Long-term Survival Results following Endobronchial RF Ablation in a Healthy-Porcine Model.

This paper presents results from long-term survival study where healthy swine were ablated with a novel technology designed for treating early-stage non-small cell lung cancer using an endobronchial flexible catheter.Methods - The radiofrequency ablation (RFA) system has been presented previously and consisted of an ablation catheter, radiofrequency generator, irrigation pump for infusion of hypertonic saline (HS) and a laptop. The catheter carried an occlusion balloon, a 5 mm long RF electrode, with irrigation holes, and a 1 mm long electrode for bipolar impedance measurements. The outer diameter (OD) was 1.4 mm for compatibility with current bronchoscopes, navigation systems and radial EBUS. Nine swine were treated in this study with survival times of 1, 4 and 12 weeks (N=3 at each time point). In all animals, the treatment sites consisted of one location in the upper right lung (RUL) and another one in the lower right lung (RLL). CTs were taken pre-op, immediately post-op and at every 2 weeks post treatment. Ablation times ranged from 6 to 8 min and average applied power was 68 W (range 63 - 72 W).Results - At 1-week survival, large zones of necrotic tissue were observed in all respective 6 ablations. Ablation volumes had an average diameter of 3.2 cm at RUL locations and 3.8 cm in RLLs (likely due to longer RLL ablation durations). As time progressed, the necrotic tissue was gradually replaced with fibrotic tissue. At 4-week survival, the replacement was almost complete in all respective 3 animals. As a result, ablation volumes decreased to an average diameter of 1.3 cm at RUL locations and 2.3 cm in RLLs (likely due to longer RLL ablation durations). At 12-week survival, as the replacement process continued, histopathology revealed zones of residual necrotic tissue that were further reduced in size. Ablation zones had been resorbed and contracted by fibrous scar tissue. The average volume of the treatment effect decreased to 1.1 cm (RUL) and to 1.6 cm (RLL) in equivalent diameter. There were no complications in any of the nine animals.Conclusion - In healthy swine lungs, RFA with a 1.4-mm OD, radial-EBUS-sheath-compatible, endobronchial catheter was effective and safe. This system and therapeutic approach may be considered for further evaluation in minimally invasive treatment of tumorous lung nodules.

Early Preclinical Experience with a Novel Endobronchial Radiofrequency Ablation System for Lung Cancer Treatment.

This paper introduces a novel technology for treating early-stage non-small cell lung cancer using an endobronchial approach via a flexible radiofrequency ablation (RFA) catheter. Methods - The RFA system consisted of an ablation catheter, radiofrequency generator, irrigation pump for infusion of hypertonic saline (HS) and a laptop. The catheter carried an occlusion balloon, a 5 mm long RF electrode, with irrigation holes, and a 1 mm long electrode for bipolar impedance measurements. The outer diameter was 1.4 mm for compatibility with current bronchoscopes, navigation systems and radial EBUS. The RFA system was extensively bench tested on fresh heart, liver and lung animal tissues using power levels of 30 - 60 W, RF energy delivery durations of 3 - 15 min and HS concentrations of 5% and 23.4%. Two swine were then treated at 60 W for 15 min per bronchus. Several bronchi were involved. For both animals and for all treatment sites, 20% HS was used. Animals were survived for six weeks. Results - Bench studies showed that 60 W, 7 - 15 min ablations can produce large ablation volumes, in excess of 3 - 4 cm diameter. In the chronic animal study, no clinically adverse events occurred. There was no evidence of hemorrhage. Animals vital signs, breathing patterns and their behavior were normal throughout the six-week period. Their appetite was normal and they gained weight according to expectations. The RF ablation created discrete volumes of thermal coagulative necrosis which were subsequently encapsulated ("walled off") by zones of organized fibrosis. The dimensions of coagulative necrotic sequestra met expectations, as at six weeks they exceeded volumes corresponding to 2 cm nodules, the size of tumors normally addressed in the peripheral lung by localized therapy. Conclusion - This therapy showed promise. Appropriate energy settings combined with suitable treatment locations safely produced large ablation volumes of uniform thermal coagulative necrosis. Further studies and optimization of treatment parameters can develop it into a mainstream therapy for treating early-stage lung tumors in humans.

Histology and clinical outcome of benign and malignant vascular lesions primary to feline cervical lymph nodes.

A novel form of primary feline hemangiosarcoma and additional cases of plexiform vascularization in the cervical lymph nodes are reported. Sixteen cases of feline lymphadenopathy attributed to abnormal vascular proliferation were identified and evaluated. Most of these lesions were diagnosed histologically as hemangiosarcoma. However, lesions of plexiform vascularization, with and without areas of putative malignant transformation, were also identified. Mean age of the cats was 11 years (range, 3-16 years) with most being domestic shorthair and medium hair (13). Two domestic long hair and 1 Maine Coon were identified. Excisional nodal biopsy was performed in 15 cases and incisional biopsy in 1 case. Six cats were euthanized due to their disease. Survival times ranged from ≤ 1 month to ≥ 30 months. We provide a new clinical differential for cervical lymphadenopathy in cats that is not widely recognized. Proper identification of primary nodal vascular lesions in cats will enable further characterization of clinical features and biologic behavior to determine specific therapy.

Nematode-associated intramural alimentary nodules in pumas are histologically similar to gastrointestinal eosinophilic sclerosing fibroplasia of domestic cats.

Intramural alimentary nodules in the gastric pylorus and proximal duodenum are a common finding in free-ranging pumas (Puma concolor) in North America, and are often associated with the presence of an indwelling nematode (most commonly Cylicospirura spp.). This study compares the histological, histochemical and immunohistochemical appearance of three proximal gastrointestinal nodules in pumas with four cases of eosinophilic sclerosing fibroplasia in domestic cats. Histologically, the pattern of inflammation and repair was strikingly similar, consisting of lamillated anastomosing trabeculae of dense sclerotic collagen with interspersed inflammatory cells and reactive fibroblasts. The stromal trabeculae were histologically reminiscent of osteoid and were uniformly positive for collagenous protein by Masson's trichrome stain and negative for mineralized osteoid deposits with Von Kossa's stain. Trabecular cells expressed osteonectin, but not osteocalcin immunohistochemically. Collectively, these findings are most consistent with a stroma comprised of dense collagenous trabeculae that resembles, but is distinct, from osteoid. Both the puma and domestic cat lesions demonstrated an eosinophilic inflammatory component; however, eosinophils were present in small numbers in the puma nodules relative to the nodules in domestic cats. These entities likely represent a unique and stereotypic gastrointestinal repair response of felids, given their similar histological, histochemical and immunohistochemical profiles.

SRY negative 64,XX intersex phenotype in an American saddlebred horse.

A female American saddlebred horse was presented for surgical correction of a possible pseudohermaphrodite condition. The horse had abnormal external genitalia and exhibited stallion-like behaviour. No evidence of uterine or ovarian tissue was identified on laparoscopic examination, but hypoplastic testicular-like tissue was removed, although this was found to contain no spermatogonia upon histopathological examination. A karyotype was performed and showed the normal chromosomal complement for a female horse (64,XX). Polymerase chain reaction to detect the SRY gene was negative in peripheral blood as well as the testicular-like tissue. This case represents the first report of an SRY negative XX-male sex reversal intersex phenotype, which is a potentially inherited condition, in an American saddlebred horse.

Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors.

A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most interesting compounds proved to have subnanomolar 5-HT transporter activity, and exhibited moderate 5-HT(1A) affinity.

A stomatin and a degenerin interact to control anesthetic sensitivity in Caenorhabditis elegans.

The mechanism of action of volatile anesthetics is unknown. In Caenorhabditis elegans, mutations in the gene unc-1 alter anesthetic sensitivity. The protein UNC-1 is a close homologue of the mammalian protein stomatin. Mammalian stomatin is thought to interact with an as-yet-unknown ion channel to control sodium flux. Using both reporter constructs and translational fusion constructs for UNC-1 and green fluorescent protein (GFP), we have shown that UNC-1 is expressed primarily within the nervous system. The expression pattern of UNC-1 is similar to that of UNC-8, a sodium channel homologue. We examined the interaction of multiple alleles of unc-1 and unc-8 with each other and with other genes affecting anesthetic sensitivity. The data indicate that the protein products of these genes interact, and that an UNC-1/UNC-8 complex is a possible anesthetic target. We propose that membrane-associated protein complexes may represent a general target for volatile anesthetics.

New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans.

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.

Effects of guanabenz on gastrointestinal absorption of hydrochlorothiazide.

The pharmacokinetics of guanabenz (16 mg) and hydrochlorothiazide (25 mg), administered separately and as a fixed-combination tablet (guanabenz 16 mg/hydrochlorothiazide 25 mg), were compared in a randomized three-period crossover study in 24 healthy men. Plasma concentrations were monitored for 48 h after each administration. No statistically significant differences between the two formulations were noted in mean plasma concentrations or the rate and extent of absorption of guanabenz. The relative bioavailability (Fr) of the combination tablet compared with guanabenz alone was 96%; thus the two formulations were bioequivalent with respect to guanabenz. For hydrochlorothiazide, mean plasma concentrations were similar for 3 h after administration but were higher for the combination tablet than for hydrochlorothiazide alone from 4 through 48 h (p less than 0.05). A significant increase in the extent, but not the rate, of absorption of hydrochlorothiazide was observed for the combination tablet (mean Fr, 120%), which is not considered clinically significant. We propose that this increase may have been due to increased systemic availability of hydrochlorothiazide in the presence of guanabenz, an alpha-adrenergic agonist, which may have delayed intestinal transport of hydrochlorothiazide, resulting in enhanced gastrointestinal absorption.

Gas chromatographic determination of guanabenz in biological fluids by electron-capture detection.

A sensitive gas chromatographic method for the determination of guanabenz[(2,6-dichlorobenzylidene)amino]guanidine in urine and plasma was developed. The method depends upon the acid hydrolysis of guanabenz to 2,6-dichlorobenzaldehyde, which has strong electron capturing properties and is volatile enough to be eluted from a gas chromatographic column. Concentrations as low as 0.1 ng of guana-benz/ml can be determined and recovery of the drug from urine and plasma samples is 81.8+/- 5.5% (SD). No interferences arising from plasma, urine, or reagents were encountered. Examples of the application of the method are given.