OASIS evaluation of the French surveillance network for antimicrobial resistance in diseased animals (RESAPATH): success factors underpinning a well-performing voluntary system.

Antimicrobial resistance is a One Health issue requiring the development of surveillance systems in the human, environmental and animal sectors. In the European Economic Area, the surveillance of antimicrobial resistance in zoonotic pathogens and indicator bacteria in healthy food-producing animals is required legally, while countries are also expected to extend their surveillance to diseased animals in the frame of national action plans. In this context, evaluating existing antimicrobial resistance surveillance systems in animal health is important to improve systems in place, but also to help other countries learn from these experiences, understand success factors and anticipate challenges. With this aim, the French surveillance network for antimicrobial resistance in bacteria from diseased animals (RESAPATH) was evaluated using the Outil d'Analyse des Systèmes d'Information en Santé (OASIS) assessment tool. Key performance factors included (i) a strong and inclusive central institutional organisation defining clear and well-accepted surveillance objectives, scope and procedures, (ii) strong skills in epidemiology and microbiology and (iii) a win-win approach enabling the voluntary participation of 71 field laboratories and where free annual proficiency testing plays a pivotal role. The main area for improvement of RESAPATH was its time-consuming data management system.

Abdominal fat distribution in diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis patients compared to controls.

AIM: To evaluate abdominal fat distribution (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]) in two enthesopathy-related diseases with known correlation to metabolic syndrome (MS): diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) compared with controls. MATERIALS AND METHODS: Abdominal computed tomography (CT) examinations of 43 DISH (Resnick radiographic criteria) patients, 31 AS (Modified New York Criteria) patients and 42 age- and gender-matched (to DISH) controls (males: 29; 29; 27 and mean age: 71.7±7; 56.1±16; 72.7±8 years, respectively) were evaluated and compared for VAT and SAT surface areas on mid L3, L4, L5 levels. RESULTS: AS patients were significantly younger compared to DISH patients and controls. No significant differences were observed between VAT and SAT of DISH and AS patients or between SAT values in all groups even after correction for age. VAT was higher in DISH and AS patients compared to controls on all three levels, but reached significance (p<0.05) only for DISH patients (L3: 24.34/23.6/18.43; L4: 23.85/22.21/18.05; L5: 19.09/18.94/14.24 mm2, respectively). This did not change after correction for age. The VAT/SAT ratio was significantly larger in DISH and AS patients on all levels compared to controls. CONCLUSION: The higher VAT surface area, a known marker for MS, which by itself is associated with bone proliferation, in DISH and AS patients compared to controls substantiates its role as a potential surrogate marker for MS as well as suggests a potential shared pathogenic pathway for enthesopathic excessive bone production in DISH and AS.

Determination of Hydrogen Density by Swift Heavy Ions.

A novel method to determine the total hydrogen density and, accordingly, a precise plasma temperature in a lowly ionized hydrogen plasma is described. The key to the method is to analyze the energy loss of swift heavy ions interacting with the respective bound and free electrons of the plasma. A slowly developing and lowly ionized hydrogen theta-pinch plasma is prepared. A Boltzmann plot of the hydrogen Balmer series and the Stark broadening of the H_{ß} line preliminarily defines the plasma with a free electron density of (1.9±0.1)×10^{16} cm^{-3} and a free electron temperature of 0.8-1.3 eV. The temperature uncertainty results in a wide hydrogen density, ranging from 2.3×10^{16} to 7.8×10^{18} cm^{-3}. A 108 MHz pulsed beam of ^{48}Ca^{10+} with a velocity of 3.652 MeV/u is used as a probe to measure the total energy loss of the beam ions. Subtracting the calculated energy loss due to free electrons, the energy loss due to bound electrons is obtained, which linearly depends on the bound electron density. The total hydrogen density is thus determined as (1.9±0.7)×10^{17} cm^{-3}, and the free electron temperature can be precisely derived as 1.01±0.04 eV. This method should prove useful in many studies, e.g., inertial confinement fusion or warm dense matter.

Prognostic impact of breast cancer subtypes in elderly patients.

We aimed to analyse the impact of breast cancer (BC) subtypes on the clinical course of disease with special emphasis on the occurrence of brain metastases (BM) and outcome in an elderly BC population. A total number of 706 patients ≥65 years receiving treatment for BC from 2007 to 2011 were identified from a BC database. 62 patients diagnosed with DCIS and 73 patients with incomplete datasets were excluded, leaving 571 patients for this analysis. Patient characteristics, biological tumour subtypes, and clinical outcome including overall survival (OS) were obtained by retrospective chart review. 380/571 (66, 5 %) patients aged 65-74 years were grouped among the young-old, 182/571 (31.9 %) patients aged 75-84 years among the old-old, and 29/571 (5.1 %) patients aged ≥85 years among the oldest-old. 392/571 (68.8 %) patients presented with luminal BC, 119/571 (20.8 %) with HER2-positive, and 59/571 (10.3 %) with triple-negative BC (TNBC). At 38 months median follow-up, 115/571 (20.1 %) patients presented with distant recurrence. A higher recurrence rate was observed in the HER2-positive subtype (43/119 (36.1 %)), as compared to TNBC (15/59 (25.4 %)) and luminal BC (57/392 (14.5 %); p < 0.001). BM were detected at a significantly higher rate in HER2-positive BC patients (9/119 (7.6 %)), as compared to TNBC (2/59 (3.4 %)) and luminal BC patients (6/392 (1.5 %); p = 0.003). Diagnosis of metastatic disease (HR 7.7; 95 % CI 5.2-11.4; p < 0.001) as well as development of BM (HR 3.5; 95 % CI 1.9-6.4; p < 0.001) had a significantly negative impact on OS in a time-dependent covariate cox regression model. In contrast to younger BC patients, outcome in this large cohort of elderly patients suggests that HER2-positive disease-not TNBC-featured the most aggressive clinical course with the highest rates of metastatic spread and BM. In-depth analysis regarding a potentially distinct biology of TNBC in elderly is therefore warranted.

Role of computer-assisted surgery in osteotomies around the knee.

PURPOSE: The goal of this article is to present our experience on navigation for osteotomies around the knee and especially osteotomies for coronal deformities. The first computer-assisted osteotomy was performed in March 2001 and since that time more than 1000 osteotomies have been performed in our department. METHODS: All the osteotomies were performed with the Orthopilot® device (B-Braun-Aesculap, Tuttlingen, Germany). The main indication was for genu varum deformities but several cases were operated for genu valgum. The surgical procedure as well as the indications and the rationale for each osteotomy (high tibial osteotomy-HTO, double-level osteotomy-DLO, femoral osteotomy-FO) are addressed in the article. RESULTS: The results are focused on several papers published by the authors since more than 10 years. Regarding HTO for genu varum, the preoperative goal (HKA angle: 184° ± 2°) was reached in 96 % of cases and the difference was statistically significant compared to the non-navigated series (71 %: p < 0.05). Regarding DLO for genu varum, the preoperative goal was reached in 92.7 % for the HKA angle and in 88.1 % for the medial proximal tibial mechanical angle (MPTMA). Regarding genu valgum deformity, the preoperative goal was achieved in 86.2 % of cases for the HKA angle and 100 % of cases for the MPTMA. CONCLUSION: According to these results, one can say that, regardless the type of osteotomy, the procedure is reliable, reproducible and accurate. Since 15 years, all the osteotomies around the knee are navigated in our department. Provided that one uses a reproducible radiograph protocol, navigation allows to perform double-level osteotomies, both for genu varum and genu valgum, with optimal accuracy in order to avoid oblique joint line, which will be difficult to revise to TKA. LEVEL OF EVIDENCE: IV.

Are results of total knee arthroplasty for isolated patellofemoral OA as good as for medial compartment OA? A medium-term retrospective comparative study.

PURPOSE: The aim of this study was to compare the results of isolated patellofemoral arthritis (IPFA) treated using a total knee arthroplasty (TKA) compared to the results of medial tibiofemoral arthritis treated with a TKA. We hypothesised that there would be no difference between functional outcomes for the two groups. METHODS: Between 2003 and 2009, 32 TKAs were performed for IPFA (group I). Over this time period, a total of 813 primary TKAs were performed from which we identified a second group of patients who had undergone TKA for isolated medial tibiofemoral arthritis (group II: n = 32). These patients were matched based on age, sex, body mass index and average follow-up. The average age of patients in group I was 72.81 ± 6.6 years (59-83) and 71.97 ± 6.8 years in group II. The global International Knee Society (IKS) score was statistically significantly better in group I (114.72 ± 22 points) than in group II (84.9 ± 23.8). This difference was accounted for by better passive flexion, better walking distance and the absence of any coronal plane deformity. RESULTS: A total of 29 patients from group I were reviewed at an average follow-up of 64.58 ± 23.4 months, and 30 patients in group II were reviewed at an average follow-up of 66.13 ± 23.9 months (three were lost to follow-up in group I and two in group II). At final follow-up, there was statistically no difference between the two groups IKS score (175.34 ± 19.26 in group I vs. 170.13 ± 24.14 for group II) or Hospital for Special Surgery patella score (89.31 ± 9.98 points for group I vs. 89.16 ± 11.45 points for group II). We found no significant radiological difference between the two groups including patella height and orientation on axial views. CONCLUSIONS: The results of TKA for IPFA are as good as the results of TKA for isolated medial tibiofemoral arthritis with well-functioning prosthetic patellofemoral articulations. These results support our institutional preference for using TKA as treatment for IPFA in patients over 65-70 years old.

Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex.

BACKGROUND: Breast cancer is the leading cause of cancer death in women living in the western hemisphere. Despite major advances in first-line endocrine therapy of advanced oestrogen receptor (ER)-positive breast cancer, the frequent recurrence of resistant cancer cells represents a serious obstacle to successful treatment. Understanding the mechanisms leading to acquired resistance, therefore, could pave the way to the development of second-line therapeutics. To this end, we generated an ER-positive breast cancer cell line (MCF-7) with resistance to the therapeutic anti-oestrogen fulvestrant (FUL) and studied the molecular changes involved in resistance. METHODS: Naive MCF-7 cells were treated with increasing FUL concentrations and the gene expression profile of the resulting FUL-resistant strain (FR.MCF-7) was compared with that of naive cells using GeneChip arrays. After validation by real-time PCR and/or western blotting, selected resistance-associated genes were functionally studied by siRNA-mediated silencing or pharmacological inhibition. Furthermore, general mechanisms causing aberrant gene expression were investigated. RESULTS: Fulvestrant resistance was associated with repression of GPER and the overexpression of CDK6, whereas ERBB2, ABCG2, ER and ER-related genes (GREB1, RERG) or genes expressed in resistant breast cancer (BCAR1, BCAR3) did not contribute to resistance. Aberrant GPER and CDK6 expression was most likely caused by modification of DNA methylation and histone acetylation, respectively. Therefore, part of the resistance mechanism was loss of RB1 control. The hSWI/SNF (human SWItch/Sucrose NonFermentable) chromatin remodelling complex, which is tightly linked to nucleosome acetylation and repositioning, was also affected, because as a stress response to FUL treatment-naive cells altered the expression of five subunits within a few hours (BRG1, BAF250A, BAF170, BAF155, BAF47). The aberrant constitutive expression of BAF250A, BAF170 and BAF155 and a deviant stress response of BRG1, BAF170 and BAF47 in FR.MCF-7 cells to FUL treatment accompanied acquired FUL resistance. The regular and aberrant expression profiles of BAF155 correlated directly with that of CDK6 in naive and in FR.MCF-7 cells corroborating the finding that CDK6 overexpression was due to nucleosome alterations. CONCLUSION: The study revealed that FUL resistance is associated with the dysregulation of GPER and CDK6. A mechanism leading to aberrant gene expression was most likely unscheduled chromatin remodelling by hSWI/SNF. Hence, three targets should be conceptually addressed in a second-line adjuvant therapy: the catalytic centre of SWI/SNF (BRG1) to delay the development of FUL resistance, GPER to increase sensitivity to FUL and the reconstitution of the RB1 pathway to overcome resistance.

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases.

BACKGROUND: Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit. METHODS: Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy. RESULTS: Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012). INTERPRETATION: This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ≥70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.

Brain metastases free survival differs between breast cancer subtypes.

BACKGROUND: Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010. METHODS: Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34-16.66) compared with 18 months (95% CI: 14.46-21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71-44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014). CONCLUSION: Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.

NF-κB mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells.

BACKGROUND: The intravasation of breast cancer into the lymphendothelium is an early step of metastasis. Little is known about the mechanisms of bulky cancer invasion into lymph ducts. METHODS: To particularly address this issue, we developed a 3-dimensional co-culture model involving MCF-7 breast cancer cell spheroids and telomerase-immortalised human lymphendothelial cell (LEC) monolayers, which resembles intravasation in vivo and correlated the malignant phenotype with specific protein expression of LECs. RESULTS: We show that tumour spheroids generate 'circular chemorepellent-induced defects' (CCID) in LEC monolayers through retraction of LECs, which was induced by 12(S)-hydroxyeicosatetraenoic acid (HETE) secreted by MCF-7 spheroids. This 12(S)-HETE-regulated retraction of LECs during intravasation particularly allowed us to investigate the key regulators involved in the motility and plasticity of LECs. In all, 12(S)-HETE induced pro-metastatic protein expression patterns and showed NF-κB-dependent up-regulation of the mesenchymal marker protein S100A4 and of transcriptional repressor ZEB1 concomittant with down-regulation of the endothelial adherence junction component VE-cadherin. This was in accordance with ∼50% attenuation of CCID formation by treatment of cells with 10 µM Bay11-7082. Notably, 12(S)-HETE-induced VE-cadherin repression was regulated by either NF-κB or by ZEB1 since ZEB1 siRNA knockdown abrogated not only 12(S)-HETE-mediated VE-cadherin repression but inhibited VE-cadherin expression in general. INTERPRETATION: These data suggest an endothelial to mesenchymal transition-like process of LECs, which induces single cell motility during endothelial transmigration of breast carcinoma cells. In conclusion, this study demonstrates that the 12(S)-HETE-induced intravasation of MCF-7 spheroids through LECs require an NF-κB-dependent process of LECs triggering the disintegration of cell-cell contacts, migration, and the generation of CCID.

Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620.

Treatment resistance to antineoplastic drugs represents a major clinical problem. Here, we investigated the long-term stability of acquired resistance to 5-fluorouracil (FU) in an in vitro colon cancer model, using four sub-clones characterised by increasing FU-resistance derived from the cell line SW620. The resistance phenotype was preserved after FU withdrawal for 15weeks (~100 cell divisions) independent of the established level of drug resistance and of epigenetic silencing. Remarkably, resistant clones tolerated serum deprivation, adopted a CD133(+) CD44(-) phenotype, and further exhibited loss of membrane-bound E-cadherin together with predominant nuclear ß-catenin localisation. Thus, we provide evidence for a long-term memory of acquired drug resistance, driven by multiple cellular strategies (epithelial-mesenchymal transition and selective propagation of CD133(+) cells). These resistance phenomena, in turn, accentuate the malignant phenotype.

Applied precision cancer medicine in metastatic biliary tract cancer.

INTRODUCTION: Advanced therapy-refractory biliary tract cancer (BTC) has poor prognosis and constitutes a major challenge for adequate treatment strategies. By mapping the molecular profiles of advanced BTC patients, precision cancer medicine may provide targeted therapies for these patients. OBJECTIVE: In this analysis, we aimed to show the potential of PCM in metastatic BTC. METHODS: In this single-center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 30 patients diagnosed with different types of metastatic BTC. Tumor samples of the patients were examined using a 161-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for chromosomal translocations. RESULTS: In total, we identified 35 molecular aberrations in 30 patients. The predominant mutations were KRAS (n = 8), TP53 (n = 7), IDH2 (n = 4), and IDH1 (n = 3) that accounted for the majority of all molecular alterations (62.86%). BRAF mutations were observed in two patients. Less frequent alterations were noted in ARID1A, CTNNB1, ESR1, FBXW7, FGFR2, MET, NOTCH2, PIK3CA, PTCH1, SMAD4, and SRC1, each in one case. FGFR fusion gene was detected in one patient. No mutations were detected in eight patients. IHC revealed EGFR and p-mTOR expression in 28 patients. Applying these results to our patients, targeted therapy was recommended for 60% of the patients (n = 18). One patient achieved stable disease. CONCLUSIONS: PCM is a feasible treatment approach and may provide molecular-guided therapy recommendations for metastatic BTC.

Diabetes mellitus and hypertension as risk factors for early diffuse idiopathic skeletal hyperostosis (DISH).

OBJECTIVES: To describe and identify factors, in clinical practice, that might be useful increasing the index of suspicion for diffuse idiopathic skeletal hyperostosis (DISH), at a relatively young age. DESIGN: A group of 18 patients with DISH (12.8) who were diagnosed before the age of 50 years (group A) was compare with a group of 20 patients of similar age with osteoarthritis (group B), and 24 patients with DISH diagnosed after the age of 60 years (group C). Data collection included demographic characteristics, body region of main complaint evidence for enthesopathies or tendonitis, length of follow-up, body mass index (BMI), serum lipid profile, family history of diabetes mellitus (DM), and hypertension (HTS). The presence of concomitant diseases and use of medications was recorded at presentation and during the follow-up period. RESULTS: Patients in group A compared with group B, had statistically significant more pain in the lumbar and thoracic spine (P=0.001 and 0.016, respectively), tendonitis/enthesopathies (P=0.004), obesity (BMI> or =30, P=0.014), and first degree relative with HTS and DM (P=0.015 and 0.05, respectively). By the end of the follow-up, significantly more patients in group A were affected by DM compared with group B (P=0.007). CONCLUSIONS: Individuals in the fifth decade of life are likely to be affected by DISH if they are obese, have a first degree relative with either HTS or DM, complain of lumbar or thoracic spinal pain, and are affected by enthesopathies or tendonitis. The likelihood of relatively young patients with > or =3 clinical parameters to be affected with DISH, was six times higher than age and sex matched controls (P=0.004).

Serum levels of tumour necrosis factor-alpha and interleukin-6 and their correlation with body mass index, weight loss, appetite and survival rate--preliminary data of Viennese outpatients with metastatic cancer during palliative chemotherapy.

The serum cytokine levels (in particular interleukine-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha)) of 61 advanced stage cancer patients receiving palliative chemotherapy as outpatients were determined with quantikine immunoassays. The values were correlated with body mass index (BMI), weight loss and appetite. Furthermore cytokine levels of patients who have died within one year were compared with those of patients who have survived more than a year. Serum levels of IL-6 (median: 1.93 pg/ml, range: 0.32-42.87) and of TNF-alpha (median: 2.55 pg/ml, range: 1.03-34.06) did not correlate with BMI, weight loss and appetite. Serum IL-6 levels of patients with survival time less than one year were significantly higher than the levels of patients who survived more than one year, no significant differences in TNF-alpha serum levels were evident. The data of this observation are consistent with current literature. Due to changes in serum levels of proinflammatory cytokines in response to chemotherapy and additional therapy, it is unlikely that IL-6 and TNF-alpha can be used as independent indicators for weight loss and appetite. Nevertheless, high serum levels of IL-6 correlate with short-time mortality.

Fate of 5-fluorouracil, doxorubicin, epirubicin, and daunorubicin in hospital wastewater and their elimination by activated sludge and treatment in a membrane-bio-reactor system.

Antineoplastic agents are applied in cancer therapy and end up in hospital wastewater by human excretions. In this study, the raw wastewater of the sewer of the oncologic in-patient treatment ward of the Vienna University Hospital was monitored for 98 d over 2 years for the cytostatics 5-fluorouracil (5-FU), doxorubicin (DOX), epirubicin, and daunorubicin. In a next step, the elimination of the drugs by a membrane-bio-reactor system was investigated. In addition, their fate in wastewater and elimination by activated sludge was investigated with radio-labelled substances. During the monitoring periods, concentration levels ranging from <8.6 to 124 microgl(-1) for 5-FU and from <0.26 to 1.35 microgl(-1) for DOX were determined. The concentrations analysed fitted the lower ranges calculated by an input-output model. Treatment of oncologic wastewater in the membrane bio-reactor as well as the analysis of the effluents of the Vienna University Hospital resulted in concentrations below the limit of detection. Investigations with radio-labelled compounds showed that 5-FU is eliminated from the liquid phase below the limit of detection. But, up to 25% of radio-labelled equivalents of the drug's amount were found in the gaseous phase and only a marginal part in the solid phase, this indicates that at least one part of the drug is biodegraded. For the anthracyclines more than 90% was eliminated from the liquid phase. In this case, adsorption to suspended solids seems to be the major elimination pathway, as up to 30% of the radio-labelled equivalents of the drug's amount was detected in the solid phase. Our results indicate that the investigated anticancer drugs are eliminated by sewage treatment plants, either by biodegradation or adsorption.

Monitoring, removal and risk assessment of cytostatic drugs in hospital wastewater.

Cytostatic agents are applied in cancer therapy and subsequently excreted into hospital wastewater. As these substances are known to be carcinogenic, mutagenic and toxic for reproduction, they should be removed from wastewater at their source of origin. In this study the fate and effects of the cancerostatic platinum compounds (CPC) cisplatin, carboplatin, oxaliplatin, 5-fluorouracil (5-FU) and the anthracyclines doxorubicin, daunorubicin and epirubicin were investigated in hospital wastewater. Wastewater from the in-patient treatment ward of a hospital in Vienna was collected and monitored for the occurrence of the selected drugs. A calculation model was established to spot the correlation between administered dosage and measured concentrations. To investigate the fate of the selected substances during wastewater treatment, the oncologic wastewater was treated in a pilot membrane bioreactor system (MBR) and in downstream advanced wastewater treatment processes (adsorption to activated carbon and UV-treatment). Genotoxic effects of the oncologic wastewater were assessed before and after wastewater treatment followed by a risk assessment. Monitoring concentrations of the selected cytostatics in the oncologic wastewater were in line with calculated concentrations. Due to different mechanisms (adsorption, biodegradation) in the MBR-system 5 - FU and the anthracyclines were removed < LOD, whereas CPC were removed by 60%. In parallel, genotoxic effects could be reduced significantly by the MBR-system. The risk for humans, the aquatic and terrestrial environment by hospital wastewater containing cytostatic drugs was classified as small in a preliminary risk assessment.

5-fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients.

Several anticancer drugs fail to exhibit sufficient activity against solid tumors in vivo despite effective inhibition of tumor cell growth in vitro. This may be due to impaired drug transfer from plasma into solid tumors. The present study, therefore, aimed at measuring interstitial tumor 5-fluorouracil (5-FU) pharmacokinetics and 5-FU transfer rates from plasma into the tumor interstitium in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of 10 breast cancer patients (8 females and 2 males) scheduled to receive neoadjuvant chemotherapy due to locally advanced breast cancer. Thereafter, patients received 5-FU (600 mg/m2, i.v). 5-FU kinetics were followed in plasma and tumor and s.c. interstitial fluid. Mean interstitial 5-FU load, expressed as area under curve (AUC), in breast tumors was 61 +/- 11% (means +/- SE) of the mean plasma 5-FU load. 5-FU displayed similar kinetics in the interstitial space of s.c. adipose tissue and tumor tissue. A high interstitial tumor AUC was associated with increased tumor response. There was no association with tumor response for s.c. or plasma AUC of 5-FU. Measurement of interstitial drug concentrations in breast tumors by in vivo microdialysis may predict response to chemotherapy. This information may explain drug resistance in some patients and help to optimize dosing and administration schedules. In the future, selection of novel cytotoxic compounds with favorable tumor penetration characteristics may become possible.