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Manchester Center, VT, United States

Weaver D.L.,University of Vermont | Weaver D.L.,Vermont Cancer Center
Modern Pathology | Year: 2010

Sentinel lymph nodes (SLN) are more likely to contain metastatic breast carcinoma than non-SLNs. The limited number of SLNs compared with an axillary dissection has prompted more comprehensive lymph node analysis increasing detection of micrometastases. National data show that many women previously classified node negative are now classified minimally node positive. As a result, our nodal classification and cancer staging have evolved to recognize the continuum of nodal tumor burden rather than a simplistic dichotomous stratification. It is quite clear that the more sections we evaluate from SLNs the more metastases we identify; however, it is impractical to expect the practicing pathologist to mount, stain, and microscopically examine every section through the SLN paraffin blocks. Despite recommendations from the College of American Pathologists and the American Society of Clinical Oncology, heterogeneity in the approach to SLN evaluation exists. What is needed is adherence to a standardized evaluation protocol. The most important aspect of the sentinel node examination is careful attention to slicing the SLN no thicker than 2.0 mm and correct embedding of the slices to assure we identify all macrometastases larger than 2.0 mm. A single section from blocks prepared in this manner will identify all macrometastases present but smaller metastases will be missed. The prognostic significance of these missed micrometastases is still being evaluated as we await SLN outcome studies. In the context of the new molecular classification of breast cancer, subgroups may be identified where detection of micrometastases has clinical significance. It is critical that both clinicians and pathologists understand there is a random component to micrometastasis distribution within the three-dimensional paraffin tissue blocks. If we ultimately adopt more comprehensive microscopic evaluation of SLNs, the candidate sampling strategies need to be carefully considered in the context of statistically valid sampling strategies. © 2010 USCAP, Inc. All rights reserved. Source


Tonato M.,Regina Elena Cancer Institute | Bria E.,Regina Elena Cancer Institute | Ballatori E.,Oncologia Medica | Espersen B.,Aarhus University Hospital | And 7 more authors.
Supportive Care in Cancer | Year: 2011

In this update of our 2005 document, we used an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents for the prevention of emesis and nausea following anticancer chemotherapies of high emetic risk. A three-drug combination of a 5-hydroxytryptamine type 3 receptor (5-HT3) receptor antagonist, dexamethasone, and aprepitant beginning before chemotherapy and continuing for up to 4 days remains the standard of care. We address issues of dose, schedule, and route of administration of five selective 5-HT3 receptor antagonists. We conclude that, for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. In trials designed to prove the equivalence of palonosetron to ondansetron and granisetron, palonosetron proved superior in emesis prevention, while adverse effects were comparable. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration. © 2010 Springer-Verlag. Source


Long P.M.,University of Vermont | Tighe S.W.,Vermont Cancer Center | Driscoll H.E.,Norwich University | Fortner K.A.,University of Vermont | And 2 more authors.
Journal of Cellular Physiology | Year: 2015

Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-l-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth. J. Cell. Physiol. 230: 1929-1943, 2015. © 2015 Wiley Periodicals, Inc. Source


Alcindor T.,McGill University | Ferri L.E.,McGill University | Marcus V.,McGill University | Andalib A.,McGill University | And 5 more authors.
Medical Oncology | Year: 2013

To determine whether metabolic or pathological response to preoperative chemotherapy can predict the relapse-free survival of gastroesophageal adenocarcinoma patients treated on a perioperative chemotherapy protocol. The prospectively collected data of a recently reported phase II trial of perioperative DCF chemotherapy (docetaxel/cisplatin/5-fluorouracil) were analyzed. Median relapse-free survival (RFS) was compared with the Wilcoxon rank-sum test between responders and non-responders according to defined metabolic (reduction in maximum standard uptake value of at least 35 %) and pathological (greater than 50 % tumor regression or ypN0 status) criteria. A double-sided p value equal or inferior to 0.05 was considered significant. Patients were followed for a median of 807 days (95 % CI: 607-896). RFS was 576 days in metabolic non-responders versus not reached in metabolic responders (p 0.009) and 562 days in ypN+ versus not reached in ypN0 patients (p 0.045). No statistically significant RFS difference was seen between low and high pathologic responders classified according to tumor regression criteria, although a trend was observed in favor of high pathologic responders. Simple metabolic and pathologic criteria used for the assessment of response to the preoperative part of perioperative chemotherapy can help to estimate the outcome of gastroesophageal adenocarcinoma patients. © 2012 Springer Science+Business Media New York. Source


Long P.M.,University of Vermont | Tighe S.W.,Vermont Cancer Center | Driscoll H.E.,Norwich University | Moffett J.R.,Uniformed Services University of the Health Sciences | And 4 more authors.
PLoS ONE | Year: 2013

Cancer is associated with globally hypoacetylated chromatin and considerable attention has recently been focused on epigenetic therapies. N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate and ultimately acetyl-Coenzyme A for histone acetylation, are reduced in oligodendroglioma. The short chain triglyceride glyceryl triacetate (GTA), which increases histone acetylation and inhibits histone deacetylase expression, has been safely used for acetate supplementation in Canavan disease, a leukodystrophy due to ASPA mutation. We demonstrate that GTA induces cytostatic G0 growth arrest of oligodendroglioma-derived cells in vitro , without affecting normal cells. Sodium acetate, at doses comparable to that generated by complete GTA catalysis, but not glycerol also promoted growth arrest, whereas long chain triglycerides promoted cell growth. To begin to elucidate its mechanism of action, the effects of GTA on ASPA and acetyl-CoA synthetase protein levels and differentiation of established human oligodendroglioma cells (HOG and Hs683) and primary tumor-derived oligodendroglioma cells that exhibit some features of cancer stem cells (grade II OG33 and grade III OG35) relative to an oligodendrocyte progenitor line (Oli-Neu) were examined. The nuclear localization of ASPA and acetyl-CoA synthetase-1 in untreated cells was regulated during the cell cycle. GTA-mediated growth arrest was not associated with apoptosis or differentiation, but increased expression of acetylated proteins. Thus, GTA-mediated acetate supplementation may provide a safe, novel epigenetic therapy to reduce the growth of oligodendroglioma cells without affecting normal neural stem or oligodendrocyte progenitor cell proliferation or differentiation. © 2013 Long et al. Source

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