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Attenuated total reflectance surface enhanced infrared absorption spectroscopy (ATR-SEIRAS) measurements have been employed to study the adsorption of dimethylaminopyridine (DMAP) and its conjugate acid (DMAPH+) on gold surfaces as a function of applied potential and solution pH. Based on our transmission measurements, we have been able to demonstrate that the acid/base forms of this pyridine derivative can be readily differentiated due to their distinct IR signals. When the solution pH is equal to the pKaof DMAPH+, we demonstrate that the adsorbing species is DMAP, oriented with its heterocyclic ring perpendicular to the electrode surface. In acidic electrolytes, our SEIRAS data provide direct spectroscopic evidence of DMAP monolayer formation even though the pH is 5 units below the pKaof the conjugate acid. Our data support a potential induced deprotonation of the endocyclic nitrogen and resulting coordination of the nitrogen lone pair to the gold surface. Both of these results confirm our existing model of DMAP adsorption previously based solely on electrochemical measurements. However, the present SEIRAS study also indicates that, at low pH, DMAPH+can electrostatically coordinate to very negatively charged surfaces. This mode of adsorption was previously unobserved, illustrating the ability of in situspectroscopic techniques to reveal new information that is not apparent from traditional electrochemical techniques such as differential capacity and chronocoulometry. [ABSTRACT FROM AUTHOR]

Introduction: Lichen sclerosus et atrophicus is an inflammatory, scarring dermatosis of the female anogenital area and may lead to pain and sexual dysfunction. In select cases which are refractory to conservative therapy, surgery may provide significant symptom improvement. The objective of this study was to expand the range of surgical treatment options for these patients by presenting the operative outcomes of a specialised reconstructive method using the anterior obturator artery perforator (aOAP) flap., Methods: A retrospective cohort study was conducted on sexual outcomes following the excision of affected vulvovestibular tissue by skinning vulvectomy and subsequent single-stage reconstruction using the aOAP flap. Additional procedures, such as the Omega-Domed (OD) flap, scar surgery and clitoral re-exposure, were performed when indicated., Results: Between 2014 and 2022, a total of 61 patients were surgically treated and retrospectively included in this study. Vulvectomy and subsequent reconstruction with bilateral aOAP flaps were performed in 53 (87%) cases. There was a significant reduction in the prevalence of dyspareunia and inability to have sexual intercourse at the 1-year follow-up compared to baseline (p < 0.001). There were several minor, reversible complications that required secondary intervention., Conclusions: The outcomes of this study indicate a substantial improvement in sexual function, evidenced by a significant reduction in dyspareunia and an increased ability to engage in sexual intercourse. Altered tissue quality in patients with lichen sclerosus et atrophicus and long-term cortisone application may predispose this patient population to a higher risk of minor post-operative complications., Clinical Trial Registration Number: DRKS00033261., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Introduction . The operating room (OR) Black Box is an innovative technology that captures and compiles extensive real-time data from the OR, allowing identification and analysis of factors that influence intraoperative procedures and performances - ultimately improving patient safety. Implementation of this kind of technology is still an emerging research area and prone to face challenges. Methods . Observational study running from May 2017 to May 2021 conducted at Copenhagen University Hospital - Rigshospitalet, Denmark, involving 152 OR staff and 306 patients. Feasibility of the OR Black Box was assessed in accordance with Bowen's framework with 8 focus areas. Results . The OR Black Box had a high level of acceptability among stakeholders with 100% participation from management, 93% from OR staff, and 98% from patients. The implementation process improved over time, and an average of 80% of the surgeries conducted were captured. The practical aspects such as numerous formal and informal meetings, ethical and legal approval, recruitment of patients were acceptable, albeit time-consuming. The OR Black Box was adopted without any changes in scheduled surgery program, but capturing hours were adjusted to match the surgery program and relocation of OR staff declining to provide consent was possible. Conclusions . Implementation of the OR Black Box was feasible yet challenging. Management, nearly all staff, and patients embraced the initiative; however, ongoing evaluation, information meetings, and commitment from stakeholders are required and crucial to sustain momentum, continue implementation and expansion. Ideas from this study can be useful in the implementation of similar initiatives.

Ovarian tissue cryopreservation (OTC) is a method of fertility preservation in girls and young women prior to gonadotoxic treatment. It is a safe and promising method to restore fertility. The initial recovery of endocrine function is high, but the longevity of the grafted tissue varies. In this single-center, combined retro- and prospective cohort study, we report the reproductive outcome and hormonal recovery following ovarian tissue transplantation (OTT) and evaluate possible predictors of the chance of pregnancy. The study includes 40 women from eastern Denmark undergoing 53 OTTs between 2003 and 2021. Permission to obtain retrospective data was given by the Danish Patient Safety Authorities and prospective data-collection by informed consent. Initial recovery of endocrine function was seen in 18/19 women with POI, and ongoing function of the grafted tissue in 7/14 two years from OTT. Live birth rate (LBR) was 41%, with 20 children to 39 women trying to conceive. Women who conceived had higher AFC at the time of OTC than women who did not ( p ± 0.04). Repeated transplantations were not successful in terms of delivery. Half of all pregnancies were achieved by ART, but PRs were lower after ART than by spontaneous conception. LBRs after OTT are encouraging. Chance of pregnancy after OTT is correlated to ovarian reserve at OTC. Repeated transplantations were not successful in terms of unfulfilled pregnancy wish.

Background: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood., Methods: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors., Results: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors., Conclusions: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: To evaluate the use of cryopreserved ovarian tissue in the Danish fertility preservation cohort., Design: Retrospective cohort study., Setting: University hospitals and fertility clinics., Patient(s): Ovarian tissue cryopreservation (OTC) was performed for 1,186 Danish girls and women from 1999-2020, of whom 117 subsequently underwent ovarian tissue transplantation (OTT). Subgroup 1 included 759 patients with a follow-up period of >5 years. Out of these, OTT rates were further analyzed for those patients who were alive and aged >24 years in July 2020 (subgroup 2; n = 554)., Intervention(s): OTC and OTT., Main Outcome Measure(s): OTT, death, donation of tissue., Result(s): In subgroup 1, 14% of the patients had undergone OTT, 18% had died, 9% had donated their tissue for research, and 59% still had their tissue stored. In subgroup 2, 19% had undergone OTT and for most diagnoses the OTT rates ranged from 15% to 22% with benign hematologic diseases having the highest OTT rate (35%). On the basis of the entire cohort, stratified age analysis indicated that women aged ≥30 years at OTC were more likely to return for OTT than women aged 18-29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged <18 years at OTC had undergone OTT., Conclusion(s): The OTT rates depended on the diagnosis, age at OTC, and follow-up time. Specific criteria are needed for reporting and comparing OTT rates. Six out of 10 patients still had their cryopreserved tissue stored and longer follow-up is needed, especially for younger girls., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Standard of care in patients with advanced ovarian cancer (AOC) is upfront surgery followed by chemotherapy. Neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) is an alternative in selected patients. Most data exist with IDS following 3-4 cycles chemotherapy, however, some patients experience a delay of IDS. So far, the impact of a "delayed" interval debulking surgery (DID) is poorly defined., Methods: We analyzed data from eight international gynecology-oncology referral centers. Patients were included if they had newly diagnosed AOC and were prone to DID (minimum 5 cycles of NACT) between 2011 and 2017., Results: 308 patients underwent DID. 89.6% had a high-grade serous ovarian cancer. The median number of pre-op NACT was 6 cycles (range 5-9) and 6.1% of patients received additionally bevacizumab. The majority of patients had stage-IV disease (51.3%). Median duration of surgery was 210 min (range 34-561), the median surgical complexity score was 4 (range 1-16). Complete resection was achieved in 60.1%. The median number of post-op chemotherapy cycles was 2 (range 0-5). The rate of severe complications (Clavien-Dindo£3°) was 9.7% and 30 days post-op mortality was 0.3%. The median PFS and OS in patients with complete resection was 19.5 and 49.2 months compared to 14.8 and 33.0 months in patients with incomplete resection (p = 0.001), respectively. We did not observe any survival benefit for patients with cytoreduction to small residuals (1-10 mm) compared to residual disease >1 cm., Conclusion: Our data may suggest that offering surgery to patients with persistent disease after 5+ cycles could be associated with favorable outcome if a complete resection is achieved. Patients who had residual disease postoperatively may experience rather peri-operative treatment burden than any benefit from DID., Competing Interests: Declaration of Competing Interest H. Plett, O.T. Filippova, J.P. Ramspott, A. Garbi, G.D. Aletti, MZ Muallem, C. Langstraat, S. Phadnis, O. Zivanovic, Y. Sonoda, G. Gardner, A. Traut, F.A. Taran, S. Kommoss, M. Rosendahl, and K. Long Roche have nothing to disclose. P. Harter: Honoraria: Astra Zeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab,MSD; Advisory Board: Astra Zeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, MSD/Merck; Research funding (Inst): Astra Zeneca, Roche, GSK, Boehringer Ingelheim,Medac, DFG, European Union, DKH, Tesaro, Genmab. A. du Bois: personal fees fromRoche, personal fees fromAstra Zeneca, personal fees fromTesaro, personal fees from Clovis, personal fees from Pfizer, personal fees from Genmab, personal fees from Pharmar, personal fees from Biocad, outside the submitted work. Dr. Chi reports personal fees from Bovie Medical Co., Verthermia Inc. (now Apyx Medical Corp.), and C Surgeries; is a former stock owner of Intuitive Surgical, Inc. (sold 12/18) and TransEnterix, Inc. (sold 12/18); and served on the Medical Advisory Board of Biom ‘Up (4/19/19). Dr. Chi is funded in part through the NIH/NCI Cancer Center Support GrantP30 CA008748. T. Baert has been an advisor for Tesaro and received research grant from Amgen, non-financial support from Amgen, MSD, Roche and Tesaro, outside the submitted work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The value of surgical staging of apparent early stage epithelial ovarian carcinoma (EOC) is unclear. The aim of this study was to evaluate the importance of surgical staging on the stage of disease and treatment plan., Material and Methods: All patients with apparent stage I EOC undergoing staging from 01/01/2005 to 30/06/2017 in all Danish hospitals and in the Radboud University Hospital Nijmegen, the Netherlands, were evaluated to identify the pathological findings responsible for upstaging and changes in treatment plans., Results: We included 1234 patients with apparent stage I EOC. The staging steps often missed were the biopsy from the right diaphragmatic surface (missed in 96.9% of all patients) and lymph node (LN) sampling or lymphadenectomy (missed in 65.5% of all patients). Upstaging occurred in 393 patients (31.8%) due to microscopic spread to both ovaries (0.8%); ovarian surface (5.8%); positive cytology (10.0%); fallopian tubes (3.1%), ovary (1.5%) and/or uterus serosa (1.2%); pelvic peritoneum (4.3%); LNs (4.7%); omentum (3.7%); abdominal peritoneum (0.6%) and right diaphragmatic surface (2.6%). Of the 393 upstaged patients, 138 (35.1%) had an altered treatment plan due to metastases found by surgical staging., Conclusion: Staging was incomplete in most patients, mainly because a biopsy of the diaphragm was omitted. However, surgical staging led to adjuvant treatment in 35.1% of the upstaged patients. Peritoneal biopsies (para-colic gutters and right diaphragm) were of little value, since few patients had an adjustment of treatment plan due to these biopsies. Omitting these biopsies, in the absence of peritoneal abnormalities, is justifiable., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Research Question: How many patients in Denmark were treated with fertility-sparing surgery (FSS) for epithelial ovarian cancer (EOC) and what was their prognosis compared with patients treated with radical surgery (RS)?, Design: This study was a retrospective Danish nationwide study, evaluating the effect of FSS compared with RS in patients with EOC, age ≤45 years and International Federation of Gynecology and Obstetrics (FIGO) stage ≤IC3 from 2005 to 2016., Results: A total of 106 patients were included. Of these, 13 were treated with FSS and 93 were treated with RS. Median age was 27 versus 42 years (P < 0.0001). Overall survival did not differ significantly between the two groups. Overall survival rate in the FSS group was 100%, while the overall survival in the RS group was 87%. Disease-specific survival was 100% in the FSS group and 91% in the RS group., Conclusions: This study shows that patients treated with FSS for FIGO stage I EOC do not have an impaired survival compared with patients treated with RS. Nevertheless, the conclusion must be interpreted with caution due to the limited number of patients and the retrospective nature of the study. Larger studies are needed before conclusions can be drawn., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Advanced epithelial ovarian cancer (EOC) often involves the peritoneum. Because complete resection of tumor and carcinosis is the most important prognostic factor, the peritoneal carcinosis index (PCI) has been evaluated in EOC. We hypothesize that specific PCI regions comprising the small intestine with mesentery (regions 9-12) and the hepatoduodenal ligament (region 2) are more predictive of complete resection (R = 0) and survival than the entire PCI., Materials and Methods: We analyzed prospectively collected nationwide data from 507 patients with International Federation of Gynecology and Obstetrics stage IIIB to IVB EOC who underwent primary surgery with complete cytoreductive intent. The PCI as a predictor of incomplete resection (R > 0) was evaluated with logistic regression and receiver operating caracteristic curves. Survival analysis was performed with Kaplan-Meier curves and Cox regression., Results: Median (range) PCI was 10 (0-33) in R = 0 patients and 24 (1-39) in R > 0 patients; P < 0.0001. The PCI of regions 9 to 12 (odds ratio [OR]:1.38 (1.29-1.47; 95% confidence interval [CI]) and 2 + 9 to 12 (OR: 1.31 [1.24-1.38; 95% CI]) were more predictive of residual tumor than the entire PCI (OR: 1.10 [1.08-1.12; 95% CI]). Similarly, in receiver operating characteristic curve analyses of R greater than 0 versus R = 0, the area under the curve was higher in regions 9 to 12 (78%) and regions 2 + 9 to 12 (79%) than for the total PCI (75%).Median overall survival was 56.8 months (48.3-65.4; 95% CI) after R = 0 and 26.7 months (21.4-32.0; 95% CI) after R greater than 0 (P < 0.0001). Overall survival was 53.8 months for patients with PCI less than median (14) versus 25.7 in patients with PCI greater than median.The PCI in regions 9 to 12 (hazard ratio [HR]: 1.10 [1.07-1.13; 95% CI]) and 2 + 9 to 12 (HR: 1.08 [1.06-1.11; 95% CI]) was associated with a poorer prognosis than the entire PCI (HR: 1.03 [1.02-1.04; 95% CI])., Conclusions: Selected PCI regions corresponding to the small intestine and hepatoduodenal ligament are more predictive of complete resection and survival than the entire PCI. This confirms that in the majority of the cases, an early intraoperative examination of those selected PCI regions - and not the entire PCI - will reveal whether R = 0 is achievable.

With 550 new cases/year ovarian cancer constitutes 3% of all cancers among women. The unspecific symptoms cause delayed diagnosis and hence poor survival rates. Screening initiatives have been disappointing. In order to accelerate diagnosis and correct surgical management, patients are referred to centralized, specialized units. The primary treatment comprises surgical total cytoreduction followed by platinum-based chemotherapy. Newer biological agents are added when randomized trials have shown a benefit. Recurrence is managed by chemotherapy alone or repeated radical surgery followed by chemotherapy.

Objective: The aim of this study was to assess the importance of appendectomy during surgery for mucinous ovarian cancer. It can be difficult to distinguish between primary ovarian and primary appendiceal cancers clinically, histologically, and immunohistochemically. Removal of the appendix may facilitate differential diagnosis, improve staging, and possibly increase 5-year survival but may also be associated with increased postsurgical morbidity. In the largest population published to date, we analyze and discuss these matters., Methods: Prospectively gathered data on 269 patients with confirmed mucinous ovarian adenocarcinoma from a national database were analyzed. The impact of appendectomy and metastases to the appendix on 5-year and overall survival was analyzed., Results: Appendectomy was performed in 172 cases (64%), and in 10 cases (4%), pathologic evaluation of the removed appendix revealed metastases from ovarian cancer. Three of the cases were macroscopically normal, and metastases were discovered only during microscopic evaluation. Patients with metastatic disease to the appendix had significantly worse 5-year survival (22%) compared with patients without metastases (73%) (χ = 31.998, P < 0.0001). Equally, 5-year survival was significantly higher in patients who had been adequately staged with hysterectomy, omentectomy, bilateral salpingo-oophorectomy, and appendectomy (74% vs 52%, χ = 7.322, P = 0.007). In multivariate analysis, increase in revised 2013 International Federation of Gynecology and Obstetrics classification stage (IA reference) was significantly associated with worsened prognosis (hazard ratio, 1.13; P < 0.0001). Equally, each stepwise increase in performance status score was related to a poorer prognosis with hazard ratio of 1.63 (P < 0.0001). Metastases to the appendix and staging did not remain significant factors of survival in multivariate analysis., Conclusions: Univariate analysis suggests that metastatic disease to the appendix and failure to perform complete staging including appendectomy are related to a worsened prognosis. A normal-looking appendix does not exclude metastatic disease, and because appendectomy is easily performed and does not increase morbidity, it should be performed during surgery for suspected mucinous ovarian cancer.

Introduction: Robot-assisted surgery has become more widespread in gynecological oncology. The purpose of this systematic review is to present current knowledge on robot-assisted surgery, and to clarify and discuss controversies that have arisen alongside the development and deployment., Material and Methods: A database search in PubMed and EMBASE was performed up until 4 March 2016. The search strategy was developed in collaboration with an information specialist, and by application of the PRISMA guidelines. Human participants and English language were the only restrictive filters applied. Selection was performed by screening of titles and abstracts, and by full text scrutiny. From 2001 to 2016, a total of 76 references were included., Results: Robot-assisted surgery in gynecological oncology has increased, and current knowledge supports that the oncological safety is similar, compared with previous surgical methods. Controversies arise because current knowledge does not clearly document the benefit of robot-assisted surgery, on perioperative outcome compared with the increased costs of the acquisition and application., Conclusions: The rapid development in robot-assisted surgery calls for long-term detailed prospective cohorts or randomized controlled trials. The costs associated with acquisition, application, and maintenance have an unfavorable impact on cost-benefit evaluations, especially when compared with laparoscopy. Future developments in robot-assisted surgery will hopefully lead to competition in the market, which will decrease costs., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

Aim: To determine if survival in stage I ovarian cancer is influenced by cyst emptying, lymph node resection and chemotherapy., Patients and Methods: A survival analysis of 607 patients with ovarian cancer in stage IA, IA with cyst emptying (IAempty) and IC1 was performed., Results: There was no difference in five-year survival between IA (87%) and IC1 (87%) (p=0.899), between IA and IAempty (86%) (p=0.500) nor between IA+IAempty (87%) and IC1 without IAempty (84%) (p=0.527). Five-year survival rate (5YSR) was significantly higher after lymph node resection in stage IA (94% vs. 85%; p=0.01) and IA+IC1 (93% vs. 85%; p=0.004). In multivariate analysis, lymph node resection improved prognosis significantly for all sub-stages, whereas stage and chemotherapy did not affect survival., Conclusion: In stage IA ovarian cancer, controlled cyst emptying without spill does not worsen prognosis. Lymph node resection is associated with improved survival in stage IA and IC1. Chemotherapy should only be offered where randomized controlled studies have shown a benefit., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: With the 2013 International Federation of Gynecology and Obstetrics (FIGO) staging for ovarian, fallopian tube, and primary peritoneal cancer, the number of substages changed from 10 to 14. Any classification of a malignancy should easily assign patients to prognostic groups, refer patients to individualized treatments, and allow benchmarking and comparison of patients and results between centers. The stage should reflect survival in particular. The objective of the study was to validate these requirements of the revised FIGO staging on a high number of ovarian cancer patients., Materials and Methods: Demographic, surgical, histological, and survival data from 4036 ovarian cancer patients were used in the analysis. Five-year survival rates (5YSR) and hazard ratios for the old and revised FIGO staging were calculated using Kaplan-Meier curves and Cox regression., Results: A total of 1532 patients were assigned to new stages. Stages IA and IC1 had similar survival (5YSR, 87%); and stages IB, IC2, and IC3 had similar survival (5YSR, 75%-80%). Stage IIC was omitted, resulting in similar survival in stages IIA and IIB (5YSR, 61% and 65%). Of 1660 patients in stage IIIC, 79 were restaged: In 16 cases, IIIC was down-staged to IIIA1, as they had only been stage IIIC owing to lymph node metastases; and in 63 cases, IIIC was down-staged to IIIB, as they had lymph node metastases and abdominal tumor of less than 2 cm. The 5YSR in stage IIIC was unchanged (22%). Stage IV (5YSR, 14% ) was restaged as IVA (13%) and IVB (13%). Both were different from IIIC; P < 0.0001., Conclusion: With introduction of new substages, staging becomes more demanding. Second, as fewer patients are allocated to each substage, statistical power is diminished, resulting in uncertainty in the results. Despite this, and most importantly, the revised coding adequately reflects survival, as there was a clear graphical and statistical tendency for poorer survival with increasing stage.

Fungal pathogens pose a major challenge to global crop production. Crop varieties that resist disease present the best defence and offer an alternative to chemical fungicides. Exploiting durable nonhost resistance (NHR) for crop protection often requires identification and transfer of NHR-linked genes to the target crop. Here, we identify genes associated with NHR of Arabidopsis thaliana to Phakopsora pachyrhizi, the causative agent of the devastating fungal disease called Asian soybean rust. We transfer selected Arabidopsis NHR-linked genes to the soybean host and discover enhanced resistance to rust disease in some transgenic soybean lines in the greenhouse. Interspecies NHR gene transfer thus presents a promising strategy for genetically engineered control of crop diseases., (© 2015 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Introduction: International literature describes that former intensive care unit (ICU) patients suffer considerable physical and neuropsychological complications. Systematic data on Danish ICU survivors are scarce as standardised follow-up after intensive care has yet to be described. This article describes and evaluates the knowledge gained from outpatient follow-up at a tertiary intensive care unit at Rigshospitalet, Copenhagen, during a three-year period., Methods: A total of 101 adult former ICU patients attended the outpatient clinic over a three-year period. Patients included were medical and surgical patients with a length of stay exceeding four days. Patients attended the clinic after discharge from hospital and for a minimum of two months from their discharge from the ICU. The patients were assessed for physical, neuropsychological and psychological problems and, if necessary, further treatment or rehabilitation was initiated., Results: Reduced physical ability was seen in 82%. A total of 89% suffered a substantial weight loss. 83.2% had signs indicating acute brain dysfunction during the ICU stay, and approximately half of the patients still had cognitive problems. A total of 66 interventions were initiated., Conclusion: Our data confirmed that a large proportion of ICU survivors suffer considerable long-term physical and neuropsychological sequelae. Intensive care follow-up may contribute to address these specific problems and to initiate the needed interventions. Research is needed to determine whether specialised rehabilitation is required., Funding: not relevant., Trial Registration: not relevant.

Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair.

Aim: Improving survival for women with early breast cancer (eBC) requires greater attention to the consequences of treatment, including risk to ovarian function. We have assessed whether biochemical markers of the ovarian reserve might improve prediction of chemotherapy related amenorrhoea., Methods: Women (n=59, mean age 42.6 years [(range 23.3-52.5]) with eBC were recruited before any treatment. Pretreatment ovarian reserve markers (anti-Müllerian hormone [AMH], follicle-stimulating hormone [FSH], inhibin B) were analysed in relation to ovarian status at 2 years., Results: Pretreatment AMH was significantly lower in women with amenorrhoea at 2 years (4.0 ± 0.9 pmol/L versus 17.2 ± 2.5, P<0.0001), but FSH and inhibin B did not differ between groups. By logistic regression, pretreatment AMH, but not age, FSH or inhibin B, was an independent predictor of ovarian status at 2 years (P=0.005; odds ratio 0.013). We combined these data with a similar cohort (combined n=75); receiver-operator characteristic analysis for AMH gave area under curve (AUC) of 0.90 (95% confidence interval (CI) 0.82-0.97)). A cross-validated classification tree analysis resulted in a binary classification schema with sensitivity 98.2% and specificity 80.0% for correct classification of amenorrhoea., Conclusion: Pretreatment AMH is a useful predictor of long term post chemotherapy loss of ovarian function in women with eBC, adding significantly to the only previously established individualising predictor, i.e. age. AMH measurement may assist decision-making regarding treatment options and fertility preservation procedures., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: The chemotherapy required to treat patients with sarcoma may as a side-effect induce infertility in girls and young women. If these patients have ovarian cortical tissue cryopreserved prior to chemotherapy, they may, if necessary, have the tissue transplanted and restore their fertility. The aim of this study was to evaluate the risk of residual cancer cells in the ovarian cortex intended for transplantation., Patients and Methods: Ovarian tissue stored for fertility preservation from 16 surviving patients diagnosed with sarcoma (nine with Ewing sarcomas, four with osteosarcomas, two with synovial sarcomas and one with chondrosarcoma) was evaluated for the presence of malignant cells by histology and by transplantation to immunodeficient mice for 20 weeks. A fraction of the tissue from patients with Ewing sarcoma was also evaluated for the presence of the molecular marker EWS-FLI1 by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The transplant itself and selected murine organs were analysed for the presence of malignant cells by histology., Results: All the mice accommodated the human tissue for 20 weeks of transplantation period with none of the mice developing any sign of cancer. In no instance were any cancer cells detected by histology or RT-qPCR., Conclusion: Ovarian tissue from patients with sarcoma appears to be without metastatic malignant cells in numbers that allow detection. Although the actual pieces of ovarian tissue used for transplantation remain unchecked, the current data indicate that the procedure is safe at least in patients that survive the sarcoma disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Transplantation of frozen/thawed ovarian tissue from patients with a malignant condition is associated with a risk of re-introduction of the disease as the tissue usually is removed before anti-cancer therapy and may thus contain malignant cells. We review studies investigating the presence of malignant cells in cryopreserved ovarian tissue from patients with malignant disease and based on the strength of the evidence, recommendations for transplantations are proposed., Materials and Methods: A systematic review of the literature. All peer reviewed studies evaluating the presence of malignant cells in cryopreserved human ovarian tissue were included. Data were searched in Pubmed and Embase with no language restrictions., Results: The majority of the reviewed papers were casuistic reports and few of the included papers were specifically designed to search for malignant cells. Ovarian tissue from 422 patients has been subject to testing for malignant cells by imaging, histology, immunohistochemistry, molecular biology, animal- or clinical transplantation. In 31 (7 %) of the cases the applied test raised suspicion of malignant cell infiltration. No transplantation-related relapse of cancer has been reported after 33 transplantations of frozen/thawed ovarian cortex., Conclusion: The quality and strength of the evidence is generally low and prospective studies are needed. The risk of re-introducing a malignant condition when transplanting ovarian tissue depends on the particular disease. Based on the available data, the risk was estimated: Leukaemia: HIGH. Gastrointestinal cancers: MODERATE. Breast cancer, sarcomas of the bone and connective tissue, gynaecological cancers, Hodgkin's and Non-Hodgkin's Lymphoma: LOW.

Some women suffering from leukemia require bone marrow transplantation to be cured. Bone marrow transplantation is associated with a high risk of sterility, and some patients are offered fertility preservation by cryopreservation of the ovarian cortex. Transplantation of the ovarian cortex to women cured of leukemia who became menopausal is currently not performed because of the risk of introducing the disease. In this study, individual pieces of ovarian cortex intended for reimplantation from 25 patients with leukemia were transplanted to each of 25 nude mice for 20 weeks. The ovarian cortex was examined before and after transplantation by histology and immunohistochemistry, and RT-quantitative PCR (in the 7 patients with a known marker). Seventeen patients had the ovarian cortex retrieved when they were in complete remission. Before transplantation, 4 of 7 pieces (2 from patients in complete remission) of ovarian cortex had a positive RT-quantitative PCR. After transplantation, none of the mice revealed any sign of disease, neither in the pieces of ovarian cortex transplanted nor in any of the murine organs evaluated. Thus, the ovaries from patients in complete remission do not appear to contain viable malignant cells contrasting ovarian tissue retrieved before treatment.

Cryopreserved ovarian cortical biopsies from 51 patients with breast cancer were examined by histologic and immunohistochemical analysis and showed no sign of metastases. Autotransplantation of ovarian cortex to patients with low-stage breast cancer disease appears safe, but confirmatory studies are required, including xenotransplantation studies., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To describe a cohort of 12 Danish women who received autotransplantation of frozen-thawed cryopreserved ovarian tissue because of premature ovarian failure after cancer treatment., Design: Retrospective study., Setting: University hospitals., Patient(s): Twelve women with autotransplanted frozen-thawed ovarian tissue., Intervention(s): Monitoring of hormonal parameters and results of 56 IVF cycles in 10 women., Main Outcome Measure(s): Levels of gonadotropins and sex steroids, functional life span of the grafts, and results of IVF., Result(s): All 12 women regained ovarian function between 8 and 26 weeks (mean 19 weeks) after transplantation. Ten women underwent a total of 56 IVF cycles, 76 follicles developed, 49 oocytes were aspirated, 18 were fertilized, and 16 embryos were transferred resulting in six pregnancies: two biochemical, one clinical that miscarried in week 7, and two ongoing resulting in the delivery of two healthy infants born at term to two women. One of these women subsequently conceived spontaneously and delivered another healthy infant. The life span of the transplanted tissue has been between 6 months and still functioning after 54 months., Conclusion(s): Autotransplantation consistently leads to recovery of ovarian function after treatment-induced ovarian failure. Four women became pregnant, after IVF or spontaneously, resulting in the delivery of three healthy infants., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This paper presents the Danish 10-year experience (1999-2009) with cryopreservation (n=386) and autotransplantation of ovarian tissue (n=18). Before applying the technique to humans, the method was thoroughly tested and validated. The cryoprotectant solution was chosen after histological evaluation of mouse and human ovarian tissue after freezing with four different combinations of cryoprotectants. Viability was confirmed by transplantation of frozen-thawed human ovarian tissue (n=49) to oophorectomized Nude mice. Viability after transport of fresh tissue 4-5h prior to freezing had previously been validated. Overnight transport of fresh ovarian tissue prior to cryopreservation was evaluated when human ovarian tissue was kept on ice for 20h and then cryopreserved. The thawed ovarian tissue was transplanted to an oophorectomized Nude mouse and histology confirmed viability. In Denmark 12 women have received a total of 18 autotransplantations of ovarian tissue. All women resumed ovarian function and three healthy babies were born to two women. In both women, the tissue was transported on ice for 4-5h prior to cryopreservation. Ovarian tissue cryopreservation is an important method for fertility preservation; however, before applying the method clinically, each laboratory should perform thorough validation of their technique., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To systematically search for leukemic cells in cryopreserved ovarian cortex from Danish female patients with leukemia, who had ovarian cortex cryopreserved for fertility preservation before potentially sterilizing treatment., Design: Retrospective analysis of data in a clinical project., Setting: University hospital laboratories., Patient(s): In total, 26 patients diagnosed with leukemia, who had ovarian tissue cryopreserved before potentially sterilizing chemotherapy and conditioning., Intervention(s): Ovarian cortex from each patient was examined with histology and immunohistochemistry. In addition, in eight cases a specific chromosomal abnormality could be used as a genetic marker for detection of malignant cells by polymerase chain reaction (PCR)., Main Outcome Measure(s): Evidence of malignant cells by immunohistochemistry or PCR., Result(s): Histology and immunohistochemistry did not reveal malignant cell infiltration in the ovarian cortex of any of the patients. In six of the eight patients (75%) with chromosomal abnormalities in the malignant cells, PCR showed evidence of leukemic cells in the ovarian tissue., Conclusion(s): Immunohistochemistry was unable to locate leukemic cells in the ovarian cortex; however, PCR detected potentially malignant cells in the majority of cases. The viability and malignancy of these cells remains to be determined. At present, reimplantation of ovarian cortex to leukemia patients cannot be recommended., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study ovarian follicular dynamics during chemotherapy to understand the mechanisms behind chemotherapy-induced ovarian follicular depletion and to evaluate whether pretreatment levels of ovarian reserve markers were predictive of the posttreatment levels., Design: Prospective clinical study., Setting: University hospital fertility center., Patient(s): Seventeen women (median age 30 years; range 19-35 years) undergoing chemotherapy., Intervention(s): Patients were seen before, frequently during, and after chemotherapy, until 1 year after the end of treatment. Antral follicle count and levels of FSH, LH, E(2), anti-Müllerian hormone (AMH), and inhibin A and B were monitored at each visit., Main Outcome Measure(s): The dynamics of the ovarian reserve markers during chemotherapy and factors predictive of posttreatment ovarian function., Result(s): Anti-Müllerian hormone level (mean +/- 2 SEM) dropped from 2.7 +/- 1.0 to 1.1 +/- 0.6 and to 0.4 +/- 0.4 ng/mL immediately after one and two series of chemotherapy, respectively. Inhibin B and antral follicle count decreased after three series whereas FSH reached menopausal levels after four series. High pretreatment AMH levels predicted higher posttreatment AMH levels., Conclusion(s): Anti-Müllerian hormone and inhibin B levels immediately declined in response to chemotherapy, and the follicular target of chemotherapy appeared to be growing follicles. High pretreatment AMH levels were predictive of a higher posttreatment AMH level., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This preliminary prospective study investigated serum anti-Müllerian hormone (AMH) through correlations to other basal parameters (123 patients) and according to ovarian response to 75 IU recombinant follicle-stimulating hormone (rFSH)/day (62 patients) in ovulatory patients' first rFSH treatment cycle before intrauterine insemination. Mean age of the patients was 33 years. Serum AMH significantly correlated to age (r=-0.38), antral follicle count (AFC) (r=0.68), ovarian volume (r=0.40), FSH (r=-0.31), (P<0.001) and cycle length (r=0.26, P=0.004). Serum AMH median (interquartile range; IQR) was 8.5 pmol/l (1.9-15.1) in hyporesponders (one mature follicle) versus 10.7 (7.3-17.3) in normal responders (2-3 follicles, with a maximum of two follicles 18 mm and no need for dose reduction) and 13.4 (4.4-24.2) in hyperresponders (>2-3 mature follicles or dose reduction). There was a significant trend over response groups for body weight (P=0.005), body mass index (P=0.035), AFC (P=0.031) and FSH (P=0.001). Serum AMH median (IQR) was 10.6 pmol/l (6.9-18.2) in the 23 patients who achieved an ongoing pregnancy versus 10.5 (5.9-17.2) in the 100 non-pregnant women. Serum AMH may not be the best marker of the ovarian response in these patients., (Copyright (c) 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The aim of the present study was to determine the intrafollicular concentrations of anti-Müllerian hormone (AMH), inhibin-B and steroids in normal human small antral follicles and to relate them to follicular size., Methods: A group of 103 women having one ovary removed for fertility preservation by cryopreservation prior to gonadotoxic treatment served as a source of a total of 272 human small antral follicles. Prior to cryopreservation of the ovarian cortex, fluid from small antral follicles were collected. On the basis of the follicular volume, the diameter was calculated and follicles with diameters from 3 to 12 mm were included., Results: Concentrations of AMH decreased significantly (P < 0.0005) from 1124 +/- 158 ng/ml (mean +/- SEM) in follicles with a diameter of 3 mm to a concentration of 392 +/- 98 ng/ml in 9 mm follicles, followed by a reduction to below 100 ng/ml in 12 mm follicles. The concentrations of inhibin-B rose from 57 +/- 10 ng/ml (mean +/- SEM) in 3 mm follicles to 142 +/- 10 ng/ml in 12 mm follicles (P < 0.0005) with a peak concentration of almost 200 ng/ml in 9-10 mm follicles. Relating hormone concentrations with age showed that even follicles from girls younger than 10 years showed the same range of AMH concentrations as those from older girls or women., Conclusions: The intrafollicular concentrations of AMH become progressively lower with increasing follicle diameters. In contrast, concentrations of inhibin-B increased with increasing follicle diameter with peak values at around 9 mm in diameter. This suggests that AMH and inhibin-B undertake important intrafollicular functions around the time of normal follicular selection in the mid-follicular phase of the menstrual cycle.

Objective: To investigate a possible difference between true ovarian volume and ovarian volume estimated with two-dimensional (2D) transvaginal ultrasound., Design: Prospective clinical and laboratory study., Setting: University hospital research laboratory., Patient(s): Premenopausal girls and women from three Danish national fertility centers (A: n = 42; B: n = 6; C: n = 18), who had one entire ovary removed for cryopreservation of ovarian cortex., Intervention(s): Transvaginal 2D ultrasound measurement of ovarian volume before oophorectomy. True ovarian volume was obtained by weighing the ovary., Main Outcome Measure(s): Ovarian volume estimated by weight and ultrasound., Result(s): Ovarian tissue density was 1.00 g/mL. Mean ovarian volume by ultrasound vs. weight in the three groups was as follows: A: 6.3 mL vs. 7.8 mL; B: 5.4 mL vs. 6.8 mL; and C: 2.8 mL vs. 6.1 ml. Ovarian volume obtained by ultrasound was at least 27% smaller than the true ovarian volume., Conclusion(s): Ovarian volume was severely underestimated by transvaginal 2D ultrasound measurement., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Aim: Amenorrhoea is a common side-effect to chemotherapy of premenopausal women. We examine the association between chemotherapy-induced leucopaenia and the development of amenorrhoea in premenopausal women with breast cancer., Materials and Methods: In a multi-centre, randomised, controlled study, 1016 premenopausal women received seven series of FEC (F: fluorouracil, E: epirubicin and C: cyclophosphamide) for early stage breast cancer. In the first series, all patients received standard dose (F: 600 mg/m(2), E: 60 mg/m(2) and C: 600 mg/m(2)). Patients with leukocyte nadir 1.0-1.9 x 10(9)/l continued with standard dose for the remaining six series (STANDARD(REGISTERED), n=279). Patients with leukocyte nadir > or =2 x 10(9)/l were randomised to standard (STANDARD(RANDOMISED), n=373) or increased (TAILORED, n=364) dose of E and C. After each series, leukocyte nadir was evaluated. Absent bleeding after the 5th-7th series of FEC was interpreted as amenorrhoea., Results: The risk of amenorrhoea increased with age. In age-stratified analysis of the STANDARD groups (equal dose, different initial leukocyte nadir) low leukocyte nadir was associated with amenorrhoea for patients in the age-group 25-39 years (P=0.010). In age-stratified analysis in the randomised groups (different doses, same initial leukocyte nadir) a dose related increased risk of amenorrhoea was found for age-groups 25-39 (RR: 1.15, 95% confidence interval (CI): 1.06-1.24) and 40-44 years (RR:1.21, 95% CI: 1.001-1.47)., Conclusion: Age is the most important risk factor of amenorrhoea after FEC chemotherapy. However, for younger patients, lower leukocyte nadir in response to STANDARD FEC treatment or increased doses of C and E were associated with increased risk of amenorrhoea.

Background: Controlled ovarian stimulation (COS) and intrauterine insemination (IUI) are often used as the first-line treatment for subfertile couples. To minimize the variability in ovarian response in patients' first treatment cycle, we recently developed a recombinant follicle-stimulating hormone (rFSH) dosage nomogram. The nomogram has now been tested., Methods: Multicentre randomized controlled trial (RCT) including 228 ovulatory patients scheduled for COS and IUI. Patients were randomized to 'individual' (50-100 IU rFSH/day, n = 113) or 'standard' (75 IU rFSH/day, n = 115) dose. 'Individual' dose was prescribed according to the nomogram, which was based on patients' body weight and antral follicle count. The primary end-point was the proportion of patients with two to three follicles > or = 14 mm (maximum two follicles > or = 18 mm) on the day of hCG (leading follicle = 18 mm). Primary analysis was made by intention-to-treat., Results: In the 'individual' group, 79/113 (70%) of the patients developed two to three follicles versus 64/115 (56%) in the 'standard' group [absolute difference = 14.3 percentage points; 95% confidence interval (CI) 2-26, P = 0.03; absolute difference = 14.4; 95% CI 2-27, P = 0.02, when adjusting for centre]. Among patients with two to three follicles, the proportion of patients with two follicles was 46/79 (58%) in the 'individual' group versus 34/64 (53%) in the 'standard' group, P = 0.54. Ongoing pregnancy rate was 23/113 (20%) in the 'individual' group and 21/115 (18%) in the 'standard' group and the rate of multiple gestations was 1/113 (1%) versus 5/115 (4%), P = 0.21., Conclusions: This RCT is the first to clinically test a dosage nomogram in ovulatory IUI patients' first rFSH treatment cycle. Dosing according to the nomogram was superior to standard dosing., Trial Registration: ClinicalTrials.gov Identifier NCT00374634.

Background: Reliable age determination of first-trimester human embryos and fetuses is an important parameter for clinical use and basic science. Age determination by ultrasound or morphometric parameters of embryos 4-6 weeks post conception (p.c.) have been questioned, and more accurate methods are required. Data on whether and how maternal smoking and alcohol consumption influence embryonic and fetal foot growth is also lacking., Methods: Embryonic tissue from 102 first-trimester legal abortions (aged 35-69 days p.c.) were collected. All women answered a questionnaire concerning smoking and drinking habits, and delivered a urine sample for cotinine analysis. Embryonic age was evaluated by vaginal ultrasound measurements and by post-termination foot length and compared with the Carnegie stages., Results: Foot bud and foot plate were defined and measured as foot length in embryos aged 35-47 days p.c. (range 0.8-2.1 mm). In embryos and fetuses aged 41-69 days p.c., heel-toe length was measured (range 2.5-7.5 mm). We found a significant linear correlation between foot length and age. Morphology of the feet was compared visually with the Carnegie collection, and we found that the mean ages of the two collections correlated well. Foot length was independent of gender, Environmental Tobacco Smoke, maternal smoking and alcohol consumption., Conclusion: Foot length correlated linearly to embryonic and foetal age, and was unaffected by gender, ETS, maternal smoking and alcohol consumption.

Intubated patients may be unable to adequately cough up secretions. Endotracheal suctioning is therefore important in order to reduce the risk of consolidation and atelectasis that may lead to inadequate ventilation. The suction procedure is associated with complications and risks including bleeding, infection, atelectasis, hypoxemia, cardiovascular instability, elevated intracranial pressure, and may also cause lesions in the tracheal mucosa. The aim of this article was to review the available literature regarding endotracheal suctioning of adult intubated intensive care patients and to provide evidence-based recommendations The major recommendations are suctioning only when necessary, using a suction catheter occluding less than half the lumen of the endotracheal tube, using the lowest possible suction pressure, inserting the catheter no further than carina, suctioning no longer than 15s, performing continuous rather than intermittent suctioning, avoiding saline lavage, providing hyperoxygenation before and after the suction procedure, providing hyperinflation combined with hyperoxygenation on a non-routine basis, always using aseptic technique, and using either closed or open suction systems.

Background: Ovarian function was studied in Danish patients who had ovarian tissue cryopreserved, and the patients' experiences with the procedure were investigated., Methods: There were 92 women who had an entire ovary removed for cryopreservation 18-75 months earlier. Reasons included: breast cancer (n = 31; 34%), Hodgkin's lymphoma (n = 23; 25%), bone marrow transplantation (BMT) (n = 19; 21%) and others (n = 19; 21%). Patients completed a questionnaire, and transvaginal ultrasonic antral follicle count and serum analysis for follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) were performed in 73 women., Results: In total, 11% of the BMT patients had normal ovarian function. Hodgkin's patients who only received ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) (n = 12) and 60% of the breast cancer patients showed little evidence of ovarian damage. Regular menstruation was shown to be a good indicator of ovarian function. The cryopreservation procedure rarely complicated cancer treatment (5%) and 84% felt comforted because they had potentially secured their fertility., Conclusions: Cryopreservation of ovarian tissue should be considered in young female patients with Hodgkin's lymphoma receiving more aggressive treatment than ABVD and in patients scheduled for BMT. The recommendation for breast cancer patient should be individualized. The cryopreservation process did not delay cancer treatment.