Florian Tomaselli

Penetration of Meropenem into Pneumonic Human Lung Tissue as Measured by In Vivo Microdialysis

ABSTRACT Until recently, information on antibiotic pharmacokinetic properties in infected human lung tissue was limited. We therefore studied a microdialysis-based approach for measurement of the penetration of meropenem into the extracellular space fluid of human pneumonic lung parenchyma. The lung penetration of meropenem was determined for seven patients with pneumonia and metapneumonic pleural empyema treated by decortication. Intraoperatively, two microdialysis probes were inserted into pneumonic lung tissue and one was inserted into healthy skeletal muscle for reference values. Serum and microdialysis samples were collected at 20-min intervals for at least 8 h following a single intravenous dose of 1 g of meropenem. The maximum free interstitial concentration (mean and standard deviation) of meropenem in infected lung tissue was 11.4 ± 10.9 mg/liter, and that in serum was 47.3 ± 21.0 mg/liter. The areas under the curve for infected lung tissue (36.2 ± 17.9 mg · h/liter) and serum (95.4 ± 46.6 mg · h/liter) revealed a significant difference. This technique enabled quasi-continuous tissue pharmacokinetic measurements of free, unbound antibiotic in pneumonic lung tissue of patients with pneumonia. The present data corroborate the use of meropenem in the treatment of lung infections caused by extracellular bacteria, demonstrating the excellent distribution profile for meropenem in the interstitial space of human pneumonic lung tissue.

Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus

The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Because of anoxic regions in tumor tissue and vascular shutdown during PDT, the efficiency is limited. Therefore, the use of hyperbaric oxygen, which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT.

Palliation of advanced esophageal carcinoma by photodynamic therapy and irradiation

BACKGROUND We wanted to determine the role of photodynamic therapy in a multimodal approach for the treatment of patients with advanced cancer of the esophagus. METHODS We reviewed the cases of 119 patients with nonresectable esophageal carcinoma who underwent endoluminal palliation. Twenty-one patients required initial dilation and tumor obliteration with a neodymium: yttrium-aluminum-garnet laser prior to therapy. Forty-four patients received photodynamic therapy followed by brachyradiotherapy, and 75 patients were treated with brachyradiotherapy. In both groups, some patients also received external-beam irradiation. RESULTS Photodynamic therapy produced a significant difference in relieving stenosis caused by tumor stenosis (mean, 6.6 mm; p = 0.0000). The dysphagia score improved by one to three levels in all patients, with a significant difference in favor of PDT (p = 0.0003). The mean number of overall treatment sessions was four (range, one to seven). The rate of major complications was 9.2%. Four esophageal perforations occurred, three after intervention and one spontaneously 5 months later. Four esophagorespiratory tract fistulas developed several months after combined PDT and irradiation. The mean overall survival was 7.7 months, and analysis of variance revealed a significant difference in favor of PDT and external-beam irradiation (p = 0.0129 and p = 0.0001, respectively). CONCLUSIONS Photodynamic therapy has been shown to be an effective palliative treatment of advanced esophageal cancer. However, proper patient selection is necessary to prevent serious complications.

Successful endoscopical sealing of malignant esophageotracheal fistulae by using a covered self-expandable stenting system

OBJECTIVE Any treatment of tracheo-esophageal fistulae in end-stage malignant stenosis of the esophagus must be weighed against associated morbidity and mortality. In a prospective study we investigated benefits and risks of the use of one type of coated, self-expandable stent. PATIENTS AND METHODS We treated four male and two female patients, (mean age 68.3 years, range: 38-90 years), with malignant esophago-tracheal fistula non-resectable due to advanced tumour stage and/or functional reasons. All were in a poor general condition suffering from aspiration pneumonia and malnutrition. Four out of the six patients had had one or multiple extra- or endoluminal palliative treatments at a mean interval of 191 days (range: 7 days-15 ms) since the last intervention. The fistulae were sealed by using a covered, self-expandable stent (ULTRAFLEX esophageal stent system, Microinvasive, Boston Scientific Corporation, Boston, MA). RESULTS Stenting did not cause any technical problems and all fistulae were successfully sealed in a one-step procedure. The median hospital stay was 4.6 days (range: 3-9 days). Except for one late stent induced recurrent fistula treated by re-stenting and tracheostomy, we did not observe any stent associated complications. Five patients died of tumour generalization. The median survival of the patients who died was 78 days (range: 35-129 days). One patient is alive and well at 120 days after stenting. CONCLUSION In spite of the small number of patients the results suggest that this type of stent represents a safe and efficient approach for palliative endoscopic treatment of this high risk group. Local pretreatment does not preclude the successful use of the self-expandable coated stent.

Combined photodynamic therapy and hyperbaric oxygenation in carcinoma of the esophagus and the esophago-gastric junction

OBJECTIVES The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Due to anoxic regions in tumor tissue and vascular shutdown during PDT the efficiency is limited. Therefore, the use of hyperbaric oxygen which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT. PATIENTS AND METHODS After diagnostic work-up, photosensitization was carried out with a hematoporphyrin-derivate 2 mg/kg BW 48 h prior to PDT. The light dose was calculated as 300 J/cm fiber tip. Thirty-one patients were treated by PDT alone and 44 patients received PDT under hyperbaric oxygen at a level of two absolute atmospheric pressure. RESULTS Improvement regarding stenosis-diameter could be obtained in both treatment arms with no significant difference (P=0.82). The dysphagia-score and tumor-length also decreased in both groups and showed a significant difference in favour of the PDT/HBO-group (P=0. 0064 and P=0.0002, respectively). The median overall survival for the PDT-group was 7 months and for the PDT/HBO-group 12 months (P=0. 0098). CONCLUSION According to this prospective non-randomized study, combined PDT/HBO represents a new approach in the treatment of esophageal and cardia cancer which appears to have enhanced the efficiency of PDT.

Photodynamic therapy enhanced by hyperbaric oxygen in acute endoluminal palliation of malignant bronchial stenosis (Clinical pilot study in 40 patients)

OBJECTIVES Photodynamic tumor therapy (PDT) is based upon a photochemical reaction that is limited by the availability of molecular oxygen in the target tissue. The use of hyperbaric oxygenation (HBO) increases the amount of oxygen available for the process may thereby enhance the efficacy of PDT. We proved in a prospective, non-randomized clinical pilot study the acute effects on malignant bronchial stenosis and the technical feasibility of combined PDT/HBO. METHODS Forty patients (29 males, 11 females, mean age: 64.3 years; range 39-82 years) with inoperable, advanced malignant bronchial tumor stenosis were studied prospectively. Photosensitization was carried out using a hematoporphyrin-derivative 2 mg/kg bw 48 h prior to PDT. The light dose was calculated as 300 J/cm fiber tip. The assessment of outcome 1 and 4 weeks after PDT/HBO was done by endoscopy, chest X-ray, spirometry, laboratory parameters, subjective report of dyspnea and Karnofsky performance status. RESULTS At 1 and 4 weeks after the treatment the patients felt a significant improvement of dyspnea and hemoptysis alongside with an objective subsiding of poststenotic pneumonia, though spirometric parameters revealed no significant difference. A significant reduction of tumor stenosis (P<0.05) and an improvement of the Karnofsky performance status (P<0.05) were documented 1 and 4 weeks after PDT/HBO. No therapy related complications were observed. CONCLUSION Although the small number of patients does not allow to draw definitive conclusions, the results suggest that combined PDT/HBO represents a new, safe and technically feasible approach. It enables efficient and rapid reduction of the endoluminal tumor load and helps conditioning the patient for further treatment procedures.

Effect of photodynamic therapy in a multimodal approach for advanced carcinoma of the gastro-esophageal junction.

We wanted to determine the role of additional photodynamic therapy in a multimodal approach for the treatment of patients with advanced cancer of the gastro‐esophageal junction.

Photosensitization with hematoporphyrin derivative compared to 5-aminolaevulinic acid for photodynamic therapy of esophageal carcinoma

BACKGROUND Hematoporphyrin derivatives (HpD) as sensitizers for photodynamic therapy (PDT) in advanced esophageal cancer carry the risk of prolonged photosensitivity of the skin. New sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared with HpD for PDT in advanced esophageal carcinoma regarding phototoxicity of the skin, reduction of dysphagia, tumor stenosis and length, and Karnovsky performance status. METHODS After diagnostic workup, photosensitization was done in 22 patients with ALA (60 mg/kg body weight, oral, 6 to 8 hours before PDT) and in 27 patients with a hematoporphyrin derivative (2 mg/kg body weight, intravenously, 48 hours before PDT). The light dose was calculated as 300 J/cm fiber tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 absolute atmospheric pressure. RESULTS Improvement regarding dysphagia, stenosis diameter, and tumor length could be obtained in both treatment arms with a significant difference in favor of the HpD group (p = 0.02; p = 0.0000; and p = 0.000014, respectively). A questionnaire of patients in the HpD group confirmed that the ability of swallowing a meal was superior compared with the discomfort from limitation to sun exposure. No sunburn or other major treatment-related complication occurred in both treatment arms. CONCLUSIONS Despite the limitations of a nonrandomized study, photosensitzation with HpD seems to be more effective in PDT of advanced esophageal carcinoma compared with ALA.

Retrosternal pedicled jejunum interposition: an alternative for reconstruction after total esophago-gastrectomy.

OBJECTIVE If the colon cannot be used for reconstruction after total esophago-gastrectomy, alternatives have to be sought. METHODS From 1990 to 2001, retrosternal jejunum loop interposition was performed in 35 patients (male/female: 29:6; mean age 59.2, range 16-83 years) due to cancer in 32 cases and to esophageal perforation in three cases. In all patients reconstruction with stomach or colon, respectively, was impossible on behalf of the underlying histology, of previous resection of the stomach and impedient colonic diseases. A jejunal segment with abundant arcades was chosen, preserving a strong, distal arteriovenous mesenteric pedicle, while 2-3 proximal mesenteric vessels were severed. The loop was pulled up retrosternally, establishing a cervical end-to-side esophagojejunostomy. A Roux-en-Y anastomosis was done in a convenient position. RESULTS Two patients died perioperatively due to mediastinitis and consecutive multiorgan failure (one Boerhaaves syndrome, one suicidal ingestion of acid). In one case the oral part of the loop developed venous congestion and was replaced by a free jejunal transplant. The perioperative course of 32 patients was uneventful. Seventeen patients are up and well (1-8.5 years). Sixteen patients died of metastatic disease. The functional results are satisfactory. In about 50% of patients recurrent dilatations became necessary due to anastomotic scars. However, none of the patients complained about severe dysphagia. CONCLUSION In cases of impedient colonic diseases, the pedicled, retrosternal jejunal loop with cervical anastomosis is an alternative for reconstruction after total esophagogastrectomy.

In vivo determination of tumor optical parameters in esophageal carcinoma.

Dose dependence of light cannot be discussed on the basis of dose alone. On a more fundamental scientific level, the propagation of light in tissue depends on optical parameters of treated tumor tissue. In a prospective, nonrandomized study, in vivo optical parameters of esophageal carcinoma were studied.