Piet C. de Groen

Esophagitis Associated with the Use of Alendronate

BACKGROUND Alendronate, an aminobisphosphonate and a selective inhibitor of osteoclast-mediated bone resorption, is used to treat osteoporosis in postmenopausal women and Pagets disease of bone. Aminobiphosphonates can irritate the upper gastrointestinal mucosa. METHODS We describe three patients who had severe esophagitis shortly after starting to take alendronate and also analyze adverse esophageal effects reported to Merck, the manufacturer, through postmarketing surveillance. RESULTS As of March 5, 1996, alendronate had been prescribed for an estimated 475,000 patients worldwide, and 1213 reports of adverse effects had been received. A total of 199 patients had adverse effects related to the esophagus; in 51 of these patients (26 percent), including the 3 we describe in case reports, adverse effects were categorized as serious or severe. Thirty-two patients (16 percent) were hospitalized, and two were temporarily disabled. Endoscopic findings generally indicated chemical esophagitis, with erosions or ulcerations and exudative inflammation accompanied by thickening of the esophageal wall. Bleeding was rare, and stomach or duodenal involvement unusual. In patients for whom adequate information was available, esophagitis seemed to be associated with swallowing alendronate with little or no water, lying down during or after ingestion of the tablet, lying down during or after ingestion of the tablet, continuing to take alendronate after the onset of symptoms, and having preexisting esophageal disorders. CONCLUSIONS Alendronate can cause chemical esophagitis, including severe ulcerations, in some patients. Recommendations to reduce the risk of esophagitis include swallowing alendronate with 180 to 240 ml (6 to 8 oz) of water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested, and discontinuing the drug promptly if esophageal symptoms develop.

BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice.

Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.

A Comparison of Routine Cytology and Fluorescence in situ Hybridization for the Detection of Malignant Bile Duct Strictures

BACKGROUND  AND  AIM:The aim of this study was to assess the relative sensitivities and specificities of fluorescence in situ hybridization (FISH) and routine cytology for the detection of malignancy in biliary tract strictures.METHODS:Bile duct brushing and aspirate specimens were collected from 131 patients being evaluated for possible malignant bile duct strictures. Both specimen types were assessed by FISH but only brushing specimens were assessed by cytology. The FISH assay used a mixture of fluorescently-labeled probes to the centromeres of chromosomes 3, 7, and 17 and chromosomal band 9p21 (Vysis® UroVysion) to identify cells having chromosomal abnormalities. A case was considered positive for malignancy if five or more cells exhibited polysomy.RESULTS:Sixty-six of the 131 patients had surgical pathologic and/or clinical evidence of malignancy. Thirty-nine patients had cholangiocarcinoma, 19 had pancreatic carcinoma, and 8 had other types of malignancy. The sensitivity of cytology and FISH for the detection of malignancy in bile duct brushing specimens in these patients was 15% and 34% (p < 0.01), respectively. The sensitivity of FISH for the bile aspirate specimens was 23%, and the combined sensitivity of FISH for aspirate and brushing specimens was 35%. The specificity of FISH and cytology brushings were 91% and 98% (p = 0.06), respectively.CONCLUSIONS:FISH is significantly more sensitive than and nearly as specific as conventional cytology for the detection of malignant biliary strictures in biliary brushing specimens. FISH may improve the clinical management of patients who are being evaluated for malignancy in bile duct strictures.

Determinants of survival and the effect of portosystemic shunting in patients with Budd-Chiari syndrome

Budd‐Chiari syndrome (BCS) is a rare disorder that is characterized by hepatic venous outflow obstruction. The aim of this study was to assess determinants of survival and to evaluate the effect of portosystemic shunting. In this international multicenter study, 237 patients with BCS, diagnosed between 1984 and 2001, were investigated. Univariate, multivariate, and time‐dependent Cox regression analyses were performed. Overall survival at 1, 5, and 10 years was 82% (95% CI, 77%–87%), 69% (95% CI, 62%–76%), and 62% (95% CI, 54%–70%), respectively. Encephalopathy, ascites, prothrombin time, and bilirubin were independent determinants of survival. A prognostic classification combining these factors could identify three classes of patients (classes I–III). The 5‐year survival rate was 89% (95% CI, 79%–99%) for class I, 74% (95% CI, 65%–83%) for class II, and 42% (95% CI, 28%–56%) for class III. Anticoagulants were administered to 72%; only for patients in class I was this associated with a trend toward improved survival (relative risk [RR], 0.14; 95% CI, 0.02–1.21). Portosystemic shunting was performed in 49% of the patients (n = 117); only for patients in class II, time‐dependent analyses suggested an improved survival (RR, 0.63; 95% CI, 0.26–1.49). In conclusion, at the time of diagnosis, patients with BCS can be classified into good (I), intermediate (II), and poor (III) prognostic classes, according to simple baseline clinical and laboratory parameters. Our results suggest an improved survival after surgical portosystemic shunting for patients with an intermediate prognosis (class II). (HEPATOLOGY 2004;39:500–508.)

A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures

BACKGROUND & AIMS Digital image analysis (DIA) allows quantification of nuclear DNA content and may help distinguish benign and malignant strictures of the biliary tract. METHODS One hundred ten consecutive patients undergoing endoscopic retrograde cholangiography for suspicious biliary tract strictures were enrolled in a prospective study comparing the accuracy of DIA and routine cytology (RC). Standard brush cytology sampling was performed twice by using 2 cytology brushes per patient. Both brushes were fixed in a single-specimen vial. Each specimen was formed into 1 pellet, and the sample was equally divided for evaluation by DIA and RC. DNA histograms were generated for ploidy analysis. The DIA criterion for malignancy was demonstration of aneuploidy. RESULTS Two patients had inadequate samples obtained for DIA analysis, 7 benign patients were excluded because of inadequate follow-up of less than 75 days, and 1 patient was lost to follow-up to clarify malignant versus benign disease. Of the remaining 100 patients, 56 strictures were malignant and 44 were benign. The sensitivities of DIA and RC were 39.3% and 17.9%, respectively (P = 0.014). The specificities of DIA and RC were 77.3% and 97.7%, respectively (P = 0.003). The accuracy of DIA (56.0%) was equivalent to RC (53.0%). CONCLUSIONS DIA is a valuable adjunct to RC for detecting malignant strictures of the biliary tract.

Automatically extracting cancer disease characteristics from pathology reports into a Disease Knowledge Representation Model

We introduce an extensible and modifiable knowledge representation model to represent cancer disease characteristics in a comparable and consistent fashion. We describe a system, MedTAS/P which automatically instantiates the knowledge representation model from free-text pathology reports. MedTAS/P is based on an open-source framework and its components use natural language processing principles, machine learning and rules to discover and populate elements of the model. To validate the model and measure the accuracy of MedTAS/P, we developed a gold-standard corpus of manually annotated colon cancer pathology reports. MedTAS/P achieves F1-scores of 0.97-1.0 for instantiating classes in the knowledge representation model such as histologies or anatomical sites, and F1-scores of 0.82-0.93 for primary tumors or lymph nodes, which require the extractions of relations. An F1-score of 0.65 is reported for metastatic tumors, a lower score predominantly due to a very small number of instances in the training and test sets.

Use of a fully covered self-expandable metal stent for the treatment of benign esophageal diseases

BACKGROUND Fully covered self-expandable metal stents (FCSEMSs) have been proposed for the treatment of benign esophageal diseases. OBJECTIVE To review our experience with FCSEMSs in patients with benign esophageal diseases. DESIGN Retrospective case review of patients who underwent FCSEMS placement for benign esophageal diseases, including (1) benign strictures from GERD--caustic and idiopathic causes, (2) radiation-induced strictures, (3) anastomotic strictures, (4) esophageal fistulae/leaks, and (5) esophageal perforations. SETTING Tertiary-care medical center. PATIENTS This study involved 37 male and 19 female patients (average age 60 years, range 25-94 years) who underwent FCSEMS placement. INTERVENTION FCSEMS placement. MAIN OUTCOME MEASUREMENTS Technical success with stent placement and removal, stent migration, long-term and short-term complications, and treatment success according to clinical symptoms, follow-up endoscopy, or imaging. RESULTS Stent placement was successful in 100 of 107 (93%) procedures, with a total of 104 stents placed. Migration was noted in 37 of 104 (35.6%) stents and was seen more frequently with proximal stents and stents placed for anastomotic strictures. Initial treatment success was seen in 56% of patients with any stricture and in 38% of patients with a fistula/leak or perforation, although data to document long-term resolution were lacking. LIMITATIONS This was a retrospective review with patients selected from a tertiary-care medical center. Two endoscopists performed the majority of procedures. CONCLUSION Temporary placement of FCSEMSs for benign esophageal diseases has moderate clinical efficacy and is limited by stent migration. Removability was easily demonstrated. Newer developments in stent design may improve clinical outcomes for these patients.

Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma

Background: Photodynamic therapy (PDT) has demonstrated promise in the palliative treatment of advanced cholangiocarcinoma. The aim of this pilot study was to assess the outcome in patients with non‐resectable cholangiocarcinoma following endoscopic application of PDT directly into the biliary tract.

The prognostic value of histology in the assessment of patients with Budd-Chiari syndrome

BACKGROUND/AIMS It is unclear whether treatment of patients with Budd-Chiari syndrome (BCS) should be based on liver histology, as large histopathological studies have not been performed. We investigated the relationship between the histopathological findings and survival. METHODS We studied the clinical features and findings on biopsy specimens in 45 patients with BCS who were admitted to four tertiary referral medical centers. Histological findings, i.e. congestion, necrosis, inflammation and fibrosis, were graded. Survival was assessed in relation to histological findings and clinical features at the time of diagnosis as well as in relation to subsequent treatment with or without portosystemic shunting. RESULTS Centrilobular congestion, centrilobular necrosis, lobular inflammation and portal inflammation were not significantly related to survival. In addition, there was no association between either pericentral or periportal fibrosis and survival. Univariate analysis revealed that the prothrombin time and Child-Pugh score were significantly related to survival (P = 0.005 and Ptrend = 0.02, respectively). Multivariate analysis yielded the Child-Pugh score, serum alanine aminotransferase (ALT) and treatment with portosystemic shunting as independent prognostic indicators. CONCLUSIONS We found no evidence for a relationship between early liver pathology and survival. Child-Pugh score, serum ALT and portosystemic shunting appeared to be prognostic indicators for patients with BCS.

Validation of the Ulcerative Colitis Colonoscopic Index of Severity and Its Correlation With Disease Activity Measures

BACKGROUND & AIMS Endoscopic healing is likely to become an important goal for treatment of patients with ulcerative colitis (UC). A simple validated endoscopic index is needed. We validated the previously developed UC Colonoscopic Index of Severity (UCCIS). METHODS In a prospective study, 50 patients with UC were examined by colonoscopy; we analyzed videos of rectum and sigmoid, descending, transverse, and cecum/ascending colon. Eight gastroenterologists blindly rated 4 mucosal lesions (for vascular pattern, granularity, friability, ulceration) and severity of damage to each segment and overall. The global assessment of endoscopic severity (GAES) was based on a 4-point scale and 10-cm visual analogue scale. Correlation of the UCCIS score with clinical indexes (clinical activity index and simple clinical colitis activity index), patient-defined remission, and laboratory measures of disease activity (levels of C-reactive protein, albumin, and hemoglobin and platelet counts) were estimated by using the Pearson (r) or Spearman (r(s)) method. RESULTS Interobserver agreement was good to excellent for the 4 mucosal lesions evaluated by endoscopy and the GAES. The UCCIS calculated for our data accounted for 74% (R(2) = 0.74) and 80% (R(2) = 0.80) of the variation in the GAES and visual analogue scores, respectively (P < .0001). The UCCIS also correlated with clinical activity index (r = 0.52, P < .001), simple clinical colitis activity index (r = 0.62, P < .0001), and patient-defined remission (r = 0.43, P < .01). The UCCIS also correlated with levels of C-reactive protein (r(s) = 0.56, P < .001), albumin (r = -0.55, P < .001), and hemoglobin (r = -0.39, P < .01). A rederivation of the equation for the UCCIS by using the data from a previous study combined with those of the current study (n = 101) yielded similar results. CONCLUSIONS The UCCIS is a simple tool that provides reproducible results in endoscopic scoring of patients with UC.