[Topicality of the fundamental and determining importance of chronic critical ischemia of the extremities and its restorative treatment using crural/pedal bypasses in Germany and in Saxony-Anhalt]. / Aktualität der grundlegenden und determinierenden Bedeutung der chronisch-kritischen Extremitätenischämie sowie ihrer sich reetablierenden Behandlung mittels kruraler/pedaler Bypässe in Deutschland und in Sachsen-Anhalt.

INTRODUCTION: Currently, there is an increase in severe stages of peripheral arterial occlusive disease (PAOD) with critical ischemia. This seems to correspond to the general demographic change as well as a consequence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic of the last 3 years. The now established and accepted interventional/endovascular approach for severe lower leg PAOD in experienced hands is still considered the first-line treatment but from the authors' perspective crural/pedal venous bypass is experiencing a renaissance. MATERIAL AND METHODS: Compact narrative review of the current state of crural/pedal bypass surgery in Germany and Saxony-Anhalt (SA) combined with selective references from the current scientific medical literature and own clinical experiences. RESULTS: The current statistics of case-related diagnosis-related groups (DRG) data show that, especially with the occurrence of the corona pandemic, a decrease in inpatient case numbers of patients with PAOD stage IIB can be observed nationwide and also in SA. The severe PAOD stages have remained approximately the same in case numbers but increased in SA. The risk stratification based on the wound, ischemia and foot infection (WIFI) classification offers the possibility to be able to make statements about the risk of amputation, benefits and type of revascularization measures. The length of the occlusion, occlusion site of the affected vessels and degree of calcification are taken into account in the global limb anatomic staging system (GLASS) to assess the prognosis. The evaluation of the case-based hospital statistics from 2015 to 2020 showed a constant use of femorocrural/femoropedal bypass surgery in Germany as well as a slight increase in reconstruction using femorocrural bypasses in SA, which seems to correlate with the tendency for an increase in the number of cases of severe PAOD. Parameter-based objectification of the severity of critical limb ischemia should be included in the indications for placement of a crural/pedal bypass. The WIFI classification and GLASS are suitable for this purpose as a relative prognosis of success is also possible. The treatment of critical limb ischemia by crural/pedal bypass surgery continues to find a constant application in Germany and SA.

Combined chemotherapy and pembrolizumab salvages multi-chemotherapy agent and avelumab resistant choriocarcinoma: A case report.

Introduction: Gestational trophoblastic neoplasia (GTN) including choriocarcinoma (CC) frequently requires multi-agent chemotherapy to achieve cure. In chemotherapy-resistant GTN, immunotherapy with the checkpoint inhibitors pembrolizumab, avelumab and camrelizumab are potential new treatment options previously described in small case series, phase 2 trials and case reports. Case description: A 32-year-old woman was diagnosed with gestational choriocarcinoma (FIGO score 5). Prior administered therapy regimes included methotrexate, actinomycin-D followed by open hysterectomy with bilateral salpingectomy (histology without GTN) as well as multi-agent chemotherapy and avelumab single-agent. After detection of a suspicious pulmonary mass video- assisted thoracoscopic left lung segmentectomy was performed confirming CC. The patient experienced an intracerebral haemorrhage and was treated with an emergency decompressive craniotomy. The cerebrospinal fluid showed an increased ratio of hCG compared to serum. Therapy with combined escalated etoposide and cisplatin with pembrolizumab was commenced followed by maintenance pembrolizumab achieving a complete hCG response and negative PET CT. Discussion: In the management of multi drug- resistant GTN, application of checkpoint inhibitor pembrolizumab is a new therapeutic strategy. In this heavily pre-treated patient incorporation of pembrolizumab resulted in complete long-term response in a patient who had also failed avelumab therapy.

[Statutory provisions, aims, motives, attitudes and thinking on the outpatient operation profile of general and abdominal surgery]. / Vorgaben, Zielvorstellungen, Motive, Haltungen und Denken zum ambulanten Operationsprofil der Allgemein- und Viszeralchirurgie.

AIM: The aim of the manuscript is to discuss and assess the implications and opportunities as well as dangers of "outpatientization" of surgical and inpatient services for general and abdominal surgery. METHOD: Narrative overview with literature reference based on a PubMed search with the search terms: outpatient operations and inpatient interventions, AOP catalog, hybrid DRG, outpatient hernia surgery, outpatient proctological surgery, selective sector-equal reimbursement and day-care forms of care. RESULTS (KEY POINTS): - In the Anglo-American area, the treatment of inguinal hernias is predominantly carried out on an outpatient clinic basis. In the USA, Sweden and Denmark, for example, over 70% of all hernias are treated in an outpatient clinic setting, in Germany it is only 20%. In Germany, the catalog of operations that can be performed on an outpatient basis and other department-replacing interventions in hospitals defines outpatient interventions in accordance with § 115b Social Security Code (SGB) V (Germany). - The conversion from inpatient to outpatient hernia surgery has also failed so far due to an enormous difference in revenues. According to the will of the Federal Ministry of Health, the planned forms of semistationary care are intended to relieve the nursing staff in the hospitals and thus relieve the tense situation of nursing professionals. By the end of March 2023, a special industry-specific reimbursement, so-called hybrid DRGs, is to be agreed, which applies regardless of whether a paid service is provided on an outpatient or inpatient basis. - According to § 115b SGB V, whether a hernia can be performed under inpatient or outpatient conditions is also decided according to the location of the hernia. In the new AOP catalog, frailty is operationalized in the context factors via the degree of care and the Barthel index. If one compares the number of encryption procedures for the 5­530 procedure (closure of an inguinal hernia) in 2005 (184,679) with the pre-corona year 2019 (179,851), it can be seen that the proportion of hernias treated in hospital remained approximately the same over a period of 14 years. - Most elective proctological procedures can be performed on an outpatient basis. For reasons of safety (bleeding) and practicality (pain management, dressing change of large abscesses), inpatient surgery is preferred: extensive hemorrhoidectomy in the case of massive findings, large abscesses, extensive perianal fistula corrections, particularly high transsphincteric or suprasphincteric fistulas. - Guidelines based on the British Guidelines for Ambulant Surgery should be required for comprehensive outpatient treatment in surgery. The introduction of corresponding hybrid DRGs seems to be the right way to cover the costs of outpatient surgery in hospitals. CONCLUSION: The restructuring of the hospital landscape and the nationwide expansion of outpatient operations is an unavoidable requirement in view of rising costs in the healthcare system and impending financing bottlenecks, which will pose challenges for the surgical disciplines in the years to come. Outpatient surgery is already practiced in many areas but has not become established due to the different remuneration. The flat rates for the same branches can be a starting point here. Furthermore, evidence-based framework conditions must be created along the lines of the British Guidelines for Ambulant Surgery.

Improvements in beam's eye view fiducial tracking using a novel multilayer imager.

Purpose.Electronic portal image devices (EPIDs) have been investigated previously for beams-eye view (BEV) applications such as tumor tracking but are limited by low contrast-to-noise ratio and detective quantum efficiency. A novel multilayer imager (MLI), consisting of four stacked flat-panels was used to measure improvements in fiducial tracking during liver stereotactic body radiation therapy (SBRT) procedures compared to a single layer EPID.Methods.The prototype MLI was installed on a clinical TrueBeam linac in place of the conventional DMI single-layer EPID. The panel was extended during volumetric modulated arc therapy SBRT treatments in order to passively acquire data during therapy. Images were acquired for six patients receiving SBRT to liver metastases over two fractions each, one with the MLI using all 4 layers and one with the MLI using the top layer only, representing a standard EPID. The acquired frames were processed by a previously published tracking algorithm modified to identify implanted radiopaque fiducials. Truth data was determined using respiratory traces combined with partial manual tracking. Results for 4- and 1-layer mode were compared against truth data for tracking accuracy and efficiency. Tracking and noise improvements as a function of gantry angle were determined.Results. Tracking efficiency with 4-layers improved to 82.8% versus 58.4% for the 1-layer mode, a relative improvement of 41.7%. Fiducial tracking with 1-layer returned a root mean square error (RMSE) of 2.1 mm compared to 4-layer RMSE of 1.5 mm, a statistically significant (p < 0.001) improvement of 0.6 mm. The reduction in noise correlated with an increase in successfully tracked frames (r = 0.913) and with increased tracking accuracy (0.927).Conclusion. Increases in MV photon detection efficiency by utilization of a MLI results in improved fiducial tracking for liver SBRT treatments. Future clinical applications utilizing BEV imaging may be enhanced by including similar noise reduction strategies.

Clinical translation of a new flat-panel detector for beam's-eye-view imaging.

Electronic portal imaging devices (EPIDs) lend themselves to beams-eye view clinical applications, such as tumor tracking, but are limited by low contrast and detective quantum efficiency (DQE). We characterize a novel EPID prototype consisting of multiple layers and investigate its suitability for use under clinical conditions. A prototype multi-layer imager (MLI) was constructed utilizing four conventional EPID layers, each consisting of a copper plate, a Gd2O2S:Tb phosphor scintillator, and an amorphous silicon flat panel array detector. We measured the detector's response to a 6 MV photon beam with regards to modulation transfer function, noise power spectrum, DQE, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and the linearity of the detector's response to dose. Additionally, we compared MLI performance to the single top layer of the MLI and the standard Varian AS-1200 detector. Pre-clinical imaging was done on an anthropomorphic phantom, and the detector's CNR, SNR and spatial resolution were assessed in a clinical environment. Images obtained from spine and liver patient treatment deliveries were analyzed to verify CNR and SNR improvements. The MLI has a DQE(0) of 9.7%, about 5.7 times the reference AS-1200 detector. Improved noise performance largely drives the increase. CNR and SNR of clinical images improved three-fold compared to reference. A novel MLI was characterized and prepared for clinical translation. The MLI substantially improved DQE and CNR performance while maintaining the same resolution. Pre-clinical tests on an anthropomorphic phantom demonstrated improved performance as predicted theoretically. Preliminary patient data were analyzed, confirming improved CNR and SNR. Clinical applications are anticipated to include more accurate soft tissue tracking.

Concurrent Vogt-Koyanagi-Harada disease and impressive response to immune checkpoint blockade in metastatic melanoma.

Background: Vogt-Koyanagi-Harada disease (VKHD)-like symptoms have previously been reported in 11 melanoma patients treated with immune checkpoint inhibitors. Materials & methods: We report a female patient with multilocular metastatic melanoma who was treated with nivolumab. Results: Following the first nivolumab dose, she experienced bilateral blurry vision, hearing loss, vertigo and ataxia. Ocular ultrasound was consistent with the diagnosis of uveitis. Audiography revealed severe bilateral sensorineural hearing loss. A high-dose corticosteroid regimen was initiated under which the patient developed generalized vitiligo. Abdominal and thoracic CT scans showed an almost complete response to nivolumab therapy. This patient fulfilled all criteria of VKHD which is characterized pathogenetically by an antimelanocytic autoimmune process. Conclusion: The present case showed an impressive response to antimelanoma immunotherapy. Based on these data, the occurrence of VKHD in melanoma patients appears to be a strong indicator for immune checkpoint inhibitor efficacy.

Automated MV markerless tumor tracking for VMAT.

Tumor tracking during radiotherapy treatment can improve dose accuracy, conformity and sparing of healthy tissue. Many methods have been introduced to tackle this challenge utilizing multiple imaging modalities, including a template matching based approach using the megavoltage (MV) on-board portal imager demonstrated on 3D conformal treatments. However, the complexity of treatments is evolving with the introduction of VMAT and IMRT, and successful motion management is becoming more important due to a trend towards hypofractionation. We have developed a markerless lung tumor tracking algorithm, utilizing the electronic portal imager (EPID) of the treatment machine. The algorithm has been specifically adapted to track during complex treatment deliveries with gantry and MLC motion. The core of the algorithm is an adaptive template matching method that relies on template stability metrics and local relative orientations to perform multiple feature tracking simultaneously. Only a single image is required to initialize the algorithm and features are automatically added, modified or removed in response to the input images. This algorithm was evaluated against images collected during VMAT arcs of a dynamic thorax phantom. Dynamic phantom images were collected during radiation delivery for multiple lung SBRT breathing traces and an example patient data set. The tracking error was 1.34 mm for the phantom data and 0.68 mm for the patient data. A multi-region, markerless tracking algorithm has been developed, capable of tracking multiple features simultaneously without requiring any other a priori information. This novel approach delivers robust target localization during complex treatment delivery. The reported tracking error is similar to previous reports for 3D conformal treatments.

Hypoxia increases susceptibility of Pacific white shrimp to whitespot syndrome virus (WSSV) / Condição de hipóxia aumenta a susceptibilidade do camarão branco do Pacíficoao vírus da mancha branca (WSSV)

The present study aimed to evaluate the mortality, reactive oxygen species production (ROS) and total hemocyte counts (THC) of the marine shrimp Litopenaeus vannamei infected with the white spot syndrome virus (WSSV) at three levels of oxygen saturation. For this, 360 shrimp (20±2g) were distributed in 24 tanks (60L), divided in two groups (infected and non-infected), which were subjected to 30, 60 and 100% of dissolved oxygen saturation (in quadruplicate). During 96 hours after infection, daily hemolymph samples were collected for hemato-immunological parameter evaluation (THC and ROS) and dead animals were removed and computed to assess cumulative mortality rates. In the infected group, animals subjected to 100% saturation showed higher ROS production (P<0.05) after 48 hours, while THC was significantly reduced (P<0.05), regardless of oxygen saturation. The hypoxia resulted in high mortality when compared to 100% saturation condition. In the uninfected group, no significant differences were observed in all evaluated parameters. Thus, the hypoxia condition increased the susceptibility of shrimp to the infection of WSSV, which may be partly related to the low ROS production showed by the animals subjected to 30% oxygen saturation.

O presente estudo teve por finalidade avaliar a mortalidade e a contagem total de hemócitos (CTH) e espécies reativas de oxigênio (EROs) de camarão Litopenaeus vannamei infectados com o vírus da mancha branca (WSSV) e submetidos a três níveis de saturação de oxigênio. Para tanto, 360 camarões (20±2g) foram distribuídos em 24 tanques (60L), divididos em dois grupos, infectados e não infectados e submetidos a 30, 60 e 100% de saturação de oxigênio (em quadruplicata). Após a infecção, diariamente foram coletadas amostras de hemolinfa dos animais para avaliação dos parâmetros hematoimunológicos (CTH e EROs) e foi estimada a mortalidade, por 96 horas. No grupo com infecção, os animais submetidos à saturação de 100% apresentaram um aumento na produção de EROs (P<0,05) após 48 horas, ao mesmo tempo em que a CTH demonstrou uma redução (P<0,05) independentemente da saturação do oxigênio, e a condição de hipóxia acarretou maiores mortalidades quando comparada à do grupo com 100% de saturação. No grupo sem infecção, não foram observadas diferenças significativas nos parâmetros avaliados nem mortalidade. Dessa forma, pode-se concluir que a hipóxia aumentou a susceptibilidade do camarão à infecção com o vírus da mancha branca, que pode estar, em parte, relacionada com a baixa contagem de hemócitos e produção de EROs observadas nos animais submetidos a essa condição.

WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. IPF is characterized by epithelial cell injury and reprogramming, increases in (myo)fibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 (WISP1) is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate WISP1 regulation and function in primary human lung fibroblasts (phLFs). We demonstrate that WISP1 is directly upregulated by Transforming growth factor ß1 (TGFß1) and Tumor necrosis factor α (TNFα) in phLFs, using a luciferase-based reporter system. WISP1 mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFß1 and TNFα in phLFs, as analysed by qPCR and ELISA, respectively. Notably, WISP1 is required for TGFß1- and TNFα-dependent induction of interleukin 6 (IL-6), a mechanism that is conserved in IPF phLFs. The siRNA-mediated WISP1 knockdown led to a significant IL-6 reduction after TGFß1 or TNFα stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of WISP1 reduced phLFs proliferation, a process that was in part rescued by IL-6. Taken together, these results strongly indicate that WISP1-induced IL-6 expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFß1 and TNFα.

Integrin α5ß1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.

Integrin α5ß1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5ß1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5ß1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5ß1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5ß1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5ß1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5ß1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5ß1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

[Bacteriologic investigation of the Eustachian tube and the implications of perioperative antibiotics before balloon dilation]. / Bakteriologische Untersuchungen der Tuba auditiva und die Implikation einer perioperativen Antibiotikagabe vor Ballondilatation.

BACKGROUND: Balloon Eustachian Tuboplasty (BET) is a new minimally invasive treatment for chronic Eustachian tube dysfunction (ETD). Initially, perioperative prophylactic antibiotic therapy with ciprofloxacin 2 × 500 mg p.o. for 5 days was administered. This study aimed to characterize the bacterial flora in the ET, nose, and pharynx in patients with chronic obstructive ETD. Additionally, we investigated the necessity of perioperative antibiotic prophylaxis in BET patients. PATIENTS AND METHODS: We examined 40 patients undergoing BET: 20 patients with and 20 patients without perioperative antibiotic prophylaxis. All patients were followed-up for clinical signs and symptoms of local infection for at least 2 weeks after surgery. Following BET, the tips of 35 balloon catheters, as well as swabs from the nose and pharynx were sent for microbiologic analysis. RESULTS: None of these 40 patients had postoperative signs of infection. Of the swabs of the balloon catheters, 46% were sterile and 23% showed standard flora. The remaining 31% of swaps revealed specific bacteria. However, none of the nasal or nasopharyngeal swaps were sterile. CONCLUSION: Due to the lack of signs of postoperative infection in either investigated group, the authors no longer favor use of perioperative antibiotic prophylaxis in patients undergoing BET. The relevance of biofilms and pathogen colonization to ET function has recently been intensively discussed, and should be further investigated in future studies.

Evaluation of tubomanometry as a routine diagnostic tool for chronic obstructive Eustachian tube dysfunction.

OBJECTIVE: The objective of this study was to demonstrate the reliability of tubomanometry (TMM) described by Estéve in the diagnosis of chronic obstructive Eustachian tube (ET) dysfunction. STUDY DESIGN: Combined prospective and retrospective clinical study. SETTING: Tertiary referral centre, affiliated to university. METHODS: Two hundred and fifteen healthy subjects were examined once, 25 healthy subjects underwent TMM weekly for 6 weeks, and six healthy subjects were tested three times a day on at least three different days. The results of tubomanometry in healthy subjects were compared to data obtained from 171 patients with chronic obstructive ET dysfunction. RESULTS: In healthy subjects, there was an immediate opening of the ET at 30-50 mbar with an R-value ≤ 1 in at least 94% of the cases. In patients with chronic ET dysfunction, an opening of the ET could be registered in only 42% of patients at 30 mbar and in 58% at 50 mbar. The average of the R-value in these subjects always indicated towards a delayed opening (R > 1). When measurements are repeated in the same subject with a weekly interval, the intraclass correlation (ICC) was 0.49 for the TMM with 30 mbar, 0.51 for the TMM with 40 mbar and 0.52 for the TMM with 50 mbar in healthy people. For the patients with symptoms of ET dysfunction, the ICC for up to four repeated measures was 0.50 for the TMM with 30 mbar, 0.53 for the TMM with 40 mbar and 0.54 for the TMM with 50 mbar. A complete agreement of the results in repeated measurements within seconds was present in 86% for 30 and 40 mbar and in 79% for 50 mbar. The ICC was 0.61 for the TMM with 50 mbar, 0.62 for the TMM with 40 mbar and 0.68 for the TMM with 30 mbar. CONCLUSIONS: Tubomanometry can support the diagnosis of ET dysfunction. An R-value ≤ 1 indicates a regular function of the ET, an R-value >1 indicates a delayed opening of the ET, and no definable R-value means no detectable opening of the ET. TMM is a reliable and valid instrument to support the diagnosis of chronic obstructive ET dysfunction.

Balloon Eustachian tuboplasty: a retrospective cohort study.

BACKGROUND: Eustachian tube dysfunction is regarded as a 'black box' term, reflecting a spectrum of dysfunction. The key to its diagnosis and management is in identifying the aetiology and exact pathophysiology of the dysfunction. DESIGN: We present our retrospective 5-year results for the technique of transnasal endoscopic balloon dilatation of the cartilaginous part of the Eustachian tube, balloon Eustachian tuboplasty (BET). The indication for treatment is chronic obstructive Eustachian tube dysfunction. MAIN OUTCOME MEASURES: Preoperatively, the Eustachian tube score (ETS) was obtained by a clinico-objective assessment involving tubomanometry (TMM) and reported patient symptom. The measurements were repeated 1, 2, 3, 4 and 5 years postoperatively. SETTING: Tertiary referral centre. PARTICIPANTS: A total of 622 patients (1076 ears) were treated with BET. RESULTS: One year after treatment, the Eustachian tube score improved from 3.13 (± 2.47 SD) to 5.75 (± 2.76 SD). The Eustachian tube score improved significantly in 73% of ears. The average Eustachian tube score 2 years after treatment improved from 2.65 (± 2.89 SD) to 6.26 (± 3.07 SD). In 82% of patients, the Eustachian tube score improved significantly at 5 years. The subjective satisfaction of the patients was approximately 80%. CONCLUSIONS: Our long-term results suggest that BET is a safe and feasible treatment for chronic obstructive Eustachian tube dysfunction with a success rate of more than 70%. This study has important implications for other Eustachian tube-related clinical entities, such as glue ear management (adults and children), continued grommet insertion and tympanomastoid surgery outcomes.

Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review.

UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.

[The patulous eustachian tube-novel surgical approaches]. / Das Syndrom der klaffenden Tube - neue chirurgische Therapieansätze.

A patulous eustachian tube (tuba aperta) may lead to an enormous reduction in quality of life. A patulous eustachian tube can cause symptoms such as autophony, breath synchronous tinnitus, pressure sensation in the ear, and hearing loss. In combination with so-called "sniffing", it can trigger the development of cholesteatoma. Due to the diffuse symptoms the correct diagnosis of this disease can be challenging. A patulous eustachian tube can be best diagnosed through a well-structured examination including patient history, physical examination with thorough observation of movements of the tympanic membrane, and tympanometry with reflex decay. This publication reviews recent literature on the patulous eustachian tube. We focused on the evaluation of the different surgical strategies such as the patulous eustachian tube reconstruction, the Kobayashi plug or the injection of Vox® implants into the torus tubarius.

[Impact of implementation strategies on adherence rates to colorectal cancer (CRC) guidelines after polypectomy in a university hospital]. / Einfluss von Weiterbildungsmaßnahmen auf die leitliniengerechten Nachsorgeempfehlungen nach Polypektomie aus dem Dickdarm in einem Universitätsklinikum.

BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in Germany. Screening colonoscopies with polypectomy have been demonstrated to reduce the incidence of CRC. Detailed recommendations on scheduling screening and follow-up colonoscopies have therefore been included into national guidelines. Knowledge about CRC guidelines and adherence to guideline recommendations varies greatly among physicians. METHODS: We combined different implementation strategies (training courses, case discussion, handouts, wall charts) to improve adherence of recommendations for scheduling follow-up colonoscopy. To assess adherence, written recommendations given at discharge after inpatient treatment for polypectomy were analysed before (n = 111) and after (n = 83) the implementation of the above-mentioned implementation measures. Additional factors possibly influencing the recommendations of physicians were collected (histology, polyp size). RESULTS: The adherence to the CRC guideline before implementation of the above-mentioned measures was moderate. After intervention, there was a non-significant increase from 47 % to 53 %. Senior physician review and editing of the discharge summaries improved guideline adherence of recommendations to 69 %. Neither the education level of residents nor their affiliation to a certain department had an impact on the quality of the recommendations. Histology and in particular information on the resection status of the polyps in the pathology report (complete versus incomplete resection) had an influence of the recommended schedule. Furthermore, size of the polyps, but not the number, had a statistically significant influence on the quality of the recommendations. CONCLUSIONS: The inadequate improvement of guideline adherence can possibly be explained by the insufficient interactive and repetitive character of interventions. As the histology reports seem to have an influence on the recommendations in regards to the interval to the next colonoscopy, interdisciplinary teaching is necessary to improve guideline concurrent care.

Three-dimensional scaffold-free fusion culture: the way to enhance chondrogenesis of in vitro propagated human articular chondrocytes.

Cartilage regeneration based on isolated and culture-expanded chondrocytes has been studied in various in vitro models, but the quality varies with respect to the morphology and the physiology of the synthesized tissues. The aim of our study was to promote in vitro chondrogenesis of human articular chondrocytes using a novel three-dimensional (3-D) cultivation system in combination with the chondrogenic differentiation factors transforming growth factor beta 2 (TGF-b2) and L-ascorbic acid. Articular chondrocytes isolated from six elderly patients were expanded in monolayer culture. A single-cell suspension of the dedifferentiated chondrocytes was then added to agar-coated dishes without using any scaffold material, in the presence, or absence of TGF-b2 and/or L-ascorbic acid. Three-dimensional cartilage-like constructs, called single spheroids, and microtissues consisting of several spheroids fused together, named as fusions, were formed. Generated tissues were mainly characterized using histological and immunohistochemical techniques. The morphology of the in vitro tissues shared some similarities to native hyaline cartilage in regard to differentiated S100-positive chondrocytes within a cartilaginous matrix, with strong collagen type II expression and increased synthesis of proteoglycans. Finally, our innovative scaffold-free fusion culture technique supported enhanced chondrogenesis of human articular chondrocytes in vitro. These 3-D hyaline cartilage-like microtissues will be useful for in vitro studies of cartilage differentiation and regeneration, enabling optimization of functional tissue engineering and possibly contributing to the development of new approaches to treat traumatic cartilage defects or osteoarthritis.

Long-term results of adjustable gastric banding in a cohort of 186 super-obese patients with a BMI≥ 50 kg/m2.

BACKGROUND: There are conflicting results concerning the bariatric effectiveness of adjustable gastric banding in super-obese patients with a Body Mass Index (BMI) more or equal to 50 kg/m(2). METHOD: A cohort of 186 patients with a BMI greater or equal to 50 kg/m(2) who underwent adjustable gastric banding (AGB) at the Bichat-Claude-Bernard University Hospital (Paris, France) were prospectively entered into a database. The following data were recorded: BMI, percentage of BMI loss, percentage of excess weight lost (%EWL), complications, and surgical re-interventions. Loss of greater than 50% of excess weight was considered a success (primary endpoint). A %EWL of less than 25% after one year, or the removal of the gastric band was considered a failure. RESULTS: Thirty-five men (18.8%) and 151 women (81.2%), with a mean age of 38.9 years (range: 16-65) underwent AGB between September 1995 and December 2007. The mean BMI was 55.06 kg/m(2) (range: 50-74.4). Mean follow-up was 112.5 months with a minimum of 28 months and a maximum of 172 months. The follow-up rate was maintained at 89% at ten years. The technique of AGB was by "peri-gastric dissection" in the first 115 patients (61.82%) and by "pars flaccida dissection" in 71 patients (38.17%). The gastric band was removed in 87 of 186 patients (46.8%); band ablation was due to a complication of the gastric band in 62 of these cases (33.3%), to failure of weight loss in 23 cases (12.4%), and to patient request in two cases (1%). The major complications requiring re-operation were: chronic dilatation of the proximal gastric pouch (27 patients - 14.5%), acute dilatation (21 patients - 11.3%), intragastric migration of the prosthesis (six patients - 3.2%), reflux esophagitis (six patients - 3.2%), infection of the gastric band (one patient - 0.5%), and Barrett's esophagus (one patient - 0.5%). No statistically significant difference was found between the two operative techniques with regard to the possibility of preserving the gastric band for ten years. For patients who underwent band removal, no further follow-up analysis of patient data after band ablation was performed. The results were best at two years after AGB with a median BMI of 42.72 kg/m(2), a band removal rate of 8.6% (16 of 186 patients), and a failure rate of 16.4% (28 of 170 patients) of those patients who still had their band in place. However, at 10 years, the picture was completely reversed with a band removal rate of 52.2% (47 of 90 patients), a failure rate of 22% (seven of 33 patients) of those who still had their band in place, and a median BMI of 43.43 kg/m(2). CONCLUSION: Laparoscopic gastroplasty using the adjustable gastric band appeared to be a promising intervention for super-obese patients when the results at two years were analyzed - fairly simple to perform, with perioperative morbidity and mortality near zero. However, these results do not persist in the long-term for super-obese patients. At ten years, only 11% of patients (nine of 80) have successful bariatric results (%EWL>50%) and we were forced to remove the gastric band in 52.2% of patients (47 of 90) because of complications, regardless of the initial operative technique used. Given these results, AGB gastroplasty is not a recommended method for super-obese patients and we believe that a BMI greater or equal to 50 kg/m(2) is a contra-indication for this procedure.

Skull repair after major crush injury.

Reconstructive surgery after trauma of the head and neck is a wide field in ENT surgery. The repair of bony defects often requires implantation of engineered prostheses. We present the case of a 48-year-old male patient who had suffered a major crush injury to his head resulting in a complex bony defect. A computer-assisted designed (CAD/CAM) Titanium implant was used for reconstruction. Direct prefabrication of the individually designed implant led to an excellent coverage of the bony defect and easy adaptation to the defect margins. Results. Treatment plan and surgery as well as implant design and manufacturing were performed in a multidisciplinary team. Skin expander implantation prior to reconstructive surgery ensured a tension-free closure. This team approach led to a satisfactory outcome for this patient. This case illustrates the necessity of a multidisciplinary approach for the optimum management of complex head and neck injuries.