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The presented paper deals with the link adaptation algorithms in mobile radio access networks based on Wideband Code Division Multiple Access (WCDMA). The mobile radio channel has a significant impact on the transmitted signal between User Equipment (UE) and Base Station (BS). The character of environment (e.g. number of received reflections) and increasing UE velocity cause unfavorable signal fadings, which have a major impact on the received signal. Due to this fact and the principle of WCDMA, fast power adaptation is essential for mobile radio access networks based on WCDMA. The prediction of mobile radio channel near-future state is one of the possible approaches how to span its unfavorable state. According to this assumption, we have improved the basic link adaptation algorithm (used to control properties of transmitter) to predictor based link adaptation algorithm. This contribution comprises the performance of basic link adaptation algorithm and predictor based algorithms, which support both variable (multi-bit) and fixed (singlebit) power steps to modify transmitter output power level. The link adaptation algorithms were simulated under various average UE velocities in urban environment. New algorithms were designed to increase the efficiency of data transmission in uplink direction.

The fast power adaptation is essential for WCDMA based mobile radio networks, as 3G UMTS. Although the first version of UMTS has been released in 1999 (Release 99) evolution was not finished yet. Quality of Service (QoS) and user data rate (e.g. HSDPA and HSUPA) are continuously increasing from release to release. Even though link adaptation frequency (1500 times per second) seems to be enough to span accidental fadings of mobile radio channel, used link adaptation algorithm is based on non-actual information about mobile radio channel state, which causes transmitter reaction delay to the actual channel state. Usage of appropriate prediction method to estimate near future channel state seems to be a valuable step to improve hybrid link adaptation algorithm. In this article we have described and simulated the new SIR-slot based advanced link adaptation algorithms. Algorithms were designed to increase efficiency of data transmission among a user equipment and base stations (uplink) for different simulation environments (pedestrian channel with mobile subscriber speed 5 km/h, 15 km/h and vehicular channel with speed 45 km/h).

In the next generation of mobile communication networks (B3G) theusing of effective handling of radio resources is supposed (channels,power and transmission rate) with simultaneous delivery of requiredservices, in which the quality of service (QoS) is guaranteed. In thisarticle we have described and simulated new BER based, SIR-frame basedand SIR-slot based link adaptation algorithms. Algorithms were designedto increase efficiency of data transmission among user equipment andbase stations (uplink) expressed by throughput and the outageprobability for each link. Simulation results of hybrid adaptation(power and modulation BPSK, QPSK, 16-QAM, 64-QAM) are compared andexpressed as data throughput and outage probability for differentsimulation environments (pedestrian channel with mobile subscriberspeed 10 km/s and vehicular channel with speed 120 km/h).

Nowadays we are witnesses of a huge development one of the mostprogressive communication technology - mobile networks. The mainproblem in these networks is an elimination of the mutual interference,which, mainly in non-orthogonal CDMA networks, is the principalobstacle for reaching high transmission rates The aim of thiscontribution is to give simplified view to mutual interference modelsfor orthogonal and non-orthogonal CDMA networks. The contribution isintended mainly for PhD. students to help them to obtain an orientationin such a complicated areas, as the interference models for CDMAnetworks are.

This paper deals with a simulation of cellular CDMA system usingbase station adaptive antennas. The model assumes two tiers area, fourtypes of antennas, lognormal shadowing corresponding to three types ofenvironments and perfect power control or two values of power controlerror, respectively. The capacity of system in up-link is evaluated bya number of mobile stations with higher signal to interference ratiothan threshold with given outage probability.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC., Competing Interests: Competing interests: G.R. reports disclosures related to consulting fees (Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Stemline), payment/honoraria (Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, Stemline, BMS) and travel/accommodations/expenses (Amgen, Daiichi Sankyo, Eli Lilly, Gilead, Merck, Pfizer, Roche). D.E. reports disclosures related to consulting fees (AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Menarini, Novartis, Pfizer, Roche, Seagen, Sirius Medical), payment/honoraria (AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Sirius Medical), expert testimony (AstraZeneca, Daiichi Sankyo, Gilead, Lilly), travel/accommodations/expenses (AstraZeneca, Daiichi Sankyo, Pfizer), an advisory role (AstraZeneca, Daiichi Sankyo) and receipt of equipment/materials from Sirius Medical. R.B. reports disclosures related to grants/contracts (Daiichi Sankyo), consulting fees (AstraZeneca, Daiichi, Eisai, Eli Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Stemline), payment/honoraria (AstraZeneca, BMS, Daiichi, Eisai, Eli Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen), travel/accommodations/expenses (Daiichi, MSD, Pfizer) and an advisory role (WSG). C.A.S. reports disclosures related to support for the paper (Roche), grants/contracts (Roche), payment/honoraria (Roche) and travel/accommodations/expenses (Roche). A.P. reports disclosures related to payments for an advisory role (Novartis, Amgen, Celgene/BMS, Sandoz, Janssen, AstraZeneca, Abbvie, Takeda, Sanofi, Kite–Gilead, Roche, Pfizer, Seagen, Daiichi Sankyo) and travel/accommodations/expenses (Roche, Gilead, Daiichi Sankyo, Janssen, Eli Lilly, Pierre Fabre). M.B. reports disclosures related to grants/contracts (Amgen, AstraZeneca, Cepheid, Daiichi Sankyo, Gilead, MSD, Novartis, Seagen), consulting fees (Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Samsung, Gilead, Seagen), payment/honoraria (Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Gilead), travel/accommodations/expenses (AstraZeneca, Daiichi Sankyo, MSD, Roche), an advisory role (Pfizer, GBG, Novartis) and a leadership/fiduciary role (OeGHO, ABCSG). E.P. reports disclosures related to support for the paper (Roche), payment/honoraria (Roche) and an advisory role (Roche). C.F.S. reports disclosures related to grants/contracts (Amgen, Roche, AstraZeneca, Daiichi), consulting fees (AstraZeneca, Novartis), payment/honoraria (Novartis, AstraZeneca, Daiichi, Seagen, Amgen), travel/accommodations/expenses (Daiichi) and an advisory role (WSG). S.P.G. reports disclosures related to consulting fees (Roche), payment/honoraria (Roche), travel/accommodations/expenses (Roche) and an advisory role (Roche). M.K. reports disclosures related to an advisory role (WSG). D.H. reports disclosures related to support for the paper (Roche). L.S. reports disclosures related to support for the paper (Roche). Z.B.-H. reports disclosures related to consulting fees (AstraZeneca, Menarini Stemline, MSD) and payment/honoraria (AstraZeneca, MSD). M. Gili reports disclosures related to support for the paper (Roche). L.W. reports disclosures related to payment/honoraria (Roche Austria) and travel/accommodations/expenses (Roche Austria). M.M. reports disclosures related to consulting fees (Roche, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Pfizer, MSD), payment/honoraria (MedMedia, Roche, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Pfizer, MS), travel/accommodations/expenses (Amgen, Roche, Novartis, MSD, Pierre Fabre, Daiichi Sankyo, Eisai), an advisory role (Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Pfizer, MSD) and receipt of equipment/materials (AstraZeneca, Astellas). B.S. reports disclosures related to travel/accommodations/expenses (Roche Austria). R.P. reports disclosures related to payment/honoraria (Myriad, Roche, Amgen, AstraZeneca, Novartis, Daiichi Sankyo, Pfizer, MedMedia), travel/accommodations/expenses (Pfizer, Novartis) and an advisory role (Novartis, Pfizer, AstraZeneca, Roche). M. Gnant reports disclosures related to consulting fees (AstraZeneca, Daiichi Sankyo, Menarini Stemline, MSD, Novartis), payment/honoraria (Amgen, Daiichi Sankyo, Eli Lilly, EPG Health (IQVIA), Menarini Stemline, Novartis, Pierre Fabre, Veracyte), expert testimony payment (Eli Lilly), travel/accommodations/expenses (Eli Lilly, Menarini Stemline, Novartis, Pierre Fabre) and an advisory role (AstraZeneca, Eli Lilly); an immediate family member is employed by Sandoz. R.G. reports disclosures related to consulting fees (Celgene, Novartis, Roche, BMS, Takeda, Abbvie, AstraZeneca, Janssen, MSD, Amgen, Merck, Gilead, Daiichi Sankyo, Sanofi), payment/honoraria (Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, Sanofi), travel/accommodations/expenses (Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, BMS, Abbvie, Daiichi Sankyo), an advisory role (Celgene, Novartis, Roche, BMS, Takeda, Abbvie, AstraZeneca, Janssen, MSD, Amgen, Merck, Gilead, Daiichi Sankyo, Sanofi) and stock/stock options (Novo Nordisk, Lilly). The other authors declare no competing interests., (© 2025. The Author(s).)

Background: In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi). Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis., Results: BRCA1-methylation was detected in 11% of the tumors, exclusively in BRCA1-wild-type (wt) HGOCs. BRCA1-methylated tumors (BRCA1-meth) had HRD-scores similar to those of BRCA-mutated (mut) tumors, and higher compared to unmethylated-BRCA-wt tumors (BRCA-wt-unmeth; P < 0.001). Platinum-refractory or -resistant HGOCs at first recurrence were all BRCA-unmeth cancers. Only one of the BRCA-mut cancers had a platinum-resistant recurrence. Thus, 99% of relapses in cancers with epigenetic or genetic BRCA-alterations were platinum-sensitive. Multivariate analysis confirmed BRCA-LOF as an independent predictor of progression-free survival (PFS) and overall survival (OS), whereas HRD-status had no predictive value for PFS and OS. Patients with BRCA-wt-unmeth cancers had the worst outcome compared to patients with cancers harboring epigenetic or genetic BRCA-alterations (PFS: P = 0.007; OS: P = 0.022). Most importantly, the BRCA-wt-unmeth subfraction of HRD-positive HGOCs exhibited the same poor survival as the entire HRD-negative cohort., Conclusion: In HGOC BRCA mutational status together with BRCA1-methylation exhibit the best predictive power for favorable clinical outcome and thus high sensitivity to platinum-based therapy, whereas BRCA-unrelated HRD positivity was not associated with improved platinum sensitivity., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Committee of the Innsbruck Medical University (reference numbers: AN2015-0038 346/4.17; 1054/2019) and conducted in accordance with the Declaration of Helsinki Principles Consent for publication: Not applicable. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. However, the following authors receive financial support for the specified activities: KL reports travel expenses from GSK, Roche, Eisai and MSD. IT reports honoraria from Roche and Astra Zeneca; travel expenses from Eisai, GSK, PharmaMar, Roche, Astra Zeneca, Pfizer; participation on advisory boards from Astra Zeneca. VW reports honoraria from Roche, Novartis; travel expenses from Roche; participation on advisory boards from Novartis. CM reports consulting fees from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, Seagen; honoraria from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, Seagen; travel expenses from Roche, Astra Zeneca; participation on advisory boards from Roche, Novartis, Amgen, MSD, Astra Zeneca, Pfizer, PharmaMar, GSK, Seagen. AGZ reports consulting fees from Amgen, Astra Zeneca, GSK, MSD, Novartis, PharmaMar, Roche-Diagnostics, Seagen; honoraria from Amgen, Astra Zeneca, GSK, MSD, Novartis, PharmaMar, Roche, Seagen; travel expenses from Astra Zeneca, Gilead, Roche; participation on advisory boards from Amgen, Astra Zeneca, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, Seagen., (© 2024. The Author(s).)

Objective: Immune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value., Methods: Tumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded by PDCD1 ), its ligand (PDL1, encoded by CD274 ), and interferon gamma ( IFNG ) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548)., Results: PD1 , PDL1, and IFNG expression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively. POLE- mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression of PD1 and IFNG . Increased expression of PD1 , PDL1, and IFNG was associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance of PD1 for recurrence-free survival (HR 0.39, p=0.009) and PDL1 for overall survival (HR 0.55, p=0.037). The prognostic value of tumoral PD1 on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort., Conclusions: Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in "hot tumors", predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials., Competing Interests: Competing interests: BF reports travel expenses from Roche, Pfizer, and Lilly. TLP reports travel expenses from MEDahead. CE reports travel expenses from GSK, PharmaMar, Pfizer, AstraZeneca, and Lilly. KL reports support for attending meeting and travel from Gilead, GSK, Eisai, and Roche. HF reports no conflicts of interest. GK reports no conflicts of interest. WK reports no conflicts of interest. KS reports travel expenses from Roche, Daiichi Sankyo, GSK, and Pharma Mar. AGZ reports consulting fees from Amgen, Astra Zeneca, GSK, MSD, Novartis, PharmaMar, Roche-Diagnostics, and Seagen; honoraria from Amgen, Astra Zeneca, GSK, MSD, Novartis, PharmaMar, Roche, and Seagen; travel expenses from Astra Zeneca, Gilead, and Roche; participation on advisory boards from Amgen, Astra Zeneca, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, and Seagen. HH reports research funding from CatalYm and Secarna. VW reports honoraria from Roche and Novartis; travel expenses from Roche; participation on advisory boards from Novartis. CM reports consulting fees from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, and Seagen; honoraria from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, and Seagen; travel expenses from Roche and Astra Zeneca; participation on advisory boards from Roche, Novartis, Amgen, MSD, Astra Zeneca, Pfizer, PharmaMar, GSK, and Seagen. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: This study aimed to demonstrate the superiority of cryocompression over cryotherapy alone in the prevention of chemotherapy-induced peripheral neuropathy (CIPN) grade 2 or above., Methods: This prospective randomized study was conducted between May 2020 and January 2023 in Innsbruck. Eligible patients had a diagnosis of gynecological cancer and received a minimum of 3 cycles of taxane-based CT (neoadjuvant, adjuvant or palliative therapy). Patients were randomized 1:1 to receive either cryotherapy or cryocompression on their upper extremities during chemotherapy (CT). We performed temperature measurements, two QoL questionnaires and neurological tests during CT and at follow-up 3 and 6-9 months after the completion of CT. CIPN was assessed using the CTCAE score., Results: Of 200 patients recruited, both groups showed a lower prevalence of CIPN in this study compared to recent literature. In the group receiving cryotherapy, the prevalence of grade 1 CIPN was 30.1 %, and that of grade 2 CIPN or above was 13.7 %; in the group treated with cryocompression, the prevalence of grade 1 CIPN was 32.8 %, and that of grade 2 or above CIPN was 17.2 %. We found a significant reduction in temperature in the cryotherapy and cryocompression groups. Regarding the two QOL questionnaires as well as the neurological tests no significant differences were found between the two groups., Conclusion: Our study suggests that cryotherapy as well as cryocompression is a safe and effective way to cool patients' extremities to lower the prevalence of CIPN. Cryocompression was not more effective than cryotherapy alone in the prevention of CIPN., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christine Brunner reports that financial support and administrative support were provided by Hilotherm (Germany) and a relationship with Hilotherm (Germany) that includes funding grants. Christine Brunner reports receiving consulting fees from Gilead Sciences and Novartis, honoraria for presentations from AMGEN, DaiichiSanyko, AstraZeneca, Gilead Sciences, SEAGEN, Pfizer and Novartis and support for attending meetings from DaiichiSanyko, AstraZeneca, and Novartis and participation on advisory board for Pfizer. Miriam Emmelheinz reports receiving support for attending meetings from Teva Ratiopharm and Sandoz. Daniel Egle reports receiving consulting fees from AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz and Seagen and honoraria for presentations from Amgen, AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Sandoz and Seagen and support for attending meetings from DaiichiSanyko, Gilead, Pfizer and AstraZeneca. Katharina Leitner reports receiving support for attending meetings from Gilead, GSK, Eisai and Roche. Verena Weiser reports receiving honoraria for presentations from Roche and Novartis and support for attending meetings from Roche. Christian Marth reports receiving consulting fees from Amgen, AstraZeneca; GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche and Seagen and honoraria for presentations from Amgen, AstraZeneca, GlaxoSmithKline, MSD, Novartis, PharmaMar, Roche and Seagen and support for attending meetings from AstraZeneca and Roche. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A better understanding of the peritumoral stroma changes due to tumour invasion using non-invasive diagnostic methods may improve the differentiation between benign and malignant breast lesions. This study aimed to assess the correlation between breast lesion differentiation and intra- and peritumoral shear-wave elastography (SWE) gradients., Methods: A total of 135 patients with newly diagnosed breast lesions were included. Intratumoral, subsurface, and three consecutive peritumoral SWE value measurements (with three repetitions) were performed. Intratumoral, interface, and peritumoral gradients (Gradient 1 and Gradient 2) were calculated using averaged SWE values. Statistical analysis included descriptive statistics and an ordinary one-way ANOVA to compare overall and individual gradients among Breast Imaging-Reporting and Data System (BI-RADS) 2, 3, and 5 groups., Results: Malignant tumours showed higher average SWE velocity values at the tumour centre (BI-RADS 2/3: 4.1 ± 1.8 m/s vs. BI-RADS 5: 4.9 ± 2.0 m/s, p = 0.04) and the first peritumoral area (BI-RADS 2/3: 3.4 ± 1.8 m/s vs. BI-RADS 5: 4.3 ± 1.8 m/s, p = 0.003). No significant difference was found between intratumoral gradients (0.03 ± 0.32 m/s vs. 0.0 ± 0.28 m/s; p > 0.999) or gradients across the tumour-tissue interface (-0.17 ± 0.18 m/s vs. -0.13 ± 0.35 m/s; p = 0.202). However, the first peritumoral gradient (-0.16 ± 0.24 m/s vs. -0.35 ± 0.31 m/s; p < 0.0001) and the second peritumoral gradient (-0.11 ± 0.18 m/s vs. -0.22 ± 0.28 m/s; p = 0.037) were significantly steeper in malignant tumours. The AUC was best for PTG1 (0.7358) and PTG2 (0.7039). A threshold value for peritumoral SWI PT1 above 3.76 m/s and for PTG1 below -0.238 m/s·mm -1 indicated malignancy in 90.6% of cases., Conclusions: Evaluating the peritumoral SWE gradient may improve the diagnostic pre-test probability, as malignant tumours showed a significantly steeper curve of the elasticity values in the peritumoral stroma compared to the linear regression with a relatively flat curve of benign lesions.

Background: Compared to conventional 2D mammography, digital breast tomosynthesis (DBT) offers greater breast lesion detection rates. Ring-like hypodense artifacts surrounding dense lesions are a common byproduct of DBT. This study's purpose was to assess whether minuscule changes spanning this halo-termed the "broken halo sign"-could improve lesion classification., Methods: This retrospective study was approved by the local ethics review board. After screening 288 consecutive patients, DBT studies of 191 female participants referred for routine mammography with a subsequent histologically verified finding of the breast were assessed. Examined variables included patient age, histological diagnosis, architectural distortion, maximum size, maximum halo depth, conspicuous margins, irregular shape and broken halo sign., Results: While a higher halo strength was indicative of malignancy in general ( p = 0.031), the broken halo sign was strongly associated with malignancy ( p < 0.0001, odds ratio (OR) 6.33), alongside architectural distortion ( p = 0.012, OR 3.49) and a diffuse margin ( p = 0.006, OR 5.49). This was especially true for denser breasts (ACR C/D), where the broken halo sign was the only factor predicting malignancy ( p = 0.03, 5.22 OR)., Conclusion: DBT-associated halo artifacts warrant thorough investigation in newly found breast lesions as they are associated with malignant tumors. The "broken halo sign"-the presence of small lines of variable diameter spanning the peritumoral areas of hypodensity-is a strong indicator of malignancy, especially in dense breasts, where architectural distortion may be obfuscated due to the surrounding tissue.

Purpose: Alopecia has been reported a distressing side-effect of chemotherapy for breast cancer patients (BCP) that is highly relevant for quality of life during treatment. For the prevention of chemotherapy-induced alopecia, scalp cooling (SC) has been reported to be an effective and safe intervention. However, data on the patient's perspective on effectiveness and applicability of SC in a clinical routine setting are scarce. In this comparative study, we aimed at a longitudinal assessment of patient-reported outcome (PRO) data on the effect of SC on alopecia and its effect on symptoms and functional health when applied in clinical routine in BCP receiving taxane or anthracycline-based chemotherapy., Patients and Methods: Study participants were allocated either to the intervention group receiving SC or to the control group based on patient preference (non-randomized study). All patients completed PRO-measures on hair preservation (EORTC Item Library items on hair loss), symptom and functional health measures (EORTC QLQ-C30 and -BR23) and the Body Image Scale (BIS). Outcomes were assessed at chemotherapy start (baseline), mid-chemotherapy, last chemotherapy cycle, 3 months follow-up and 6-9 months follow-up., Results: Overall, we included 113 patients: 75 patients underwent SC (mean age = 51.3 years, 52.7% premenopausal); 38 patients standard care (mean age = 55.6 years, 39.5% premenopausal). A total of 53 patients (70.7%) discontinued SC, with 39 patients (73.5%) stating alopecia as the primary reason. On average, BCP stayed on treatment with the cooling cap for 40.2% of the duration of their chemotherapy (SD 25.3%). In an intention-to-treat analysis, we found no difference between the SC group and the control group with regard to their patient-reported hair loss ( p =0.831) across the observation period, overall QOL ( p =0.627), emotional functioning ( p =0.737), social functioning ( p =0.635) and body image ( p =0.463) did not differ between groups., Conclusion: We found a high rate of SC-decliners and no beneficial effects of SC for patient-reported hair loss, symptoms and functional health. The efficacy and tolerability of SC applied in a clinical routine setting hence appeared to be limited. The further determination and up-front definition of criteria prognostic for effectiveness of SC may be helpful to identify patient subgroups that may experience a treatment benefit., Competing Interests: Christine Brunner has received grant funding from Paxman UK. Daniel Egle reports personal fees from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Novartis, Pfizer, Sirius; grants from Sirius; non-financial support from Roche, outside the submitted work. All other authors declare no conflicts of interest in this work., (© 2023 Brunner et al.)

Objective: Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts., Methods: mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial., Results: The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment., Conclusions: Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials., Competing Interests: Declaration of Competing Interest VW reports honoraria from Roche, Novartis; travel expenses from Astra Zeneca, GSK, Novartis, MSD, Takeda, Lilly; participation on advisory boards from Novartis. IT reports travel expenses from MSD. CM reports consulting fees from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, Seagen; honoraria from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, Seagen; travel expenses from Roche, Astra Zeneca; participation on advisory boards from Roche, Novartis, Amgen, MSD, Astra Zeneca, Pfizer, PharmaMar, GSK, Seagen. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs., Methods: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts., Results: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1 -/-IEC and Gpx4 +/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients., Conclusions: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The opioid agonist D,L-methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management. In preclinical tumor-models D,L-methadone shows apoptotic and chemo-sensitizing effects and was therefore hyped as an off-label "anticancer" drug without substantiation from clinical trials. Its effects in ovarian cancer (OC) are completely unexplored., Methods: We analyzed OPRM1-mRNA expression in six cisplatin-sensitive, two cisplatin-resistant OC cell-lines, 170 OC tissue samples and 12 non-neoplastic control tissues. Pro-angiogenetic, cytotoxic and apoptotic effects of D,L-methadone were evaluated in OC cell-lines and four patient-derived tumor-spheroid models., Results: OPRM1 was transcriptionally expressed in 69% of OC-tissues and in three of eight OC cell-lines. D,L-methadone exposure significantly reduced cell-viability in five OC cell-lines irrespective of OPRM1 expression. D,L-methadone, applied alone or combined with cisplatin, showed no significant effects on apoptosis or VEGF secretion in cell-lines. Notably, in two of the four spheroid models, treatment with D,L-methadone significantly enhanced cell growth (by up to 121%), especially after long-term exposure. This is consistent with the observed attenuation of the inhibitory effects of cisplatin in three spheroid models when adding D,L-methadone. The effect of methadone treatment on VEGF secretion in tumor-spheroids was inconclusive., Conclusions: Our study demonstrates that certain OC samples express OPRM1, which, however, is not a prerequisite for D,L-methadone function. As such, D,L-methadone may exert also detrimental effects by stimulating the growth of certain OC-cells and abrogating cisplatin's therapeutic effect., Competing Interests: Declaration of Competing Interest The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for cardiovascular disease. This study aimed to investigate the relationship between pulmonary hyperinflation and baroreceptor reflex sensitivity (BRS), a surrogate for cardiovascular risk. Methods: 33 patients with COPD, free from clinical cardiovascular disease, and 12 healthy controls were studied. Participants underwent pulmonary function and non-invasive hemodynamic measurements. BRS was evaluated using the sequence method during resting conditions and mental arithmetic stress testing. Results: Patients with COPD had evidence of airflow obstruction [forced expiratory volume in 1 s predicted (FEV 1 %) 26.5 (23.3-29.1) vs. 91.5 (82.8-100.8); P < 0.001; geometric means (GM) with 95% confidence interval (CI)] and lung hyperinflation [residual volume/total lung capacity (RV/TLC) 67.7 (64.3-71.3) vs. 41.0 (38.8-44.3); P < 0.001; GM with 95% CI] compared to controls. Spontaneous mean BRS (BRSmean) was significantly lower in COPD, both during rest [5.6 (4.2-6.9) vs. 12.0 (9.1-17.6); P = 0.003; GM with 95% CI] and stress testing [4.4 (3.7-5.3) vs. 9.6 (7.7-12.2); P < 0.001; GM with 95% CI]. Stroke volume (SV) was significantly lower in the patient group [-21.0 ml (-29.4 to -12.6); P < 0.001; difference of the means with 95% CI]. RV/TLC was found to be a predictor of BRS and SV ( P < 0.05 for both), independent of resting heart rate. Conclusion: We herewith provide evidence of impaired BRS in patients with COPD. Hyperinflation may influence BRS through alteration of mechanosensitive vagal nerve activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mayr, Wieser, Funk, Asadi, Sperk, Urban and Valipour.)

Lipid bilayer interactions are essential to a vast range of biological functions, such as intracellular transport mechanisms. Surface charging mediated by concentration dependent ion adsorption and desorption on lipid headgroups alters electric double layers as well as van der Waals and steric hydration forces of interacting bilayers. Here, we directly measure bilayer interactions during charge modulation in a symmetrically polarized electrochemical three-mirror interferometer surface forces apparatus. We quantify polarization and concentration dependent hydration and electric double layer forces due to cation adsorption/desorption. Our results demonstrate that exponential hydration layer interactions effectively describe surface potential dependent surface forces due to cation adsorption at high salt concentrations. Hence, electric double layers of lipid bilayers are exclusively dominated by inner Helmholtz charge regulation under physiological conditions. These results are important for rationalizing bilayer behavior under physiological conditions, where charge and concentration modulation may act as biological triggers for function and signaling.

Introduction HE4 and CA 125, two established biomarkers for assessing adnexal masses in non-pregnant women, are hardly investigated in pregnancy, especially in pregnancy-associated conditions. The aim was to evaluate HE4 and CA 125 levels in the course of pregnancy and to assess the impact of pregnancy disorders, contractions and rupture of membranes on HE4 and CA 125 serum levels in order to use these parameters for evaluation of adnexal masses in pregnancy. Patients and Methods Blood samples (n = 238) of 201 women seen at the Medical University of Innsbruck, Austria, were prospectively obtained during pregnancy and postpartum. Serum concentrations of HE4 and CA 125 were analyzed. ROMA index was calculated by the premenopausal formula. Results HE4 serum levels were highest in the third trimester. Contractions (p < 0.001), rupture of membranes (p = 0.005) and pregnancy-associated diseases (p = 0.003) were associated with higher HE4 levels. As much as 97.5% of HE4 measurements remained below the recommended cut-off for premenopausal women (70 pmol/l). CA 125 levels were not altered by pregnancy-associated conditions. Generally, CA 125 exhibited a wider serum level variability, exceeding the established cut-off of 35 U/ml in 16.4%. Conclusions HE4 serum levels are influenced by several pregnancy-related conditions leading to significantly higher levels in these cases. Despite differing medians according to trimester, the 95th percentile cut-offs and almost all maximum values during the entire course of pregnancy were below the established cut-off for premenopausal women. It was also superior to the performance of ROMA index. Therefore, HE4 can be used as a valuable negative predictive marker for the assessment of adnexal masses during pregnancy., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The present work highlights a new approach to write, erase, and rewrite micropatterns into the same region of covalent adaptable polymer networks. Thermal curing of an epoxy-terminated o-nitrobenzyl ester (o-NBE) derivative with hexahydrophthalic anhydride in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene yields a dynamic covalent network, whose solubility is locally controlled by irradiation with ultraviolet (UV) light. The photolysis of the o-NBE chromophores enables a well-defined cleavage of the epoxy-anhydride network, and the formation of soluble photolysis products is confirmed by sol-gel analysis. The photo-induced change in solubility is exploited to inscribe micropatterns by photolithographic techniques and after development in an organic solvent positive tone structures with a feature size of 20 µm are obtained. Due to the thermo-activated exchange reactions of the hydroxyl ester links and the related macroscopic reflow, the polymer patterns are fully erased at temperatures well above the topological freezing transition of the vitrimer network. The regenerated film has a smooth surface topology and can be reused to inscribe new micropatterns via mask lithography., (© 2020 Wiley-VCH GmbH.)

Background: In high-risk patients with cervical incompetence, laparoscopic cerclage is a promising treatment option. However, the procedure exhibits relevant surgical risks., Aims: The purpose of this study was to evaluate a surgical "needle-free" technique for minimally invasive, laparoscopically placed cervico-isthmic cerclage in high-risk patients., Methods: This was a retrospective observational study over a 10-year period of pre- and postconceptional cerclage placement. The included patients either experienced previous transvaginal cerclage (TVC) failure or were not eligible for TVC. Laparoscopic transabdominal cerclage using a needle-less mersilene tape was performed via a broad ligament window lateral to the uterine vessels., Results: Laparoscopic transabdominal cerclage was successfully performed in all included women with a median operation time of 62 min. We did not observe any intra- or postoperative complications, particularly no bleeding complications. Nine of 11 women became pregnant and/or carried out a successful pregnancy, respectively. Importantly, we did not observe any cases of miscarriage or mid-trimester loss. Two patients did not conceive; however, their medical histories did include Asherman's syndrome and advanced maternal age., Conclusion: Transabdominal laparoscopic "needle-free" cerclage is a safe and effective treatment option for a well-selected group of women at high risk of cervical incompetence. It provides good obstetric results without increasing perioperative morbidity., (© 2020 S. Karger AG, Basel.)

Background: In an experimental murine liver clamping model, we aimed to investigate the efficacy of real-time confocal microscopy (RCM) in assessing viability of steatotic livers in comparison to standard assessment tools, including histopathological evaluation., Methods: C57Bl/6 mice were subjected to a methionine-choline-deficient diet causing nonalcoholic fatty liver disease or to Lieber DeCarli diet causing ethanol-induced liver injury. Untreated animals served as controls. Liver biopsies were analyzed following challenge with 45 min of warm ischemia time and either 4 h of reperfusion or 24 h of cold storage. Organ quality assessment was performed at defined time points by RCM, histological staining, measurement of serum alanine aminotransferase activity, and expression analyses of proinflammatory cytokines. Additionally, survival analysis was performed., Results: Cold as well as warm ischemia time resulted in a significant decrease in cell viability when compared with naive livers as well as nonischemic-challenged steatotic livers (P < 0.05) as assessed by RCM. Furthermore, RCM revealed the actual cellular damage at early time points, while established methods including H&E-staining and serum transaminase profile failed., Conclusions: In a translational attempt, we demonstrate that RCM is a suitable diagnostic tool to obtain information about functional damage of the liver apart from standard approaches.

SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients' outcome. Optimal thresholds for high and low expression of both variables were calculated by the Youden's index based on receiver operating characteristic (ROC) curves. High SMARCA4 mRNA expression was independently associated with favorable progression-free survival (PFS) (P = 0.03) and overall survival (OS) (P = 0.018). As Youden's threshold determination for EZH2 yielded a S-shaped ROC-curve, two cut-off points (29th and 94th percentile) predicting opposite features were defined. Whereas EZH2 mRNA levels beyond the 29th percentile independently predicted poor PFS (P = 0.034), Cox-regression in EZH2 transcripts above the 94th percentile revealed a conversion from unfavorable to favorable PFS and OS (P = 0.009 and P = 0.032, respectively). High SMARCA4 expression associates with improved survival, whereas moderate/high EZH2 expression predicts poor outcome, which converts to favorable survival in ultra-high expressing OCs. This small OC subgroup could be characterized by REV7-abrogated platinum hypersensitivity but concomitant PARP-inhibitor resistance.

Endometrial cancer (EC) is the most common gynaecologic tumour in the Western world. Previous studies have implicated an imbalance of oestrogens and progestogens in the development of most ECs, while the role of low-grade tissue inflammation remains largely unexplored. We investigated the impact of tumour necrosis factor alpha (TNFα), a central mediator of inflammation and spermatogenesis-associated protein 2 (SPATA2), a regulator of TNF receptor signalling, on clinical outcomes in EC. We evaluated TNFA and SPATA2 transcript levels in 239 EC patients and 25 non-malignant control tissues. Findings were validated in a cohort of 332 EC patients from The Cancer Genome Atlas (TCGA). Expression of TNFA and SPATA2 was increased in EC when compared with control tissues (P < 0.001). TNFA expression correlated with SPATA2 expression in non-malignant (P = 0.003, rS = 0.568) and EC tissue (P = 0.005, rS = 0.179). High TNFA and SPATA2 expression were associated with poor recurrence-free survival (RFS; P = 0.049 and P = 0.018) and disease-specific (P = 0.034 and P = 0.002) survival. Increased SPATA2 expression was also associated with decreased overall survival (OS; P = 0.013). In multivariate analysis, both TNFA and SPATA2 were predictors of clinical outcome. The impact of SPATA2 on RFS and OS could be validated in the TCGA cohort. Our study demonstrates that ECs exhibit a TNF signature which predicts clinical outcome. These findings indicate that TNF signalling modulates the course of EC, which could be therapeutically utilized in the future., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum-based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real-time quantitative PCR to assess the expression of retinoic acid-inducible gene-I (RIG-I) in primary tumor and healthy ovarian control tissues. RIG-I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG-I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG-I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type-II cancers and cancers with inactivating p53 mutations exhibited higher RIG-I expression. RIG-I levels were also elevated in cancers that recurred after remission or were platinum-refractory. Survival analyses disclosed RIG-I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG-I expression in the tumor microenvironment, including interferon production and a distinct immune-regulatory signature involving checkpoint molecules (PD-L1/PD-1), the RNA-editing enzyme ADAR1 and the regulatory T cell-specific transcription factor FoxP3. We conclude that high RIG-I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG-I expression may inform checkpoint blockade and/or RIG-I agonistic targeting in a subset of high-risk OC patients., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues ( P =0.002, P <0.001, P <0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with BRCA1/2 mRNA-expression (BRCA1: miR34 b/c P =0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and BRCA2 mRNA-expression ( P <0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in TP53 -mutated compared with TP53 -wild-type ovarian cancers ( P <0.001, P =0.002, P =0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, P =0.033; miR-34b: HR 0.2, P =0.001 and miR-34c: HR 0.3, P =0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, P =0.016) and miR-34c (HR 0.6, P =0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK , RANKL and OPG expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor-α (TNF-α) as a key mediator. Recently, spermatogenesis-associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF-induced inflammation and apoptosis. The available data on TNF-α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real-time polymerase chain reaction in tissues of 171 patients with low-grade serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non-malignant control tissues. We stimulated OC cells (OVCAR3) with pro-inflammatory (TNF-α, interleukin [IL]-1β) and mitogenic stimuli (IL-6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro-inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, r s  = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression-free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF-α and IL-1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)