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Purpose: To retrain a model based on a previously identified prognostic imaging biomarker using apparent diffusion coefficient (ADC) values from diffusion-weighted magnetic resonance imaging (DW-MRI) in a preclinical setting and validate the model using clinical DW-MRI data of patients with locally advanced head-and-neck cancer (HNC) acquired before radiochemotherapy., Material and Methods: A total of 31 HNC patients underwent T2-weighted and DW-MRI using 3 T MRI before radiochemotherapy (35 x 2 Gy). Gross tumor volumes (GTV) were delineated based on T2-weighted and b500 images. A preclinical model previously revealed that the size of high-risk subvolumes (HRS) defined by a band of ADC-values was correlated to radiation resistance. To validate this model, different bands of ADC-values were tested using two-sided thresholds on the low-ADC histogram flank to determine HRSs inside the GTV and correlated to treatment outcome after three years. The best model was used to fit a logistic regression model. Stratification potential regarding outcome was internally validated using bootstrap, receiver-operator-characteristic (ROC)-analysis, Kaplan-Meier- and Cox-method, and compared to GTV, ADC mean and clinical factors., Results: The best model was defined by 800-6 mm 2 /s and correlated significantly to treatment outcome (p = 0.003). Optimal HRS cut-off value was found to be 5.8 cm 3 according to ROC-analysis. This HRS demonstrated highly significant stratification potential (p < 0.001, bootstrap AUC ≥ 0.84) similar to GTV size (p < 0.001, AUC ≥ 0.79), in contrast to ADC mean (p = 0.361, AUC = 0.53)., Conclusions: A preclinical prognostic model defined by an ADC-based HRS was successfully retrained and validated in HNC patients treated with radiochemotherapy. After thorough external validation, such functional HRS based on a band of ADC values may in the future allow interventional response-adaptive MRI-guided radiotherapy in online and offline approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Neoadjuvant chemoradiotherapy (NCRT) is a standard treatment option for locally advanced rectal cancer. However, there is still conflicting data about the genetic landscape and potential dynamics during and after NCRT. This study evaluated oncogenic driver mutations before NCRT and investigated corresponding resection samples after treatment., Materials and Methods: In 17 patients the pre-therapeutic biopsy and in ten cases the related resection specimen were investigated by next-generation sequencing using a dedicated cancer panel (708 genes). Oncogenic driver mutations and tumor mutational burden (TMB) were compared pre- and post NCRT to evaluate stability of the genomic landscape. TMB and frequently detected driver mutations were correlated with outcome parameters., Results: In our corresponding tumor samples before and after NCRT 95.2 % of the oncogenic driver mutations could be found in both specimens whereas one ATM and one RYR1 mutation were not detectable after NCRT. TMB decreased in all patients after neoadjuvant treatment. KRAS  ±  TP53 mutations and TMB ≥ 5 were associated with impaired outcome., Conclusion: Most oncogenic driver mutations investigated persisted after neoadjuvant treatment. At the same time, we did not observe ascending TMB after treatment but decline. Thus, NCRT does not seem to induce a relevant number of new driver mutations or mutational burden. Genetic profiling implies the potential to support tumor-informed approaches and outcome estimation in future., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KC, CG and MN report institutional collaborations including financial and non-financial support by Elekta, Philips, Siemens, Dr. Sennewald, PTW Freiburg, Kaiku and Therapanacea. CS reports institutional grants from Novartis and Illumina as well as research grants from BMS Stiftung Immunonkologie outside the submitted work., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: In locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification., Methods: In 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters., Results: Most patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5., Conclusions: Weekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found., (© 2024. The Author(s).)

Background: Target volume definition for curative radiochemotherapy in head and neck cancer is crucial since the predominant recurrence pattern is local. Additional diagnostic imaging like MRI is increasingly used, yet it is usually hampered by different patient positioning compared to radiotherapy. In this study, we investigated the impact of diagnostic MRI in treatment position for target volume delineation., Methods: We prospectively analyzed patients who were suitable and agreed to undergo an MRI in treatment position with immobilization devices prior to radiotherapy planning from 2017 to 2019. Target volume delineation for the primary tumor was first performed using all available information except for the MRI and subsequently with additional consideration of the co-registered MRI. The derived volumes were compared by subjective visual judgment and by quantitative mathematical methods., Results: Sixteen patients were included and underwent the planning CT, MRI and subsequent definitive radiochemotherapy. In 69% of the patients, there were visually relevant changes to the gross tumor volume (GTV) by use of the MRI. In 44%, the GTV&#95;MRI would not have been covered completely by the planning target volume (PTV) of the CT-only contour. Yet, median Hausdorff und DSI values did not reflect these differences. The 3-year local control rate was 94%., Conclusions: Adding a diagnostic MRI in RT treatment position is feasible and results in relevant changes in target volumes in the majority of patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Biomarkers are of major interest to optimize diagnosis, prognosis and to guide treatment in head and neck cancer patients. Especially blood-based biomarkers appear promising as they can be easily collected and repeatedly analyzed during the course of radiochemotherapy., Patients and Methods: At first, for a broad overview, multiple immune markers were evaluated in six plasma samples of three head and neck squamous cell carcinoma (HNSCC) patients at the beginning and the end of radio-chemotherapy. In this pre-selection, the soluble Intercellular Adhesion Molecule 1 (sICAM-1) appeared most promising. Thus, this marker was measured in multiple samples (n = 86) during treatment and follow-up in a cohort of eleven patients and correlated with tumor features and clinical data., Results: We found a strong correlation between the initial levels of sICAM-1 in the plasma and the gross tumor volumes of the primary tumor and the involved lymph nodes. However, during the course of treatment no systematic dynamics could be identified. Toxicity or infections did not seem to influence sICAM-1 concentrations., Conclusions: sICAM-1 appears to reflect the pre-treatment total tumor burden (primary tumor and involved lymph nodes) in head and neck tumor patients. However, it does not seem to be a dynamic marker reflecting response during radiochemotherapy. Thus, if our findings are confirmed in future, sICAM-1 could be used as a staging marker: if high sICAM-1 levels but low tumor burden are found it might be reasonable to intensify staging investigations to rule out further, yet undetected, tumor sites., (© 2022 Kerstin Clasen, Stefan Welz, Heidrun Faltin, Daniel Zips, Franziska Eckert, published by Sciendo.)

Purpose: Willingness-to-pay (WTP) analyses can support allocation processes considering the patients preferences in personalized medicine. However, genetic testing especially might imply ethical concerns that have to be considered. Methods: A WTP questionnaire was designed to compare preferences for imaging and genetic testing in cancer patients and to evaluate potential ethical concerns. Results: Comparing the options of imaging and genetics showed comparable WTP values. Ethical concerns about genetic testing seemed to be minor. Treatment success was the top priority irrespective of the diagnostic modality. In general, the majority of patients considered personalized medicine to be beneficial. Conclusion: Most patients valued personalized approaches and rated the benefits of precision medicine of overriding importance irrespective of modality or ethical concerns.

Purpose: High Mobility Group Box 1 (HMGB1) protein has been described as a consensus marker for immunogenic cell death (ICD) in cancer. To personalize treatments, there is a need for biomarkers to adapt dose prescription, concomitant chemotherapy, and follow-up in radiation oncology. Thus, we investigated the levels of HMGB1 in plasma of patients with head and neck squamous cell carcinoma (HNSCC) during the course of radiochemotherapy and follow-up in correlation with oncologic outcome and clinical confounders., Methods: In our pilot study, 11 patients with advanced HNSCC were treated with definitive radiochemotherapy. Blood samples were taken weekly during treatment and frequently at follow-up visits. HMGB1 levels as well as routine laboratory values were measured and clinical information was collected including tumor volume, infections, toxicity, and follow-up data., Results: In total, 85 samples were analyzed. In eight patients, HMGB1 levels (baseline vs. last available sample during treatment) were increasing and in three patients HMGB1 values were decreasing toward the end of treatment. All three patients with decreasing values developed tumor recurrence. By contrast, no relapse occurred in patients that showed increasing HMGB1 levels during therapy. Moreover, a positive correlation of HMGB1 levels with tumor volumes, C‑reactive protein (CRP) levels, infections, and grade three toxicity (RTOG) was observed., Conclusion: HMGB1 might be a promising marker to monitor ICD in HNSCC during the course of radiochemotherapy. However, HMGB1 seems to reflect complex and diverse immunogenic responses and potential confounders. Infections and treatment-associated toxicity should be considered when interpreting the dynamics of HMGB1., (© 2021. The Author(s).)

Background and Aims: The 13 C-methacetin breath test (MBT) is a noninvasive, quantitative hepatic metabolic function test. The aim of this prospective, multicenter study was to determine the utility of initial and serial 13 C-MBT in predicting 21-day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI)., Approach and Results: The 13 C-MBT BreathID device (Exalenz Biosciences, Ltd.) provided the percent dose recovery (PDR) for a duration of 60 minutes after administration of 13 C-methacetin solution as the change in exhaled 13 CO 2 / 12 CO 2 compared with pre-ingestion ratio on study days 1, 2, 3, 5, and 7. Results were correlated with 21-day transplant-free survival and other prognostic indices. A total of 280 subjects were screened for enrollment between May 2016 and August 2019. Median age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian, 76% had ALF with the remaining 24% having ALI. The mean PDR peak on day 1 or day 2 was significantly lower in nonsurvivors compared with transplant-free survivors (2.3%/hour vs. 9.1%/hour; P < 0.0001). In addition, serial PDR peaks were consistently lower in nonsurvivors versus survivors (P < 0.0001). The area under the receiver operating characteristic curve (AUROC) of the 13 C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King's College (AUROC = 0.70) and Model for End-Stage Liver Disease scores (AUROC = 0.83). The 13 C-MBT was well tolerated with only two gastrointestinal adverse events reported., Conclusions: The 13 C-MBT is a promising tool to estimate the likelihood of hepatic recovery in patients with ALF and ALI. Use of the PDR peak data from the 13 C-MBT point-of-care test may assist with medical decision making and help avoid unnecessary transplantation in critically ill patients with ALF and ALI., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival., Approach and Results: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 10 9 /L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P < 0.001], assembly [P = 0.02], firmness at 10 minutes [P = 0.05], and maximal firmness [P = 0.06]). Patients with more severe systemic complications (high-grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver., Conclusions: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study., (© 2021 by the American Association for the Study of Liver Diseases.)

Background: Atypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated., Methods: The clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions., Results: Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth., Conclusions: The model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients' stratification for dose escalation.

Purpose: Does IDEF mapping help monitor the technical process of IUI and explore the potential improvements which might contribute to increased pregnancy and live birth rates?, Method: Retrospective analysis of 1729 homologous IUI cycles of couples attending a fertility clinic in a university hospital setting. Standardized conventional semen parameters were analyzed and the semen samples prepared via discontinuous density gradient centrifugation., Results: There was no significant association between sperm concentration, motility and morphology (analysis phase), and pregnancy outcome. Only female and male ages were significantly associated with the pregnancy outcome. There was a significant difference in the odds on clinical pregnancies and live births when analysis was ≤ 21 min initiated, and < 107 min between sample production and IUI, adjusted for male and female age., Conclusions: Adjusting for the couple's age, we could show that time intervals between semen production and analysis and IUI when kept low significantly influenced clinical pregnancies and live births.

Purpose: Definitive radiochemotherapy (RCTX) with curative intent is one of the standard treatment options in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Despite this intensive therapy protocol, disease recurrence remains an issue. Therefore, we tested the predictive capacity of liquid biopsies as a novel biomarker during RCTX in patients with HNSCC., Material and Methods: We sequenced the tumour samples of 20 patients with locally advanced HNSCC to identify driver mutations. Subsequently, we performed a longitudinal analysis of circulating tumour DNA (ctDNA) dynamics during RCTX. Deep sequencing and UMI-based error suppression for the identification of driver mutations and HPV levels in the plasma enabled treatment-response monitoring prior, during and after RCTX., Results: In 85% of all patients ctDNA was detectable, showing a significant correlation with the gross tumour volume (p-value 0.032). Additionally, the tumour allele fraction in the plasma was negatively correlated with the course of treatment (p-value <0.05). If ctDNA was detectable at the first follow-up, disease recurrence was seen later on. Circulating HPV DNA (cvDNA) could be detected in three patients at high levels, showing a similar dynamic behaviour to the ctDNA throughout treatment, and disappeared after treatment., Conclusions: Monitoring RCTX treatment-response using liquid biopsy in patients with locally advanced HNSCC is feasible. CtDNA can be seen as a surrogate marker of disease burden, tightly correlating with the gross tumour volume prior to the treatment start. The observed kinetic of ctDNA and cvDNA showed a negative correlation with time and treatment dosage in most patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The relation between functional imaging and intrapatient genetic heterogeneity remains poorly understood. The aim of our study was to investigate spatial sampling and functional imaging by FDG-PET/MRI to describe intrapatient tumour heterogeneity., Methods: Six patients with oropharyngeal cancer were included in this pilot study. Two tumour samples per patient were taken and sequenced by next-generation sequencing covering 327 genes relevant in head and neck cancer. Corresponding regions were delineated on pretherapeutic FDG-PET/MRI images to extract apparent diffusion coefficients and standardized uptake values., Results: Samples were collected within the primary tumour (n = 3), within the primary tumour and the involved lymph node (n = 2) as well as within two independent primary tumours (n = 1). Genetic heterogeneity of the primary tumours was limited and most driver gene mutations were found ubiquitously. Slightly increasing heterogeneity was found between primary tumours and lymph node metastases. One private predicted driver mutation within a primary tumour and one in a lymph node were found. However, the two independent primary tumours did not show any shared mutations in spite of a clinically suspected field cancerosis. No conclusive correlation between genetic heterogeneity and heterogeneity of PET/MRI-derived parameters was observed., Conclusion: Our limited data suggest that single sampling might be sufficient in some patients with oropharyngeal cancer. However, few driver mutations might be missed and, if feasible, spatial sampling should be considered. In two independent primary tumours, both lesions should be sequenced. Our data with a limited number of patients do not support the concept that multiparametric PET/MRI features are useful to guide biopsies for genetic tumour characterization.

Background: As optic nerve sheath meningiomas (ONSM) are rare, there are no prospective studies. Our retrospective analysis focusses on a cohort of patients with uniform disease characteristics all treated with the same radiotherapy regimen. We describe treatment decision making, radiotherapy planning and detailed neuro-ophthalmological outcome of the patients., Methods: 26 patients with unilateral ONSM extending only to the orbit and the optic canal were evaluated for neuro-ophthalmological outcome. Radiation treatment was planned in a simultaneous integrated boost approach to gross tumor volume (GTV) + 2 mm / 5 mm to 54 Gy / 51 Gy in 1.8 Gy / 1.7 Gy fractions. Follow-up was done by specialized neuro-ophthalmologists. Visual acuity and visual field defects were evaluated after therapy as well as during follow-up., Results: Interdisciplinary treatment decision for patients with ONSM follows a rather complex decision tree. Radiation treatment planning (equivalent uniform dose (EUD), maximum dose to the optic nerve) improved with experience over time. With this patient selection visual acuity as well as visual field improved significantly at first follow-up after treatment. For visual acuity this also applied to patients with severe defects before treatment. Long term evaluation showed 16 patients with improved visual function, 6 were stable, in 4 patients visual function declined. Interdisciplinary case discussion rated the visual decline as radiation-associated in two patients., Conclusions: With stringent patient selection radiotherapy for unilateral primary ONSM to 51 Gy / 54 Gy is safe and leads to significantly improved visual function. Interdisciplinary treatment decision and experience of the radiation oncology team play a major role.

Background: Sperm DNA fragmentation measured by different techniques make comparisons impossible due to lack of standardization. Induction of DNA damage after sperm preparation in the entire fraction has been observed on independent occasions but findings are not consistent., Methods: Men presenting at a University hospital setup for infertility treatment. DNA damage via TUNEL assay was validated on fresh semen samples, as conventional semen parameters, to reduce variability of results., Results: Sperm motility in neat semen inversely correlated with sperm DNA fragmentation in the total fraction, but, total count, leukocytes and immature germ cells significantly affected the vital fraction. Sperm DNA fragmentation was observed both in normal and subnormal semen samples, but was significantly different in the total fraction of astheno-, asthenoterato- and oligoteratozoospermic men. After density gradient centrifugation, sperm DNA fragmentation increased significantly in the total but decreased in the vital fraction. Advancing male age significantly influenced damage in the total but not in the vital population., Conclusions: These findings provide opportunities to investigate the significance of the total and the vital fractions both in natural conception and after different assisted reproductive technologies., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Effects of playing high stringed bow instruments on the upper body posture have not been analysed so far. The instrument-specific seating position when playing in an orchestra is compared to the habitual seating position., Methods: Three dimensional back scans were performed in 13 professional violinists and viola players of a radio orchestra (8 f / 5 m). Trunk position in their habitual seating position and in the instrument- specific seating position imitating playing was compared. Statistical differences were calculated using Wilcoxon Matched Pairs Test with Bonferroni Holm correction., Results: Significant differences were found between the seated position with instrument and without ( p  < 0.001, 0.03, 0.02 or 0.01) in the spine (trunk length, sagittal trunk decline, lumbar bending angle, maximal rotation, standard deviation rotation, lumbar lordosis), the shoulder (scapula distance, scapula rotation, scapula angle right) and pelvis distance., Conclusions: Playing an instrument changes the static seating position by increased rotation of the spine and specific shoulder adaptations holding the instrument (left arm) and the bow (right arm), with minor effects on the pelvis. This forced position may result in chronic health effects. The method used in this study is an approach to better understand the involved muscular structures and possible resulting health damages., Competing Interests: This study was approved by the ethics board for research involving human subjects of the Goethe University (305/12) in Frankfurt am Main, Germany. All participants will sign an informed consent to take part in the study in advance.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] μg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting., Conclusion: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013)., (© 2017 by the American Association for the Study of Liver Diseases.)

History and Clinical Findings: A 77-year-old man presented with acute pain and femoral swelling in his right groin., Examinations: The clinical finding resulted in the suspicion of an irreducible, possibly incarcerated inguinal hernia. Transcutaneous ultrasound did not reveal any hints confirming the clinical suspicion. Because of the impressive clinically finding, the patient was subjected to open exploration of the groin., Treatment and Course: Intraoperatively, the initial clinical finding could be confirmed. Herniotomia showed incarcerated ileal segment with Meckel's diverticle, a so-called Littré's hernia. Subsequently, median laparotomy and ileum segment resection with side-to-side ileoileostomy were performed. The postoperative course was uneventful. The patient was discharged in good health status on the seventh postoperative day., Conclusion: Littré's hernia is a rare pathological finding, which can also be considered as an infrequent manifestation of a variant of a commonly encountered clinical/surgical finding such as hernia. The presented case elucidates the difficulty in the timely establishment of the correct preoperative diagnosis. The clinician needs to be aware of this albeit exceptionally rare variation because the symptoms can vary greatly and severe complications can occur. This threat must be encountered via rapid diagnosis-finding and initiation of appropriate therapy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: For the acquisition of practical skills, the separate learning atmosphere of a skills lab(oratory) is very suitable. Numerous educational objectives of surgical teaching can be pursued using phantoms, manikins or mutual training among students prior to real practical use during clinical traineeships or internships., Aim and Method: This article provides a compact, systematic overview of the skills lab concept, based on published aspects in selected and relatively recent topic-related references from PubMed® including our own approaches, as well as comments and experiences with regard to its further development. In particular, the Magdeburg concept to use the local skills lab MAMBA for surgical teaching within the practical training is demonstrated, which has developed step by step from a basically pure bedside teaching and which includes student tutors in practical teaching in surgery., Results: By founding the Magdeburg educational and training center options for a practical education, in particular, in surgery were created. The great majority of students accepted the conceptual idea and it has so far been well received. As a first step several well selected topics of practical training during human medical studies were increasingly taught by students who received a didactic course of instruction which also included aspects of the educational objectives. For the future tutorials led by students are planned going beyond the teaching contents of the practical courses and can, thus, lead to a networking with educational objectives of other disciplines. There are not only curricular but also facultative courses in MAMBA which have been steadily optimized since the beginning. This Magdeburg's concept is planned to be further developed for which there is enough room for development with regard to organizational aspects (personnel and room).

This study was designed to find out the incidence of ovarian torsion in the patients who were in ovulation induction treatment for either In vitro fertilization (IVF) or Intracytoplasmic sperm injection (ICSI). Also operative laparoscopic conservative treatment (detorsion or unwinding the twisted adnex) was tried to perform to all the patients. Among 10,583 cycles 9 ovarian torsion cases had been diagnosed laparoscopically between January 1994 and October 1998. 104 ovarian hyperstimulation syndrome (OHSS) patients were evaluated during that time. From 104 hyperstimulated cases three had torsion of the adnex and two of them were pregnant. Five of the patients were clinically and one was chemically pregnant. First, laparoscopy was done to all the patients and 8 of them could be detorsioned, in one case unwinding performed by laparotomy because of the large size of the ovary. No complications were observed after conservative surgery. These results demonstrate that, in the IVF or ICSI clinics ovarian torsion has to be regarded as one of the major complications especially if the patients are hyperstimulated or pregnant or both. Immediate manipulation is needed conservatively, preserving the ovaries which were very important for those infertile patients.

An auto-controlled study was conducted in couples with tubal infertility and normozoospermic semen. The fertilization rates and embryonic development in sibling oocytes treated, using the same semen sample, either by conventional in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) at the same time were compared. Sibling oocyte-cumulus complexes (OCC) of 56 different couples with tubal infertility and normozoospermic semen were randomly divided in order of retrieval into two groups inseminated either by conventional IVF or by ICSI. Of the retrieved OCC in the same cohort, 53.0 +/- 31.2 and 62.0 +/- 26.6% showed two distinct pronuclei after conventional IVF and ICSI respectively (not significant). Complete fertilization failure occurred after conventional IVF in 12.5% (7/56 couples). After ICSI, the comparable figure was 3.6% (2/56). The number of cases was too small to apply a statistical test to this difference. Total cleavage rates were quite similar: 86.7 +/- 28.0 and 90.1 +/- 21% of the zygotes developed into transferable embryos after IVF and ICSI respectively (not significant). Similarly, no difference in embryo quality was observed. Although injection and insemination of the oocytes were performed at the same time in the two groups, at 42 h post-insemination more embryos were at the four-cell stage after ICSI (P < 0.001) than after conventional IVF, where more embryos were still at the two-cell stage (P < 0.02). Embryo transfer was possible in all 56 couples, resulting in 16 positive serum human chorionic gonadotrophin tests (28.6% per embryo transfer), from which a clinical pregnancy resulted in 15 couples. The best embryos were selected for transfer independently of the insemination procedure, but preferably from the same origin. There appeared to be no difference in implantation potency of the embryos obtained with either technique after the non-randomized transfers.

Fifty-seven patients who underwent hysteroscopic septum resection between January 1991 and December 1996 were studied; nine patients presented with recurrent abortions, 46 with infertility (26 primary and 20 secondary), one with dysmenorrhoea and one with an asymptomatic complete septum. Their reproductive history included 78 pregnancies: 69 (88.4%) abortions, two (2.6%) ectopics, two (2.6%) preterm deliveries and five (6.4%) term deliveries. In patients with infertility, the incidence of unexplained infertility was 19.6% and the incidence of endometriosis was 26.1%. After hysteroscopic septum resection, 42 patients were interested in pregnancy. All patients with recurrent abortions conceived spontaneously. Twenty-one (63.6%) infertile patients achieved a pregnancy, 13 (61.9%) of them after treatment with various assisted reproduction techniques. The reproductive outcome after septum resection yielded 44 pregnancies, including three sets of twins and one set of triplets reduced to twins: 11 (25%) abortions, one (2.3%) ectopic pregnancy, two (4.5%) preterm deliveries (both twins), 28 (63.7%) term deliveries and two (4.5%) as-yet ongoing pregnancies. It seems that the hysteroscopic treatment of uterine septum has a beneficial effect on pregnancy outcome. A septate uterus does not seem to be an infertility factor. The achievement of pregnancy is normal in patients with recurrent abortions, while the chances of conception in patients with infertility seem to be similar to those for the general infertile population.

This retrospective controlled study aimed at comparing two techniques for recovering testicular spermatozoa in azoospermic patients undergoing intracytoplasmic sperm injection (ICSI). 102 men suffering from infertility because of obstructive azoospermia had ICSI using testicular spermatozoa recovered either by open excisional biopsy (n = 51), or by fine needle aspiration (FNA) (n = 51). A higher average number of spermatozoa were recovered after open biopsy than after FNA, but no significant differences in either fertilization rates or cleavage rates were observed after ICSI with spermatozoa retrieved by the two techniques. Neither was there any significant difference in ongoing pregnancy and implantation rates: in the FNA group, these figures were respectively 19.6% per cycle and 7.8% per embryo transferred and in the open biopsy group 21.6 and 7.1%. We conclude that ICSI with testicular spermatozoa recovered by FNA yields results comparable to those obtained with spermatozoa recovered by open biopsy in azoospermic patients with normal spermatogenesis. However a prospective study is needed to confirm the present results and to assess recovery rates and patient comfort for the two methods.

To assess the efficiency of transvaginal ultrasonography (TVUS) in the screening of pelvic pathologies in the initial workup of infertile women, we carried out a prospective comparison of sonographic diagnosis with laparoscopic and pathological findings. Between February 1994 and April 1995, 133 premenopausal non-pregnant women underwent TVUS on the day before laparoscopy. The efficiency of TVUS in detecting pelvic pathologies was 90.2% with a sensitivity of 86.2%, a specificity of 97.8% and positive and negative predictive values of 98.6 and 78.8% respectively. If the six false-negative cases with a histological diagnosis of minimal endometriosis were defined as 'normal pelvis', sensitivity and specificity could be corrected to 92.5 and 98.6% respectively. Endometriomas were diagnosed by TVUS with an efficiency of 96.4%, with a sensitivity and a specificity of 90 and 96.7 % and with positive and negative predictive values of 75 and 99.1% respectively. The sensitivity of vaginal sonographic characterization of pelvic adhesions was 61.1% with a specificity and positive predictive value of 98.2 and 84.6%. The negative predictive value of TVUS was 94.1%. These data suggest that it is not possible to characterize pelvic adhesions, especially filmy adhesions, with acceptable accuracy. However, in the initial workup of infertile women, if the patient is young, if both hysterosalpingography and TVUS are negative, laparoscopy could be postponed. In couples with severe male factor infertility and for whom in-vitro fertilization or intracytoplasmic sperm injection is the treatment of choice, laparoscopy might be avoided where the TVUS is negative.

From March 1989 to December 1995, 194 cases of ectopic pregnancy were diagnosed in our centre and treated following a strict laparoscopic protocol. A total of 193 cases was treated surgically and only one case was treated medically, because general anaesthesia was contraindicated. Altogether, eight laparotomies (4.1%) had to be performed; three primary and five secondary, due to uncontrollable haemorrhage (n = 3) and too large pregnancy size (n = 2). Peri- or postoperative complications were encountered in 24 cases (12.4%). Residual disease occurred in 14 cases (7.2%), all after a technically successful operative laparoscopic procedure. These cases received adjuvant therapy, either systemic administration of methotrexate or a second intervention. The overall laparoscopic cure rate was 88.1% (171/194). Conclusive follow-up data could be obtained concerning 110 cases with an active desire for pregnancy. Overall conception rate was 77.3%, with an ongoing pregnancy rate of 81.2% and a recurrency rate of 10.6%. A critical overview of the available data on non-surgical approaches is made, while the reported results are evaluated according to published data. It is concluded that at this stage a surgical approach by means of operative laparoscopy should remain the gold standard in treating ectopic pregnancies.

The rationale and results of using epididymal and testicular spermatozoa with intracytoplasmic sperm injection (ICSI) for zoospermic patients are reviewed. A total of 128 consecutive ICSI/MESA cycles and a total of 120 consecutive ICSI/TESE cycles were performed up to December 1994. The two-pronuclei fertilization rate per intact oocyte (observed after the injection) was 58% and 60%, respectively, when epididymal and testicular spermatozoa were used. The embryo transfer rate was similar for the two procedures (91% after ICSI/MESA and 90% after ICSI/TESE). Fifty women became pregnant (positive HCG) when epididymal spermatozoa were used (39% per cycle and 40% per embryo transfer). These results are comparable to those obtained when ejaculated spermatozoa are used.

Objective: Does a warm tub bath relieve labor pain? How is it experienced by the parturient?, Design: prospective randomised trial., Setting: labor ward of a teaching hospital with a uniform active labor management., Participants: one hundred and ten nulliparous low risk women, at term, in true spontaneous labor. Fifty-four women had a bath, 56 women served as controls., Mean Outcome Measures: labor pain (assessed by means of a visual analogue scale) and post partum patients' bathing experience (by means of a self-made questionnaire)., Results: The study group and the control group were comparable with respect to maternal age, weight, length, duration of gestation, cervical status and labor pain sensation before randomisation. Absolute values of labor pain were not statistically different between the two groups, yet this latter progressed differently: in the bathing group the initial pain sensation (V.A.S.) was 6.8, and this remained stable during the first 25 minutes (V.A.S. = 6.7) and then rose to 8.2 after a mean of 53 minutes. In the control group, labor pain rose progressively from 6.3 to 7.3 after 25 min and to 8.7 after a mean of 52 min (p < 0.01, Student t-test). There was no difference in the use of epidural analgesia. There were no differences in labor duration nor in the frequencies of either operative deliveries or neonatal complications. Eighty percent of the bathers experienced soothing of the pain and all but one reported body relaxation. Ninety percent wanted to bathe again during a next labor., Conclusion: Bathing provided no objective pain relief. It had, however, a temporal pain stabilizing effect possibly mediated through the improved ability to relax in between contractions. No side effects were found. It gives great satisfaction to users. Bathing, in conjunction with other forms of analgesia, is recommended.

The oxidation of sparteine and mephenytoin was examined in a group of subjects living in Greenland: 300 in East Greenland and 171 in West Greenland. The distribution of the ratio between the chromatographic peak areas of S- and R-mephenytoin in the urine, the S/R ratio was clearly bimodal in both populations. Thus 9.3% of the East Greenlanders had S/R ratios of 0.9 or more and were phenotyped as poor metabolizers of mephenytoin. In the West Greenlanders, 2.9% of the sample had S/R ratios of 0.90 or more and were accordingly phenotyped as poor metabolizers. The intraethnic difference with regard to the frequency of the mephenytoin poor metabolizer is probably attributable in part to a much higher proportion of admixed Caucasian genes in the West Greenlanders than in the East Greenlanders. In both the East and the West Greenlanders, the sparteine metabolic ratio displayed marked interindividual differences without a clear bimodal distribution. Poor metabolizers arbitrarily defined as subjects with an metabolic ratio of 20 or more made up 3.3% of the East Greenlanders and 2.3% of the West Greenlanders, but the difference between the two groups was not statistically significant.