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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., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Although implantation of a central venous device such as a Port-a-Cath was initially considered safe, extravasation rates up to 4.7% have been reported. Therefore, the objective of this study was to propose a structured procedure for the management of extravasation of a cytotoxic treatment., Methods: A total of eight patients were evaluated after port extravasation of epirubicin (n = 3), platinum compounds (n = 3), paclitaxel (n = 1), or trabectedin (n = 1) into the subcutaneous space. Immediate explantation of the port was performed in combination with a "Subcutaneous Wash-Out Procedure" (SWOP). When removal of the port was delayed, débridement and flap coverage were performed as necessary. Epirubicin concentrations present in the samples obtained during surgical intervention were subsequently analysed using high-performance liquid chromatography (HPLC). Patients were followed for at least six months and were examined for sequelae such as pain, induration, redness, and limited movement., Results: All three patients whose extravasation event was detected during chemotherapy administration benefited from SWOP with acceptable side effects (e.g., erythema). The analysis of epirubicin concentrations demonstrated the active removal of relevant amounts of the compound by wound rinsing. In contrast, late detection of extravasation led to major débridement and flap coverage in four out of five patients. A high body mass index (BMI) value was associated with all of the patients that experienced port extravasation., Conclusion: Depending on when Port-a-Cath extravasations into subcutaneous tissue are detected, different treatments are appropriate. When extravasation is detected early, the SWOP was found to be beneficial., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

At the beginning of the 21st century, obesity has become an epidemic with the greatest prevalence in the western world. For morbidly obese patients, conservative treatment has yielded disappointing results: On the other hand, bariatric surgery offers a sustained substantial weight loss for these patients. Common bariatric procedures including results and complications are described. Different Bariatric procedures including Gastric Banding, Vertical Banded Gastroplasty, Gastric Bypass, Duodenal Switch and Gastric Pacing are introduced. Bariatric procedures can result in permanent excessive weight loss ranging from 25 to 78% and thus are an effective treatment for morbidly obese patients. Efficacy, morbidity and late term complications, however, should be considered in choosing the most effective bariatric approach.

Background: So far, there is no approved tumour marker for diagnosis or follow-up in Wilms tumour (WT). Tissue polypeptide-specific antigen (TPS), a cytokeratin 18 proteolytic fragment, has been suggested to be of value in the clinical management of WT patients. Cytokeratin 18 fragments are an early indicator of apoptosis and cytokeratin 18 might influence tumour cell behaviour. We investigated TPS expression in specimens of WT and other paediatric renal malignancies, Procedure: Immunoreactivity of WT sections (n = 9), clear cell sarcomas (CCSK, n = 3), and a renal cell carcinoma (RCC), and two pediatric kidney tumour cell lines (WT: SK-NEP-1 and rhabdoid tumour of the kidney: G-401) were investigated using the monoclonal antibody M3. Additionally, immunoblotting and RT-PCR analysis were performed. Cell culture supernatants were evaluated for TPS release. Serum TPS was measured in five patients at diagnosis, during chemotherapy and after surgical resection., Results: Moderate to strong immunoreactivity for TPS was found in tubular and blastemal components of nearly all (8/9) WT specimens. This was confirmed by Western-blotting. Cystic and epithelial-like portions of CCSKs and RCC showed distinct reactivity (3/3). The supernatant of G-401 but not of SK-NEP-1 showed a time- and cell number-dependent increase of TPS release. Interestingly, TPS synthesis was demonstrated in SK-NEP-1 cells. Median preoperative serum TPS was elevated (293 U/l) compared to healthy children and lowest after surgical resection (49.5 U/l)., Conclusions: This is the first study demonstrating the synthesis and release of TPS by WTs and other paediatric renal malignancies. Considering the elevated levels of TPS in serum of these patients, a further investigation of this marker by larger clinical trials seems to be justified., (Copyright 2001 Wiley-Liss, Inc.)

Background: Solid-pseudopapillary tumor of the pancreas (SPT) is an exceptionally rare neoplasm in children. Its origin remains enigmatic. It is of low malignant potential and occurs most frequently in young females., Patients and Methods: A cumulative review of the tumor's clinicopathological characteristics from the world's literature is presented. The clinical course, pathohistologic data and outcome of surgery of four Austrian children treated at the general hospital of Vienna are analyzed., Results: Between 1987 and 1999, four girls (age: 12--16 years) with SPT were diagnosed at our institution. All patients presented with an abdominal mass and uncharacteristic abdominal pain. Two tumors were located in the tail, one in the body and tail and one in the head of the pancreas (diameter: 7--15 cm). Surgical procedures included three distal pancreatectomies and one partial duodenopancreatectomy (Whipple procedure). One patient had two recurrences with metastases that could only be partially resected. Chemotherapy was initiated for this patient. In the follow-up period (range: 6 months to 12 years) all patients are alive with no evidence of recurrence., Conclusions: SPT is a rare differential diagnosis of a pancreatic mass in children. It is mandatory to establish this diagnosis since complete surgical removal of the tumor even in case of metastases or local invasion offers an excellent prognosis., (Copyright 2001 Wiley-Liss, Inc.)

Although between 4% and 20% of all appendectomies in adults are performed laparoscopically, this procedure is rarely done in the pediatric age group because of the substantially more difficult technique, the expected risks and suspected higher rate of complications. In a prospective study of 500 consecutive appendectomies, we tried to assess the actual rate of complications of each operative approach. We included 362 conventional and 138 laparoscopic appendectomies, the median age of the patients was 10.8 years. The mortality was 0 in both groups. We observed 89 minor and 11 major complications. All major complications (wound infections needing re-operation under general anesthesia, intra-abdominal abscesses, ileus due to adhesions and a case of renal insufficiency because of glomerulonephritis) occurred in the conventional group (n=11, ie, 3% of 362 open appendectomies). Seventy-two minor complications were seen in the same group (20%). In the laparoscopic group, there were 17 (13%) minor complications and no severe complications. This difference was statistically significant. We conclude that in children laparoscopic appendectomy does not carry a greater risk of intra- or postoperative complications and can therefore safely be established as a standard procedure.

Progressive familial intrahepatic cholestasis (PFIC) is a congenital liver disease. First symptoms can frequently be seen shortly after birth. Quality and expectation of life are substantially reduced due to severe pruritus and the complications of progressive liver cirrhosis. PFIC is diagnosed on the basis of characteristic clinical and laboratory parameters and genetic analysis after exclusion of other liver diseases leading to intrahepatic cholestasis. Medical therapy is only effective in a proportion of children with PFIC. Partial biliary diversion (PBD) is nowadays considered the therapy of choice in patients with therapy-refractive pruritus. If performed in time, damage to the liver can be delayed or arrested, thus orthotopic liver transplantation (OLT) can be postponed or even avoided in at least some patients with PFIC. Besides providing a current overview of PFIC, we report on three patients who were successfully treated surgically. One patient was subjected to a new technique of PBD (cholecysto-appendicostomy), the other two had OLT.

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). The standard surgical procedure was cystotomy followed by capitonnage. The main postoperative complications were fever and wound infection. There were two recurrences after a mean follow-up of 4.8 years, and one patient died because of multiple organ involvement. We conclude that the therapy of choice in pediatric pulmonary hydatidosis is complete surgical elimination of the cyst by cystotomy and capitonnage, whereas more extended resections should be avoided. Ideally, benzimidazole treatment should be combined with surgery. New serological tests can improve diagnostic accuracy.

Measurement of serum concentrations of tissue polypeptide-specific Antigen (TPS) has been demonstrated to the useful in diagnosis and monitoring of adult epithelial tumors. So far, no data have been available on normal or pathologic TPS values in children. Therefore, the present study was designed to evaluate the normal values of TPS in childhood. Using a commercial enzyme linked immunosorbent assay (ELISA) kit, serum TPS was determined in 361 healthy children. Median (M) TPS was found to be 107 U/l at birth (n = 124). By the end of the first week, the value rose to M = 150 U/l (n = 68) and then continuously decreased with age (1 week-1 year, n = 45, M = 88 U/l; 1-7 years, n = 75, M = 51 U/l) until reaching the adult level (8-18 years, n = 49, M = 34 U/l). Additionally, the serum TPS values of 45 mothers right after delivery (M = 161 U/l) were assessed, and there was no correlation to the marker levels determined in the cord blood of their children. The age-dependent distribution of serum TPS in healthy children must be taken into account in the clinical application of this tumor marker.

Patients and Methods: According to previous literature incomplete tumor resection, coccygeal or ovarian primary site and immaturity are known risk factors for relapse in teratoma. To establish a risk score points are allocated for resection, primary site and histology in the following manner and added: incomplete resection 4 points, primary site coccyx 3 points, ovary 2 points, other site 1 point, histological grading 0-3 points. This score system is evaluated on 270 extracranial non-testicular teratoma cases collected between 1982 and 1995 in the MAKEI cooperative treatment protocols of the German Society of Pediatric Oncology and Hematology. Treatment was resection alone (230 patients) or resection followed by postoperative adjuvant chemotherapy (40 patients)., Results: Patients treated with surgery alone: 28/230 (12%) patients relapsed, 14/230 (6%) patients showed highly malignant histology (mostly yolk sac tumor) in relapse. Mortality in case of relapse was 6/28 (21%). Patients scoring > or = 6 points (n = 45) had a relapse rate of 21/45 (47%) resulting in a 23%-mortality (5/21). Patients scoring < 6 points (n = 185) had a 4%-relapse risk (8/185) resulting in 13%-mortality (1/8) (p < 0.01). Patients treated with surgery and adjuvant chemotherapy: 7/40 patients (18%) suffered a relapse, none of them showing malignant histology. Mortality rate in case of relapse was 3/7 (43%). Patients scoring > or = 6 points initially treated with adjuvant chemotherapy (n = 18) had a relapse rate of 7/18 (39%), compared to patients scoring < 6 points (n = 22), in whom no relapses occurred (p < 0.01). There were no highly malignant relapses in the group treated with adjuvant chemotherapy. Regardless of the scored points the difference in highly malignant relapse histology comparing the group treated with surgery and adjuvant chemotherapy to the group treated with surgery was statistically significant (p = 0.02)., Conclusion: The risk score system marks a high risk group including 63/270 (23%) of all evaluated extracranial non-testicular teratoma cases (scoring > or = 6 points). In this group 28/35 (80%) of relapses and 8/9 (89%) of tumor deaths occurred. For this high risk group a randomized trial will be suggested to evaluate the effect of adjuvant chemotherapy on the rate of malignant relapses. It should also be investigated, if adjuvant chemotherapy will influence relapse rate and mortality.

Tissue Polypeptide Specific Antigen (TPS) may soon be routinely used as a proliferation marker in adult epithelial tumors. So far, no data have been available on normal or pathologic TPS values in children. Therefore the present study was designed to test the marker for the first time in pediatric malignancies. Using a commercial ELISA kit (Beki Diagnostics), serum TPS levels were determined in 270 healthy children and compared with various benign (n = 143) and malignant (n = 58) diseases. In healthy children, we found an age-dependent distribution of TPS values. Median (M) TPS was found to be 105.05 U/l at birth as determined from umbilical cord blood (n = 96). By the end of the first week, the value rose to M = 164 U/l and then continuously decreased with age until reaching the adult level at around 14 years. Patients with benign masses (n = 29) did not show elevated serum TPS in contrast to children with malignancies. Advanced tumor stage, metastases, and low dignity correlated with an increase in serum values. In many cases, chemotherapy and especially surgical resection of the tumor were followed by a decrease of the previously markedly elevated TPS levels. Severe infections and impaired renal function were however related with very high values and this must be taken into account when judging the validity of TPS measurements. The marker appears useful for the differential diagnosis between benign and malignant processes. While previous investigators described its use exclusively in epithelial tumors of adults, we cannot confirm this specifity in pediatric patients: Our data show that elevated TPS values in children can also be observed in nonepithelial tumors.

The interaction between P-glycoprotein modulators and P-glycoprotein mediated transport was investigated using rhodamine 123 in the isolated perfused rat liver of a mutant (TR-) rat strain. TR- rats, deficient in the canalicular multispecific anion transport system, are unable to extrude organic anions (glucuronides) and therefore excrete solely unconjugated rhodamine 123 via P-glycoprotein. Cyclosporin A, a modulator of multidrug resistance in tumor cells, inhibited the biliary secretion of rhodamine 123 dose dependently in a non-competitive manner. Both cyclosporin A and rhodamine inhibited photoaffinity labeling of immunoprecipitated P-glycoprotein with azidopine, indicating binding to hepatic P-glycoprotein. Our results indicate that monitoring the biliary rhodamine 123 secretion in the isolated perfused liver of TR- rats offers a new system for testing modulators of P-glycoprotein like cyclosporin A.

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.

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 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.