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Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays., Methods: Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection., Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (p<0.05), while all WHO grade 3 tumours were considered high-risk. Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays., Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool which will improve prognostication, inform patient selection for RT, and allow for molecularly-stratified clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

IgE-mediated atopic diseases such as allergic rhinitis and rhinoconjunctivitis are common chronic diseases in the western world. Allergen immunotherapy (AIT) plays a fundamental role in the treatment of allergic patients by modulating the underlying immune mechanisms. Though this treatment is integrated in practice-patterns globally, many differences are found in the application of AIT on the national or international level due to heterogeneous methods, and clinical recommendations are given in different parts of the world. This review from authors in Europe and the United States highlights differences and similarities in important aspects of AIT application in the 2 global regions. First, the regulatory situation differs regarding marketing authorization and licensing. Secondly, differences are elaborated in manufacturing practices, marketing distribution and formulations of AIT products. Thirdly, clinical administration patterns in the current guidelines show similarities in indications and contraindications of AIT, but also are divergent in some practical aspects. Informing the readership on similarities, as well as differences of standards in AIT in the United States and Europe, the authors highlight the unmet need of thorough harmonization of standards of AIT, as it is the only disease modifying treatment option available for patients with allergic rhinitis and rhinoconjunctivitis., (© 2023 The Authors.)

Background: Choanal Atresia is a congenital condition that presents as a blockage from the nasal cavity to the nasopharynx. According to the German statistical Institute (Statistisches Bundesamt), the incidence in Germany in 2018 reached 2.74 in 10,000 live births. It can present unilaterally or bilaterally. As newborns are obligate nasal breathers, management of bilateral atresia has to be performed early after birth. As for unilateral atresia, the optimal age for treatment was determined to be between 6 and 12 months in a recently published consensus., Objective: The main purpose of this study is to characterize the patients treated for choanal atresia in the Department of Otorhinolaryngology and Head and Neck Surgery at a tertiary hospital in the south of Germany and, based in the demographic characteristics as well as intra- and post-operative treatment, to identify factors for success or failure of the surgery. A secondary goal was to describe the complications in the use of stents and analyse its influence in the results., Material and Methods: The cohort-based observational study included 29 patients, with a minimum follow up of one year, who underwent surgical endoscopic correction of both unilateral and bilateral choanal atresia from 2003 to 2020. Analysis of the demographics, intraoperative, and postoperative treatment, and their results, was performed. Multinomial logistic regression was applied for categorical values. Comparisons were performed using Fischer/chi-square test where applicable. A significance level of 0.05 was reached., Results: The population was comprised of 34.5% male and 65.5% female patients. The age varied from 2 days to 20 years old, with a mean of 4.98 years and Standard Deviation (SD) 6.88. The weight of the patients varied between 1.4 kg and 85.0 kg, with a mean of 19.36 and SD 22.58. Unilateral choanal atresia was present in 58.6%, and bilateral in 41.4%. Out of this population, 48.3% presented with associated malformations. The number of procedures per patient performed in general anesthesia varied from 1 to 9, with a mean of 2.52 and SD of 2.23: statistically higher for patients presenting with bilateral atresia with a p value of 0.001*. 20 patients had a tube (Vygon, France) placed at first surgery. In 5 patients, a drug-eluting stent (Propel mini (R) ; Intersect ENT, USA) was applied intraoperatively, without complications. In unilateral choanal atresia, surgical and functional success was attained in 88.2% of the cases. In bilateral cases, it reached 75%. We observed a strong linear relationship between the weight of the patient and the size of the choana perioperatively: R quadrat 0.596, which may be a determinant factor in the wound healing. Weight, age, and concomitant pathology achieved statistical significance in the logistic regression model (p respectively 0.001*, 0.001* and 0.010*), which shows its influence in the result of the surgery. In particular, weight inferior to 3 kg (p 0.001*, chi-square test) at the time of the first surgery is a determinant demographic factor for need of revision in order to achieve patency. There were no major complications associated with the use of a stent, besides its dislodgement. We could not infer an implication of its use on the success of the surgery in the present cohort., Limitations: for this study were the small size of the cohort and non-standardized records for some variables., Conclusions: Younger patients presenting with low weight and concomitant pathology have worse results after surgical endoscopic treatment of choanal atresia, revealing these characteristics to be determinant for success. The size of the neochoana is related to the weight of the patient, which is a limiting factor. In particular, patients under 3 kg had to undergo more procedures in order to achieve patency. The implication of the use of locally applied medication needs to be further studied., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence., Methods: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist., Results: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length., Conclusions: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: With increasing advances in minimally invasive endoscopic therapies and endoscopic resection techniques for luminal disease, there is an increased risk of post-procedure bleeding. This can contribute to significant burden on patient's quality of life and health resources when reintervention is required. Hemospray (Cook Medical, North Carolina, USA) is a novel haemostatic powder licensed for gastrointestinal bleeding. The aim of this single-arm, prospective, non-randomised multicentre international study is to look at outcomes in patients with upper gastrointestinal bleeds following elective endoscopic therapy treated with Hemospray to achieve haemostasis., Methods: Data was prospectively collected on the use of Hemospray from 16 centres (January 2016-November 2019). Hemospray was used during the presence of progressive intraprocedural bleeding post-endoscopic therapy as a monotherapy, dual therapy with standard haemostatic techniques or rescue therapy once standard methods had failed. Haemostasis was defined as the cessation of bleeding within 5 min of the application of Hemospray. Re-bleeding was defined as a sustained drop in haemoglobin (>2 g/l), haematemesis or melaena with haemodynamic instability after the index endoscopy., Results: A total of 73 patients were analysed with bleeding post-endoscopic therapy. The median Blatchford score at baseline was five (interquartile range 0-9). The median Rockall score was six (interquartile range 5-7). Immediate haemostasis following the application of Hemospray was achieved in 73/73 (100%) of patients. Two out of 57 (4%) had a re-bleed post-Hemospray, one was following oesophageal endoscopic mucosal resection and the other post-duodenal endoscopic mucosal resection. Both patients had a repeat endoscopy and therapy within 24 h. Re-bleeding data was missing for 16 patients, and mortality data was missing for 14 patients. There were no adverse events recorded in association with the use of Hemospray., Conclusion: Hemospray is safe and effective in achieving immediate haemostasis following uncontrolled and progressive intraprocedural blood loss post-endoscopic therapy, with a low re-bleed rate.

Background: The optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Although β-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy., Methods: A multinational retrospective study (9 countries, 25 centers) including 767 hospitalized patients with P. aeruginosa bacteremia treated with β-lactam monotherapy during 2009-2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate, including propensity-adjusted, analyses were conducted introducing monotherapy type as an independent variable., Results: Thirty-day mortality was 37/213 (17.4%), 42/210 (20%), and 55/344 (16%) in the ceftazidime, carbapenem, and piperacillin-tazobactam groups, respectively. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate, or propensity-adjusted analyses (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.52-2.46, for ceftazidime; OR, 1.3; 95% CI, 0.67-2.51, for piperacillin-tazobactam, with carbapenems as reference in propensity adjusted multivariate analysis; 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequent with carbapenems (36/206 [17.5%]) versus ceftazidime (25/201 [12.4%]) and piperacillin-tazobactam (28/332 [8.4%] (P = .007)., Conclusions: No significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems, and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Various treatments, many of them considerably invasive, are currently applied to infants with Robin sequence (RS) and accompanying upper airway obstruction (UAO). We present a narrative review of our data on the Tübingen palatal plate (TPP) which show the following: a) in a randomized trial, the TPP was superior to a sham procedure in alleviating UAO; b) children treated with the TPP in infancy showed an intellectual development within the reference range; c) prone positioning is no alternative, as it is ineffective and associated with an increased risk of sudden death; d) the TPP reduces the mixed-obstructive apnea index to near-normal values, both in isolated and most (83%) syndromic RS, e) of 443 infants (129 syndromic) treated with the TPP in our center, 23 (5%) ultimately received a tracheostomy (all with syndromic RS), f) recent data suggest that the TPP may induce mandibular catch-up growth, g) the TPP may also help to reduce respiratory complications following cleft closure in RS, and h) TPP treatment is applied by various centers around the world, although it is unclear if its effectiveness is invariably controlled by endoscopy and sleep studies, although both are necessary. Given these data from peer-reviewed studies, it may be questioned whether the "First do no harm" principle is always adhered to when subjecting RS infants to more invasive procedures such as mandibular distraction osteogenesis or tongue-lip adhesion., (Copyright © 2019 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine the involvement of dorsal root ganglia and peripheral nerves in children with neurofibromatosis type 2 compared to healthy controls and symptomatic adults by in vivo high-resolution magnetic resonance neurography., Methods: In this prospective multicenter study, the lumbosacral dorsal root ganglia and sciatic, tibial, and peroneal nerves were examined in 9 polyneuropathy-negative children diagnosed with neurofibromatosis type 2 by a standardized magnetic resonance neurography protocol at 3T. Volumes of dorsal root ganglia L3 to S2 and peripheral nerve lesions were assessed and compared to those of 29 healthy children. Moreover, dorsal root ganglia volumes and peripheral nerve lesions were compared to those of 14 adults with neurofibromatosis type 2., Results: Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in children with neurofibromatosis type 2 (L3 +255%, L4 +289%, L5 +250%, S1 +257%, and S2 +218%, p < 0.001) with an excellent diagnostic accuracy. Moreover, peripheral nerve lesions occurred with a high frequency in those children compared to healthy controls (18.89 ± 11.11 vs 0.90 ± 1.08, p < 0.001). Children and adults with neurofibromatosis type 2 showed nonsignificant differences in relative dorsal root ganglia hypertrophy rates ( p = 0.85) and peripheral nerve lesions ( p = 0.28)., Conclusions: Alterations of peripheral nerve segments occur early in the course of neurofibromatosis type 2 and are evident even in children not clinically affected by peripheral polyneuropathy. While those early alterations show similar characteristics compared to adults with neurofibromatosis type 2, the findings of this study suggest that secondary processes might be responsible for the development and severity of associated polyneuropathy., (© 2019 American Academy of Neurology.)

Scope: The aim of these guidelines is to provide recommendations for decolonizing regimens targeting multidrug-resistant Gram-negative bacteria (MDR-GNB) carriers in all settings., Methods: These evidence-based guidelines were produced after a systematic review of published studies on decolonization interventions targeting the following MDR-GNB: third-generation cephalosporin-resistant Enterobacteriaceae (3GCephRE), carbapenem-resistant Enterobacteriaceae (CRE), aminoglycoside-resistant Enterobacteriaceae (AGRE), fluoroquinolone-resistant Enterobacteriaceae (FQRE), extremely drug-resistant Pseudomonas aeruginosa (XDRPA), carbapenem-resistant Acinetobacter baumannii (CRAB), cotrimoxazole-resistant Stenotrophomonas maltophilia (CRSM), colistin-resistant Gram-negative organisms (CoRGNB), and pan-drug-resistant Gram-negative organisms (PDRGNB). The recommendations are grouped by MDR-GNB species. Faecal microbiota transplantation has been discussed separately. Four types of outcomes were evaluated for each target MDR-GNB:(a) microbiological outcomes (carriage and eradication rates) at treatment end and at specific post-treatment time-points; (b) clinical outcomes (attributable and all-cause mortality and infection incidence) at the same time-points and length of hospital stay; (c) epidemiological outcomes (acquisition incidence, transmission and outbreaks); and (d) adverse events of decolonization (including resistance development). The level of evidence for and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached through a nominal-group technique for the final list of recommendations., Recommendations: The panel does not recommend routine decolonization of 3GCephRE and CRE carriers. Evidence is currently insufficient to provide recommendations for or against any intervention in patients colonized with AGRE, CoRGNB, CRAB, CRSM, FQRE, PDRGNB and XDRPA. On the basis of the limited evidence of increased risk of CRE infections in immunocompromised carriers, the panel suggests designing high-quality prospective clinical studies to assess the risk of CRE infections in immunocompromised patients. These trials should include monitoring of development of resistance to decolonizing agents during treatment using stool cultures and antimicrobial susceptibility results according to the EUCAST clinical breakpoints., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Contact precautions have been recommended for hospitalized patients colonized or infected with extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC). Despite such recommendations, a steady, worldwide increase of ESBL-EC has been reported. We discuss arguments in favor of and against contact precautions for ESBL-EC carriers. Healthcare settings with high ESBL-EC colonization pressure, extended hospital stay, and close contact between patients may serve as amplification platforms, further accelerating transmission. However, the evidence base for justifying the implementation of contact precautions for all ESBL-EC carriers remains weak. Until more high-level evidence is available, we support the attitude that hospitals and countries should carefully evaluate their decision on whether to implement contact precautions for ESBL-EC carriers. It is likely that a majority of patients and wards do not need to rely on contact precautions for preventing nosocomial ESBL-EC transmission in nonepidemic settings, without harming patient safety, providing sufficient compliance with standard precautions and ongoing surveillance., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH., Methods: We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915., Findings: Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7-197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism)., Interpretation: In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA., Funding: Octapharma., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Hysterectomy is the second most common operation in obstetrics and gynecology after Cesarean section. Until now, there has not been any German clinical guideline with recommendations concerning the indications for hysterectomy for benign uterine conditions, in consideration of the available uterus-preserving alternative treatments., Methods: We systematically searched the Medline database in 2013, in 2014, and in December 2015, focusing on aggregate evidence, and assessed the retrieved literature. The guideline recommendations were developed by a consensus process with structured independent moderation., Results: 30 systematic reviews and 8 randomized controlled trials were analyzed. Among the study patients treated with either hysterectomy (by any technique) or an organ-preserving alternative, at least 75-94% were satisfied with their treatment. Vaginal hysterectomy was associated with lower complication rates, shorter procedure duration, and more rapid recovery than abdominal hysterectomy and is therefore the preferred technique. If vaginal hysterectomy is not possible, a laparoscopic approach should be considered. Abdominal hysterectomy should be reserved for special indications. In 2012, the frequency of abdominal hysterectomy in Germany, Austria, and Switzerland was lower than elsewhere in the world, at 15.7% , 28.0% , and 23.9% , respectively. Uterus-preserving techniques were associated with higher reintervention rates compared to hysterectomy (11-36% vs 4-10% )., Conclusion: The main objective is to reduce the frequency of abdominal hysterectomy. Patients should be counseled and made aware of uterus-sparing alternatives to hysterectomy so that they are able to make informed decisions.

Extremity soft tissue and bone sarcomas represent a rare group of bone and connective tissue cancers. In literature, there is little information about psycho-emotional status and impact on quality of life after the diagnosis and treatment of this kind of tumors. The aim of this survey was to define the profile of the patients at risk and their need for psychooncological care. Our self-created questionnaire consists of 71 items related to the individual emotional, mental and physical situation after the diagnosis of soft tissue and bone sarcoma. Sixty-six patients, surgically treated at our department, were included. Only 37.5% of the patients considered themselves to be completely emotional stable. Psychooncological treatment was accepted mostly by female patients, by patients with higher education level and by married patients. Emotional stability and confidence in future were associated with a strong familiar background, with numerous consultations of psychooncological service and also to gender and physical condition. Current quality of life was strongly correlated to physical condition. Thanks to our questionnaire, we disclosed few risk factors for negative emotional outcome after therapy, such as higher age, social isolation, female gender and poor physical status.

Aim: In locally advanced ovarian cancer with bowel involvement appropriate surgical treatment is still controversial. Objective was to delineate factors to select those most likely to benefit from radical surgery in patients with locally advanced ovarian cancer., Methods: Therefore, we retrospectively evaluated 207 consecutive patients with primary stage IIB-IV ovarian cancer who underwent primary surgery between 2000 and 2007. Every patient received stage-related surgery and adjuvant platinum-based chemotherapy. Median follow-up was 53.5 months. Data collected included stage, histology, extent of cytoreduction and type of bowel resection. Univariate survival analyses were performed to investigate variables associated with outcome., Results: Optimal cytoreduction (OCR) (R ≤ 1 cm) was achieved in 76.8%. Most patients presented histologic grade 2/3 (96.6%), serous ovarian cancers (84.1%) and lymph node involvement (52.2%). Complete cytoreduction (R = 0 mm) has significant best prognostic impact in FIGO IIB-IV (p = .026). Regarding bowel involvement, bowel resection was performed in 82 patients (39.6%). In this subgroup of patients complete cytoreduction led to significant better overall survival than R > 0 mm-1 cm, even in FIGO IIIC-IV patients (p = .027); this fact is independent of bowel resection. Noticeably, for survival bowel resection achieving residual tumor mass below 1 cm was also one main prognostic factor and even recurrence rate was associated with residual tumor mass., Conclusion: Our findings suggest that the major prognostic factor in patients with advanced ovarian cancer needing colorectal resection is completeness of cytoreduction. Therefore, in advanced ovarian cancer patients, multivisceral surgery is indicated to achieve OCR (R ≤ 1 cm) with or without bowel resection with best prognostic impact.

Background: Recently the "Union for International Cancer Control" (UICC) and the "American Joint Committee on Cancer" (AJCC) changed their TNM (tumor, node, metastasis) classification of cutaneous carcinomas., Methods: We compared these classifications, tested their practicability with 615 prospectively collected, unselected, primary cutaneous squamous cell carcinomas, and introduced additional classification criteria., Results: Neither classification contains information about prognosis. Non-metastasizing types of cutaneous carcinoma should be excluded. The vermilion border of the lower lip and the eyelids should be included. Both systems have been improved, but in part they are irreproducible. The AJCC has introduced six "high-risk features" to differentiate between T1 and T2. However, this does not seem reasonable. Only rare cases are classified as T4. Both systems have different N classifications. A clinical cT classification based on tumor size 2 cm seems reasonable but not sufficient. It should be complemented by a postoperative p (pathologic) T classification based on tumor thickness: "no risk"≤ 2 mm thickness (0% risk of metastasis), "low risk" > 2 mm to 6 mm thickness (4% risk of metastasis), and "high risk" > 6 mm thickness (16% risk of metastasis). Immune suppression, poor differentiation/desmoplasia, and the ear as tumor site are additional risk factors for metastasis, currently not evaluable., Conclusions: The classifications are unsuitable for a realistic estimate of the risk of metastasis which is possible using a combination of tumor size and thickness. The N staging system should consider histopathologic findings., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Background: About 30-50 % of rosacea patients have ocular involvement. The symptoms range from a foreign-body sensation to conjunctivitis or blepharitis and may even include severe corneal ulcerations. Systemic treatment is generally with tetracycline. Side effects can occur with the usual antimicrobial dose., Patients and Methods: In a retrospective study, seven patients were evaluated who had been treated for ocular rosacea with a sub-antimicrobial dose of doxycycline 40 mg in a slow-release form (Oraycea). The responses were evaluated on the basis of clinical findings., Results: Seven patients with an average age of 63 took slow release doxycycline 40 mg every day for at least two months. In five patients, other systemic drugs had already failed. All patients experienced a clear improvement in their ocular rosacea after an average of 2.29 months of treatment. One patient had complete clearance and another had almost complete clearance. None of the patients experienced side effects., Conclusions: A sub-antimicrobial dose of slow release doxycycline 40 mg daily is an effective long-term therapy for ocular rosacea. It is not associated with the side effects of long-term antibiotic therapy or the risk of resistance., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

An increasing number of patients with the zoonosis tularemia have been reported in the last few years in Europe. Tularemia can be divided into different forms depending on its appearance. Tularemia must be considered in the differential diagnosis of diseases that present with an ulcer and regional lymphadenopathy. The diagnosis can be confirmed by culturing Francisella tularensis. With effective antibiotic intervention, the prognosis is favorable. Typically tularemia develops after outdoor activities; it is generally transferred by blood-sucking arthropods from infected wild animals to humans., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Background: TNM classifications are the basis for diagnostic and therapeutic procedures in oncology. Histopathological reports have to enable a proper indexing of tumor specific findings into recent classifications., Methods: A systematic review of the literature was performed to identify reports dealing with the assessment of mitotic rate and the processing and evaluation of sentinel node biopsies in malignant melanoma. On the basis of this review an expert panel of dermatopathologists and general pathologists discussed and agreed recommendations for general practice., Results: Following recommendations were agreed with a broad consensus (93-100 % agreement): The determination of the mitotic rate in primary melanoma is performed on HE slides. The evaluation of an area of 1 mm(2) is sufficient. Only dermal mitoses are considered. The counted number of mitoses is provided as an integer value. The mitotic rate shall be determined in primary melanomas of ≤1.00 mm vertical tumor thickness according to the hot-spot method and provided as an integer value in relation to an area of 1 mm(2) . The determination of the mitotic rate in the case of thicker primary melanomas is desirable. In general, for the evaluation of each sentinel lymph node, 4 slides should be prepared. For diagnostic purposes, immunohistochemistry (preferably with antibodies against S100ß, Melan A and HMB-45) should be performed in addition to HE staining. The pathology report should provide information about micro-metastases and their longest extension (one-tenth of a millimeter)., Conclusions: These recommendations are suitable for standardizing the histopathological diagnosis of malignant melanoma and for providing a common basis for clinical decisions and scientific research., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Background: Little is known about the quality of life of patients who are allergic to insect venom. This fact is due to the lack of specific instruments assessing the interaction of type 1 allergy and its psychological burden., Patients and Methods: The only established questionnaire on health-related quality-of-life in patients with wasp venom allergies is the "Vespid Allergy Quality of Life Questionnaire" (VQLQ). This questionnaire was translated from Dutch into German and validated with 79 patients with wasp venom allergy, including the use of the well-established general quality-of-life questionnaire WHOQOL-BREF., Results: In the German version VQLQ-d we could reproduce the validity and reliability of the original Dutch version. Cronbach's alpha of the VQLQ-d was α= 0.95. The results of the VQLQ-d corresponded to the total score of the WHOQOL-BREF., Conclusion: The VQLQ-d enables measurement of quality-of-life in patients with wasp venom allergy in the German-speaking population. This economic tool makes it possible to better describe and treat affected patients. Furthermore, it can be used to advance research in this field., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Background: After coronary artery bypass grafting ischemia/reperfusion injury inducing cardiomyocyte apoptosis may occur. This surgery-related inflammatory reaction appears to be of extreme complexity with regard to its molecular, cellular and tissue mechanisms and many studies have been performed on animal models. However, finding retrieved from animal studies were only partially confirmed in humans. To investigate this phenomenon and to evaluate possible therapies in vitro, adequate human cardiomyocyte models are required. We established a tissue model of human cardiomyocytes preserving the complex tissue environment. To our knowledge human cardiac tissue has not been investigated in an experimental setup mimicking extracorporeal circulation just in accordance to clinical routine, yet., Methods: Cardiac biopsies were retrieved from the right auricle of patients undergoing elective coronary artery bypass grafting before cardiopulmonary bypass. The extracorporeal circulation was simulated by submitting the biopsies to varied conditions simulating cardioplegia (cp) and reperfusion (rep) in a microperfusion chamber. Cp/rep time sets were 20/7, 40/13 and 60/20 min. For analyses of the calcium homoeostasis the fluorescent calcium ion indicator FURA-2 and for apoptosis detection PARP-1 cleavage immunostaining were employed. Further the anti-apoptotic effect of carvedilol [10 microM] was investigated by adding into the perfusate., Results: Viable cardiomyocytes presented an intact calcium homoeostasis under physiologic conditions. Following cardioplegia and reperfusion a time-dependent elevation of cytosolic calcium as a sign of disarrangement of the calcium homoeostasis occurred. PARP-1 cleavage also showed a time-dependence whereas reperfusion had the highest impact on apoptosis. Cardioplegia and carvedilol could reduce apoptosis significantly, lowering it between 60-70% (p < 0.05)., Conclusions: Our human cardiac preparation served as a reliable cellular model tool to study apoptosis in vitro. Decisively cardiac tissue from the right auricle can be easily obtained at nearly every cardiac operation avoiding biopsying of the myocardium or even experiments on animals.The apoptotic damage induced by the ischemia/reperfusion stimulus could be significantly reduced by the cold crystalloid cardioplegia. The additional treatment of cardiomyocytes with a non-selective beta-blocker, carvedilol had even a significantly higher reduction of apoptotis.

Background: Cardiac allograft rejection and vasculopathy are the main factors limiting long-term survival after heart transplantation.In this pilot study we investigated whether non-invasive methods are beneficial to detect cardiac allograft rejection (Grade 03 R) and cardiac allograft vasculopathy. Thus we compared multi-slice computed tomography and magnetic resonance imaging with invasive methods like coronary angiography and left endomyocardial biopsy., Methods: 10 asymptomatic long-term survivors after heart transplantation (8 male, 2 female, mean age 52.1 +/- 12 years, 73 +/- 11 months after transplantation) were included. In a blinded fashion, coronary angiography and multi-slice computed tomography and ventricular endomyocardial biopsy and magnetic resonance imaging were compared against each other., Results: Cardiac allograft vasculopathy and atherosclerosis were correctly detected by multi-slice computed tomography and coronary angiography with positive correlation (r = 1). Late contrast enchancement found by magnetic resonance imaging correlated positively (r = 0.92, r2 = 0.85, p < 0.05) with the histological diagnosis of transplant rejection revealed by myocardial biopsy. None of the examined endomyocardial specimen revealed cardiac allograft rejection greater than Grade 1 R., Conclusion: A combined non-invasive approach using multi-slice computed tomography and magnetic resonance imaging may help to assess cardiac allograft vasculopathy and cardiac allograft rejection after heart transplantation before applying more invasive methods.

FOXP3-expressing naturally occurring CD4(+)CD25(high) T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4(+) T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4(+) T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.

Extracellular ATP liberated during hypoxia and inflammation can either signal directly on purinergic receptors or can activate adenosine receptors following phosphohydrolysis to adenosine. Given the association of polymorphonuclear leukocytes (PMNs) with adenine-nucleotide/nucleoside signaling in the inflammatory milieu, we hypothesized that PMNs are a source of extracellular ATP. Initial studies using high-performance liquid chromatography and luminometric ATP detection assays revealed that PMNs release ATP through activation-dependent pathways. In vitro models of endothelial barrier function and neutrophil/endothelial adhesion indicated that PMN-derived ATP signals through endothelial adenosine receptors, thereby promoting endothelial barrier function and attenuating PMN/endothelial adhesion. Metabolism of extracellular ATP to adenosine required PMNs, and studies addressing these metabolic steps revealed that PMN express surface ecto-apyrase (CD39). In fact, studies with PMNs derived from cd39(-/-) mice showed significantly increased levels of extracellular ATP and lack of ATP dissipation from their supernatants. After excluding lytic ATP release, we used pharmacological strategies to reveal a potential mechanism involved in PMN-dependent ATP release (eg, verapamil, dipyridamole, brefeldin A, 18-alpha-glycyrrhetinic acid, connexin-mimetic peptides). These studies showed that PMN ATP release occurs through connexin 43 (Cx43) hemichannels in a protein/phosphatase-A-dependent manner. Findings in human PMNs were confirmed in PMNs derived from induced Cx43(-/-) mice, whereby activated PMNs release less than 15% of ATP relative to littermate controls, whereas Cx43 heterozygote PMNs were intermediate in their capacity for ATP release (P<0.01). Taken together, our results identify a previously unappreciated role for Cx43 in activated PMN ATP release, therein contributing to the innate metabolic control of the inflammatory milieu.

We present two patients with myelodysplasia in association with Takayasu's arteritis (TA). In both patients intensive immunosuppressive treatment could not control the vascular inflammation. Subsequently both patients developed myelodysplasia, rapidly progressing to secondary acute myelogenous leukaemia. One patient had a peripheral blood stem cell transplant from a compatible sibling donor, but died of refractory leukaemia 5 months later. The other patient died of fungal sepsis. These are the first two patients reported to have TA associated with myelodysplasia/secondary leukaemia.

Objective: To study the relative contribution of antibiotics and bacterial virulence factors in the process of translocation of Enterococcus faecalis from the gut to extraintestinal organs., Design: Prospective controlled animal study., Setting: Animal experimental laboratory at a university medical center., Subjects: Fifty-two female Balb/c mice., Interventions: We developed a mouse model to study the translocation of Enterococcus faecalis from the intestinal tract. Balb/c mice received sterile drinking water or antibiotic combinations to deplete their indigenous intestinal microflora. The animals subsequently were fed genetically engineered enterococci expressing different combinations of the putative enterococcal virulence factors aggregation substance and binding substance. Animals were killed, and their livers, spleens, and mesenteric lymph nodes were aseptically removed and cultured along with fecal samples for enumeration of bacteria., Measurements and Main Results: All animals were colonized with the test strains at 2-6 x 109 colony forming units/g of feces; in the antibiotic-treated animals, feces were free from anaerobes and Enterobacteriaceae. In animals fed the identical bacterial mutant, the colony counts in mesenteric lymph nodes were significantly lower in mice not treated with antibiotics than in those treated with antibiotics (p =.016). Multigroup analysis of variance revealed no significant differences of the translocation frequencies for the different mutant strains; however, the differences were statistically significant for all groups receiving antibiotics vs. the group not receiving antibiotics (p <.05-.01). There was a trend (although not statistically significant) for a higher proportion of positive cultures from either spleen or liver in mice that had enterococci recovered from their mesenteric lymph nodes (28%) relative to those that did not have enterococci isolated from the lymph nodes (12%; rate ratio 2.39, p =.30 by logistic regression analysis)., Conclusions: Oral antibiotics can select for extraintestinal translocation of Enterococcus faecalis, and neither aggregation substance nor binding substance seems to be required for this process. The experiments encourage further exploration of host and microbial factors contributing to translocation and may provide a better understanding of the pathogenesis of enterococcal infections in patients in intensive care units.

Methylmalonic acidemia with associated homocystinuria is a rare inborn error of amino acid metabolism affecting energy supply on the cellular level. Its effects on recovery from surgically induced organ ischemia are largely unknown. We report the successful closure of a nonrestrictive ventricular septal defect by following a normothermic strategy combined with ample metabolic substrate supply.

Delayed sternal closure is an established method to overcome circulatory instability, especially in pediatric cardiac surgery. We describe the management of complications in a seven-year-old boy in whom staged chest closure augmented by sternal stenting was used twice within three weeks, once for right heart and once for left heart failure.

Background: Newborns undergoing cardiac operation may acquire some extent of neuronal damage. An early diagnosis is especially hard regarding neonates. In the past years, S-100 has been widely discussed as a marker revealing perioperative damage to the brain., Methods: Sequential blood samples from 33 neonates undergoing repair of congenital heart disease were taken perioperatively. Samples of 12 healthy neonates were taken at birth as a control group. The newborns were divided into four groups: cyanotic and acyanotic disease operated on in deep hypothermic circulatory arrest, operation without deep hypothermic cardiac arrest, and operation without extracorporeal circulation., Results: Even in healthy neonates, serum S-100 levels were at 10-fold values compared with adults. On admission, S-100 values in the operative groups were similar. During extracorporeal circulation, levels rose to a certain degree. Cyanotic newborns operated on in deep hypothermic cardiac arrest had significantly higher S-100 levels compared with acyanotic newborns also operated on in deep hypothermic cardiac arrest (p < 0.001). Two newborns who experienced seizures postoperatively had the highest absolute S-100 levels. One child with a poor neurologic outcome but no seizures did not have different values when compared with her group., Conclusions: In this study, S-100 seemed to be a possible marker for a certain degree of neurologic deficit after cardiac operation in neonates, especially regarding postoperative seizures. The missing peaks of this protein in one newborn with poor neurologic outcome show that it is not possible to exclude damage to the brain with normal postoperative values. These results suggest that the mechanism of cerebral damage and S-100 release into the blood in neonates with a developing central nervous system and blood-brain barrier is not fully understood.

Intravenously administered ciprofloxacin is partially secreted into the intestinal lumen and thereby eliminates fecal Enterobacteriaceae. Sucralfate inhibits the antimicrobial activity of ciprofloxacin by chelate binding. In a prospective study, we investigated the impact of intravenous ciprofloxacin on the intestinal microflora during oral administration of sucralfate. A total of 45 stool specimens were analyzed in 20 hospitalized patients who were treated with 200 mg of ciprofloxacin i.v. bid. Ten patients concomitantly received 1 g sucralfate p.o. tid (group A). After more than 3 days of i.v. ciprofloxacin, the mean fecal ciprofloxacin concentration was 185.3 +/- 158.7 micrograms/g in patients of group A and 108.7 +/- 76.9 micrograms/g in patients without concurrent sucralfate (group B). There was no significant difference in mean fecal ciprofloxacin levels between both groups (Wilcoxon's test). Enterobacteriaceae were below the threshold of detection (10(2) cfu/g) in all patients of group B after 3 days of treatment whereas small numbers were found in only 2 samples of patients of group A (10(4) cfu/g). Intravenous ciprofloxacin eliminates or largely reduces intestinal Enterobacteriaceae irrespective of concurrent administration of sucralfate.

Native pericardium can be valuable material for the construction of extracardiac vascular connections. To avoid its scarring by adhesions and to preform future vascular connections, ringed polytetrafluoroethylene prostheses were implanted into the pericardial sac during staged operations for univentricular heart disease. At reoperation, extracardiac connections were found to be greatly facilitated by this approach.

Background: In cardiac operations, aprotinin therapy is used either locally as a component of commercially available fibrin tissue adhesives, intravenously, or combined. Our aim was to examine the formation of aprotinin-specific antibodies with regard to the application mode., Methods: Sera of 150 patients who had undergone cardiac operations and were receiving aprotinin therapy for the first time were sampled before the operation and at medians of 3.5 and 13.3 months after the operation. Aprotinin-specific IgG including all subgroups and aprotinin-specific IgE were analyzed. Aprotinin was given locally (as contained in fibrin sealant; n = 45; median dose, 6000 KIU), intravenously (n = 46; 2.000 x 10(6) KIU), and combined (n = 59; 2.012 x 10(6) KIU)., Results: At 3.5 months, the prevalence of aprotinin-specific IgG antibodies was 33% (15/45 patients) after local, 28% (13/46 patients) after intravenous, and 69% (41/59 patients) after combined exposure (P =.0001). At 13.3 months, the prevalence of aprotinin-specific IgG antibodies was 10% (4/41 patients) after local, 31% (13/42 patients) after intravenous, and 49% (28/57 patients) after combined exposure. Total aprotinin dose was similar in patients who were antibody positive and negative. Before the operation, no aprotinin-specific antibodies were detected. Aprotinin-specific IgE were not found after the operation., Conclusion: Local aprotinin contact induces a specific immune response and reinforces that of intravenous exposure. The antibody spectrum is identical to the immune response induced by intravenous exposure. Any exposure should be documented. For use in cardiac operations as a hemostyptic, the necessity itself and alternatives for aprotinin as a stabilizing agent merit consideration.

Ciprofloxacin, when given intravenously (i.v.), is secreted in significant amounts via the mucosa into the intestinal lumen. Sucralfate inhibits the antimicrobial activity of ciprofloxacin. The effect of combined therapy on the intestinal flora was investigated in 16 healthy volunteers. They were randomly assigned to two groups. Group A received 2 g of sucralfate orally three times a day for 7 days and 400 mg of ciprofloxacin i.v. twice a day (b.i.d.) starting 3 days after the sucralfate administration began. Group B was given only 400 mg of ciprofloxacin i.v. b.i.d. for 4 days. A total of 9 stool samples were collected from each subject beginning the week before ciprofloxacin was administered and on days -1, 1, 2, 3, 4, 7, 9, and 10 or 11 after commencement of the infusion period. The aerobic fecal flora was determined by standard microbiological methods. Measurements of fecal ciprofloxacin levels were based on high-performance liquid chromatography. Counts of bacteria of the family Enterobacteriaceae decreased in all subjects and were below 10(2) CFU/g in eight of eight subjects (group A) and six of eight subjects (group B) on day 4, but they returned to normal in all but one subject (group A) 10 days after the last infusion. The decreases in levels of bacteria of the family Enterobacteriaceae were not significantly different in groups A and B (Kaplan-Meier test). Staphylococci and nonfermenters responded variably, enterococci and lactobacilli remained unchanged, and candida levels increased transiently in four subjects (two in each group). Maximum fecal drug levels ranged from 251 to 811 microg/g. No significant difference could be found between the two groups. The i.v. application of ciprofloxacin eliminates intestinal bacteria of the family Enterobacteriaceae in a rapid and selective manner. This effect is not affected by simultaneous oral application of sucralfate.

Objective: One aim of coronary reperfusion after myocardial ischemia is to restore the myocardial content of high energy phosphates. The superiority of the artificial oxygen carrier perfluorocarbon emulsion FC43 over blood solution is known, therefore, in this paper we examined the temperature-dependence of this substance., Method: The changes of the high energy phosphates phosphocreatine (PCr) and inorganic phosphate (Pi) were documented in 29 isolated pig hearts, employing a 4.7 Tesla magnetic-resonance-spectroscope (MRS). After 15 min warm ischemia, reperfusion with warm blood and a cardioplegic ischemia period of 45 min, these hearts were reperfused with either 11 or 25 degrees C hypothermic oxygenated perfluorocarbon emulsion FC43, both under continuous spectroscopy. MRS is able to directly measure PCr as well as Pi. Their relation expresses the state of myocardial energy stores., Results: Reperfusion with 11 degrees C hypothermic FC43 (n = 14) caused an increase of the relation PCr to Pi by a factor of 9, compared to an increase by a factor of 4 with 25 degrees C emulsion (n = 15) (P < 0.05). During 80 min of reperfusion with 11 degrees C cold FC43 emulsion the average flow rate was 90 +/- 12 and 96 +/- 11 ml/min during reperfusion with 25 degrees C hypothermic FC43 emulsion. Both rates fell only slightly in the course of time., Conclusion: We conclude that reperfusion with 11 degrees C hypothermic oxygenated FC43 in isolated ischemic porcine hearts leads to a clear increase of the index PCr/Pi compared with reperfusion at 25 degrees C. The correlation between the synthesis of myocardial high energy phosphates with postcardioplegic ventricular function is questionable. If further studies will show an improvement of myocardial function after perfusion with hypothermic oxygenated perfluorocarbon emulsion FC43, this solution may find clinical application in the storage of explanted human hearts for transplantation, during transportation to the recipient.