Awareness of somatisation disorder among Swedish physicians at emergency departments: a cross-sectional survey.

BACKGROUND: Somatisation is a highly prevalent psychiatric syndrome in both women and men, in which psychological distress is manifested in physical symptoms without a medical explanation. Many patients with somatisation disorder are high healthcare utilisers, particularly at emergency departments. Unnecessary investigations and diagnostic operations occur frequently, which cause both patient suffering and a significant burden on the healthcare system. Emergency department physicians' awareness of somatisation and its manifestations has not previously been studied. This study aimed to investigate awareness about somatisation disorder among physicians working at emergency departments in western Sweden, and to explore differences between gender, specialty, and work experience. METHODS: A web-based, cross-sectional survey consisting of six dichotomous questions about somatisation disorder was conducted, in December 2021 - January 2022, among licensed physicians of various specialties working at emergency departments in western Sweden. Descriptive analyses and comparative analyses were performed to investigate differences between gender, type of specialty, and years of practice. Data were analysed using chi2 tests and Fisher's exact test. RESULTS: Of the 526 eligible physicians who received the survey, 241 responded; response rate 45.8%. The majority of the respondents (56.4%) were women, and most (35.3%) were specialised in obstetrics/gynaecology. Average years of work experience was 11.1 (SD 8.7) years. Although 71% of respondents were aware of the diagnosis, only 7% knew the diagnostic criteria and only 6% had ever diagnosed a patient with somatisation disorder. Female physicians were more aware of underlying factors than their male colleagues (55.7% vs. 38.2%; p = .010). Type of specialty or years of practice did not affect awareness. CONCLUSIONS: Awareness of somatisation disorder is low among physicians working at emergency departments in western Sweden. The findings suggest a need to increase awareness and knowledge and provide training in diagnosing the condition, to ensure correct decisions and optimal patient management. Clinical guidelines need to be developed to support diagnosis, investigation, and treatment, in Sweden as well as internationally.

Sulfation of O-glycans on Mucin-type Proteins From Serous Ovarian Epithelial Tumors.

Despite sulfated O-linked glycans being abundant on ovarian cancer (OC) glycoproteins, their regulation during cancer development and involvement in cancer pathogenesis remain unexplored. We characterized O-glycans carrying sulfation on galactose residues and compared their expression with defined sulfotransferases regulated during OC development. Desialylated sulfated oligosaccharides were released from acidic glycoproteins in the cyst fluid from one patient with a benign serous cyst and one patient with serous OC. Oligosaccharides characterized by LC-MSn were identified as core 1 and core 2 O-glycans up to the size of decamers and with 1 to 4 sulfates linked to GlcNAc residues and to C-3 and/or C-6 of Gal. To study the specificity of the potential ovarian sulfotransferases involved, Gal3ST2 (Gal-3S)-, Gal3ST4 (Gal-3S)-, and CHST1 (Gal-6S)-encoding expression plasmids were transfected individually into CHO cells also expressing the P-selectin glycoprotein ligand-1/mouse immunoglobulin G2b (PSGL-1/mIg G2b) fusion protein and the human core 2 transferase (GCNT1). Characterization of the PSGL-1/mIg G2b O-glycans showed that Gal3ST2 preferentially sulfated Gal on the C-6 branch of core 2 structures and Gal3ST4 preferred Gal on the C-3 branch independently if core-1 or -2. CHST1 sulfated Gal residues on both the C-3 (core 1/2) and C-6 branches of core 2 structures. Using serous ovarian tissue micro array, Gal3ST2 was found to be decreased in tissue classified as malignant compared with tissues classified as benign or borderline, with the lowest expression in poorly differentiated malignant tissue. Neither Gal3ST4 nor CHST1 was differentially expressed in benign, borderline, or malignant tissue, and there was no correlation between expression level and differentiation stage. The data displays a complex sulfation pattern of O-glycans on OC glycoproteins and that aggressiveness of the cancer is associated with a decreased expression of the Gal3ST2 transferase.

Diagnostic potential of nanoparticle aided assays for MUC16 and MUC1 glycovariants in ovarian cancer.

Our study reports the discovery and evaluation of nanoparticle aided sensitive assays for glycovariants of MUC16 and MUC1 in a unique collection of paired ovarian cyst fluids and serum samples obtained at or prior to surgery for ovarian carcinoma suspicion. Selected glycovariants and the immunoassays for CA125, CA15-3 and HE4 were compared and validated in 347 cyst fluid and serum samples. Whereas CA125 and CA15-3 performed poorly in cyst fluid to separate carcinoma and controls, four glycovariants including MUC16MGL , MUC16STn , MUC1STn and MUC1Tn provided highly improved separations. In serum, the two STn glycovariants outperformed conventional CA125, CA15-3 and HE4 assays in all subcategories analyzed with main benefits obtained at high specificities and at postmenopausal and early-stage disease. Serum MUC16STn performed best at high specificity (90%-99%), but sensitivity was also improved by the other glycovariants and CA15-3. The highly improved specificity, excellent analytical sensitivity and robustness of the nanoparticle assisted glycovariant assays carry great promise for improved identification and early detection of ovarian carcinoma in routine differential diagnostics.

Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma.

BACKGROUND: Ovarian carcinoma is the eighth most common cause of cancer death in women worldwide. The disease is predominantly diagnosed at a late stage. This contributes to high recurrence rates, eventually leading to the development of treatment-resistant disease. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor and regulator of growth factor signaling. LRIG1 levels have not been investigated in human plasma previously. MATERIALS AND METHODS: A quantitative LRIG1-specific single molecule array assay was developed and validated. LRIG1 levels were quantified in plasma samples from 486 patients with suspicious ovarian masses. RESULTS: Among women with ovarian carcinoma, LRIG1 levels were significantly elevated compared to women with benign or borderline type tumors. High LRIG1 plasma levels were associated with worse overall survival and shorter disease-free survival both in the group of all malignant cases and among the stage 3 cases only. LRIG1 was an independent prognostic factor in patients with stage 3 ovarian carcinoma. CONCLUSION: LRIG1 plasma levels were elevated in patients with ovarian carcinoma, and high levels were associated with poor prognosis, suggesting that LRIG1 might be an etiologic factor and a potentially useful biomarker in ovarian carcinoma.

Late follow-up of genital and ophthalmologic chronic graft-vs-host disease in females after allogeneic stem cell transplantation.

INTRODUCTION: Genital chronic graft-vs-host disease (cGvHD) is a common late effect after allogeneic stem cell transplantation. In a previous cross-sectional study, prevalence, signs and symptoms of genital and extra-genital cGvHD were accounted for in a cohort of 42 women. Classifications of cGvHD were performed as per the National Institutes of Health (NIH) 2005 criteria. In this follow-up study on surviving women, the aim was to assess genital and extra-genital cGvHD status after long period of time. Our hypothesis was that signs and symptoms of cGvHD alleviate over time. MATERIAL AND METHODS: All surviving women (n = 38) were re-examined by an ophthalmologist, a gynecologist and a hematologist. Signs and symptoms were classified according to the NIH 2014 criteria. Clinical scorings of affected organs were combined for estimating global score of cGvHD. To make possible comparisons between the two studies, data from the original study were re-classified as per the NIH 2014 criteria, and the four dead women were excluded. The same questionnaires were completed. Cervical smear, human papilloma virus test and vulvar photo-documentation were performed. RESULTS: Median time after original study was 8.4 (5.8-12) years and after transplant 14.5 (10-19.3) years. The prevalence of genital cGvHD was similar in the original (50%) and follow-up (58%) studies (p = 0.646) as well as extra-genital cGvHD. Systemic corticosteroid treatment of cGvHD was ongoing in 34% and 29%, respectively (p = 0.805). Ocular cGvHD was found in 24 of 37 examined women (65%) in the follow-up study. Genital cGvHD had disappeared in three women and developed in two women 5-12 and 9-17 years, respectively, after transplantation. The severity of global cGvHD changed over time in 14 women, but was the same on group level (p = 0.345). Atrophic mucous membranes as in estrogen deficiency were seen in 66%. Three women had human papilloma virus genotypes associated with the risk of developing cervical cancer. CONCLUSIONS: Chronic GvHD did not alleviate over time. Allotransplanted women require early and continuous life-long contact with a gynecologist and an ophthalmologist for the detection of cGvHD. Specific attention should be given to the need for local estrogen and the risk of genital epithelial malignancies.

Analysis of blood group antigens on MUC5AC in mucinous ovarian cancer tissues using in situ proximity ligation assay.

MUC5AC has been indicated to be a marker for mucinous ovarian cancer (OC). We investigated the use of in situ proximity ligation assay (PLA) for blood group ABH expressing MUC5AC to differentiate between serous and mucinous OC, to validate preceding observations that also MUC5AC ABH expression is increased in mucinous OC. We developed PLA for anti-A, B, and H/anti-MUC5AC and a PLA using a combined lectin Ulex europaeus agglutinin I (UEA I)/anti-MUC5AC assay. The PLAs were verified with mass spectrometry, where mucinous OC secretor positive patients' cysts fluids containing ABH O-linked oligosaccharides also showed positive OC tissue PLA staining. A nonsecretor mucinous OC cyst fluid was negative for ABH and displayed negative PLA staining of the matched tissue. Using the UEA I/MUC5AC PLA, we screened a tissue micro array of 410 ovarian tissue samples from patients with various stages of mucinous or serous OC, 32 samples with metastasis to the ovaries and 34 controls. The PLA allowed differentiating mucinous tumors with a sensitivity of 84% and a specificity of 97% both against serous cancer but also compared to tissues from controls. This sensitivity is close to the expected incidence of secretor individuals in a population. The recorded sensitivity was also found to be higher compared to mucinous type cancer with metastasis to the ovaries, where only 32% were positive. We conclude that UEA 1/MUC5AC PLA allows glycospecific differentiation between serous and mucinous OC in patients with positive secretor status and will not identify secretor negative individuals with mucinous OC.

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics.

OBJECTIVES: To evaluate the impact of different biologic, histopathologic and lifestyle factors on serum levels of human epididymis protein 4 (HE4) and Cancer antigen 125 (CA125) in the diagnostic work up of women with an ovarian cyst or pelvic tumor. METHODS: The statistical evaluation was performed on a population of 445 women diagnosed with a benign ovarian disease, included in a large Swedish multicenter trial (ClinicalTrials.gov NCT03193671). Multivariable logistic regression analyses were performed to distinguish between the true negatives and false positives through adjusting for biologic, histopathologic and lifestyle factors on serum samples of CA125 and HE4 separately. The likelihood ratio test was used to determine statistical significance and Benjamini-Hochberg correction to adjust for multiple testing. RESULTS: A total of 31% of the women had false positive CA125 but only 9% had false positive results of HE4. Smoking (OR 6.62 95% CI 2.93-15.12) and impaired renal function, measured by eGFR (OR 0.18 95% CI 0.08-0.39), were independently predictive of falsely elevated serum levels of HE4. Endometriosis was the only variable predictive of falsely elevated serum levels of CA125 (OR 7.96 95% CI 4.53-14.39). Age correlated with increased serum levels of HE4. CONCLUSIONS: Smoking, renal failure, age and endometriosis are factors that independently should be considered when assessing serum levels of HE4 and CA125 in women with an ovarian cyst or pelvic mass to avoid false indications of malignant disease.

Symptoms within somatization after sexual abuse among women: A scoping review.

INTRODUCTION: Somatization, defined as a number of medically unexplained physical symptoms for many years, is a resource-intensive condition with much suffering. Adult somatization has been linked to childhood trauma in both men and women. Among women, sexual trauma affects somatization level to a greater extent than nonsexual trauma. Early diagnosis of a somatization disorder would be of great help for both patients and society. The purpose of this scoping review is to map and summarize the literature on symptoms within somatization in women who have been sexually abused, and investigate if any specific symptom can be linked to previous sexual abuse. MATERIAL AND METHODS: A scoping review methodology was used. The databases PubMed, PsycINFO, and the Cochrane Library were searched for original qualitative and quantitative research published between 2008 and 2019 that matched the objectives of the review. RESULTS: The database search identified 195 articles, of which 43 were retrieved in full text. Seven articles were included, involving 2076 women. All studies were quantitative. The included studies were heterogeneous. Four studies showed inconsistent findings regarding a link between sexual abuse and chronic or acute pain. Two studies showed an association between sexual abuse and increased incidence of somatic symptoms. One study showed an association between sexual abuse and symptoms of irritable bowel syndrome. No specific somatic symptoms in somatization were identifiable within the scope of this study. CONCLUSIONS: This is to our knowledge the first scoping review on sexual abuse and symptoms of somatization. The findings suggest a link between sexual abuse and somatic symptoms, but the identified association with pain and irritable bowel syndrome is inconsistent. No studies have clearly identified specific symptoms within somatization associated with sexual abuse. Qualitative research on the topic was identified as a knowledge gap.

Long-term survival in obese patients after robotic or open surgery for endometrial cancer.

OBJECTIVE: To evaluate surgical outcomes and survival after primary robotic or open surgery in obese women with endometrial cancer (EC). METHODS: The study included obese women (BMI ≥ 30 kg/m2) with EC who underwent primary surgery before and after the introduction of robotics between 2006 and 2014. Data on complications, survival, and recurrence was obtained through the National Cancer Registry and medical files. Survival curves were calculated for overall (OS), relative (RS) and disease-free survival (DFS). Cox proportional hazards regression models to assess OS and DFS. RESULTS: In total, 217 patients were identified, 131 robotic and 86 open surgical procedures. Significantly lower estimated blood loss, surgical time and hospital stay were found in the robotic group and the relative risk ratio of complications grades II-V, using the Clavien Dindo classification, was 0.54 (95% CI 0.31-0.93) for the robotic compared to the open group. A significant difference in OS (p = 0.029) and RS (p = 0.024) in favor of robotics was shown in the univariable survival curves, using log rank tests. No difference was seen for DFS. The 5-year RS was 96.2% (95% CI 89.7-103.3) for the robotic and 81.6% (95% CI 72.1-92.3) for the open group. Multivariable analysis showed high risk histology to be an independent risk factor, for both OS (HR 2.90; 95% CI 1.42-5.93; p < 0.05) and DFS (HR 2.74; 95% CI 1.45-5.17; p < 0.05). Robotic surgery was not found a significant independent factor for survival. CONCLUSIONS: Robotic surgery in obese women with EC had equivalent long-term and disease-free survival compared to open with significantly less complications, lower estimated blood loss, shorter surgical time and hospital stay.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Immunohistochemical validation of COL3A1, GPR158 and PITHD1 as prognostic biomarkers in early-stage ovarian carcinomas.

BACKGROUND: Ovarian cancer is the main cause of gynecological cancer-associated death. However, 5-year survival rates differ dramatically between the five main ovarian carcinoma histotypes. Therefore, we need to have a better understanding of the mechanisms that promote histotype-specific ovarian carcinogenesis and identify novel prognostic biomarkers. METHODS: Here, we evaluated the prognostic role of 29 genes for early-stage (I and II) ovarian carcinomas (n = 206) using immunohistochemistry (IHC). RESULTS: We provide evidence of aberrant protein expression patterns for Collagen type III alpha 1 chain (COL3A1), G protein-coupled receptor 158 (GPR158) and PITH domain containing 1 (PITHD1). Kaplan-Meier survival analysis revealed that COL3A1 expression was associated with shorter overall survival in the four major histotypes of epithelial ovarian carcinoma patients (P value = 0.026, HR = 2.99 (95% CI 1.089-8.19)). Furthermore, GPR158 and PITHD1 were shown to be histotype-specific prognostic biomarkers, with elevated GPR158 expression patterns in mucinous ovarian carcinoma patients with unfavorable overall survival (P value = 0.00043, HR = 6.13 (95% CI 1.98-18.98)), and an association with lower PITHD1 protein expression and unfavorable overall and disease-specific survival in clear-cell ovarian carcinoma patients (P value = 0.012, HR = 0.22 (95% CI 0.058-0.80); P value = 0.003, HR = 0.17 (95% CI 0.043-0.64)). CONCLUSIONS: The novel biomarkers identified here may improve prognostication at the time of diagnosis and may assist in the development of future individualized therapeutic strategies for ovarian carcinoma patients.

Sociodemographic disparities in stage-specific incidences of endometrial cancer: a registry-based study in West Sweden, 1995-2016.

Background: For a few types of cancer, lower socioeconomic status (SES) is associated with higher incidence, and for even more cancer types it is associated with having a less favorable tumor stage at diagnosis. For endometrial cancer (EC), however, there is no clear evidence of such associations with SES. There is a need for analysis of sociodemographic disparities in EC incidences according to stage at diagnosis, which may provide support for trying to improve early detection of EC. Material and methods: Stage-specific incidences of endometrioid and non-endometrioid endometrial carcinomas [EECs (∼90% of all EC cases) and NECs (∼10%)] were analyzed for the population of the Western Swedish Healthcare Region, taking into account year (1995-2016), age, educational level (low, intermediate and high), and immigrant status (Swedish-born, foreign-born). All EC cases were identified and data were obtained from population-based registries. Results: Stage distribution of diagnosed EECs differed significantly according to the educational level of patients who were aged between 50 and 74 years at diagnosis, but not in the case of younger or older patients. An analysis based on 3113 EEC cases aged 50-74 years at diagnosis revealed marked disparities in the stage-II to stage-IV EEC incidences but not in the stage-I EEC incidence. Compared to women with a high level of education, the incidence rate ratios of stage-I, stage-II and stage-III and -IV EEC in women with a low level of education were 1.00 (95% CI: 0.90-1.12), 1.65 (1.13-2.42), and 1.82 (1.33-2.49), respectively. For NEC, we found no such association. Conclusions: Elevated incidences of stage-II to stage-IV EEC in 50- to 74-year-old women with a low level of education suggest that there should be targeted health service trials aimed at improving awareness of EC. Well-targeted EC awareness programs might lead to considerable health benefits.

DNA ploidy status, S-phase fraction, and p53 are not independent prognostic factors for survival in endometrioid endometrial carcinoma FIGO stage I-III.

OBJECTIVES: To assess the effects on relative survival of established and new prognostic factors in stage I-III grade 1-3 endometrioid endometrial carcinoma and in the subgroup of stage I grade 1-2. METHODS: This was a population-based, retrospective study including all women (n=1113) in the western Swedish healthcare region diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I-III grade 1-3 endometrioid endometrial carcinoma in 2006-2011. Histology, grade, stage, and age were prospectively reported to the regional clinical and national cancer registers. DNA ploidy and S-phase fraction were analyzed by flow cytometer. S-phase fraction cut-off was set at ≥8%. Tumor biopsies were classified as diploid if there was one G0/G1 peak or the DNA index was 1.0±0.04. Overexpression of p53 as determined by immunohistochemistry was positive if strong nuclear staining was found in >30% of the neoplastic cells. RESULTS: Based on univariable statistical analyses we found that 5-year relative survival was significantly associated with S-phase fraction, DNA ploidy, p53, stage, grade, and age. Excess mortality for S-phase fraction ≥8%, aneuploidy, and p53 overexpression was 8, 14, and 8 and times higher, respectively. However, in a multivariable regression model, adjusted for stage, grade, and age, S-phase fraction, DNA ploidy, and p53 were not statistically independent prognostic factors (p=0.413, p=0.107, p=0.208, respectively) for 5-year relative survival in stage I-III grade 1-3 endometrioid endometrial carcinoma. In a subgroup analysis of stage I grade 1-2, aneuploidy identified a subgroup with impaired 5-year relative survival. CONCLUSION: We can conclude that S-phase fraction, DNA ploidy, and p53 overexpression did not improve identification of high-risk patients by stage, grade, and age in stage I-III endometrioid endometrial carcinoma. In stage I, aneuploidy and grade 2 predicted lower relative survival rates than other variables.

A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer.

BACKGROUND: Over 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening. METHODS: In the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n = 106), endometrial cancer (n = 74), benign ovarian tumors (n = 150) and healthy population controls (n = 399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n = 280), endometrial cancer (n = 228), women with benign ovarian tumors (n = 76) and healthy controls (n = 57). RESULTS: In the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC = 0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p = 9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC = 0.89). CONCLUSION: The PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination. FUNDING: The Swedish Cancer Foundation, Vinnova (SWELIFE), The Foundation for Strategic Research (SSF), Assar Gabrielsson Foundation.

A multicenter clinical trial validating the performance of HE4, CA125, risk of ovarian malignancy algorithm and risk of malignancy index.

OBJECTIVE: To validate, in a multicenter clinical trial, the performance of biomarkers and algorithms for differential diagnosis in a population of women diagnosed with an unknown ovarian cyst or pelvic tumor. METHODS: Six hospitals in Western Sweden consecutively enrolled 638 women from September 2013 to February 2016. Serum, transvaginal ultrasound data, and basic patient characteristics were collected preoperatively. Biomarker levels, risk of malignancy algorithm (ROMA), and risk of malignancy index (RMI) were calculated and compared with the final pathology report. RESULTS: Our sample of 638 patients had 445 benign, 31 borderline, and 162 malignant tumors recorded, and the overall incidence of epithelial ovarian cancer was 21%. In postmenopausal women, RMI (>200), ROMA (≥29.9), CA125 (>35 U/mL), and HE4 (>140 pmol/L) showed sensitivity at 89%, 91%, 92%, and 72%, respectively, and specificity at 80%, 77%, 80%, and 92%. In premenopausal women, sensitivity of RMI, ROMA (≥11.6), CA125, and HE4 (>70 pmol/L) was 87%, 87%, 96%, and 83%, respectively, and specificity was 90%, 81%, 60%, 91%. Diagnostic accuracy (ROC AUC) of RMI and ROMA in postmenopausal women was 0.85 and 0.84, and in premenopausal women, 0.90 and 0.81. CONCLUSION: Our results suggest that CA125 is superior to HE4 as a biomarker to identify women with ovarian cancer. HE4 more correctly identifies benign lesions, which may help in differential diagnoses to guide the level of care and decrease overtreatment. This study confirms prior results from single-center studies and suggests the implementation of HE4 measurement in daily practice.

Robotic vs Open Surgery for Endometrial Cancer in Elderly Patients: Surgical Outcome, Survival, and Cost Analysis.

OBJECTIVE: This study aimed to compare robotic and open surgery in elderly women diagnosed as having endometrial cancer, in terms of costs, survival, surgical outcome, and operating time. METHODS: Women 70 years or older undergoing open and robotic surgery for endometrial cancers were included consecutively before and after the introduction of robotic surgery at a tertiary center. Costs were calculated using the case-costing system, cost per patient, including the first 30 postoperative days. Relative and overall survival outcomes were obtained from the Swedish National Cancer Registry and analyzed using the Kaplan-Meier method. Surgical outcomes including operating and anesthesia times, estimated blood loss, hospital stay, and intraoperative and postoperative complications were reviewed. RESULTS: In all, 137 and 141 women 70 years or older were identified to have undergone open and robotic surgery, respectively. The groups showed similar body mass index, comorbidities, and tumor characteristics. No statistically significant differences were seen in costs (robotic &OV0556;11,874 vs open &OV0556;11,521, P = 0.463) or 5-year survival outcomes (robotic 94% [95% confidence interval {CI}, 84-105] vs open 87% [95% CI, 78-98], P = 0.529). Robotic surgery was associated with significantly lower estimated blood loss (P < 0.001) and shorter hospital stay (P < 0.001) but longer anesthesia time (186 vs 174 minutes; P < 0.05) and operating theater time (205 vs 190 minutes; P < 0.05). There were no significant differences in intraoperative complications, but robotic surgery resulted in fewer postoperative Clavien-Dindo grade II complications. CONCLUSIONS: Elderly women can safely undergo robotic surgery for endometrial cancer and could be offered this technique to the same extent as younger patients. They may benefit from shorter hospital stay, decreased blood loss, and postoperative complications, without resulting in higher costs to the health care system or jeopardizing their survival.

A prospective study of female genital chronic graft-versus-host disease symptoms, signs, diagnosis and treatment.

INTRODUCTION: Female genital chronic graft-versus-host disease (cGvHD) is a complication of allogeneic hematopoietic cell transplantation (alloHCT) for blood malignancies. Unattended inflammation and fibrosis in the vulva and vagina may lead to total vaginal stenosis. The course and treatment of genital cGvHD was observed in this population-based prospective study. MATERIAL AND METHODS: Women (n = 41) receiving alloHCT in 2005-10 were examined before and at 3, 6, 9, 12, 18, 24, 30 and 36 months post-transplant. Vulvovaginal signs were documented, National Institutes of Health clinical scores were calculated, and women completed questionnaires on symptoms, the Female Sexual Distress Scale and the Beck Depression Inventory. Local immunosuppressive treatment was given weekly. RESULTS: Genital cGvHD was diagnosed in 27 women (incidence 56% at 12 months; 66% at 36 months); extragenital cGvHD was found in 21/27. The most common signs at diagnosis were red and white spots, reticular white lines, fissures, synechiae and telangiectasia; symptoms included dryness, itching, dyspareunia, pain or no symptoms. Thirteen women were treated on a schedule of tacrolimus and clobetazol ointments. Although some signs progressed during treatment, only two women developed total stenosis. At 36 months, 12 women still had genital cGvHD. CONCLUSIONS: Genital cGvHD develops mainly in the first year after alloHCT. Early intervention may halt its progress to severe fibrosis, but despite correct diagnosis and treatment, symptoms and signs may become chronic. Women who develop genital cGvHD following alloHCT require life-long gynecological supervison and care.

Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b.

BACKGROUND: To characterize the expression of the membrane transporter NaPi2b and antigen targeted by the MX35 antibody in ovarian tumor samples. The current interest to develop monoclonal antibody based therapy of ovarian cancer by targeting NaPi2b emphasizes the need for detailed knowledge and characterization of the expression pattern of this protein. For the majority of patients with ovarian carcinoma the risk of being diagnosed in late stages with extensive loco-regional spread disease is substantial, which stresses the need to develop improved therapeutic agents. METHODS: The gene and protein expression of SLC34A2/NaPi2b were analyzed in ovarian carcinoma tissues by QPCR (n = 73) and immunohistochemistry (n = 136). The expression levels and antigen localization were established and compared to the tumor characteristics and clinical data. RESULTS: Positive staining for the target protein, NaPi2b was detected for 93% of the malignant samples, and we identified three separate distribution patterns of the antigen within the tumors, based on the localization of NaPi2b. There were differences in the staining intensity as well as the distribution pattern when comparing the tumor grade and histology, the mucinous tumors presented a significantly lower expression of both the targeted protein and its related gene. CONCLUSION: Our study identified differences regarding the level of the antigen expression between tumor grade and histology. We have identified differences in the antigen localization between borderline tumors, type 1 and type 2 tumors, and suggest that a pathological evaluation of NaPi2b in the tumors would be helpful in order to know which patients that would benefit from this targeted therapy.

Patient-reported lower urinary tract symptoms after hysterectomy or hysteroscopy: a study from the Swedish Quality Register for Gynecological Surgery.

INTRODUCTION AND HYPOTHESIS: Hysterectomy is sometimes considered the cause of lower urinary tract symptoms (LUTS). We hypothesized that hysterectomy for abnormal uterine bleeding and/or symptoms of fibroids is more likely to cause LUTS than a hysteroscopic procedure for the same indications. METHODS: Two groups of women were compared: one group comprised 3,618 women who had had a hysterectomy due to abnormal uterine bleeding or symptoms of fibroids and the other group comprised 238 women who had had hysteroscopic treatment for the same indications. The main outcome measures were occurrence of LUTS before and 1 year after the surgical intervention. The frequencies of LUTS before and after surgery were compared between the groups. Binary logistic regression was used to model the odds of having postoperative urinary leakage and urgency while controlling for uterine size, surgical procedure and preoperative LUTS. RESULTS: There were no statistically significant differences between women after hysterectomy and after hysteroscopy in the frequencies of LUTS before or after surgery, when uterine size was comparable. However, there was a difference in the rates of de novo urinary incontinence between women with hysterectomy and women with hysteroscopy (7.6%, 95% CI 6.3-9.0, and 3.2%, 95% CI 1.6-6.5, respectively). Of the women with a large uterus, 58.6% (95% CI 51.5-65.5) reported relief of urinary incontinence and 85.5% (95% CI 82.3-88.4) reported relief of urinary urgency postoperatively. CONCLUSIONS: Our results suggest that it is important to individualize preoperative information in women prior to hysterectomy since the outcome concerning LUTS depends on preoperative symptoms and uterine size.