PerBrain: a multimodal approach to personalized tracking of evolving state-of-consciousness in brain-injured patients: protocol of an international, multicentric, observational study.

BACKGROUND: Disorders of consciousness (DoC) are severe neurological conditions in which consciousness is impaired to various degrees. They are caused by injury or malfunction of neural systems regulating arousal and awareness. Over the last decades, major efforts in improving and individualizing diagnostic and prognostic accuracy for patients affected by DoC have been made, mainly focusing on introducing multimodal assessments to complement behavioral examination. The present EU-funded multicentric research project "PerBrain" is aimed at developing an individualized diagnostic hierarchical pathway guided by both behavior and multimodal neurodiagnostics for DoC patients. METHODS: In this project, each enrolled patient undergoes repetitive behavioral, clinical, and neurodiagnostic assessments according to a patient-tailored multi-layer workflow. Multimodal diagnostic acquisitions using state-of-the-art techniques at different stages of the patients' clinical evolution are performed. The techniques applied comprise well-established behavioral scales, innovative neurophysiological techniques (such as quantitative electroencephalography and transcranial magnetic stimulation combined with electroencephalography), structural and resting-state functional magnetic resonance imaging, and measurements of physiological activity (i.e. nasal airflow respiration). In addition, the well-being and treatment decision attitudes of patients' informal caregivers (primarily family members) are investigated. Patient and caregiver assessments are performed at multiple time points within one year after acquired brain injury, starting at the acute disease phase. DISCUSSION: Accurate classification and outcome prediction of DoC are of crucial importance for affected patients as well as their caregivers, as individual rehabilitation strategies and treatment decisions are critically dependent on the latter. The PerBrain project aims at optimizing individual DoC diagnosis and accuracy of outcome prediction by integrating data from the suggested multimodal examination methods into a personalized hierarchical diagnosis and prognosis procedure. Using the parallel tracking of both patients' neurological status and their caregivers' mental situation, well-being, and treatment decision attitudes from the acute to the chronic phase of the disease and across different countries, this project aims at significantly contributing to the current clinical routine of DoC patients and their family members. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04798456 . Registered 15 March 2021 - Retrospectively registered.

Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.

STUDY QUESTION: What is the success rate in terms of ovarian activity (menstrual cycles) as well as pregnancy and delivery rates 1 year after orthotopic ovarian transplantations conducted in a three-country network? SUMMARY ANSWER: In 49 women with a follow-up >1 year after transplantation, the ovaries were active in 67% of cases and the pregnancy and delivery rates were 33 and 25%, respectively. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. However, published case series have not allowed either a more detailed analysis of patients with premature ovarian insufficiency (POI) or calculation of success rates based on the parameter 'tissue activity'. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of 95 orthotopic transplantations in 74 patients who had been treated for cancer, performed in the FertiPROTEKT network from 2008 to June 2015. Of those 95 transplantations, a first subgroup (Subgroup 1) was defined for further analysis, including 49 women with a follow-up period >1 year after transplantation. Of those 49 women, a second subgroup (Subgroup 5) was further analysed, including 40 women who were transplanted for the first time and who were diagnosed with POI before transplantation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Transplantation was performed in 16 centres and data were transferred to the FertiPROTEKT registry. The transplantations were carried out after oncological treatment had been completed and after a remission period of at least 2 years. Tissue was transplanted orthotopically, either into or onto the residual ovaries or into a pelvic peritoneal pocket. The success rates were defined as tissue activity (menstrual cycles) after 1 year (primary outcome) and as pregnancies and deliveries achieved. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of all transplanted 74 women was 31 ± 5.9 years at the time of cryopreservation and 35 ± 5.2 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded. In Subgroup 1, tissue was cryopreserved at the age of 30 ± 5.6 and transplanted at 34 ± 4.9 years. Ovaries remained active 1 year after transplantation in 67% of cases (n = 33/49), the pregnancy rate was 33% (n = 16/49) and the delivery rate was 25% (n = 12/49). In Subgroup 5, tissue was cryopreserved at the age 30 ± 5.9 years and transplanted at 34 ± 5.2 years. Ovaries remained active 1 year after transplantation in 63% of cases (n = 25/40), the pregnancy rate was 28% (n = 11/40) and the delivery rate was 23% (n = 9/40). The success rates were age dependant with higher success in women who cryopreserved at a younger age. In Subgroup 5, tissue was exclusively transplanted into the ovary in 10% (n = 4/40) of women and into a peritoneal pocket in 75% (n = 30/40), resulting in spontaneous conceptions in 91% of patients (n = 10/11). LIMITATIONS, REASONS FOR CAUTION: The data were drawn from a retrospective analysis. The cryopreservation and transplantation techniques used have changed during the study period. The tissue was stored in many tissue banks and many surgeons were involved, leading to heterogeneity of the procedures. However, this does reflect the realistic situation in many countries. Although patients with POI were evaluated before transplantation to allow specific analysis of the transplanted tissue itself, the possibility cannot be excluded that residual ovarian tissue was also reactivated. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest case series worldwide to date and it confirms that cryopreservation and transplantation of ovarian tissue can be a successful option for preserving fertility. Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomized study is required. STUDY FUNDING/COMPETING INTEREST: This study was in part funded from the Deutsche Forschungsgemeinschaft (# DI 1525) and the Wilhelm Sander Foundation (2012.127.1) and did not receive any funding from a commercial company. No competing interests. TRIAL REGISTRATION NUMBER: None.

[Torsion of a pedunculated subserous myoma - a rare differential diagnosis of the acute abdomen]. / Torsion eines gestielten subserösen Myoms - eine seltene Differentialdiagnose des akuten Abdomens.

We report about a rare case of acute abdomen in a 43 years old female patient who noticed a sudden onset of severe lower abdominal pain, increasing in strength within a few hours. The transabdominal and transvaginal ultrasound showed an enlarged leiomyomatous uterus with a questionable torsion of a pedunculated subserous leiomyoma. The following magnetic resonance imaging confirms this diagnosis. During the laparoscopy a myomectomy has been performed.

Effects of AT1- and beta-adrenergic receptor antagonists on TGF-beta1-induced fibrosis in transgenic mice.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is involved in interstitial remodelling promoting collagen synthesis and suppressing collagen degradation by inhibition of collagenases. TGF-beta1 mediates angiotensin II-dependent effects and modulates beta1-adrenergic signalling. To study the effect of neuroendocrine antagonism on TGF-beta-induced hypertrophic and fibrotic phenotype, we treated TGF-beta1 (Cys223,225Ser) transgenic mice (TGF-beta1-TG) with either the beta1-receptor blocker metoprolol (MET), the angiotensin II type I (AT1)-receptor antagonist telmisartan (TEL) or an antibody blocking TGF-beta1 signalling (TGFbeta1-sR-Ab). MATERIAL AND METHODS: Transforming growth factor-beta1-TG mice (8 weeks) overexpressing TGF-beta1 were treated with either TEL (10 mg kg(-1)), MET (350 mg kg(-1)) or a soluble TGF-beta1 receptor antibody (1 mg kg(-1)) for 6 weeks. Morphological analyses of interstitium and cardiomyocytes were related to expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by immunoblotting and zymography. RESULTS: In TGF-beta1-TG mice, myocardial interstitial total collagen content was fourfold elevated compared to that of controls (P < 0.05) and was lowered under the treatment with TEL (P < 0.05). Protein expression of TIMP-1 and -4 was increased in TGF-beta1-TG but inhibited by TEL (TIMP-1 and TIMP-4) and MET (TIMP-1), while collagenase activity was decreased in TGF-beta1-TG and normalized by treatment with TEL (MMP-1 and MMP-13) and MET (MMP-1) (P < 0.05). Morphometric measurements of cardiomyocyte diameter and area demonstrated similar antihypertrophic effects for all treatment groups. CONCLUSION: The AT1-antagonist TEL reduced myocardial hypertrophy and interstitial fibrosis in TGF-beta1-TG mice by normalizing MMP/TIMP ratio. beta1-Adrenergic inhibition by MET as well as TGF-beta1 antagonism induced antihypertrophic rather than antifibrotic effects. Inhibition of both renin-angiotensin system and beta1-adrenergic system may exert different but synergistic effects to reduce myocardial remodelling.

[Laparoscopy in the management of endometrial cancer]. / Place de la laparoscopie dans le traitement du cancer de l'endomètre.

Recent advance in laparoscopy have changed the surgical approach of endometrial cancer patients. The Swissendos Center, Fribourg, in collaboration with AGO (Groupe de travail pour la gynécologie oncologique) and AGE (groupe de travail pour la gynécologie endoscopique) have established a consensus based on the available evidence for the use of laparoscopy in the management of patients with endometrial cancer The main objective was to define Swiss clinical practice guidelines appropriate to the country and consistent with the needs of the physicians.

[Stereotactic Mammotome breast biopsy: routine clinical experience and correlation with BI-RADS--classification and histopathology]. / Die stereotaktische Mammotome-Brustbiopsie: Erfahrungen im klinischen Alltag und Korrelation der BI-RADS--Klassifikation mit der Histopathologie.

BACKGROUND: Stereotactic breast biopsy using the Mammotome system allows minimal invasive tissue sampling of suspicious lesions of the breast cancer, e.g. clustered microcalcifications BI-RADS type 3 and 4, and has widely replaced open surgical biopsies. The aim of this retrospective study was to review the results of these biopsies in regard of technical feasibility and complications as well as to correlate initial BI-RADS assessment with histopathology. METHODS: One hundred thirty-five vacuum-assisted breast biopsies in 124 patients were evaluated. Before biopsy, the mammograms were classified according to the Breast Imaging Reporting and Data System (BI-RADS). All mammograms were reviewed with knowledge of the final histologic diagnosis. Patients with benign diagnoses underwent mammographic follow-up. Excisional biopsy was recommended for diagnoses of in-situ or invasive carcinoma. RESULTS: No serious complications of the biopsies were observed. Histopathology revealed 105 (78%) benign lesions. Benign lesions were classified as BI-RADS 3 in 49 (36%) and as suspicious (BI-RADS 4) in 56 (41%). Thirty lesions (22%) were malignant, of which 26 (87%) were classified BI-RADS 4 or 5. The frequency of malignancy in BI-RADS 4 and 5 was 19 of 75 (25%) and 7 of 7 (100%), respectively. Of the 53 BI-RADS 3 lesions, 4 (8%) were malignant. CONCLUSIONS: Mammotome biopsy was shown to be a safe and well-tolerated technique for the work-up of mammographic lesions. The frequency of malignant histopathologic findings in BI-RADS 3 lesions was higher than expected, reflecting the difficulties in the mammographic differentiation of benign and malignant clustered microcalcifications.

[Right sided lower abdominal pain two weeks after delivery]. / Rechtsseitige Unterbauchschmerzen zwei Wochen postpartal.

We report the CT imaging findings of a 33 year old patient who presented to the emergency department with increasing right lower abdominal pain and shivering. She delivered a healthy baby two weeks ago after induction in the 39th week of pregnancy due to a large fetus. Two days after delivery, sterilisation was performed. Clinically the primary differential diagnosis was appendicitis. However, computed tomography revealed thrombosis of the right ovarian vein. Consequently, management was altered appropriately with administration of antibiotics as well as a therapeutic dose of low molecular weight heparin.

Shorter PFA-100-closure times in laparoscopic versus conventional hysterectomy are not caused by increased vasopressin levels.

BACKGROUND/OBJECTIVES: Bleeding problems during laparoscopic surgery are infrequent. We hypothesised that increased abdominal pressure during the application of the pneumoperitoneum would lead to an increased release of endogenous vasopressin which could then contribute to the hemostasis by increasing platelet reactivity, FVIII and von Willebrand-factor. PATIENTS AND METHODS: We compared the vasopressin levels, the platelet function as measured by the PFA-100-test, aPTT and FVIII in 39 consecutive patients who underwent elective hysterectomy (20 with the laparoscopic and 19 with the conventional, "open" method). Blood was sampled the day before surgery and 2, 4 and 72 h after the induction of anaesthesia. RESULTS: After two hours, the PFA-100 closure times with collagen/ADP decreased to lower levels in the laparoscopic group (from 93 +/- 22 to 82 +/- 20, mean +/- SD) and even further down to 65 +/- 13 s (compared to 82 +/- 20 s) (p = 0.024)) four hours after the beginning of surgery. Vasopressin levels and F VIII increased in both groups but there was no significant difference between the groups (21 vs. 17.8 pmol/l for vasopressin, differences of the mean). Bleeding was minimal, with a trend to lower Hb-levels in the laparotomy group. CONCLUSIONS: The procedural difference of laparoscopic vs. open hysterectomy appears to enhance platelet reactivity by other mechanisms than increased vasopressin levels and may contribute to an enhanced hemostatic competence in laparoscopic surgery.

[Ultrasound-guided fine-needle aspiration of the breast]. / Stellenwert der Ultraschallgesteuerten Feinnadelpunktion der Mamma.

PURPOSE: Retrospective analysis of the results of all ultrasound (US)-guided fine needle aspirations (FNA) of the breast performed at our institution between 1988-2002. MATERIALS AND METHODS: The radiologic and pathologic information database was retrospectively searched for all referrals, in whom an US-guided FNA of the breast was performed as further diagnostic work-up of sonographically unclear or suspicious findings. Percutaneous tissue diagnosis was performed under US-guidance using a 20-Gauge-needle. Results were correlated with histology or sonographic and/or mammography follow-up examination, respectively. RESULTS: The total study population consisted of 324 patients (19-92 years). In 20 cases (6.2%), results of FNA were non-diagnostic, a cytologic diagnosis was established in the remaining 304 (93.8%) cases. Cytologically, malignancy was diagnosed in 60 cases; 2 of those were shown to be false positive by subsequent histologic work-up. In 33 of 244 surgery was performed. 9 cases were false negative. No complication was observed. The accuracy was 96.4% with a sensitivity of 86.6% and specificity of 99.2%. CONCLUSION: If a skilled cytopathologist is available, US-guided FNA is a highly accurate and minimal-invasive technique. False negative findings may occur, thus clinical and imaging findings should be taken into account for further therapeutic decision.

[Evaluation of bloody nipple discharge]. / Abklärung einer blutigen Mamillensekretion.

A 64-year old woman was referred for radiological evaluation of right sided bloody nipple discharge lasting for five months. Finally galactography supposed the diagnosis of an intraductal papilloma which was confirmed by surgery. Histopathologically an eight millimeter measuring intraductal papilloma with atypical ductal hyperplasia with signs of a carcinoma in situ was seen.

[End-to-end anastomosis in the primary repair of anal sphincter laceration occurring during delivery]. / Suffizienz der End-zu-Endanastomose bei primärer Versorgung eines geburtstraumatischen Analsphinkterrisses.

PURPOSE: To assess the quality of end-to-end anastomosis in the primary repair of anal sphincter laceration occurring during delivery. METHODS: Forty-nine women with third degree perineal laceration (PL III) and 42 controls were included in a 3-year postpartal follow-up study. RESULTS: Ultrasound showed end-to-end anastomosis to be inadequate in 22 (48.1 %) women. Thirty-one (63.2 %) women developed grade I-III anal incontinence. DISCUSSION: There was no correlation between ultrasound findings and the presence of anal incontinence. The unsatisfactory sonomorphometric outcome after 6 weeks results from inadequate repair with retraction of the sphincter ends. Defects newly demonstrated after 36 months indicate dedifferentiating atrophy with damage to peripheral motor nerves.

Binding and repair of mismatched DNA mediated by Rhp14, the fission yeast homologue of human XPA.

Rhp14 of Schizosaccharomyces pombe is homologous to human XPA and Saccharomyces cerevisiae Rad14, which act in nucleotide excision repair of DNA damages induced by ultraviolet light and chemical agents. Cells with disrupted rhp14 were highly sensitive to ultraviolet light, and epistasis analysis with swi10 (nucleotide excision repair) and rad2 (Uve1-dependent ultraviolet light damage repair pathway) revealed that Rhp14 is an important component of nucleotide excision repair for ultraviolet light-induced damages. Moreover, defective rhp14 caused instability of a GT repeat, similar to swi10 and synergistically with msh2 and exo1. Recombinant Rhp14 with an N-terminal hexahistidine tag was purified from Escherichia coli. Complementation studies with a rhp14 mutant demonstrated that the tagged Rhp14 is functional in repair of ultraviolet radiation-induced damages and in mitotic mutation avoidance. In bandshift assays, Rhp14 showed a preference to substrates with mismatched and unpaired nucleotides. Similarly, XPA bound more efficiently to C/C, A/C, and T/C mismatches than to homoduplex DNA. Our data show that mismatches and loops in DNA are substrates of nucleotide excision repair. Rhp14 is likely part of the recognition complex but alone is not sufficient for the high discrimination of nucleotide excision repair for modified DNA.

Prognostic and predictive significance of ErbB-2 breast tumor levels measured by enzyme immunoassay.

PURPOSE: A retrospective analysis to assess the prognostic and predictive clinical value of breast tumor ErbB-2 receptor expression quantified by enzyme immunoassay (EIA), to compare levels measured by EIA with ErbB-2 status determined by immunohistochemistry (IHC), and to correlate receptor content with levels of phosphorylated (Y1248-P) ErbB-2, a measure of functional tyrosine kinase activity. MATERIALS AND METHODS: EIA quantification of ErbB-2 was performed on membrane extracts from 3,208 well-characterized primary breast cancers. Overall, relapse-free, distant disease-free, and local/regional-free patient survival data were available on 1,123 of these tumors. IHC scoring for ErbB-2 status (HercepTest; DAKO, Glostrup, Denmark) was performed on adjacent sections of 151 cases, and receptor functionality was measured in 230 tumors by an antibody specific for phosphorylated (Y1248-P) ErbB-2. RESULTS: Unlike nonmalignant breast tissues, breast tumors showed increased ErbB-2 levels in a bimodal distribution, with 12% constituting a distinct set of ErbB-2-overexpressing tumors. The intermodal threshold value for ErbB-2 overexpression distinguished tumors with reduced estrogen and progesterone receptor content, high IHC score for ErbB-2, and significantly increased levels of phosphorylated (Y1248-P) ErbB-2 receptor. By multivariate analysis, EIA-determined ErbB-2 overexpression predicted significantly reduced patient survival that was unaffected by tamoxifen or cyclophosphamide, methotrexate, and fluorouracil adjuvant therapy. CONCLUSION: Determination of ErbB-2 receptor expression by EIA offers a clinically valuable alternative to semiquantitative IHC assessment of breast tumor ErbB-2 overexpression and affords the opportunity to evaluate ErbB-2 phosphorylation, which may represent an important predictive parameter of receptor functionality.

Are cumulus cells necessary for the spontaneous maturation of germinal vesicle-stage oocytes to metaphase II.

PURPOSE: In this study we investigated the need of the support from cumulus cells for germinal-vesicle (GV) oocytes collected from stimulated ovaries to complete their maturation to metaphase II (MII). METHODS: We compared the maturation rate of GV oocytes after coculture with cumulus cells (study group) with their spontaneous maturation in culture medium alone (control group). RESULTS: Sixty-four and nine-tenths percent of the GV oocytes matured to metaphase II in the coculture group, and of these, 43.5% gave normal 2pn zygotes following intracytoplasmic sperm injection (ICSI), while 73.8% of the GV oocytes spontaneously matured to the MII stage and 30% of these reached the zygote stage after ICSI. CONCLUSIONS: It is probable that a follicular factor is responsible for this arrested maturation in the human and that maturation occurs spontaneously when the oocytes are separated from their follicular fluid environment after collection.

Transitional cell carcinoma of the vagina with pagetoid spread pattern.

A distinctive variant of a papillary noninvasive transitional cell carcinoma (TCC) of the vagina removed from a postmenopausal woman is described. The neoplasm was evaluated by immunohistochemistry. The designation of this neoplasm as a TCC is supported by its morphological features and its coexpression for cytokeratin (CK) 7 and CK 20. Its main feature is pagetoid infiltration into adjacent vaginal epithelium. This is the second reported case involving a transitional cell metaplasia (TCM) of the vagina, a possible precursor lesion of the TCC.

[Breast preserving therapy of breast carcinoma: analysis of over 1,300 patients treated in the Basel region]. / Brusterhaltende Therapie beim Mamma-Karzinom: Analyse bei über 1300 in der Region Basel behandelten Patientinnen.

From 1977 to 1994 a total of 1329 breast cancer patients have been treated with breast conserving surgery in the region of Basel. This analysis is based on 832 patients treated from 1977 to 1990 according to a prospective treatment protocol, which was adjusted only once (1985). In comparison with the most known international publications this analysis represents one of the greatest homogeneous series of breast conserving treatment. We observe an overall 5-year survival of 91% and a 10-year survival rate of 77%. 94% of the women remain locally recurrence free at 5 years and 86% at 10 years respectively. At 5 years, freedom of local recurrence totals to 97% in patients without (pN0) and to 89% in patients with tumor involvement of the axillary lymph nodes (pN+) (p = 0.00008), as well as to 96% for pT1 and 91% for pT2-tumors (p = 0.08328). In our analysis the R0-resection significantly influences local recurrence free survival.

Intracytoplasmic sperm injection (ICSI) with testicular sperm extraction (TESE) in non-obstructive azoospermia--two case reports.

Intracytoplasmic sperm injection (ICSI) with microsurgical epididymal sperm extraction (MESA) or testicular sperm extraction (TESE) can be offered to azoospermic men. We report our initial experience of two cases with ICSI-TESE in non-obstructive azoospermia. Both couples had a successful ICSI with embryo transfer. An ongoing triplet pregnancy at 21 weeks is observed.