Franz X. Felberbauer

Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels.

Background: Different changes of plasma ghrelin levels have been reported following gastric banding, Roux-en-Y gastric bypass, and biliopancreatic diversion. Methods: This prospective study compares plasma ghrelin levels and weight loss following laparoscopic sleeve gastrectomy (LSG) and laparoscopic adjustable gastric banding (LAGB) in 20 patients. Results: Patients who underwent LSG (n=10) showed a significant decrease of plasma ghrelin at day 1 compared to preoperative values (35.8 ± 12.3 fmol/ml vs 109.6 ± 32.6 fmol/ml, P=0.005). Plasma ghrelin remained low and stable at 1 and 6 months postoperatively. In contrast, no change of plasma ghrelin at day 1 (71.8 ± 35.3 fmol/ml vs 73.7 ± 24.8 fmol/ml, P=0.441) was found in patients after LAGB (n=10). Increased plasma ghrelin levels compared with the preoperative levels at 1 (101.9 ± 30.3 fmol/ml vs 73.7 ± 24.8 fmol/ml, P=0.028) and 6 months (104.9 ± 51.1 fmol/ml vs 73.7 ± 24.8 fmol/ml, P=0.012) after surgery were observed. Mean excess weight loss was higher in the LSG group at 1 (30 ± 13% vs 17 ± 7%, P=0.005) and 6 months (61 ± 16% vs 29 ± 11%, P=0.001) compared with the LAGB group. Conclusions: As a consequence of resection of the gastric fundus, the predominant area of human ghrelin production, ghrelin is significantly reduced after LSG but not after LAGB. This reduction remains stable at follow-up 6 months postoperatively, which may contribute to the superior weight loss when compared with LAGB.

Does Gastric Dilatation Limit the Success of Sleeve Gastrectomy as a Sole Operation for Morbid Obesity

Background: Sleeve gastrectomy as the sole bariatric operation has been reported for high-risk super-obese patients or as first-step followed by Roux-en-Y gastric bypass (RYGBP) or duodenal switch (DS) in super-super obese patients. The efficacy of laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients with a BMI of <50 kg/m2 and the incidence of gastric dilatation following LSG have not yet been investigated. Methods: 23 patients (15 morbidly obese, 8 super-obese) were studied prospectively for weight loss following LSG. The incidence of sleeve dilatation was assessed by upper GI contrast studies in patients with a follow-up of >12 months. Results: Patients who underwent LSG achieved a mean excess weight loss (EWL) at 6 and 12 months postoperatively of 46% and 56%, respectively. No significant differences were observed in %EWL comparing obese and super-obese patients. At a mean follow-up of 20 months, dilatation of the gastric sleeve was found in 1 patient and weight regain after initial successful weight loss in 3 of the 23 patients. Conclusion: LSG has been highly effective for weight reduction for morbid obesity even as the sole bariatric operation. Gastric dilatation was found in only 1 patient in this short-term follow-up. Weight regain following LSG may require conversion to RYGBP or DS. Follow-up will be necessary to evaluate long-term results.

Pulmonary echinococcosis (hydatidosis) in children: Results of surgical treatment

From 1986–1996, 33 children with 49 pulmonary hydatid cysts underwent surgical treatment in Vienna and Istanbul. Cysts were unilateral in 28 and bilateral in 5 cases; unruptured cysts (URC) were diagnosed in 19 patients, and 14 children presented with ruptured cysts (RC). Ten patients had cysts in other organs (liver, spleen, central nervous system) in addition to pulmonary cysts. Diagnosis was primarily based on chest X‐ray and computed tomography scan. In Austrian children, a new combination of serological tests was used successfully (71% positive).

Relationship of hepatic cholate transport to regulation of intracellular pH and potassium

Modulation of hepatic cholate transport by transmembrane pH-gradients and during interferences with the homeostatic regulation of intracellular pH and K+ was studied in the isolated perfused rat liver. Within the concentration range studied uptake into the liver was saturable and appeared to be associated with release of OH- and uptake of K+. Perfusate acidification ineffectually stimulated uptake. Application of NH4Cl caused intracellular alkalinization, release of K+ and stimulation of cholate uptake, withdrawal of NH4Cl resulted in intracellular acidification, regain of K+ and inhibition of cholate uptake. Inhibition of Na+/H(+)-exchange with amiloride reduced basal release of acid equivalents into the perfusate, initiated K(+)-release, and inhibited both, control cholate uptake and its recovery following intracellular acidification. K(+)-free perfusion caused K(+)-release and inhibited cholate uptake. K(+)-readmission resulted in brisk K(+)-uptake and recovery of cholate transport. Both effects were inhibited by amiloride. Interference with cholate transport through modulation of pH homeostasis by diisothiocyanostilbenedisulfonate (DIDS) could not be demonstrated because DIDS affected bile acid transport directly. Biliary bile acid secretion was stimulated by intracellular alkalinization and by activation of K(+)-transport. Uncoupling of the mutual interference between pH-dependent cholate uptake and K(+)-transport by amiloride indicates tertiary active transport of cholate. In this, Na+/K(+)-ATPase provides the transmembrane Na(+)-gradient to sustain Na+/H(+)-exchange which maintains the transmembrane pH-gradient and thus supports cholate uptake. Effects of canalicular bile acid secretion are consistent with a saturable, electrogenic transport.

Strategies for weight regain after sleeve gastrectomy.

With a rapid increase in the number of surgeries performed, sleeve gastrectomy (SG) has gained enormous popularity in the bariatric world during the last 5 years. In 2008, SG represented 5.4% of all the bariatric procedures performed worldwide for that year, as shown by Buchwald and Oien, and the case numbers are expected to increase further. This popularity is mainly the result of excellent short-term outcomes for weight loss and a wide range of advantages compared with the technically more demanding Roux-en-Y gastric bypass (RYGBP); no dumping syndrome is expected after SG and the biliary tract remains accessible by endoscopic retrograde cholangiopancreatography. Furthermore, nutrient deficiencies seem less likely to occur after SG than after RYGBP. Weight regain is observed in bariatric procedures such as laparoscopic adjustable gastric banding and vertical banded gastroplasty (VBG) with restriction as the main weight loss mechanism; RYGBP combines restriction with mild malabsorption. As SG is also seen as a restrictive procedure, some weight regain is also expected. In some patients, significant weight regain may even limit the success of SG as the sole bariatric procedure, which may lead to reoperations such as sleeve resizing, completion of the duodenal switch, or conversion to RYGBP.

Fiber-optic measurement of intracellular pH in intact rat liver using pH-sensitive dyes.

The pH-sensitive fluorescent dye 1,3-dihydroxypyrene-6,8-disulfonic acid (DHPDS) was used to measure intracellular pH (pHi) from the surface fluorescence of the isolated perfused rat liver.Monochromatic light from a fluorometer was focused on the liver with a fiber optic, emitted light was collected with a second fiber bundle and returned to the spectrometer. To correct for changes in intracellular dye concentration, the excitation wavelength was changed between the pH-sensitive excitation peak wavelength and the isosbestic wavelength, then a ratio was computed between fluorescence intensities at these two wavelengths.Intracellular calibration of the dye was performed by clamping the intracellular to the extracellular pH with H+/K+-ionophore Nigericin.This method was used to monitor transient changes in intracellular pH caused either by addition and removal of NH4Cl or by changing perfusate CO2 and HCO3− concentrations while keeping their ratio constant. The effects of these maneuvers on bileflow were studied, too.Data obtained in the perfused liver were in good agreement with those obtained in isolated liver cells except that the steady-state pHi (7.46 ± 0.02) was slightly higher than reported values.Measurements in livers of mutant TR− rats that are defective of dye secretion revealed similar pHi values, indicating that secretion of the dye into bile canaliculi did not affect measurements.The technique appears adequate to measure pHi in the liver and will allow to study pH regulatory mechanisms in the intact organ.

Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study

Summary Background Patients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited. Methods We investigated the feasibility and clinical impact of multiparametric, single-cell, drug-response profiling in patient biopsies by immunofluorescence, automated microscopy, and image analysis, an approach we call pharmacoscopy. First, the ability of pharmacoscopy to separate responders from non-responders was evaluated retrospectively for a cohort of 20 newly diagnosed and previously untreated patients with acute myeloid leukaemia. Next, 48 patients with aggressive haematological malignancies were prospectively evaluated for pharmacoscopy-guided treatment, of whom 17 could receive the treatment. The primary endpoint was progression-free survival in pharmacoscopy-treated patients, as compared with their own progression-free survival for the most recent regimen on which they had progressive disease. This trial is ongoing and registered with ClinicalTrials.gov, number NCT03096821. Findings Pharmacoscopy retrospectively predicted the clinical response of 20 acute myeloid leukaemia patients to initial therapy with 88·1% accuracy. In this interim analysis, 15 (88%) of 17 patients receiving pharmacoscopy-guided treatment had an overall response compared with four (24%) of 17 patients with their most recent regimen (odds ratio 24·38 [95% CI 3·99–125·4], p=0·0013). 12 (71%) of 17 patients had a progression-free survival ratio of 1·3 or higher, and median progression-free survival increased by four times, from 5·7 (95% CI 4·1–12·1) weeks to 22·6 (7·4–34·0) weeks (hazard ratio 3·14 [95% CI 1·37–7·22], p=0·0075). Interpretation Routine clinical integration of pharmacoscopy for treatment selection is technically feasible, and led to improved treatment of patients with aggressive refractory haematological malignancies in an initial patient cohort, warranting further investigation. Funding Austrian Academy of Sciences; European Research Council; Austrian Science Fund; Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Anniversary Fund of the Austrian National Bank; MPN Research Foundation; European Molecular Biology Organization; and Swiss National Science Foundation.

Complications of elective surgery for rectal cancer

ZusammenfassungGRUNDLAGEN: Chirurgische Standardisierung, neue Operationsmethoden sowie multimodale Therapieansätze erzielten deutliche Fortschritte in der Behandlung des Rektumkarzinoms. METHODIK: Übersicht zur Vermeidung und zum Management von Komplikationen bei Rektum Karzinom Chirurgie. ERGEBNISSE: Anatomische Dissektion des Mesorektums ermöglicht optimale lokale Kontrolle sowie eine Reduktion der Lokalrezidivrate. Die Technik der intersphinkteren Resektion erlaubt eine Kontinenzerhaltung selbst bei tiefsitzenden Rektumkarzinomen. J-Pouch und die rezent beschriebene Koloplastik verbessern die funktionellen Ergebnisse nach Rektumresektion. Neoadjuvante Therapieansätze erzielen eine bessere lokale Tumorkontrolle sowie eine erhöhte Rate an kontinenzerhaltenden Operationen. Obwohl die postoperative Morbidität bei elektiven Eingriffen niedrig ist, sollten trotz onkologischer Verbesserung und dem Wunsch nach Kontinenzerhaltung mögliche Komplikationen bedacht werden. Dieser Literaturübersicht konzentriert sich auf operationsspezifische Komplikationen nach elektiver Chirurgie des Rektumkarzinoms sowie auf den Einfluss von neoadjuvanten Therapieregimen und perioperativen Management auf die postoperative Morbidität. SCHLUSSFOLGERUNGEN: Bei entsprechender Erfahrung und Berücksichtigung anatomischer, physiologischer und technischer Besonderheiten des Rektums sowie des Beckenbodens lässt sich die onkologische Rektumchirurgie mit niedriger Komplikationsrate realisieren.SummaryBACKGROUND: Standardization of surgery and new procedures have led to significant advances in the treatment of rectal cancer. METHODS: Review on avoidance and management of complications in rectal cancer surgery. RESULTS: Anatomical dissection of the mesorectum permits optimal local control and reduction of local recurrence. Sphincter preservation can be achieved by the technique of intersphincteric resection even for low tumours. A J-pouch or a recently designed coloplasty pouch improve functional results after coloanal anastomoses. Neoadjuvant treatments have a role in local control of the disease after TME surgery and in new strategies of sphincter-saving procedures. Although perioperative morbidity in elective surgery for rectal cancer is very low, radical local control of the disease and the patients wish for sphincter preservation have to be weighed against possible complications. The literature was carefully reviewed to evaluate data on the procedure-specific complications in elective surgery for rectal cancer and the impact of neoadjuvant treatment regimens and perioperative management on postoperative morbidity. CONCLUSIONS: Meticulous attention to detail achieve low complication rates in modern rectal surgery. In experienced hands, the total mesorectal excision operation is not associated with increased postoperative morbidity and mortality.

Value of circulating immune parameters in renal transplantation

Abstract Diagnosis of acute kidney graft rejection is based on conventional parameters such as creatinine (Crea), Crea-clearance, body temperature, urinary volume, body weight. Taken together they are inexpensive, noninvasive and attain a relatively high sensitivity. In many patients, however, kidney biopsies have to be obtained to ascertain the presence of acute rejection. The presence or absence of rejection might also be authenticated by monitoring serum immune parameters, capable of predicting the onset of clinically relevant immunologic activity. This would provide information on the response to antirejection therapy before graft dysfunction becomes clinically manifest. The following parameters were selected based on their specific characteristics: • ⊎ c-ICAM-1 (intercellular adhesion molecule). Allograft transplantation leads to a chronic or acute immune response that is related to increased expression and release of c-ICAM-1. c-ICAM-1 is expressed on almost all cell types, including macrophages, T- and B-lymphocytes during activation, as well as unstimulated vascular endothelial cells. Healthy individuals show a mean serum level of 230 (130 to 300) ng/mL. • ⊎ s-TNF-R (tumour-necrosis-factor receptor). Elevated s-TNF-R levels are observed in any type of immune response but also eventuate in acute or chronic renal failure as a retention phenomenon. s-TNF-R binds with high affinity and specificity to TNF and acts as an immunobiological regulator of the pluripotent TNF-mediated functions. The complete receptor molecule is expressed on fibroblasts, endothelial cells (EC), myeloid cells, as well as on mitogen-stimulated lymphocytes. • ⊎ s-IL2-R (interleukin-2-receptor). Monoclonal antibodies to IL2-R inhibit T-cell proliferation and counteract renal allograft rejection. IL2-R-bearing cells are crucial in graft rejection, and agents that kill these cells boost graft survival: anti-IL2-R antibodies administered prophylactically to renal allograft patients reduce the rate of early graft rejection. Its mean level in normal individuals is 256 ± 112 U/mL. • ⊎ Neopterin. Is significantly related to T-cell-mediated pathologies and, therefore, can provide clinically useful information on infection, cancer, autoimmunity and graft rejection. Neopterin release from renal epithelial cells has been shown to be stimulated by IFN-γ. Its mean serum level in normal individuals is 5.4 ± 2.3 nmol/L. • ⊎ s-MHC-1 (major histocompatibility complex). Consists of a 44,000-kD intracellular and a short extracellular polypeptide chain designated β2-microglobulin (β2-MG). MHC-1 is the receptor for CD8+ cytotoxic T cells, with the amount of MHC products apparently determining the susceptibility of target cells to being lysed. • ⊎ ELAM-1 (endothelial leukocyte adhesion molecule). Is a glycoprotein (E-selectin) expressed on cytokine-activated (TNF-alpha, IL2, LPS) endothelial cells. Endothelial cells constitute the interface between allograft and the hosts immune system. Endothelial cell functions play a pivotal role in inflammatory responses and vessel behaviour, and might assume a pathogenic role in allograft rejection. E-selectin is the most likely mediator of initial lymphocyte binding to endothelial cells by mediating, in contrast to the integrins, adhesion of resting lymphocytes. The ligands for ELAM-1 are carbohydrates. The present study was performed to establish (1) potential correlations of these parameters with the course of rejection, infection, or of stable condition, in renal allograft recipients and (2) whether antirejection therapy is capable of influencing these parameters. As noninvasive methods for measuring target-organ levels of cytokines or inflammatory markers are not available, a critical appraisal of the sensitivity and specificity of these parameters in peripheral blood during graft rejection appears warranted.

Fiber optic measurement of intracellular pH in intact rat liver using pH-sensitive dyes

The pH-sensitive fluorescent dye 1,3-dihydroxy-pyrene-6,8-disulfonic acid (DHPDS) was used to measure intracellular pH (pHi) from the surface fluorescence of the isolated perfused rate liver. 1 micrometers of the diacetyl ester of DHPDS was added to the perfusate. The dye readily accumulated in hepatocytes where it was hydrolyzed to form the fluorescent pH indicator. Surface fluorescence was excited by focusing monochromatic light from a spectrofluorometer onto the end of a fiber light guide that illuminated a part of the liver surface. Two excitation wavelengths were used, one where fluorescence intensity was pH sensitive, the other at the isosbestic point. Emitted light was collected by a second fiber optic and returned to the emission side of the spectrometer. A ratio was computed between fluorescence intensities at the pH-sensitive excitation peak wavelength and the isosbestic wavelength, thus yielding measurement insensitive to changes in dye concentration and in excitation light intensity. Intracellular calibration of dye fluorescence was done by clamping pHi to perfusate pH with the use of the cell membrane H+/K+ -ionophore Nigericin. The method was used to monitor changes in pHi caused by addition and removal of NH4Cl. Data obtained in the perfused liver were in good agreement with those reported for isolated liver cells. The technique appears adequate to determine hepatocellular pH in the liver and will allow study of regulatory mechanisms of hepatocyte pHi in the intact organ.