Spatial tumor immune microenvironment phenotypes in ovarian cancer.

Immunotherapy has largely failed in ovarian carcinoma (OC), likely due to that the vast tumor heterogeneity and variation in immune response have hampered clinical trial outcomes. Tumor-immune microenvironment (TIME) profiling may aid in stratification of OC tumors for guiding treatment selection. Here, we used Digital Spatial Profiling combined with image analysis to characterize regions of spatially distinct TIME phenotypes in OC to assess whether immune infiltration pattern can predict presence of immuno-oncology targets. Tumors with diffuse immune infiltration and increased tumor-immune spatial interactions had higher presence of IDO1, PD-L1, PD-1 and Tim-3, while focal immune niches had more CD163 macrophages and a preliminary worse outcome. Immune exclusion was associated with presence of Tregs and Fibronectin. High-grade serous OC showed an overall stronger immune response and presence of multiple targetable checkpoints. Low-grade serous OC was associated with diffuse infiltration and a high expression of STING, while endometrioid OC had higher presence of CTLA-4. Mucinous and clear cell OC were dominated by focal immune clusters and immune-excluded regions, with mucinous tumors displaying T-cell rich immune niches.

Large-scale proteomics reveals precise biomarkers for detection of ovarian cancer in symptomatic women.

Ovarian cancer is the 8th most common cancer among women and has a 5-year survival of only 30-50%. While the survival is close to 90% for stage I tumours it is only 20% for stage IV. Current biomarkers are not sensitive nor specific enough, and novel biomarkers are urgently needed. We used the Explore PEA technology for large-scale analysis of 2943 plasma proteins to search for new biomarkers using two independent clinical cohorts. The discovery analysis using the first cohort identified 296 proteins that had significantly different levels in malign tumours as compared to benign and for 269 (91%) of these, the association was replicated in the second cohort. Multivariate modelling, including all proteins independent of their association in the univariate analysis, identified a model for separating benign conditions from malign tumours (stage I-IV) consisting of three proteins; WFDC2, KRT19 and RBFOX3. This model achieved an AUC of 0.92 in the replication cohort and a sensitivity and specificity of 0.93 and 0.77 at a cut-off developed in the discovery cohort. There was no statistical difference of the performance in the replication cohort compared to the discovery cohort. WFDC2 and KRT19 have previously been associated with ovarian cancer but RBFOX3 has not previously been identified as a potential biomarker. Our results demonstrate the ability of using high-throughput precision proteomics for identification of novel plasma protein biomarker for ovarian cancer detection.

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.

Toward ovarian cancer screening with protein biomarkers using dried, self-sampled cervico-vaginal fluid.

Early detection is key for increased survival in ovarian cancer, but no general screening program exists today due to lack of biomarkers and overall cost versus benefit over traditional clinical methods. Here, we used dried cervico-vaginal fluid (CVF) as sampling matrix coupled with mass spectrometry for detection of protein biomarkers. We find that self-collected CVF on paper cards yields robust results and is suitable for high-throughput proteomics. Artificial intelligence-based methods were used to identify an 11-protein panel that separates cases from controls. In validation data, the panel achieved a sensitivity of 0.97 (95% CI 0.91-1.00) at a specificity of 0.67 (0.40-0.87). Analyses of samples collected prior to development of symptoms indicate that the panel is informative also of future risk of disease. Dried CVF is used in cervical cancer screening, and our results opens the possibility for a screening program also for ovarian cancer, based on self-collected CVF samples.

SALpingectomy for STERilisation (SALSTER): study protocol for a Swedish multicentre register-based randomised controlled trial.

INTRODUCTION: Salpingectomy is currently suggested as an alternative to tubal ligation for sterilisation. Precursor lesions of ovarian carcinoma can be found in the fallopian tubes; thus, salpingectomy could possibly reduce the incidence. Most of the existing trials on safety are small, on caesarean section and report on surrogate ovarian function measures. Randomised trials in laparoscopy are lacking. Well-designed trials are needed to evaluate safety of laparoscopic opportunistic salpingectomy. METHODS AND ANALYSIS: In SALSTER, a national register-based randomised controlled non-inferiority trial, 968 women <50 years, wishing laparoscopic sterilisation will be randomised to either salpingectomy or tubal ligation. The Swedish National Quality Register of Gynecological Surgery (GynOp) will be used for inclusion, randomisation and follow-up. Primary outcomes are any complication up to 8 weeks postoperatively, and age at menopause. Both outcomes are measured with questionnaires, complications are also assessed by a gynaecologist. In a nested trial, ovarian function will be evaluated comparing the mean difference of anti-Müllerian hormone (AMH), assessed preoperatively and 1 year after surgery. ETHICS AND DISSEMINATION: Performing salpingectomy for sterilisation has become increasingly common, despite the unclear risk-benefit balance. SALSTER studies the safety of salpingectomy compared with tubal ligation. Regardless of the result, SALSTER will provide gynaecologists with high quality evidence to inform women to decide on salpingectomy or not. The central ethical review board of Gothenburg, Sweden (Dnr. 316-18) approved the trial in 2018. Results will be presented at scientific congresses and published in peer-reviewed scientific journals. The results will be communicated through professional organisations and research networks. TRIAL REGISTRATION NUMBER: NCT03860805.

Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients.

Women with ovarian cancer have limited therapy options, with immunotherapy being unsatisfactory for a large group of patients. Tumor cells spread from the ovary or the fallopian tube into the abdominal cavity, which is commonly accompanied with massive ascites production. The ascites represents a unique peritoneal liquid tumor microenvironment with the presence of both tumor and immune cells, including cytotoxic lymphocytes. We characterized lymphocytes in ascites from patients with high-grade serous ovarian cancer. Our data reveal the presence of NK and CD8+ T lymphocytes expressing CD103 and CD49a, which are markers of tissue residency. Moreover, these cells express high levels of the inhibitory NKG2A receptor, with the highest expression level detected on tissue-resident NK cells. Lymphocytes with these features were also present at the primary tumor site. Functional assays showed that tissue-resident NK cells in ascites are highly responsive towards ovarian tumor cells. Similar results were observed in an in vivo mouse model, in which tissue-resident NK and CD8+ T cells were detected in the peritoneal fluid upon tumor growth. Together, our data reveal the presence of highly functional lymphocyte populations that may be targeted to improve immunotherapy for patients with ovarian cancer.

Aberrant glycosylation of α3 integrins as diagnostic markers in epithelial ovarian cancer.

BACKGROUND: Glycans are strongly involved in stability and function of integrins (ITG) and tetraspanin protein CD63 and their respective interaction partners as they are dysregulated in the tumorigenic processes. Glycosylation changes is a universal phenomenon of cancer cells. In this study, glycosylation changes in epithelial ovarian cancer (EOC) are explored using tetraspanin and integrin molecules. METHODS: ITG and CD63 were immobilized from 10 EOC and 5 benign ovarian cyst fluid on microtiter wells and traced with 3 glycan binding proteins (STn, WGA, UEA) conjugated on europium nanoparticles. Total protein measurements (ITG & CD63 immunoassays) were also performed. The most promising glycovariant candidates identified were then clinically evaluated on the whole cohort of 77 ovarian cyst fluids. Additional testing was performed in ascites fluid samples of liver cirrhosis (n = 2) and EOC (n = 4). RESULTS: Sialylated Tn antibody based glycovariants of ITGα3 (ITGα3STn) and CD63 (CD63STn) performed better than corresponding protein epitope-based immunoassays, ITGα3IA and CD63IA respectively. Combined ITGα3 based assays (ITGα3IA + ITGα3STn) detected 49 out of 55 malignant & borderline cases without detecting any of the 22 benign and healthy cysts. CONCLUSION: Our findings indicate the potential diagnostic application of ITGα3STn along with total ITGα3IA, which could help reduce the unnecessary surgeries. The results encourage studying further the potential use of these novel assays to detect EOC at earlier clinical stages.

HOPPSA update: changes in the study protocol of Hysterectomy and OPPortunistic SAlpingectomy, a registry-based randomized controlled trial.

BACKGROUND: The HOPPSA trial is a multi-center national registry-based randomized controlled trial to test the safety and effectiveness of performing opportunistic salpingectomy at hysterectomy to reduce the risk of epithelial ovarian cancer (EOC). The study protocol was first published in January 2019 and is available at https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3083-8 . Here, we report amendments made to the study protocol since commencement of the trial. CHANGES IN METHODS AND ANALYSIS: The primary outcomes analyses have been changed. (1) Complications will be analyzed using binomial generalized estimating equation (GEE) with log link function, while the unadjusted analyses according to Miettinen and Nurminen will be performed as a sensitivity analysis. (2) Absolute change in Menopause Rating Scale (MRS) will primarily be analyzed using a mixed effects model, adjusted for baseline MRS and center as a random effect. (3) Time to EOC will be analyzed using the mixed effects Cox regression model with center as random effect, while the unadjusted log-rank test will be performed as a sensitivity analysis. The primary outcome Complications will be based solely on the specific assessment in the GynOp quality registry. The Clavien-Dindo classification will be evaluated as a secondary outcome. Furthermore, MRS is also measured three years postoperatively to better pinpoint the onset of menopausal symptoms. DISCUSSION: The changes to the protocol mainly concern the analyses of data. No changes to recruitment, randomization, intervention, or follow-up of primary outcomes have been made. An interim analysis during 2021 concluded that the study should continue until the target sample size is reached. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03045965 . Registered 8 February 2017.

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.

Data-driven analysis of a validated risk score for ovarian cancer identifies clinically distinct patterns during follow-up and treatment.

Background: Ovarian cancer is the eighth most common cancer among women and due to late detection prognosis is poor with an overall 5-year survival of 30-50%. Novel biomarkers are needed to reduce diagnostic surgery and enable detection of early-stage cancer by population screening. We have previously developed a risk score based on an 11-biomarker plasma protein assay to distinguish benign tumors (cysts) from malignant ovarian cancer in women with adnexal ovarian mass. Methods: Protein concentrations of 11 proteins were characterized in plasma from 1120 clinical samples with a custom version of the proximity extension assay. The performance of the assay was evaluated in terms of prediction accuracy based on receiver operating characteristics (ROC) and multiple hypothesis adjusted Fisher's Exact tests on achieved sensitivity and specificity. Results: The assay's performance is validated in two independent clinical cohorts with a sensitivity of 0.83/0.91 and specificity of 0.88/0.92. We also show that the risk score follows the clinical development and is reduced upon treatment, and increased with relapse and cancer progression. Data-driven modeling of the risk score patterns during a 2-year follow-up after diagnosis identifies four separate risk score trajectories linked to clinical development and survival. A Cox proportional hazard regression analysis of 5-year survival shows that at time of diagnosis the risk score is the second-strongest predictive variable for survival after tumor stage, whereas MUCIN-16 (CA-125) alone is not significantly predictive. Conclusion: The robust performance of the biomarker assay across clinical cohorts and the correlation with clinical development indicates its usefulness both in the diagnostic work-up of women with adnexal ovarian mass and for predicting their clinical course.

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.

Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer.

BACKGROUND: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. METHODS: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). RESULTS: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. CONCLUSIONS: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.

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.

Lifestyle and Chronic Pain in the Pelvis: State of the Art and Future Directions.

During their lifespan, many women are exposed to pain in the pelvis in relation to menstruation and pregnancy. Such pelvic pain is often considered normal and inherently linked to being a woman, which in turn leads to insufficiently offered treatment for treatable aspects related to their pain experience. Nonetheless, severe dysmenorrhea (pain during menstruation) as seen in endometriosis and pregnancy-related pelvic girdle pain, have a high impact on daily activities, school attendance and work ability. In the context of any type of chronic pain, accumulating evidence shows that an unhealthy lifestyle is associated with pain development and pain severity. Furthermore, unhealthy lifestyle habits are a suggested perpetuating factor of chronic pain. This is of specific relevance during lifespan, since a low physical activity level, poor sleep, or periods of (di)stress are all common in challenging periods of women's lives (e.g., during menstruation, during pregnancy, in the postpartum period). This state-of-the-art paper aims to review the role of lifestyle factors on pain in the pelvis, and the added value of a lifestyle intervention on pain in women with pelvic pain. Based on the current evidence, the benefits of physical activity and exercise for women with pain in the pelvis are supported to some extent. The available evidence on lifestyle factors such as sleep, (di)stress, diet, and tobacco/alcohol use is, however, inconclusive. Very few studies are available, and the studies which are available are of general low quality. Since the role of lifestyle on the development and maintenance of pain in the pelvis, and the value of lifestyle interventions for women with pain in the pelvis are currently poorly studied, a research agenda is presented. There are a number of rationales to study the effect of promoting a healthy lifestyle (early) in a woman's life with regard to the prevention and management of pain in the pelvis. Indeed, lifestyle interventions might have, amongst others, anti-inflammatory, stress-reducing and/or sleep-improving effects, which might positively affect the experience of pain. Research to disentangle the relationship between lifestyle factors, such as physical activity level, sleep, diet, smoking, and psychological distress, and the experience of pain in the pelvis is, therefore, needed. Studies which address the development of management strategies for adapting lifestyles that are specifically tailored to women with pain in the pelvis, and as such take hormonal status, life events and context, into account, are required. Towards clinicians, we suggest making use of the window of opportunity to prevent a potential transition from localized or periodic pain in the pelvis (e.g., dysmenorrhea or pain during pregnancy and after delivery) towards persistent chronic pain, by promoting a healthy lifestyle and applying appropriate pain management.

Targeted Selected Reaction Monitoring Verifies Histology Specific Peptide Signatures in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (OC) is a disease with high mortality due to vague early clinical symptoms. Benign ovarian cysts are common and accurate diagnosis remains a challenge because of the molecular heterogeneity of OC. We set out to investigate whether the disease diversity seen in ovarian cyst fluids and tumor tissue could be detected in plasma. Using existing mass spectrometry (MS)-based proteomics data, we constructed a selected reaction monitoring (SRM) assay targeting peptides from 177 cancer-related and classical proteins associated with OC. Plasma from benign, borderline, and malignant ovarian tumors were used to verify expression (n = 74). Unsupervised and supervised multivariate analyses were used for comparisons. The peptide signatures revealed by the supervised multivariate analysis contained 55 to 77 peptides each. The predictive (Q2) values were higher for benign vs. low-grade serous Q2 = 0.615, mucinous Q2 = 0.611, endometrioid Q2 = 0.428 and high-grade serous Q2 = 0.375 (stage I-II Q2 = 0.515; stage III Q2 = 0.43) OC compared to benign vs. all malignant Q2 = 0.226. With targeted SRM MS we constructed a multiplexed assay for simultaneous detection and relative quantification of 185 peptides from 177 proteins in only 20 µL of plasma. With the approach of histology-specific peptide patterns, derived from pre-selected proteins, we may be able to detect not only high-grade serous OC but also the less common OC subtypes.

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.

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.

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.

Comprehending the Proteomic Landscape of Ovarian Cancer: A Road to the Discovery of Disease Biomarkers.

Despite recent technological advancements allowing the characterization of cancers at a molecular level along with biomarkers for cancer diagnosis, the management of ovarian cancers (OC) remains challenging. Proteins assume functions encoded by the genome and the complete set of proteins, termed the proteome, reflects the health state. Comprehending the circulatory proteomic profiles for OC subtypes, therefore, has the potential to reveal biomarkers with clinical utility concerning early diagnosis or to predict response to specific therapies. Furthermore, characterization of the proteomic landscape of tumor-derived tissue, cell lines, and PDX models has led to the molecular stratification of patient groups, with implications for personalized therapy and management of drug resistance. Here, we review single and multiple marker panels that have been identified through proteomic investigations of patient sera, effusions, and other biospecimens. We discuss their clinical utility and implementation into clinical practice.

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.