Does dissemination of guidelines alone increase the use of palliative single-fraction radiotherapy? Initial report of a longitudinal change management campaign at a provincial cancer program.

Background: Despite level 1 evidence demonstrating the equivalence of single-fraction radiotherapy (sfrt) and multiple-fraction radiotherapy (mfrt) for the palliation of painful bone metastases, sfrt remains underused. In 2015, to encourage the sustainable use of palliative radiation oncology resources, CancerCare Manitoba disseminated, to each radiation oncologist in Manitoba, guidelines from Choosing Wisely Canada (cwc) that recommend sfrt. We assessed whether dissemination of the guidelines influenced sfrt use in Manitoba in 2016, and we identified factors associated with mfrt. Methods: All patients treated with palliative radiotherapy for bone metastasis in Manitoba from 1 January 2016 to 31 December 2016 were identified from the provincial radiotherapy database. Patient, treatment, and disease characteristics were extracted from the electronic medical record and tabulated by fractionation schedule. Univariable and multivariable logistic regression analyses were performed to identify risk factors associated with mfrt. Results: In 2016, 807 patients (mean age: 70 years; range: 35-96 years) received palliative radiotherapy for bone metastasis, with 69% of the patients having uncomplicated bone metastasis. The most common primary malignancies were prostate (27.1%), lung (20.6%), and breast cancer (15.9%). In 62% of cases, mfrt was used-a proportion that was unchanged from 2015. On multivariable analysis, a gastrointestinal [odds ratio (or): 5.3] or lung primary (or: 3.3), complicated bone metastasis (or: 4.3), and treatment at a subsidiary site (or: 4.4) increased the odds of mfrt use. Conclusions: Dissemination of cwc recommendations alone did not increase sfrt use by radiation oncologists in 2016. A more comprehensive knowledge translation effort is therefore warranted and is now underway to encourage increased uptake of sfrt in Manitoba.

RNA-sequencing profiles hippocampal gene expression in a validated model of cancer-induced depression.

To investigate the pathophysiology of cancer-induced depression (CID), we have recently developed a validated CID mouse model. Given that the efficacy of antidepressants in cancer patients is controversial, it remains unclear whether CID is a biologically distinct form of depression. We used RNA-sequencing (RNA-seq) to investigate differentially expressed genes (DEGs) in hippocampi of animals from our CID model relative a positive control model of depressive-like behavior induced with chronic corticosterone (CORT). To validate RNA-seq results, we performed quantitative real-time RT-PCR (qRT-PCR) on a subset of DEGs. Enrichment analysis using DAVID was performed on DEGs to identify enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and biological process gene ontologies (GO:BP). qRT-PCR results significantly predicted RNA-seq results. RNA-seq revealed that most DEGs identified in the CORT model overlapped with the CID model. Enrichment analyses identified KEGG pathways and GO:BP terms associated with ion homeostasis and neuronal communication for both the CORT and CID model. In addition, CID DEGs were enriched in pathways and terms relating to neuronal development, intracellular signaling, learning and memory. This study is the first to investigate CID at the mRNA level. We have shown that most hippocampal mRNA changes that are associated with a depressive-like state are also associated with cancer. Several other changes occur at the mRNA level in cancer, suggesting that the CID model may represent a biologically distinct form of a depressive-like state.

Biological therapy of salivary duct carcinoma.

BACKGROUND: The incidence of human epidermal growth factor receptor 2 positivity in salivary duct carcinoma ranges from 25 to 100 per cent and is associated with a poor outcome. Salivary duct carcinoma has significant pathological similarities to ductal carcinoma of the breast. METHODS AND RESULTS: A 49-year-old man developed lung and liver metastasis a few months after surgery and adjuvant radiotherapy for salivary duct carcinoma of the parotid gland. There was no response to palliative chemotherapy with doxorubicin. We followed the biological model of breast cancer, whereby two-thirds of human epidermal growth factor receptor 2 positive patients respond to a combination of docetaxel and human epidermal growth factor receptor 2 blocker (trastuzumab). A durable, complete response was achieved with this combination. A rationalised treatment approach targeting the biological characteristics of salivary duct carcinoma had proven successful.

Huge peripheral osteoma of the mandible: a case report and review of the literature.

Osteomas are rare benign tumors of bone commonly occurring in the maxillofacial skeleton. In the course of their slow but steady increase in size, osteomas of the maxillofacial bones remain asymptomatic until they attain sufficient sizes as to cause disfigurement and/or direct interference with the normal function of their anatomic location. Here, we report a case of a huge solitary peripheral osteoma of the lingual posterior mandible in a 50-year-old woman who was otherwise in good health. The patient reported at the dental clinic because the lesion interfered with speech, swallowing, and caused occasional gagging. Histological examination confirmed the clinical impression of a peripheral osteoma. Treatment was by surgical excision and histological examination. The patient remains free of recurrence after 5 years.

Possible atypical cross-sensitivity between phenytoin and carbamazepine in the anticonvulsant hypersensitivity syndrome.

Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening reaction that occurs in response to common anticonvulsants in predisposed individuals. It is often characterized by fever, rash, lymphadenopathy, hepatitis, and laboratory abnormalities. Consequently, it often is overlooked or even misdiagnosed by practitioners unfamiliar with AHS. Cross-sensitivity manifests frequently between phenytoin, phenobarbital, and carbamazepine as an exacerbation of presenting signs and symptoms. We report a case of AHS in a patient whose clinical features changed significantly when switching from phenytoin to carbamazepine. Physicians and pharmacists must become aware of the extreme variability in AHS manifestation so that the offending anticonvulsant regimen can be discontinued in a timely manner.

An improved synthesis of 4-azido-4-deoxy- and 4-amino-4-deoxy-alpha,alpha-trehalose and their epimers.

The order of esterification of the eight hydroxyl groups of alpha,alpha-trehalose is HO-6.6' > HO-2.2' > HO-3.3' > HO-4.4'. Under the appropriate conditions of benzoylation, the heptabenzoate with HO-4' free was obtained in good yield (58%), along with the octabenzoate and the hexabenzoate having HO-4.4' free. The readily isolated heptabenzoate was a convenient starting material for the synthesis of 4-azido-4-deoxy- (84%) and 4-amino-4-deoxy-alpha-D-galactopyranosyl alpha-D-glucopyranoside, and the heptabenzoate of alpha-D-galactopyranosyl alpha-D-glucopyranoside with HO-4' free, which was used as a synthetic precursor of 4-azido-4-deoxy-alpha-D-glucopyranosyl alpha-D-glucopyranoside and its amino analogue.

Structural requirements for the carbohydrate ligand of E-selectin.

The acute inflammatory response requires that circulating leukocytes adhere to, and then migrate through, the vascular wall at the site of injury or infection. Several receptors have been implicated in this adhesion and migration process, including the selectins, a family of carbohydrate-binding proteins. The ligand for one of these proteins, E-selectin (LECAM-2, ELAM-1) has been described by several groups to contain a polylactosamine structure bearing a terminal sialic acid residue and at least one fucose residue. We report here a more detailed investigation into the minimum structural requirements for carbohydrate recognition by E-selectin. Using both direct binding and inhibition studies we demonstrate that the sialyl Lewisx tetrasaccharides Sia(alpha 2-3)Gal(beta 1-4)[Fuc(alpha 1-3)]GlcNAc, and Sia(alpha 2-3)Gal(beta 1-4)[Fuc(alpha 1-3)]Glc are the smallest oligosaccharides recognized by the lectin. In addition, an oligosaccharide containing the sialyl Lewisa epitope is also recognized, but less avidly. We propose a structural model of functional groups necessary for recognition by E-selectin, based on these data and additional experiments on modifications of sialic acid and the reducing terminal saccharide.

An improved synthesis of trehalose 6-mono- and 6,6'-di-corynomycolates and related esters.

A simplified synthesis of 6-mono- and 6,6'-di-corynomycolate esters of alpha,alpha-trehalose, and related compounds, was achieved by coupling the (hydroxyl-protected) acids to the partially trimethylsilylated sugar in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine. As acid reactants, (2-RS,3-RS)-3-hydroxy-2-tetradecyloctadecanoic acid (DL-corynomycolic acid) and its 2RS,3SR diastereomer were prepared from methyl palmitate by sequential Claisen condensation, reduction, chromatographic separation, and saponification. Reaction with tert-butylchlorodimethylsilane (imidazole) gave the disubstituted ether-esters, which were converted into the required 3-tert-butyldimethylsilyl ethers by partial hydrolysis. 6-Linked monocorynomycolate was obtained in excellent yield (78%) from the reaction of the RS,SR acid with the known heptakis-O-(trimethylsilyl)trehalose, and in good yield from equimolar portions of RS,RS acid and hexakis-O-(trimethylsilyl)trehalose. An excess (2.5-molar portions) of the RS,RS acid gave the 6,6'-diester (69%). The mono- and di-palmitate were similarly obtained from (Me3Si)6-trehalose. The mono (RS,RS)-(Me3Si)6-trehalose coupling product was partially resolved on a silica gel column into its RR and SS diastereomers, the former corresponding to the naturally occurring trehalose monocorynomycolate. All coupling products were deprotected to free trehalose esters by treatment first with K2CO3 in methanol, then tetrabutylammonium fluoride-trifluoracetic acid in oxolane.

A convergent approach to the synthesis of lipid A.

To accomplish the synthesis of compounds having the essential structural features of bacterial lipid A, one must assemble a glucosamine disaccharide bearing five to seven substituents (fatty acyl groups, phosphate ester groups) at specific positions. In the convergent synthesis described, a protected glycoside prepared from D-glucosamine hydrochloride serves as the common intermediate from which both halves of the lipid A structure are fashioned. The glycoside is then converted, by separate series of reactions, into precursors of the reducing half and the nonreducing half of the molecule. The coupling of these precursors yields a product that is readily processed into analogues of lipid A.

Fatty acyl derivatives of glucosamine 1-phosphate in Escherichia coli and their relation to lipid A. Complete structure of A diacyl GlcN-1-P found in a phosphatidylglycerol-deficient mutant.

We have determined the complete structure of a glycolipid (designated lipid X) previously found to accumulate in certain Escherichia coli mutants defective in phosphatidylglycerol synthesis (Nishijima, M., and Raetz, C.R.H. (1979) J. Biol. Chem. 254, 7837-7844). Based on fast atom bombardment mass spectrometry and proton nuclear magnetic resonance studies, this substance is an acylated metabolite of glucosamine 1-phosphate. Lipid X of E. coli has a Mr = 711.87 as the free acid (C34H66NO12P) and contains two beta-hydroxymyristate moieties, one attached as an amide at the 2 position and the other as an ester at the 3 position of the sugar. It has free hydroxyl groups at the 4 and 6 positions, and the anomeric configuration is alpha. The structure of lipid X from E. coli closely resembles the reducing end subunit of lipid A, and it might represent a very early precursor in the biosynthesis of lipid A. To our knowledge, fatty acyl derivatives of glucosamine 1-phosphate have not been reported previously.

Oligosaccharides from "standardized intermediates". Synthesis of a branched tetrasaccharide glycoside isomeric with the blood-group B, type 2 determinant.

Building block derivatives of the component monosaccharides were used to construct the tetrasaccharide glycoside 15, in which an alpha-D-Galp-(1 leads to 4)-D-Gal linkage replaces the alpha-(1 leads to 3) linkage of the human blood-group B, type 2, determinant structure. The initial coupling of 2-O-benzoyl-3,6-di-O-benzyl-4-O-(tetrahydropyran-2-yl)-alpha-D-galactopyranosyl chloride to allyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside was followed by selective deprotection of the disaccharide product, either at O-4' (to give 8) or O-2' (to give 3). The conversion of 8 into 15 involved successive coupling with tetra-O-benzyl-alpha-D-galactopyranosyl bromide (8 leads to 11), O-debenzoylation at O-2' (11 leads to 12), coupling with tri-O-benzyl-alpha-L-fucopyranosyl bromide (12 leads to 14), and O-debenzylation by hydrogenolysis (14 leads to 15). Alternatively, 3 was alpha-L-fucosylated to give 6, and 6 was selectively deprotected at O-4' to give 7. However, attempts to alpha-D-galactosylate 7 were unsuccessful. The unsubstituted forms of the intermediate disaccharide (8) and trisaccharide (12) glycosides were obtained by appropriate deblocking procedures.

Oligosaccharides from "standardized intermediates". The 2-amino-2-deoxy-D-galactose analog of the blood-group O(H) determinant, type 2, and its precursors.

The selectively benzylated glycoside allyl 2-acetamido-4,6-di-O-benzyl-2-deoxy-beta-D-galactopranoside (4) was prepared from the corresponding derivative of 2-acetamido-2-deoxy-D-glucose via the p-bromobenzenesulfonate and the benzoate. 2-O-Benzoyl-3,4,6-tri-O-benzyl-alpha-D-galactopyranosyl (10) was obtained from allyl 6-O-benzyl-2-O-(2-butenyl)-alpha-D-galactopyranoside via known intermediates. To complete the sequence, the 1-propenyl 3,4,6-tri-O-benzyl galactoside was successively converted into the 2-benzoate, the free sugar, and the chloride 10. A fully protected form (11) of the trisaccharide alpha-L-Fucp-(1 leads to 2)-beta-D-Galp-(1 leads to 4)-D-GalNAc was then synthesized by coupling 10 to 4, partially deblocking the disaccharide product, and L-fucosylating the resulting intermediate. Cleavage of the O-benzyl groups from 11, with concomitant saturation of the allyl group, gave the propyl beta-glycoside of the unsubstituted trisaccharide.