Signs Of Dysplasia Research Articles

Genetic analyses of elbow and hip dysplasia in the German shepherd dog

Results from radiographic screening for canine hip dysplasia (CHD) and elbow dysplasia (CED) of 48 367 German shepherd dogs born in 2001-07 were used for the population genetic analyses. Available information included CHD scores for 47 730 dogs, CED scores for 28 011 dogs and detailed veterinary diagnoses of primary ED lesions for a subsample of 18 899 dogs. Quasi-continuous traits were CHD, CED and cases of CED without radiographically visible primary lesion (CED-ARTH). Binary coding was used for fragmented medial coronoid process of the ulna (FCP), borderline findings and mild to severe signs of dysplasia in hip and elbow joints. Genetic parameters were estimated in univariate threshold and multivariate linear and mixed linear-threshold models using Gibbs sampling. Correlations between univariately predicted breeding values (BV) indicated genetic differences between borderline and affected disease status for both CHD (r(BV) = 0.5) and CED (r(BV) = 0.3). Multivariate genetic analyses with separate consideration of borderline findings revealed moderate heritabilities of 0.2-0.3 for the quasi-continuous traits with positive additive genetic correlation of 0.3 between CHD and both CED and CED-ARTH. For FCP, heritability of 0.6 and additive genetic correlations of +0.1 to CHD and -0.1 to CED-ARTH were estimated. Results supported the relevant genetic determination of CHD and CED, argued for both diseases against interpretation of borderline findings as healthy and implied genetic heterogeneity of CED. Accordingly, future breeding strategies to reduce the prevalences of CHD and CED in the German shepherd dog should be most efficient when based on BV from multivariate genetic evaluation for CHD, CED-ARTH and FCP with use of the whole scale of categories for classification of CHD and CED.

The occipital area in medieval dogs and the role of occipital dysplasia in dog breeding

An investigation was carried out on 42 dog skulls from the early medieval period. The skulls were excavated in Wroclaw, Poland, and in Novgorod and Moscow, Russia. Craniometric measurements were taken. On the basis of the basion-ethmoid measurement, the shoulder height was estimated. The foramen magnum height and width were measured and the foramen magnum index was calculated. The foramen magnum was typical in shape, and any occipital dysplasia signs observed were in the skulls. The results of the investigation, in comparison to other investigations of modern breeds and archaeozoological material, suggest that occipital dysplasia is not a pathology but rather a morphological variation connected with intentional dog breeding that can occur as a result of inbreeding.

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

Abstract The p16/INK4A protein is a cellular regulatory polypeptide over-expressed in the presence of high levels of the Human Papillomavirus (HPV) coded E7 protein. This review outlines the use of p16 antigen staining in cervical biopsies as well as in PAP smears summarizing the corresponding literature and commenting the authors’ own experience. The p16 antigen is a reliable marker for dysplastic cells in CINII/CINIII (HSIL) lesions as viewed in cervical biopsies. When PAP smears were examined at large scale screening for p16 antigenreactive and atypical cells, considerable variations could be found especially in ASCUS graded lesions. Therefore, the presence of p16-reactive atypical cells in PAP smears should be interpreted together with the cytological signs of dysplasia, such as the altered N/C ratio. In addition, women revealing p16-positive ASCUS/LSIL specimens should be examined for the presence of HPV DNA. Detection of HPV DNA alone, i.e. in the absence of cytological screening has a low predictive value, since the clearance of HPV may occur even in the absence of morphological alterations. Combined cytological as well as molecular follow up contributes to the efficiency of diagnostic and increases the probability of correct interpretation of the pre-cancerous lesions by non-invasive techniques.

Découverte fortuite de fixations colorectales focales du FDG en TEP/TDM : corrélation aux données de la coloscopie

Purpose FDG-PET is an established tool for the diagnosis of recurrent or metastatic colorectal carcinoma. Several case series suggest that FDG-PET often detects incidental adenomatous polyps or colorectal adenocarcinomas. The aim of this study was to correlate unexpected colorectal foci of FDG uptake to pathology findings after systematic colonoscopy. Patients and methods We reviewed the records of 3541 patients who underwent FDG PET/CT in our institution over a 30-month period for the assessment of a known or suspected malignancy. In 85 of them, incidental, nodular shaped and well-circumscribed foci of abnormal uptake were identified in the area of the colon or rectum. Patients with segmental or diffuse abnormal colorectal uptake were excluded, as well as patients with known benign or malignant colorectal disease. Colonoscopy and complete pathology report was available in 29 patients. Maximal standardized uptake value (SUV max) was measured in all lesions. Results Unexpected colorectal foci of FDG uptake were associated with colonoscopic abnormalities in 23 patients (true positive rate: 79 %). Adenocarcinomas were found in six patients (SUV max = 7.3 ± 2.6), tubulous adenomas in four patients (SUV max = 7.3 ± 4.9) and tubulovillous adenomas in 12 patients (SUV max = 4.2 ± 1.1). Hyperplasic polyps with no sign of dysplasia were found in the last patient (SUV max = 3.3). Concomitant CT abnormalities were found on PET/CT fusion in eight patients and consisted of wall thickening ( n = 5) or nodular mass ( n = 3). Conversely, PET was falsely positive in six patients (21 %), with no concomitant CT abnormalities and no abnormal findings at endoscopy (SUV max = 6.2 ± 2.8, no significant difference with true positive lesions). Conclusion Our findings emphasize the need to perform a colonoscopy in front of incidental nodular colorectal foci of FDG uptake because malignant or pre-malignant neoplasms, which are not clinically apparent, are found in more than three-quarter of cases.

Increased Bone Marrow Activity on F-18-FDG PET/CT in Granulocyte Colony Stimulating Factor Producing Anaplastic Thyroid Carcinoma

A 57-year-old man presented with jugular swelling. A leukocytosis of 50,000 WBC/μL (95% neutrophils) was found. PET/CT demonstrated increased fluorine-18-fluorodeoxyglucose uptake in the cervical/retrosternal mass, in the bone marrow, and in the enlarged spleen. Bone marrow biopsy confirmed myeloid hypercellularity with a left shift, but there were no signs of dysplasia and no evidence of tumor infiltration. Pathology of the thyroidectomy specimen confirmed an anaplastic thyroid carcinoma. Serum granulocyte-colony stimulating factor was elevated to 38.8 pg/mL (normal range, <0.6 pg/mL); granulocyte/macrophage-colony stimulating factor was normal (<2 pg/mL).

Castleman's disease arising from the gallbladder neck causing difficulty in the differential diagnosis.

We report a patient with Castleman's disease arising from the gallbladder neck, which caused difficulty in making the differential diagnosis against gallbladder malignancies. A 50-year-old woman presented to our institution with epigastric pain. An abdominal computed tomography scan (CT) and magnetic resonance cholangiopancreatography (MRCP) study showed a 20-mm tumor located in the gallbladder neck for which malignancy could not be completely ruled out. For the definitive diagnosis and treatment, cholecystectomy was performed. In the operation, the main tumor and resection margins of the cystic duct were submitted for frozen section. The tumor was composed of a proliferation of lymphoid tissue with no signs of dysplasia. The ductal margin was free of tumor. The final histopathological diagnosis was unicentric Castleman's disease, a hyaline vascular variant that developed in the gallbladder. The patient is currently in good condition without any signs of recurrence 28months after the operation. This is the first detailed report of Castleman's disease of the gallbladder. Making a correct diagnosis was very difficult before the operation, and only a surgical approach enabled confirmation of the diagnosis for this patient.

多精巣症の１例

A 28-year-old male presented with a small painless lump in his left hemiscrotum. A physical examination revealed a non-tender mass that was palpable on the tail of left epididymis, and the testis and spermatic cord were normal. Ultrasonography showed an isoechoic round shaped tumor, 16 mm in diameter. An exploration of the scrotum was performed, based on a preoperative diagnosis of a left epididymal tumor. The tumor was located below the tail of epididymis, and had a whitish capsule, which looked similar to tunica albuginea testis. A frozen section revealed testicular tissue without any malignant change, and therefore polyorchidism was diagnosed. The accessory testis was resected because there was no connection with the epididymis and vas deferens. Polyorchidism is a rare congenital anomaly with 24 cases reported in the Japanese literature. The indications for the resection of an accessory testis are controversial. Patients with intrascrotal polyorchidism might be recommended to undergo a resection of the accessory testes if there are signs of dysplasia during an intraoperative biopsy. Patients must be followed up with regular clinical and ultrasonic examinations when accessory testes are preserved. However, extrascrotal supernumerary testes should be managed by an orchiectomy because of the increased risk of malignancy.

The role of alcohol in oral precancer: observations from a North-East England population

Alcohol is known to be a risk factor for oral precancerous lesions, but evidence has been weakened by subjective estimates of alcohol intake from patients, and confounded by their use of tobacco. Red cell macrocytosis, assessed by calculation of mean corpuscular volume (MCV), may be a useful objective indicator of chronic alcohol intake. The aim of this study was to compare subjective and objective measures of alcohol intake in patients with oral precancerous lesions and assess the use of reported alcohol intake and MCV on assessing the degree of dysplasia at presentation and their role as markers of the behaviour of such lesions by assessing clinical outcome after treatment. Fifty-four new patients were recruited. All were smokers and had histologically confirmed single dysplastic oral precancerous lesions, but had had no previous treatment. Subjective data about their alcohol consumption were recorded, and blood samples taken for the assessment of MCV. All patients had laser excision of their lesions, which were assessed histopathologically for signs of dysplasia. Patients were followed up for 2 years. The significance of differences was assessed using Fisher's exact test. Alcohol intake of more than 28 units/week and MCV of over 100 were associated with increased dysplasia at presentation ( p = 0.01 and p = 0.03, respectively). Thirty-six patients were disease-free at 2 years, but 18 developed further disease, often at new sites. Alcohol intake of more than 28 units/week was significantly associated with an increased risk of further disease ( p = 0.03), particularly recurrence at the same site ( p = 0.02).

The reticular point of view in dermatoscopy

Different dermatoscopic algorithms have been developed to evaluate pigmented lesions of the skin, with pattern analysis being the most commonly used. We sought to develop and evaluate a diagnostic scoring system, the reticular point of view, to distinguish common melanocytic nevus from dysplastic nevus and from melanoma. We analyzed 1543 pigmented lesions, most of which contained a pigment network, and assessed the presence of linear extensions, thickened or hyperpigmented lines, areas of abrupt cut off, and areas with large "holes." We then conducted statistical analyses on these parameters to verify which of these exerted the most influence on the dermatologist's decision to surgically excise the lesion and to verify which feature was most linked to histopathologic signs of dysplasia or malignancy. Among the lesions excised, histopathologic examination revealed 33 (10.28%) melanomas. Among these, 25 (75.75%) showed an asymmetric distribution of the pigment network, whereas 20 (60.6%) showed a linear extension of it. The analysis of our data showed that all the evaluated criteria were statistically significant and played an important role in the dermatologist's decision to perform surgical excision of the lesion. Regarding the diagnosis of melanoma, only the presence of large holes, areas of abrupt cut off, and linear extensions revealed statistical significance. Reticular point of view may be useful only in lesions with a large pigment network. It is not applicable in nodular, thick, and amelanotic melanomas that are usually lacking in pigment network. Although pattern analysis represents the most effective analytical method in dermatoscopy, our scoring system may be useful to distinguish between benign lesions, which need only clinical follow-up, and malignant lesions, which need surgical excision.

High prevalence of esophageal involvement in lichen planus: a study using magnification chromoendoscopy

The first cases of squamous cell carcinoma in esophageal lichen planus were recently described. We performed a study to establish the prevalence of endoscopic and histopathologic abnormalities consistent with lichen planus and (pre-) malignancy in a cohort of patients with lichen planus. A total of 24 patients with lichen planus were prospectively studied using high-magnification chromoendoscopy. Focal esophageal abnormalities were mapped, classified, and biopsied. Biopsies were also taken from normal-appearing esophageal mucosa at three levels (proximal, middle, and distal). The presence of a lymphohistiocytic interface inflammatory infiltrate and Civatte bodies (i. e. apoptotic basal keratinocytes) at histopathologic examination was considered diagnostic for esophageal lichen planus. Symptoms were assessed using validated questionnaires. A total of 38 focal abnormalities were biopsied. These consisted of: layers of mucosa peeling off, hyperemic lesions, papular lesions, submucosal plaques/papules, a flat polypoid lesion, and segments of cylindrical epithelium. No endoscopic signs of dysplasia were present. Esophagitis consistent with gastroesophageal reflux disease was noted in 12 / 24 patients. Histopathology showed chronic inflammation of the esophageal mucosa in the majority (18 / 24) of patients. In 50 % (12 / 24), the diagnosis of esophageal lichen planus was made. Dysplasia was not present. There were no differences in symptoms between patients with and without esophageal lichen planus. At screening endoscopy a high prevalence (50 %) of esophageal lichen planus was found in patients with orocutaneous lichen planus. No dysplasia was found.

Role of Zinc in Modulating Histoarchitectural and Biochemical Alterations During Dimethylhydrazine (DMH)-Induced Rat Colon Carcinogenesis

The aim of the present work was to gain insight into the putative anticancer effect of dietary zinc during 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis. The rats were segregated into four groups, namely, normal control, DMH-treated, zinc-treated, and (DMH + zinc)-treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 12 weeks. Zinc in the form of zinc sulfate was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum for the entire duration of the study. The effects of different treatments were studied on lipid peroxidation (LPO), reduced glutathione (GSH), and antioxidative enzymes, which included superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR), as well as on the histoarchitecture of the colon. A total of 12 weeks of DMH treatment resulted in a significant increase in LPO. GSH levels and the activities of SOD, CAT, and GST were found to be significantly decreased following DMH treatment. A significant elevation in the activity of GR was observed following 12 weeks of DMH treatment. Histopathological studies showed well-differentiated signs of dysplasia, which included nuclei enlargement, epithelial thickening, and nuclear pleomorphism indicative of promotional phase of colon carcinogenesis in DMH-administered rats. Administration of zinc to DMH-treated rats decreased the levels of LPO and GSH significantly, but the activities of SOD and CAT were found to be significantly increased following zinc treatment. Zinc supplementation along with DMH treatment did not reveal any significant change in the activity of GR but significantly improved the activity of GST, which was depressed following DMH treatment. Also, zinc treatment in DMH-treated rats showed signs of great improvement, but structureless masses of the cells and hyperchromic nuclei were still visible occasionally. In conclusion, the results of this study suggest that zinc has a positive beneficial effect against chemically DMH-induced colonic preneoplastic progression in rats.

Duodenal adenocarcinoma arising at the strictureplasty site in a patient with Crohn’s disease: report of a case

Dear Editor: The patient was a 51-year-old man, a heavy smoker, with a 24-year history of Crohn’s Disease (CD). He was initially diagnosed as having Crohn’s proctosigmoiditis with stenosis of the anal canal treated with several endoscopic dilatations. Barium enteroclysis was performed, giving negative results. The patient was administered mesalazine and oral steroids for 17 years, achieving symptomatic improvement. In 2000, he had experienced a peri-anal fistula and relapse of the anal stricture, together with abdominal pain and diarrhoea, and was subjected to fistulectomy and anal dilatation. Consequent to the worsening of the abdominal pain refractory to medical therapy and the occurrence of rectal tenesmus, the patient was clinically re-assessed. At anorectal exploration, apart from the scar of the fistulectomy, severe strictures both in the upper part of the anal canal and in the distal rectum were noted. There was no evidence of damage from the fistulectomy to the anal sphincter. In March 2002, left colectomy, proctectomy and mucosectomy of the anal canal, with colo-anal anastomosis and transient ileostomy, were performed. The post-operative outcome was regular and, in July 2002, the patient was readmitted for closure of the protective ileostomy. On account of post-prandial vomiting and weight loss (10 kg in 2 months), the patient was readmitted to hospital in September 2002. An abdominal computerised tomography (CT) scan showed a stenosis of the third duodenal portion measuring 1 cm in length, with marked gastroduodenal dilatation. No duodenal compression by the superior mesenteric artery was evident. After 10 days of total parenteral nutrition, the patient was operated. The duodenum was entirely mobilised by cutting the Treitz’s ligament, and the short, fibrous stricture of the third portion of the duodenum was confirmed. A Heineke–Mikulicz (HM) strictureplasty was carried out and the patient’s clinical condition improved. In May 2003, he presented again with post-prandial vomiting, and endoscopy showed segmental narrowing of the second portion of the duodenum. Endoscopic dilatation was successfully performed and the biopsies concurrently taken demonstrated inflammatory alteration without signs of dysplasia or cancer. Four months later, due to deterioration of the obstructive symptoms, the patient was submitted to intestinal transit with hydrosoluble contrast medium, displaying exacerbation of the stenosis previously treated endoscopically. Further dilatation was then carried out, but to little benefit, and, in December 2004, surgery was scheduled. At laparotomy, the duodenum appeared dilated up to the second portion, where a stenosis consisting of a thickened, whitish, fibrous tissue involved the posterior wall for 2–3 cm, adherent to the vena cava. Frozen sections of the stenotic tissue showed fibroblasts and inflammatory cells with no signs of malignant transformation. As further strictureplasty was not feasible, a Roux-en-Y jejunal loop was implanted on the second part of the duodenum. Definitive histological examination of the duodenal specimen revealed a poorly differentiated adenocarcinoma and, in January 2005, the patient underwent duodeno-pancreatectomy according to Whipple. Int J Colorectal Dis (2009) 24:475–477 DOI 10.1007/s00384-008-0582-1

Chemopreventive potential of zinc in experimentally induced colon carcinogenesis

The present study was performed to evaluate the efficacy of zinc treatment on colonic antioxidant defense system and histoarchitecture in 1,2-dimethylhydrazine- (DMH) induced colon carcinogenesis in male Sprague–Dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH + zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 16 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum for the entire duration of the study. Increased tumor incidence, tumor size and number of aberrant crypt foci (ACF) were accompanied by a decrease in lipid peroxidation, glutathione- S-transferase, superoxide dismutase (SOD) and catalase. On the contrary, significantly increased levels of reduced glutathione (GSH) and glutathione reductase (GR) were observed in DMH treated rats. Administration of zinc to DMH treated rats significantly decreased the tumor incidence, tumor size and aberrant crypt foci number with simultaneous enhancement of lipid peroxidation, SOD, catalase and glutathione- S-transferase. Further, the levels of GSH and GR were also decreased following zinc supplementation to DMH treated rats. Well-differentiated signs of dysplasia were evident in colonic tissue sections by DMH administration alone. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of neoplasia. EDXRF studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplementation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats induced by DMH.

Induction of inducible nitric oxide synthase: a protective mechanism in colitis-induced adenocarcinoma

A close association between inflammatory bowel disease (IBD) and increased risk of developing adenocarcinoma exists. Moreover, chronic induction of high levels of nitric oxide (NO) produced from inducible nitric oxide synthase (iNOS) is a consistent observation in IBD. In this study we made interleukin-10/inducible nitric oxide synthase double-deficient (IL-10(-/-)/iNOS(-/-)) mice and studied the development of adenocarcinoma. Mice >6 months of age were compared with healthy wild-type (WT) controls. Inflammation was assessed using macroscopic/histological scores and myeloperoxidase activity as an indication of granulocyte infiltration. Mucosal polyps were scored macroscopically and hyperproliferation was quantified by 5-bromo-2-deoxyuridine immunohistochemistry. Dysplastic changes were assessed histologically based on cytologic and architectured atypia as well as the presence of submucosal invasion. The p53 and beta-catenin messenger RNA mRNA and protein expression were assessed using real-time polymerase chain reaction and immunohistochemistry, respectively. Inflammatory indices were significantly elevated in interleukin-10-deficient (IL-10(-/-)) over WT and not significantly different from IL-10(-/-)/iNOS(-/-) mice. The incidence of mucosal polyps was similar between IL-10(-/-) (79%) and IL-10(-/-)/iNOS(-/-) (83%) mice; however, significantly higher numbers of polyps were observed in the absence of iNOS (P < 0.05). Hyperproliferation was noted in both groups. Signs of dysplasia and submucosal invasion were significantly higher in IL-10(-/-)/iNOS(-/-) compared with IL-10(-/-) mice (P < 0.05). No significant increase in p53 and beta-catenin mRNA levels was observed in IL-10(-/-) over WT mice; however, a 2-fold (P = 0.06) and 3-fold (P < 0.05) increase, respectively, was noted in IL-10(-/-)/iNOS(-/-) mice. Our data suggest exposure to chronic NO limits abnormal p53 and beta-catenin expression and reduces incidence of adenocarcinoma in IL-10(-/-) mice.

Strengths and weaknesses of dark‐lumen MR colonography: Clinical relevance of polyps smaller than 5 mm in diameter at the moment of their detection

To assess the clinical relevance of dark-lumen MR colonography (MRC) for the detection of colorectal lesions using conventional colonoscopy (CC) and histopathologic examinations as reference standard. A total of 72 patients underwent MRC and CC. MRC was performed using a contrast-enhanced high spatial resolution T1 weighted 3D volumetric interpolated breathhold examination (VIBE)-sequence. All removed colorectal lesions were evaluated by an experienced pathologist. CC confirmed 65 polyps less than 5 mm in diameter. Non of those lesions could be detected using MRC. Just two (4%) of the 49 removed lesions smaller than 5 mm showed signs of dysplasia. Additionally, CC confirmed 25 polyps between 6-15 mm in diameter (MRC 22). All those 25 lesions were removed in CC. Only four (16%) of those polyps showed signs of dysplasia and malignancy (11, 13, 13 and 15 mm). Dark-lumen MRC failed to detect all polyps smaller than 5 mm in diameter which are generally not clinically relevant at the moment of their detection and thus can be kept under surveillance. However, MRC as a non-invasive imaging modality is a promising alternative to CC in the detection of clinically relevant polyps larger than 5 mm in diameter.

Histopathologic Evaluation of an Animal Model for Barrett’s Esophagus and Adenocarcinoma of the Distal Esophagus

Barrett's esophagus and adenocarcinoma of the esophagus are related to long-standing duodeno-gastroesophageal reflux. The development of an animal model in which Barrett's esophagus and/or carcinoma is induced by duodeno-(gastro-)esophageal reflux could provide better understanding of the pathogenesis of the metaplasia-dysplasia-carcinoma sequence and would create the possibility of investigating new treatment strategies for this aggressive disease. Two rat models were analyzed. In the first experiment, 44 male Sprague Dawley rats underwent end-to-side esophagojejunostomy with gastric resection, to ensure duodenoesophageal reflux without gastric acid. In the second experiment a side-to-side esophago-gastrojejunostomy was performed in 30 rats, ensuring duodeno-gastroesophageal reflux. In both experiments animals were not exposed to any exogenous carcinogens during the experiment. Sequential morphological changes (i.e., esophagitis, intestinal metaplasia, dysplasia, and carcinoma) were studied after 4, 6, and 12 months. To analyze histopathologic characteristics, evaluation of the hematoxylin and eosin specimens was combined with immunohistochemical stainings for high-iron diamine-alcian blue, alcian blue/periodic acid-Schiff, the proliferation marker PCNA, and mutations in the tumor suppressor gene p53. In the first experiment, only 11 animals survived the postoperative period. These animals had to be sacrificed at a median of 11 weeks due to persistent weight loss and failure to thrive. Severe ulcerative esophagitis was seen in all animals, with a 2-mm segment of metaplastic epithelium found at the anastomosis. In four animals a large, well-differentiated, mucinous tumor without malignant characteristics was observed. In the second experiment, eight animals died postoperatively. Twelve animals were sacrificed according to protocol at 4 or 6 months. In these animals, extensive esophagitis with squamous cell hyperplasia was found. In addition, a short (2 mm) segment of metaplastic epithelium was observed, without dysplasia. The remaining animals survived 1 year. After 1 year, 9 of the 10 animals had developed a glandular metaplastic segment (median length, 10 mm), which was histologically and immunohistologically characteristic for the specialized columnar epithelium of Barrett's esophagus without signs of dysplasia. Finally, in seven animals a mucinous tumor with cytologic characteristics of a well-differentiated mucinous adenocarcinoma was found without infiltrative growth. These tumors were always found at the site of the anastomosis, originated in the submucosa, and did not reach either the luminal surface or the muscular layer. The mucinous lesions were not positive for p53, and PCNA was only slightly increased. Although they showed cytological characteristics of malignancy, histopathologic evaluation was more suggestive of a reactive mucous producing lesion fitting the diagnosis "esophagitis cystica profunda." This study demonstrates the development of a long Barrett's segment in an animal duodeno-gastroesophageal reflux model. Although mucinous tumors resembling adenocarcinomas develop around the anastomosis, these are probably not reflux induced and are more likely to be reactive lesions. However, the true nature of these tumors remains to be elucidated.

The morphological pathway for mouse forestomach cancer

We analyzed the morphological changes accompanying the development of cancer in the mouse forestomach. The main aim of the study was to evaluate whether cancer in this area of the stomach arises de novo or undergoes a series of precancerous changes. Tumors were induced by the 1,2-dimethylbenz(a)antracene (DMBA) at a total dose of 4 mg/mouse. The suspected areas of the stomach were studied morphologically in 79 mice. Benign tumors (squamous-cell papillomas) and malignant tumors (squamous-cell carcinomas) were found in 40 mice. Tumors arose in all cases together with differential changes in the forestomach epithelium. These changes were seen as irregular diffuse hyperplasia or focal proliferation, with or without differential signs of dysplasia. Destruction of the basal epithelial membrane indicated transformation of the process into malignant invasive carcinoma. Thus, in chemically induced cancer of the forestomach, squamous-cell carcinoma develops as the final stage of morphologically recognizable precancerous changes in the epithelial layer. De novo formation of such tumors in the forestomach was not observed.

Prevalence and genetic parameters for hip dysplasia in Italian population of purebred dogs

This paper aimed to assess the prevalence of hip dysplasia (HD) in some breeds of dogs widely diffused in Italy and to estimate heritability of HD in German Shepherd and Boxer Italian populations. Data consisted of radiographic findings taken on 32,900 dogs (18,665 females and 14,225 males) of 7 breeds (German Shepherd; Boxer; Labrador Retriever; Golden Retriever; Rottweiler; Dobermann; Cane Corso) screened at an age of 17.9 ± 7.0 months. Radiographs of the coxofemoral joints, taken by 478 veterinarians, were scored for HD grade by a single veterinarian panelist according to a grading procedure based on a 5-class linear system (from A, no signs of dysplasia, to E, severe dysplastic hip changes). Logistic regression analysis was used for studying the relationships between selected explanatory variables with the outcome of the diagnosis for HD. Variance components, direct and maternal heritability have been estimated for German Shepherd and Boxer dogs using a REML animal model procedure. Prevalence of HD (hip joint graded C or worse) for the pool of breeds involved approached 22%, with large differences among breeds. In dogs diagnosed as dysplastic, the mild form (grade C) was largely prevalent for all breeds. When compared to the German Shepherd, the Cane Corso exhibited a significantly higher risk, whereas the Dobermann, Labrador and Rottweiler showed a significantly lower risk of being affected by HD. The probability of being diagnosed as dysplastic increased with the increasing of the age of dogs at screening and with the decreasing of experience of x-raying veterinarians. The effect of birth year of dogs on the outcome of the HD diagnosis was significant, but evidenced an inconsistent trend through years. Heritability estimates approached 0.24 and 0.15 for Boxers and German Shepherds, respectively, whereas maternal heritability was close to 0.03 for both breeds. Results from this study demonstrated that HD is fairly prevalent in some breeds of dogs commonly found in Italy, and its reduction should be a goal in breeding schemes of purebred dogs. Age at screening and experience of the x-raying veterinarians are disturbance factors to be considered in screening programs for HD. Heritability estimates for HD was low, but additive genetic variance seems enough for conjecturing selection programs aimed to decrease hip joints disease. Given the low heritability values, current selection schemes based on phenotypic records seem ineffective, whereas the use of breeding values estimated under BLUP animal model procedures should be recommended for gaining genetic progress of Italian dog populations.

NUP98-HOXD13 Transgenic Mice Develop Myelodysplastic Syndrome, Acute Myeloid Leukemia, and Pre-T Lymphoblastic Leukemia.

The NUP98 gene is located at chromosome 11p15 and encodes the 98 kd component of the nuclear pore complex; this protein normally functions as a docking protein involved in nucleocytoplasmic transport. NUP98 is fused to at least 15 different partner genes by chromosomal translocation in a wide spectrum of hematological malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and pre-T lymphoblastic leukemia (pre-T LBL). Over half of the known NUP98 gene fusions involve fusions to a HOX family member; these fusions invariably retain the amino terminal FG repeats of NUP98 and the homeodomain DNA-binding region of the HOX partner. The NUP98-HOXD13 fusion was initially identified in a patient with MDS that subsequently transformed to erythroleukemia, and has subsequently been identified in AML M1 and M2 patients as well. To model this disease in vivo, we generated transgenic mice which expressed the NUP98-HOXD13 (NHD13) fusion from vav regulatory elements.The NHD13 transgene is ubiquitously expressed in hematopoietic tissues such as thymus, spleen, and bone marrow, and is not expressed in other tissues. Serial CBCs from clinically healthy mice aged 4–7 months demonstrated a progressive neutropenia, lymphopenia, anemia, and macrocytosis. Peripheral blood smears showed signs of dysplasia including giant platelets and hypersegmented neutrophils; bone marrow exam showed an increase number of dysplastic binucleate erythroblasts and increased apoptosis, consistent with a diagnosis of MDS. 10/10 (100%) of the NHD13 mice died of hematologic disease by 14 months of age; in contrast, none of the non-transgenic control littermates developed evidence of hematologic disease. We classified the hematologic diseases according to the Bethesda proposals. Three mice died with MDS, two mice had pre-T LBL, two had acute undifferentiated leukemia, one had megakaryocytic leukemia, one had myeloid leukemia with maturation, and one had both pre-T LBL and erythroid leukemia.The malignant blasts from mice with pre-T LBL showed monoclonal T-cell receptor B gene rearrangements and were positive for CD3, 4, and 8. The mouse with megakaryocytic leukemia had serial CBCs documenting a platelet count of 3.2 million/uL, rising to >15million/uL at the time of death. This mouse had CD41+ megakaryocytes and megakaryoblasts invading the liver and spleen, and an osteosclerotic bone marrow reminiscent of chronic idiopathic myelofibrosis (CIMF). The mouse with concurrent pre-T LBL and erythroid leukemia had replacement of the thymus and infiltration of the lung with T-lymphoblasts which had a clonal TCRB gene rearrangement; interestingly, the spleen, liver, and bone marrow of this mouse were invaded with erythroblasts that were negative for CD3 and TCRB gene rearrangements.We conclude that the NHD13 transgene consistently induces an MDS, of variable severity, in these mice. Some mice die of severe anemia due to MDS, and MDS transforms into an acute non-lymphoid leukemia in other mice. Still other mice die of pre-T LBL which we believe evolves in the thymus separately from the MDS. These data demonstrate that the NHD13 fusion gene is transforming in both lymphoid and myeloid cells.

Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice

Ethanol consumption represents a major risk factor for cancer development, and a significant fraction of hepatocarcinomas arises in alcoholic liver cirrhosis. Increasing evidence indicates that ethanol acts as a tumor promoter on genetically initiated cells, by increasing the intracellular concentration of reactive oxygen species and promoting tissue necrosis/regeneration and cell proliferation. The tumor suppressor p53 restrains the expansion of carcinogen-initiated cells by inducing cell cycle arrest and apoptosis; accordingly, p53-deficient mice develop spontaneous and chemically induced neoplasms at a much higher frequency than normal mice. In normal mice exposed to a subacute (3 weeks) ethanol intoxication, a significant increase in the number of apoptotic hepatocytes was observed in concomitance with the up-regulation of the mitochondrial superoxide scavenger MnSOD, a reliable indicator of oxidative stress. Cell death occurred in the absence of liver inflammation and necrosis. Ethanol-induced hepatocyte apoptosis was completely abrogated in the p53 null background, suggesting that the tumor suppressor is necessary for hepatocyte death by ethanol. Accordingly, p53 −/− MEF were, unlike wild type cells, completely insensitive up to 0.5M ethanol in the culture medium. Strikingly, marked and widespread signs of dysplasia, with nuclear pleomorphisms and initial loss of normal architecture, heralding malignant transformation, were scored in all the mutant mice exposed to ethanol, but not in the control-fed littermates nor in ethanol-fed normal mice. These observations suggest that p53-dependent apoptosis restrains the tumorigenic effect of ethanol on liver cells, in agreement with the frequent loss of p53 function in HCC, and reveal an unexpected carcinogenic potential of alcohol which appears to be independent from the induction of cirrhosis and hepatocyte regeneration.