Low dose endoluminal photodynamic therapy improves murine T cell-mediated colitis.

BACKGROUND AND STUDY AIMS: Low dose photodynamic therapy (LDPDT) may modify the mucosal immune response and may thus provide a therapy for Crohn's disease. We evaluated the efficacy and safety of this technique in a murine T cell-mediated colitis model. METHODS: The safety of LDPDT was first tested in BALB/c mice. Naïve T cells were used to induce colitis in mice with severe combined immunodeficiency, which were followed up endoscopically, and a murine endoscopic index of colitis (MEIC) was developed. The efficacy of LDPDT (10 J/cm (2); delta-aminolevulinic acid, 15 mg/kg bodyweight) was then tested on mice with moderate colitis, while a disease control group received no treatment. The MEIC, weight, length, and histology of the colon, cytokine expression indices, number of mucosal CD4 (+) T cells, percentage of apoptotic CD4 (+) T cells, body weight, and systemic side effects were evaluated. RESULTS: LDPDT improved the MEIC ( P = 0.011) and the histological score ( P = 0.025), diminished the expression indices of the proinflammatory cytokines, interleukin-6 ( P = 0.042), interleukin-17 ( P = 0.029), and interferon-gamma ( P = 0.014), decreased the number of mucosal CD4 (+) T cells, and increased the percentage of apoptotic CD4 (+) T cells compared with the disease control group. No local or systemic side effects occurred. CONCLUSION: LDPDT improves murine T cell-mediated colitis, decreases the proinflammatory cytokines interleukin-6, interleukin-17, and interferon-gamma, and decreases the number of CD4 (+) T cells. No adverse events were observed. Therefore, this technique is now being evaluated in patients with inflammatory bowel disease.

The pharmacokinetics and safety of porfimer after repeated administration 30-45 days apart to patients undergoing photodynamic therapy.

BACKGROUND: Porfimer is an intravenous (i.v.) injectable photosensitizing agent used in the photodynamic treatment of tumours and of high-grade dysplasia in Barrett's oesophagus. AIM: To assess the pharmacokinetics as well as the safety profiles of porfimer after a first and a second dose administered 30-45 days apart in patients undergoing photodynamic therapy. METHODS: Nineteen patients (16 with cholangiocarcinoma) were enrolled. Porfimer sodium was administered by i.v. injection over 3-5 min. Blood samples were collected prior to starting i.v. drug injection and postdose at different time points after the first and second administrations. RESULTS: Porfimer exposure values after the second administration were statistically higher than those observed after the first administration, suggesting a slight accumulation of porfimer following repeated administration. The apparent mean elimination half-life of porfimer increased from 410 h after the first administration to 725 h after the second administration. The safety profiles of porfimer after a first and a second administration were similar and did not raise additional concern. Eight patients experienced nine serious adverse events. Only photosensitivity was deemed study-drug related. CONCLUSION: Porfimer appears to display a safe and tolerable profile when used in patients requiring a second photodynamic therapy within 45 days.

[Klatskin tumors--diagnostic and interventional therapy]. / Klatskin-Tumoren--Diagnostik und interventionelle Therapie.

Klatskin tumors are defined as malignant tumors of the bile duct involving the bifurcation and intrahepatic bile ducts. The most common presenting clinical feature, obstructive jaundice, usually occurs with advanced disease. Diagnostic tools currently available are therefore either performed too late or are not able to detect early disease stage. Imaging procedures for diagnosis and staging are ultrasonography, magnetic resonance imaging with cholangiopancreaticography, intravenous bolus-enhanced spiral computed tomography and endoscopic retrograde cholangiopancreaticography. Before initiating any palliative measure, a proper staging and a surgical consultation at a hepatobiliary center is necessary. To assess resectability, additional diagnostic methods like angiography, positron emission tomography, cholangioscopy, endoscopic or intraluminal ultrasonography and finally even explorative laparoscopy may be required. At time of diagnosis only a small percentage of Klatskin tumors is curative resectable. Therefore, palliative treatment options play an important role. Endoprostheses insertion is the method of choice to relieve jaundice. Although it improves quality of life, it does not seem to improve survival time. Definitive evidence for a benefit of additional radio and/or chemotherapy is still missing. Photodynamic therapy, a light therapy, is the first approach leading to an improvement of cholestasis and quality of life as well as to a prolongation of survival time. PDT should therefore be offered to all patients with nonresectable cholangiocarcinoma.

[Contribution of endoscopy in palliative oncology (endoprosthesis, photodynamic therapy, parenteral nutrition]. / Apport de l'endoscopie en oncologie palliative (endoprothèse, thérapie photodynamique, sonde de nutrition).

The aim of this review is to give an overview of palliative endoscopic treatment options in patients with advanced cancers of the esophagus, stomach, pancreas and bile ducts. With regard to esophageal cancers, we will also speak about curative endoscopic treatment (photodynamic therapy, mucosectomy) of early cancers and dysplasias. We will not approach to this subject in other types of carcinoma, since this has already been covered by the acquisitions of the last years.

[Endoscopic diagnosis and therapy for gastrointestinal bleeding]. / Endoskopische Diagnostik und Therapie der gastrointestinalen Blutung.

Gastrointestinal bleeding is still one of the most frequent medical emergencies. Despite improvements in endoscopic diagnosis and therapy, mortality from bleeding is still high (15%). Since conclusive trials are lacking, the endoscopist often has to rely on personal experience in the selection of therapeutic options. Therefore this article gives an overview of new publications in this field and recommendations based on personal experience.

Is early endoscopy in the emergency room beneficial in patients with bleeding peptic ulcer? A "fortuitously controlled" study.

BACKGROUND AND STUDY AIMS: In previous randomized trials, early endoscopy improved the outcome in patients with bleeding peptic ulcer, though most of these studies defined "early" as endoscopy performed within 24 hours after admission. Using the length of hospital stay as the primary criterion for the clinical outcome, we compared the results of endoscopy done immediately after admission (early endoscopy in the emergency room, EEE) with endoscopy postponed to a time within the first 24 hours after hospitalization, but still during normal working hours ("delayed" endoscopy in the endoscopy unit, DEU). PATIENTS AND METHODS: We conducted a retrospective analysis of data from 81 consecutive patients with bleeding peptic ulcer admitted in 1997 and 1998 (age range 16 - 90 years). Of these 81 patients, 38 underwent DEU (the standard therapy at the hospital) and 43 underwent EEE. Patients in the two groups were comparable with regard to admission criteria, were equally distributed with respect to their risk of adverse outcome (assessed using the Baylor bleeding score and the Rockall score), and differed only in the treatment they received. Endoscopic hemostasis was performed whenever possible in all patients with Forrest types I, IIa, and IIb ulcer bleeding. RESULTS: We found similar rates in the two groups for recurrent bleeding (16 % in DEU patients vs. 14 % in EEE patients), persistent bleeding (8 % in DEU patients vs. none in EEE patients), medical complications (21 % in DEU patients vs. 26 % in EEE patients), the need for surgery (8 % in DEU patients vs. 9 % in EEE patients), and the length of hospital stay (5.1 days for DEU patients vs. 5.9 days for EEE patients). None of the differences between the two groups in these parameters were statistically significant. None of the patients died. CONCLUSIONS: Early endoscopy in an emergency room did not improve the clinical outcome in our 81 consecutive patients with bleeding peptic ulcer.

Small bowel involvement in Crohn's disease: a prospective comparison of wireless capsule endoscopy and computed tomography enteroclysis.

BACKGROUND: Wireless capsule endoscopy (WCE) offers endoscopic access to the small bowel and may therefore change diagnostic and therapeutic strategies in small bowel diseases. AIM: The aim of this prospective study was to validate the gain in information and therapeutic impact of WCE in patients with Crohn's disease. METHODS: Fifty six consecutive patients with Crohn's disease underwent computed tomography (CT) enteroclysis, and if stenoses <10 mm were excluded, WCE was carried out. RESULTS: In 15 patients (27%), WCE could not be performed due to strictures detected by CT enteroclysis. From the other 41 patients, jejunal or ileal lesions were found in 25 patients by WCE compared with 12 by CT enteroclysis (p=0.004). This gain in information was mainly due to detection of small mucosal lesions such as villous denudation, aphthoid ulcerations, or erosions. Both methods were not significantly different in the detection of lesions in the terminal/neoterminal ileum (WCE 24 patients, CT enteroclysis 20 patients). Therapy was changed due to WCE findings in 10 patients. Consecutively, all of them improved clinically. CONCLUSIONS: Capsule endoscopy improves the diagnosis of small bowel Crohn's disease. This may have significant therapeutic impact.

Endoscopic injection of mitomycin adsorbed on carbon particles for advanced esophageal cancer: a pilot study.

BACKGROUND AND STUDY AIMS: Patients with advanced, unresectable esophageal carcinoma have an extremely poor prognosis, with dysphagia being the major problem. The aim of this prospective pilot study was to evaluate the efficacy of local injections of mitomycin adsorbed onto activated carbon particles (MMC-CH) in advanced unresectable esophageal squamous-cell carcinoma. The primary outcome parameter was survival time; secondary parameters were dysphagia and quality of life. PATIENTS AND METHODS: Ten consecutive patients with stage IV esophageal carcinoma (age: median 58, range 32 - 78), median tumor length 11 cm (range 5 - 15) received four weekly injections of 15 mg (10 ml) MMC-CH into the endoscopically visualized tumor, via a 5-mm sclerotherapy needle. The tumor stage, symptom score, and quality of life (measured using the Karnofsky index) were assessed before and after therapy and every 2 months thereafter. RESULTS: The median survival time after MMC-CH therapy was 16 weeks (95 % CI, 11.7 to 20.4). Dysphagia was reduced ( P < 0.001) in parallel with the reduction in the tumor mass ( r = 0.82, P = 0.01). The Karnofsky index ( P < 0.01) also improved after MMC-CH treatment. MMC-CH was well tolerated, and no side effects were observed. CONCLUSIONS: Endoluminal MMC-CH therapy appears to be an effective, inexpensive, and well-tolerated treatment for unresectable advanced squamous-cell esophageal carcinoma.

Time gated fluorescence spectroscopy in Barrett's oesophagus.

BACKGROUND AND AIMS: Specialised intestinal metaplasia and its dysplastic transformation, which precedes cancer in Barrett's oesophagus cannot be differentiated in standard gastroscopy. The aim of this study was to investigate whether laser induced protoporphyrin IX fluorescence permits the detection of specialised intestinal metaplasia and dysplasia during endoscopy and to take biopsy specimens in a guided rather than random manner. METHODS: In 53 patients with Barrett's oesophagus 5-aminolaevulinic acid was sprayed on the mucosa. Approximately 60 to 120 minutes later, biopsy specimens were taken based on point-like measurements of delayed fluorescence intensity ratios of protoporphyrin IX in vivo. Two independent pathologists examined the 596 biopsy specimens taken, 168 of which were selected to be investigated by a third pathologist. Among these specimens only those (n=141) with a consensus diagnosis by at least two pathologists and p53 expression as additional marker were included in the analysis. RESULTS: The median of normalised fluorescence intensity (ratio of delayed PpIX fluorescence intensity to immediate autofluorescence intensity) in non-dysplastic specialised intestinal metaplasia (0.51, 68% CI 0.09 to 1.92) and low grade dysplasia (1.89, 68% CI 0.55 to 3.92) differed significantly (p<0.005). Dysplasia was detected at a rate 2.8-fold higher compared with screening endoscopy despite taking fewer specimens. In addition, three early cancers were detected for the first time. Moreover, this method permitted differentiation of specialised intestinal metaplasia from junctional or gastric-fundic type epithelium (p<0.013). CONCLUSIONS: For the first time it was possible to differentiate low grade dysplasia from non-dysplastic Barrett's mucosa during endoscopy based on delayed laser induced fluorescence endoscopy of PpIX. Furthermore, the method helps to detect specialised intestinal metaplasia in short Barrett's oesophagus.

Is topical delta-aminolevulinic acid adequate for photodynamic therapy in Barrett's esophagus? A pilot study.

BACKGROUND AND STUDY AIMS: The methods of endoscopic ablation of metaplastic and dysplastic areas in Barrett's esophagus so far described, are not satisfactory with respect to efficacy and safety. Therefore we investigated whether photodynamic therapy (PDT) with topical delta-aminolevulinic acid (delta-ALA) leads to ablation of specialized columnar epithelium and eradication of low-grade dysplasia while not producing phototoxicity and systemic side effects. PATIENTS AND METHODS: 14 patients with histologically proven Barrett's esophagus, seven of whom had evidence of low-grade dysplasia, underwent endoscopic treatment with topical delta-ALA. Photoactivation (wavelength, 632 nm) was performed at 1.5 - 2 hours after drug administration using an argon dye laser. Patients received omeprazole 80 mg daily for 2 months; thereafter; maintenance therapy depended on reflux symptoms. Patients were endoscopically re-evaluated after 7 days, and subsequently at 3, 6, 12 and up to 48 months (mean follow up 33 months). Re-treatment with high-dose topical delta-ALA was offered to the 11 patients with remaining metaplasia and was carried out in five of them. RESULTS: Low-grade dysplasia was eradicated in all patients. One patient with no dysplasia before PDT developed a high-grade dysplasia after PDT. Complete ablation of Barrett's metaplasia was observed in 21 % of the patients after the first treatment session and in 20 % after the second treatment session. The mean reduction in the length of Barrett's metaplasia was 1.54 +/- 1.29 cm after the first PDT session and 1.02 +/- 0.80 cm after the second PDT session. Post-endoscopic pain and photosensitivity reactions were less frequent with low-dose delta-ALA PDT than with high-dose PDT (pain 15 %, 100 %, respectively; P = 0.001 by Fisher's exact test; phototoxicity, 0 %, 50 %, respectively; P = 0.021 by Fisher's exact test). CONCLUSION: Low-dose topical administration of delta-ALA provides ablation of low-grade dysplasia in the range obtained with oral delta-ALA. In addition, it is safe and well tolerated. Since, however, topical administration of delta-ALA is not able to consistently eradicate Barrett's esophagus, alternative methods will have to be developed.

[Reflux disease: conservative therapy]. / Refluxkrankeit: Konservative Therapie.

Gastroesophageal reflux disease--one of the most common gastroenterological disorders--is characterized by reflux symptoms (occasionally respiratory symptoms or laryngeal complaints) and/or mucosal lesions. Improvement of symptoms and thus of the quality of life, prevention of relapse and of complications are the most important aims of short and long term treatment. Proton pump inhibitors are superior to histamine receptor antagonists and are the treatment of choice. Relapses occur in about 75% of patients within one year after stopping of acute treatment. The treatment strategy depends on the severity of symptoms and esophageal lesions. Patients with mild esophagitis or endoscopic negative disease can be treated with proton pump inhibitors on demand. In severe and complicated cases, the uninterrupted long-term use of proton pump inhibitors is indicated. In these cases laparoscopic fundoplication could be a possible--albeit problematic--alternative. New endoscopic interventional therapies should only be used in controlled studies. Their role in the treatment of GERD will only be known in a few years when adequately controlled long term studies will be available.

Photodynamic therapy of cholangiocarcinoma cancer.

Prognosis of nonresectable cholangiocarcinoma is not good, and in Bismuth type III and IV tumors relief of jaundice is seldom achieved, despite successful endoprosthesis insertion. Additional photodynamic therapy seems to be a promising new approach to these tumors. First pilot studies show relief of jaundice, mainly because of opening of the intrahepatic ducts and improvements in quality of life indices. Survival time seems to be long; however, randomized studies are necessary to confirm these results.

De novo hemolytic uremic syndrome postrenal transplant after cytomegalovirus infection.

After renal transplantation, hemolytic uremic syndrome (HUS) may occur as recurrent disease or de novo. Here, we describe the de novo occurrence of HUS immediately after the onset of primary cytomegalovirus (CMV) disease in two renal allograft recipients. Patient no. 1 had primary CMV disease with biopsy-proven CMV esophagitis 2 months after transplantation. Patient no. 2 experienced primary CMV disease with fever and leukopenia 8 years after transplantation. Both patients were treated with intravenous ganciclovir. Both patients developed HUS with biopsy-proven thrombotic microangiopathy in the renal allograft only a few days (3 to 5 days) after the onset of CMV disease. The short interval between the onset of CMV disease and HUS, as well as the parallel course of CMV viremia and HUS in both patients, indicate there may be a pathophysiological link between both diseases. However, because antiviral therapy with ganciclovir was started before the onset of HUS in both patients, we cannot definitely rule out that HUS was triggered by ganciclovir.

Photodynamic therapy of nonresectable cholangiocarcinoma.

BACKGROUND & AIMS: Successful treatment in nonresectable Bismuth type III and IV cholangiocarcinoma is seldom achieved. The aim of this study was to evaluate the effect of photodynamic therapy on cholestasis, quality of life, and survival in these patients. METHODS: Nine patients with advanced nonresectable cholangiocarcinomas Bismuth type III and IV, who showed no sufficient drainage (bilirubin decrease <50%) after endoscopic stent insertion, underwent photodynamic therapy. Two days after intravenous application of a hematoporphyrin derivate, intraluminal photoactivation was performed cholangioscopically. Serum bilirubin, quality of life, and survival time were assessed in two monthly intervals after photodynamic therapy. RESULTS: After photodynamic therapy, bilirubin serum levels declined from 318 +/- 72 to 103 +/- 35 micromol/L (P = 0.0039) with no significant increase during the two monthly follow-ups. Quality of life indices improved dramatically and remained stable (e.g., Karnofsky index from 32.2% +/- 8.13% to 68.9% +/- 6.1%; P = 0.0078). Thirty-day mortality was 0%, and median survival time was 439 days. CONCLUSIONS: This study provides clear evidence that photodynamic therapy is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas Bismuth type III and IV. Compared with published data, survival time seems to be prolonged.