FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer

Background

Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.     

Enhanced MYCN expression and lsochromosome 17q in pineoblastoma cell lines

We have established two cell lines, PER-452 and PER-453, from an 8-month-old girl with an extensive pineoblastoma. Characterization of these lines revealed that the proto-oncogenes MYC and MYCN were not amplified, but both cell lines showed MYCN expression comparable to a cell line with 200-fold MYCN amplification. Both cell lines contained an i( 17q). These results support the concept that pineoblastomas belong to a larger group of primitive neuroectodermal tumors of the central nervous system. These two cell lines provide a unique opportunity to investigate the molecular genetic mechanisms underlying these neoplasms further. Genes Chrom Cancer 9:129-135 (1994).© 1994 Wiley-Liss, Inc.     

Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa

The aim of this study was to examine the potencies of several recently identified selective somatostatin (SRIF)-receptor ligands as inhibitors of electrogenic ion transport in the rat distal colonic mucosa with the view to identifying the SRIF receptor type involved. Under basal conditions, cumulative administration of SRIF and SRIF2g decreased short circuit current (SCC), a measure of electrogenic ion transport, with EC₅₀ values of 4 nM and 9 nM respectively. The peptidase inhibitors, phosphoramidon (1 M) and amastatin (10 M), had no effect on the potencies of either SRIF or SRIF₂₈. The inhibitory action of SRIF on basal SCC was suppressed by piretanide and diphenylamine-2-carboxylate, compatible with the assumption that the Na⁺K⁺2Cl^– co-transporter and Cl^– channels, respectively, may be involved in this antisecretory action of SRIF. Tetrodotoxin (1 M) had no effect on the antisecretory action of SRIF, suggesting that the process was not neuronally mediated.All of the SRIF analogues examined, with the exception of BIM-23056, maximally inhibited basal SCC to a similar extent as SRIF. Seglitide and octreotide were both more potent antisecretory agents than SRIF (respective EC₅₀ values, 0.4 nM and 1.5 nM) suggesting that this effect was mediated by a receptor belonging to the SRIF₁ receptor group. The most distinguishing feature of the rank order of agonist potencies was the high potency of the selective sst₂ receptor ligand, BIM-23027 (EC₅₀, value 0.32 nM), the weaker potency exhibited by the selective sst₅ receptor ligand, L-362855 (EC₅₀ value 21 nM), and the lack of agonist activity displayed by the selective sst₃ receptor ligand, BIM-23056 (EC₅₀ value > 1000 nM). This profile is comparable with that observed in binding studies on the recombinant sst₂ receptor.Forskolin-stimulated secretion was suppressed by SRIF analogues with the rank order of agonist potencies BIM-23027 > SRIF > L-362855 > BIM-23056 which resembled that exibited under basal conditions. However, the absolute potencies of these agonists were lower (respective EC₅₀ values 2 nM, 14 nM, 38 nM and > 1000 nM) whilst the magnitude of inhibition was about three fold greater. BIM-23027 and SRIF (both 30 nM) also inhibited carbachol-stimulated increases in basal SCC by 60–70%, while a similar concentration of L-362855 inhibited these responses by 11 %. BIM-23056 (1 M) had no effect on carbachol-simulated secretion. Radioligand binding studies on rat colonic mucosal membranes using [¹²⁵I]-Tyr¹¹-SRIF suggested heterogeneity of SRIF binding sites. Thus, SRIF and SRIF₂₈ competed for binding (IC₅₀ values, 0.32 and 0.63 nM, respectively) with Hill slopes less than unity; while seglitide and BIM-23027 both maximally displaced only 30–40% of specific binding with apparent high affinity (respective pIC₅₀ values, 10.1 nM and 10.0).In conclusion, SRIF decreases basal as well as both cAMP and Ca²⁺-dependent Cl^– secretion in rat colonic mucosa. The rank order of agonist potencies suggests that receptors resembling the recombinant sst₂ receptor mediate inhibition of basal and forskolin-stimulated secretion. Radioligand binding studies suggest that BIM-23027 interacts with a sub-population of [¹²⁵I]Tyr¹¹-SRIF binding sites in rat colonic mucosal membranes which probably correspond to the receptors mediating the antisecretory effects described here.     

Techniques for Toddlers: Linear Band Incision for Harlequin Ichthyosis with Associated Compartment Syndrome

Harlequin ichthyosis (HI) is a rare autosomal recessive disorder of cornification in which children are born with an extremely thick stratum corneum that becomes a restrictive circumferential encasement around the orifices, limbs, chest, and abdomen, resulting in limb contractures. We present a neonate diagnosed in utero with HI. The infant was born with encasing bands of thickened skin creating strictures that were causing digital and limb cyanosis (compartment syndrome). We treated the child using a new technique of lysis of the encasing bands that we call linear band incision, using a new escharotomy‐like procedure while the infant was undergoing a 3‐week course oral acitretin therapy. The technique involved linear incision and lysis of encasements that resulted in reperfusion of the injured limbs and prevention of further digital necrosis. The child is currently a healthy 8‐year‐old boy with skin manifestations resembling congenital ichthyosiform erythroderma. He has use of all of the limbs that were released in the procedures and is maintained on frequent application of bland emollients. Linear band incision is a potentially life‐ and limb‐saving technique in children with HI.     

Mercury biomarkers and DNA methylation among michigan dental professionals

Modification of the epigenome may be a mechanism underlying toxicity and disease following chemical exposure. Animal and human data suggest that mercury (Hg) impacts DNA methylation. We hypothesize that methylmercury and inorganic Hg exposures from fish consumption and dental amalgams, respectively, may be associated with altered DNA methylation at global repetitive elements (long interspersed elements, LINE‐1) and candidate genes related to epigenetic processes (DNMT1) and protection against Hg toxicity (SEPW1, SEPP1). Dental professionals were recruited at Michigan Dental Association (MDA) meetings in 2009 and 2010. Subjects (n = 131) provided survey data (e.g. exposure sources, demographics) and biological samples for Hg measurement and epigenetic analysis. Total Hg was quantified via atomic absorption spectrophotometry in hair and urine, indicative of methylmercury and inorganic Hg exposures, respectively. Global repetitive and candidate gene methylation was quantified via pyrosequencing of bisulfite converted DNA isolated from buccal mucosa. Hair Hg (geometric mean (95% CI): 0.37 (0.31–0.44) µg/g) and urine Hg (0.70 (0.60–0.83) µg/L) were associated with sources of exposure (fish consumption and dental amalgams, respectively). Multivariable linear regression revealed a trend of SEPP1 hypomethylation with increasing hair Hg levels, and this was significant (P < 0.05) among males. The trend remained when excluding non‐dentists. No significant relationships between urine Hg and DNA methylation were observed. Thus, in a limited cohort, we identified an association between methylmercury exposure and hypomethylation of a potentially labile region of the genome (SEPP1 promoter), and this relationship was gender specific. Environ. Mol. Mutagen. 54:195–203, 2013. © 2013 Wiley Periodicals, Inc.