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Clinical data for calibration and validation cohorts.

Detailed description of mathematical model and parameter estimation.

Platinum-based chemotherapy constitutes the backbone of clinical care in advanced solid cancers such as high-grade serous ovarian cancer (HGSOC) and has prolonged survival of millions of patients with cancer. Most of these patients, however, become resistant to chemotherapy, which generally leads to a fatal refractory disease. We present a comprehensive stochastic mathematical model and simulator approach to describe platinum resistance and standard-of-care (SOC) therapy in HGSOC. We used pre- and posttreatment clinical data, including 18F-FDG-PET/CT images, to reliably estimate the model parameters and simulate “virtual patients with HGSOC.” Treatment responses of the virtual patients generated by our mathematical model were indistinguishable from real-life patients with HGSOC. We demonstrated the utility of our approach by evaluating the survival benefit of combination therapies that contain up to six drugs targeting platinum resistance mechanisms. Several resistance mechanisms were already active at diagnosis, but combining SOC with a drug that targets the most dominant resistance subpopulation resulted in a significant survival benefit. This work provides a theoretical basis for a cancer treatment paradigm in which maximizing platinum's killing effect on cancer cells requires overcoming resistance mechanisms with targeted drugs. This freely available mathematical model and simulation framework enable rapid and rigorous evaluation of the benefit of a targeted drug or combination therapy in virtual patients before clinical trials, which facilitates translating preclinical findings into clinical practice.Significance: These findings present a comprehensive mathematical model for platinum resistance and standard-of-care therapy in a solid cancer, allowing virtual evaluation of novel therapy regimens. Cancer Res; 78(14); 4036–44. ©2018 AACR.

Supplementary Figure S1. Outcome of PSFinder. Supplementary Figure S2. Kaplan-Meier survival curves. Supplementary Figure S3. Kaplan-Meier survival curves on time to progression in month. Supplementary Figure S4. Expression boxplot of validated transcript markers. Supplementary Figure S5. Promoter methylation changes. Supplementary Figure S6. Expression of genes affected by promoter hyper- and hypo- methylation. Supplementary Figure S7. DNMT3B expression. Supplementary Figure S8. Decitabine treatment result. Supplementary Figure S9. Kaplan-Meier survival curves on overall survival time. Tables Supplementary Table S1. PSFinder identified 61 transcripts at isoform-level for Poor I, Poor II and Good prognostic patient characterization. Supplementary Table S2. PSFinder identified 32 genes at gene-level for Poor I, Poor II and Good prognostic patient characterization. Supplementary Table S3. CpG loci with promoter hypermethylation (N=32) and hypomethylation (N=1) in Poor I patients. Supplementary Table S4. Primers and probes used in Taqman qRT-PCR. Supplementary Table S5. PSFinder identified subgroups and BRCA1/2 mutation status in patients from the TCGA discovery set. Supplementary Table S6. LPS predicted subgroups and BRCA1/2 mutation status in patients from the TCGA validation set.

Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting., Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.

OBJECTIVE Human epididymis protein 4 (HE4) is a validated, complementary biomarker to cancer antigen 125 (CA125) for high grade serous ovarian carcinoma (HGSC). Currently, there are insufficient data on the utility of longitudinal HE4 measurement during HGSC treatment and follow up. We set to provide a comprehensive analysis on the kinetics and prognostic performance of HE4 with serial measurements during HGSC treatment and follow up. METHODS This prospective study included 143 patients with advanced HGSC (ClinicalTrials.gov identifier: NCT01276574). Serum CA125 and HE4 were measured at baseline, before each cycle of chemotherapy and during follow up until first progression. Baseline biomarker values were compared to the tumor load assessed during surgery and to residual disease. Biomarker nadir values and concentrations at progression were correlated to survival. RESULTS The baseline HE4 concentration distinguished patients with a high tumor load from patients with a low tumor load assessed during surgery (p

Background/aim The combination of paclitaxel and carboplatin is the standard chemotherapy for ovarian cancer. Previous studies have implied that vitamin D (1,25-D3) may have growth inhibitory effects in ovarian cancer. This study aimed to investigate the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of ovarian cancer cells in vitro, based on the hypothesis that 1,25-D3 might potentiate the effect of paclitaxel and/or carboplatin. Materials and methods Three non-commercial ovarian carcinoma cell lines UT-OV-1(mucinous), UT-OV-3B (serous) and UT-OV-4 (endometrioid) were exposed to different concentrations of 1,25-D3, paclitaxel and carboplatin, respectively. The cell viability was measured using a Crystal violet assay kit. The cellular vitamin D receptor (VDR) mRNA levels were measured by qRT-PCR using the LightCycler equipment. Results The growth-inhibitory effect of the combination of paclitaxel and carboplatin was 56% in UT-OV-1, 33% in UT-OV-3B and 47% in UT-OV-4 cells. Single 1,25-D3 (10 μM) inhibited the growth of UT-OV-3B and UT-OV-4 by 23% and 28%, respectively, whereas no effect was seen in UT-OV-1 cells. These results are in line with the finding that the expression of VDR was high in UT-OV-3B and UT-OV-4, but very low in UT-OV-1. The combination of 1,25-D3, paclitaxel and carboplatin resulted in 61%, 46% and 58% growth reduction in UT-OV-1, UT-OV-3B and UT-OV-4 cells, respectively. The additive effect of 1,25-D3 was 21% in UT-OV-4, 20% in UT-OV-3B and 12% in UT-OV-1 cell line. Conclusion The results imply that combining 1,25-D3 with paclitaxel and carboplatin may potentiate their growth inhibitory effect on ovarian cancer cells with high VDR expression.

Background The cancer antigen 125 (CA125) immunoassay (IA) does not distinguish epithelial ovarian cancer (EOC) from benign disease with the sensitivity needed in clinical practice. In recent studies, glycoforms of CA125 have shown potential as biomarkers in EOC. Here, we assessed the diagnostic abilities of two recently developed CA125 glycoform assays for patients with a pelvic mass. Detailed analysis was further conducted for postmenopausal patients with marginally elevated conventionally measured CA125 levels, as this subgroup presents a diagnostic challenge in the clinical setting. Methods Our study population contained 549 patients diagnosed with EOC, benign ovarian tumors, and endometriosis. Of these, 288 patients were postmenopausal, and 98 of them presented with marginally elevated serum levels of conventionally measured CA125 at diagnosis. Preoperative serum levels of conventionally measured CA125 and its glycoforms (CA125-MGL and CA125-STn) were determined. Results The CA125-STn assay identified EOC significantly better than the conventional CA125-IA in postmenopausal patients (85% vs. 74% sensitivity at a fixed specificity of 90%, P = 0.0009). Further, both glycoform assays had superior AUCs compared to the conventional CA125-IA in postmenopausal patients with marginally elevated CA125. Importantly, the glycoform assays reduced the false positive rate of the conventional CA125-IA. Conclusions The results indicate that the CA125 glycoform assays markedly improve the performance of the conventional CA125-IA in the differential diagnosis of pelvic masses. This result is especially valuable when CA125 is marginally elevated.

PURPOSE Circulating tumor DNA (ctDNA) detection is a minimally invasive technique that offers dynamic molecular snapshots of genomic alterations in cancer. Although ctDNA markers can be used for early detection of cancers or for monitoring treatment efficacy, the value of ctDNA in guiding treatment decisions in solid cancers is controversial. Here, we monitored ctDNA to detect clinically actionable alterations during treatment of high-grade serous ovarian cancer, the most common and aggressive form of epithelial ovarian cancer with a 5-year survival rate of 43%. PATIENTS AND METHODS We implemented a clinical ctDNA workflow to detect clinically actionable alterations in more than 500 cancer-related genes. We applied the workflow to a prospective cohort consisting of 78 ctDNA samples from 12 patients with high-grade serous ovarian cancer before, during, and after treatment. These longitudinal data sets were analyzed using our open-access ctDNA-tailored bioinformatics analysis pipeline and in-house Translational Oncology Knowledgebase to detect clinically actionable genomic alterations. The alterations were ranked according to the European Society for Medical Oncology scale for clinical actionability of molecular targets. RESULTS Our results show good concordance of mutations and copy number alterations in ctDNA and tumor samples, and alterations associated with clinically available drugs were detected in seven patients (58%). Treatment of one chemoresistant patient was changed on the basis of detection of ERBB2 amplification, and this ctDNA-guided decision was followed by significant tumor shrinkage and complete normalization of the cancer antigen 125 tumor marker. CONCLUSION Our results demonstrate a proof of concept for using ctDNA to guide clinical decisions. Furthermore, our results show that longitudinal ctDNA samples can be used to identify poor-responding patients after first cycles of chemotherapy. We provide what we believe to be the first comprehensive, open-source ctDNA workflow for detecting clinically actionable alterations in solid cancers.

The host genetic factors that influence the natural history of human papillomavirus (HPV) infection in men are not well known. Our aim was to evaluate the role of human leukocyte antigen (HLA)-G polymorphism in oral and genital HPV infection in men. Altogether, 130 men from the Finnish Family HPV Study, with a 6-year follow-up, were included in the analyses. HLA-G alleles were tested by direct sequencing. Oral, urethral, and semen samples were collected and analyzed for 24 different HPV genotypes. Unconditional logistic regression was used to determine associations between HLA-G alleles and genotypes with HPV infection and its outcomes. Overall, eight different HLA-G alleles were identified with 15 different HLA-G genotype combinations. The most common HLA-G allele among the men was G*01:01:01 (86.2%, n = 112) followed by G*01:01:02 (36.2%, n = 47). Allele G*01:01:02 showed to be protective against any- and high-risk (HR) oral HPV (OR range of 0.20–0.24, 95% CI range of 0.06–0.85). Men having allele G*01:01:01 showed a reduced risk for incident (OR 0.30, 95% CI 0.11–0.84) and persistent (OR 0.24, 95% CI 0.08–0.69) oral infections. Allele G*01:01:03 was associated with increased risk for urethral HR-HPV infections (OR 4.94, 95% CI 1.34–18.27). Among self-reported demographic data, genotype G*01:01:01/01:01:03 was associated with an increased risk for oral warts (OR 8.00, 95% CI 1.23–51.89) and allele G*01:03:01 increased the risk of pollen and/or animal allergy (OR 13.59, 95% CI 1.57–117.25). To conclude, HLA-G polymorphism in men largely impacts the outcome of an oral HPV infection and seems to associate with self-reported allergies. Supplementary Information The online version contains supplementary material available at 10.1007/s10096-021-04362-8.

OBJECTIVE To revise FIGO staging of carcinoma of the cervix uteri, allowing incorporation of imaging and/or pathological findings, and clinical assessment of tumor size and disease extent. METHODS Review of literature and consensus view of the FIGO Gynecologic Oncology Committee and related societies and organizations. RESULTS In stage I, revision of the definition of microinvasion and lesion size as follows. Stage IA: lateral extension measurement is removed; stage IB has three subgroups-stage IB1: invasive carcinomas ≥5 mm and

Backround Human leukocyte antigen (HLA)-G may have an important role in the natural history of human papillomavirus (HPV) infection. Our aim was to evaluate the role of HLA-G in the outcome of genital and oral HPV infections in women. Methods Analyses included 306 women from the Finnish Family HPV-study and were followed-up for six years. Genital and oral samples were tested for 24 different HPV types with multiplex HPV genotyping. HLA-G alleles were determined through direct DNA-sequencing. Unconditional logistic regression was used to determine the associations between HLA-G genotypes and HPV infection outcomes. Results Ten HLA-G alleles were identified. Most common HLA-G genotypes were the wild type G*01:01:01/01:01:01 (31.3%) followed by G*01:01:01/01:01:02 (26.8%). G*01:01:01/01:01:01 genotype was associated with increased risk of oral HPV infections by any HPV type or single-type with OR = 1.86 (95% CI 1.14–3.04, P = 0.01) and 2.22 (95% CI 1.14–3.71, P = 0.02), respectively. G*04:01+ allele and the G*01:01:01/01:04:01 genotype both protected from any and single oral HPV infections; OR = 0.46 (95% CI 0.23–0.89, P = 0.02) and 0.53 (95% CI 0.23–0.97, P = 0.03), respectively. G*01:01:02/01:04:01 genotype increased significantly the risk of infertility and its treatments, with respective OR = 5.06 (95% CI 1.22–21.02, P = 0.03) and OR = 9.07 (95% CI 1.22–39.50, P = 0.03). Both HLA-G alleles and genotypes showed several significant associations with the outcomes of oral HPV infections, but none of them had any impact on the outcomes of genital HPV infections in these women. Conclusions The host HLA-G genotypes appear to impact the outcomes of oral HPV infections in women but have little if any effect on genital HPV status or infection outcomes.

Human papillomavirus (HPV) infections are found in children, but transmission modes and outcomes are incompletely understood. We evaluated oral samples from 331 children in Finland who participated in the Finnish Family HPV Study from birth during 9 follow-up visits (mean time 51.9 months). We tested samples for 24 HPV genotypes. Oral HPV prevalence for children varied from 8.7% (at a 36-month visit) to 22.8% (at birth), and 18 HPV genotypes were identified. HPV16 was the most prevalent type to persist, followed by HPV18, HPV33, and HPV6. Persistent, oral, high-risk HPV infection for children was associated with oral HPV carriage of the mother at birth and seroconversion of the mother to high-risk HPV during follow-up (odds ratio 1.60–1.92, 95% CI 1.02–2.74). Children acquire their first oral HPV infection at an early age. The HPV status of the mother has a major impact on the outcome of oral HPV persistence for her offspring.

Erythropoietin producing hepatocellular (Eph) receptors and their membrane-bound ligands ephrins are variably expressed in epithelial cancers, with context-dependent implications to both tumor-promoting and -suppressive processes in ways that remain incompletely understood. Using ovarian cancer tissue microarrays and longitudinally collected patient cells, we show here that ephrinA5/EFNA5 is specifically overexpressed in the most aggressive high-grade serous carcinoma (HGSC) subtype, and increased in the HGSC cells upon disease progression. Among all the eight ephrin genes, high EFNA5 expression was most strongly associated with poor overall survival in HGSC patients from multiple independent datasets. In contrast, high EFNA3 predicted improved overall and progression-free survival in The Cancer Genome Atlas HGSC dataset, as expected for a canonical inducer of tumor-suppressive Eph receptor tyrosine kinase signaling. While depletion of either EFNA5 or the more extensively studied, canonically acting EFNA1 in HGSC cells increased the oncogenic EphA2-S897 phosphorylation, EFNA5 depletion left unaltered, or even increased the ligand-dependent EphA2-Y588 phosphorylation. Moreover, treatment with recombinant ephrinA5 led to limited EphA2 tyrosine phosphorylation, internalization and degradation compared to ephrinA1. Altogether, our results suggest a unique function for ephrinA5 in Eph-ephrin signaling and highlight the clinical potential of ephrinA5 as a cell surface biomarker in the most aggressive HGSCs.

Objective. Cancer antigen 125 (CM 25) is generally considered the gold standard of biomarkers in the diagnosis and monitoring of high grade serous ovarian carcinoma (HGSC). We recently reported, that two CM 25 glycoforms (CA125-STn and CA125-MGL) have a high specificity to HGSC and further hypothesized, that these cancer specific glycoforms are feasible candidates as biomarkers in HGSC treatment and follow up. Methods. Our cohort consisted of 122 patients diagnosed with HGSC. Serum samples were collected longitudinally at the time of diagnosis, during treatment and follow up. Serum levels of CA125, CM 25-STn and CA125MGL were determined and compared or correlated with different end points (tumor load assessed intraoperatively, residual disease, treatment response, progression free survival). Results. Serum CA125-STn levels at diagnosis differentiated patients with low tumor load and high tumor load (p = 0,030), indicating a favorable detection of tumor volume. Similarly, the CA125-STn levels at diagnosis were significantly lower in patients with subsequent complete cytoreduction than in patients with suboptimal cytoreduction (p = 0,025). Conventional CA125 did not differentiate these patients (p = 0,363 and p = 0,154). The CA125-STn nadir value predicted the progression free survival of patients. The detection of disease relapse was improved with CA125-STn, which presented higher fold increase in 80,0% of patients and earlier increase in 37,0% of patients. Conclusions. CA125-STn showed promise as a useful biomarker in the monitoring and follow up of patients with HGSC utilizing a robust and affordable technique. Our findings are topical as a suitable indicator of tumor load facilitates patient selection in an era of new targeted therapies. (C) 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

More people are living with the long-term effects of cancer owing to improvements in cancer treatments and an aging population. Many people diagnosed with cancer report a negative impact on sexual identity, sexual functioning, and their sexual relationship. Gynecologic cancer survivors are often the most severely affected. These cancers involve cancers of the ovaries, uterus, cervix, vagina, and vulva. The impact of these cancers on sexual health results not only from the disease process itself, but may also be due to the necessary treatments required. These can have a profound impact on psychological, physiological, and social well-being both in the short and long term, which may result in negative impact on the quality of life of the patient as well as her partner. Although most patients express that they would like to be more informed about sexual health and would like to have the opportunity to discuss these issues with their therapeutic team, sexual health is often not discussed with the patient.

Objective. In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods. A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results. A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (295%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P

To evaluate the predictive potential of total metabolic tumor volume (MTV) reduction during neoadjuvant chemotherapy (NACT) with 18F–FDG-PET/CT in an advanced FIGO stage III/IV epithelial ovarian cancer (EOC) patient cohort. Twenty-nine primarily inoperable EOC patients underwent 18F–FDG-PET/CT before and after NACT. The pre- and post-NACT total MTV, in addition to the percentage MTV reduction during NACT, were compared with primary therapy outcome and progression-free survival (PFS). ROC-analysis determined an optimal threshold for MTV reduction identifying patients with progressive or stable disease (PD/SD) at the end of primary therapy. A multivariate analysis with residual tumor (0/>0), FIGO stage (III/IV) and MTV reduction compared to PFS was performed. The association between MTV reduction and overall survival (OS) was evaluated. The median pre- and post-NACT total MTV were 352 cm3 (range 150 to 1322 cm3) and 51 cm3 (range 0 to 417 cm3), respectively. The median MTV reduction during NACT was 89% (range 24% to 100%). Post-NACT MTV and MTV reduction associated with primary therapy outcome (MTV post-NACT p = 0.007, MTV reduction p = 0.001) and PFS (MTV post-NACT p = 0.005, MTV reduction p = 0.005). MTV reduction

Persistent human papillomavirus (HPV) infection is a key event in HPV-induced carcinogenesis. As part of the prospective Finnish Family HPV Study, we analysed the physical state and viral copy numbers of HPV16 in asymptomatic oral infections that either persisted or cleared during the 6-year follow-up. The persister group comprised 14 women and 7 men with 51 and 21 HPV16-positive brush samples. The clearance group included 41 women and 13 men, with 64 and 24 samples, respectively. Physical state and viral DNA load were assessed by using quantitative PCR for HPV16 E2 and E6 genes. E2/E6 ratio was calculated and HPV16 was classified as episomal, mixed or integrated with values of 0.93-1.08, The Finnish Family HPV Study has been supported by the Academy of Finland (no. 116438/2006, no. 130204/2008), Finnish Cancer Foundation, Solberg Foundation, Finnish Dental Society Apollonia and the Government Special Foundation (EVO) to Turku University Hospital. The funders had no role in the study design and data analysis, decision to publish or preparation of the manuscript

Human papillomavirus (HPV) DNA has been detected in breast milk, but its origin has remained obscure. The aim of the study was to analyze the prevalence and persistence of HPV in breast milk in the Finnish Family HPV cohort study. The association of breast milk HPV positivity with the family members' oral HPV status was evaluated.We included 308 families to the study where the mother was breast feeding her offspring. Mothers collected the milk samples manually at day 3, and at months 2, 6 and 12. Cervical and/or oral samples were collected from all family members. HPV testing was performed using nested polymerase chain reaction and Luminex-based Multimetrix kit.Breast milk HPV DNA was found in 10.1% (31/308), 20.1% (39/194) and 28.8% (17/59) of samples at day 3, months 2 and 6, respectively. The following HPV genotypes were detected: 6, 16, 18, 33, 45, 53, 56, 59, 66 and 82. Breast milk HPV persisted among 5.5% (9/164) of the lactating mothers. No significant associations were detected between the persistent breast milk HPV and the offspring's oral incident HPV infection. Breast milk HPV positivity showed a strong association with the fathers' oral HPV positivity at baseline, as well as at 6- and 12-month follow-up visits, with odds ratio (OR) = 3.24 [95% confidence interval (CI): 1.04-10.12], OR = 6.34 (95% CI: 1.84-21.89) and OR = 14.25 (95% CI: 1.16-174.80), respectively.HPV in breast milk is prevalent among the lactating mothers and HPV can also persist in breast milk. The breast milk is a potential vehicle for HPV transmission to oral mucosa of the spouse but not of the offspring.

The extracellular matrix proteoglycan decorin is well-known for its oncosuppressive activity. Here, decorin expression was examined in human vulva carcinoma tissue samples and in primary and commercial cell lines representing this malignant disease. Furthermore, the effect of adenovirus-mediated decorin cDNA (Ad-DCN) transduction on the viability, proliferation, and the expression and activity of the epidermal growth factor receptor (ErbB/HER) family members of the cell lines were investigated. Using in situ hybridization and immunohistochemistry for decorin, it was demonstrated that malignant cells in human vulva carcinoma tissues lack decorin expression. This result was true independently on tumor stage, grade or human papillomavirus status. RT-qPCR analyses showed that the human vulva carcinoma cell lines used in this study were also negative for decorin expression. Transduction of the cell lines with Ad-DCN caused a marked reduction in cell viability, while the proliferation of the cells was not affected. Experiments examining potential mechanisms behind the oncosuppressive effect of Ad-DCN transduction revealed that ErbB2/HER2 expression and activity in carcinoma cells were markedly downregulated. In conclusion, the results of this study showed that human vulva carcinoma cells lack decorin expression, and that Ad-DCN transduction of these cells induces oncosuppressive activity in part via downregulation of ErbB2/HER2.

Background Epithelial ovarian cancer (EOC) typically spreads intra-abdominally, but preoperative evaluation with FDG PET/CT often reveals metabolically active supradiaphragmatic lymph nodes (sdLNs). Their clinical significance and behavior during treatment has not been established. Methods EOC patients with PET positive sdLNs at diagnosis were prospectively followed with PET/CT after primary chemotherapy and at the first recurrence. In each patient, 2 most active LNs in 5 different supradiaphramatic regions were evaluated and the size and changes in FDG uptake (SUVmax) were recorded. The patients´ overall response to primary treatment was defined with RECIST criteria. The behavior of sdLNs during chemotherapy were compared in treatment responders and non-responders. Recurrence patterns were monitored. Results Forty-one patients with 127 PET/CT scans were systematically evaluated. In pretreatment scan, 76% (31/41) of patients had FDG-avid sdLNs in multiple anatomical sites. Only a minority (22/136) of the sdLNs were enlarged in size, but their histopathologic confirmation by biopsy was not possible. Only 6/41 patients had FDG-avid sdLNs in a single surgically approachable site. The sdLNs became inactive during primary chemotherapy more often in the RECIST responders compared to the non-responders (HR 1.46 (95%CI: 1.09–1.96), p = 0.002). The size and SUVmax values did not predict treatment outcome. In 50% of the responders the same sdLNs reactivated when recurrence occurred. Persistent post-treatment metabolic activity did not predict earlier disease relapse (p = 0.59). Conclusion The behavior of metabolically active sdLNs during chemotherapy supports their metastatic nature. Due to their distribution to multiple regions, the benefit of removal of reachable sdLNS seems unlikely. Trial registration NCT, NCT01276574. Registered 1 September 2010. Electronic supplementary material The online version of this article (10.1186/s40644-019-0215-7) contains supplementary material, which is available to authorized users.

Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Data on genotype-specific concordance of oral-oral and genital-oral HPV infections among marital couples are key to understand HPV transmission between spouses. Genotype-specific concordance of HPV infections (oral/genital) and their co-variates among 131 marital couples were determined during 6-year follow-up (FU). Seven oral scrapings were taken from both spouses, accompanied by six genital samplings from the women and one (at baseline) from the male partners. HPV-genotyping was performed by nested PCR and a Luminex®-based Multimetrix Assay. Demographic data were collected with questionnaires at baseline and study conclusion. Prevalence of oral HPV varied from 10.3 to 27.0 % and 15.8 to 31.3 % in women and men, respectively. At baseline, 37.6 % of the male genital samples were HPV-positive while in female genital samples, HPV prevalence varied from 13.3 to 59.4 %. Only 15 couples had HPV genotype-specific concordance (oral-oral n = 7; male oral-female genital n = 9; female oral-male genital n = 2). In the nested case-control setting, higher number of deliveries (OR 0.145, 95%CI 0.030-0.706, p = 0.017) and higher number of intercourse (OR 0.488, 95%CI 0.243-0.978, p = 0.043) decreased the likelihood of concordant HPV infections while practicing oral sex increased the risk (OR 0.299, 95%CI 0.120-0.748, p = 0.010). In multivariate analysis, the likelihood of concordance was decreased by higher number of pregnancies of the female partner (p = 0.020) and by higher frequency of intercourse reported by the male spouse (p = 0.027). To conclude, asymptomatic HPV infections were common in both spouses while genotype-specific concordance was low. This supports the view that HPV profile of the spouses has been established before the current marital relationship.

Objective The aim of this study was to examine the relationship between the reduction of maximum standardized uptake values (SUVmax) in 18 F-FDG-PET/CT to histopathological changes obtained with neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). We wanted to evaluate whether 18 F-FDG-PET/CT is useful for identifying patients who will not respond to NACT and would therefore benefit from second-line chemotherapy instead of interval debulking surgery (IDS). Methods Twenty-six primarily inoperable EOC patients treated with NACT were enrolled in this study. 18 F-FDG-PET/CT imaging was performed before diagnostic laparoscopy and after three to four NACT cycles. The relationship between the decrease in omental SUVmax from before to after NACT with omental histopathological response was examined in samples taken from the corresponding anatomical sites during IDS. Patients were divided into three groups according to chemotherapy-induced histopathological changes. Serum CA125 and HE4 halftimes during NACT as well as Ki-67 antigen expression in IDS samples were determined. Results The median omental SUVmax change during NACT was −64% (range−16% to −84%), and it was associated with histopathological response (p=0.004, OR 0.9, CI 0.84-0.97). A SUVmax decrease of less than 57% identified histopathological non-responders. Progression-free survival (PFS) differed between the poor, moderate and good histopathological response groups (0.9year vs 1.2years vs 1.4years, respectively, p=0.05). The SUVmax change was not associated with PFS. Conclusion 18 F-FDG-PET/CT was able to identify patients who would not respond to NACT. To obtain a histopathological response in EOC, a substantial metabolic response in 18 F-FDG-PET/CT is necessary.

Extracellular matrix (ECM) interactions contribute to cancer metastasis and chemotherapy resistance by regulating invasive cancer growth and apoptosis evasion. However, the key ECM pathways activated during cancer evolution, including tumor metastasis and tissue responses to chemotherapy, remain to be systematically identified. Using a unique longitudinal high-grade serous ovarian carcinoma (HGSOC) cohort to understand the ECM deposition and remodeling in response to disease development and chemotherapeutics, we conducted ECM proteome, i.e., matrisome, analysis on HGSOC tissues of distinct anatomic sites from treatment-naïve and post-chemotherapy primary samples. Together with an unbiased functional ECM screen for platinum-treatment responses, we report how the solid tumor ECM evolves with disease progression and how specific stromal ECM proteins, including fibronectin, promote ovarian cancer cell motility, invasion, and resistance to platinum treatment. Importantly, we observed these specific stromal ECM proteins to be expressed already at HGSOC omental microlesions with remarkable desmoplastic reaction, as shown by immunohistochemistry of longitudinally collected patient cohort samples. Further, by using clinical The Cancer Genome Atlas (TCGA) microarray data we found that at transcriptional level the overexpression of a specific ECM protein, with platinum-induced cancer cell spreading and migratory response, also associated with poor survival in the treatment-naïve TCGA patient data, and was specifically upregulated after chemotherapy in our longitudinal cohort. In ovarian cancer cell cultures and in patient-derived 3D HGSOC organoid cultures, this specific ECM-rich microenvironment associated with an epithelial-to-mesenchymal transition transcriptional markers coupled to a stem-like morphology and properties with increased resistance. These results underline the importance of cell-matrix communication in invasion and chemotherapy response, revealing certain ECM proteins as important promoters of aggressiveness and chemotherapy resistance in the metastatic HGSOC lesions. Citation Format: Elina A. Pietilä, Jordi Gonzales-Molina, Lidia Moyano-Galceran, Laura Lehtinen, Pauliina Turunen, Tomas Santos Martins, Ville Rantanen, Antti Häkkinen, Sanaz Jamalzadeh, Kaiyang Zhang, Tarja Lamminen, Katja Kaipio, Johanna Hynninen, Sakari Hietanen, Seija Grénman, Rainer Lehtonen, Sampsa Hautaniemi, Olli Carpén, Kaisa Lehti. Extracellular matrix proteins increase invasive growth and chemotherapy resistance of ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A64.

Tumor heterogeneity in high-grade serous ovarian cancer (HGSOC) stems from highly variable copy number changes that lack shared actionable drug targets and contribute to inevitable recurrence and death. To unveil the vast heterogeneity in HGSOC, and understand the molecular changes that occur during chemotherapy, we analyzed single-cell transcriptomes of 49 dissociated HGSOC tumor or ascites specimens, along with six normal postmenopausal fimbria/tuba specimens as controls. This set contains 13 pairs of samples from patients who underwent neoadjuvant chemotherapy, taken before treatment (primary), and after three cycles of standard carboplatin-paclitaxel chemotherapy (interval). Clustering single-cell transcriptomes based on acknowledged cell type markers revealed epithelial cancer cells, as well as diverse stromal and immune cell types. The cell type proportions displayed high variability across HGSOC tumors, intriguingly with lowest tumor purity in patients with short platinum-free interval. To identify the impact of chemotherapy on transcriptional programs, we extracted shared transcriptomic differences in the cancer cells of seven primary-interval pairs. Regardless of the clinical response, three cycles of chemotherapy induced an oxidative stress response program that inhibits apoptosis, while inducing genes involved in MHC II antigen presentation to T helper cells. Next, to study how cell states change during chemotherapy, we ordered the cells in pseudotime based on their transcriptomic similarity, revealing a mixture of primary and interval cells in all but two primary-interval pairs. Furthermore, based on inferred copy number analysis, we estimate that genomic differences contribute variably, between 20%, to the overall transcriptomic differences between the primary and interval pairs. These results suggest that pre- and post-chemotherapy states are not completely separate and that genomic evolution has a highly variable effect on the state differences, providing support for an intrinsic chemoresistance model with genomic and nongenomic components. To further the understanding of intrinsic resistance, we next focused on patients’ clinical response mechanisms in HGSOC cancer cells. Genes encoding well-known serum markers of HGSOC, WFDC2 and MUC16, were expressed at higher levels in primary specimens of patients with incomplete response, whereas patients with complete response displayed higher expression of genes related to chromatin repression/heterochromatin. Finally, we focused on tumor resectability to understand the transcriptomic patterns underlying HGSOC metastasis. Already prior to chemotherapy, patients with residual disease showed induced FOXO3-driven regulon linked to quiescence, stress resistance, and stemness, whereas patients with no residual disease express increased level of E2F1/DP1-driven regulon linked to BRCAness, high proliferation, and high metabolic rate. Citation Format: Erdogan Pekcan Erkan, Jun Dai, Kaiyang Zhang, Katja Kaipio, Tarja Lamminen, Naziha Mansuri, Lasse Suominen, Amjad Alkodsi, Kaisa Huhtinen, Sakari Hietanen, Johanna Hynninen, Seija Grénman, Olli Carpén, Sampsa Hautaniemi, Anna Vähärautio. Singling out tumor heterogeneity and chemoresistance in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A40.

High-grade serous ovarian cancer (HGSOC) is the most common and difficult to treat ovarian cancer subtype. HGSOC is diagnosed typically at late stage when it has already metastasized to many tissues in peritoneal cavity. In order to gain understanding of ovarian cancer evolution and reasons for chemoresistance, patients’ sequencing and clinical data were extensively analyzed. We studied 124 cancerous samples from 30 HGSOC patients and sequenced whole genomes from multiple tissues collected at diagnosis (N=92), interval debulking surgery (N=17), and relapse (N=15), and in addition deep sequencing data (600 genes) from seven patients with longitudinal circulating tumor DNA (ctDNA). Subclones were identified using somatic mutations and copy number variants (CNV). Patients were divided into three primary therapy response groups (poor, intermediate, and good) using platinum free interval (PFI), primary therapy outcome, and residual tumor size after surgery. The poor response group consisted of patients having progressive disease. Phylogenetic analysis revealed clearly distinct evolutionary models in HGSOC. Briefly, patients can be first divided into two main groups based on genetic diversity between tissues at diagnosis and secondly into three subgroups by comparing them to patients’ relapse samples affected by chemotherapy. In our study 70% of patients fall into the model displaying high genetic diversity between tissues. Although genetic diversity did not correlate with clinical outcome, the number of subclones differed significantly between primary therapy response groups (ANOVA, p=0.013): good outcome patients had more subclones. Relapse or interval stage samples were available from ten patients. Four of them displayed static pattern, continuing the low genetic diversity detected at diagnosis. In this evolution model, subclonal composition is very similar in all the samples regardless of tissue or treatment stage. In the six other patients, we identified models with a) complete subclonal turnover (N=2), b) accumulation of novel mutations (N=2), or c) mixed pattern (N=2). Accumulation of novel mutations in the two patients (PFI 6.0 and 2.7 months) may result from the defective homologous recombination machinery identified by relapse-specific mutational signature (COSMIC signature SBS3). As a common feature of metastasis, evidence of polyclonal seeding was detected in almost all the patients. HGSOC tumors exhibit multiple distinct models of evolution. The most patients are highly genetically different. However, in a quarter of the patients tumors were quite static at diagnosis and half of them remained static even after chemotherapy despite obvious selection pressure. In the majority of cases, the largest number of changes were detected once influenced to chemotherapy. Because of inter-tissue heterogeneity and diverging nature of HGSOC on-time samples, for example through ctDNA, are needed to find optimal drug combinations for this moving target. Citation Format: Jaana Oikkonen, Nil Campamà Sanz, Antti Häkkinen, Yilin Li, Ingrid Schulman, Mikko Kivikoski, Kaisa Huhtinen, Sakari Hietanen, Seija E. Grénman, Johanna Hynninen, Rainer Lehtonen, Sampsa Hautaniemi. Phylogenetic analyses reveal variable patterns of tumor evolution in HGSOC [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A60.

Aims: To prospectively evaluate the use of F-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG-PET/CT) in the definition of the treatment response after primary treatment of advanced epithelial ovarian cancer (EOC). Materials and methods: Forty-nine patients with advanced EOC had an F-18-FDG PET/CT scan before and after primary treatment. The treatment response was defined with the currently used radiological and serological Response Criteria in Solid Tumors (RECIST1.1/GCIC) criteria and the modified PET Response Criteria in Solid Tumors (PERCIST). The concordance of the two methods was analysed. If the patient had a complete response to primary treatment by conventional criteria, the end of treatment F-18-FDG PET/CT scan (etPET/CT) was not opened until retrospectively at the time of disease progression. The ability of etPET/CT to predict the time to disease recurrence was analysed. The recurrence patterns were observed with an F-18-FDG PET/CT at the first relapse. Results: The agreement of the RECIST1.1/GCIC and modified PERCIST criteria in defining the primary treatment response in the whole patient cohort was good (weighted kappa coefficient = 0.78 ). Of the complete responders (n = 28), 34% had metabolically active lesions present in the etPET/CT, most typically in the lymph nodes. The same anatomical sites tended to activate at disease relapse, but were seldom the only site of relapse. In patients with widespread intra-abdominal carsinosis at diagnosis, the definition of metabolic response was challenging due to problems in distinguishing the physiological FDG accumulation in the bowel loops from the residual tumour in the same area. The presence of metabolically active lesions in the etPET/CT did not predict earlier disease relapse in the complete responders. Conclusions: In the present study, etPET/CT revealed metabolically active lesions in complete responders after EOC primary therapy, but they were insignificant for the patient's prognosis. The current study does not favour routine use of F-18-FDG PET/CT after EOC primary treatment for complete responders. (C) 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Role of host factors in transmission of human papillomavirus (HPV)-infection from mother to her offspring is not known. Our aim was to study whether human leukocyte antigen (HLA)-G allele concordance among the mother-child pairs could facilitate vertical transmission of HPV, because HLA-G may contribute to immune tolerance in pregnancy. Altogether, 310 mother-child pairs were included from the Finnish Family HPV study. Overall, nine different HLA-G alleles were identified. The HLA-G genotype concordance of G∗01:01:01/01:04:01 increased the risk of high risk (HR)-HPV genotype positivity in cord blood and infant's oral mucosa. The mother-child concordance of G∗01:01:02/01:01:02 increased the risk of oral HPV positivity with HR-HPV genotypes both in the mother and offspring; OR 2.45 (95%CI 1.24-4.85). Discordant HLA-G allele for G∗01:04:01 and for G∗01:06 was significantly associated with infant's oral low risk (LR)-HPV at birth, OR 3.07 (95%CI 1.01-9.36) and OR 5.19 (95%CI 1.22-22.03), respectively. HLA-G had no association with HPV genotype-specific concordance between the mother and child at birth nor influence on perinatal HPV status of the child. Taken together, our results show that HLA-G molecules have a role in predicting the newborn's likelihood for oral HPV infection at birth.

Purpose: Homologous recombination deficiency (HRD) correlates with platinum sensitivity in patients with ovarian cancer, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. Experimental Design: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n = 32). Samples clustered in 3 categories: HR-deficient, HR-low, and HR-proficient. We analyzed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (P = 0.0103), associated with longer PFI (HR-deficient vs. HR-proficient: 531 vs. 53 days), and significantly correlated with improved OS (HR score Conclusions: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of patients with ovarian cancer. Clin Cancer Res; 24(18); 4482–93. ©2018 AACR.

Motivation DNA methylation aberrations are common in many cancer types. A major challenge hindering comparison of patient-derived samples is that they comprise of heterogeneous collection of cancer and microenvironment cells. We present a computational method that allows comparing cancer methylomes in two or more heterogeneous tumor samples featuring differing, unknown fraction of cancer cells. The method is unique in that it allows comparison also in the absence of normal cell control samples and without prior tumor purity estimates, as these are often unavailable or unreliable in clinical samples. Results We use simulations and next-generation methylome, RNA and whole-genome sequencing data from two cancer types to demonstrate that the method is accurate and outperforms alternatives. The results show that our method adapts well to various cancer types and to a wide range of tumor content, and works robustly without a control or with controls derived from various sources. Availability and implementation The method is freely available at https://bitbucket.org/anthakki/dmml. Supplementary information Supplementary data are available at Bioinformatics online.

Prolonged steroid hormone therapy increases the risk of breast cancer, especially the risk of lobular cancer, but the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) use is controversial. In this study we aimed to test the hypothesis that risk for lobular breast cancer is elevated among LNG-IUS users.We identified from the national Medical Reimbursement Registry of Finland the women aged 30-49 who had used LNG-IUS for the treatment or prevention of menorrhagia in 1994-2007, and from the Finnish Cancer Registry breast cancers diagnosed before the age of 55 and by the end of 2012.A total of 2015 women had breast cancer diagnosed in a cohort of 93 843 LNG-IUS users during follow-up consisting of 1 032 767 women-years. The LNG-IUS users had an increased risk for both ductal breast cancer [standardized incidence ratio (SIR) 1.20, 95% confidence interval (CI) 1.14-1.25] and for lobular breast cancer (SIR 1.33, 95% CI 1.20-1.46), as compared with the general female population. The highest risk was found in LNG-IUS users who purchased the device at least twice, whose SIR for lobular cancer was 1.73 (95% CI 1.37-2.15).The results imply that intrauterine administration of levonorgestrel is not only related to an excess risk of lobular breast cancer but also, in contrary to previous assumptions, to an excess risk of ductal breast cancer.

Endometrial cancer cells are known to be sensitive to carboplatin and paclitaxel. Furthermore, vitamin D (1,25-D3) has been reported to inhibit endometrial cancer cell growth both as a single agent and combined with carboplatin. However, there are no studies comparing the effect of paclitaxel and carboplatin as single agents vs. in combination in endometrial cancer cell lines. Neither has the effect of 1,25-D3 been studied with paclitaxel. The present study investigated the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of endometrial cancer cells in vitro.Two endometrial adenocarcinoma cell lines (UT-EC-1 and UT-EC-3) were cultured with different doses of paclitaxel, carboplatin and 1,25-D3. The cellular VDR (vitamin D receptor) mRNA levels were measured and the expression of estrogen (ER) and progesterone (PR) receptors by the cells was determined.In the UT-EC-1 cell line the growth inhibition was 72% with paclitaxel, 54% with carboplatin and 73% with the combination of these compounds. The corresponding numbers in UT-EC-3 were 70%, 33% and 65%, respectively. 1,25-D3 suppressed cell growth 88% with paclitaxel, 63% with carboplatin and 87% with their combination in the UT-EC-1 cell line.In both cell lines, single-agent paclitaxel was as effective as the combination of the compounds and more effective than single carboplatin. 1,25-D3 may further contribute to the cytotoxic effect of these agents.

More data are needed on the role of abnormal vaginal microbiota in the natural history of cervical human papillomavirus (HPV) infections. Our purpose was to study the prevalence of mixed flora (MF), bacterial vaginosis (BV) and yeast infection in women with known HPV outcomes during the 72-month follow-up (FU). Asymptomatic pregnant women (N = 329) were enrolled in the third trimester of their pregnancy. Pap smears and HPV genotyping samples were taken at baseline and at 12-, 24-, 36- and 72-month FU visits, with one additional sample at 2 months for HPV. HPV testing was done with nested PCR and Multimetrix assay to determine the point prevalence and persistence of HPV. Conventional Pap smears were scored for MF, BV and yeast infection. Covariates of the outcomes were analyzed using generalized estimating equation (GEE) and Poisson regression. Of the women, 76.6% (252/329) tested HPV-positive at least once during the FU. BV was detected in 12.2% (40/329), MF in 57.4% (189/329) and yeast infection in 22.9% (73/329) of the women. HPV-positive women had significantly more leucocytes in their Pap smear (p = 0.023) than the HPV-negative ones. MF (OR 2.75, 95% CI 1.77-4.27) and yeast infection (p = 0.007) were linked with HPV positivity. BV but not yeast infection was a significant covariate of HPV persistence (p = 0.024; OR 2.15, 95% CI 1.13-4.08). MF and yeast infection were associated with prevalent cervical HPV infection. In the longitudinal setting, BV predicted HPV persistence, implicating that treatment of asymptomatic BV in women with cervical HR-HPV infections might be justified.

To study the risk of endometrial cancer and breast cancer and the hysterectomy rate after endometrial ablation.In this retrospective cohort study, records of all women with endometrial ablation at ages 30-49 years in Finland (1997-2014) were extracted from the Hospital Discharge Register and linked to the Cancer Registry and Finnish Central Population Register. The primary outcome was cancer incidences in the endometrial ablation cohort compared with those in the background population of the same age. Secondarily, the postablation hysterectomy rate was compared with that of a control cohort of similar-aged women extracted from the Finnish Central Population Register. Multivariate regression models with adjustment for age, parity, number of cesarean deliveries, history of sterilization, and the duration of follow-up were evaluated as risk factors for postablation hysterectomy.In total, 154 cancers (standardized incidence ratio [observed-to-expected ratio] 0.96, 95% CI 0.82-1.13) were diagnosed among 5,484 women treated with endometrial ablation during the follow-up of 39,892 women-years. The standardized incidence ratio for endometrial cancer was 0.56 (95% CI 0.12-1.64) and for breast cancer 0.86 (95% CI 0.67-1.09). A total of 1,086 (19.8%) women had postablation hysterectomy. Risk of hysterectomy was almost fourfold in the endometrial ablation cohort compared with 26,938 women in a control group (adjusted hazard ratio [HR] 3.63, 95% CI 3.32-3.96). Factors predisposing to postablation hysterectomy were leiomyomas (adjusted HR 1.78, 95% CI 1.03-3.10), age younger than 35 years (adjusted HR 1.44, 95% CI 1.15-1.81), at least two prior cesarean deliveries (adjusted HR 1.27, 95% CI 1.04-1.55), and history of sterilization (adjusted HR 1.15, 95% CI 1.01-1.32).Endometrial ablation was not associated with an elevated endometrial cancer or breast cancer risk in Finland. Leiomyomas, young age, and history of prior cesarean deliveries or sterilization were associated with an increased risk of postablation hysterectomy.

Persistence of high-risk (HR-) human papillomavirus (HPV) infection of the uterine cervix increases the risk of cervical cancer. Oral HPV infections are among potential covariates of long-term genotype-specific persistent cervical HR-HPV infections. It is not known whether this persistence reflects inability of the host to reject HPV infections in general. A case–control setting was designed to estimate the covariates of long-term persistent cervical HR-HPV infections using multivariate generalized estimating equation (GEE) models. HPV was detected with PCR using GP05+/GP06+-primers and genotyped for 24 HPVs with a Multimetrix-kit. The cases (n = 43) included women who had genotype-specific persistent cervical HR-HPV infection for at least 24 months (24M+) and controls were women who tested repeatedly HPV-negative in their cervical samples (n = 52). These women represent a sub-cohort of the Finnish Family HPV Study. The cases differed significantly from the HPV-negative controls in several aspects: they were younger, had a longer mean time to incident oral HPV infection (40.7 versus 23.6 months), longer duration of oral HPV persistence (38.4 versus 14.1 months), and longer time to clearance of their oral HPV infection (50.0 versus 28.2 months). In multivariate GEE analysis, the second pregnancy during the follow up was the only independent predictor with significant protective effect against 24M+ persistent cervical HR-HPV infections, OR of 0.15 (95% CI 0.07–0.34). To conclude, long-term persistent cervical HR-HPV infections are associated with a prolonged clearance of oral HR-HPV infections while new pregnancy protects against persistent cervical HR-HPV infections.

Human epididymis protein 4 (HE4) is a novel tumour marker in epithelial ovarian cancer (EOC). Data on its profile and predictive potential for subsequent outcome after neoadjuvant chemotherapy (NACT) are still under investigation. The aim of this study was to compare CA125 and HE4 profiles with radiologic response after NACT and to evaluate their potential as predictors of clinical outcome in a primarily inoperable EOC patient cohort. Twenty-five EOC patients of high-grade subtype (HGSC) treated with NACT were enrolled in the study. Serum HE4 and CA125 samples were taken at the time of diagnosis and before interval debulking surgery (IDS). Pre-NACT and pre-IDS HE4 and CA125 and their percentage changes were compared with NACT response seen on CT and surgical outcome in IDS. We also evaluated the biomarkers' abilities to predict platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). All 25 patients were considered inoperable in laparoscopy at the time of diagnosis. HE4 and CA125 changes during NACT did not correlate with the changes seen on CT. Surgical outcome in IDS was associated with pre-IDS biomarker values but not with those taken before diagnosis. In IDS, 87 % had1-cm residual tumour. In patients with HE4 change80 and80 % during NACT, the median OS was 3.38 and 1.60 years (p = 0.01), respectively. Serum HE4 is a promising additional tool when evaluating advanced HGSC patient's response to NACT. It may be helpful when deciding whether to proceed to IDS or to second-line chemotherapy.