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Competing Interests: Declaration of competing interest All authors are employees of the Quirónsalud healthcare network and JA, JAA and CC hold management roles at the company.

Purpose: Uterine fibroids are the most common pelvic tumors in women, representing the primary indication of hysterectomy. Gonadotropin-releasing hormone (GnRH) antagonists represent a new therapeutic option for premenopausal women. The aim of this review is to evaluate the efficacy and safety of GnRH antagonists in the treatment of uterine fibroids (size reduction and symptom control)., Methods: A review of studies from electronic databases (PubMed and Cochrane Central) published up to December 2023 was performed. Eleven randomized clinical trials with a total of 4164 patients were included in the review, which evaluated GnRH antagonists (Relugolix, Elagolix, Linzagolix and Cetrorelix) against placebo or GnRH agonists in premenopausal women with uterine fibroids and heavy menstrual bleeding., Results: The results of the measures evaluated to determine the efficacy and safety of GnRH antagonists versus placebo are favorable for the variables of control of uterine bleeding (Relative risk (RR) = 5.09; 95% CI 3.19 to 8.14), percentage reduction of fibroid volume (Mean difference (MD) = -27.36; 95% CI -38.89 to -15.83) and lower reduction of bone density (MD -0.35; 95% CI -0.47 to -0.24). The results do not allow us to conclude whether there are differences between the alternatives compared in the control of vasomotor symptoms., Conclusions: GnRH antagonists represent an effective alternative for uterine fibroids treatment as they allow a superior reduction in menstrual bleeding and uterine fibroid volume compared to the placebo group., Competing Interests: Declarations. Conflicts of interest: There are no conflicts of interest., (© 2025. The Author(s).)

Controversy surrounds the current debate regarding the effects of outsourcing health services, as recent studies claim that increased outsourcing leads to reduced costs at the expense of worse patient outcomes. The goal of the value-based model is to enable healthcare systems to create more value for patients, and evidence points to improvements in public health outcomes, patient experience, and health expenditure in systems incorporating components of value-based healthcare. Some emerging evidence indicates promising results for outsourced hospitals which follow a value-based model of healthcare delivery. Although additional future studies are still needed to confirm these benefits, value-based healthcare merits discussion as a new perspective on the public versus private management debate. In fact, we argue that outsourcing to value-based health providers could represent a valid alternative for public health management, encouraging greater competition within the healthcare sector while ensuring quality of care for both public and private sectors., Competing Interests: All authors are employees of the Quirónsalud Healthcare Network and JA, JAÁ, and CC hold management roles at the company., (Copyright © 2024 Caramés, Arcos, Pfang, Cristóbal and Álvaro de la Parra.)

Objective: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification., Methods: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens., Results: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001)., Conclusions: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The aim of this case report is to emphasize the significance of the growing teratoma syndrome. Growing teratoma syndrome is frequently misdiagnosed due to its low prevalence, with an estimated incidence of 19% among all immature ovarian teratomas and a lack of experience among healthcare professionals. It is characterized by the growth of benign tumoral tissue during or after chemotherapy for malignant germ cell tumors., Case Report: Our case is about a 46-year-old patient diagnosed with an immature teratoma who was treated unsuccessfully with surgery and chemotherapy. The patient was then referred to our hospital for a second opinion, where this unknown entity was diagnosed and underwent complete surgical debulking, including abdominal wall resection and subsequent repair., Conclusion: Physicians need to be aware of rapidly growing masses during or after chemotherapy because early recognition of this syndrome is essential for the adequate treatment of our patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: MSB11022 is a biosimilar of adalimumab that has been shown comparable bioequivalence, safety, tolerability, and immunogenicity profiles to the reference adalimumab in healthy volunteers or in patients with psoriasis or rheumatoid arthritis (RA). This is the first study conducted under clinical practice conditions evaluating the switch from reference adalimumab to MSB11022 in patients with RA., Methods: Retrospective and multicenter study with data from the medical records of patients with RA who switched from reference adalimumab or another biosimilar to MSB11022 and maintained this treatment for at least 6 months. Information registered comes from baseline visit, the moment of the switch, and the follow-up visits., Results: Data from 86 patients were evaluated (median age 63.5 years, 75.6% female, 44.2% had erosive RA). Only 3.5% of the patients received biologic therapy prior to adalimumab. At baseline, median DAS28-CRP was 1.77 (80.2% in remission and 96.5% with low disease activity) and median CDAI was 4.00 (44.2% in remission and 90.7% with low disease activity). After a median follow-up of 8 months, median DAS28-CRP was 1.87 (86.0% in remission and 94.2% with low disease activity) and median CDAI was 4.00 (38.5% in remission and 95.3% with low disease activity). Only three patients experienced pain, swelling, and stinging at the injection site or a locally extensive hematoma in the area of administration., Conclusions: Adalimumab biosimilar MSB11022 maintained the efficacy benefits provided by previous adalimumab treatments with a safety profile in line with that already described for other biosimilars.

Carcinoma-associated fibroblasts (CAFs) are highly accumulated in the tumor-surrounding stroma of primary epithelial ovarian cancer (OC). CAFs exert important functions for the vascularization, growth, and progression of OC cells. However, the origin of CAFs in primary OC had not yet been studied, and they were assumed to arise from the activation of resident fibroblasts. Here, we compared CAFs in the ovary to CAFs found in peritoneal metastases from patients with advanced OC. Our findings show that CAFs from primary tumors and peritoneal metastases share the expression of mesothelial markers. Therefore, similar to peritoneal carcinomatosis, CAFs in primary ovarian carcinomas may originate from mesothelial cells via a mesothelial-to-mesenchymal transition. The detection of mesothelial-derived CAFs in tumors confined to the ovary and identification of biomarkers could be the key to the early detection of OC and peritoneal spread.

The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy.

Problem: Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) represent distinct clinical conditions with established definitions, both of which have been linked to an underlying pro-inflammatory state. This study aimed to explore the levels of monocytic-myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (T Reg ) in a cohort of RPL and RIF women and their potential contribution to RPL and RIF., Method of Study: One hundred and eight non-pregnant women were evaluated: 40 RPL, 41 RIF, and 27 fertile healthy controls (HC). A multiparametric flow cytometry approach was utilized to measure and quantify the frequency of M-MDSCs and T Reg cells. Cytokine levels in plasma samples were evaluated through a multiplex assay. M-MDSCs levels were significantly higher in RPL and RIF patients compared to HC., Results: M-MDSCs levels were significantly higher in RPL (9.4% [7-11.6]) and RIF (8.1% [5.9-11.6]) patients compared to HC (6% [4.2-7.6]). An optimal cut-off of 6.1% for M-MDSCs disclosed a sensitivity of 75.6% and 89.7% and a specificity of 57.7% and 57.7% in RIF and RPL groups, respectively. A significant negative correlation was observed between M-MDSCs and T Reg (p = .002, r = -.51)., Conclusions: Our preliminary data allowed us to build a predictive model that may aid as a potential diagnostic tool in the clinic. These findings could provide a better understanding of these pathologies and a better definition of patients that could benefit from personalized treatments to promote pregnancy. Additional exploration and confirmation in distinct study groups are needed to fully assess the diagnostic capabilities of this biomarker., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The contraceptive preferences of obstetricians and gynecologists (OB/GYNs) are thought to influence the contraceptive counseling they provide. The purpose of this study was to assess contraceptive preferences of OB/GYNs and women in the general population (WGP) in the current Spanish contraceptive scenario., Materials and Methods: Anonymous online survey of 100 OB/GYNs and 1,217 WGP aged 23-49 years., Results: WGP were younger (35.3 ± 7.3 vs. 37.9 ± 6.2 years, respectively) and less likely to have stable partners (64.7% vs. 84.0%) and children (49.1% vs. 62.0%) (all p  < 0.05 vs. OB/GYNs). Seventy-nine percent versus 82%, respectively, used contraceptive methods, with condoms used most frequently by WGP (37% vs. 22% by OB/GYNs; p  < 0.05) and pills by OB/GYNs (26% vs. 21% by WGP; p  > 0.05). Intrauterine devices (IUDs) were more frequently used by OB/GYNs (20% vs. 5%; p  < 0.05), especially the levonorgestrel-releasing intrauterine devices (LNG-IUDs) (18% vs. 2.6%; p  < 0.05). The highest-rated methods were condoms among WGP and LNG-IUDs among OB/GYNs. Effectiveness was the most valued attribute of contraceptive methods for both. Reasons related to convenience were the main reason for choosing IUDs. OB/GYNs prescribed the contraceptive method in 40% of cases., Conclusions: Our study reveals differences between female OB/GYNs and WGP in contraceptive methods use and rating. The use of LNG-IUDs was much higher among OB/GYNs., Competing Interests: J.P-.C. has received honoraria for consulting, participation in advisory boards or lecturing for Bayer Hispania, MSD, Theramex, Exeltis, Gynea-Kern and Organon outside the submitted work. J.C.Q-.C. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer and Gedeon Richter outside the submitted work. J.G-.A. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer, Exeltis and Organon outside the submitted work. P.L-.A. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer, Exeltis, Gedeon Richter, Medtronic and Organon outside the submitted work. I.P-.R. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer and MSD outside the submitted work. I.C-.G. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer, Gedeon Richter, MSD and Organon outside the submitted work. M.A-.G. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer, Gedeon Richter and Hologyc outside the submitted work. M.H.-C. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer, Gedeon Richter, MSD and Organon outside the submitted work. J.R-.T. is full-time employee of Bayer Hispania S.L. J.C-.A. has received honoraria for consulting, participation in advisory boards or lecturing from Bayer, Gedeon Richter-Preglem and Theramex outside the submitted work., (© Josep Perelló-Capo et al., 2023; Published by Mary Ann Liebert, Inc.)

Background: The cognitive distraction caused by Virtual Reality (VR) seems to cause a decrease both in pain and its perception as in the time spent thinking about possible pain, among anxiety about hysteroscopy procedure. The main objective of this investigation was to evaluate the efficacy of virtual reality for pain relief during outpatient hysteroscopy. Method : A total of 83 patients underwent outpatient diagnostic hysteroscopy in a single-centre, open-label, randomized control trial. Overall, 180 women with medical indication for an outpatient diagnostic hysteroscopy were randomized. Ten were excluded due to the impossibility of entering the endometrial cavity caused by a cervical canal that was not permeable, and 15 did not tolerate the pain at the beginning and during the procedure, excluding themselves from the final model. Finally, 154 were analysed per protocol to use VR ( n = 82, study group) or standard treatment ( n = 72, control group) assessing the differences between both groups by reduction in pain using Visual Analogue Scale score (VAS: 0-10 cm) and clinical data (arterial pressure, heart rate, and oxygen saturation) at the end of hysteroscopy, at 15 and 30 min after hysteroscopy. Results : Women with VR outpatient diagnostic hysteroscopy experienced less pain at final (VAS score 2.451 vs. 3.972, standard mean difference (SMD) -1.521, 95% CI -2.601 to -0.440; p = 0.006), at 15 min (VAS 1.769 vs. 3.300, SMD -1.531, 95% CI -2.557 to -0.504; p = 0.004), and at 30 min (VAS 1.621 vs. 2.719, SMD -1.099, 95% CI -2.166 to -0.031; p = 0.044) after the ending of the hysteroscopy, compared with no VR. Conclusions : The use of VR during outpatient diagnostic hysteroscopy proved effective in the reduction of pain in this randomized control trial. It shows wide potential role in ambulatory gynaecologic procedures to avoid repeating tests, perform surgeries without anaesthesia, and the use of medication and its side effects.

MicroRNA (miR)-19b is deregulated in colorectal cancer (CRC) and locally advanced rectal cancer (LARC), predicting worse outcome and disease progression in CRC patients, and acting as a promising prognostic marker of patient recurrence and pathological response to 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy in LARC. Moreover, there is a strong inverse correlation between miR-19b and PPP2R5E in LARC, and both predict the response to neoadjuvant therapy in LARC patients. However, the functional role of the miR-19b/PPP2R5E axis in CRC cells remains to be experimentally evaluated. Here, we confirm with luciferase assays that miR-19b is a direct negative regulator of PPP2R5E in CRC, which is concordant with the observed decreased PP2A activity levels after miR-19b overexpression. Furthermore, PPP2R5E downregulation plays a key role mediating miR-19b-induced oncogenic effects, increasing cell viability, colonosphere formation ability, and the migration of CRC cells. Lastly, we also confirm the role of miR-19b mediating 5-FU sensitivity of CRC cells through negative PPP2R5E regulation. Altogether, our findings demonstrate the functional relevance of the miR-19b/PPP2R5E signaling pathway in disease progression, and its potential therapeutic value determining the 5-FU response of CRC cells.

Competing Interests: Declaration of interests The authors declare no competing interests.

The main objective was to analyze the rate of bilateral sentinel lymph node (SLN) detection in endometrial cancer using indocyanine green (ICG) as a unique tracer compared to Technetium99 + ICG. As secondary objectives, we analyzed the drainage pattern and factors that might affect the oncological outcomes. A case-control ambispective study was carried out on consecutive patients at our center. Data on the SLN biopsy with ICG collected prospectively were compared to retrospective data on the use of a double-tracer technique including Technetium99 + ICG. In total, 194 patients were enrolled and assigned to both groups, in which the group with both tracers (controls) included 107 (54.9%) patients and the ICG-alone group (cases) included 87 (45.1%) patients. The rate of bilateral drainage was significantly higher in the ICG group (98.9% vs. 89.7%; p = 0.013). The median number of nodes retrieved was higher in the control group (three vs. two nodes; p < 0.01). We did not find survival differences associated with the tracer used ( p = 0.85). We showed significant differences in terms of disease-free survival regarding the SLN location ( p < 0.01), and obturator fossa retrieved nodes showed better prognosis compared to external iliac. The use of ICG as a single tracer for SLN detection in endometrial cancer patients seemed to obtain higher rates of bilateral detection with similar oncological outcomes.

Human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer accounts for 15 to 25% of breast cancer cases. Although therapies based on the use of monoclonal anti-HER2 antibodies present clinical benefit for a subtype of patients with HER2-positive breast cancer, more than 50% of them are unresponsive to targeted therapies or they eventually relapse. In recent years, reactivation of the adaptive immune system in patients with solid tumors has emerged as a therapeutic option with great potential for clinical benefit. Since the approval of the first treatment directed against HER2 as a therapeutic target, the range of clinical options has expanded greatly, and, in this sense, cellular immunotherapy with T cells relies on the cytotoxicity generated by these cells, which ultimately leads to antitumor activity. Lymphocytic infiltration of tumors encompasses a heterogeneous population of immune cells within the tumor microenvironment that exhibits distinct patterns of immune activation and exhaustion. The prevalence and prognostic value of tumor-infiltrating lymphocyte (TIL) counts are associated with a favorable prognosis in HER2-positive breast cancers. This review discusses emerging findings that contribute to a better understanding of the role of immune infiltrates in HER2-positive breast cancer. In addition, it summarizes the most recent results in HER2-positive breast cancer immunotherapy and anticipates which therapeutic strategies could be applied in the immediate future.

Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) are two well-defined clinical entities, but the role of the monocytes in their pathophysiology needs to be clarified. This study aimed to evaluate the role of the three monocyte subsets (classical, intermediate, and non-classical) and relevant cytokines/chemokines in a cohort of RPL and RIF women to better characterize a baseline proinflammatory profile that could define inflammatory pathophysiology in these two different conditions. We evaluated 108 non-pregnant women: 53 RPL, 24 RIF, and 31 fertile healthy controls (HC). Multiparametric flow cytometry was used to quantify the frequency of surface chemokine receptors (CCR2, CCR5, and CX3CR1) on the monocyte subsets. Cytokines were assessed in plasma samples using a multiplex assay. The CX3CR1 + and CCR5 + intermediate monocytes were significantly higher in RPL and RIF compared to HC. A significant positive correlation was observed between CX3CR1 + intermediate monocytes and IL-17A (P = .03, r = 0.43). The Boruta algorithm followed by a multivariate logistic regression model was used to select the most relevant variables that could help define RPL and RIF: in RPL were CX3CR1 non-classical monocytes, TGF-β1, and CCR5 intermediate monocytes; in RIF: CCR5 intermediate monocytes and TGF-β3. The combination of these variables could predict RPL and RIF with 90 % and 82 %, respectively. Our study suggests that a combination of specific blood monocyte subsets and cytokines could aid in identifying RPL and RIF women with a pro-inflammatory profile. These findings could provide a more integrated understanding of these pathologies. Further investigation and validation in independent cohorts are warranted., Competing Interests: Conflict of interest The authors declare that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript, and they have seen and approved the final version of the manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As the number of observations submitted to the citizen science platform iNaturalist continues to grow, it is increasingly important that these observations can be identified to the finest taxonomic level, maximizing their value for biodiversity research. Here, we explore the benefits of acting as an identifier on iNaturalist., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome and pathological response to preoperative CRT in this disease. Moreover, it has been discovered that this miR increases its expression in 5-FU resistant colon cancer cells after 5-FU exposure. Despite the fact that these observations suggest a functional role of miR-19b modulating 5-FU response of LARC cells, this issue still remains to be clarified. Here, we show that downregulation of miR-19b enhances the antitumor effects of 5-FU treatment. Moreover, ectopic miR-19b modulation was able to restore sensitivity to 5-FU treatment using an acquired resistant model to this compound. Notably, we also evaluated the potential clinical impact of miR-19b as a predictive marker of disease progression after tumor surgery resection in LARC patients, observing that miR-19b overexpression significantly anticipates patient recurrence in our cohort ( p = 0.002). Altogether, our findings demonstrate the functional role of miR-19b in the progressively decreasing sensitivity to 5-FU treatment and its potential usefulness as a therapeutic target to overcome 5-FU resistance, as well as its clinical impact as predictor of tumor progression and relapse.

Objective: Assess the surgeons' workload during deep endometriosis surgery after ureteral ICG., Design: Prospective, consecutive, comparative, single-center study., Population: 41 patients enrolled to deep endometriosis surgery with ureteral ICG from January 2019 to July 2021 at La Paz University Hospital., Methods: Patients were divided into 2 groups: patients operated during the learning curve of ureteral ICG instillation and patients operated after the technique was implemented and routinely performed. After surgery, the SURG-TLX form was completed by the surgeons. We evaluated whether a workload reduction occurred., Main Outcomes Measures: Surgeon's workload was measured using the SURG-TLX form, obtaining the total workload and 6 different dimensions (distractions, temporal demands, task complexity, mental demands, situational stress and physical demands)., Results: A significant positive correlation was found between surgical complexity and situational stress ( p  = 0.04). Mental demands ( p  = 0.021), physical demands ( p  = 0.03), and total workload ( p  = 0.025) were significantly lower when the technique was routinely performed. The mental demand, physical demands, and total workload perceived by the surgeons at the beginning of the implementation was higher (68 [39-72], 27 [11-46.5], 229 [163-240], respectively) than in the latter ones (40 [9-63], 11.5 [0-32.8], 152 [133.3-213.8], respectively). Distractions appeared to be higher in the latter surgeries (8.5 [0-27.8]) than in the first surgeries (0 [0-7]; p  = 0.057)., Conclusions: Ureter ICG instillation prior to DE surgery significantly reduces the mental and physical demands and total workload of the surgeons in DE surgeries after overcoming the learning curve. Distractions appear to increase as surgical stress decreases., 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., (© 2022 Spagnolo, Cristóbal Quevedo, Gortázar de las Casas, López Carrasco, Carbonell López, Pascual Migueláñez and Hernández Gutiérrez.)

Gynecological cancer accounts for an elevated incidence worldwide requiring responsiveness regarding its care. The comprehensive genomic approach agrees with the classification of certain tumor types. We evaluated 49 patients with gynecological tumors undergoing high-throughput sequencing to explore whether identifying alterations in cancer-associated genes could characterize concrete histological subtypes. We performed immune examination and analyzed subsequent clinical impact. We found 220 genomic aberrations mostly distributed as single nucleotide variants (SNV, 77%). Only 3% were classified as variants of strong clinical significance in BRCA1 and BRCA2 of ovarian high-grade serous (HGSC) and uterine endometrioid carcinoma. TP53 and BRCA1 occurred in 72% and 28% of HGSC. Cervical squamous cell carcinoma was entirely HPV-associated and mutations occurred in PIK3CA (60%), as well as in uterine serous carcinoma (80%). Alterations were seen in PTEN (71%) and PIK3CA (60%) of uterine endometrioid carcinoma. Elevated programmed death-ligand 1 (PD-L1) was associated with high TILs. Either PD-L1 augmented in deficient mis-matched repair (MMR) proteins or POLE mutated cases when compared to a proficient MMR state. An 18% received genotype-guided therapy and a 4% immunotherapy. The description of tumor subtypes is plausible through high-throughput sequencing by recognizing clinically relevant alterations. Additional concomitant assessment of immune biomarkers identifies candidates for immunotherapy.

Background: It has not been determined whether ileal appearance differs among dogs with chronic inflammatory enteropathy (CIE) and different serum concentrations of cobalamin., Objective: To compare endoscopic and histologic ileal findings in dogs with CIE and different serum cobalamin concentrations and then evaluate the correlation of ileal changes to cobalamin serum concentration using updated scoring systems to assess the ileum., Animals: Sixty-eight dogs with CIE., Methods: Retrospective study. Frequency of ileal features and ileal histologic and endoscopic scores (IHS and IES) were obtained and compared among CIE dogs with severe hypocobalaminemia (SHC; <200 ng/L), hypocobalaminemia (HC; 200-350 ng/L), or normocobalaminemia (NC; >350 ng/L). The correlation of IHS and IES with cobalamin was evaluated., Results: Friability, villus atrophy, crypt dilatation, epithelial injury, and intraepithelial lymphocytes were more frequent in SHC than in NC dogs (all P ≤ .01). Median SHC-IES (2; range, 0-4) was higher than NC-IES (1; range, 0-5; P = .004). Median SHC-IHS (6; range, 3-9) was higher than HC-IHS (4; range, 1-7; P < .001) and NC-IHS (3; range, 1-8; P < .001). Cobalamin concentration correlated negatively with IES (ρ = -.34, P = .005) and IHS (ρ = -.58, P < .001)., Conclusions and Clinical Importance: Ileal features and involvement degree markedly differed when cobalamin was <200 or >350 ng/L in CIE dogs. With updated scales to assess the mucosa, greater ileal damage was associated with lower serum cobalamin concentration., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Together with its reported ability to modulate AKT phosphorylation (p-AKT) status in several tumor types, the oncoprotein CIP2A has been described to induce breast cancer progression and drug resistance. However, the clinical and therapeutic relevance of the CIP2A/AKT interplay in breast cancer remains to be fully clarified. Here, we found high p-AKT levels in 80 out of 220 cases (36.4%), which were associated with negative estrogen receptor expression (p = 0.049) and CIP2A overexpression (p < 0.001). Interestingly, p-AKT determined substantially shorter overall (p = 0.002) and progression-free survival (p = 0.003), and multivariate analyses showed its CIP2A-independent prognostic value. Moreover, its clinical relevance was further confirmed in the triple negative and HER2-positive subgroups after stratifying our series by molecular subtype. Functionally, we confirmed in vitro the role of CIP2A as a regulator of p-AKT levels in breast cancer cell lines, and the importance of the CIP2A/AKT axis was also validated in vivo. Finally, p-AKT also showed a higher predictive value of response to doxorubicin than CIP2A in ex vivo analyses. In conclusion, our findings suggest that CIP2A overexpression is a key contributing event to AKT phosphorylation and highlights the CIP2A/AKT axis as a promising therapeutic target in breast cancer. However, our observations highlight the existence of alternative mechanisms that regulate AKT signaling in a subgroup of breast tumors without altered CIP2A expression that determines its independent value as a marker of poor outcome in this disease.

Background: COVID-19 spread quickly around the world shortly after the first outbreaks of the new coronavirus disease at the end of December 2019, affecting all populations, including pregnant women., Objective: The aim of this study was to analyze the relationship between different publications on COVID-19 in pregnancy and their authors through citation networks, as well as to identify the research areas and to determine the publication that has been the most highly cited., Methods: The search for publications was carried out through the Web of Science database using terms such as "pregnancy," "SARS-CoV-2," "pregnant," and "COVID-19" for the period between January and December 2020. Citation Network Explorer software was used for publication analysis and VOSviewer software was used to construct the figures. This approach enabled an in-depth network analysis to visualize the connections between the related elements and explain their network structure., Results: A total of 1330 publications and 5531 citation networks were identified in the search, with July being the month with the largest number of publications, and the United States, China, and England as the countries with the greatest number of publications. The most cited publication was "Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records" by Chen and colleagues, which was published in March 2020. Six groups identified as being close in the citation network reflect multidisciplinary research, including clinical characteristics and outcomes in pregnancy, vertical transmission, delivery mode, and psychological impacts of the pandemic on pregnant women., Conclusions: Thousands of articles on COVID-19 have been published in several journals since the disease first emerged. Identifying relevant publications and obtaining a global view of the main papers published on COVID-19 and pregnancy can lead to a better understanding of the topic. With the accumulation of scientific knowledge, we now know that the clinical features of COVID-19 during pregnancy are generally similar to those of infected nonpregnant women. There is a small increase in frequency of preterm birth and cesarean birth, related to severe maternal illness. Vaccination for all pregnant women is recommended. Several agents are being evaluated for the treatment of COVID-19, but with minimal or no information on safety in pregnancy. These results could form the basis for further research. Future bibliometric and scientometric studies on COVID-19 should provide updated information to analyze other relevant indicators in this field., (©Rebeca Ruiz-Roman, Clara Martinez-Perez, Inés Gil Prados, Ignacio Cristóbal, Miguel Ángel Sánchez-Tena. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 03.03.2022.)

The identification of robust prognostic markers still represents a need in locally advanced rectal cancer (LARC). MicroRNAs (miRs) have progressively emerged as promising circulating markers, overcoming some limitations that traditional biopsy comprises. Tissue miR-199b deregulation has been reported to predict outcome and response to neoadjuvant chemoradiotherapy (nCRT) in LARC, and was also found to be associated with disease progression in colorectal cancer. However, its biological and clinical relevance remains to be fully clarified. Thus, we observed here that miR-199b regulates cell migration, aggressiveness, and cell growth, and inhibits colonosphere formation and induces caspase-dependent apoptosis. Moreover, miR-199b expression was quantified by real-time PCR in plasma samples from LARC patients and its downregulation was observed in 22.7% of cases. This alteration was found to be associated with higher tumor size ( p = 0.002) and pathological stage ( p = 0.020) after nCRT. Notably, we observed substantially lower global miR-199b expression associated with patient downstaging ( p = 0.009), as well as in non-responders compared to those cases who responded to nCRT in both pre- ( p = 0.003) and post-treatment samples ( p = 0.038). In concordance, we found that miR-199b served as a predictor marker of response to neoadjuvant therapy in our cohort ( p = 0.011). Altogether, our findings here demonstrate the functional relevance of miR-199b in this disease and its potential value as a novel circulating marker in LARC.

The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy. It is well known that the tumour microenvironment (TME) has a significant impact on cancer behaviour. Cancer-associated fibroblasts (CAFs) are essential components of the tumour stroma that have been linked to acquired therapeutic resistance and poor prognosis in breast cancer. For this reason, it would be of interest to identify novel biomarkers in the tumour stroma that could emerge as therapeutic targets for the modulation of resistant phenotypes. Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of the CAF-conditioned medium that may be relevant in the promotion of BCCL resistance, we implemented a multiomics strategy to identify cytokines, transcription factors, kinases and miRNAs in the secretome that have specific targets in cancer cells. The combination of cytokine arrays, label-free LC-MS/MS quantification and miRNA analysis to explore the secretome of CAFs under treatment conditions revealed several up- and downregulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer.

Proper communication between natural killer cells and the human leukocyte antigens of the embryonic trophoblast at the maternal-fetal interface during pregnancy is essential for successful reproduction. However, specific combinations of embryonic human leukocyte antigen-C with killer immunoglobulin-like receptors on decidual natural killer cells (the immunological code of pregnancy) can be associated with obstetric morbidity and pregnancy loss. This article presents an updated review of the mechanisms underlying the interaction between embryonic human leukocyte antigen-C and maternal killer immunoglobulin-like receptors and their relevance to the physiology and pathophysiology of human reproduction.

Background: Ovarian cancer has a low incidence, but high mortality due to a habitual diagnosis in advanced cancer stages. Currently, used biomarkers have good sensitivity, but low specificity., Aim: To determine the usefulness of the biomarkers and algorithms used up to now in the screening, diagnosis, response to treatments and identification of recurrence in patients with ovarian masses., Methodology: Systematic search of publications in English in the Medline-PubMed database with the terms: "biomarkers", "tumour", "tumour biomarkers", "marker", "tumour marker", "ovarian cancer", "ovarian", "Neoplasms", "cancer", CA-125 Antigen; Human Epididymis-specific Protein E4; Risk of Malignancy Index (RMI); Risk of Ovarian Malignancy Algorithm (ROMA); Ovarian Neoplasms. Original articles, clinical trials, reviews, systematic reviews and meta-analyses, published between January 2000 and November 2020, were selected to determine the usefulness (among others) of CA 125 and HE4 antigen in ovarian cancer., Results: Finally, 39 transcendental publications were selected to write this article to determine the usefulness of tumour markers and algorithms in ovarian cancer., Conclusions: The usefulness of the tumour markers antigen CA125 and antigen HE4 individually or as a basis for decision-making algorithms has low specificity; however, there is little evidence that confirms their usefulness as markers in ovarian cancer screening.

The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size ( p = 0.026) and positive lymph node after CRT ( p = 0.005), and higher pathological stage ( p = 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT ( p = 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall ( p < 001) and event-free survival ( p < 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence ( p = 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.

Problem: Expansion of circulating NK cells has been related to pregnancy complications. This study aims at investigating several surface NK cell markers to identify a baseline inflammatory profile in women with recurrent pregnancy loss (iRPL) and recurrent implantation failure (iRIF)., Method of Study: Expression of NKp30, TIGIT, NKp46, and DNAM-1 on total peripheral blood NK subsets, regulatory (CD56 bright CD16 neg ), and cytotoxic (CD56 dim CD16 pos/neg ) NK cells was measured., Results: Eighty-three women were recruited and classified into two groups, 58 women with RPL and 25 with RIF. A control group of 31 fertile women was included. Expression of NKp30 on cytNK was significantly higher in RPL (p = .019) and RIF (p < .001) than HC. TIGIT on cytNK cells was also higher in both RPL (p < .001) and RIF (p < .01). An optimal cutoff of 70% for NKp30 + cytNK disclosed a sensitivity of 82%, a specificity of 55%, and 83% PPV for RPL diagnosis. A cutoff level of 83% for TIGIT + cytNK was chosen to discriminate between healthy controls and RPL women, with PPV of 84%., Conclusion: Our preliminary data on this RPL and RIF cohorts suggest a simple diagnostic tool by combining NKp30 and TIGIT on cytNK cells to better identify a subgroup of RPL and RIF patients with a baseline inflammatory profile. A more rigorous selection of these patients through phenotyping peripheral cytNK cells may better define patients that could benefit from an immunomodulatory treatment to prevent further pregnancy losses. The performance of these biomarkers requires further investigation and validation in independent cohorts., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorectal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired toxicities in those non-responder cases. Thus, the identification of effective and robust biomarkers to predict response to preoperative CRT represents an urgent need in the current clinical management of LARC. The oncomiR microRNA-19b (miR-19b) has been reported to functionally play oncogenic roles in colorectal cancer (CRC) cells as well as regulate 5-FU sensitivity and determine outcome in CRC patients. However, its clinical impact in LARC has not been previously investigated. Here, we show that miR-19b deregulation is a common event in this disease, and its decreased expression significantly associates with lower tumor size after CRT ( p = 0.003), early pathological stage ( p = 0.003), and absence of recurrence ( p = 0.001) in LARC patients. Interestingly, low miR-19b expression shows a predictive value of better response to neoajuvant CRT ( p < 0.001), and the subgroup of LARC patients with low miR-19b levels have a markedly longer overall ( p = 0.003) and event-free survival ( p = 0.023). Finally, multivariate analyses determined that miR-19b independently predicts both patient outcome and response to preoperative CRT, highlighting its potential clinical usefulness in the management of LARC patients.

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences ( p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall ( p < 0.001) and event-free survival ( p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

Background: Next-generation sequencing (NGS) is a high-throughput technology that has become widely integrated in molecular diagnostics laboratories. Among the large diversity of NGS-based panels, the Trusight Tumor 26 (TsT26) enables the detection of low-frequency variants across 26 genes using the MiSeq platform., Methods: We describe the inter-laboratory validation and subsequent clinical application of the panel in 399 patients presenting a range of tumor types, including gastrointestinal (GI, 29%), hematologic (18%), lung (13%), gynecological and breast (8% each), among others., Results: The panel is highly accurate with a test sensitivity of 92%, and demonstrated high specificity and positive predictive values (95% and 96%, respectively). Sequencing testing was successful in two-thirds of patients, while the remaining third failed due to unsuccessful quality-control filtering. Most detected variants were observed in the TP53 (28%), KRAS (16%), APC (10%) and PIK3CA (8%) genes. Overall, 372 variants were identified, primarily distributed as missense (81%), stop gain (9%) and frameshift (7%) altered sequences and mostly reported as pathogenic (78%) and variants of uncertain significance (19%). Only 14% of patients received targeted treatment based on the variant determined by the panel. The variants most frequently observed in GI and lung tumors were: KRAS c.35G > A (p.G12D), c.35G > T (p.G12V) and c.34G > T (p.G12C)., Conclusions: Prior panel validation allowed its use in the laboratory daily practice by providing several relevant and potentially targetable variants across multiple tumors. However, this study is limited by high sample inadequacy rate, raising doubts as to continuity in the clinical setting., Competing Interests: Víctor Manuel Fernández-Soria and Ricardo Ramos-Ruiz are employed by Genomics Unit, Madrid Science Park. The authors declare that they have no other competing interests., (©2020 Prieto-Potin et al.)

Prolapsed submucosal myomas during pregnancy are uncommon, and few cases of patients undergoing vaginal myomectomy during pregnancy have been reported. In our center, a 13 weeks pregnant patient with prolapsed cervical myoma was diagnosed. Because of intermittent vaginal bleeding, surgery was scheduled at 13 weeks and 5 days of pregnancy. A vaginal myomectomy was performed. The postoperative course was uneventful. Cervical leiomyomas and prolapsed submucosal leiomyomas in pregnancy are rare clinical entities, and the literature is comprised of only case reports. We reviewed the current literature in regard to prolapsed cervical leiomyomas in pregnancy and provide an updated vision of the literature., (Copyright © 2020 Elsevier B.V. All rights reserved.)