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Background: Cancer treatment during reproductive ages may negatively impact fertility and there is a need of firm knowledge about the prevalence and predictors of fertility-related distress. The aim was to examine fertility-related distress in a population-based sample of young women and men recently treated for cancer and to identify predictors for this outcome., Material and Methods: This nationwide cohort study included 1010 individuals (694 women and 316 men), mean age 34.5 ± 4.9 and 32.1 ± 5.5, respectively, diagnosed with breast, cervical, ovarian, testicular cancers, brain tumors or lymphoma at ages 18-39 in Sweden. Participants completed a survey 1.5-year post-diagnosis to assess fertility-related distress (RCAC), emotional distress (HADS) and self-efficacy, as well as sociodemographic and clinical factors and fertility preservation. Logistic regression was used to examine associations between explanatory factors and high fertility-related distress (RCAC subscale mean >4)., Results: Many participants (69% of women and 47% of men) had previous children and about half reported a wish for future children. High fertility-related distress was more prevalent among women (54%) than men (27%), and women were more likely than men to report distress concerning all but one RCAC dimension after adjustment for sociodemographic factors. Use of fertility preservation was unevenly distributed (15% of women and 71% of men) and was not associated with decreased fertility-related distress. In multivariable logistic regression models, a wish for future children, being single, not having previous children, symptoms of anxiety and low self-efficacy regarding one's ability to handle threats of infertility were associated with high fertility-related distress., Conclusion: This nationwide study found a high prevalence of fertility-related distress in young women and men recently treated for cancer and identified sociodemographic and psychological predictors. Fertility preservation was not found to act as a buffer against fertility-related distress, indicating the continuous need to identify strategies to alleviate fertility distress following cancer.

Bioelectronics can potentially complement classical therapies in nonchronic treatments, such as immunotherapy and cancer. In addition to functionality, minimally invasive implantation methods and bioresorbable materials are central to nonchronic treatments. The latter avoids the need for surgical removal after disease relief. Self-organizing substrate-free organic electrodes meet these criteria and integrate seamlessly into dynamic biological systems in ways difficult for classical rigid solid-state electronics. Here we place bioresorbable electrodes with a brain-matched shear modulus-made from water-dispersed nanoparticles in the brain-in the targeted area using a capillary thinner than a human hair. Thereafter, we show that an optional auxiliary module grows dendrites from the installed conductive structure to seamlessly embed neurons and modify the electrode's volume properties. We demonstrate that these soft electrodes set off a controlled cellular response in the brain when relaying external stimuli and that the biocompatible materials show no tissue damage after bioresorption. These findings encourage further investigation of temporary organic bioelectronics for nonchronic treatments assembled in vivo., (© 2023. The Author(s).)

Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA), allowing for analysis of tumor DNA in a simple blood test, that is, liquid biopsy. Cervical cancer is one of the most common malignancies among women worldwide and high-risk human papillomavirus (HR-HPV) is the cause of the majority of cases. HR-HPV integrates into the host genome and is often present in multiple copies per cell and should thus also be released as ctDNA. Such ctHPV DNA is therefore a possible biomarker in cervical cancer. In this review, we first give a background on ctDNA in general and then a comprehensive review of studies on ctHPV DNA in cervical cancer and pre-malignant lesions that may develop in cervical cancer. Furthermore, studies on ctHPV DNA in other HPV related malignancies (eg, head-and-neck and anogenital cancers) are briefly reviewed. We conclude that detection of ctHPV DNA in plasma from patients with cervical cancer is feasible, although optimized protocols and ultra-sensitive techniques are required for sufficient sensitivity. Results from retrospective studies in both cervical cancer and other HPV-related malignancies suggests that ctHPV DNA is a promising prognostic biomarker, for example, for detecting relapses early. This paves the way for larger, preferably prospective studies investigating the clinical value of ctHPV DNA as a biomarker in cervical cancer. However, there are conflicting results whether ctHPV DNA can be found in blood from patients with pre-malignant lesions and further studies are needed to fully elucidate this question., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Sexual dysfunction is common following a cancer diagnosis in young adulthood (18-39 years) and problems related to sex life are ranked among the core concerns in this age group. Yet, few studies have investigated to what extent adults younger than 40, receive information from healthcare providers about the potential impact of cancer and its treatment on their sex life., Methods: A population-based cross-sectional survey study was conducted with 1010 young adults 1.5 years after being diagnosed with cancer (response rate 67%). Patients with breast, cervical, ovarian and testicular cancer, lymphoma, and brain tumors were identified in national quality registries. Sociodemographic and clinical factors associated with receiving information were examined using multivariable binary logistic regression., Results: Men to a higher extent than women reported having received information about potential cancer-related impact on their sex life (68% vs. 54%, p < 0.001). Receipt of information varied across diagnoses; in separate regression models, using lymphoma as reference, both women and men with brain tumors were less likely to receive information (women: OR 0.10, CI = 0.03-0.30; men: OR 0.37, CI = 0.16-0.85). More intensive treatment was associated with higher odds of receiving information in both women (OR 1.89; CI = 1.28-2.79) and men (OR 2.08; CI = 1.09-3.94). None of the sociodemographic factors were associated with receipt of information., Conclusions: To improve sexual health communication to young adults with cancer, we recommend diagnosis-specific routines that clarify when in the disease trajectory to discuss these issues with patients and what to address in these conversations., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Interfacing electronics with neural tissue is crucial for understanding complex biological functions, but conventional bioelectronics consist of rigid electrodes fundamentally incompatible with living systems. The difference between static solid-state electronics and dynamic biological matter makes seamless integration of the two challenging. To address this incompatibility, we developed a method to dynamically create soft substrate-free conducting materials within the biological environment. We demonstrate in vivo electrode formation in zebrafish and leech models, using endogenous metabolites to trigger enzymatic polymerization of organic precursors within an injectable gel, thereby forming conducting polymer gels with long-range conductivity. This approach can be used to target specific biological substructures and is suitable for nerve stimulation, paving the way for fully integrated, in vivo-fabricated electronics within the nervous system.

Objectives: Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA) or liquid biopsy. Here, we analyze if cell-free human papillomavirus DNA (ctHPV DNA) is detectable before, during and after treatment, in patients with cervical cancer or pre-malignant lesions that may develop into cervical cancer, and whether ctHPV DNA levels were correlated to patient or tumor characteristics and outcome. Furthermore, total cell-free DNA load is studied using cfAlbumin DNA as a surrogate marker., Methods: 18 patients with locally advanced CC (LACC), 15 patients with early stage CC (ESCC) and 21 patients with pre-malignant lesions, all with verified HPV16, 18 or 45-positive lesions, were included. Pre- during- and post-treatment plasma were tested for HPV16, 18 & 45 and total cfDNA load using droplet digital PCR., Results: ctHPV DNA was found in 94.4% and 26.7% of pre-treatment plasma of patients with LACC and ESCC respectively, while all samples from patients with pre-malignant lesions were negative. Higher levels of ctHPV DNA were correlated to higher FIGO2018 stage. Patients with LACC and persistent ctHPV DNA at end-of-treatment had significantly worse progression-free survival (PFS) than patients who had cleared the ctHPV DNA (p = 0.007). Patients with total ctDNA-levels above median in pre-treatment plasma had a worse PFS (p = 0.026), compared to patients with total ctDNA-levels below median., Conclusion: ctHPV DNA is a promising prognostic biomarker in locally advanced cervical cancer that should be studied further for clinical use., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Self-reported sex problems among women diagnosed with reproductive and nonreproductive cancers before the age of 40 are not fully understood. This study aimed to determine sexual dysfunction in young women following a cancer diagnosis in relation to women of the general population. Furthermore, to identify factors associated with sexual dysfunction in women diagnosed with cancer., Materials and Methods: A population-based cross-sectional study with 694 young women was conducted 1.5 years after being diagnosed with cancer (response rate 72%). Potential participants were identified in national quality registries covering breast and gynecological cancer, lymphoma and brain tumors. The women with cancer were compared to a group of women drawn from the general population ( N  = 493). Sexual activity and function were assessed with the PROMIS® SexFS. Logistic regression was used to assess differences between women with cancer and the comparison group, and to identify factors associated with sexual dysfunction., Results: The majority of the women with cancer (83%) as well as the women from the comparison group (87%) reported having had sex the last month (partner sex and/or masturbation). More than 60% of the women with cancer (all diagnoses) reported sexual dysfunction in at least one of the measured domains. The women with cancer reported statistically significantly more problems than women of the comparison group across domains such as decreased interest in having sex, and vaginal and vulvar discomfort. Women with gynecological or breast cancer and those receiving more intense treatment were at particular high risk of sexual dysfunction (≥2 domains). Concurrent emotional distress and body image disturbance were associated with more dysfunction., Conclusion: The results underscore the need to routinely assess sexual health in clinical care and follow-up. Based on the results, development of interventions to support women to cope with cancer-related sexual dysfunction is recommended.

Introduction: Minimally invasive methods to reduce menorrhagia were introduced in the 1980s and 1990s. Transcervical endometrial resection (TCRE) and endometrial ablation (EA) are two of the most frequently used methods. As none of them can guarantee a complete removal of the endometrium, there are concerns that the remaining endometrium may develop to endometrial cancer (EC) later in life. The primary aim was to analyze the long-term incidence of EC after TCRE and EA in a nationwide population. The secondary aim was to assess the two treatment modalities separately., Material and Methods: The Swedish National Patient Registry and National Quality Registry for Gynecological Surgery were used for identification of women who had TCRE or EA performed between 1997-2017. The cohort was followed from the first TCRE or EA until hysterectomy, diagnosis of EC, or death. Follow-up data were retrieved from the National Cancer Registry and the National Death Registry. Expected incidence for EC in Swedish women was calculated using Swedish data retrieved from the NORDCAN project after having taken into account differences of age and follow-up time. Cumulative incidence of EC after TCRE and EA, was calculated. A standardized incidence ratio was calculated based on the expected and observed incidence, stratified by age and year of diagnosis., Results: In total, 17 296 women (mean age 45.1 years) underwent TCRE (n = 8626) or EA (n = 8670). Excluded were 3121 who had a hysterectomy for benign causes during follow up. During a median follow-up time of 7.1 years (interquartile range 3.1-13.3 years) the numbers of EC were 25 (0.3%) after TCRE and 2 (0.02%) after EA, respectively. The observed incidence was significantly lower than expected (population-based estimate) after EA but not after TCRE, giving a standardized incidence ratio of 0.13 (95% confidence interval [CI] 0.03-0.53) after EA and 1.27 (95% CI 0.86-1.88) after TCRE. Median times to EC were 3.0 and 8.3 years after TCRE and EA, respectively., Conclusions: There was a significant reduction of EC after EA, suggesting a protective effect, whereas endometrial resection showed an incidence within the expected rate., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Injectable bioelectronics could become an alternative or a complement to traditional drug treatments. To this end, a new self-doped p-type conducting PEDOT-S copolymer ( A5 ) was synthesized. This copolymer formed highly water-dispersed nanoparticles and aggregated into a mixed ion-electron conducting hydrogel when injected into a tissue model. First, we synthetically repeated most of the published methods for PEDOT-S at the lab scale. Surprisingly, analysis using high-resolution matrix-assisted laser desorption ionization-mass spectroscopy showed that almost all the methods generated PEDOT-S derivatives with the same polymer lengths (i.e., oligomers, seven to eight monomers in average); thus, the polymer length cannot account for the differences in the conductivities reported earlier. The main difference, however, was that some methods generated an unintentional copolymer P(EDOT-S/EDOT-OH) that is more prone to aggregate and display higher conductivities in general than the PEDOT-S homopolymer. Based on this, we synthesized the PEDOT-S derivative A5 , that displayed the highest film conductivity (33 S cm -1 ) among all PEDOT-S derivatives synthesized. Injecting A5 nanoparticles into the agarose gel cast with a physiological buffer generated a stable and highly conductive hydrogel (1-5 S cm -1 ), where no conductive structures were seen in agarose with the other PEDOT-S derivatives. Furthermore, the ion-treated A5 hydrogel remained stable and maintained initial conductivities for 7 months (the longest period tested) in pure water, and A5 mixed with Fe 3 O 4 nanoparticles generated a magnetoconductive relay device in water. Thus, we have successfully synthesized a water-processable, syringe-injectable, and self-doped PEDOT-S polymer capable of forming a conductive hydrogel in tissue mimics, thereby paving a way for future applications within in vivo electronics., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D 2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC., Methods: A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression., Results: Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model., Conclusion: Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Poor survival rates in different cancer types are sometimes blamed on diagnostic and treatment delays, and it has been suggested that such delays might be related to sociodemographic factors such as education and ethnicity. We examined associations of the wait time from diagnosis to surgery and survival in endometrial cancer (EC) and explored patient and tumour factors influencing the wait time., Material and Methods: In this historical population-based cohort study, The Swedish Quality Registry for Gynaecologic Cancer (SQRGC) was used to identify EC patients who underwent primary surgery between 2010 and 2018. Factors associated with a wait time > 32 d were analysed with logistic regression. The 32-d time point was defined in accordance with the Swedish Standardisation Cancer Care programme. Adjusted Poisson regression analyses were used to analyse excess mortality rate ratio (EMRR)., Results: Out of 7366 women, 5535 waited > 32 d for surgery and 1098 > 70 d. The overall median wait time was 44 d. The factors most strongly associated with a wait time > 32 d were surgery at a university hospital (adjusted odds ratio [OR] 1.34, 95% confidence interval [CI] 1.08-1.66) followed by country of birth (OR 1.31, 95% CI 1.10-1.55) and year of diagnosis. There were no associations between wait time and histology or age. A wait time < 15 d was associated with higher mortality (adjusted EMRR 2.29,95% CI 1.36-3.84) whereas no negative survival impact was seen with a wait time of 70 d. Age, tumour stage, histology and risk group were highly associated with survival, whereas education, country of origin and hospital level did not have any impact on survival., Conclusions: Surgery within the first two weeks after EC diagnosis was associated with worsened survival. A prolonged wait time did not seem to have any significant adverse effect on prognosis.HighlightsSurgery within the first two weeks after diagnosis of endometrial cancer (EC) was associated with poorer survival.A prolonged wait time to surgery did not worsen prognosis.Delay in time to surgery was associated with sociodemographic factors.

Primary vaginal cancer (PVC) is a rare gynaecological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53β), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53β in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prognosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53β was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was significantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53β was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Ranhem et al.)

Introduction: Deep myometrial invasion (≥50%) is a prognostic factor for lymph node metastases and decreased survival in endometrial cancer. There is no consensus regarding which pre/intraoperative diagnostic method should be preferred. Our aim was to explore the pattern of diagnostic methods for myometrial invasion assessment in Sweden and to evaluate differences among magnetic resonance imaging (MRI), transvaginal sonography, frozen section, and gross examination in clinical practice., Material and Methods: This is a nationwide historical cohort study; women with endometrial cancer with data on assessment of myometrial invasion and FIGO stage I-III registered in the Swedish Quality Registry for Gynecologic Cancer (SQRGC) between 2017 and 2019 were eligible. Data on age, histology, FIGO stage, method, and results of myometrial invasion assessment, pathology results, and hospital level were collected from the SQRGC. The final assessment by the pathologist was considered the reference standard., Results: In the study population of 1401 women, 32% (n = 448) had myometrial invasion of 50% of more. The methods reported for myometrial invasion assessment were transvaginal sonography in 59%, MRI in 28%, gross examination in 8% and frozen section in 5% of cases. Only minor differences were found for age and FIGO stage when comparing methods applied for myometrial invasion assessment. The sensitivity, specificity, and accuracy to find myometrial invasion of 50% or more with transvaginal sonography were 65.6%, 80.3%, and 75.8%, for MRI they were 76.9%, 71.9%, and 73.8%, for gross examination they were 71.9%, 93.6%, and 87.3%, and for frozen section they were 90.0%, 92.7%, and 92.0%, respectively., Conclusions: In Sweden, the assessment of deep myometrial invasion is most often performed with transvaginal sonography, but the sensitivity is lower than for the other diagnostic methods. In clinical practice, the accuracy is moderate for transvaginal sonography and MRI., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Infertility is a well-known sequela of cancer treatment. Despite guidelines recommending early discussions about risk of fertility impairment and fertility preservation options, not all patients of reproductive age receive such information., Aims: This study aimed to investigate young adult cancer patients' receipt of fertility-related information and use of fertility preservation, and to identify sociodemographic and clinical factors associated with receipt of information., Materials and Methods: A population-based cross-sectional survey study was conducted with 1010 young adults with cancer in Sweden (response rate 67%). The inclusion criteria were: a previous diagnosis of breast cancer, cervical cancer, ovarian cancer, brain tumor, lymphoma or testicular cancer between 2016 and 2017, at an age between 18 and 39 years. Data were analyzed using logistic regression models., Results: A majority of men (81%) and women (78%) reported having received information about the potential impact of cancer/treatment on their fertility. A higher percentage of men than women reported being informed about fertility preservation (84% men vs. 40% women, p < .001) and using gamete or gonadal cryopreservation (71% men vs. 15% women, p < .001). Patients with brain tumors and patients without a pretreatment desire for children were less likely to report being informed about potential impact on their fertility and about fertility preservation. In addition, being born outside Sweden was negatively associated with reported receipt of information about impact of cancer treatment on fertility. Among women, older age (>35 years), non-heterosexuality and being a parent were additional factors negatively associated with reported receipt of information about fertility preservation., Conclusion: There is room for improvement in the equal provision of information about fertility issues to young adult cancer patients.

Background: The aim of this study was to analyze overall survival in endometrial cancer patients' FIGO stages I-III in relation to surgical approach; minimally invasive (MIS) or open surgery (laparotomy)., Methods: A population-based retrospective study of 7275 endometrial cancer patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed from 2010 to 2018. Cox proportional hazard models were used in univariable and multivariable survival analyses., Results: In univariable analysis open surgery was associated with worse overall survival compared with MIS hazard ratio, HR, 1.39 (95% CI 1.18-1.63) while in the multivariable analysis, surgical approach (MIS vs open surgery) was not associated with overall survival after adjustment for known risk factors (HR 1.12, 95% CI 0.95-1.32). Higher FIGO stage, non-endometrioid histology, non-diploid tumors, lymphovascular space invasion and increasing age were independent risk factors for overall survival., Conclusion: The minimal invasive or open surgical approach did not show any impact on survival for patients with endometrial cancer stages I-III when known prognostic risk factors were included in the multivariable analyses.

Objective: To examine the patterns of recurrence and how these patterns are associated with survival in vulvar squamous cell carcinoma. We also explored the survival impact of surgical groin staging (SGS)., Methods: Nationwide population-based study including women diagnosed with vulvar squamous cell carcinoma between 2012 and 2015 and registered in the Swedish Quality Registry for Gynecologic Cancer. Cumulative incidence rates (CIR), recurrence-free (RFS) and overall survival (OS) were calculated by Kaplan Meier estimates. The impact of SGS on RFS and OS was analyzed by proportional hazards models., Results: 489 eligible women were included. Median follow-up time was 64 months. The overall recurrence rate was 22.3%. Site of recurrence: local in 61.0%, groin in 30.0%, distant in 9.0%. The CIR for local recurrences increased with time (5.9% at 2-years, 14.7% at 5-years) while the rate of groin and distant recurrences was nearly steady (5.5% to 6.3% and 1.5% to 1.7%, respectively). Median 2-year and 4-year OS post-recurrence was 57.8% and 37.4% for local, 17.2%, 10.3% for groin and 0% for distant recurrences, respectively. SGS was omitted in 23.7% of surgically treated women with FIGO stages IB-II and significantly associated with worse RFS (Hazard ratio, HR, 1.9; 95%CI, 1.0-3.5; p = 0.04) and OS (HR 2.0; 95%CI, 1.1-3.8; p = 0.04) after adjustment for age, FIGO stage, tumor size, resection margins and performance status., Conclusion: The cumulative incidence of isolated vulvar recurrence was low but for those affected the prognosis was poor. Surgical groin staging is a crucial part of primary treatment and should not be omitted., Competing Interests: Declaration of Competing Interest EÅL: Honoraria, Roche. Advisory boards, Clovis Oncology; Astra Zeneca; Tesaro; Genmab. All other authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Competing Interests: Financial Disclosure Kevin Hellman disclosed that money was paid to his institution from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) R01HD098193. The other author did not report any potential conflicts of interest.

Aim: The first Swedish National Guidelines for Ovarian Cancer (NGOC) were published in 2012. We aimed to evaluate surgical outcomes and survival in patients with stage IIIC-IV disease, before and after the NGOC implementation., Method: Women with primary epithelial ovarian cancer, FIGO stage IIIC-IV, registered in the Swedish Quality Registry for Gynecologic Cancer 2008-2011 and 2013-2016 were included. Surgical outcomes were analyzed, including frequency of complete cytoreduction (R0). Relative survival (RS) and excess mortality rate ratios (EMRRs) were computed as measures of survival. Univariable and multivariable regression (Poisson) were calculated., Results: In total, 3728 women were identified, 1746 before and 1982 after NGOC. After adjusting for age and stage, survival was improved 2013-2016 vs. 2008-2011 (EMRR 0.89; 95%CI:0.82-0.96, p < 0.05). For women undergoing primary debulking surgery (PDS), R0 frequency (28.9% vs. 53.3%; p < 0.001) and 5-year RS (29.6% (95%CI:26.8-32.8) vs. 37.4% (95%CI:33.6-41.7)) were increased, but fewer patients (58% vs. 44%, p < 0.001) underwent PDS after NGOC implementation. Median survival for the PDS cohort increased from 35 months (95%CI,32.8-39.2) to 43 months (95%CI,40.9-46.4). In the neoadjuvant chemotherapy (NACT) + interval debulking surgery (IDS) cohort, R0 increased (36.8% to 50.1%, p < 0.001), but not 5-year RS (17.5% vs. 20.7%, ns). Compared to PDS, the EMRR was 1.32 (95%CI,1.19-1.47, p < 0.001) for NACT+IDS and 3.00 (95%CI,2.66-3.38, p < 0.001) for chemotherapy alone. In multivariable analyses, PDS, R0, age ≤ 70 years, and stage IIIC were found to be independent factors for improved RS., Conclusion: Implementation of the first National Guidelines for Ovarian Cancer improved relative survival in advanced ovarian cancer., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Vulvar cancer affects mainly elderly women and with an ageing population the incidence has increased. We explored the primary treatment patterns and relative survival of patients with vulvar squamous cell carcinoma (VSCC) by stage and age-group., Methods: A population-based nationwide study on women diagnosed with VSCC between 2012 and 2016 and registered in the Swedish Quality Registry for Gynecologic Cancer (SQRGC). Main outcome was 5-year relative survival (RS) estimated by the Pohar Perme method. The relative risk of excess mortality (EMRR) between different groups was analyzed by Poisson regression. The age-standardized relative survival (AS-RS) was estimated for the total cohort., Results: Median follow-up time was 41 months. The study population included 657 women; 33% were ≥ 80 years old. FIGO stage I was most common (55%). Primary surgery was performed in 96% stage I, 65% stage II, 80% stage III and 28% stage IV. In women ≥80 years, exploration of the groins and chemoradiotherapy was less often performed. They also received lower mean doses of radiation than younger women. The 5-year AS-RS was 74%. 5-year RS was 84% for stage I, 60% for stage II, 54% for stage III and 35% for stage IV. The EMRR for women ≥80 years compared with women <60 years was 4.3 (p < 0.001); 4.9 (p < 0.001) for stages I-II and 3.5(p = 0.007) for stage III., Conclusions: In general, primary treatment of patients with vulvar squamous cell carcinoma in Sweden adhered to guidelines. Areas of improvement include treatment for stage II and for the very old., Competing Interests: Declaration of Competing Interest Dr. Avall-Lundqvist: Honoraria: Roche; Advisory board: Astra Zeneca, Clovis Oncology, Tesaro and Genmab. The other authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Inflammation is an established risk factor for colorectal cancer. We and others have shown that colorectal cancer patients with elevated cysteinyl leukotriene receptor 2 (CysLT 2 R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT 2 R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C 4 (LTC 4 )-induced differentiation in colon cancer via CysLT 2 R signalling. Here, we investigated the involvement of Hedgehog (Hh)-GLI1 signalling, which is often hyperactivated in colorectal cancer. We found that the majority of colorectal cancer patients had high-GLI1 expression, which was negatively correlated with CysLT 2 R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC 4 -induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC 4 -induced increase in differentiation markers and reduction in Wnt targets remained unaltered in GLI1-knockdown cells. The restoration of GLI1 in 15-PGDH-knockdown cells did not ameliorate the LTC 4 -induced effects, indicating the importance of both 15-PGDH and GLI1. LTC 4 -mediated reduction in the DCLK1 and LGR5 stemness markers in colonospheres was abolished in cells lacking 15-PGDH or GLI1. Both DCLK1 and LGR5 were highly increased in tumour tissue compared with the matched controls. Reduced Mucin-2 levels were observed both in zebrafish xenografts with GLI1-knockdown cells and in the cysltr2 -/- colitis-associated colon cancer (CAC) mouse model. Furthermore, GLI1 expression was positively correlated with stemness and negatively correlated with differentiation in CRC patients when comparing tumour and mucosal tissues. In conclusion, restoring 15-PGDH expression via CysLT 2 R activation might benefit colorectal cancer patients.

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N -Desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M 1 receptor (M 1 ) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M 1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesized to establish a structure-activity relationship (SAR) at the M 1 receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M 1 agonist activity was established by functionalization in the 4- and 8-positions in the tricyclic core. In vivo behavioral response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M 1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M 1 agonist activity. Cotreatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f , in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential procognitive activity.

Background: The aim of this study is to evaluate the impact of lymphovascular space invasion (LVSI) on the risk of lymph node metastases and survival in endometrioid endometrial adenocarcinoma. Material and methods: As regard the study design, this is a cohort study based on prospectively recorded data. Patients with endometrioid endometrial adenocarcinoma registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2017 with FIGO stages I-III and verified nodal status were identified ( n  = 1587). LVSI together with established risk factors, namely DNA ploidy, FIGO grade, myometrial invasion and age, were included in multivariable regression analyses with lymph node metastases as the dependent variable. Associations between the risk factors and overall and relative survival were included in multivariable models. Estimates of risk ratios (RR), hazard ratios (HR), excess mortality rate ratios (EMR), and 95% confidence intervals (95% CI) were calculated. Results: The presence of LVSI presented the strongest association with lymph node metastases ( RR  = 5.46, CI 3.69-8.07, p  < .001) followed by deep myometrial invasion ( RR  = 1.64, CI 1.13-2.37). In the multivariable survival analyses, LVSI (EMR = 7.69, CI 2.03-29.10,) and non-diploidy (EMR = 3.23, CI 1.25-8.41) were associated with decreased relative survival. In sub-analyses including only patients with complete para-aortic and pelvic lymphadenectomy and negative lymph nodes ( n  = 404), only LVSI ( HR  = 2.50, CI 1.05-5.98) was associated with a worsened overall survival. Conclusion: This large nationwide study identified LVSI as the strongest independent risk factor for lymph node metastases and decreased survival in patients with endometrioid adenocarcinomas. Moreover, decreased overall survival was also seen in patients with LVSI-positive tumors and negative lymph nodes, indicating that hematogenous dissemination might also be important.

Objective: Survival in cervical cancer has improved little over the last decades. We aimed to elucidate primary treatment patterns and survival., Methods: Population-based study of patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed 2011-2015. Main outcome was 5-year relative survival (RS). Age-standardised RS (AS-RS) was estimated for the total cohort and for the pooled study population of squamous, adenosquamous-, adenocarcinoma., Results: Median follow-up time was 4.6 years. The study population consisted of 2141 patients; 97% of the 2212 patients in the total cohort and the 5-year AS-RS was 71% and 70%, respectively. RS stage IB1: surgery alone 95% vs. 72% for definitive chemoradiotherapy (CT-RT) (p < 0.001). In stage IIA1 74% had CT-RT, and 47% of operated patients received adjuvant (CT)-RT. RS stage IB2: surgically treated 81% (69% received adjuvant (CT)-RT) vs. 76% for (CT)-RT (p = 0.73). RS stage IIB: 77% for CT-RT + brachytherapy (BT), 37% for RT + BT (p = 0.045) and 27% for RT-BT (p < 0.001). Stages III-IVA; <40% received CT-RT + BT, RS 45% vs. 18% for RT-BT (RR 4.1, p < 0.001). RS stage IVB 7%., Conclusion: Primary treatment of cervical cancer in Sweden adhered to evidence-based standard of care. Areas of improvement include optimising treatment for stages III-IVA, and avoiding combining surgery and radiotherapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial., Methods: The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors., Results: Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%)., Conclusions: For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Studying how and where drugs are metabolized in the brain is challenging. In an entire organism, peripheral metabolism produces many of the same metabolites as those in the brain, and many of these metabolites can cross the blood-brain barrier from the periphery, thus making the relative contributions of hepatic and brain metabolism difficult to study in vivo. In addition, drugs and metabolites contained in ventricles and in the residual blood of capillaries in the brain may overestimate drugs' and metabolites' concentrations in the brain. In this study, we examine locusts and zebrafish using matrix assisted laser desorption ionization mass spectrometry imaging to study brain metabolism and distribution. These animal models are cost-effective and ethically sound for initial drug development studies.

Aim: The aim of this study is to evaluate the quality of data on endometrial (EC) and ovarian, fallopian tube, peritoneal, abdominal or pelvic cancers (OC) registered in the Swedish Quality Register of Gynecologic Cancer (SQRGC)., Method: A random sample of 500 patients was identified in the SQRGC and their medical charts were reviewed for re-abstraction of 31 selected core variables by an independent validator. The data in the SQRGC and the re-abstracted data were compared. The data were collected from 25 hospitals evenly distributed throughout Sweden. The main outcomes were comparability, timeliness, completeness and validity. Coverage was compared with the National Cancer Register (NCR). Timeliness was defined as the speed of registration i.e. when patients were registered in the SQRGC relative to date of diagnosis. Internationally accepted coding systems for stage, grading and histologic type were used ensuring a high degree of comparability. Correlations were estimated using Pearson's correlation coefficient and Cohen´s kappa coefficient., Results: The completeness was 95%. The timeliness was 88-91% within 12 months of diagnosis. The median degree of agreement between re-abstracted data and data in the SQRGC was 82.1%, with a median kappa value of 0.73 for ordinate variables and a median Pearson's correlation coefficient of 0.96. The agreements for the type of surgery were 76% (95% CI 70-81%; kappa 0.49) and type of primary treatment 90% (95% CI 87-94%; kappa 0.85) in OC and in EC 88% (95% CI 84-93%; kappa 0.84). The agreements for the FIGO stage were in OC and EC 74% (95% CI 68-80%; kappa 0.69) and 87% (95% CI 82-91%; kappa 0.79), respectively., Conclusions: The data in the Swedish Quality Register for Gynecologic Cancer are of adequate quality in order to be used as a basis for research and to evaluate possible differences in treatment, lead times and treatment results.

Background: The International Federation of Gynecology and Obstetrics (FIGO) ovarian cancer staging system includes no sub-stage for lymph nodes (LN) as only distant disease manifestation. We explore the prognostic implication of LN as only stage IV classifier in serous ovarian cancer., Method: This is a nation-wide, population-based study on 551 women with serous stage IV cancers diagnosed between 2009-2014. We compare overall survival (OS) in women with LN as only distant metastatic site to those with pleural metastases only and to patients with other/multiple stage IV manifestations. Cox regression models were used for uni- and multivariable estimations., Results: Of 551stage IV cases, distant metastatic site was registered in 433. Median OS for women with LN (n = 51) was 41.4 months, compared to 25.2 and 26.8 months for patients with pleural (n = 195) or other/multiple (n = 187) distant metastases (p = .0007). The corresponding five-year survival rates were 32, 11 and 22%, respectively. Multivariable analyzes confirmed shorter survival for women with pleural (HR 2.99, p = .001) or other/multiple distant sites (HR 2.67, p = .007), as compared to LN cases. LN only patients lived 9.1 months longer after primary than after interval surgery, but this difference was not significant (p = .245)., Conclusion: Women with stage IV serous ovarian cancer having lymph nodes as only distant metastatic site live longer than other stage IV patients.

Background: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients., Methods: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses., Results: The majority of PVC patients (72%) had >50% LRIG1- and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival., Conclusion: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified.

Background: As the choice of treatment in patients with cervical carcinoma depends on cancer stage at diagnosis, accurate staging is essential., Purpose: To compare three different combinations of magnetic resonance (MR) sequences for preoperative staging., Material and Methods: Fifty-seven consecutive patients with biopsy proven cervical carcinoma underwent MR imaging (MRI) staging followed by primary surgical treatment. Thirty-two of 57 patients had had a cone biopsy prior to MRI. Three MR pulse sequence combinations were retrospectively reviewed by two experienced radiologists. The first imaging protocol consisted of pre-contrast sagittal and transverse images (protocol A), the second protocol included additionally oblique high-resolution T2-weighted (T2W) MR images of the cervix (protocol A+B), and the third included also contrast-enhanced sequences (protocol A+B+C). The imaging findings in the three steps (A, A+B, A+B+C) were recorded. The TNM stage was used for comparison between preoperative imaging and histopathology. Histopathology, together with surgical findings, served as gold standard., Results: In 4/57 (7%) patients, the MR assessment of tumor stage (mrT) was altered when oblique sequences were added to the standard two plane imaging protocol (A+B). The mrT stage was altered in 1/57 (2%) patient when contrast-enhanced sequences were added to standard and oblique sequences (protocol A+B+C). The correlation between visible tumor on MRI and presence of tumor in the resected specimen did not change by adding oblique or contrast-enhanced images., Conclusion: It is not necessary to perform oblique and contrast-enhanced sequences in small cervical carcinomas, i.e. without parametrial invasion. To avoid erroneous interpretation, information on previous cone biopsy is essential.

The metabolism of drugs in the brain is difficult to study in most species because of enzymatic instability in vitro and interference from peripheral metabolism in vivo. A locust ex vivo model that combines brain barrier penetration, efflux, metabolism, and analysis of the unbound fraction in intact brains was evaluated using known drugs. Clozapine was analyzed, and its major metabolites, clozapine N-oxide (CNO) and N-desmethylclozapine (NDMC), were identified and quantified. The back-transformation of CNO into clozapine observed in humans was also observed in locusts. In addition, risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data in the literature for mammals except for the stated fact that CNO is a highly blood-brain barrier permeant compound. Overall, the experiments indicated that invertebrates might be useful for screening of blood-brain barrier permeation, efflux, metabolism, and analysis of the unbound fraction of drugs in the brain in early drug discovery.

In earlier studies insects were proposed as suitable models for vertebrate blood-brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain barrier of the desert locust (Schistocerca gregaria). In an in vivo study on the locust, we found an increased uptake of the two well-known Pgp substrates, rhodamine 123 and loperamide after co-administration with the Pgp inhibitors cyclosporine A or verapamil. Furthermore, ex vivo studies on isolated locust brains demonstrated differences in permeation of high and low permeability compounds. The vertebrate Pgp inhibitor verapamil did not affect the uptake of passively diffusing compounds but significantly increased the brain uptake of Pgp substrates in the ex vivo model. In addition, studies at 2°C and 30°C showed differences in brain uptake between Pgp-effluxed and passively diffusing compounds. The transcriptome data show a high degree of sequence identity of the locust Pgp transporter protein sequences to the human Pgp sequence (37%), as well as the presence of conserved domains. As in vertebrates, the locust brain-barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model has the potential to act as a robust and convenient model for assessing BBB permeability in early drug discovery.

Since the introduction of screening programs for cervical cancer (CC) the incidence has decreased and CC is discovered at an earlier stage. The purpose of this study was to analyze time trends in age, stage, and histopathology over a 90-year period and to our knowledge this is the largest single institutional series in the literature of invasive cervical carcinoma (CC) cases. This is a retrospective study comprising 18,472 women treated for CC from 1914 until 2004 at Radiumhemmet, Stockholm. The material is part of the international CC statistics published since 1937 in the League of Nations' Annual Reports, and since 1958 under the patronage of International Federation of Gynecology and Obstetrics (FIGO). During the 90-year study period, the annual number of cases treated increased to over 400 up until 1965, after which there was a gradual drop to less than 100 cases in 2004. A pronounced shift toward earlier stages at diagnosis was noted. The mean age at diagnosis increased in all stages, predominantly in advanced stages. A reduction in squamous cell carcinoma (SCC) cases and a sixfold increase in the proportion of adenocarcinoma (AC) cases were observed. The mean age at diagnosis for squamous and AC cases shifted after 1970, when the SCC cases ultimately became 3 years older than the AC cases in contrast to around 1950 when they were 3 years younger than the AC cases. The changes in the distribution by age, stage, and histopathology during this 90-year period are probably associated with: improved social conditions and increased access to health care, the introduction of screening programs for CC in the 1960s, and a change in the risk factors for CC (changed sexual behavior, introduction of contraceptive pills, and changed smoking habits)., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict. Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro-like exposure conditions is presented. This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtained in vertebrates. Moreover, this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates.

Background: Human papillomavirus (HPV) testing is not currently used in primary cervical cancer screening in Sweden, and corresponding cost-effectiveness is unclear., Objective: From a societal perspective, to evaluate the cost-effectiveness of high-risk (HR)-HPV testing using self-collected vaginal samples., Design: A cost-effectiveness analysis., Setting: The Swedish organized cervical cancer screening program., Methods: We constructed a model to simulate the natural history of cervical cancer using Swedish data on cervical cancer risk. For the base-case analysis we evaluated two screening strategies with different screening intervals: (i) cytology screening throughout the woman's lifetime (i.e. "conventional cytology strategy") and (ii) conventional cytology screening until age 35 years, followed by HR-HPV testing using self-collected vaginal samples in women aged ≥35 years (i.e. "combination strategy"). Sensitivity analyses were performed, varying model parameters over a significant range of values to identify cost-effective screening strategies., Main Outcome Measures: Average lifetime cost, discounted and undiscounted life-years gained, reduction in cervical cancer risk, incremental cost-effectiveness ratios with and without the cost of added life-years., Results: Depending on screening interval, the incremental cost-effectiveness ratios for the combination strategy ranged from €43,000 to €180,000 per life-years gained without the cost of added life-years, and from €74,000 to €206,000 with costs of added life-years included., Conclusion: The combination strategy with a 5-year screening interval is potentially cost-effective compared with no screening, and with current screening practice when using a threshold value of €80,000 per life-years gained., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: This study aimed to analyze the prognostic value of DNA content and biological markers for cell cycle regulation and invasion in primary carcinoma of the vagina (PCV)., Material and Methods: Seventy-two consecutive patients with PCV, categorized as short-term (≤ 2 years) and long-term (≥ 8 years) survivors, were evaluated for DNA content by image cytometry, and for expression of p53, p21, cyclin A, Ki67, E-cadherin, and laminin-5γ2 chain by immunohistochemistry. The relationship between these biological markers and histopathological and clinical parameters was assessed., Results: All PCV showed aneuploid DNA content. Most of the PCV patients showed no overexpression of p53 and high expression of p21, cyclin A, and Ki67. Loss or underexpression of E-cadherin was found in 94% (68/72) of PCV patients, and all patients showed immunopositivity for the laminin-5γ2 chain. Tumors with a vaginal longitudinal location in the lower third or in the entire vagina more often had overexpression of p53, high expression of Ki67 (P = 0.044), and underexpression of E-cadherin (P = 0.038), than tumors confined only to the upper third. Overexpression of p53 was significantly associated with short-term survival in the univariate analysis, but not in the multivariate analysis adjusted for age at diagnosis and tumor size., Conclusions: The expression level of some markers was related to tumor location, which might be indicative of different genesis. Overexpression of p53 was associated with short-term survival, but the only independent predictors of survival were age at diagnosis and tumor size.

P34 and P37 are two previously identified RNA binding proteins in the flagellate protozoan Trypanosoma brucei. RNA interference studies have determined that the proteins are involved in and essential for ribosome biogenesis. The proteins interact with the 5S rRNA with nearly identical binding characteristics. We have shown that this interaction is achieved mainly through the LoopA region of the RNA, but P34 and P37 also protect the L5 binding site located on LoopC. We now provide evidence to show that these factors form a novel pre-ribosomal particle through interactions with both 5S rRNA and the L5 ribosomal protein. Further in silico and in vitro analysis of T. brucei L5 indicates a lower affinity for 5S rRNA than expected, based on other eukaryotic L5 proteins. We hypothesize that P34 and P37 complement L5 and bridge the interaction with 5S rRNA, stabilizing it and aiding in the early steps of ribosome biogenesis.

Objective: To compare profiles of a prescreening and screening cohort of women with cervical cancer regarding histopathology and clinical variables in order to identify those remaining at risk despite successful screening programs. By analyzing these profiles we hope to improve future screening methods., Methods: The prescreening and screening cohorts consisted of 5,046 and 1,174 women, respectively, treated for cervical cancer at the Department of Gynecological Oncology at Radiumhemmet, Karolinska University Hospital, during the periods 1944-1957 and 1990-2004., Results: Mean age increased from 48.9 years to 55.3 years in the cohorts treated 1944-1957 and 1990-2004, respectively. The percentage of patients older than 69 years was 5.4% and 27.3% in the prescreening and screening period, respectively. A shift towards earlier stages at diagnosis, a reduction of squamous cervical cancer and an increase of adenocarcinoma were observed in the screening cohort. The percentage of adenocarcinoma was about 6 times higher among younger patients. Cases of stump cancer and cervical cancer associated with pregnancy have declined. Eighty-seven women in the screening cohort had a history of treatment for in situ carcinoma by conization; 28% of these cases developed cervical cancer within one year after conization., Conclusion: The profile changed in the screening era indicating a need to refine screening for improved detection of in older women. This study, one of the largest clinical series of cervical cancer, provides an important baseline with which later studies can be compared to evaluate the effects of human papillomavirus vaccine and other important changes in this field.

A series of patients with carcinoma of the cervical stump in relation to age, clinical stage, histopathology, changes in relative incidence, treatment outcome and long-term survival, were studied and the findings were compared with matched controls that have an intact uterus and cancer of the cervix. Of 8,028 women treated for invasive cervical carcinoma between 1959-2004, 161 were diagnosed with stump cancer, accounting for 2.0% of all cervical cancers. The mean time interval between subtotal hysterectomy and stump cancer diagnosis was 17.6 years, with a range of 1-46 years. In 80% of cases, symptoms drove the patient to seek medical attention and postcoital, intermenstrual or postmenopausal bleeding was the main reason. Among 161 stump cancer cases 89% were squamous cell carcinoma (SCC) and the remaining 17 cases were adenocarcinomas (AC). Cumulative cause-specific survival rate was significantly worse for adenocarcinoma than for squamous cell carcinoma (SCC) of the cervical stump (Log-rank p = 0.027, Cox-Mantel p = 0.015, Cox F-test p = 0.01). The stump cancer cases show a worse stage profile compared with the cancer cases in intact uterus. We conclude that the total effect of stump cancers following subtotal hysterectomies is not to be neglected.

Purpose: Cervical cancer is the second most prevalent malignancy of women. Our aim was to identify additional marker protein patterns for objective diagnosis of squamous cervical cancer (SCC)., Experimental Design: Collected tissue biopsies of SCC, squamous vaginal cancer (SVC), normal cervical and vaginal mucosa were subjected to 2-DE, SameSpot analysis, MALDI-TOF-MS protein identification, and analysis of the expression of selected proteins by immunohistochemistry., Results: In 148 protein spots selected by the difference in expression 99 proteins were identified. A differential protein pattern for SCC was, e.g. over-expressed (OE) eukaryotic translation initiation factor 3-2β, neutrophil cytosolic factor 2, annexin A6 (ANXA6), for SVC it was OE cathepsin D, γ-catenin, RAB2A, for both cancers it was OE apolipoprotein E, tropomyosin 3, HSPA8, and underexpressed cytokeratin 13, osteoglycin. In SCC nuclear expression of neutrophil cytosolic factor 2, PRDX2, HSP27 (nine of ten cases), ANXA6 (nine of ten cases) was observed while tropomyosin 4 was expressed only in two of ten cases. There was 81.1% (43/53) agreement between the expression of protein spots and the immune expression of proteins (www.proteinatlas.org)., Conclusions and Clinical Relevance: SCC is characterized by specific tissue marker protein patterns that allow objective detection of the disease. They can become a basis for objective automated cytology-based screening and improve current diagnostics of SCC., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Control of serum glucose levels is essential for the reduction of complications of diabetes. Telemedicine is one strategy through which serum glucose control can be improved., Methods: A total of 35 adult, insulin-treated patients with diabetes (type 1 and type 2) were enrolled in the present study (63.0 +/- 10 years of age, 63% female) and randomized to telemedicine monitoring (including cordless, remote glucose monitor, and transmitter, n = 17), or conventional follow-up (n = 18). Metabolic parameters were evaluated, and a quality of life questionnaire was administered both pre- and post-treatment., Results: Groups were similar at baseline in terms of demographic, quality of life, and metabolic parameters. Significant differences in post-treatment metabolic parameters were not observed, although serum glucose was marginally elevated in the control group compared to the telemedicine group (214 +/- 65 mg/dL vs. 171 +/- 77 mg/dL, P = 0.09). On the other hand, being clinically symptom-free (71% vs. 11%, P = 0.003), having no hypoglycemic events (82% vs. 17%, P = 0.0001), and having no hyperglycemic events (65% vs. 17%, P = 0.004) were all significantly more frequently reported in the telemedicine group compared to the control group. Compared to the control group, the telemedicine group reported experiencing significantly less anxiety, treatment difficulty, depression, disease-associated life complications, and feelings of impotence or ineptitude and significantly greater improvement in personal control over glucose, weight, and overall diabetes., Conclusions: Though post-treatment metabolic differences were not observed between treatment groups, the telemedicine group reported significantly greater post-treatment experiences of improved quality of life and sense of control over the disease. Thus patient satisfaction can be enhanced through the use of telemedicine.

We have previously identified and characterized two novel nuclear RNA binding proteins, p34 and p37, which have been shown to interact with a family of nucleolar phosphoproteins, NOPP44/46, in Trypanosoma brucei. These proteins are nearly identical, the major difference being an 18-amino-acid insert in the N terminus of p37. In order to characterize the interaction between p34 and p37 and NOPP44/46, we have utilized an RNA interference (RNAi) cell line that specifically targets p34 and p37. Within these RNAi cells, we detected a disruption of a higher-molecular-weight complex containing NOPP44/46, as well as a dramatic increase in nuclear NOPP44/46 protein levels. We demonstrated that no change occurred in NOPP44/46 mRNA steady-state levels or stability, nor was there a change in cellular protein levels. These results led us to investigate whether p34 and p37 regulate NOPP44/46 cellular localization. Examination of the p34 and p37 amino acid sequences revealed a leucine-rich nuclear export signal, which interacts with the nuclear export factor exportin 1. Immune capture experiments demonstrated that p34, p37, and NOPP44/46 associate with exportin 1. When these experiments were performed with p34/p37 RNAi cells, NOPP44/46 no longer associated with exportin 1. Sequential immune capture experiments demonstrated that p34, p37, NOPP44/46, and exportin 1 exist in a common complex. Inhibiting exportin 1-mediated nuclear export led to an increase in nuclear NOPP44/46 proteins, indicating that they are exported from the nucleus via this pathway. Together, our results demonstrate that p34 and p37 regulate NOPP44/46 cellular localization by facilitating their association with exportin 1.

To understand the role that sleep may play in memory storage, the authors investigated how fear conditioning affects sleep-wake states by performing electroencephalographic (EEG) and electromyographic recordings of C57BL/6J mice receiving fear conditioning, exposure to conditioning stimuli, or immediate shock treatment. This experimental design allowed us to examine the effects of associative learning, presentation of the conditioning stimuli, and presentation of the unconditioned stimuli on sleep-wake states. During the 24 hr after training, fear-conditioned mice had approximately 1 hr more of nonrapid-eye-movement (NREM) sleep and less wakefulness than mice receiving exposure to conditioning stimuli or immediate shock treatment. Mice receiving conditioning stimuli had more delta power during NREM sleep, whereas mice receiving fear conditioning had less theta power during rapid-eye-movement sleep. These results demonstrate that a single trial of fear conditioning alters sleep-wake states and EEG oscillations over a 24-hr period, supporting the idea that sleep is modified by experience and that such changes in sleep-wake states and EEG oscillations may play a role in memory consolidation., ((c) 2007 APA, all rights reserved)

Classical fear conditioning requires the recognition of conditioned stimuli (CS) and the association of the CS with an aversive stimulus. We used Affymetrix oligonucleotide microarrays to characterize changes in gene expression compared to naive mice in both the amygdala and the hippocampus 30 min after classical fear conditioning and 30 min after exposure to the CS in the absence of an aversive stimulus. We found that in the hippocampus, levels of gene regulation induced by classical fear conditioning were not significantly greater than those induced by CS alone, whereas in the amygdala, classical fear conditioning did induce significantly greater levels of gene regulation compared to the CS. Computational studies suggest that transcriptional changes in the hippocampus and amygdala are mediated by large and overlapping but distinct combinations of molecular events. Our results demonstrate that an increase in gene regulation in the amygdala was partially correlated to associative learning and partially correlated to nonassociative components of the task, while gene regulation in the hippocampus was correlated to nonassociative components of classical fear conditioning, including configural learning.

Many experiments have suggested that the adrenergic system is important for arousal and the regulation of sleep/wake states. Electrophysiological studies have found strong correlations between the firing of adrenergic neurons and arousal state. Lesions of adrenergic neurons have been reported to cause changes in sleep/wake regulation, although findings have been variable and sometimes transient. To more specifically address the role of adrenergic signaling in sleep/wake regulation, we performed electroencephalographic and electromyographic recordings in mice with a targeted disruption of the gene for dopamine beta-hydroxylase, the enzyme that converts dopamine to norepinephrine. These mice are unable to synthesize the endogenous adrenergic ligands norepinephrine and epinephrine. The mutant mice sleep approximately 2 h more each day. The decrease in waking is due to a considerable decrease in the duration of waking bouts in spite of an increase in the number of waking bouts and transitions from sleep to waking. In contrast, the amount of rapid-eye-movement (REM) sleep is only half that in control mice due to a decrease in the number and duration of REM sleep bouts. Delta power is selectively increased in the mutant mice, and there is much less variation in non-REM sleep delta power over 24 h. After 6 h of total sleep deprivation during the first half of the light period, there is no rebound recovery of sleep time in the mutant mice. These results provide genetic evidence that adrenergic signaling acts to maintain waking and is important for the regulation of REM sleep and possibly sleep homeostasis.

Primary carcinomas of the vagina are rare tumors, accounting for 2%-3% of all gynecologic malignancies. Only a few karyotypes based on chromosome banding techniques have been reported. We have, therefore, used comparative genomic hybridization to establish a pattern of genomic imbalances in vaginal squamous cell carcinomas. Analysis of 16 formalin-fixed and paraffin-embedded tumors revealed that 70% of vaginal carcinomas carry relative copy number increases that map to chromosome arm 3q. Other recurring gains were observed on chromosome arms 5p and 19p. Chromosomal losses were infrequent. Most tumors were aneuploid, as measured by image cytometry on Feulgen-stained tissue sections. The cytogenetic data were related to the presence of human papillomavirus genomes, expression of laminin-5 as a marker for invasiveness, and expression levels of markers for proliferative activity and mutated TP53. All relevant clinical data were recorded. The results suggest that vaginal carcinomas are defined by a specific distribution of chromosomal aneuploidies and that the pattern of genomic imbalances is strikingly similar to that observed in squamous cell carcinomas of the uterine cervix. Age at diagnosis (P=0.031), tumor size (P=0.025), and increased laminin-5 expression (P=0.006) have a significant influence on the survival time.

CYP1A2 polymorphism has been well studied in white persons and Asians but not in Africans. We performed CYP1A2 genotype and phenotype analysis using caffeine in Ethiopians living in Ethiopia (n = 100) or in Sweden (n = 73). We sequenced the CYP1A2 gene using genomic DNA from 12 subjects, which revealed a novel intron 1 single-nucleotide polymorphism (SNP), -730C>T. We developed SNP-specific polymerase chain reaction-restriction fragment length polymorphism genotyping and molecular haplotyping methods for the intron 1 SNPs, and four different haplotypes were identified: CYP1A2*1A (wild-type for all SNPs), CYP1A2*1F (-164A), CYP1A2*1J (-740G and -164A), and CYP1A2*1K (-730T, -740G, and -164A), having frequencies of 39.9, 49.6, 7.5, and 3.0%, respectively. The frequency of CYP1A2*1J and CYP1A2*1K among Saudi Arabians (n = 136) was 5.9% and 3.6%, and among Spaniards (n = 117) 1.3% and 0.5%, respectively. Functional significance of the different intron 1 haplotypes was analyzed. Subjects with CYP1A2*1K had significantly decreased CYP1A2 activity in vivo, and reporter constructs with this haplotype had significantly less inducibility with 2,3,7,8-tetrachlorodibenzo-p-dioxin in human B16A2 hepatoma cells. Electrophoretic mobility shift assay using nuclear extracts from B16A2 cells revealed a specific DNA binding protein complex to an Ets element. Efficient competition was obtained using oligonucleotide probes carrying the wt sequence and Ets consensus probe, whereas competition was abolished using probes with the -730C>T SNP alone or in combination with -740T>G (CYP1A2*1K). The results indicate a novel polymorphism in intron 1 of importance for Ets-dependent CYP1A2 expression in vivo and inducibility of the enzyme, which might be of critical importance for determination of interindividual differences in drug metabolism and sensitivity to carcinogens activated by CYP1A2.

Aims: To determine CYP2C19 and CYP2D6 activity in patients with multiple sclerosis (MS) before and during interferon (IFN)-beta treatment., Methods: CYP2C19 and CYP2D6 activities were assessed using the probe drugs mephenytoin and debrisoquine, respectively. Urinary mephenytoin (S/R) and debrisoquine (debrisoquine/hydroxy-debrisoquine) metabolic ratios (MR) were determined in 10 otherwise healthy Caucasian multiple sclerosis (MS) patients in the initial stage of the disease, prior to and 1 month after commencing treatment with IFN-beta (Avonex, Rebif or Betaferon). In addition, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, and CYP2D6*5 genotyping was performed., Results: There was no significant difference in the (S)/(R) mephenytoin ratio (mean difference 0.04; 95% CI -0.03, 0.11) or the debrisoquine MR (mean difference 0.29; 95% CI -0.44, 1.02) before and during regular IFN-beta treatment in extensive metabolizers (EM) (P = 0.5 and P = 0.4 for the respective probe drugs; n = 9 subjects). There were also no differences between the different IFN-beta treatments (P = 0.6 for the (S)/(R) mephenytoin ratio and P = 0.7 for the debrisoquine MR; anova; n = 10)., Conclusions: IFN-beta treatment did not affect the activity of CYP2C19 or CYP2D6. The results suggest that it is safe to administer CYP2C19 or CYP2D6 substrates, without dose adjustment, to patients treated with IFN-beta.

The cyclic AMP-response element binding protein (CREB) is an activity-dependent transcription factor important for synaptic plasticity and memory storage. Levels of phosphorylated CREB within the cortex are higher in waking than in sleep, suggesting that CREB plays a role in sleep/wake regulation in mammals. We tested the hypothesis that CREB is critical for sleep/wake regulation by examining behavioral state parameters in mice lacking the alpha and Delta isoforms of CREB. Over 24 h, time spent awake was significantly decreased in CREB alphaDelta mutant mice by approximately 100 min, and time spent in nonrapid eye movement sleep (NREM) sleep was increased correspondingly. Wake and REM sleep periods were shorter in CREB alphaDelta mice, and CREB alphaDelta mice had decreased levels of -activity during wake and REM sleep, consistent with an impairment in the ability to maintain an activated electroencephalogram. These results suggest that the CREB protein contributes to the mechanisms by which wakefulness is maintained and demonstrate that specific genetic alterations in species as diverse as Drosophila and mice produce similar phenotypes in arousal and wakefulness.