 days. Six patients(10%) were downstaged from their original disease status. Of these, four were treated with surgery and two with RFA. Neither number of liver lesions, size of liver lesions or extent of liver replacement(<= 25% vs >25%) were predictors of overall survival. Only the presence of extrahepatic disease(p = 0,001), extent of prior chemotherapy (failed 1^st and 2^nd line vs > 2 line failure)(p = 0,007) were predictors of overall survival in multivariate analysis.

Conclusion

Chemoembolization using Irinotecan loaded beads was safe and effective in the treatment of patients as demonstrated by a minimal complication rate and acceptable tumor response.     

BIOCHEMICAL STUDIES ON DEGENERATIVE NEUROLOGICAL DISORDERS: 1. ACUTE EXPERIMENTAL ENCEPHALITIS

—Weanling mice were either injected with viruses or fed cuprizone. Changes in total activity of two cathepsins and two β-glycosidases were characteristic of each of the five acute encephalopathies studied. Comparisons made between morphological change and hydrolase activity shows that β-galactosidase and cathepsin A may be useful indices of neuronal degeneration and cellular infiltration into white matter, respectively. β-Glucuronidase appears to be a particularly sensitive index of cellular reactions to injury. Cathepsin D activity does not appear to reflect any one type of neural cell. Although the morphological changes included neuronal degeneration, perivascular cuffing with mononuclear cells, astrocytic hypertrophy and microgliosis none of the experimental conditions mimicked biochemical changes in multiple sclerosis or senile dementia. The measurement of lysosomal enzymes appears to be a more sensitive indication of acute neurological disorder than the screening of brain proteins by polyacrylamide gel clectrophoresisor the measurement of enzymes (acetylcholinesterase, DOPA decarboxylase and carbonic anhydrase) characteristic of neural cells.     

Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma

Centrosome amplification (CA), the presence of centrosomes that are abnormally numerous or enlarged, is a well-established driver of tumor initiation and progression associated with poor prognosis across a diversity of malignancies. Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses of all cancer types. A majority of these tumors are characterized by numerical and structural centrosomal aberrations, but it is unknown how CA contributes to the disease and patient outcomes. In this study, we sought to determine whether CA was associated with worse clinical outcomes, poor prognostic indicators, markers of epithelial-mesenchymal transition (EMT), and ethnicity in PDAC. We also evaluated whether CA could precipitate more aggressive phenotypes in a panel of cultured PDAC cell lines. Using publicly available microarray data, we found that increased expression of genes whose dysregulation promotes CA was associated with worse overall survival and increased EMT marker expression in PDAC. Quantitative analysis of centrosomal profiles in PDAC cell lines and tissue sections uncovered varying levels of CA, and the expression of CA markers was associated with the expression of EMT markers. We induced CA in PDAC cells and found that CA empowered them with enhanced invasive and migratory capabilities. In addition, we discovered that PDACs from African American (AA) patients exhibited a greater extent of both numerical and structural CA than PDACs from European American (EA) patients. Taken together, these findings suggest that CA may fuel a more aggressive disease course in PDAC patients.     

Differential profiling studies of N-linked glycoproteins in glioblastoma cancer stem cells upon treatment with γ-secretase inhibitor

We have recently demonstrated that Notch pathway blockade by γ-secretase inhibitor (GSI) depletes cancer stem cells (CSCs) in Glioblastoma Multiforme (GBM) through reduced proliferation and induced apoptosis. However, the detailed mechanism by which the manipulation of Notch signal induces alterations on post-translational modifications such as glycosylation has not been investigated. Herein, we present a differential profiling work to detect the change of glycosylation pattern upon drug treatment in GBM CSCs. Rapid screening of differential cell surface glycan structures has been performed by lectin microarray on live cells followed by the detection of N-linked glycoproteins from cell lysates using multi-lectin chromatography and label-free quantitative mass spectrometry analysis. A total of 51 and 52 glycoproteins were identified in the CSC- and GSI-treated groups, respectively, filtered by a combination of decoy database searching and Trans-Proteomic Pipeline (TPP) processing. Although no significant changes were detected from the lectin microarray experiment, 7 differentially expressed glycoproteins with high confidence were captured after the multi-lectin column including key enzymes involved in glycan processing. Functional annotations of the altered glycoproteins suggest a phenotype transformation of CSCs toward a less tumorigenic form upon GSI treatment.     

Impact of diatomaceous biofilms on the frictional drag of fouling-release coatings

Skin-friction results are presented for fouling-release (FR) hull coatings in the unexposed, clean condition and after dynamic exposure to diatomaceous biofilms for 3 and 6 months. The experiments were conducted in a fully developed turbulent channel flow facility spanning a wide Reynolds number range. The results show that the clean FR coatings tested were hydraulically smooth over much of the Reynolds number range. Biofilms, however, resulted in an increase in skin-friction of up to 70%. The roughness functions for the biofilm-covered surfaces did not display universal behavior, but instead varied with the percentage coverage by the biofilm. The effect of the biofilm was observed to scale with its mean thickness and the square root of the percentage coverage. A new effective roughness length scale (k_eff) for biofilms based on these parameters is proposed. Boundary layer similarity-law scaling is used to predict the impact of these biofilms on the required shaft power for a mid-sized naval surface combatant at cruising speed. The increase in power is estimated to be between 1.5% and 10.1% depending on the biofilm thickness and percentage coverage.     

Bacteria–bacteria interactions within the microbiota of the ancestral metazoan Hydra contribute to fungal resistance

Epithelial surfaces of most animals are colonized by diverse microbial communities. Although it is generally agreed that commensal bacteria can serve beneficial functions, the processes involved are poorly understood. Here we report that in the basal metazoan Hydra, ectodermal epithelial cells are covered with a multilayered glycocalyx that provides a habitat for a distinctive microbial community. Removing this epithelial microbiota results in lethal infection by the filamentous fungus Fusarium sp. Restoring the complex microbiota in gnotobiotic polyps prevents pathogen infection. Although mono-associations with distinct members of the microbiota fail to provide full protection, additive and synergistic interactions of commensal bacteria are contributing to full fungal resistance. Our results highlight the importance of resident microbiota diversity as a protective factor against pathogen infections. Besides revealing insights into the in vivo function of commensal microbes in Hydra, our findings indicate that interactions among commensal bacteria are essential to inhibit pathogen infection.     

Short communication. First record of Torticaecum sp. (Trematoda: Didymozoidae) in the chaetognath Serratosagitta serratodentata (Krohn, 1853) from Caribbean waters

From samples collected in the Caribbean Sea during February, March, May and August 1991, a total of 22 508 holoplanktonic chaetognaths were caught. During the analyses of the samples, one non-cysted specimen of didymozoid metacercaria was found in the coelom of the chaetognath Serratosagitta serratodentata (prevalence 0.004%). Owing to the lack of an authentic stomach and the morphology of the intestine, this trematode seems to belong to the Torticaecum larval type. This is the first report of both the chaetognath species as a host and the geographical locality for this parasite.      

In situ toxicity tests of fishes in acid waters

Toxicity of waters within the North Branch of the Moose River to various life stages of lake trout (Salvelinus namaycush), brook trout (Salvelinus fontinalis), creek chub (Semotilus atromaculatus), and blacknose dace (Rhinichthys atratulus) were examined in situ. Study sites were selected that were expected to range from toxic to favourable water quality. For example, pH varied from 4.25 to 7.17, inorganic monomeric Al ranged from ND (< 0.01 mg/l) to 0.40 mg/l, and Ca, from 0.41 to 4.27 mg/l.Toxicity tests were conducted at times when the life stages would naturally occur in these waters and were continued until a range of mortality was observed at the various sites. These experiments suggested that the extent of the drainage system that is toxic to fish increases during snowmelt and major runoff events. Summer base flow water quality was generally the least toxic.Critical life stages were upon hatching and as early feeding fry. In general, young of the year fish were the most tolerant life stage tested. Yearling and adult fish, however, were very sensitive. Blacknose dace were the most sensitive fish of the four species tested, and brook trout were the most tolerant.Hydrogen ion (H⁺) concentration was the most toxic variable in the majority of tests. Inorganic monomeric Al was the most toxic in several, and the combination of H⁺ and Al seemed to cause increased toxicity in many instances. A three-variable model employing hours of exposure, H⁺ concentration, and inorganic monomeric Al predicted mortality quite well. A simple two-variable model using H⁺ and color was nearly as good (R² from 0.49 to 0.94).Documented differences in toxicity among sites and species agreed with observed patterns of fish distribution. These in situ results indicated that laboratory estimates of safe levels of pH and concentrations of Al can result in mortality of fishes in surface waters subject to acidification.