Lars Zimmermann

Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo

Peroxisome proliferator‐activated receptor γ (PPARγ) has been implicated in the differentiation and growth inhibition of cancer cells. We examined the effects of PPARγ activation by troglitazone on hepatocellular carcinoma (HCC) cell growth, proliferation, and apoptosis in vitro and in vivo. We also studied relationships between PPARγ activation and cyclooxygenase‐2 (COX‐2) expression. Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST‐1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen (PCNA) Western blotting, and apoptosis by flow cytometry and TUNEL. Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored, and the effects of treatment with troglitazone were determined. In resected HCCs, PPARγ expression was less compared with the histologically normal surrounding liver. In cultures of Hep3B and Huh7 cells, basal expression of PPARγ was relatively low, but troglitazone caused dose‐dependent induction of PPARγ expression. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. Concomitant downregulation of PCNA and an increase in TUNEL staining, cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone. Troglitazone‐mediated PPARγ activation also suppressed COX‐2 expression and induced p27 in HCC cells. Administration of troglitazone to Huh7 tumor‐bearing mice significantly reduced tumor growth and caused tumor regression. In conclusion, collectively, these results indicate that PPARγ could be a regulator of cell survival and growth in HCC. PPARγ therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth.. (HEPATOLOGY 2006;43:134–143.)

Feasibility of endoscopic closure of an iatrogenic colon perforation occurring during colonoscopy.

BACKGROUND Colon perforation is one of the most dreaded complications of colonoscopy. Traditionally, patients with a colon perforation have been treated surgically. Although there are several case reports documenting the usefulness of endoscopic closure of colon perforations, there are few current data evaluating the feasibility of endoscopic closure for an iatrogenic perforation on consecutive patients undergoing colonoscopy. OBJECTIVE To assess the incidence of colon perforations and the utility of immediate endoscopic closure during colonoscopy. DESIGN Retrospective, observational study. SETTING Tertiary-care academic medical center. PATIENTS All patients who underwent colonoscopy at 1 institution from June 2002 to December 2008 were identified. INTERVENTION An attempt at immediate colon perforation closure by endoscopic means. MAIN OUTCOME MEASUREMENTS Successful endoscopic closure of colon perforation. RESULTS During the study period, a total of 8601 colonoscopies were performed (2472 therapeutic interventions, 28.7%). A total of 12 iatrogenic colon perforations occurred, yielding a rate of 1.4/1000. Five (41.7%) occurred during a diagnostic colonoscopy (0.8/1000), and 7 perforations (58.3%) occurred as the result of a therapeutic intervention (2.8/1000). Endoscopic closure of the perforation site was possible in 5 patients (42%). Seven patients were treated surgically (large defects [n = 3], including 1 failed endoscopic closure, difficult endoscope position [n = 2], stool contamination [n = 1], and endoscopists inexperience with closure of mucosal defects [n = 1]). LIMITATION Retrospective design. CONCLUSIONS In this study, the incidence of colon perforations was 1.4/1000. Endoscopic closure of iatrogenic colon perforations was attempted in 50% of patients and was successful in 83%. All patients with successful endoscopic closure had lesions smaller than 10 mm.

Sorafenib Therapy in Patients with Advanced Hepatocellular Carcinoma in Advanced Liver Cirrhosis

Background and Aim: Sorafenib has become the treatment standard for patients with advanced hepatocellular carcinoma (HCC). It is not clear whether patients with advanced liver function impairment (Child B) and patients undergoing additional locoregional therapy may tolerate treatment with sorafenib and benefit. We aimed to evaluate the tolerability and efficiency of sorafenib in patients with advanced HCC and different stages of liver cirrhosis, and in combination with locoregional therapy. Methods: In 50 patients with advanced HCC treated with sorafenib tolerability and efficiency of the therapy with respect to stage of liver cirrhosis, existence of extrahepatic tumor spread, and additional locoregional therapy were evaluated. Results: Fifty patients with advanced HCC were treated with sorafenib, and 13 received additional locoregional therapy. Tolerability of the systemic treatment was moderate in all patients, with no significant differences between the subgroups, while the median survival was better in patients with Child A than Child B cirrhosis. Conclusion: Tolerability and toxicity of a systemic treatment with sorafenib are moderate in patients with liver cirrhosis in Child A or B. Prospective randomized studies are required to evaluate the efficacy and tolerability of combined systemic and locoregional treatment approaches in patients with advanced HCC.

Advanced Endoscopic Imaging Methods for Colon Neoplasia

The main goal of lumenal endoscopic visualization of the colon is to detect mucosal pathologies, which when removed will result in cure or palliation of a disease process. Whereas traditionally endoscopic imaging was performed with fiber-optic technology, currently there are many new methods that improve our visual acuity when evaluating the colon mucosa. Most of these methods are collectively called ‘advanced colonic imaging’. The 2 main aims of standard (white light) and advanced colonic imaging are to enhance the superficial mucosal detail (i.e. ‘pit pattern’) and allow a detailed view of the submucosal capillary pattern, thus potentially improving the detection characterization of pathological lesions. However, the current literature dealing with most methods used for advanced endoscopic imaging of the colon is fraught with many controversial findings which have resulted in opposing views regarding its utility. Whereas some investigators vehemently support the use of most of these methods in routine clinical practice, most experts and practicing endoscopists still refuse to accept that these methods aid in the clinical routine. For now, white light video-colonoscopy and high-definition white light video-colonoscopy will remain the standard endoscopic methods for investigating the colon mucosa until new methods convincingly and clearly prove their superiority over white light endoscopy.

Therapeutic Double-Balloon Enteroscopy: A Binational, Three-Center Experience

Background/Aims: There are few reports focusing on therapeutic small bowel endoscopy. The aim of this study was to analyze the results of therapeutic small bowel endoscopy in a large cohort of patients. Methods: A retrospective study of a prospectively collected database comprising all patients undergoing diagnostic and therapeutic small bowel endoscopy in three centers. Results: A total of 614 double-balloon enteroscopies were performed in 534 patients. The most common pathological findings were angiodysplasias and vascular lesions (n = 98, 18%), mucosal ulcers and erosions (n = 95, 17.8%), polyps and tumors (including patients with familiar polyposis syndrome such as Peutz-Jeghers syndrome, familiar adenomatous polyps syndrome, neurofibromatosis, adenocarcinoma, neuroendocrine tumors and gastrointestinal stromal tumors) (n = 52, 9.7%), and strictures (Crohn’s disease, ischemia, tumors) (n = 12, 2.2%). The mean duration of therapeutic small bowel enteroscopy was 67 min (range 30–115) compared to 50 min (range 25–105) for diagnostic procedures (p < 0.05). A therapeutic small bowel endoscopy was performed in 121 patients (22%). Therapeutic procedures included argon plasma coagulation of vascular lesions (n = 73), polypectomy (n = 49), mucosectomy (n = 5), stricture dilation (n = 7), foreign body extraction (n = 7), injection of fibrin glue (n = 10), and clip placement (n = 5). There were a total of 5 complications (0.9%; paralytic ileus, n = 2, pancreatitis, n = 1, bleeding n = 2). No perforations or deaths occurred. Conclusion: Endoscopists performing double-balloon enteroscopy should be trained and prepared to provide therapeutic interventions for small bowel disorders including argon plasma coagulation, injection, hemoclipping, polypectomy, mucosectomy and foreign body extraction. Therapeutic small bowel endoscopy, albeit associated with complications in about 1% of cases, can be considered a relatively safe procedure.

An advanced chromocolonoscopic picture is worth a thousand words, but is it worth the effort?

Abstract: Chromocolonoscopy is a commonly used advanced or multimodal colon imaging method to interrogate the colon mucosa and colon polyps. The two main objectives of chromocolonosopy are to (a) detect a colon polyp and (b) define (differentiate) the lesion. Although data supporting the use of chromocolonoscopy for colon polyp detection are not strongly founded, this technique may be helpful in differentiating colon polyps and may aid in their endoscopic resection.

Propofol and Fospropofol Sedation During Bronchoscopy

We read with interest the excellent editorial by Michael Jantz (January 2009) 1 that nicely summarized the existing data on the safety of propofol for pulmonary endoscopy. We would like to add that propofol also has an excellent record of safety for GI endoscopy. A recently published study documented the safety of propofolassisted sedation in . 500,000 patients undergoing various GI endoscopies. 2 When using propofol sedation, we basically need to follow the same precautions as when using any other drugs for analgosedation, such as benzodiazepine and opioids. This means that the physician and nurse performing the endoscopy should properly select the patient, adequately monitor the patient during the procedure, and be qualifi ed to rescue patients whose levels of sedation become deeper than initially intended. The physician should be educated and trained in the pharmacology of sedative drugs used, airway management, and advanced life support. An advantage of pulmonary endoscopists over GI endoscopists, though, is their familiarity with the upper airways, potentially enabling a more effi cient and smooth endotracheal intubation in an emergency situation. In addition, if an intubation should become diffi cult, the bronchoscope itself also could be used as a guiding instrument to advance the endotracheal tube and achieve proper tracheal intubation. To fi nish, we disagree with Jantz regarding the classifi cation of propofol. Jantz asked us to keep in mind “that fospropofol is a different drug than propofol and that fospropofol is not a general anesthetic.” 1 Indeed, propofol is not classifi ed as an anesthetic either. Propofol (2,6 diisopropylphenol) is an ultra-short-acting sedative-hypnotic agent with amnesic but no analgesic properties. Originally, it was mainly used for the induction of general anesthesia, 3 but currently, it is widely used for sedation of patients on mechanical ventilation and various types of endoscopic procedures. Thus, we conclude that based on the available data, propofol (and not only fospropofol) appears safe for mild-to-moderate sedation in gastrointestinal and pulmonary endoscopy.

Endoscopic Examination of the Stomach in Situs Inversus

A male was referred for an esophagogastroduodenoscopy because of chronic heartburn, regurgitation, nd epigastric abdominal pain. His past medical history was ignificant for chronic obstructive pulmonary disease. He menioned that his inside organs were “twisted” around. Physical xamination was remarkable for epigastric tenderness. The liver argin was palpated and percussed on the left side; the midlavicular liver size was estimated at 12 cm. Esophagogasroduodenoscopy demonstrated situs inversus. The greater curature was located on the right side (Figure A). Figure B shows an anatomically normal stomach, with greater curvature on the left and the lesser curvature on the right. Upon retroflexion, the fundus was clearly located on the right (Figure C). Figure D shows the normal fundic location on the left side. Biopsies of the stomach revealed a chronic gastritis without Helicobacter pylori infection. A diagnosis of nonerosive esophagitis was made. He was started on proton pump inhibitor therapy and remains well at 3-months follow-up. Complete situs inversus is a rare congenital anomaly that results in a complete left-right inversion of the viscera.1 Alhough there is a link to various associated malformations and he immotile cilia or Kartagener syndrome, most patients with itus inversus have completely normal lives. Nevertheless, nowledge of this conditions is of paramount importance for he patient and the treating physician, as many gastrointestinal isease processes will manifest differently, ie, with pain on the “wrong” side. If an endosocpy is necessary, such as in our patient, careful attention should be paid to scope advancement. A useful maneuver is the endoscopic “mirror technique.”1 This technique mandates that all endoscopic maneuvers are performed inversely, as during a normal procedure.1 The basic principle of this technique is to perform the procedure as if the endoscopic exploration were the reflection of a standard endoscopy.1 Once the cardia is reached, a left lateral deflection of the tip of the scope is followed by advancing the scope to the left instead of to the right. The “mirror” changes during scope advancement should also be paralleled by manipulation of the handle wheels, ie, the lateral and up-and-down movements of the tip of the scope should also follow a “mirror technique.” This is especially important when the scope is inside the duodenal bulb.

Self-Expanding Metallic Stents for the Palliation of Malignant Esophageal Obstruction

Every endoscopist will encounter patients with malignant dysphagia that will require some sort of palliative therapy. Self-expanding metallic stents (SEMS) are a major mode of palliative therapy in esophageal cancer. SEMS have become increasingly popular as a result of improvement in design and the availability of different models. Hence, the use of SEMS for the palliation of malignant dysphagia has increased dramatically over the last few years. When choosing stents as palliative therapy, several aspects need to be taken into consideration such as patient condition, tumor location and characteristics, presence of fistula and previous or planned treatments such as chemo- or radiation therapy. This chapter reviews the indications, technique, complications and outcome of expandable metal stents for malignant dysphagia.