Global methylation analysis identifies PITX2 as an upstream regulator of the androgen receptor and IGF-I receptor genes in prostate cancer.

The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes ("methylome") in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i. e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease.

A survey of evidence in the Journal of Veterinary Internal Medicine oncology manuscripts from 1999 to 2007.

OBJECTIVES: To survey and monitor trends in evidence for oncology manuscripts published in the Journal of Veterinary Internal Medicine (JVIM) between 1999 and 2007 based on an evidence-based medicine (EBM) standard. METHODS: All veterinary oncology-related articles published in JVIM and 7 other high-impact journals from 1999 to 2007 were collected by database searches. Relevant manuscripts then were characterized including investigator affiliation, subject matter investigated, retrospective or prospective study design, manuscript type, and classifications of manuscripts using an EBM standard. RESULTS: A total of 172 relevant veterinary oncology manuscripts were identified in JVIM between 1999 and 2007. The proportion of oncology manuscripts published each year rose with the total number of manuscripts published in JVIM (mean, 13%; range, 8-15%). The author affiliations and subject matter were similar during this evaluation period. Case series represented the most common manuscript type (40%). With the exception of a progressive increase in prospective manuscripts and a reduction in case reports, no significant changes in the classification of manuscripts using EBM standards were seen. During this same period, veterinary oncology manuscripts published in 7 high-impact journals were associated with higher standards of evidence including prospective studies and randomized trials. CONCLUSIONS: The standards of evidence for veterinary oncology manuscripts published in JVIM have remained static between 1999 and 2007. This survey provides an informative benchmark for the state of evidence in previous JVIM oncology manuscripts and may be useful in identifying specific opportunities that may raise the standards of evidence in future publications in JVIM.

Phase I clinical evaluation of carboplatin in tumor-bearing cats: a Veterinary Cooperative Oncology Group study.

BACKGROUND: The dosage of carboplatin in cats has been reported anecdotally and experimentally in non-tumor-bearing cats, but the dosage for carboplatin treatment in tumor-bearing cats has yet to be defined in a prospective clinical trial. PURPOSE: To determine the maximally tolerated dose (MTD) and dose-limiting toxicosis (DLT) of carboplatin in tumor-bearing cats. CATS: Fifty-nine cats with measurable solid tumors. METHODS: The starting dose of carboplatin was 160 mg/m(2) of body surface area IV. Doses were increased by 20 mg/m(2) in cohorts of 3-14 cats until the MTD was reached. RESULTS: The 59 cats entered into this multi-institutional phase I study received 1 or more doses of carboplatin at various dosages and were evaluated for toxicity, response to treatment, or both. The MTD was 240 mg/m(2) and neutropenia was the DLT. For the 1st cycle of treatment in 44 cats evaluated for neutropenia, 6 episodes of grade 3 or greater neutropenia occurred on days 7 (n=1), 14 (n=4), and 21 (n=1). There was no evidence of drug-induced nephrotoxicosis or pulmonary edema. Preliminary evidence of antitumor activity was observed in 7 of 59 (11.9%; 95% CI, 5.6-22.8%) cats evaluated for response to treatment. There was 1 complete response (cutaneous hemangiosarcoma) and 6 partial responses (4 injection site sarcomas, 1 oral squamous cell carcinoma, 1 lymphoma). Responses were of short duration (median, 42 days; range, 7-168 days). CONCLUSIONS AND CLINICAL IMPORTANCE: The dose of carboplatin recommended to treat tumor-bearing cats is 240 mg/m(2) IV every 3-4 weeks.

Obesity and Associated Comorbidities in People and Companion Animals: A One Health Perspective.

This article reviews the biology, prevalence and risks for obesity in people and companion dogs and cats, and explores the links between obesity and diabetes mellitus and cancer across these species. Obesity is a major healthcare problem in both human and veterinary medicine and there is an increasing prevalence of obesity in people and pets. In people and animals, obesity is a complex disorder involving diet, level of physical activity, behavioural factors, socioeconomic factors, environment exposures, genetics, metabolism and the microbiome. Pets and people share a number of obesity-related comorbidities. Obesity is a major risk factor for type 2 diabetes mellitus in people and in cats, but this association is not recognized in dogs. Obesity is a recognized risk factor for a number of human cancers, but there are fewer data available describing this association with canine neoplastic disease. One approach to addressing the problem of obesity is by taking a 'One Health' perspective. Comparative clinical research examining shared lifestyle and environmental risk factors and the reasons underlying species differences should provide new perspectives on the fundamental biology of obesity. One Health programmes involving human healthcare professionals and veterinarians could help address obesity with simple interventions at the community level.

Metastasis-associated differences in gene expression in a murine model of osteosarcoma.

Despite advances in the management of osteosarcoma (OSA) and other solid tumors, the development of metastasis continues to be the most significant problem and cause of death for cancer patients. To define genetic determinants of pulmonary metastasis, we have applied cDNA microarrays to a recently described murine model of OSA that is characterized by orthotopic tumor growth, a period of minimal residual disease, spontaneous pulmonary metastasis, and cell line variants that differ in metastatic potential. Microarray analysis defined 53 genes (of 3166 unique cDNAs) that were differentially expressed between the primary tumors of the more aggressive (K7M2) and less aggressive (K12) OSA models. By review of the literature, these differentially expressed genes were assigned to six nonmutually exclusive metastasis-associated categories (proliferation and apoptosis, motility and cytoskeleton, invasion, immune surveillance, adherence, and angiogenesis). Functional studies to evaluate K7M2 and K12 for differences in each of these metastasis-associated processes revealed enhanced motility, adherence, and angiogenesis in the more aggressive K7M2 model. For this reason, 10 of the 53 differentially expressed genes that were assigned to the motility and cytoskeleton, adherence, and angiogenesis categories were considered as most likely to define differences in the metastatic behavior of the two models. Ezrin, a gene not described previously in OSA, with functions in motility, invasion, and adherence, was 3-fold overexpressed in K7M2 compared with K12 by microarray. Differential expression for RNA was confirmed by Northern analysis and for protein by immunostaining. Alterations in ezrin protein levels and concomitant cytoskeletal changes in our model confirmed predictions from the arrays. The potential relevance of ezrin in OSA was suggested by its expression in five of five human OSA cell lines. This work represents a rationale approach to the evaluation of microarray data and will be useful to identify genes that may be causally associated with metastasis.

In vitro and in vivo cytotoxicity of an anti-osteosarcoma immunotoxin containing pokeweed antiviral protein.

Successful treatment of many patients with osteosarcoma requires more effective chemotherapy. Since new agents are needed, we have developed an immunotoxin using TP-3, an IgG2b mAb which recognizes human and canine osteosarcomas and budding capillaries of tumors. The plant hemitoxin, pokeweed antiviral protein (PAP), was conjugated to TP-3 to produce an immunotoxin highly active against osteosarcoma. After 48 h no viable human OHS osteosarcoma cells were present in cultures containing TP-3-PAP as demonstrated by the absence of [3H]thymidine uptake into DNA. Furthermore, clonogenic assays indicated > 3.9 log kill of OHS at 18 h. The IC50 of TP-3-PAP against OHS was 3.5 +/- 1.0 (SD) x 10(-12) M. TP-3 mAb without PAP had no effect on OHS proliferation; PAP alone had no effect on OHS growth unless concentrations > 1000 pM were used. When TP-3-PAP (1.25 micrograms-10.0 micrograms) was given i.p. q.d. on days 3-5 after tumor inoculation, a dose-dependent reduction of the number of lung metastases was observed (P < 0.001). These results indicate that the TP-3-PAP immunotoxin may be useful in the treatment of osteosarcoma and some soft tissue sarcomas.

Aerosol delivery of interleukin 2 liposomes is nontoxic and biologically effective: canine studies.

Administration of interleukin 2 (IL-2) has been associated with potent in vitro antitumor effects. However, systemic in vivo toxicity has been problematic. Because local delivery and liposomal formulations of IL-2 may improve the therapeutic index, we used dogs to evaluate and compare immunological activation of inhaled free IL-2 and IL-2 liposomes. Twelve normal dogs were treated with nebulized IL-2 formulations and controls for 2 to 7 weeks. Cellular immune activation of peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) effector leukocytes against tumor cell lines, changes in effector leukocyte populations, and toxicity were monitored. No toxicity was seen with either aerosolized free IL-2 or IL-2 liposomes. Free IL-2 given at 0.5 x 10(6) Biologic Response Modifier Program (BRMP) units twice daily to dogs resulted in increased peripheral blood mononuclear cell activation compared with saline control-treated dogs. IL-2 liposomes given at 0.5 x 10(6) BRMP units twice daily to dogs resulted in significantly increased BAL effector activation compared with IL-2 liposomes given at 1.0 x 10(6) BRMP units once daily (P = 0.018) and empty liposome controls (P = 0.016). The BAL leukocyte cell count was increased significantly after inhalation of IL-2 liposomes versus inhalation of free IL-2 (P = 0.011). BAL effector populations included a greater proportion and total number of lymphocytes and eosinophils after treatment with IL-2 liposomes. Nontoxic activation of pulmonary immune effectors for the treatment of cancer in the lung may be possible using nebulized IL-2 liposomes.

Pretreatment with a monoclonal antibody/interleukin-2 fusion protein directed against DNA enhances the delivery of therapeutic molecules to solid tumors.

The efficacy of molecular therapies for human malignancies is limited by inadequate accumulation within solid tumors. Our laboratory has developed a novel approach that uses monoclonal antibodies (MAbs) to direct vasoactive proteins to tumor sites to increase local vascular permeability and, in turn, improve the delivery of therapeutic reagents. Previously, we demonstrated that pretreatment with immunoconjugates containing interleukin-2 (IL-2) enhances specific tumor uptake of radiolabeled MAbs without affecting normal tissues. In the present study, we describe a fusion protein consisting of a chimeric antinuclear antibody and IL-2 (chTNT-3/IL-2) and illustrate its potential for improving the delivery of both MAbs and drugs. The ability of pretreatment with chTNT-3/IL-2 to increase specific tumor uptake of the MAb B72.3 was demonstrated in LS174T colon tumor-bearing mice. Tumor accretion of B72.3 increased nearly 3-fold, with no changes in normal tissues. Abrogation of this effect with N(G)-methyl-1-arginine, a chemical inhibitor of nitric oxide synthase, suggests that rapid generation of nitric oxide in the tumor is responsible for the enhanced uptake. To demonstrate that pretreatment with chTNT-3/IL-2 can improve the uptake of other clinically relevant MAbs in different tumor models, additional studies were performed in both lung and prostate xenograft models. Pretreatment with the fusion protein increased specific tumor uptake of the MAb NR-LU-10 in A427 lung tumor-bearing mice and enhanced tumor uptake of the MAb CYT-351 in LNCaP prostate tumor-bearing mice, 2.1-fold and 1.7-fold, respectively. Finally, tumor uptake of the radiolabeled thymidine analogue 125IUdR also increased approximately 3-fold after pretreatment, indicating that this approach can be extended to small molecules such as chemotherapeutic drugs. Because TNT-3 recognizes a universal nuclear antigen accessible in degenerating and necrotic cells within all solid tumors, this strategy may be applicable to the majority of human cancers.

A Review of Paclitaxel and Novel Formulations Including Those Suitable for Use in Dogs.

Paclitaxel is a commonly used chemotherapeutic agent with a broad spectrum of activity against cancers in humans. In 1992, paclitaxel was approved by the U.S. Food and Drug Administration (FDA) as Taxol(®) for use in advanced ovarian cancer. Two years later, it was approved for the treatment of metastatic breast cancer. Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia in 1971. Taxanes are a family of microtubule inhibitors. As a member of this family, paclitaxel suppresses spindle microtubule dynamics. This activity results in the blockage of the metaphase-anaphase transitions, and ultimately in the inhibition of mitosis, and induction of apoptosis in a wide spectrum of cancer cells. Additional anticancer activities of paclitaxel have been defined that are independent of these effects on the microtubules and may include the suppression of cell proliferation as well as antiangiogenic effects. Based on its targeting of a fundamental feature of the cancer phenotype, the mitotic complex, it is not surprising that paclitaxel has been found to be active in a wide variety of cancers in humans. This review summarizes the evidence in support of paclitaxel's broad anticancer activity and introduces the rationale for, and the progress in development of novel formulations of paclitaxel that may preferentially target cancers and that are not associated with the risks for hypersensitivity in dogs. Of note, a novel nanoparticle formulation of paclitaxel that substantially limits hypersensitivity was recently given conditional approval by the FDA Center for Veterinary Medicine for use in dogs with resectable and nonresectable squamous cell carcinoma and nonresectable stage III, IV and V mammary carcinoma.

An orthotopic model of murine osteosarcoma with clonally related variants differing in pulmonary metastatic potential.

To provide an investigative tool for the study of osteosarcoma (OSA) biology we have developed a syngeneic (balb/c) murine model of OSA, using cell lines derived from a spontaneously occurring murine OSA (Schmidt et al. Differentiation 1988; 39: 151-60). This model is characterized by orthotopic primary tumor growth, a period of minimal residual disease, spontaneous pulmonary metastasis, and clonally related variants (K7M2 and K12) that differ in pulmonary metastatic potential. Primary tumor and pulmonary metastasis histology was consistent with OSA in human patients. Expression of bone sialoprotein, biglyan, decorrin, and osteopontin was suggestive of bone lineage cells. The development and use of a more aggressive OSA cell line (K7M2) resulted in spontaneous metastasis to the lungs in over 90% of mice, whereas metastases were seen in only 33% of mice when a less aggressive OSA cell line (K12; Schmidt et al. Differentiation 1988; 39: 151-60) was used. Death from metastasis occurred at a median of 76 days using K7M2 whereas no median was achieved after 140 days using K12. Angiogenic potential, characterized by CD31 and factor VIII staining of primary tumors and pulmonary metastases, was greater in the K7M2 model compared to the K12 model. No significant differences in the in vitro or in vivo expression of angiogenesis associated genes (flt1, flt4, TIE1, TIE2, and VEGF) was found between K7M2 and K12. This well characterized and relevant model of OSA will be a valuable resource to improve our understanding of the biology and treatment of metastasis in OSA.

Spontaneous and genetically engineered animal models; use in preclinical cancer drug development.

The preclinical development of anticancer drugs has been based primarily on the transplantation of murine or human cancers into mice. Alternatives to these transplantation models are animals that naturally develop cancers with features relevant to the human disease. The first group of these models arises in mice that are genetically engineered to develop cancer. The second group includes pet dogs and cats that naturally develop cancer. This review will discuss the use and integration of these spontaneous cancer models into a comprehensive and comparative approach to preclinical drug development. Examples of their successful use and an outline of their relative strengths and weaknesses will be provided.

Nebulized interleukin 2 liposomes: aerosol characteristics and biodistribution.

Although interleukin 2 (IL-2) has been associated with modest anti-tumour responses in man, treatment-related toxicity has limited its widespread use. The local delivery of liposomal formulations of interleukin 2 to the lung as aerosols has been demonstrated to be non-toxic, biologically active, and associated with regression of spontaneous pulmonary metastases in dogs. This study was undertaken to evaluate the physical and biological characteristics of nebulized interleukin 2 liposomes. The aerosol droplet size distribution and the physical stability of interleukin 2 liposomes were examined in-vitro using an Andersen cascade impactor and studies of liposome entrapment of interleukin 2 before and after nebulization. The biological stability of interleukin 2 liposomes after nebulization was demonstrated using the CTLL-2 bioassay for interleukin 2. In-vivo studies of pulmonary biodistribution and clearance of inhaled technetium (99mTc)-labelled interleukin 2 liposomes were undertaken in a normal dog. Aerosols of free interleukin 2 and of interleukin 2 liposomes were compared in both in-vitro and in-vivo experiments. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of interleukin 2 liposomes were 1.98 microns and 2.02, respectively. Independent analysis of aerosol particle-size distribution using the constitutive components of the interleukin 2 liposomes (interleukin 2: lipid:HSA) demonstrated a close correlation of size distributions (r = 0.9445; P < 0.001). The entrapment of interleukin 2 in liposomes was 93 +/- 4.3% before nebulization and 90 +/- 8.9% after. After delivery to an anaesthetized dog, interleukin 2 liposome aerosols were deposited evenly throughout the lung (mean +/- s.d. central lung-to-peripheral lung deposition was 1.12 +/- 0.03). After approximately 24 h inhalation, interleukin 2 liposomes were retained within the lung and were taken up in part by the spleen. The results of this study are indicative of the stability of this interleukin 2 liposome formulation to nebulization. Such nebulization might be an attractive immunotherapeutic strategy for treatment of pulmonary metastases and primary lung cancers.

Solitary nodular goiter. Review of cytomorphologic features in 441 cases.

OBJECTIVE: To study the cytomorphologic features of solitary nodular goiters (SNG). STUDY DESIGN: May-Grünwald-Giemsa-stained smears in 441 SNG diagnosed by ultrasonography and fine needle aspiration (FNA) and found to have optimum cellular material at review were subjected to detailed cytologic assessment. The age of the patients ranged from 11 to 75 years, with a median of 35. Male: female ratio was 69:372. The parameters for cytologic assessment included cellularity, colloid content, acinar formation, papillary formation, intranuclear cytoplasmic inclusions, nuclear grooves, marginal vacuoles, Hürthle cells and various inflammatory cells. Histopathology reports on thyroidectomy specimens were available in 27 cases from two Delhi hospitals. RESULTS: Hyperplastic nodules (68 cases) differed significantly from colloid goiters (269 cases) by having more cases with excessive cellularity, acinar formation and marginal vacuoles (P < .001). There was also a significant difference with respect to papillary formation and moderate-to-excessive colloid content (P < .001). As compared to hyperplastic nodules, neoplasms (60 cases) had a significantly higher number of cases with papillary formation, intranuclear inclusions and nuclear grooves but lower number of cases with marginal vacuoles (P < .01-.001). Among neoplasms, usual papillary carcinoma (19 cases) differed from follicular neoplasms (20 cases) with respect to acinar formation, papillary formation and nuclear grooves (P < .001). A significant difference was also observed with respect to colloid content and nuclear inclusions. Follicular variant of papillary carcinomas (FVPC) (10 cases) emerged as a distinct cytologic entity following review and differed from usual papillary carcinomas in having a higher number of cases with acinar formation, tubular formation and marginal vacuoles (P < .01-.001) and lower number of cases with nuclear grooves (P = .05). FVPC also differed from follicular neoplasms with respect to papillary formation, tubular formation, intranuclear inclusions and nuclear grooves (P < .01-.001). Overall cytohistologic agreement was achieved in 24 of 27 (88.9%) cases. CONCLUSION: Detailed cytologic assessment of FNA smears-in SNG was helpful in highlighting parameters that differentiate between various types of goiters.

Hypomagnesemia in 188 dogs: a hospital population-based prevalence study.

Magnesium is a divalent cation involved in more than 300 metabolic processes. Magnesium acts as an intracellular regulator of most energy-demanding pathways. Clinical investigation in the human medical field has determined risk factors for hypomagnesemia and its relationship to a number of disease processes. Experimental studies have established the effects of hypomagnesemia in dogs, but little is known of its prevalence, risk factors, or clinical associations in a hospital population of dogs. To study the prevalence, risk factors, and clinical associations of hypomagnesemia in dogs, a retrospective cross-sectional study of dogs admitted to the University of Minnesota Veterinary Teaching Hospital over a 2.5-year period was undertaken. The prevalence of hypomagnesemia in the study population was 6.1% (188 of 3,102 dogs). Using both categorical and continuous variables in a univariate analysis, significant associations with hypomagnesemia were identified and used to construct a multivariate analysis of the relative risk of hypomagnesemia. Results from evaluation of 3,102 dogs indicate that the most significant predictors of hypomagnesemia were albumin (P < or = .0001; odds ratio [OR] = 0.2), potassium (P < or = .0001; OR = 0.5), total CO2 (P < or = .05; OR = 0.9), and blood urea nitrogen concentrations (P < .0001; OR = 0.9), a diagnosis of cardiovascular disease (P < .02; OR = 1.9); and being a Collie (P < .02; OR = 3.9) or German Shepherd Dog (P < .002; OR = 2.2). These results can be used to better understand and predict hypomagnesemia in dogs.

Blood mercury in workers exposed to the preparation of mercury cadmium telluride layers on cadmium telluride base.

Study was conducted in a group of 32 persons engaged in liquid phase epitaxial growth of mercury cadmium telluride (MCT) layers for nearly 11 years. Airborne mercury concentrations in work environment have been exceeding the threshold limit value of 0.05 mg/m3 recommended by ACGIHD. Hg concentration in workplace during peak working hours remained between 0.04-0.08 mg/m3. Findings were compared with 32 unexposed referents. Mercury value was estimated 1.60 +/- 0.20 (mean +/- SD) in control, and in Phase I and II, 10.72 +/- 1.34 ng Hg/ml and 8.08 +/- 1.15 ng Hg/ml of blood respectively. Results indicate a fall in blood mercury level during the second phase of study. But the values did not return to normal even after a gap of 3 months. An individual who met with a mercury accident showed 226 ng Hg/ml of blood which decreased to 25 ng/ml after 3 months. It is inferred from the present study that Hg level has increased significantly in MCT workers during working period, and also in non-working period, the values were higher than controls.

Effects of long-term thyroid hormone suppressive treatment on the cardiac functions.

Long-term effects of thyroid hormone suppressive therapy on the heart were evaluated in 45 patients by non-invasive techniques. Fifteen patients were athyreotic after surgery for differentiated thyroid cancer and 30 had diffuse or nodular goiter. Mean age of the group was 42 +/- 12 years. Twenty-four age- and sex-matched subjects were taken as controls. Mean daily dose of levothyroxine was 158 +/- 36 micrograms. Plasma thyroid stimulating hormone (TSH) levels were within normal range. Mean serum T4 and free T4 were significantly higher (p < 0.001) whereas mean serum T3 and free T3 did not differ from the control levels. Non-invasive cardiac assessment was done by a standard 12 lead electrocardiogram (ECG), ambulatory electrocardiographic (Holter) monitoring and echocardiographic study. Six patients had left ventricular hypertrophy in ECG. Holter monitoring demonstrated a higher average heart rate in patients compared to controls (86 +/- 10 vs 72 +/- 6 beats/min; p < 0.001). Supraventricular premature beats were more frequent in patients than in the control group (98% vs 60%; p < 0.06). Echocardiogram showed an increased left ventricular (LV) mass index in patient group (98 +/- 28 vs 78 +/- 16 gm/m2; p < 0.02). LV systolic function was increased with higher values of fractional shortening (40 +/- 8% vs 34 +/- 6%; p < 0.05) and rate-adjusted velocity of shortening (1.4 +/- 0.12 vs 1.02 +/- 0.16 circumferences/sec; p < 0.01). It is concluded that long-term levothyroxine suppressive therapy has significant effects on the cardiac functions.

Diagnosing protein losing enteropathy. A new approach using Tc-99m human immunoglobulin.

Tc-99m HIG has recently come into prominence as an inflammation seeking radiotracer. The authors describe a novel use of the agent for imaging protein-losing enteropathy. The agent may have certain advantages over Tc-99m HSA, which is currently being used for imaging protein loss.

Efficacy of hepatobiliary scintigraphy in demonstrating cholangio-colic fistulae. Is formation of internal biliary fistula related to external leak closure?

The authors present four cases of internal biliary fistulae (IBF) identified on hepatobiliary scintigraphy. All of the cases share common history of external biliary leak closure. Scintigraphy in all four cases showed a similar pattern of direct visualization of transverse colon without any significant small bowel activity. This suggests an increased frequency of IBF formation in cases with external fistulous tract closure. Retrospectively, it appears that spontaneous closure of external leak may be pathological consequence of formation of IBF involving hepatic flexure.

Randomized controlled trial of doxorubicin versus dactinomycin in a multiagent protocol for treatment of dogs with malignant lymphoma.

OBJECTIVE: To compare efficacy and toxicity of 2 multiagent chemotherapeutic protocols similar in all respects except that 1 incorporated dactinomycin and the other incorporated doxorubicin for treatment of dogs with malignant lymphoma. DESIGN: Randomized controlled trial. ANIMALS: 45 dogs with malignant lymphoma. PROCEDURE: Dogs were randomly assigned to a doxorubicin or dactinomycin treatment group. Time to first remission, duration of first remission, survival time, and prevalence of toxicoses, particularly number of episodes of dose-limiting neutropenia and gastrointestinal toxicoses, were compared between groups. RESULTS: 37 dogs received at least 1 dose of doxorubicin (21 dogs) or dactinomycin (16). Median time to first remission was not significantly different between groups, but median duration of first remission and median survival time were significantly longer for dogs in the doxorubicin treatment group than for dogs in the dactinomycin treatment group. Number of dogs that died, number of episodes of dose-limiting neutropenia, and number of episodes of gastrointestinal toxicoses were not significantly different between groups. CLINICAL IMPLICATIONS: A multiagent chemotherapeutic protocol incorporating doxorubicin was significantly more effective in dogs with malignant lymphoma than a similar protocol incorporating dactinomycin. Despite the lower cost and lack of cardiotoxicity, dactinomycin is not an equivalent substitute for doxorubicin in the initial treatment of dogs with malignant lymphoma.

Investigations of thyroid diseases--an update on diagnostic methods.

Iodine deficiency disorders (IDD) are an important public health problem in India. It requires further refinement and improvements in thyroid disease diagnosis, especially in the early diagnosis of thyroid malfunctioning and risk assessment of autonomously functioning thyroid tissue. Scintigraphy with technetium-99m pertechnetate under exogenous or endogenous thyroid stimulating hormone (TSH) suppression provides the best results. There has been significant improvement in methodology in various laboratory investigations that have resulted from the application of newer luminescent techniques and gene technology in various thyroid function tests. TSH measurement especially by using second or third generation assays has ensured diagnostic accuracy and thyrotropin releasing hormone (TRH) test now almost always unnecessary. Determination of glycosaminoglycans in urine may become a helpful tool in the follow up of endocrine ophthalmopathy. The differentiation of blocking and stimulating TSH receptor antibodies is relevant when discrepant results are obtained with respect to thyroid function. Some newer imaging agents have been used in thyroid disease scintigraphy such as octreotide or in thyroid diseases diagnosis such as fluorodeoxyglucose. Both improve the detectability of thyroid cancer metastasis especially if radioiodine scan is negative.