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Vlad Moisoiu,1,2,* Andrei Stefancu,1,3,* Diana Gulei,3,* Radu Boitor,4 Lorand Magdo,2,5 Lajos Raduly,5,6 Sergiu Pasca,2 Paul Kubelac,2,7 Nikolay Mehterov,8,9 Vasile Chiș,1 Marioara Simon,10 Mihai Muresan,2,11–12 Alexandra Iulia Irimie,13 Mihaela Baciut,14 Rares Stiufiuc,3,15 Ioana E Pavel,3,16 Patriciu Achimas-Cadariu,17,18 Calin Ionescu,2,11 Vladimir Lazar,19 Victoria Sarafian,8,9 Ioan Notingher,4 Nicolae Leopold,1,3 Ioana Berindan-Neagoe3,5,201Faculty of Physics, Babeș-Bolyai University, Cluj-Napoca, Romania; 2Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 3MedFuture - Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 4School of Physics and Astronomy, University of Nottingham, Nottingham, UK; 5Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 6Department of Pathophysiology, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania; 7Department of Medical Oncology, Prof. Dr. Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania; 8Department of Medical Biology, Faculty of Medicine, Medical University-Plovdiv, Plovdiv, Bulgaria; 9Technological Center for Emergency Medicine, Plovdiv, Bulgaria; 10Department of Bronchology, Leon Daniello Pneumophysiology Clinical Hospital, Cluj-Napoca, Romania; 115th Surgical Department, Cluj-Napoca Municipal Hospital, Cluj-Napoca, Romania; 12Department of Surgical and Gynecological Oncology, Prof. Dr. Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania; 13Department of Prosthetic Dentistry and Dental Materials, Division Dental Propaedeutics, Aesthetics, Faculty of Dentistry, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 14Department of Cranio-Maxillofacial Surgery and Dental Emergencies, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 15Department of Pharmaceutical Physics-Biophysics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 16Department of Chemistry, Wright State University, Dayton, OH, USA; 17Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 18Department of Surgical Oncology, Prof. Dr. Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania; 19Worldwide Innovative Network for Personalized Cancer Therapy, Villejuif, France; 20Department of Functional Genomics and Experimental Pathology, Prof. Dr. Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania*These authors contributed equally to this workPurpose: Surface-enhanced Raman scattering (SERS) spectroscopy on serum and other biofluids for cancer diagnosis represents an emerging field, which has shown promising preliminary results in several types of malignancies. The purpose of this study was to demonstrate that SERS spectroscopy on serum can be employed for the differential diagnosis between five of the leading malignancies, ie, breast, colorectal, lung, ovarian and oral cancer.Patients and methods: Serum samples were acquired from healthy volunteers (n=39) and from patients diagnosed with breast (n=42), colorectal (n=109), lung (n=33), oral (n=17), and ovarian cancer (n=13), comprising n=253 samples in total. SERS spectra were acquired using a 532 nm laser line as excitation source, while the SERS substrates were represented by Ag nanoparticles synthesized by reduction with hydroxylamine. The classification accuracy yielded by SERS was assessed by principal component analysis–linear discriminant analysis (PCA-LDA).Results: The sensitivity and specificity in discriminating between cancer patients and controls was 98% and 91%, respectively. Cancer samples were correctly assigned to their corresponding cancer types with an accuracy of 88% for oral cancer, 86% for colorectal cancer, 80% for ovarian cancer, 76% for breast cancer and 59% for lung cancer.Conclusion: SERS on serum represents a promising strategy of diagnosing cancer which can discriminate between cancer patients and controls, as well as between cancer types such as breast, colorectal, lung ovarian and oral cancer.Keywords: surface-enhanced Raman scattering, SERS, serum, principal component analysis-linear discriminant analysis, solid malignancies

This study aimed to assess the effectiveness of saline sealing in reducing the incidence of pneumothorax after a CT-guided lung biopsy. This was a retrospective case-control study of patients who underwent CT-guided biopsies for lung tumors using 18 G semiautomatic core needles in conjunction with 17 G coaxial needles. The patients were divided into two consecutive groups: a historical Group A (n = 111), who did not receive saline sealing, and Group B (n = 87), who received saline sealing. In Group B, NaCl 0.9% was injected through the coaxial needle upon its removal. The incidence of pneumothorax and chest tube insertion was compared between the two groups. Multivariate logistic regression was performed to verify the contribution of other pneumothorax risk factors. The study included 198 patients, with 111 in Group A and 87 in Group B. There was a significantly (p = 0.02) higher pneumothorax rate in Group A (35.1%, n = 39) compared to Group B (20.7%, n = 18). The difference regarding chest tube insertion was not significant (p = 0.1), despite a tendency towards more insertions in Group A (5.4%, n = 6), compared to Group B (1.1%, n = 1). Among the risk factors for pneumothorax, only the presence of emphysema (OR = 3.5, p = 0.0007) and belonging to Group A (OR = 2.2, p = 0.02) were significant. Saline sealing of the needle tract after a CT-guided lung biopsy can significantly reduce the incidence of pneumothorax. This technique is safe, readily available, and inexpensive, and should be considered as a routine preventive measure during this procedure.

IntroductionMuch drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC).Methods3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved.ResultsMedian age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common.DiscussionSpecific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites.

Background and Objectives: Local and distant relapse (LR, DR) in breast cancer vary according to its molecular subtypes, with triple-negative breast cancer (TNBC) being the most aggressive. The surgical resection margin width (SRMW) for breast-conserving surgery (BCS) has been intensely debated, especially for the aforementioned subtype. The aim of this study was to examine the impact of SRMW on LR following BCS in TNBC patients. Materials and Methods: We conducted a retrospective study including all patients with TNBC for whom BCS was performed between 2005 and 2014. Results: Final analysis included a total of 92 patients, with a median tumor size of 2.5 cm (range 0–5 cm) and no distant metastasis at the time of diagnosis. A total of 87 patients had received neoadjuvant and/or adjuvant chemotherapy, and all patients had received adjuvant whole-breast radiotherapy. After a median follow-up of 110.7 months (95% CI, 95.23–126.166), there were 5 local recurrences and 8 regional/distant recurrences with an overall LR rate of 5.4%. The risk of LR and DR was similar between groups of patients with several SRMW cut-off values. Conclusions: Our study supports a safe “no ink on tumor” approach for TNBC patients treated with BCS.

The Hippo signaling pathway, one of the most conserved in humans, controlling dimensions of organs and tumor growth, is frequently deregulated in several human malignancies, including ovarian cancer (OC). The alteration of Hippo signaling has been reported to contribute to ovarian carcinogenesis and progression. However, the prognostic roles of individual Hippo genes in OC patients remain elusive. Herein we investigated the expression level and prognostic value of key Hippo genes in OC using online databases, followed by a qRT-PCR validation step in an additional patient cohort. Using the GEPIA database, we observed an increased level for TP53 and reduced expression level for LATS1, LATS2, MST1, TAZ, and TEF in tumor tissue versus normal adjacent tissue. Moreover, LATS1, LATS2, TP53, TAZ, and TEF expression levels have prognostic significance correlated with progression-free survival. The qRT-PCR validation step was conducted in an OC patient cohort comprising 29 tumor tissues and 20 normal adjacent tissues, endorsing the expression level for LATS1, LATS2, and TP53, as well as for two of the miRNAs targeting the TP53 gene, revealing miR-25-3p upregulation and miR-181c-5p downregulation. These results display that there are critical prognostic value dysregulations of the Hippo genes in OC. Our data demonstrate the major role the conserved Hippo pathway presents in tumor control, underlying potential therapeutic strategies and controlling several steps modulated by miRNAs and their target genes that could limit ovarian cancer progression.

B Background: b Local recurrence (LR) and distant metastasis in breast cancer vary according to its molecular subtypes, triple-negative breast cancers (TNBCs) having the highest rates of LR. In conclusion, we recommend further prospective studies in order to determine the impact of margin status on LR in TNBC patients treated with BCT. [Extracted from the article]

Abstract Ovarian cancer is composed of a complex system of cells best described by features such as clonal evolution, spatial and temporal genetic heterogeneity, and development of drug resistance, thus making it the most lethal gynecologic cancer. Seminal work on cancer as an evolutionary process has a long history; however, recent cost-effective large-scale molecular profiling has started to provide novel insights coupled with the development of mathematical algorithms. In the current review, we have systematically searched for articles that focused on the clonal evolution of ovarian cancer to offer the whole landscape of research that has been done and highlight future research avenues given its characteristic features and connections to evolutionary biology.

So far, the polyphenolic components of turmeric have shown a significant pharmacological preventative activity for a wide spectrum of diseases, including oncological disorders. This type of natural product could be of great interest for the inhibition of cancer cell proliferation, displaying less side effects in comparison to classical chemotherapeutics. The poor bioavailability and quick metabolism of such natural compounds require new investigative methods to improve their stability in the organisms. A synthetic approach to increase the efficiency of curcuminoids is to coordinate them to metals through the beta-dicarbonyl moiety. We report the synthesis and the biological attempts on human ovarian carcinoma A2780 of ruthenium(II) complexes 1–4, containing curcuminoid ligands. The cytotoxicity of complexes 1–4 proves their antiproliferative capability, and a correlation between the IC50 values and NF-κB transcription factor, FGF-2, and MMP-9 levels was figured out through the principal component analysis (PCA).

Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) improved advanced ovarian cancer treatment. Most patients progress during or following PARPi exposure, however, with concerns about sensitivity of subsequent chemotherapy., Patients and Methods: In this international cohort study, we evaluated the efficacy of a subsequent chemotherapy following PARPi exposure in high-grade ovarian carcinoma patients. Endpoints included progression-free survival (PFS), overall survival and a multivariable Cox model was built to identify factors influencing PFS., Results: We included 291 patients from four international centers treated between January 2002 and December 2021. The median number of previous chemotherapy was 1 (1.0-7.0), the median duration of PARPi exposure was 6.5 months (0.2-54.3 months). PARPi was used in first line in 14.1% patients. Most progressions occurred under PARPi exposure (89.1%). A BRCA pathogenic variant was identified in 130 patients (44.7%), absent in 157 patients (54.0%), and undocumented in 4 patients (1.4%). Platinum-based CT (PBC) and non-PBC were administered as subsequent treatments in, respectively, 182 patients (62.5%) and 109 patients (37.5%). Multivariable analyses showed that platinum-free interval (PFI) >6 months [adjusted hazards ratio (HR), 0.52; 95% confidence interval (CI) 0.39-0.70] and type of initial surgery (adjusted HR, 1.41; 95% CI 1.07-1.87; interval or closing surgery versus primary surgery) were associated with PFS, independent of BRCA status or line of therapy (≥2 versus 1). In patients with a PFI >6 months, PBC was numerically associated with the best PFS (adjusted HR, 0.68; 95% CI 0.46-1.01)., Conclusion: This is the largest real-world study assessing the efficacy of subsequent chemotherapy in patients progressing during PARPi exposure. The patients have poor outcomes. PBC is the best option in patients progressing on PARPi and eligible for PBC rechallenge (PFI >6 months)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study aimed to assess the effectiveness of saline sealing in reducing the incidence of pneumothorax after a CT-guided lung biopsy. This was a retrospective case-control study of patients who underwent CT-guided biopsies for lung tumors using 18 G semiautomatic core needles in conjunction with 17 G coaxial needles. The patients were divided into two consecutive groups: a historical Group A (n = 111), who did not receive saline sealing, and Group B (n = 87), who received saline sealing. In Group B, NaCl 0.9% was injected through the coaxial needle upon its removal. The incidence of pneumothorax and chest tube insertion was compared between the two groups. Multivariate logistic regression was performed to verify the contribution of other pneumothorax risk factors. The study included 198 patients, with 111 in Group A and 87 in Group B. There was a significantly ( p = 0.02) higher pneumothorax rate in Group A (35.1%, n = 39) compared to Group B (20.7%, n = 18). The difference regarding chest tube insertion was not significant ( p = 0.1), despite a tendency towards more insertions in Group A (5.4%, n = 6), compared to Group B (1.1%, n = 1). Among the risk factors for pneumothorax, only the presence of emphysema (OR = 3.5, p = 0.0007) and belonging to Group A (OR = 2.2, p = 0.02) were significant. Saline sealing of the needle tract after a CT-guided lung biopsy can significantly reduce the incidence of pneumothorax. This technique is safe, readily available, and inexpensive, and should be considered as a routine preventive measure during this procedure.

Introduction: Much drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC)., Methods: 3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved., Results: Median age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common., Discussion: Specific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites., Competing Interests: Authors BL, WS, HF, NN and MG-K were employed by IQVIA Oncology Evidence Network. The remaining 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 © 2023 Cheeseman, Levick, Sopwith, Fenton, Nam, Kim, Lim, Martin, Frenel, Bocquet, Kubelac, Achimas-Cadariu, Vlad, Chevrier, Rouzier, Carton, Savva-Bordalo, Magalhães, Borges, Wolf, Becker, Niklas, Guergova-Kuras and Hall.)

Background: Interleukin-6 (IL-6) has been implicated in various malignancies, including ovarian cancer. However, mixed results have been observed regarding IL-6 levels in different ovarian conditions. This meta-analysis was performed to determine IL-6 levels in the peritoneal fluid and peripheral blood among patients with various adnexal masses., Methods: Most popular English databases were searched using a predefined search formula. All studies comparing IL-6 levels in plasma, serum or peritoneal fluid of patients with benign tumors, ovarian neoplasms, and healthy controls were included based on inclusion and exclusion criteria., Results: 5953 patients from 22 primary publications raging from 1994 to 2021 were included in the meta-analyses. A pooled IL-6 Mean Difference (MD) of 41 pg/mL for malignant tumors compared to benign ones, with a Confidence Interval (CI) between 19.8 and 62.2, a Z-score of 3.79, and statistical significance with a p = 0.0002 was observed. Pooled results for healthy versus benign ovarian conditions showed an MD of 5.45 pg/mL for serum or plasma IL-6 measurements in favor of benign tumors (CI:0.66-10.25, Z = 2.23 and p = 0.03). The analysis showed an MD for IL-6 levels of 19.59 pg/mL for healthy controls versus malignant ovarian tumors. Peritoneal fluid measurements regarding IL-6's levels showed no significant difference between benign or malignant masses., Discussion/conclusions: Higher levels of plasma or serum IL-6 in ovarian neoplasia patients compared to benign conditions or healthy controls identify IL-6 as a discerning factor between benign or malignant ovarian tumors and a potential biomarker for ovarian malignancy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors reports administrative support was provided by Iuliu Hatieganu University of Medicine and Pharmacy. All authors reports administrative support was provided by Romanian Government Ministry of Research Innovation and Digitization.., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. In literature, there are discordant data regarding the therapeutic value of systematic lymphadenectomy whereas the importance of lymph node status for determining prognosis and the need for adjuvant treatment is undoubted. Given the low risk of lymph node metastases in stage I-II of EC and the significant surgical and postoperative risks when performing a complete pelvic lymphadenectomy, the surgical approach in these patients is controversial, ranging from no nodal evaluation to comprehensive pelvic and aortic lymphadenectomy. The recent introduction of sentinel node detection represents the mid-way between the execution and omission of node dissection in EC patients. Indeed, the sentinel node mapping has rapidly emerged as an alternative to complete lymphadenectomy to reduce morbidity. In the present research, we discuss the role of sentinel node mapping in the surgical management of EC in early stage. Results of study on SLN in EC in early stages seem to be promising, but only a small series have been published so far., (Celsius.)

Introduction: Historically, the incidence rate of cervical cancer (CC) in Eastern Europe and particularly in Bulgaria has constantly been higher than that in the other European countries. Adenosquamous carcinoma (ASC) is a rare histological subtype of CC with incidence rate of less than 6 per 100,000. We aimed to analyze the epidemiology and prognosis of all Bulgarian patients with ASC, registered at the Bulgarian National Cancer Registry (BNCR), and to compare patients' characteristics and outcomes with those of patients, treated at a large specialized institution - the Department of Gynecologic Oncology, University Hospital in Pleven, Bulgaria., Materials and Methods: This is a retrospective study of all cases of ASC, registered at the BNCR for a 10-year period of time. The Kaplan-Meier analysis with Log rank test was used to estimate the significant differences., Results: The incidence rate of ASC was calculated as 3.2% of all CC registered in BNCR and 4.97% of all stage I patients, treated in our department. The 5-year overall survival (OS) rate of all patients with ASC tumors from the registry was 50.5%. A total of 171 (48.4%) of the patients had T1 tumors and a 5-year OS of 67.1%. Lymph node status was a significant prognostic factor for OS (p=0.001). Thirty-one patients with T1 tumors and ASC histology were treated in our department for the same period of time. Lymph node metastases were found in 10 of them (32.2%). The 5-year observed OS in ASC group was 74.19%., Conclusion: The histological subtype of cancer of the uterine cervix has an impact on prognosis and should not be simply considered as a descriptive characteristic but a poor prognostic feature and should be an integral part of the decision-making in clinical management of patients., Competing Interests: The authors declare no competing interests in this work., (© 2021 Yordanov et al.)

Purpose: Salvage therapy represents a rescue therapy, given after the first line of treatment had failed.The purpose of this study was to review the outcomes of patients who underwent salvage laparoscopic radical prostatectomy (sLRP) in our department and to review current published studies., Methods: Our mini-series consisted of 6 patients with recurrent prostate cancer(PCa) after non-surgical primary treatment. All interventions were performed by a single surgeon from the Oncological Institute "Prof. Dr. Ion Chiricuta" Cluj Napoca, Romania.A literature review was carried out in June 2020 using the PubMed and MEDLINE databases to identify relevant studies published in the literature between 2000 and 2020. Six papers were selected for our review.We reviewed the oncological and functional outcomes of patients that underwent sLRP., Results: Extraperitoneal sLRP was performed in 6 patients. Biochemical failure after primary treatment developed between one and five years. Mean operative time was 135.5 min, mean blood loss was 328 ml. No intraoperative complications occurred and no conversions to open surgery. R0 was achieved in 5 out of the 6 patients (83.5%). Out of the 6 patients 2 are incontinent., Conclusions: SLRP remains an underused procedure and a missed therapeutic opportunity for selected patients. From published data and personal experience, we conclude that in experienced hands sLRP for localized prostate cancer is a feasible, safe and efficient method to treat recurrent PCa. Short-term oncological outcomes are optimistic but further studies need to be made to observe the long-term outcomes.

Ovarian cancer is one of the most common cancers worldwide, and is associated with a prior diagnosis of endometriosis in several cases. Our aim was to correlate genetic and methylation profile of ovarian endometrioid ovarian cancer and endometriosis patients. We evaluated the genetic profile of 50 ovarian endometriosis and 20 ovarian endometrioid carcinoma samples using next generation sequencing technology. In addition, the DNA methylation profile was evaluated for both cohorts of patients. We observed several mutated genes that were common for both types of patients, but we also identified mutated genes that were characteristic for each group: JAK3, KRAS and RB1 for endometriosis; and ATM, BRAF, CDH1, EGFR, NRAS, RET and SMO for ovarian endometrioid cancer. Also we idenfied genes that are highly methylated only in endometriosis samples ( PYCARD, RARB, RB1, IL2, CFTR, CD44 and CDH13) and MLH3 gene was methylated only in endometrioid ovarian carcinoma samples. Also, BRCA1, CADM1, PAX6 and PAH genes are mainly methylated in endometrioid ovarian carcinoma patients. We identified a correlation for the cancer group between tumor stage, copy number aberrations and the presence of metastases; more specifically, the presence of BRCA1 pathogenic variants was correlated with tumor differentiation degree, TP53 variants and copy number aberrations. This study was able to demonstrate the presence of similar pathways being altered in both endometriosis and ovarian endometrioid carcinoma, which could mean that a diagnosis of endometriosis could be an early marker for cancer diagnosis. In addition, we showed that GATA2 hypomethylation, ATM hypermethylation, CREM hypomethylation, higher tumor differentiation degree or higher tumor stage is associated with a poor prognosis in patients with ovarian endometrioid carcinoma., Competing Interests: None., (AJCR Copyright © 2021.)

The Hippo signaling pathway, one of the most conserved in humans, controlling dimensions of organs and tumor growth, is frequently deregulated in several human malignancies, including ovarian cancer (OC). The alteration of Hippo signaling has been reported to contribute to ovarian carcinogenesis and progression. However, the prognostic roles of individual Hippo genes in OC patients remain elusive. Herein we investigated the expression level and prognostic value of key Hippo genes in OC using online databases, followed by a qRT-PCR validation step in an additional patient cohort. Using the GEPIA database, we observed an increased level for TP53 and reduced expression level for LATS1, LATS2, MST1, TAZ, and TEF in tumor tissue versus normal adjacent tissue. Moreover, LATS1, LATS2, TP53, TAZ, and TEF expression levels have prognostic significance correlated with progression-free survival. The qRT-PCR validation step was conducted in an OC patient cohort comprising 29 tumor tissues and 20 normal adjacent tissues, endorsing the expression level for LATS1, LATS2, and TP53, as well as for two of the miRNAs targeting the TP53 gene, revealing miR-25-3p upregulation and miR-181c-5p downregulation. These results display that there are critical prognostic value dysregulations of the Hippo genes in OC. Our data demonstrate the major role the conserved Hippo pathway presents in tumor control, underlying potential therapeutic strategies and controlling several steps modulated by miRNAs and their target genes that could limit ovarian cancer progression.

More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100,000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on expert opinion, retrospective studies, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges through the creation of a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, “Basic and Translational Research on Rare Gynecological Cancer”) have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state-of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide.

Purpose: Tumor infiltrating lymphocytes (TILs) in cutaneous malignant melanoma are classified as brisk, non-brisk or absent. Numerous studies suggest the presence of TILs, especially brisk, are associated with a lower rate of lymph node metastasis and with an improved overall survival (OS). Our purpose was to assess the value of TILs as a prognostic factor for the lymph node metastasis and survival in completely resected pT3 stage malignant melanoma patients., Methods: We included a number of 114 patients with pathological pT3 cutaneous malignant melanoma, treated exclusively in our institution, between 2000-2015. Correlations of clinical and pathological factors with lymph node status and OS were analyzed., Results: A brisk infiltrate was present in 60% of the patients, whereas 40% presented a non-brisk infiltrate or absent TILs. In univariate analysis, the presence of ulceration was correlated with a non-brisk infiltrate, whereas in multivariate analysis, lymph node invasion and a non-brisk infiltrate were associated with a higher risk of death., Conclusions: TILs density grade represents an independent prognostic factor for the OS. Therefore, we conclude that an accurate prognosis may be provided by TILs status in patients with pT3 malignant melanoma.

Purpose: The purpose of this study was to evaluate the predictive performance of OncoOVARIAN Dx algorithm, which takes into account tumor markers (beta HCG, CA 19.9, CEA, AFP, CA 125, HE4), general biochemistry and clinical data (age, menopause, comorbidities) in patients scheduled for surgical removal of a suspicious adnexal tumor in comparison with the Risk of Malignancy Algorithm (ROMA) model., Methods: Consecutive women diagnosed with an adnexal tumor mass and scheduled for surgical intervention at a single tertiary cancer between October 2018 - June 2019 were enrolled. Preoperative values of tumor markers and general biochemistry (ASAT, ALAT, GGT, total bilirubin, creatinine) were determined. Following surgery with adequate surgical staging, a definite pathological diagnosis was made and used as reference., Results: A total of 50 patients were selected, including 20 benign, 5 borderline and 25 malignant epithelial ovarian cancer (EOC) cases on final pathology. Borderline tumors comprised 3 serous and 2 mucinous FIGO stage I cases. Malignant tumors included 17 high grade serous, 4 endometrioid and 4 mucinous types, FIGO stage IA-IIIC. The two models demonstrated very good correlation (Phi 0.78, p<0.001). The sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) of OncoOVARIAN Dx versus ROMA model were 76.66% vs. 60%, 95% vs. 100%, 95.83% vs. 100%, 73.07% vs. 62.5%, respectively. In postmenopausal patients higher Se (85.71%), Sp (100%) and PPV (100%) were observed for OncoOVARIAN Dx., Conclusions: OncoOVARIAN Dx model demonstrated higher Se and NPV compared to ROMA and could be a useful marker in the preoperative management of adnexal masses; however larger studies are warranted to validate and further refine this algorithm.

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0-300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1-/RAD51+, hazard ratio (HR) 3.13, p = 0.009 and HR 2.78, p = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, p = 0.05 and HR 2.38, p = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, p = 0.038 and HR 2.04, p = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi).

Purpose: We report our experience with 23 cases in utilizing ileum to perform totally intracorporeal 3D laparoscopic neobladder reconstruction using two different surgical techniques., Methods: Patients candidates for reconstructive surgery were in a good biological status with a body mass index (BMI) in the range of 18.5-25 and presented a muscle-infiltrative bladder tumor with negative nodal frozen sections performed during the operation. Twenty-one modified Studer neobladder and 2 modified Y-shaped neobladder techniques for totally intracorporeal 3D laparoscopic ileal neobladder cases were performed using drawings and intra-operative images. An emphasis was made on different tips and tricks that can be applied when using ileum for the neobladder reconstruction, to avoid surgical complications and obtain optimal functional results., Results: The operations were performed in a mean time of 5 h, with a mean blood loss of 350 ml and grade II postoperative Clavien Dindo complications. The 23 patients were discharged after a mean hospital stay of 21 days and had a functional ileal neobladder after a mean of 30 days. The results were monitored also on the long-term, taking into account functional results and possible complications from utilizing ileum as a urinary reservoir., Conclusion: Resecting a digestive segment and using it as a urinary reservoir may lead to multiple complications. Therefore, laparoscopic technical adaptations and highly skilled surgical teams are required for performing a totally intracorporeal 3D laparoscopic orthotopic ileal neobladder reconstruction.

Purpose: The treatment of ovarian cancer continues to pose a challenge especially through the development of platinum-resistant disease and still has the highest mortality rate among gynecologic cancers. Patients are usually diagnosed with advanced stages where complete cytoreduction and standard platinum-based chemotherapy are the mainstay of treatment. Advances into the molecular underpinnings of DNA damage repair highlighted BRCA 1/2 and other related genes as key regulators of platinum sensitivity. Our study characterizes clinical features and outcomes associated with BRCA mutations in a cohort of ovarian cancer patients., Methods: Patient data from our Institute was retrospectively extracted for all patients that were tested for the presence of BRCA germline or somatic mutations through next generation sequencing between May 2016 and August 2018., Results: Eighty-eight patients were included in the present analysis. Advanced FIGO stage IIIC-IV was common at presentation (71.6%), with 58% of patients undergoing primary debulking surgery. BRCA mutant cases represented 44% and were associated with a significantly higher frequency for complete pathologic response, first and second platinum sensitive relapse and a significantly longer overall survival for advanced stage cases treated with neoadjuvant chemotherapy. Mean age at presentation was significantly lower in the BRCA mutated (52 years) compared to BRCA wildtype patients (54.2 years, p=0.045)., Conclusions: Upfront knowledge of BRCA status is encouraged, given the recent advent of targeted therapies and for the decision regarding optimal sequence of available therapeutic strategies.

Purpose: Ovarian cancer continues to be the most lethal gynecologic malignancy, with a complex tumor microenvironment (TME). We investigated the immunohistochemical (IHC) expression of toll like receptors (TLRs) 4,5,7 and 9 together with CD68 and CD 163 as markers for tumor-associated macrophages (TAM) in relation to clinicopathological data., Methods: Data from 102 patients with serous ovarian cancer treated between 2006 and 2011 was retrospectively reviewed. A TLR IHC score was developed and CD68, CD163 density scores were calculated as the mean number of positive cells from three 0.5 mm2 areas., Results: Advanced-stage disease (FIGO IIIC-IV) was present in 65.7% of cases. A TLR4 score above median was associated with peritoneal carcinomatosis (odds ratio/OR) 3.02, p=0.019) or ascites (OR 2.5, p=0.041). In FIGO stage IIIC-IV patients with a platinum-free interval (PFI) >12 months had, in comparison with patients with PFI ≤12 months, a higher CD68 density score (191.9 ± 95.2 vs. 152.7 ± 69.4, p=0.066) and a lower CD163 density score (106.7 ± 73.3 vs. 154.5 ± 73.9, p=0.011). In early-stage ovarian cancer patients, TLR9 positivity was associated with a higher overall survival than in patients with absent expression (110.2 vs. 22 months, p<0.001), while advanced-stage patients with TLR7 positivity had a lower overall survival than patients with negative TLR7 (38.3 vs. 66.2 months, p=0.01)., Conclusions: Our data shows that TLRs and TAM are important prognostic markers and future studies are needed to better comprehend the immune response in ovarian cancer.

Pupose: Nestin and CD133 are regarded as putative markers of cancer stem cells (CSCs) and related to poor prognosis in various cancer sites. Since few studies have focused on their role in ovarian cancer, we aimed to investigate their predictive value and association with neoangiogenesis., Methods: Immunohistochemical analysis for nestin and CD133 was performed on 85 serous ovarian carcinoma tumor samples using tissue microarray technique. Nestin immunoreactivity was detected in both tumor and endothelial cells, whilst CD133 was only identified in tumor cells. CD34 endothelial expression was used to assess intratumor microvessel density (MVD)., Results: Of the tissue samples 49.4% were nestin-positive and 24.7% were positive for CD133. In both univariate and multivariate analysis nestin or CD133 expressions in tumor cells were not significantly associated with clinicopathological parameters (age, serum CA125, peritoneal carcinomatosis, malignant ascites, tumor grade). However, in multivariate analysis nestin expression in tumor cells proved to be an independent prognostic factor, associated with poorer survival and time to progression (p=0.025 and p=0.05, respectively). This has not been achieved for CD133. Furthermore, a significant concordance between nestin endothelial expression (nestin-determined MVD) and CD34-determined MVD was achieved., Conclusion: In addition to the well-known clinicopathological characteristics, tumor expression of nestin might be a valuable prognostic factor for survival in patients with advanced ovarian cancer. With regard to its endothelial expression, nestin might be as reliable as CD34 for quantifying tumor angiogenesis. Further investigation is justified in order to better clarify the role of these biomarkers.

Purpose: The tumor microenvironment in ovarian cancer (OC) seems to play an important role, and besides tumor cells, biomarkers can derive from endothelial cells. We investigated CDCP1 and ADAM12 expression in relation with other clinical and pathological characteristics in OC patients., Methods: We retrospectively evaluated patient files between 2006-2011. A histochemical score was developed to evaluate tumor staining, the microvessel density (MVD), and stromal expression patterns for both ADAM12 and CDCP1. A CD34 antibody was used to assess tumor MVD., Results: 102 patients were selected and 83% had FIGO stage III/IV. A high CDCP1 tumor score correlated significantly with a shorter overall survival (OS) (p<0.01). Cases with positive CDCP1 had an elevated CD34 MVD (p<0.01). An absent/low ADAM12 tumor score correlated with significantly improved OS (p<0.01). Mean CD34 MVD was higher in cases with positive ADAM12 MVD (p=0.012)., Conclusions: Our results indicate that both tumor markers are negative prognostic factors for overall survival and additional studies are required to validate their future potential.

Ovarian cancer (OC) is the second most common gynecological cancer and the deadliest in industrialized countries, with poor outcomes that indicate an urgent need to provide a greater insight into the molecular mechanisms underlying OC. Insights into the complex tumor microenviroment show that besides tumor islets, OC biomarkers can derive from newly formed blood vessels that have endothelial cells with a different molecular signature in comparison with their normal counterparts. In this view, recent research has been able to highlight promising candidates such as CDCP1 and ADAM12. Our present review summarises their implications in cancer progression with a focus on OC.

Tumor angiogenesis is regarded as a hallmark of cancer and provides an important target for therapy. Nestin is an intermediate filament protein (IF) originally recognized as a neural stem cell marker. Development and progression of cancer requires sustained angiogenesis, dependent on the proliferation and migration of endothelial cells which seem to be better portrayed by nestin expression in various malignancies such as central nervous system, gastro-intestinal cancers, malignant melanoma, lung, prostate or breast cancer. The purpose of the present review was to emphasize the insights into nestin expression in relation to tumor angiogenesis in different types of cancer. Current evidence suggests that nestin positivity in tumor cells reflects stem-like properties of those cells. Whether or not expressed in both tumor and endothelial cells, nestin overexpression might reflect the extent of angiogenesis and function as a molecular anti-angiogenic target for cancer.

Purpose: The evaluation of CD3(+) T-cell density is believed to have a higher prognostic value than the conventionally used TMN stage in colorectal cancer (CRC), but the role of regulatory T lymphocytes (Treg) is still debated. Our study determined the prognostic value of forkhead box P3 nuclear transcription factor (FOXP3) positive Treg and CD3(+) T-cells in the invasive margin of CRC compared with other known prognostic factors., Methods: The prognostic factors analysed in 42 patients with CRC stage II (N=13) and III (N=29), were age, tumor location, TNM stage, histological grade, vascular, lymphatic and perineural invasion. CD3(+) T-cells and FOXP3(+) Treg density was evaluated by immunohistochemistry., Results: The median CD3(+) T-cells and FOXP3(+) Treg density was 438.93/mm(2) and 162.25/mm(2), respectively. Patients with high FOXP3(+) Treg density showed improved 5-year survival rate of 89.41%, compared with 64.6% of those with low density (p=0.024)., Conclusions: Increased CD3(+) T-cells and FOXP3(+) Treg density is associated with improved survival, but only the latter proved to be an independent prognostic factor. FOXP3(+) Treg infiltrate may play an important prognostic role, which, in combination with other predictive factors, could lead to the development of specific treatment regimens.

Purpose: Morphopathological factors continue to be the most important prognostic factors in colorectal cancer, but there is evidence regarding the prognostic value of some factors that are not yet used in current clinical practice. The purpose of the present study was to evaluate the most important clinical, morphopathological and therapeutic prognostic factors in rectal cancer., Methods: This study retrospectively analyzed 317 patients diagnosed and treated at the Ion Chiricuta Institute of Oncology between 2000-2008. The prognostic value of 13 variables was analyzed and correlations between them were established. Nine variables were included in a multivariate analysis model., Results: The 5-year overall survival (OS) was 55.6%, significantly higher for patients with TNM stage I disease 7l.7%), compared to stage II (71.4%), stage III (45.4%) and stage IV (12.5%; p<0.001). In multivariate analysis, the independent prognostic factors were tumor stage, age, lymph node invasion, venous, lymphatic and perineural invasion., Conclusions: In addition to the TNM stage and lymph node invasion, age, venous, lymphatic and perineural invasion were also proved to have prognostic significance in rectal cancer. Further studies are required for the validation of prognostic assessment models in patients diagnosed with rectal cancer.