Search

Purpose To investigate the oncologic and reproductive outcome of a conservative treatment with progestin agents in early-stage grade 1 endometrial cancer (G1EC), grade 2 endometrial cancer (G2EC) or complex atypical hyperplasia (CAH) in young premenopausal women. Methods Women treated for early-stage endometrial cancer or atypical hyperplasia of the endometrium with a conservative therapy between 2006 and 2018 were enrolled in this retrospective analysis. Progestin agents were orally administered on a daily basis for 3 months for at least one cycle. Endometrial tissue was obtained by hysteroscopy and Dilatation & Curettage (D&C) being performed before and after end of treatment. Therapeutic response was assessed by pathological examination. Results A total of 14 patients were included. After treatment with progestin agents, 11 of these patients initially showed a complete or partial response. Three patients with early-stage endometrial cancer did not respond. Of the three patients with initially diagnosed atypical hyperplasia, none showed any remaining disease later. Of the eight patients with initially diagnosed endometrial cancer, who had responded to first treatment, three patients were re-diagnosed with endometrial cancer later. One patient with initial endometrial cancer became pregnant but aborted in the 10th week. Conclusion Due to its good efficacy, progestin agents offer a feasible therapeutic option in the fertility-preserving treatment of early-stage endometrial cancer in young premenopausal women. However, recurrence rate remains high. Therefore, a close follow-up is mandatory, also in responders. Patients should be informed of limitations and risks of conservative treatment. Yet after completion of family planning, hysterectomy should be performed.

Purpose Surgery and radiotherapy as part of breast cancer treatment can lead to lymphoedema of the upper extremities (breast cancer-related lymphoedema = BCRL) and reduce the quality of life (health-related quality of life = HRQoL). The aim of the present study was to investigate the influence of paddling in a dragon boat (PP), on HRQoL and BCRL in breast cancer survivors (BCS). Methods Between April and October 2017, a prospective case-control study evaluated the effects of PP compared to a control group. In the paddle group (n = 28), weekly arm circumference measurements were taken at four defined anatomic areas of the arm before and after training; in the control group (n = 70) the measurements were taken once a month. At the beginning and end of the study, questionnaires from both groups (SF 36, EORTC QLQ-C30) were evaluated to understand the differences in HRQoL. Results The paddle group started with a higher HRQoL compared to in the control group. Most interesting, whether the affected or unaffected arm, whether before or after training - the arm circumference decreased over time in the paddling group. A pre-existing lymphoedema was not negatively influenced by paddling. In the paddle group the physical health was constant over the season, while the physical health of the control group decreased significantly over time. Conclusion PP in a dragon boat does not lead to the development or worsening of pre-existing lymphoedema due to breast cancer therapy and seems to have a positive effect on the quality of life.

Background:Endometrial cancer ranges among the most common gynecologic cancers worldwide. As the incidence of causing risk factors increases it is also becoming more prevalent in younger, premenopausal women who havent´ completed family planning yet. Our study aimed to investigate the oncologic and reproductive outcome of a conservative treatment with progestin agents in early stage grade 1 endometrial cancer (G1EC), grade 2 endometrial cancer (G2EC) or complex atypical hyperplasia (CAH) in young premenopausal women. Methods:Women treated for early stage endometrial cancer or atypical hyperplasia of the endometrium with a conservative therapy between 2006 and 2018 were enrolled in this retrospective analysis. Progestin agents were orally administered on a daily basis for 3 months for at least one cycle. Endometrial tissue was obtained by hysteroscopy and Dilatation & Curettage (D&C) being performed before and after end of treatment. Therapeutic response was assessed by pathological examination.Results:A total of 14 patients were included. After treatment with progestin agents, 11 of these patients initially showed a complete or partial response. Three patients with early stage endometrial cancer did not respond. Of the three patients with initially diagnosed atypical hyperplasia, none showed any remaining disease later. Of the 8 patients with initially diagnosed endometrial cancer, who had responded to first treatment, 3 patients were re-diagnosed with endometrial cancer later. One patient with initial endometrial cancer became pregnant but aborted in the 10th week. Conclusion:Due to its good efficacy progestin agents offer a feasible therapeutic option in the fertility preserving treatment of early stage endometrial cancer in young premenopausal women. However, recurrence rate remains high in early stage endometrial cancer. Therefore, a close follow-up is mandatory, also in responders. Patients should be informed of limitations and risks of conservative treatment. Yet after completion of family planning, hysterectomy should be performed.

Serial longitudinal enumeration of circulating tumor cells (CTCs) has shown its prognostic value on progression-free survival and overall survival (OS) in patients with stage IV breast cancer. This study prospectively evaluated the role of CTCs as a prognostic marker during further progression of metastatic breast cancer (MBC). Among 476 MBC patients recruited between 2010 and 2015, the 103 patients with a known CTC status at baseline (CTCBL) and within 4 weeks of tumor progression (CTCPD) were included. Progressive disease (PD) was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Using the CellSearch method

ObjectiveIn cancer patients, the pathology report serves as an important basis for treatment. Therefore, a correct cancer diagnosis is crucial, and diagnostic discrepancies may be of clinical relevance. It was the aim of this study to perform a specialized histopathology review and to investigate potential clinical implications of expert second opinion pathology in endometrial cancer.MethodsPatients treated for endometrial carcinoma at the Tübingen University Women's hospital between 2003 and 2013 were identified. Original pathology reports were reviewed, and contributing pathologists were asked to submit original slides and paraffin blocks. Case review was subsequently performed by 3 pathologists specialized in gynecological pathology who were blinded for clinical information. For histological typing, the World Health Organization 2014 classification was used, grading and staging were performed according to International Federation of Gynecology and Obstetrics 2009. Risk assignment was performed based on the 2013 European Society for Medical Oncology clinical practice guidelines.ResultsIn 565 of 745 cases, which had originally been diagnosed as endometrial carcinoma, archival histological slides and blocks were available. In 55 (9.7%) of 565 cases, a major diagnostic discrepancy of potential clinical relevance was found after expert review. In 38 of these 55 cases, the diagnostic discrepancy was related to tumor type (n = 24), grade (n = 10) or myoinvasion (n = 4). In 17 cases, the diagnosis of endometrial carcinoma could not be confirmed (atypical hyperplasia, n = 10; endometrial carcinosarcoma, n = 4; neuroendocrine carcinoma, n = 1; leiomyosarcoma, n = 1; atypical polypoid adenomyoma, n = 1). Minor discrepancies not changing risk classification were also noted in 214 (37.9%) of 565, most frequently for grade within the low-grade (G1/G2) category (n = 184).ConclusionsA retrospective gynecopathological case review was shown to reveal limited but significant discrepancies in histological diagnoses as well as typing and grading of endometrial carcinomas, some directly impacting clinical management. Second opinion pathology therefore not only helps to improve the quality of translational research study cohorts but might also help to optimize patient care in difficult cases.

Minimally invasive surgery is a major pillar of gynecological surgery. However, there are very few training opportunities outside the operation theater (OR) due to the cost and equipment requirements of organ simulators, virtual reality trainers (VRT) are promising tools to fill this gap. Experienced and inexperienced participants of a minimally invasive surgery course followed the standardized HystSim™-VRT training program. Performance of 39 Participants (15 inexperienced and 24 experienced) was evaluated in the standardized hysteroscopic program HystSim™. Tasks included three rounds of both a polyp and a myoma resection. Primary measurements were improvement in resection time, cumulative resection path length, and distention media use. The HystSim™-VRT is an effective tool to improve the psychomotor skills needed in hysteroscopic surgery for experienced and inexperienced surgeons prior to OR exposure. Additional organ models training is advisable for hysteroscopic haptic skills

BACKGROUND/AIM Only 30-50% of patients with sentinel lymph node (SLN) metastases present with further axillary lymph node metastases. Therefore, up to 70% of patients with positive SLN are overtreated by axillary dissection (AD) and may suffer from complications such as sensory disturbances or lymphedema. According to the current S3 guidelines, AD can be avoided in patients with a T1/T2 tumor if breast-conserving surgery with subsequent tangential irradiation is performed and no more than two SLNs are affected. Additionally, use of nomograms, that predict the probability of non-sentinel lymph node (NSLN) metastases, is recommended. Therefore, models for the prediction of NSLN metastases in our defined population were constructed and compared with the published nomograms. PATIENTS AND METHODS In a retrospective study, 2,146 primary breast cancer patients, who underwent SLN biopsy at the University Women's Hospital in Tuebingen, were evaluated by dividing the patient group in a training and validation collective (TC or VC). Using the SLN-positive TC patients, three models for the prediction of the likelihood of NSLN metastases were adapted and were then validated using the SLN-positive VC patients. In addition, the predictive power of nomograms from Memorial Sloan Kettering Cancer Center (MSKCC), Stanford, and the Cambridge model were compared with regard to our patient collective. RESULTS A total of 2,146 patients were included in the study. Of these, 470 patients had positive SLN, 295 consisted the training collective and 175 consisted the validation collective. In a regression model, three variants - with 11, 6 and 2 variables - were developed for the prediction of NSLN metastases in our defined population and compared to the most frequently used nomograms. Our variants with 11 and with 6 variables were proven to be a particularly suitable model and showed similarly good results as the published MSKCC nomogram. CONCLUSION Our developed nomograms may be used as a prediction tool for NSLN metastases after positive SLN.

To investigate in a large cohort of young university women whether different progestins and different ethinyl estradiol (EE) dosages in oral hormonal contraceptives (OHCs) adversely affect sexual function.Female medical students from German, Austrian, and Swiss universities (14/1/1) completed an anonymous online questionnaire comprising the 19 Female Sexual Function Index (FSFI) questions and 17 additional questions concerning demographics, lifestyle, sexual activity, and contraceptive use. OHCs were categorized by EE dose (≤20,20 to ≤30, and30 µg) and partially androgenic or antiandrogenic progestins. FSFI scores were analyzed by contraceptive method using descriptive statistics and standard nonparametric tests.We analyzed 2612 questionnaires submitted by respondents aged ≤30 years [mean age (SD) 23.5 (2.5) years]. Of 2126 contraceptive users, 1535 (72.2 %) used OHCs. Median FSFI total scores (ranges) were 28.2 (2.0-36.0) for all respondents. Median FSFI was significantly lower in non-users (24.4) versus users (28.7) of contraception (p 0.001). Stratified analysis showed that 279/486 (57.4 %) respondents using no contraceptives, 563/1535 (36.7 %) using OHCs, 71/227 (31.3 %) using non-oral hormonal contraceptives, and 96/351 (27.4 %) using non-hormonal contraceptives were at risk for female sexual dysfunction (FSFI total score26.55). FSFI scores for the three EE dosage categories and progestin components did not differ significantly.For OHCs, the FSFI score was lower than for other contraceptives but there was no significant association with EE dose or progestins, possibly due to small sample sizes. Further research needs to clarify the role of OHCs in female sexual function.

Several classification systems for female genital tract anomalies exist but are of limited use in clinical practice. We, therefore, assessed the applicability and ease of use of the new ESHRE/ESGE classification, using only patient records. This retrospective, single-center, proof-of-principle study systematically analyzed the surgical reports and other hospital records of 920 inpatients and outpatients treated for confirmed female genital tract congenital malformations at a major German university hospital during 2003–2013. Using only this information, a non-expert (medical student) assigned patients to an ESHRE/ESGE class, rating ease of classification based on the time and the number of additional medical records required. Results were verified by an expert gynecologist, who also classified any malformations previously left unclassified. Data analysis used descriptive statistics. The non-expert successfully classified 859/920 patients (93.4%), rating classification as “easy” for 836/859 (90.9%) and “moderately difficult” for 23/859 (2.5%) patients. The expert gynecologist successfully classified 60 (60/920, 6.5%) of the remaining 61 patients rated as “difficult” by the non-expert, but was unable to accurately subclassify 1 patient (1/920, 0.1%) because the operative report lacked the relevant details. 251/920 (27.3%) patients had associated non-Mullerian anomalies, most frequently renal (20.9%) and skeletal (9.1%) malformations. The ESHRE/ESGE classification provides a generally applicable, comprehensive, and adequately specific classification of female genital tract congenital malformations. It offers an efficient basis for communication between non-experts and experts in the field and is, therefore, useful in clinical management and treatment planning.

Objective The main objectives of our study were to demonstrate that laparoscopic supracervical hysterectomy (LSH) or total laparoscopic hysterectomy (TLH) can be performed safely even in patients with a uterine weight ≥ 500 g, to analyze the rate of conversions to laparotomy due to uterine size and to estimate the incidence and type of intraoperative and long-term postoperative complications. Study Design Retrospective open, single-center, comparative interventional study of LSH and TLH. Results The present study comprised a total of 138 patients that underwent laparoscopic hysterectomy with a uterine weight ≥ 500 g; 109 patients (79.0 %) underwent LSH and 29 patients (21.0 %) underwent TLH. Median uterine weight across the entire cohort was 602 g, with the largest uterus weighing 1860 g. A total of 24 cases (17.4 %) among the 138 hysterectomies were converted to a laparotomy due to lack of adequate intraabdominal space and size of the uterus. Mean uterine weight of the patients in the LSH group that underwent conversion was 883 g (SD 380 g, n = 13) and 757 g (SD 371 g, n = 11) in the TLH group. The rate of conversion to laparotomy due to the uterine weight was significantly lower in the LSH group (11.9 %) compared to the TLH group (37.9 %) (p = 0.002). Intraoperative complications requiring laparotomy for other reasons but uterine size occurred in 6 patients of the study cohort (6/138; 4.3 %). Long-term postoperative complications occurred in 2 patients (2/138, 1.4 %), both patients from LSH group had to be re-operated on due to adhesions. Conclusions Our study adds further insight in the limited data set of laparoscopic hysterectomy for increased uterine weight and shows that LSH and TLH are safe and feasible even in patients with very large uteri (≥ 500 g).

Study Objective To assess the long-term outcome of an optimized minimally invasive neovaginoplasty technique in vaginal agenesis. Design Combined retrospective and prospective study. Setting University hospital. Participants 240 patients with congenital vaginal agenesis. Interventions Patients with an indication for neovagina creation underwent laparoscopically assisted neovaginoplasty involving vaginoabdominal blunt perforation and intracorporeal traction using tension threads and an abdominally positioned extracorporeal traction device. Main Outcome Measures Long-term anatomic success, functional success compared with similar-aged controls, long-term complications, and incidence of human papilloma virus (HPV) infections. Results During median follow-up for 16 (range 11-141) months, mean functional neovaginal length remained stable at 9.5 cm in all patients, including those who had no sexual intercourse and had stopped wearing the vaginal dummy. Median dummy wearing time was 8.6 months. Time to epithelialization depended on the time of onset and frequency of sexual intercourse. At long-term follow-up, median total Female Sexual Function Index score was 30.0, comparable with similar-aged controls. No common long-term complications occurred. Four patients required cauterization of granulation tissue. 7/240 (2.9%) patients were HPV-positive with low- to high-grade squamous intraepithelial lesions, 3 patients reverting to HPV-negative status at long-term follow-up. Conclusions Our technique creates a neovagina of adequate size and secretory capacity for normal coitus, requiring no prolonged dilation postoperatively, even in the absence of sexual intercourse. The procedure is fast, effective and minimally traumatic, has a very low long-term complication rate and provides very satisfactory long-term functional results.

The aim of this study is to systematically investigate under standardized experimental conditions the effects of instrument contamination and wear on the quality of bipolar vessel sealing (BVS) achieved using a reusable instrument.The study was designed as a prospective, randomized, and controlled in vitro study and conducted in an academic research environment. Reusable bipolar coagulation forceps (BiClamp® 200 C, ERBE Elektromedizin) were used to apply sealing pressures of 300-1,100 mN/mm(2) to 239 renal arteries from commercially slaughtered female pigs (Swabian-Hall Swine). Forceps jaws were coated with porcine blood, blood and collagen, or blood, collagen, and fat to simulate instrument contamination with biological material during surgery. Clinical wear was mimicked by sandpaper abrasion. The main outcome measures were seal success (resistance to 250 mmHg intraluminal pressure for 2 min) and seal stability (burst pressure).Sealing pressure had a significant impact, with 800 mN/mm(2) producing the best sealing results. Seal success increased with total energy applied to the tissue, a higher maximum temperature, and longer coagulation as indicated by desiccation time. Experimental contamination had no significant impact on seal success and only a limited effect on seal stability. Similarly, abrasive wear also had no significant effect on either seal quality or seal strength.The impact of bipolar forceps contamination and wear on seal success and quality was negligible in our in vitro model. To achieve high-quality seals, it is essential to use adequate sealing pressures. Our findings could have direct implications for the design and clinical handling of BVS instruments.

Low- and intermediate-risk endometrial carcinomas have an excellent prognosis. Nonetheless, a small subgroup of such patients will experience unexpected relapse. Recently L1CAM was suggested to be a strong prognosticator in endometrial carcinoma. The focus of our study was on low- and intermediate-risk disease, where no or only limited adjuvant treatment is recommended according to current guidelines.Endometrial carcinomas of low, intermediate and high-intermediate risk according to published 2016 consensus guidelines were identified. The study was limited to cases with previous central pathology review focusing on histotype, depth of myometrial invasion, presence of lymphovascular space invasion (LVSI) and MELF pattern of invasion. Standard L1CAM immunohistochemistry was performed. Disease-specific uni- and multivariate survival analyses were calculated.A total of 344 cases were available for immunohistochemistry (low-risk: n = 250; intermediate-risk: n = 67; high-intermediate-risk: n = 27). L1CAM positivity rates were: 29/344 (8.4 %; all cases), 18/250 (7.2 %; low-risk), 6/67 (9.0 %; intermediate-risk) and 5/27 (18.5 %; high-intermediate-risk). Expression of L1CAM was independent of LVSI and MELF. L1CAM was a significant independent prognosticator for disease-specific survival with a hazard ratio of 5.98 [CI 1.50-22.14, p = 0.012]. Adverse prognostic significance of L1CAM positivity was maintained after low-risk subgroup analysis (5-year disease-specific survival rates 71.8 vs. 100 %, p 0.0001). All four tumour-related deaths in the subgroup of low-risk disease occurred in patients with L1CAM-positive tumours.The current definition of "low-risk" in endometrial carcinoma should be amended. "Low-risk carcinomas" should be limited to L1CAM-negative tumours. L1CAM status will play a key role in future algorithms to tailor adjuvant treatment and patient follow-up strategies.

While intact circulating tumor cells (iCTC) have independent negative prognostic impact on patients with metastatic breast cancer (MBC), the prognostic relevance of apoptotic CTC (aCTC) has not been validated in larger patient cohorts. This study assessed aCTC and iCTC statuses at baseline (CTCBL) and CTC kinetics (CTCKIN) as changes from CTCBL to one completed treatment cycle for their utility in predicting response, progression-free survival (PFS), and overall survival (OS) in MBC. Status of iCTC and aCTC was prospectively assessed in 442 patients using the CellSearch™ system. Different cutoffs were analyzed both for iCTC and aCTC (≥5, ≥10, ≥25 and ≥50 CTC/7.5 ml). CTCKIN were characterized by ≥25 % changes in CTC counts. Numbers of iCTC and aCTC at baseline correlated strongly (r = 0.7). For iCTCBL positive patients, additional detection of aCTCBL had a significant prognostic impact on OS (aCTCBL positive 10.3 vs. aCTCBL negative 16.4 months, p = 0.012). Worst prognosis for OS was observed in patients with ≥50 iCTC/7.5 ml and simultaneously detected aCTC. Determination of aCTCKIN showed stronger discriminating power than iCTCKIN, with higher PFS and OS for the group with decreasing CTCs (PFS 7.7 vs. 6.1; OS 22.2 vs. 16.4). Intact and aCTC are predictive of outcome in MBC. Apoptotic CTC counts ≥ 5/7.5 ml in conjunction with iCTC at baseline have an independent unfavorable prognostic impact on OS. Decreasing aCTCKIN at ≥ 5/7.5 ml in serial enumeration is associated with favorable outcome. Therefore, separate enumeration of iCTC and aCTC is useful in tailoring systemic treatment.

The potential advantage of using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) methodology to detect metastasis in sentinel lymph nodes (SLNs) of breast cancer (BC) patients was evaluated in this prospective study. We measured the expression of relevant gene transcripts in SLNs using an innovative algorithm and compared the results of single-marker assays versus multi-marker assays with conventional histological detection methods. SLNs from women aged ≥ 18 years diagnosed with unilateral BC were examined by haematoxylin-eosin staining and immunohistochemistry and analysed for transcripts of several relevant genes using qRT-PCR (learning group). Four candidate panels of expressed transcript combinations with high sensitivity and specificity were selected for further investigation. The candidate panels were then validated using SLNs from a second group of BC patients (validation group). In the learning group, 74/314 SLN sections from 150 patients were positive for metastasis by histology. The transcripts analysed showed the following individual sensitivities/specificities: cytokeratin 19 (CK19) 94.6%/97.9%; mammaglobin 1 (MGB1) 82.4%/91.7%; mammaglobin 2 (MGB2) 82.4%/96.7%; carcinoembryonic antigen (CEA) 71.6%/97.5%; EPCAM (epithelial cell adhesion molecule) 91.9%/97.1%; and NY-BR-1 82.4%/93.8%. The optimal panel based on the predefined criteria comprised four markers: CK19, MGB1, EPCAM, and NY-BR-1, of which ≥ 2 had to be positive (95.9% sensitivity, 95.0% specificity, 85.5% positive predictive value (PPV), and 98.7% negative predictive value (NPV)). Overall concordance with histology was 95.2%. In the validation group, 84/315 SLN sections from 235 patients were histologically positive, and panel sensitivity, specificity and overall accuracy were 88.1, 95.2 and 93.3%, respectively, at the SLN section level. In conclusion, molecular staging using expression patterns of relevant transcripts in SLNs could serve as a useful complement to standard diagnostic work-up in BC patients. The proposed flexible multi-parametric approach does not improve the overall accuracy compared with the single-marker approach. However, it overcomes several limitations of the previously reported molecular assays for SLN diagnosis.

Introduction According to the World Health Organization definition, sexual health is more than mere physical sexual function; it also encompasses emotional, mental, and social well-being in relation to sexuality and is not merely the absence of dysfunction or disease. In line with this definition, various studies have reported that female sexual function is associated with partnership quality, body image, and body self-acceptance. Aim To investigate whether female sexual function is influenced by (i) body self-acceptance and (ii) partnership quality, as important factors in psychosocial well-being, and (iii) whether the effects of body self-acceptance are moderated by partnership quality. Methods In total, 2,685 female medical students no older than 35 years from Germany, Austria, and Switzerland completed an anonymous online questionnaire comprising the Female Sexual Function Index (FSFI) and the Self-Acceptance of the Body Scale. Respondents were asked to state whether they had been in a steady partnership in the preceding 6 months. When present, the quality of the partnership status was rated (enamoredness, love, friendship, or conflicted). To determine correlations, group differences, and moderating effects among body self-acceptance, partnership quality, and sexual function, the data were analyzed using Spearman correlations, Kruskal-Wallis tests, and analyses of variance. Main Outcome Measures Female sexual function (FSFI total score). Results (i) In sexually active women, higher FSFI scores were significantly associated with greater body self-acceptance and a steady partnership during the preceding 6 months. (ii) Total FSFI scores were highest in women who described their partnership as enamored (29.45) or loving (28.55). Lower scores were observed in single women (26.71) and in women who described their partnerships as friendship (25.76) or as emotionally conflicted (23.41). (iii) Total FSFI score was affected by an interaction between body self-acceptance and partnership quality. Body self- acceptance was positively associated with FSFI total scores, particularly in single women and women in emotionally conflicted partnerships. Conclusion Our findings suggest that in young women, body self-acceptance and partnership quality are positively associated with better sexual function, and that high body self-acceptance might buffer the negative impact on sexual function of partnership quality. The present data suggest that psychological interventions to improve the body image of younger women can positively affect sexual function and thereby improve sexual health.

The main part of cytosolic protein degradation depends on the ubiquitin-proteasome system. Proteasomes degrade their substrates into small peptide fragments, some of which are translocated into the endoplasmatic reticulum and loaded onto MHC class I molecules, which are then transported to the cell surface for inspection by CTL. A reliable prediction of proteasomal cleavages in a given protein for the identification of CTL epitopes would benefit immensely from additional cleavage data for the training of prediction algorithms. To increase the knowledge about proteasomal specificity and to gain more insight into the relation of proteasomal activity and susceptibility to prion disease, we digested sheep prion protein with human constitutive and immuno-20S proteasomes. All fragments generated in the digest were quantified. Our results underline the different cleavage specificities of constitutive and immunoproteasomes and provide data for the training of prediction programs for proteasomal cleavages. Furthermore, the kinetic analysis of proteasomal digestion of two different alleles of prion protein shows that even small changes in a protein sequence can affect the overall efficiency of proteasomal processing and thus provides more insight into the possible molecular background of allelic variations and the pathogenicity of prion proteins.

To compare patient-reported quality-of-life and sexual function outcomes in women after laparoscopic supracervical hysterectomy (LSH) or total laparoscopic hysterectomy (TLH) for benign uterine disease. Out of a cohort of 1,952 patients from a previous implementation study of LSH and TLH, 1,886 patients who had not undergone intraoperative conversion to laparotomy or were ineligible for other reasons were invited by mail to participate in this prospective, questionnaire-based follow-up study. Of the 915/1,952 (48.5 %) survey respondents included in the analysis, 788 (86.1 %) and 127 (13.9 %) had undergone LSH or TLH, respectively. Women undergoing LSH reported significantly lower pain levels (p = 0.037) and faster partial (p = 0.015) and complete (p

Background To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC). Methods CTCBL and CTC1C status was determined as negative (-) or positive (+) for

We investigate the effect of spatial migration of cells in cellular automata that have been used in the study of excitable media and epidemiology, with an infinite range migration. While the periods of oscillation of the densities of cells in each state are mostly unaffected by migration, the amplitudes of these oscillations behave very differently when migration is present. Spatial structures which develop in the absence of migration are shown to be unstable to even the lowest possible level of migration. Decay of these structures is shown to scale with system size, demonstrating the absence of structure in the asymptotic regime for any system size. Decay of structure is also shown to occur on a time scale, T, scaling roughly as T ∼ t · m, where m is the migration rate and t is time elapsed. The exact shape of the decay of structure, however, is not self-similar. Overall, structure decays almost entirely after each cell has migrated twice on an average. We conclude from this that the asymptotic behavior, after the structure has subsided, is governed by the mean field approximation.

Objective: Currently available monopolar loop electrodes are difficult to handle in laparoscopic supracervical hysterectomy (LSH) and are entirely disposable devices, generating additional operating costs. The aim of this interventional study was the comparison of the efficiency and safety of cervical detachment with a newly developed monopolar loop electrode (SupraLoop™) with a conventional method of cervical detachment in LSH. Material and Methods: Our study sample included 1598 patients; 1070 patients that underwent LSH with cervical detachment using the monopolar SupraLoop™ (study group) and 528 patients that underwent LSH with cervical detachment using the monopolar needle (control group). We also assessed cervical detachment time and total device application and cutting time in a subgroup of 49 patients (23 patients from the study group and 26 patients from the control group). Results: Total operation time for LSH was significantly shorter among SupraLoop™ patients (93 ± 41 minutes) when compared to patients in whom cervical detachment was performed with the needle (105 ± 44 minutes) (p

The auence of the memory effects on the Poissonian clocks with fluctuating counting rates is investigated by using the technique of characteristic functionals. A general approach for computing all cumulants of the number of counts is suggested based on an analogy with the theory of rate processes with dynamical disorder. The large time behavior of the cumulants is investigated for stationary random processes with short and long memory, respectively. For short memory in the long run all cumulants increase linearly in time and the averaged stochastic process describing the statistics of the number of counts, although generally non-Poissonian, is nonintermittent and can be used as a clock. For finite long memory described by a stationary fractal random process, even though the cumulants of the number of events increase faster than linearly in time, the fluctuations are still non-intexmittent and the averaged random process is also a clock. For infinite memory, however, the fluctuations of the number of counts are intermittent and the averaged random process is not a clock any more. An alternative stochastic approach is developed based on the use of a dynamical analogue of the Porter-Thomas formula; the results are consistent with the first version of the theory. Three applications of the general theory are presented. The 6rst application is related to the connection between the Kimura's neutral theory of molecular evolution and the Gillespie's episodic clock for the rate of amino acid substitutions through the evolutionary process. If the fluctuations of the rate of substitution have short memory or long finite memory then Gillespie's episodic clock is consistent with Kimura's theory. Only the infinite memory is not consistent with the neutral hypothesis. The second application is the study of a hopping mechanism for enhanced diffusion. A biased random walk is investigated by assuming that the distribution of the number of jumps is given by a Poissonian process with a fluctuating counting rate. If the fluctuations of the counting rate have short memory then the resulting biased diffusion is normal and obeys Einstein's linear equation for the mean square displacement of the moving particle. For long memory the mean square displacement of the moving particle increases faster than linearly in time and the diffusion is enhanced. An alternative approach for a random walk in the velocity space is developed. In this case the diffusion process is even more

A mean-field approach for epidemic processes with high migration is suggested by analogy with non-equilibrium statistical mechanics. For large systems a limit of the thermodynamic type is introduced for which both the total size of the system and the total number of individuals tend to infinity but the population density remains constant. In the thermodynamic limit the infection rate is proportional to the product of the proportion of individuals susceptible to infection and the average probability of infection. The limit form of the average probability of infection is insensitive to the detailed behaviour of the fluctuations of the number of infectious individuals and may belong to two universality classes: (1) if the fluctuation of the number of infectives is non-intermittent it increases with the increase of the partial density of infectives and approaches exponentially the asymptotic value one for large densities; (2) for intermittent fluctuations obeying a power-law scaling the average probability of infection also displays a saturation effect for large densities of infectives but the asymptotic value one is approached according to a power law rather than exponentially. For low densities of infectives both expressions for the average probability of infection are linear functions of the proportion of infectives and the infection rate is given by the mass-action law.

A statistical-mechanical model for the propagation of a space-dependent epidemic is suggested based on the following assumptions. (1) The population is made up of three types of individuals, susceptibles, infectives and recovered. The total population size is constant and confined in a given region of d s -dimensional Euclidean space ( d s = 1, 2, 3). (2) An infected individual has a constant probability of recovery and an immune recovered individual has a constant probability of resensibilization. (3) Any infected individual from a given neighborhood of a susceptible individual has a probability p ( r ) of transmitting the disease which depends on the distance r between the two individuals. (4) The individuals migrate from one position to another with a rate depending on the displacement vector between the two positions. A statistical-mechanical description of the epidemic spreading is given in terms of a set of grand canonical probability densities for the positions and states of the individuals. An exact nonlinear evolution equation is derived for these probability densities and a self-consistent procedure of solving it is suggested. An explicit computation is presented for the case of very fast migration based on the adiabatic elimination of the coordinates of the individuals. An eikonal approximation for the fluctuations of the different types of individuals irrespective of their positions is developed in the limit of very large systems with constant total population density resulting in a Hamilton-Jacobi equation for the logarithm of the probability density of the proportions of susceptibles, infective and recovered. The deterministic equations of the process are identified with the evolution equations for the most probable fluctuation paths. If the individuals are confined at discrete positions in space this approach leads to the ordinary differential equation description of cellular automata epidemics presented in the literature. A continuous space alternative description is also presented. It is shown that the logarithm of the probability density of population fluctuations is a Liapunov function for the deterministic evolution equations. This Liapunov function is used for developing a generalized thermodynamic formalism of the epidemic process similar to the thermodynamic and stochastic theory of Ross, Hunt and Hunt from nonequilibrium thermodynamics of transport processes and reaction-diffusion systems.

A general method for constructing self-similar scalar fractal random fields is suggested based on the assumption that the fields are generated by a broad distribution of punctual sources. The method is illustrated by a problem of population biology, the evolution on a random fitness landscape. A random fitness landscape is constructed based on the following hypotheses. The landscape is defined by the dependence of a fitness variable φ on the state vector x of the individuals: φ = φ( x ) ; the corresponding hypersurface has a large number of local maxima characterized by a local probability law with variable parameters. These maxima are uniformly randomly distributed throughout the state space of the individuals. From generation to generation the heights and the shapes of these local maxima can change; this change is described in terms of two probabilities p and α that an individual modification occurs and that the process of variation as a whole stops, respectively. A general method for computing the stochastic properties of the evolutionary landscape is suggested based on the use of characteristic functionals. An explicit computation of the Fourier spectrum of the cumulants of the evolutionary landscape is performed in a limit of the thermodynamic type for which the number of maxima and the volume of the state space of the individuals tend to infinity but the density of maxima remains constant. It is shown that, although a typical realization of the evolutionary landscape is very rough, its average properties expressed by the Fourier spectrum of its cumulants are smooth and characterized by scaling laws of the power law type. The average landscape which is made up of the frozen contributions of the changes corresponding to different generations is flat, a result which is consistent with the Kimura's theory of molecular evolution. Some general implications of the suggested approach for the statistical physics of systems with random ultrametric topology are also investigated.

The possible occurrence of ergodic behavior for large times is investigated in the case of stationary random processes with memory. It is shown that for finite times the time average of a state function is generally a random variable and thus two types of cumulants can be introduced: for the time average and for the statistical ensemble, respectively. In the limit of infinite time a transition from the random to the deterministic behavior of the time average may occur, resulting in an ergodic behavior. The conditions of occurrence of this transition are investigated by analyzing the scaling behavior of the cumulants of the time average. A general approach for the computation of these cumulants is developed; explicit computations are presented both for short and long memory in the particular case of separable stationary processes for which the cumulants of a statistical ensemble can be factorized into products of functions depending on binary time differences. In both cases the ergodic behavior emerges for large times provided that the cumulants of a statistical ensemble decrease to zero as the time differences increase to infinity. The analysis leads to the surprising conclusion that the scaling behavior of the cumulants of the time average is relatively insensitive to the type of memory considered: both for short and long memory the cumulants of the time average obey inverse different from zero for large time differences, then the time averaage is random even as the length of the total time interval tends to infinity and the ergodic behavior no longer holds. The theory is applied to the study of long range correlations of nucleotide sequences in DNA; in this case the length t of a sequence of nucleotides plays the role of the time variable. A proportionality relationship is established between the cumulants of the pyrimidine excess in a sequence of length t and the cumulants of the time (length) average of the probability of occurrence of a pyrimidine. It is shown that the statistical analysis of the DNA data presented in the literature is consistent with the occurrence of the ergodic behavior for large lengths. The implications of the approach to the analysis of the large time behavior of stochastic cellular automata and of fractional Brownian motion are also investigated.

The large time behavior of stochastic cellular automata is investigated by means of an analogy with Van Kampen's approach to the ergodic behavior of Markov processes in continuous time and with a discrete state space. A stochastic cellular automaton with a finite number of cells may display an extremely large, but however finite number M of lattice configurations. Since the different configurations are evaluated according to a stochastic local rule connecting the variables corresponding to two successive time steps, the dynamics of the process can be described in terms of an inhomogeneous Markovian random walk among the M configurations of the system. An infinite Lippman-Schwinger expansion for the generating function of the total times q 1 , …, q M spent by the automaton in the different M configurations is used for the statistical characterization of the system. Exact equations for the moments of all times q 1 , …, q M are derived in terms of the propagator of the random walk. It is shown that for large values of the total time q = Σ u q u the average individual times 〈 q u 〉 attached to the different configurations u = 1, …, M are proportional to the corresponding stationary state probabilities P u st : 〈 q u 〉 ∼ q P u st , u = 1, …, M . These asymptotic laws show that in the long run the cellular automaton is ergodic, that is, for large times the ensemble average of a property depending on the configurations of the lattice is equal to the corresponding temporal average evaluated over a very large time interval. For large total times q the correlation functions of the individual sojourn times q 1 , …, q M increase linearly with the total number of time steps q : 〈 Δq u Δq u ′ 〉 ∼ q as q → ∞ which corresponds to non-intermittent fluctuations. An alternative approach for investigating the ergodic behavior of Markov processes in discrete space and time is suggested on the basis of a multiple averaging of a Kronecker symbol; this alternative approach can be extended to non-Markovian random processes with infinite memory. The implications of the results for the numerical analysis of the large time behavior of stochastic cellular automata are also investigated.

A unified description for the parallel relaxation in systems with static disorder and for the competitive risk mortality theory in population biology is suggested by combining the physical and biological approaches presented in the literature. A multichannel parallel decay process is investigated by assuming that each channel is characterized by a state vector x and by a probability of decaying p~x;t!. A general fluctuation-dissipation relation is derived which relates the effective decay rate of the process to the fluctuations of the density of channels characterized by different state vectors. A limit of the thermodynamic type in x space is introduced for which both the volume available and the average number of channels tend to infinity, but the average volume density of channels remains constant. By using scaling arguments combined with a stochastic renormalization group approach, two types of universal laws are identified in the thermodynamic limit for the relaxation ~survival! function corresponding to nonintermittent and intermittent fluctuations of the density of channels, respectively. For nonintermittent fluctuations the general relaxation equation of Huber is recovered, which includes the stretched exponential equation as a particular case, whereas for intermittent fluctuations a more complicated universal relaxation equation is obtained which includes Huber’s equation, the stretched exponential, and the inverse power law relaxation equations as particular cases. @S1063-651X~96!07805-1#

A stochastic model for stretched or compressed exponential survival statistics is suggested based on the following assumptions. (1) The state of an individual is characterized by a finite set of random variables z=(y1, y2,…); the time evolution of these variables is described by a non-Markovian stochastic process with long memory. (2) In the state space of an individual there are some critical regions for which the death of an individual can occur; for a state vector z belonging to a critical region, there is a probability 0

The finite-size effect on the statistics of independent random point processes is analyzed in connection with the theory of cellular automata with randomized grids. The space distribution of a large but finite number N0 of independent particles confined in a large region of ds-dimensional Euclidean space of size VΣ is investigated by using the technique of characteristic functionals. Exact formal expressions are derived for all many-body correlation functions of the positions of the particles as well as for all cumulants of the concentration field. These functions are made up of the contributions of the different negative powers of the total number N0 of particles from the system [Formula: see text] where n =1, 2, … are the orders of the correlation functions or of the cumulants of the concentration field. In the thermodynamic limit N0, VΣ → ∞ with N0 / VΣ = constant only the terms An(0) survive; the other terms An(m) with m > 0 express the finite-size effects. It is shown that, even though the particles are independent, for a finite size of the system a correlation effect different from zero exists among their positions and this correlation vanishes in the limit of an infinite size. The correlation among the positions of the different particles is a finite-size effect due to the conservation of the total number of particles which is similar to the correlation among ideal bosons or fermions at low absolute temperatures. The stochastic properties of an additive scalar field generated by a random distribution of independent particles are investigated. The approach can be applied to the study of stochastic gravitational fluctuations generated by a random distribution of stars or galaxies, of the short-range mean field generated by the particles making up a disordered medium, or of the distribution of the offspring number generated by a plant population randomly distributed in space. Special attention is paid to the finite-size scaling corrections to the long-range self-similar fractal fields. The computations lead to the surprising result that for large values of the resulting field the finite size of the system has practically no influence on the tails of the probability densities of the resulting field, which obey a statistical fractal scaling law of the negative power law type. This apparent paradoxical effect is due to the fact that the very large values of the field corresponding to the tails of the probability densities are generated by the closest neighbor of the test particle considered and are not influenced by the more distant particles.

A method for constructing cutoff values of the probability densities attached to statistical fractals is introduced for which only the beginning of the tail of a probability density is slowly decaying and given by an inverse power law; the end of the tail, however, is short, decaying exponentially or faster. This method is illustrated by an example from the theory of epidemics. The probability density \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)dt of the time interval t within which an infected individual is able to spread an epidemic is evaluated based on the following assumptions. (1) The spreading of the epidemic depends on the size of the germ load carried by an infected individual; the total germ load is measured in large units containing at least ${10}^{5}$--${10}^{6}$ germs. It is assumed that for each unit there is a constant probability p of infecting other individuals. (2) The total number of germ units carried by an individual is a random variable; the corresponding distribution is evaluated by assuming that there is a constant probability \ensuremath{\alpha} that an infected individual carries a unit load of germs. (3) The encounters of an infected individual with healthy individuals susceptible to receiving the illness is a random event occurring with an average time-independent contact frequency \ensuremath{\nu}.The probability density \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)dt determined by these three assumptions has a long tail characteristic of an ideal statistical fractal behavior: \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)dt\ensuremath{\sim}(\ensuremath{\nu}t${)}^{\mathrm{\ensuremath{-}}(\mathit{H}+1)}$\ensuremath{\Xi}(ln(\ensuremath{\nu}t))d(\ensuremath{\nu}t) as t\ensuremath{\gg}1/\ensuremath{\nu}, where H=ln(\ensuremath{\alpha})/ln(1-p) is a positive fractal exponent and \ensuremath{\Xi}(ln(\ensuremath{\nu}t)) is a periodic function of ln(\ensuremath{\nu}t) with a period -ln(1-p). In this case all positive moments 〈${\mathit{t}}^{\mathit{q}}$〉 of the infection time with q\ensuremath{\ge}H are infinite. A statistical fractal with a cutoff emerges if a fourth hypothesis is added: (4) Due to the healing process the bacterial load of an individual decreases exponentially in time with a rate coefficient b. If the healing process is slower than the encounter process of healthy individuals, \ensuremath{\nu}\ensuremath{\gtrsim}b, then only the beginning of the tail of \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)dt obeys an inverse power law scaling \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)dt\ensuremath{\sim}(\ensuremath{\nu}t${)}^{\mathrm{\ensuremath{-}}(\mathit{H}+1)}$\ensuremath{\Xi}(ln(\ensuremath{\nu}t))d(\ensuremath{\nu}t) for 1/bgtg1/\ensuremath{\nu}; the end of the tail, however, is exponential and determined by the healing process \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)\ensuremath{\sim}const\ifmmode\times\else\texttimes\fi{}exp(-bt) as t\ensuremath{\gg}1/b.Due to the cutoff the moments 〈${\mathit{t}}^{\mathit{q}}$〉 of the infection time, although finite, have an intermittent behavior characterized by the scaling law 〈${\mathit{t}}^{\mathit{q}}$〉\ensuremath{\sim}const\ifmmode\times\else\texttimes\fi{}${\mathit{b}}^{\mathrm{\ensuremath{-}}(\mathit{q}\mathrm{\ensuremath{-}}\mathit{H})}$ as b\ensuremath{\rightarrow}0. A generalization of the epidemic model is given by assuming that the size of the germ load carried by an infected individual is an arbitrary random function of time with known stochastic properties and that the encounters with healthy individuals can be described by a correlated random point process. An analytical expression is derived for the probability density \ensuremath{\psi}\ifmmode \tilde{}\else \~{}\fi{}(t)dt of the infection time in terms of the characteristic functionals of the germ load and of the encounter process. A comparison is performed between the onset of an epidemic and the passage over a fluctuating energy barrier with dynamical disorder. Some implications of the cutoff of a statistical fractal for the physics of fractal time are also analyzed. \textcopyright{} 1996 The American Physical Society.

The problem of propagation of fronts (traveling fronts) is investigated for two classes of two-dimensional cellular automata: simple totalistic automata with states 0,1, and Greenberg-Hastings automata that minic infection processes. These automata are investigated with analytic and with simulation methods. In the deterministic case the exact shapes of (anisotropic) fronts are determined as well as the propagation speed in several directions. In the stochastic case the fronts are investigated by simulation.

To compare laparoscopic supracervical hysterectomy (LSH) with total laparoscopic hysterectomy (TLH) with regard to relevant surgical parameters and risk factors of conversion to laparotomy and complications. This prospective, open, single-center, interventional study included women with benign gynecologic disease who underwent standardized LSH or TLH. The techniques were compared for conversion rate and mean operating time, hemoglobin drop, hospital stay, and complication rates using descriptive statistics and standard non-parametric statistical tests. Risk factors of conversion and complications were identified by logistic regression analysis. During January 2003 to December 2010, 1,952 women [mean age (SD): 47.5 (7.2) years] underwent LSH [1,658 (84.9 %)] or TLH [294 (15.1 %)], mostly (>70 %) for uterine fibroids. Significant differences in surgical parameters were observed for conversion rate (LSH/TLH: 2.6/6.5 %), mean operating time [87 (34)/103 (36) min], hemoglobin drop [1.3 (0.8)/1.6 (1.0) g/dL], and hospital stay [4.3 (1.5)/4.9 (2.8) days]. Overall intraoperative (0.2/0.7 %) and long-term (>6 weeks) post-operative (0.8/1.7 %) complication rates did not differ significantly, but the short-term LSH complication rate was significantly lower (0.6 vs. 4.8 %). Spotting (LSH, 0.2 %) and vaginal cuff dehiscence (TLH, 0.7 %) were long-term method-specific complications. Logistic regression showed that uterine weight and extensive adhesiolysis were significant factors for conversion while previous surgery, age, and BMI were not. Major risk factors of short-term complications were age, procedure (LSH/TLH), and extensive adhesions. Both procedures proved effective and were well tolerated. LSH performed better than TLH regarding most outcome measures. LSH is associated with very low rates of re-operation and spotting.

PURPOSE To study the rate of multifocal electroretinographic (mfERG) response amplitude changes and their relation to other parameters of disease development in retinitis pigmentosa (RP). METHODS Twenty-three patients (9 men and 14 women) with clinically defined RP were included in the study. Disease progression was monitored during a period of up to 10 years by psychophysical techniques and Ganzfeld electroretinography. In addition, ERGs were recorded with a mfERG imaging system (VERIS; Electro-Diagnostic Imaging, Inc., Redwood City, CA). The black and white stimulus consisted of 61 hexagons covering a visual field of approximately 60 degrees x 55 degrees . Responses were analyzed according to concentric ring averages. RESULTS The progression of visual field loss for target III4e was approximately 14.5%. Using the same type of regression model, the yearly progression according to the mfERG values was found to be approximately 6% to 10% in the outer three rings. Visual acuity (median 0.8) correlated well with the amplitude of the central segment of the mfERGs, ring 5 amplitudes of the mfERG strongly correlated with the scotopic Ganzfeld ERG mixed cone-rod response amplitude. However, in advanced cases, reliable mfERG responses could still be recorded, even if the ISCEV scotopic Ganzfeld ERG was not reproducible. MfERG ring 5 amplitudes as well as the Ganzfeld ERG mixed cone-rod response amplitude showed only a mild correlation with visual field area. CONCLUSIONS The mfERG allows long-term follow-up of disease progression in retinitis pigmentosa. It does not replace, but complements psychophysical methods and could be used as an objective outcome measure in upcoming treatment studies involving patients with advanced retinal diseases.

This prospective study was designed to determine the diagnostic value of adenosine stress cardiac magnetic resonance imaging (CMRI) in patients referred to elective coronary angiography. Myocardial perfusion measurements at rest and adenosine stress were performed in 141 patients (105 men, 36 women, mean age 63.4 years) at 1.5 T with a Turbo Flash sequence. Stress-induced perfusion deficits were correlated to angiographic stenoses ≥75%. The overall sensitivity for CMRI depicting coronary artery disease (CAD) with relevant stenoses was 90.4%, the specificity was 77.4%, the positive predictive value was 85.9%, the negative predictive value was 84.2% and the accuracy 85.2%. Subgroup analysis was performed for 3-vessel disease (n = 44, sensitivity 92.3%, specificity 75.0%), 2-vessel disease (n = 43, sensitivity 92.6%, specificity 92.9%), 1-vessel disease (n = 27, sensitivity 93.1%, specificity 71.4%) and patients without CAD (n = 27, specificity 70.4%) as well as for patients with prior myocardial infarction (n = 44, sensitivity 92.9%, specificity 86.7%), prior coronary artery bypass surgery (n = 21, sensitivity 88.2%, specificity 66.7%), prior coronary interventions (n = 88, sensitivity 91.9%, specificity 75.0%), or diabetics (n = 27, sensitivity 90.5%, specificity 83.3%). Our study shows that stress perfusion CMRI can accurately predict relevant CAD and contributes to the identification of hemodynamic relevant stenoses in patients scheduled for coronary angiography.