Extent Of Dysplasia Research Articles

Coronal and sagittal spinopelvic alignment in the patients with unilateral developmental dysplasia of the hip: a prospective study

BackgroundHow the hip dysplasia affects the spinopelvic alignment in developmental dysplasia of the hip (DDH) patients is unclear, but it is an essential part for the management of this disease. This study aimed to investigate the coronal and sagittal spinopelvic alignment and the correlations between the spinopelvic parameters and the extent of hip dysplasia or the low back pain in unilateral DDH patients.MethodsFrom September 2016 to March 2021, 22 unilateral patients were enrolled in the DDH group with an average age of 43.6 years and 20 recruited healthy volunteers were assigned to the control group with an average age of 41.4 years. The Cobb angle, seventh cervical vertebra plumbline–central sacral vertical line (C7PL–CSVL), third lumbar vertebra inclination angle (L3IA), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), thoracic kyphosis (TK), thoracolumbar kyphosis (TLK) and lumbar lordosis (LL) were measured on the standing anteroposterior and lateral full-length standing spine radiographs. Additionally, the Oswestry Disability Index (ODI) and Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were used to assess the degree of low back pain.ResultsCobb angle (8.68 ± 6.21° vs. 2.31 ± 0.12°), L3IA (4.80 ± 5.47° vs. 0.83 ± 0.51°), C7PL–CSVL (1.65 ± 1.57 cm vs. 0.48 ± 0.33 cm), PT (15.02 ± 9.55° vs. 9.99 ± 2.97°) and TLK (7.69 ± 6.66° vs. 3.54 ± 1.63°) were significantly larger in DDH patients, whereas LL (37.41 ± 17.17° vs. 48.79 ± 7.75°) was significantly smaller (P < 0.05). No correlation was found between significantly different spinopelvic parameters and the extent of dysplasia. Statistical analysis revealed correlations between ODI and Cobb angle (r = 0.59, P < 0.01), PT (r = 0.49, P = 0.02), TK (r = −0.46, P = 0.03) and TLK (r = 0.44, P = 0.04). Correlations between JOABPQE score and the Cobb angle (r = −0.44, P = 0.04), L3IA (r = −0.53, P = 0.01), PT (r = −0.44, P = 0.04), and TK (r = 0.46, P = 0.03) were also observed.ConclusionsCobb angle, L3IA, C7PL–CSVL in coronal plane and PT, TLK in sagittal plane increased, while LL decreased in unilateral DDH patients. These significantly different spinopelvic parameters have no correlation with the extent of dysplasia. Changes in coronal and sagittal plane including Cobb angle, L3IA, PT, TK and TLK were associated with the low back pain in the patients with unilateral DDH.

Clonal Architecture of TET2 Mutations Influences the Clinical Phenotype of Patients with Myeloid Neoplasms

Somatic TET2 mutations (TET2MT) are frequently found in myeloid neoplasia (MN) with a frequency that increases with age, consistent with the presence of subclinical TET2MT clones in asymptomatic older controls. Despite the prominent pathophysiologic role they play based on their prevalence; phenotype-genotype and prognostic associations have not been reliably established. We hypothesized that the diversity of TET2MT with regard to their configuration, genetic topography, and sub-clonal context, result in differences in biological, morphological, and clinical features.We studied blood and bone marrow samples from 4930 patients with MN using deep sequencing for common myeloid somatic mutations, including TET2 . This analysis identified 1205 TET2MT patients with 1781 distinct TET2MT, as many had more than one TET2MT. The most common TET2MT were frame shift (47%) and nonsense (34%) mutations, both gene truncating events. Truncations were subdivided into those occurring upstream enough to effectively delete the whole gene (46%) and those that only led to deletion of the catalytic domain. TET2MT were found in 17% of patients with MDS, 46% with MDS/myeloproliferative neoplasm (MDS/MPN), 19% with MPN, 21% with pAML and 24% with sAML. Across all MN's, single mutations were more common than biallelic or homozygous, except in MDS/MPN, where there were similar proportions of single and multiple mutant cases (22% single vs . 24% biallelic/homozygous TET2).TET2MT co-occurred most commonly with another TET2MT (43%), ASXL1 (21%), SRSF2 (18%), and NPM1 (13%). A similar distribution was seen in MDS, but with SF3B1 replacing NPM1 ; and in MDS/MPN, but with SF3B1 replaced by RUNX1 and CBL . In sAML the distribution of sub clonal lesions was similar to pAML, though with more mutations in NPM1 and FLT3ITD/TKD in pAML. Genes with the most significant differences in mutation rates between TETMTvs . TET2WT MDS/MPN patients were increased SRSF2 (34% vs . 15%, p<.001) and KRAS (8% vs . 3%, p<.001).The rank of TET2MT within the clonal hierarchy is heterogeneous. TET2MT were found to be ancestral hits in 40% of mutant cases. A second TET2MT was the most common secondary hit following an ancestral TET2 hit. Other common 2nd hits included mutations in SRSF2, ASXL1, DNMT3A, and SF3B1 . TET2MTirrespective of ancestral or secondary configurations had no impact on survival outcome. However, when comparing TET2MT clonal size, TET2 allelic burden negatively affected survival (p=.016) for all patients with MNs.Having ascertained that the majority of TET2 lesions are ancestral hits, we set to determine their impact on progression, extent of dysplasia, and proliferation (monocytosis, increase megakaryocytes fibrosis). We used logistic regression to assess odds ratios (OR) of a gene being associated with MDS vs. MDS/MPN. We then determined univariate Cox regression hazard ratios for each gene and used these to construct 2-dimensional regression plots (Figure 1). This plot shows that TET2MT as a sole ancestral hit implies a greater likelihood of dysplasia and less of progression to high risk (HR) disease as compared to low risk (LR). Subsequent secondary hits change the features of the disease as shown in Figure 1. A second (biallelic) hit in TET2 increased the odds for the disease being myeloproliferative (OR=1.17), a secondary U2AF1 hit increased the odds of progression (OR=2.64), and a sub clonal SRSF2 mutation increased both (OR=6.61, 3.89). RAS family mutations had a moderate effect on progression (OR=2.66, 1.71), but induced proliferative features (OR=8.77, 7.80), whereas SF3B1 mutations associated with dysplasia and LR (OR=0.26, 0.32). In comparison, all combined TET2 hits (irrespective of the secondary context) were plotted as a circle (Figure 1).In sum, our analyses demonstrate the genotypic/phenotypic impact of primary TET2 hits and how each subsequent mutation can affect the clinical phenotype of the disease. [Display omitted] DisclosuresMeggendorfer:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Prediction of time to prosthesis implantation as a function of joint anatomy in patients with developmental dysplasia of the hip

BackgroundDevelopmental dysplasia of the hip (DDH) can lead to pain and premature secondary osteoarthritis at an early stage. Joint-preserving osteotomy is an established solution to this problem. In contrast, a conservative approach would result in pain persistence, ultimately raising the patients question for a possible date of expected prosthesis implantation.The aim of the study was to identify the relationship between the dysplastic hip anatomy and the time of prosthesis implantation in order to enable prognostic predictions in younger patients with symptomatic DDH.Materials and methodsData from 129 hips who received THA due to secondary DDH osteoarthritis were evaluated. The preoperative hip anatomy was evaluated for AI and LCE angle. Multiple linear regression analyses were then used to correlate the influence of these parameters with the patient’s age at the time of surgery. In addition, a graphical relationship was derived by the method of power least squares curve fitting with second-degree polynomials.ResultsThe mean age for THA was 54.3 ± 11 years. The time of surgery correlated significantly with LCE (0.37) and AI (− 0.3) (p < 0.001). The mean age of patients with LCE angle ≤ 10° was 41.9 ± 14.0 years, for LCE 11–20° 52.7 ± 9.5 years, and for LCE 21–30° 57.0 ± 10.3 years. The following formula could then be determined for the calculation of the potential patient age at the time of THA as a function of LCE angle: age pTHA = 40.2 + 0.8 × LCE angle − 0.01 × (LCE angle)2.ConclusionA significant correlation between the extent of dysplasia and the time of prosthesis implantation was identified. In particular, the LCE and the AI correlated strongly with the time of implantation. The more dysplastic the angles were, the sooner the THA was necessary. Using the calculations presented in this study, the probable age of prosthesis implantation can be prognosticated and included in a counseling session about treatment options for DDH.

Myelodysplasia as assessed by multiparameter flow cytometry refines prognostic stratification provided by genotypic risk in systemic mastocytosis.

Systemic mastocytosis (SM) is characterized by extreme heterogeneity of manifestations and prognosis. Several disease-related biomarkers, including clinical, hematological and molecular variables, have been correlated with prognosis. Although relevant, the mutation profile closely reflects the WHO classification that has per se prognostic value. High-risk mutations (HRM) are largely confined to advanced forms, and thus fail in providing information regarding progression and outcome in the not-advanced variants. In this work, we studied hematopoietic cells by multi-parameter flow cytometry (MFC) in order to highlight dysplastic traits that might provide insights into outcome. A score previously validated for myelodysplastic syndromes, with high reproducibility in standard diagnostics, was used. The application of an MFC score to a cohort of 71 SM cases, concurrently genotyped for configuring a HRM category, resulted in the identification of two separate patients' categories (MFC+ and MFC-) characterized by significantly different clinical and laboratory features at presentation. The extent of dysplasia by MFC tended to parallel WHO-category and genotype-related stratification. MFC+ patients had shorter survival compared to MFC- ones, for whom the incidence of progression and/or death was virtually null. Of note, MFC score remained prognostically informative in unadvanced subsets. Furthermore, the integration of MFC and HRM was an independent predictor for outcome, also overcoming WHO-categories in multivariate analysis for EFS. Our results support the use of MFC analysis in the evaluation of patients with SM, alone and in combination with HRM, for refinement of prognosis assessment.

Prevalence and modern aspects of the treatment of patients with Barrett’s esophagus

The article analyzes the prevalence and principles in treatment of Barrett’s esophagus. The prevalence of Barrett’s esophagus varies widely from region to region of the world and has ethnic differences. The use of endoscopic methods and the histological examination of the biopsies of esophageal mucosa are of utmost importance in the diagnosis of this pathology. The prevention of esophageal cancer is the main task in managing patients with Barrett’s esophagus. The length of the Barrett’s esophagus segment, the presence and extent of dysplasia is of the greatest importance to select tactics for managing patients. Endoscopic methods are widely used for the eradication of metaplasia sites, among which the radiofrequency ablation is the most effective one. Prolonged treatment with proton pump inhibitors is safe and reduces the risk of transformation of Barrett’s esophagus into adenocarcinoma of the esophagus. There is evidence that small doses of aspirin, nonsteroidal anti-inflammatory drugs, statins and ursodeoxycholic acid have the preventive effect on the development of esophageal cancer. However, the possibilities of using these drugs for this purpose are still limited. Anti-reflux surgery still holds relevance, but at the same time, it has no advantages over the drug therapy for the prevention of esophageal cancer.

Intracholecystic papillary-tubular neoplasm of gallbladder: A 5-year retrospective pathological study.

Intracholecystic papillary-tubular neoplasm (ICPN) is a relatively new entity which includes neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm. This study is done to evaluate the pathological features of ICPN and to find out the factors associated with invasion. This is a 5-year retrospective study in a referral pathology center. A total of 19 cases of ICPN are found. The cases are analyzed for age and sex distribution, clinical suspicion, stages, histological architecture, differentiation, and grade of dysplasia. Descriptive statistics and test of significance by Chi-square and t-test are used in the study. ICPN comprises 23.5% of all gallbladder neoplasms. Two-thirds of the cases were suspected radiologically. Age range is 26-65 years with mean age of 50 years. They are 2.8 times more common in female. Approximately one-third of the cases show invasion. The most common histological pattern is papillary, followed by papillary-tubular and finally by tubular pattern. Pyloric and biliary are the most common differentiation pattern followed by oncocytic and intestinal pattern. About three-fourths of the cases are associated with high-grade dysplasia mostly diffuse high-grade dysplasia. We have found the younger age of presentation, less proportion of invasive tumors, fewer tumors with biliary phenotypes, and fewer tumors with high-grade dysplasia as compared to previous studies. Factors significantly associated with invasion are grade and extent of dysplasia particularly diffuse high-grade dysplasia.

Effect of green tea catechins on gastric mucosal dysplasia in insulin-gastrin mice.

Green tea catechins (GTCs) have been implicated in various physiological effects, including anti-carcinogenic activities. In the present study, we evaluated the effects of GTCs specifically on the development of gastritis and pre-malignant lesions in insulin-gastrin mice. Nine-week-old male INS-GAS mice (n=38) were supplemented with GTCs for 4 and 28 weeks, and their body weights, serum gastrin levels, histopathology and pro-inflammatory cytokine levels in gastric tissue and mucosal cell proliferation were monitored. Body weights of the GTC-treated mice were significantly lower than those of the untreated controls (P≤0.05). Serum gastrin levels were suppressed at the age of 37-weeks (P≤0.05). The histopathological scores indicated that the extent of dysplasia was significantly diminished (P≤0.05), although GTC supplementation did not affect the inflammation scores. The messenger RNA levels of interferon (IFN)-γ were significantly reduced at the age of 13 weeks (P≤0.05), although the changes did not reach statistical significance at the age of 37 weeks (P=0.056). The labeling index of Ki-67 immunohistochemistry was significantly decreased (P≤0.05). These results demonstrated that GTCs may play a protective role in the development of gastritis and pre-malignant lesions via an IFN-γ, gastrin, and mucosal cell proliferation-dependent mechanism in this rodent model and potentially in humans.

Positive Margin Status in Uterine Cervix Cone Specimens is Associated With Persistent/Recurrent High-grade Dysplasia

The frequency of positive cone margins and its significance in cervical intraepithelial neoplasia are under controversy. The purpose of the current study was to identify factors associated with positive cone margin status and to evaluate its clinical significance in high-grade cervical intraepithelial neoplasia. Medical records of women who underwent loop electrosurgical excision procedure at the Soroka Medical Center (January 2001-July 2011) were reviewed retrospectively. Patient age, extent of dysplasia, endocervical glands involvement, positive margin status, type of margin involved, degree of margin involvement, and postcone endocervical curettage results were evaluated as possible factors associated with persistent/recurrent disease. A total of 376 women were included in the study. Cone margin involvement was observed in 33% (endocervical-22%, ectocervical-8%, both margins-3%). Factors significantly associated with cone margin involvement were older age (older than 35 y), widespread dysplasia in the cone specimen (≥4 sections) (P<0.001 for each), and endocervical glands involvement (P=0.003). Fifty patients (13%) had persistent/recurrent disease. Involvement of the cone margins (focal: hazard ratio=17, P<0.001; extensive: hazard ratio=28, P<0.001) and older age (hazard ratio=1.18 for every 5 additional years, P=0.03) were associated with persistent/recurrent disease. We conclude that women older than 35 yr with widespread high-grade dysplasia in the cone specimen and involvement of endocervical glands are more likely to have positive cone margins. Positive cone margins, particularly when extensively involved, and increased patient age are associated with persistent/recurrent disease. These factors should be considered while planning for further management.

Early seizure onset and dysplastic lesion extent independently disrupt cognitive networks

To determine the most important factors influencing neuropsychological performance in children with intractable epilepsy due to focal cortical dysplasia and the nature of the interaction among significant variables. Surgical patients with histologically verified focal cortical dysplasia were retrospectively evaluated to determine the impact of histopathology, extent of lobar involvement, hemispheric laterality, age at onset, and duration of epilepsy on cognitive functioning. A composite neuropsychological variable was obtained by transforming data from 5 major cognitive domains using principal components analysis. Multiple regression was used to examine the unique contributions of predictor variables on composite cognition and Full Scale IQ. Data were qualitatively evaluated for nonstatistical trends. Poor cognitive outcomes were associated with early age at onset of epilepsy (AOE) and widespread dysplastic involvement. Extent of dysplasia and AOE together accounted for 35% of Full Scale IQ variance, and 21% of composite cognitive performance. Each factor contributed independently to cognitive dysfunction. Early AOE disrupts critical periods of development and leads to poor cognitive outcome, but children with multilobar dysplasia are likely to have diminished cognitive skills regardless of AOE. Later AOE is not expected to mitigate deficits because of widespread pathology, nor would a localized lesion be likely to mollify the developmental deficits resulting from early AOE.

A randomised controlled trial of ALA vs. Photofrin photodynamic therapy for high-grade dysplasia arising in Barrett’s oesophagus

Photofrin photodynamic therapy (PDT) is a licenced treatment for Barrett's oesophagus (BE) with high-grade dysplasia (HGD) but causes strictures and photosensitivity and complete reversal of dysplasia (CR-HGD) by 50 % at 5 years. 5-Aminolaevulinic acid (ALA) is an alternative treatment with non-randomised data suggesting 85 % CR-HGD and a low risk of side effects. We aimed to compare efficacy and side effect profile between the drugs. A single-centre randomised controlled trial was conducted. Presence of HGD was confirmed on three occasions by two specialist GI pathologists. Stratification was by length of BE and extent of dysplasia. Standard protocols for ALA and Photofrin-PDT were followed. Endoscopic follow-up with 2-cm four-quadrant biopsy was at 6 weeks, 4 months, and then annually. All adverse event data were collected. Sixty four patients were randomised, 34 ALA and 30 Photofrin-PDT. Median follow-up is 24 months. On intention-to-treat analysis, CR-HGD was 16/34 (47 %) with ALA-PDT and 12/30 (40 %) with Photofrin-PDT. The overall cancer incidence was 14 % (9/64). On sub-group log-rank analysis, for BE ≤ 6 cm, CR-HGD was significantly higher with ALA-PDT than Photofrin-PDT (χ(2) =5.39, p=0.02). Strictures and skin photosensitivity were significantly more common after treatment with Photofrin-PDT than ALA-PDT (33 vs. 9 % and 43 vs. 6 %, respectively, p<0.05). The rate of buried glands with either drug was significantly higher post-PDT (48 % of patients) than pre-PDT (20 %). ALA-PDT has a better risk profile than Photofrin-PDT. In patients with BE length ≤ 6 cm, preliminary results show ALA-PDT is associated with significantly higher CR-HGD. In longer segments of BE, neither PDT drug is sufficiently efficacious to warrant routine use.

A Randomised Controlled Trial of ALA V Photofrin PDT for High Grade Dysplasia in Barrett's Esophagus

Introduction Sodium porfimer photodynamic therapy (sp-PDT) is a licensed minimally invasive treatment for Barrett9s Oesophagus (BO) with high grade dysplasia (HGD). Complete reversal (CR)-HGD is 50% at 5 years. sp-PDT is associated with a significant risk of strictures and prolonged photosensitivity up to 3 months. 5 aminolaevulinic acid (ALA) is an alternative treatment with 36 h photosensitivity. Non-randomised data suggests 85% CR-HGD and low risk of side effects. The aim of this study was to compare the side effect profile between the drugs and outcomes of therapy. Methods Single centre randomised controlled trial. Presence of HGD was confirmed on two occasions by two specialist GI pathologists. All patients had Endoscopic Ultrasound and endoscopic resection of visible lesions prior to PDT. Stratification was by length of BO ( 6 cm) and extent of dysplasia. Standard protocols for ALA and sp-PDT were followed. Endoscopic follow-up with 2 cm four-quadrant biopsy was at 6 weeks, 4 months, then annually. All adverse event data were collected. Results Sixty-four patients were randomised, 34 ALA and 30 sp-PDT. Median follow-up is currently 23 months. Strictures and skin photosensitivity were significantly more common with sp-PDT than ALA-PDT (33% vs 9% and 43% vs 6% respectively) p 2 = 4.34, p=0.037. For BO length >6 cm there was no significant difference. Rate of buried glands was significantly higher post PDT (48%) than pre PDT (20%), no significant difference between groups. Conclusion ALA-PDT has a better risk profile than sp-PDT. In patients with BO length ≤6 cm, preliminary results show ALA-PDT is associated with significantly higher CR-HGD. In longer segments of BO neither PDT drug was sufficiently efficacious to warrant use.

A randomised controlled trial of ALA versus photofrin PDT for high grade dysplasia in barrett's oesophagus

IntroductionSodium porfimer photodynamic therapy (sp-PDT) is a licensed minimally invasive treatment for Barrett's Oesophagus (BO) with high grade dysplasia (HGD). Complete reversal (CR)-HGD is 50% at 5 years. sp-PDT is...

Barrett’s oesophagus: past, present and future

Barrett's oesophagus (BE) is the most common cause of oesophageal adenocarcinoma. Adenocarcinoma develops through a meta-plasia-dysplasia-carcinoma sequence, but there are many unknown and controversial issues related to the diagnosis, classification, pathological criteria, molecular progression, natural history and treatment of metaplastic and dysplastic precursor lesions in BE. The purpose of this lecture (review) is to provide an evidence-based summary of the diagnosis and classification of BE-associated metaplasia and dysplasia, to provide a summary of the key pathological features of the most common types of precursor lesions, to outline common areas of diagnostic difficulties, and to evaluate adjunctive markers of cancer progression in BE. The current American College of Gastroenterologists (ACG) definition of BE is partially flawed, since not all cases of BE are endoscopically recognisable, non-goblet epithelium is biologically intestinalised and genetically abnormal, and determination of the presence or absence of goblet cells is susceptible to sampling error and variability with time. Metaplastic epithelium in BE shows clonal molecular abnormalities that precede morphological expression of dysplasia. Dysplasia in BE begins in the crypt bases and then extends more superficially to include the upper portion of the crypts and surface epithelium with time and progression. Low and high grade dysplasia are distinguished by the presence of marked cytological and/or architectural abnormalities in the latter compared to the former, but there are newly discovered subtypes of dysplasia, such as the foveolar and serrated type, in which differentiation of low from high grade dysplasia is difficult and the significance of grading dysplasia is unknown. For instance, one type of dysplasia (foveolar dysplasia) may occur in non-goblet metaplastic columnar epithelium and shows a high progression rate to carcinoma compared to conventional (intestinal type) dysplasia. There are few, if any, reliable adjunctive diagnostic techniques that can help differentiate non-dysplastic from dysplastic epithelium in BE, but α-methylacyl coenzyme A racemase (AMACR) staining has been shown to be useful in several different studies. Both low and high grade dysplasia are progressive lesions, and in general, the extent of dysplasia is a strong risk factor for progression to carcinoma. Of all the biological and genetic biomarkers studied to date, evaluation of DNA content is the most reliable and specific marker of progression in BE. The management of patients with dysplasia is variable between institutions, and ranges from aggressive surveillance, endoscopic mucosal resection, either with or without mucosal ablation, or total oesophagectomy. Recent data on radiofrequency ablation in BE is promising.

Barrett esophagus: histology and pathology for the clinician

The incidence of adenocarcinoma of the esophagus and gastroesophageal junction has increased dramatically over the past 30 years. The major precursor to this type of adenocarcinoma is Barrett esophagus, which is defined as the conversion of normal squamous epithelium into metaplastic columnar epithelium. Abundant evidence suggests that adenocarcinoma in the setting of Barrett esophagus develops via a progressive sequence of histological and molecular events. Consequently, patients with Barrett esophagus routinely undergo endoscopic surveillance for early detection of neoplasia. Histological evaluation of mucosal biopsy samples from the esophagus and gastroesophageal junction for identification of goblet cells and evaluation of the presence, grade and extent of dysplasia is the mainstay of risk assessment for these patients. This Review provides physicians with a summary of the pertinent, clinically relevant histological features of Barrett esophagus and its neoplastic complications. The histology of Barrett esophagus and the gastroesophageal junction is summarized, and an overview of information necessary to interpret pathology reports from patients either with or without endoscopic evidence of Barrett esophagus is provided to appropriately guide management of patients. Close interaction between the clinician and the pathologist is essential for proper interpretation of biopsy results and to provide optimal surveillance or treatment strategies.

Update on the Diagnosis and Treatment of Barrett Esophagus and Related Neoplastic Precursor Lesions

At present, Barrett esophagus is the most common cause of esophageal adenocarcinoma. In the past 20 years, the incidence of esophageal adenocarcinoma in white males has exceeded that of tumors of the colorectum, lung, prostate, and skin. To (1) provide an evidence-based review of the diagnosis, classification, and histologic differentiation of Barrett esophagus from gastric carditis, (2) provide a summary of the key pathologic features of precursor lesions, such as dysplasia, and (3) evaluate adjunctive markers of dysplasia and predictive markers for the development of cancer. The natural history and risk of cancer in patients with Barrett esophagus is also reviewed. For this review, selected published peer reviewed articles were chosen from a search through PubMed between the years 1970 and 2007. The current definition of Barrett esophagus is partially flawed because not all cases are endoscopically recognizable, nongoblet epithelium is biologically intestinalized, and determination of the presence or absence of goblet cells is susceptible to sampling error. Differentiation of ultrashort segment Barrett esophagus from chronic gastric carditis can be accomplished, in a minority of cases, by evaluating for the presence or absence of histologic features that are known to be associated with Barrett esophagus. Dysplasia in Barrett esophagus begins in the crypt bases and then extends more superficially to include the upper portions of the crypts and surface epithelium. Low- and high-grade dysplasia are distinguished by the presence of marked cytologic and/or architectural abnormalities in the latter compared with the former. There are few, if any, reliable adjunctive diagnostic techniques that can help differentiate nondysplastic from dysplastic epithelium. However, alpha-methylacyl coenzyme A racemase staining has been shown to be useful in 2 separate studies. Both low- and high-grade dysplasia are progressive lesions, and in general, the extent of dysplasia, particularly low grade, is a strong risk factor for progression to carcinoma. Of all the biologic and genetic biomarkers studied to date, evaluation of DNA content is the most reliable and specific. The management of patients with dysplasia is variable among institutions and ranges from aggressive surveillance, endoscopic mucosal resection, mucosal ablation, or total esophagectomy.

The high affinity peroxisome proliferator‐activated receptor‐gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane‐treated mice

We evaluated RS5444, a thiazolidinedione high affinity PPARgamma agonist, for the ability to inhibit colon carcinogenesis in azoxymethane (AOM)-treated mice. In our initial experiment, mice were treated with RS5444 during AOM treatment, and the drug was withdrawn 12 weeks after the last injection of AOM. RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to RS5444 during the course of AOM treatment effectively blocked colon tumor formation after withdrawal of the agonist. PPARgamma expression and nuclear localization were reduced in adenomas. RS5444 did not inhibit DNA synthesis in tumor cells, suggesting that PPARgamma activity was impaired in adenomas. To test this hypothesis, pre-existing adenomas were treated with RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in tumor incidence in RS5444-treated mice. However, histological examination revealed that tumors from RS5444-treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore, carcinoma in situ was observed in about one-third of control tumors, but was never observed in RS5444-treated tumors. We conclude that RS5444 inhibits both initiation and progression of colon tumors in the AOM model of sporadic colon carcinogenesis.

414 IMMUNOHISTOCHEMISTRY FOR AGRIN AND CD34 IN THE DISCRIMINATION OF BENIGN VERSUS MALIGNANT LESIONS OF THE LIVER PARENCHYMA

Background and Aims: Agrin is a recently identified proteoglycan component of vascular and bile duct basement membranes in the liver. The selective deposition of agrin in tumor microvessels versus sinusoidal walls prompted us to investigate whether immunohistochemistry (IHC) for agrin may help to discriminate between benign and malignant hepatocellular lesions. We focused on the differential diagnostic problems often presented by hepatocellular adenomas (HAs) and dysplastic nodules. Our aim was to devise a novel immunohistochemical method that sensitively and selectively detects hepatocellular malignancy. Also, an attempt was made to interpret the observed agrin immunostaining patterns in the context of vascular changes, ductular reaction and parenchymal regeneration. Methods: Eighty-eight formalin-fixed, paraffin-embedded surgical specimens from 68 patients included 24 cirrhotic liver tissues, 10 cases with focal nodular hyperplasia (FNH), 8 large regenerative nodules, 18 lowgrade and 6 high-grade dysplastic nodules (LGDN and HGDN), 6 small HCCs, 21 HCCs, and 29 HAs. Immunoreactions for agrin and, when necessary, for CD34 were evaluated in a semi-quantitative fashion, and the outcome was compared with histological diagnosis. Results: In our method, agrin IHC was complemented with CD34 immunoreaction in ambiguous cases. This combination was found highly informative in the assessment of dignity (sensitivity 92.6%, specificity 91.8%). Whereas most benign lesions (regenerative nodules, LGDN, FNH, HA without cellular atypia) were clearly negative, the strength of immunoreactions and consequent ranking of the sample faithfully reflected the degree and extent of dysplasia in HA and HGDN. Malignant lesions were uniformly positive. Conclusion: Agrin IHC, besides allowing insight into a multitude of nonmalignant pathological processes such as ductular reaction and parenchymal regeneration, is a sensitive indicator of hepatocellular dysplasia and changes in vascular phenotype. Therefore, the admission of agrin to the immunohistochemical panel used in routine liver pathology is worth consideration.

Conservative treatment of cervical intraepithelial neoplasia using a cold-knife section technique

Objective: The purpose of this study was to evaluate a conservative cold-knife section technique for treatment of cervical intraepithelial neoplasia (CIN). This procedure can be adapted to patient age, preservation of childbearing potential and extent of dysplasia. Design: Prospective study. Setting: Gynecological Oncology Department in French Public Hospital. Population: A total of 460 women treated for CIN between 1985 and 1999 were included. Methods: A conservative cold-knife cervical section followed by blanket suture reconstruction was used in all cases. Main outcome measures: Immediate operative results, recurrence and reproductive function were assessed. Results: The mean length of the cervical specimen was 11.4 mm (range, 4–22 mm). Mean specimen thickness was strongly correlated with age: 10.6 ± 4.1 mm in women <40 years versus 12.1 in women >40 years; p < 0.001. Complete excision was achieved in 395 cases (85.8%). Post-operative bleeding was observed in 5 cases (1.1%). The mean duration of follow-up was 62 months (range, 12.3–156.5 months). Recurrences developed in 26 patients (6.6%) including CIN 1 in 9 cases, CIN 2 in 9 and CIN 3 in 8. No patient developed carcinoma. The actuarial risk of recurrence was 2.4% (±S.D., 0.9) at 24 months and 7.8% (±S.D., 1.9) at 60 months. A total of 52 pregnancies were observed in 39 patients. No case of de novo infertility was reported post-operatively. Amenorrhea was noted in 1 patient (0.1%) and dysmenorrhea in 1 patient (0.1%). Conclusions: This conservative cold-knife section technique is effective for treatment of CIN with low morbidity and little adverse effect on childbearing potential. Exposure of the squamocolumnar junction (SCJ) greatly facilitates follow-up.

Extent of Dysplasia in BE Correlates with Cancer Risk

Dysplasia has been the primary predictor for esophageal adenocarcinoma in patients with Barrett's esophagus (BE). Additionally, the degree of dysplasia

Midface anomalies in children.

A variety of congenital midface anomalies occur in children. High-resolution computed tomography (CT) and magnetic resonance (MR) imaging have proved helpful in determining the nature and extent of dysplasia, thereby facilitating treatment planning. A classification system has been developed that groups these anomalies into four categories based on embryogenesis and anatomic location. These categories comprise anomalies that are related to the nasal cavity, nasofrontal region, nasolacrimal apparatus, and craniofacial syndromes. CT is the imaging modality of choice in children with possible choanal atresia, pyriform aperture stenosis, or anomalies of the nasolacrimal duct (eg, nasolacrimal duct stenosis, dacryocystoceles). MR imaging is the modality of choice in patients with congenital midface masses (eg, dermoid and epidermoid cysts, nasal gliomas, encephaloceles) and craniofacial syndromes (eg, Apert syndrome, Crouzon syndrome, Treacher Collins syndrome). In many cases, however, both CT and MR imaging are required to adequately evaluate midface anomalies. Familiarity with the characteristic imaging features of these anomalies along with knowledge of midface embryogenesis and normal developmental anatomy is essential to prevent misinterpretation of anatomic variations that may simulate disease.