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Context: DNA mismatch repair (MMR) deficiency (dMMR) testing is now recommended in endometrial cancer. Defect identification in the molecules participating in this pathway, or the presence of microsatellite instability, are commonly employed for this purpose. Novel methods are continuously evolving to report dMMR/microsatellite instability and to easily perform routine diagnoses., Objective: The main aim of this study was to compare the concordance of the Idylla microsatellite instability test for the identification of dMMR endometrial cancer samples defined by immunohistochemistry and MMR genomic status., Design: We applied the Idylla MSI test to 126 early-stage endometrial cancer cases with MMR testing by immunohistochemistry and genomic characterization (methylation in MLH1 and sequence alterations in MLH1, PMS2, MSH2 and MSH6). Individual markers and overall specific performance indicators were explored., Results: The Idylla platform achieved a higher global concordance rate with MMR genomic status than with immunohistochemistry (75 % and 66 %, respectively). Sensitivity and specificity are also higher (75 % vs 66 % and 96 % vs 90 %, respectively). Clustering analysis split the patients into 2 well-differentiated clusters, the pMMR and the dMMR group, represented by MLH1/PMS2 loss and the MLH1 methylated promoter. Overall, immunohistochemistry and MMR genomic status identified more dMMR cases than did the Idylla test, although correlations were improved with a modified Idylla test cut-off., Conclusions: Performance of the Idylla test was better correlated with MMR genomic status than MMR immunohistochemistry status, which improved with a modified test cut-off. Further studies are needed to confirm the cut-off accuracy., (Copyright © 2024. Published by Elsevier Ltd.)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. The current challenge remains the absence of predictive biomarkers. Cytokines are crucial factors in the pathogenesis and prognosis of PDAC. Furthermore, there is growing interest in differentiating between molecular subtypes of PDAC. The aim of our study is to evaluate the association between the analyzed cytokines and the molecular subtypes of PDAC and to determine their prognostic value. Cytokine levels were measured in 73 patients, and molecular subtypes were analyzed in 34 of these patients. Transforming Growth Factor Beta 2 (TGF-β2) levels were independently associated with the basal-like and null subtypes. In patients with locally advanced and metastatic PDAC, elevated levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-9, and IL-15 were associated with a higher risk of progression during first-line treatment, and increased levels of IL-1β, IL-6, IL-8, IL-9, and IL-15 were related to increased mortality. Furthermore, a significant association was observed between higher percentiles of IL-6 and IL-8 and shorter progression-free survival (PFS) during first-line treatment, and between higher percentiles of IL-8 and shorter overall survival (OS). In the multivariate analysis, only elevated levels of IL-8 were independently associated with a higher risk of progression during first-line treatment and mortality. In conclusion, the results of our study suggest that cytokine expression varies according to the molecular subtype of PDAC and that cytokines also play a relevant role in patient prognosis.

Anticancer systemic therapy comprises a complex and growing group of drugs. Some of the new agents with novel mechanisms of action that have appeared are difficult to fit in the groups of classical chemotherapy, hormones, tyrosine-kinase inhibitors, and monoclonal antibodies. We propose a classification based on two levels of information: the site of action and the mechanism of action. Regarding the former, drugs can exert their action in the tumor cell, the tumor vasculature, the immune system, or the endocrine system. The mechanism of action refers to the molecular target., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child-Pugh class A., (© 2024. The Author(s).)

Background: The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, only MSI tumour patients have seen a change in their disease management in clinical practice. This study aims to characterise the proteome of colon cancer CMS and broaden CMS's clinical utility., Methods: One-hundred fifty-eight paraffin samples from stage II-III colon cancer patients treated with adjuvant chemotherapy were analysed through DIA-based mass-spectrometry proteomics., Results: CMS1 exhibited overexpression of immune-related proteins, specifically related to neutrophils, phagocytosis, antimicrobial response, and a glycolytic profile. These findings suggested potential therapeutic strategies involving immunotherapy and glycolytic inhibitors. CMS3 showed overexpression of metabolic proteins. CMS2 displayed a heterogeneous protein profile. Notably, two proteomics subtypes within CMS2, with different protein characteristics and prognoses, were identified. CMS4 emerged as the most distinct group, featuring overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. CMS4 showed a high metastatic profile and suggested possible chemoresistance that may explain its worse prognosis., Conclusions: DIA proteomics revealed new features for each colon cancer CMS subtype. These findings provide valuable insights into potential therapeutic targets for colorectal cancer subtypes in the future., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Angiosarcoma is a rare soft tissue sarcoma originating from endothelial cells. Given that current treatments for advanced disease have shown limited efficacy, alternative therapies need to be identified. In rare diseases, patient-derived cell models are crucial for screening anti-tumour activity. In this study, cell line models were characterised in 2D and 3D cultures. The cell lines' growth, migration and invasion capabilities were explored, confirming them as useful tools for preclinical angiosarcoma studies. By screening a drug library, we identified potentially effective compounds: 8-amino adenosine impacted cell growth and inhibited migration and invasion at considerably low concentrations as a single agent. No synergistic effect was detected when combining with paclitaxel, gemcitabine or doxorubicin. These results suggest that this compound could be a potentially useful drug in the treatment of AGS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marta Mendiola reports financial support was provided by VYDA-GEIS. Andres Redondo reports financial support was provided by VYDA-GEIS. Marta Mendiola reports a relationship with MSD that includes: consulting or advisory. Marta Mendiola reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory. Marta Mendiola reports a relationship with GSK that includes: consulting or advisory. Marta Mendiola reports a relationship with Eisai Inc that includes: funding grants. Marta Mendiola reports a relationship with PharmaMar Ltd that includes: funding grants. Marta Mendiola reports a relationship with AstraZeneca Pharmaceuticals LP that includes:. Marta Mendiola reports a relationship with GSK that includes: travel reimbursement. Marta Mendiola reports a relationship with PharmaMar Ltd that includes: travel reimbursement. Marta Mendiola reports a relationship with Roche that includes: travel reimbursement. Marta Mendiola reports a relationship with Pfizer that includes: travel reimbursement. Marta Mendiola reports a relationship with Biocartis that includes: travel reimbursement. Andres Redondo reports a relationship with MSD that includes: consulting or advisory. Andres Redondo reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory. Andres Redondo reports a relationship with GSK that includes: consulting or advisory. Andres Redondo reports a relationship with Eisai Inc that includes: consulting or advisory. Andres Redondo reports a relationship with Clovis Oncology that includes: consulting or advisory. Andres Redondo reports a relationship with PharmaMar Ltd that includes: consulting or advisory. Andres Redondo reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Andres Redondo reports a relationship with Eisai Inc that includes: funding grants. Andres Redondo reports a relationship with PharmaMar Ltd that includes: funding grants. Andres Redondo reports a relationship with Roche that includes: funding grants. Andres Redondo reports a relationship with MSD that includes: travel reimbursement. Andres Redondo reports a relationship with AstraZeneca Pharmaceuticals LP that includes: travel reimbursement. Andres Redondo reports a relationship with GSK that includes: travel reimbursement. Andres Redondo reports a relationship with Clovis Oncology that includes: travel reimbursement. Andres Redondo reports a relationship with PharmaMar Ltd that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Evidence on how menstrual characteristics may differ based on socioeconomic factors and self-rated health is significantly scarce. The main aim of this study was to investigate the associations between menstrual characteristics, sociodemographic factors and self-rated health among women and people who menstruate (PWM) aged 18-55 in Spain., Methods: This cross-sectional study includes data from an online survey collected in March-July 2021 across Spain. Descriptive statistical analyses and multivariate logistic regression models were performed., Results: The analyses included a total of 19,358 women and PWM. Mean age at menarche was 12.4 (SD = 1.5). While 20.3% of our participants experienced a menstrual abundance over 80 ml, 64.1% reported having menstrual blood clots; 6.4% menstruated for longer than 7 days. 17.0% had menstrual cycles that were shorter than 21 days or longer than 35 days. Reports of moderate (46.3%) and high (22.7%) intensity menstrual pain were common. 68.2% of our participants experienced premenstrual symptoms in all or most cycles. The odds for lighter menstrual flow, shorter bleeding days and menstrual cycles were higher as age increased, and amongst participants with less educational attainment. Caregivers presented higher odds for abundant menstrual flow and longer menstruations. Reporting financial constraints and a poorer self-rated health were risk factors for abundant menstrual flow, menstrual blood clots, shorter/longer menstruations and menstrual cycles, premenstrual symptoms, moderate and intense menstrual pain., Conclusions: This study suggests that age, educational attainment, caregiving, experiencing financial hardship and a poorer self-rated health may shape or mediate menstrual characteristics. It thus highlights the need to investigate and address social inequities of health in menstrual research., (© 2024. The Author(s).)

Background: MUTYH has been implicated in hereditary colonic polyposis and colorectal carcinoma. However, there are conflicting data refgarding its relationship to hereditary breast cancer. Therefore, we aimed to assess if MUTYH mutations contribute to breast cancer susceptibility., Methods: We retrospectively reviewed 3598 patients evaluated from June 2018 to June 2023 at the Hereditary Cancer Unit of La Paz University Hospital, focusing on those with detected MUTYH variants., Results: Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2-2.0). Of the 766 patients with breast cancer, 14 patients were carriers of MUTYH mutations (1.8%, 95%CI: 0.5-3.0). The prevalence of MUTYH mutation was significantly higher in the subpopulation with colonic polyposis (11.3% vs. 1.1%, p < 0.00001, OR = 11.2, 95%CI: 6.2-22.3). However, there was no significant difference in the prevalence within the subpopulation with breast cancer (1.8% vs. 1.5%, p = 0.49, OR = 1.2, 95%CI: 0.7-2.3)., Conclusion: In our population, we could not establish a relationship between MUTYH and breast cancer. These findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in breast cancer risk.

Aim: To describe the evolution of regorafenib use, since its approval, in patients with previously treated metastatic colorectal cancer (mCRC) in routine clinical practice in Spain. Methods: We extracted patient characteristics, dosing, safety and efficacy data for the Spanish cohorts of the CORRECT and CONSIGN trials, and the real-world CORRELATE study. Results: The Spanish cohorts represented 10.7-13.8% of the global cohorts. Efficacy and safety in the Spanish cohorts reflected findings from the global cohorts, with evidence of a flexible dosing approach being adopted in routine clinical practice. Conclusion: Regorafenib use in patients with mCRC has evolved in the real-world setting, emphasizing the need for further research evaluating dosing patterns that can optimize clinical outcomes in these patients. Clinical trial registration: The CORRECT trial is registered at ClinicalTrials.gov, number NCT01103323; the CONSIGN trial is registered at ClinicalTrials.gov, number NCT01538680; the CORRELATE study is registered at ClinicalTrials.gov, number NCT02042144.

Background: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison., Methods: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy)., Results: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma., Conclusions: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

The proteome characterization of complex, deteriorated, or cross-linked protein mixtures as paired clinical FFPE or exosome samples isolated from low plasma volumes (250 µL) might be a challenge. In this work, we aimed at investigating the benefits of FAIMS technology coupled to the Orbitrap Exploris 480 mass spectrometer for the TMT quantitative proteomics analyses of these complex samples in comparison to the analysis of protein extracts from cells, frozen tissue, and exosomes isolated from large volume plasma samples (3 mL). TMT experiments were performed using a two-hour gradient LC-MS/MS with or without FAIMS and two compensation voltages (CV = -45 and CV = -60). In the TMT experiments of cells, frozen tissue, or exosomes isolated from large plasma volumes (3 mL) with FAIMS, a limited increase in the number of identified and quantified proteins accompanied by a decrease in the number of peptides identified and quantified was observed. However, we demonstrated here a noticeable improvement (>100%) in the number of peptide and protein identifications and quantifications for the plasma exosomes isolated from low plasma volumes (250 µL) and FFPE tissue samples in TMT experiments with FAIMS in comparison to the LC-MS/MS analysis without FAIMS. Our results highlight the potential of mass spectrometry analyses with FAIMS to increase the depth into the proteome of complex samples derived from deteriorated, cross-linked samples and/or those where the material was scarce, such as FFPE and plasma-derived exosomes from low plasma volumes (250 µL), which might aid in the characterization of their proteome and proteoforms and in the identification of dysregulated proteins that could be used as biomarkers.

(1) Background: Seed storage mobilization, together with oxidative metabolism, with the ascorbate-glutathione (AsA-GSH) cycle as a crucial signaling and metabolic functional crossroad, is one of the main regulators of the control of cell morphogenesis and division, a fundamental physiological process driving seed germination and seedling growth. This study aims to characterize the cellular changes, composition, and patterns of the protein mobilization and ROS-dependent gene expression of redox metabolism in Lupinus angustifolius L. (narrow-leafed lupin, NLL) cotyledons during seed germination. (2) Methods: We performed gene expression analyses via RT-qPCR for conglutins α (1, 2, and 3), β (1, 2, and 5), γ (1, 2), and δ (2 and 4), including a ubiquitin gene as a control, and for redox metabolism-related genes; GADPH was used as a control gene. A microscopic study was developed on cotyledon samples from different germination stages, including as IMB (imbibition), and 2-5, 7, 9, and 11 DAI (days after imbibition), which were processed for light microscopy. SDS-PAGE and immunocytochemistry assays were performed using an anti-β-conglutin antibody (Agrisera), and an anti-rabbit IgG Daylight 488-conjugated secondary antibody. The controls were made while omitting primary Ab. (3) Results and Discussion: Our results showed that a large amount of seed storage protein (SSP) accumulates in protein bodies (PBs) and mobilizes during germination. Families of conglutins (β and γ) may play important roles as functional and signaling molecules, beyond the storage function, at intermediate steps of the seed germination process. In this regard, metabolic activities are closely associated with the regulation of oxidative homeostasis through AsA-GSH activities (γ-L-Glutamyl-L-cysteine synthetase, NOS, Catalase, Cu/Zn-SOD, GPx, GR, GS, GsT) after the imbibition of NLL mature seeds, metabolism activation, and dormancy breakage, which are key molecular and regulatory signaling pathways with particular importance in morphogenesis and developmental processes. (4) Conclusions: The knowledge generated in this study provides evidence for the functional changes and cellular tightly regulated events occurring in the NLL seed cotyledon, orchestrated by the oxidative-related metabolic machinery involved in seed germination advancement.

Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing has become part of the routine diagnosis. The aim of this study was to establish and compare the MMR status using various approaches. Immunohistochemistry (IHC), PCR-based MSI, and the detection of defects in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) via methylation-specific multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) were performed. MSH3 expression was also evaluated. A set of 126 early-stage EC samples were analyzed, 53.2% of which were dMMR and 46.8% of which were proficient MMR (pMMR) as determined using IHC, whereas 69.3% were classified as microsatellite stable, while 8.8% and 21.9% were classified MSI-low (MSI-L) and MSI-high (MSI-H), respectively. In total, 44.3% of the samples showed genetic or epigenetic alterations in one or more genes; MLH1 promoter methylation was the most common event. Although acceptable concordance was observed, there were overall discrepancies between the three testing approaches, mainly associated with the dMMR group. IHC had a better correlation with MMR genomic status than the MSI status determined using PCR. Further studies are needed to establish solid conclusions regarding the best MMR assessment technique for EC.

Background: Determining the risk of grade 3-5 toxicity and early death (ED) is important to plan chemotherapy in older adult patients with cancer. Our objective was to identify factors predicting these complications at the time of treatment initiation., Methods: 234 patients aged ≥70 were subjected to a geriatric assessment and variables related to the tumor and the treatment were also collected. Logistic regression multivariable analysis was used to relate these factors with the appearance of grade 3-5 toxicity and ED. Predictive scores for both toxicity and ED were then developed., Results: Factors related to grade 3-5 toxicity were hemoglobin, MAX2 index, ADL, and the CONUT score. Factors related to ED were tumor stage and the GNRI score. Two predictive scores were developed using these variables. ROC curves for the prediction of toxicity and ED were 0.71 (95% CI: 0.64-0.78) and 0.73 (95% CI: 0.68-0.79), respectively., Conclusions: Two simple and reliable scores were developed to predict grade 3-5 toxicity and ED in older adult patients with cancer. This may be helpful in treatment planning.

Background: The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic., Methods: We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old., Results: A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%)., Conclusions: EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determined.

Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes., Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors., Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV., Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients., Plain Language Summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Available research suggests that menstrual inequity has an impact on (menstrual) health outcomes and emotional wellbeing. It is also a significant barrier to achieve social and gender equity and compromises human rights and social justice. The aim of this study was to describe menstrual inequities and their associations with sociodemographic factors, among women and people who menstruate (PWM) aged 18-55 in Spain., Methods: A cross-sectional survey-based study was conducted in Spain between March and July 2021. Descriptive statistical analyses and multivariate logistic regression models were performed., Results: A total of 22,823 women and PWM were included in the analyses (Mean age = 33.2, SD = 8.7). Over half of the participants had accessed healthcare services for menstruation (61.9%). The odds for accessing menstrual-related services were significantly higher among participants with university education (aOR: 1.48, 95% CI, 1.13-1.95). Also, 57.8% reported having had partial or no menstrual education pre-menarche, with odds being higher among participants born in non-European or Latin American countries (aOR: 0.58, 95% CI, 0.36-0.93). Lifetime self-reported menstrual poverty was between 22.2-39.9%. Main risk factors for menstrual poverty were identifying as non-binary (aOR: 1.67, 95% CI, 1.32-2.11), being born in non-European or Latin American countries (aOR: 2.74, 95% CI, 1.77-4.24), and not having a permit to reside in Spain (aOR: 4.27, 95% CI, 1.94-9.38). Completed university education (aOR: 0.61, 95% CI, 0.44-0.84) and no financial hardship < 12 months (aOR: 0.06, 95% CI, 0.06-0.07) were protective factors for menstrual poverty. Besides, 75.2% reported having overused menstrual products due to lack of access to adequate menstrual management facilities. Menstrual-related discrimination was reported by 44.5% of the participants. Non-binary participants (aOR: 1.88, 95% CI, 1.52-2.33) and those who did not have a permit to reside in Spain (aOR: 2.11, 95% CI, 1.10-4.03) had higher odds of reporting menstrual-related discrimination. Work and education absenteeism were reported by 20.3% and 62.7% of the participants, respectively., Conclusions: Our study suggests that menstrual inequities affect a high number of women and PWM in Spain, especially those more socioeconomically deprived, vulnerabilised migrant populations and non-binary and trans menstruators. Findings from this study can be valuable to inform future research and menstrual inequity policies., (© 2023. The Author(s).)

Narrow-leafed lupin (NLL; Lupinus angustifolius L.) has multiple nutraceutical properties that may result from unique structural features of β-conglutin proteins, such as the mobile arm at the N-terminal, a structural domain rich in α-helices. A similar domain has not been found in other vicilin proteins of legume species. We used affinity chromatography to purify recombinant complete and truncated (without the mobile arm domain, tβ5 and tβ7) forms of NLL β5 and β7 conglutin proteins. We then used biochemical and molecular biology techniques in ex vivo and in vitro systems to evaluate their anti-inflammatory activity and antioxidant capacity. The complete β5 and β7 conglutin proteins decreased pro-inflammatory mediator levels (e.g., nitric oxide), mRNA expression levels (iNOS, TNFα, IL-1β), and the protein levels of pro-inflammatory cytokine TNF-α, interleukins (IL-1β, IL-2, IL-6, IL-8, IL-12, IL-17, IL-27), and other mediators (INFγ, MOP, S-TNF-R1/-R2, and TWEAK), and exerted a regulatory oxidative balance effect in cells as demonstrated in glutathione, catalase, and superoxide dismutase assays. The truncated tβ5 and tβ7 conglutin proteins did not have these molecular effects. These results suggest that β5 and β7 conglutins have potential as functional food components due to their anti-inflammatory and oxidative cell state regulatory properties, and that the mobile arm of NLL β-conglutin proteins is a key domain in the development of nutraceutical properties, making NLL β5 and β7 excellent innovative candidates as functional foods.

The potential use of agomelatine as an alternative treatment for colorectal cancer is evaluated in this work. The effect of agomelatine was studied in an in vitro model using two cell lines with different p53 statuses (HCT-116, wild-type p53, and HCT-116 p53 null) and an in vivo xenograft model. The inhibitory effects of agomelatine and melatonin were stronger in the cells harboring the wild-type p53, although in both cell lines, the effect of agomelatine was greater than that of the melatonin. In vivo, only agomelatine was able to reduce the volumes of tumors generated by the HCT-116-p53-null cells. Both treatments induced changes in the rhythmicity of the circadian-clock genes in vitro, albeit with some differences. Agomelatine and melatonin regulated the rhythmicity of Per1-3, Cry1, Sirt1, and Prx1 in the HCT-116 cells. In these cells, agomelatine also regulated Bmal1 and Nr1d2, while melatonin changed the rhythmicity of Clock. In the HCT-116-p53-null cells, agomelatine regulated Per1-3, Cry1, Clock, Nr1d2, Sirt1, and Prx1; however, melatonin only induced changes in Clock, Bmal1, and Sirt1. The differences found in the regulation of the clock genes may explain the greater oncostatic effect of agomelatine in CRC.

Competing Interests: Disclosure PS reports personal fees as an invited speaker for the Oxford Advanced Course in Pain and Symptom Management and as a consultant for Nuffield Cancer Centre London; institutional fees as an invited speaker at the Nordic Specialist Course in Palliative Medicine; institutional funding from Marie Curie; non-remunerated roles as project lead for Marie Curie and the National Institute for Health Research United Kingdom (UK) and a member of the Association of Palliative Medicine UK. JF reports personal fees for advisory board expert testimony from Amgen, Baxter, Eisai, Ipsen, Novartis, Organon, Roche and Viatris; research grants from Amgen; and roles as local principal investigator for Bristol-Myers Squibb, Ipsen and Sanofi. DH reports personal fees as Senior Associate Editor of the Journal of Pain and Symptom Management; non-remunerated roles as co-Chair of the American Society of Clinical Oncology (ASCO) Dyspnea Guideline and a member of the board of directors of the Multinational Association of Supportive Care in Cancer (MASCC). BJAL reports personal fees for consultancy to Artelo and an institutional educational grant from Artelo; has received consultancy fees from Nutricia and Kyowa Kirin; non-remunerated roles as a member of the steering committee of the British Thoracic Oncology Group and member of the Cancer Cachexia Society. SM reports non-financial interests as a member of the board of directors of the European Association for Palliative Care (EAPC) and an advisory role with the Guidelines Development Group of the World Health Organization. TM reports personal fees as an invited speaker from Daiichi Sankyo. MN reports personal fees as an invited speaker from Ferrer Farma and Teva; non-financial interests as a member of EAPC and the Sociedad Española de Cuidados Paliativos. CIR reports personal fees as an invited speaker from Angelini, Kyowa Kirin, Molteni and Mundipharma. All other authors have declared no conflicts of interest.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a protein involved in multiple physiological processes. Elevated PARP-1 expression has been found in several tumours, being associated with stemness and tumorigenesis. In colorectal cancer (CRC), some controversy among studies has been described. In this study, we analysed the expression of PARP-1 and cancer stem cell (CSC) markers in CRC patients with different p53 status. In addition, we used an in vitro model to evaluate the influence of PARP-1 in CSC phenotype regarding p53. In CRC patients, PARP-1 expression correlated with the differentiation grade, but this association was only maintained for tumours harbouring wild-type p53. Additionally, in those tumours, PARP-1 and CSC markers were positively correlated. In mutated p53 tumours, no associations were found, but PARP-1 was an independent factor for survival. According to our in vitro model, PARP-1 regulates CSC phenotype depending on p53 status. PARP-1 overexpression in a wild type p53 context increases CSC markers and sphere forming ability. By contrast, those features were reduced in mutated p53 cells. These results could implicate that patients with elevated PARP-1 expression and wild type p53 could benefit from PARP-1 inhibition therapies, meanwhile it could have adverse effects for those carrying mutated p53 tumours.

Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on clinical practice. The purpose of this study is to deepen the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means-consensus cluster layer analyses, was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then sparse k-means-consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Three different layers based on biological features were identified: adhesion, immune, and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, the Wnt signaling pathway, and extracellular functions. Immune-high patients, with higher expression of immune-related genes and genes involved in the viral mimicry response, may benefit from immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful in searching for new therapeutic targets and specific therapeutic strategies in CRC disease.

Breast cancer (BC) is the most widespread tumor in women and the second type of most common cancer worldwide. Despite all the technical and medical advances in existing therapies, between 30 and 50% of patients with BC will develop metastasis, which contributes to the failure of existing treatments. This situation urges the need to find more effective prevention and treatment strategies like the use of plant-based nutraceutical compounds. In this context, we purified three Narrow Leafed Lupin (NLL) β-conglutins isoforms using affinity-chromatography and evaluated their effectiveness in terms of viability, proliferation, apoptosis, stemness properties, and mechanism of action on both BC cell lines and a healthy one. NLL β-conglutins proteins have very promising effects at the molecular level on BC cells at very low concentrations, emerging as a potential natural cytotoxic agent and preserving the viability of healthy cells. These proteins could act through a dual mechanism involving tumorigenic and stemness-related genes such as SIRT1 and FoxO1, depending on the state of p53. More studies must be carried out to completely understand the underlying mechanisms of action of these nutraceutical compounds in BC in vitro and in vivo, and their potential use for the inhibition of other cancer cell types.

GATA4 and GATA6 are transcription factors involved in the differentiation and development of PDAC. GATA6 expression is related to the classic molecular subtype, while its absence is related to the basal-like molecular subtype. The aim was to determine the clinical utility of IHC determination of GATA4 and GATA6 in a series of patients with resected PDAC. GATA4 and GATA6 expression was studied by IHC in TMA samples of normal tissue, PanIN, tumor tissue and lymph node metastases from a series of 89 patients with resected PDAC. Its relationship with clinicopathologic variables and the outcome was investigated. Seventy-two (81%) tumors were GATA6+ and 37 (42%) were GATA4+. While GATA4 expression was reduced during tumor progression, GATA6 expression remained highly conserved, except in lymph node metastases. All patients with early stages and well-differentiated tumors were GATA6+. The absence of GATA4 expression was related to smoking. Patients with GATA4+ or GATA6+ tumors had significantly lower Ca 19.9 levels. The expression of GATA4 and GATA6 was related to DFS, being more favorable in the GATA4+/GATA6+ group. The determination of the expression of GATA4 and GATA6 by IHC is feasible and provides complementary clinical and prognostic information that can help improve the stratification of patients with PDAC.

Background and Aim: Only 10% of pancreatic ductal adenocarcinoma (PDAC) patients survive longer than five years. Factors underlining long-term survivorship in PDAC are not well understood. Therefore, we aimed to identify the key players in the tumor immune microenvironment (TIME) associated with long-term survivorship in PDAC patients., Methods: The immune-related gene expression profiles of resected PDAC tumors of patients who survived and remained recurrence-free of disease for ≥36 months (long-term survivors, n=10) were compared to patients who had survived ≤6 months (short-term survivors, n=10) due to tumor recurrence. Validation was performed by the spatial protein expression profile of immune cells using the GeoMx™ Digital Spatial Profiler. An independent cohort of samples consisting of 12 long-term survivors and 10 short-term survivors, was used for additional validation. The independent validation was performed by combining qualitative immunohistochemistry and quantitative protein expression profiling., Results: B cells were found to be significantly increased in the TIME of long-term survivors by gene expression profiling ( p =0.018). The high tumor infiltration of B cells was confirmed by spatial protein profiling in the discovery and the validation cohorts ( p =0.002 and p =0.01, respectively). The higher number of infiltrated B cells was found mainly in the stromal compartments of PDAC samples and was exclusively found within tumor cells in long-term survivors., Conclusion: This is the first comprehensive study that connects the immune landscape of gene expression profiles and protein spatial infiltration with the survivorship of PDAC patients. We found a higher number and a specific location of B cells in TIME of long-term survivors which emphasizes the importance of B cells and B cell-based therapy for future personalized immunotherapy in PDAC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aziz, Saida, de Koning, Stubbs, Li, Sideras, Palacios, Feliu, Mendiola, van Eijck and Mustafa.)

Background: Available evidence suggests that menstrual health and management have been impaired during the COVID-19 syndemic. However, research in this area is scarce, and it is failing to voice the experiences of women and people who menstruate regarding their menstrual experiences., Objectives: This study aimed to explore the experiences of menstrual health and menstrual management among women and people who menstruate in the Barcelona area (Spain) during the COVID-19 syndemic., Design: This is a qualitative study, conducted taking a critical feminist approach, is embedded in the 'Equity and Menstrual Health in Spain' project., Methods: It includes photo-elicitation individual interviews with 34 women and people who menstruate in the area of Barcelona (Spain). Data were collected in person and through telephone calls between December 2020 and February 2021. Analyses were performed using Thematic Analysis., Results: Main findings navigated through the menstrual changes experienced by some participants, especially women living with long COVID-19, and the barriers to access healthcare and menstrual products during COVID-19. While some participants experienced menstrual poverty, this did not appear to be exacerbated during COVID-19. Instead, access to menstrual products was compromised based on products' availability and mobility restrictions. Menstrual management and self-care were generally easier, given that menstrual experiences were almost exclusively relegated to private spaces during lockdown periods., Conclusions: Our findings highlight the need to further research and policy efforts towards promoting menstrual health and equity, considering social determinants of health, and taking intersectional and gender-based approaches. These strategies should be further encouraged in social and health crises such as the COVID-19 syndemic.

Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKβ8-1 for OS, were shown to be predictive biomarkers for nab -paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC.

Background: The prognosis of patients with stage II and stage III colon cancer is heterogeneous. Clinical and pathological characteristics, such as tumor budding, may help to further refine the recurrence risk. Methods: We included all the patients with localized colon cancer at Hospital Universitario La Paz from October 2016 to October 2021. We built a prognostic score for recurrence in the training cohort based on multivariate cox regression analysis and categorized the patients into two risk groups. Results: A total of 440 patients were included in the training cohort. After a median follow-up of 45 months, 81 (18%) patients had a first tumor recurrence. T4, N2, and high tumor budding remained with a p value <0.05 at the last step of the multivariate cox regression model for time to recurrence (TTR). We assigned 2 points to T4 and 1 point to N2 and high tumor budding. Forty-five percent of the patients were assigned to the low-risk group (score = 0). Compared to the high-risk group (score 1−4), patients in the low-risk group had a significantly longer TTR (hazard ratio for disease recurrence of 0.14 (95%CI: 0.00 to 0.90; p < 0.045)). The results were confirmed in the validation cohort. Conclusions: In our study, we built a simple score to predict tumor recurrence based on T4, N2, and high tumor budding. Patients in the low-risk group, that comprised 44% of the cohort, had an excellent prognosis.

Background: The role of neoadjuvant chemotherapy (NC) in resectable pancreatic cancer (RPC) has yet to be defined. This review aims to analyze the benefit of NC in RPC compared with upfront surgery (US) in terms of overall survival (OS) and disease-free survival (DFS)., Patients and Methods: PubMed, CENTRAL (The Cochrane Library), and Embase were systematically reviewed until 3 November 2021. Abstract proceedings and virtual meeting presentations from the American Society of Clinical Oncology and the European Society of Medical Oncology conferences, reference articles of published clinical trials, and review articles were considered. Only randomized clinical trials (RCTs) comparing NC administration with or without radiotherapy previous with surgery (experimental arm) versus US followed by adjuvant chemotherapy with or without radiotherapy (control arm) for RPC were included., Results: A total of 1135 studies were screened. Of these, 1117 studies were primarily excluded. Of the remaining 18 studies, 5 were excluded because of no adequate trial design for this work and 7 others had no available results. Finally, 6 trials with 469 patients with pancreatic cancer randomized to NC (n = 212) or US (n = 257) were selected. Compared with US, NC significantly improved OS [hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.58-0.98; P = 0.033] and DFS (HR 0.73; 95% CI 0.59-0.89; P = 0.002). While the NC approach was not significantly associated with lower resection rate [relative risk (RR) 0.92; 95% CI 0.84-1.01; P = 0.069], the R0 resection rate was significantly higher for NC than for US (RR 1.31; 95% CI 1.13-1.52; P = 0.0004)., Conclusion: This is the first meta-analysis of RCTs showing that NC improves OS for RPC compared with US followed by adjuvant therapy. Ongoing RCTs should confirm these findings with FOLFIRINOX to generalize the indication of NC., Competing Interests: Disclosure IG reports receiving honoraria or consultation fees from Amgen, Merck Serono, Pierre Fabre, Roche, and Servier, and research funding from Roche. GdV reports receiving grants/research supports from Ipsen, Roche, BMS, honoraria, or consultation fees from Roche, Ipsen, MSD, MERK, BMS, Pfizer, and Bayer; participation in a company-sponsored speaker’s bureau: EUSA Pharma, BMS, MSD, Pfizer, Astellas, and Sanofi; JF reports receiving consulting and advisory honoraria from Amgen, Ipsen, Eisai, Sirtex, Merck, Roche, Novartis, Organon, Viatris, and Baxter; research funding from Merck. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an overall 5-year survival rate of just 5%. A better understanding of the carcinogenesis processes and the mechanisms of the progression of PDAC is mandatory. Fifty-two PDAC patients treated with surgery and adjuvant therapy, with available primary tumors, normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases, were selected for the study. Proteins were extracted from small punches and analyzed by LC-MS/MS using data-independent acquisition. Proteomics data were analyzed using probabilistic graphical models, allowing functional characterization. Comparisons between groups were made using linear mixed models. Three proteomic tumor subtypes were defined. T1 (32% of patients) was related to adhesion, T2 (34%) had metabolic features, and T3 (34%) presented high splicing and nucleoplasm activity. These proteomics subtypes were validated in the PDAC TCGA cohort. Relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. Carcinogenesis in the T1 subtype seems to be related to an increase of adhesion and complement activation node activity, whereas tumor progression seems to be related to nucleoplasm and translation nodes. Regarding the T2 subtype, it seems that metabolism and, especially, mitochondria act as the motor of cancer development. T3 analyses point out that nucleoplasm, mitochondria and metabolism, and extracellular matrix nodes could be involved in T3 tumor carcinogenesis. The identified processes were different among proteomics subtypes, suggesting that the molecular motor of the disease is different in each subtype. These differences can have implications for the development of future tailored therapeutic approaches for each PDAC proteomics subtype.

Transarterial radioembolization (TARE) with yttrium-90 (Y90) is a promising alternative strategy to treat liver tumors and liver metastasis from colorectal cancer (CRC), as it selectively delivers radioactive isotopes to the tumor via the hepatic artery, sparring surrounding liver tissue. The landscape of TARE indications is constantly evolving. This strategy is considered for patients with hepatocellular carcinoma (HCC) with liver-confined disease and preserved liver function in whom neither TACE nor systemic therapy is possible. In patients with liver metastases from CRC, TARE is advised when other chemotherapeutic options have failed. Recent phase III trials have not succeeded to prove benefit in overall survival; however, it has helped to better understand the patients that may benefit from TARE based on subgroup analysis. New strategies and treatment combinations are being investigated in ongoing clinical trials. The aim of this review is to summarize the clinical applications of TARE in patients with gastrointestinal malignancies., (© 2021. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Introduction: Available evidence suggests that there might be an association between the stressors experienced during the COVID-19 syndemic and changes in menstrual patterns. The aim of this study was to assess self-reported menstrual alterations during the COVID-19 syndemic among women and people who menstruate aged 18-55 in Spain., Materials and Methods: A cross-sectional online survey-based study was conducted (March-July 2021). Descriptive statistics were calculated and multivariate logistic regression models were constructed. This study was conducted as part of the "Equity and Menstrual Health in Spain" research project., Results: Among participants (N=17,455), 39.4% reported menstrual alterations since the start of the syndemic. Participants self-reporting long COVID-19 presented higher odds of menstrual alterations (aOR: 1.34, 95% CI, 1.15-1.57). In participants with no history of COVID-19, the risk for self-reported menstrual alterations was significantly higher based on employment situation, among participants experiencing financial issues (eg, financial issues always/many times <12 months: aOR: 1.68, 95% CI, 1.48-1.90), poorer self-perceived health (eg, poor: aOR: 2.00, 95% CI, 1.31-3.07), and those diagnosed with polycystic ovary syndrome (aOR: 1.13, 95% CI, 1.02-1.26). Among participants with a self-reported COVID-19 diagnosis, factors that significantly increased the odds for menstrual alterations were experiencing financial strains (eg, financial issues always/many times <12 months: aOR: 1.53, 95% CI, 1.09-2.14), poorer self-perceived health (eg, poor: aOR: 3.09, 95% CI, 1.01-9.52). Overall, factors that decreased the odds of reporting menstrual alterations included age >25, being a carer, not having a gynecological condition and using hormonal contraception., Discussion and Conclusions: Findings suggest an impact of the COVID-19 syndemic on menstrual patterns. Social inequities in reporting menstrual alterations were identified. While the risk of reporting menstrual alterations was higher among participants with long COVID-19, evidence is not conclusive. Further research on menstrual health in the context of COVID-19 is needed, also to inform policy and practice., Competing Interests: Anna Sofie Holst reports personal fees from World Health Organisation for a project-based consultancy contract working in the Digital Health Flagship in WHO/Europe, outside the commited work. The authors declare no other competing interests in this work., (© 2022 Medina-Perucha et al.)

Background: Menstrual products are necessary goods for women and people who menstruate to manage menstruation. Understanding the use and perceptions of menstrual products is key to promote menstrual equity and menstrual health. This study aimed at assessing the use and perceptions on menstrual products among women and people who menstruate aged 18-55 in Spain., Methods: A mixed-methods study was conducted, including a cross-sectional study (N = 22,823), and a qualitative study (N = 34)., Results: Participants used a combination of products. Non-reusable products were the most used, while over half used reusable products. Usage changed when data were stratified by age, gender identification, completed education, country of birth and experiencing financial issues. It also varied between trans and cis participants. Menstrual products' use also shifted based on experiences of menstrual poverty and access to information and products. Overall, reusable products were perceived to be more acceptable than non-reusable. Barriers to use the menstrual cup were also identified, including experiences of menstrual inequity (e.g., menstrual poverty, lack of access to information or menstrual management facilities)., Conclusion: Perceptions and choices of menstrual products need to be acknowledged, especially when designing and implementing menstrual policies to address menstrual inequity and menstrual health., Competing Interests: The authors have declared that no competing interests exist.

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation., Competing Interests: AG reports honoraria (Clovis, MSD, AstraZeneca, GSK, PharmaMar and Roche) and travel/accommodation/expenses (Merck Sharp and Dohme, PharmaMar, Roche, Eisai, Pfizer, Pierre-Fabre and Tesaro-A GSK Company), outside the submitted work. MM-D is employee and shareholder of PharmaMar S.A. (Madrid, Spain). AR reports honoraria and advisory/consultancy (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, Amgen), research grant/funding to his institution (Eisai, PharmaMar, Roche), travel/accommodation/expenses (AstraZeneca, Tesaro: A GSK Company, PharmaMar, Roche), and speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar), outside the submitted work. MMe reports honoraria (MSD, AstraZeneca and GSK), research grant/funding to her institution (Eisai and PharmaMar), travel/accommodation/expenses (AstraZeneca, GSK, PharmaMar, Roche and Pfizer), outside the submitted work. The authors declare that this study received funding from PharmaMar S.A. (MM-D). The funder had the following involvement with the study: performed immunofluorescence experiments and reviewed draft preparation., (Copyright © 2022 Heredia-Soto, Escudero, Miguel, Ruiz, Gallego, Berjón, Hernández, Martínez-Díez, Zheng, Tang, Hardisson, Feliu, Redondo and Mendiola.)

Introduction: Menstrual health and menstrual inequity have been neglected in social, economic, healthcare and political spheres. Although available evidence is scarce, it already suggests a link between experiencing menstrual inequity (which refers to the systematic disparities in accessing menstrual health and education, menstrual products and spaces for menstrual management, among other aspects) and menstrual health outcomes. The aim of this study was to explore experiences of menstrual health and menstrual inequity among women and people who menstruate aged 18-55 in Barcelona and surrounding areas (Spain)., Methods: A qualitative study, using a critical feminist perspective, was conducted. Sampling was purposeful and selective. Recruitment was through sexual and reproductive health centres, social media and snowball sampling techniques. Thirty-four semi-structured photo-elicitation interviews were conducted between December 2020 and February 2021. Interviews took place in sexual and reproductive health centres, public spaces, and by telephone. Data were analysed using Reflexive Thematic Analysis., Results: Three themes were identified: "Systemic neglect of menstruation and the menstrual cycle", "When "the private" becomes public: menstrual management" and "Navigating menstrual health: between medicalization and agency". Experiences of menstrual inequity appeared to be widespread among participants. They referred to the impact of having to conceal menstruation and the barriers to managing menstruation in public spaces. Choosing menstrual products was often influenced by price and availability; several participants reported menstrual poverty. A general lack of menstrual education was described. Menstrual education was usually gained through personal experience and self-learnings, or through families and friends. Menstruation and the menstrual cycle had a significant impact on participants' day-to-day. Accessing and navigating the healthcare system was challenging, as participants mostly reported feeling dismissed and almost exclusively offered hormonal contraception as a panacea to address menstrual health., Conclusions: The impact of menstrual inequity appears to be far-reaching. Multidimensional structural policies should promote agency in individuals and communities to enable opportunities for menstrual education, access to menstrual products, healthcare services and adequate menstrual-management facilities. Health professionals' training is also necessary to improve access to and quality of menstrual healthcare. Policies need to be inclusive of non-binary and trans people, and vulnerable populations., (© 2022. The Author(s).)

There are three prognostic stratification tools used for endometrial cancer: ESMO-ESGO-ESTRO 2016, ProMisE, and ESGO-ESTRO-ESP 2020. However, these methods are not sufficiently accurate to address prognosis. The aim of this study was to investigate whether the integration of molecular classification and other biomarkers could be used to improve the prognosis stratification in early-stage endometrial cancer. Relapse-free and overall survival of each classifier were analyzed, and the c-index was employed to assess accuracy. Other biomarkers were explored to improve the precision of risk classifiers. We analyzed 293 patients. A comparison between the three classifiers showed an improved accuracy in ESGO-ESTRO-ESP 2020 when RFS was evaluated (c-index = 0.78), although we did not find broad differences between intermediate prognostic groups. Prognosis of these patients was better stratified with the incorporation of CTNNB1 status to the 2020 classifier (c-index 0.81), with statistically significant and clinically relevant differences in 5-year RFS: 93.9% for low risk, 79.1% for intermediate merged group/ CTNNB1 wild type, and 42.7% for high risk (including patients with CTNNB1 mutation). The incorporation of molecular classification in risk stratification resulted in better discriminatory capability, which could be improved even further with the addition of CTNNB1 mutational evaluation.

Patients with endometrial cancer differ in terms of the extent of T-cell infiltration; however, the association between T-cell subpopulations and patient outcomes remains unexplored. We characterized 285 early-stage endometrial carcinoma samples for T-cell infiltrates in a tissue microarray format using multiplex fluorescent immunohistochemistry. The proportion of T cells and their subpopulations were associated with clinicopathological features and relapse-free survival outcomes. CD3+ CD4+ infiltrates were more abundant in the patients with higher grade or non-endometrioid histology. Cytotoxic T cells (CD25+, PD-1+, and PD-L1+) were strongly associated with longer relapse-free survival. Moreover, CD3+ PD-1+ stromal cells were independent of other immune T-cell populations and clinicopathological factors in predicting relapses. Patients with high stromal T-cell fraction of CD3+ PD-1+ cells were associated with a 5-year relapse-free survival rate of 93.7% compared to 79.0% in patients with low CD3+ PD-1+ fraction. Moreover, in patients classically linked to a favorable outcome (such as endometrioid subtype and low-grade tumors), the stromal CD3+ PD-1+ T-cell fraction remained prognostically significant. This study supports that T-cell infiltrates play a significant prognostic role in early-stage endometrial carcinoma. Specifically, CD3+ PD-1+ stromal cells emerge as a promising novel prognostic biomarker., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Objective: Endometriosis greatly impacts women's health and quality of life. However, research on the prevalence and incidence of endometriosis remains inconclusive. This study assesses time trends in the prevalence and incidence of endometriosis diagnoses in Catalonia (Spain) from 2009 to 2018, considering differences by age and socioeconomic status., Methods: Population-based cohort study using data from the Information System for Research in Primary Care (SIDIAP) database. Data were included from over 2.4 million women aged 15-55 years between 1 January 2006 and 31 December 2018., Results: A total of 2,337,717 women were selected as the incident population; 0.7% had an endometriosis diagnosis. Median (interquartile range) age at diagnosis was 37 (32-43) years. Most women were European (92.3%) and lived in urban areas (73.6%). Overall prevalence of endometriosis consistently increased during the 2009-2018 period, and it was 1.24% in 2018. Trends were the highest for women with less socioeconomic deprivation and for the 35-44 years age group. Median incidence rates were 94.9 (92.6-102.9) per 100,000 women-years, being the highest in women aged 35-44 years throughout the whole study period. Overall, incidence increased between 2015 and 2017, and plateaued or decreased in 2018. Incidence rates in women from the most deprived and rural areas were lower, although incidence time trends by socioeconomic status were unclear., Conclusion: Healthcare services and public health strategies need to be strengthened to ensure timely endometriosis diagnosis and treatment. Special attention should be given to the most affected populations and the social inequities of health.

Purpose: Malnutrition is a common problem among pancreatic cancer (PC) patients that negatively impacts on their quality of life (QoL) and clinical outcomes. The main objective of this consensus is to address the role of Medical Nutrition Therapy (MNT) into the comprehensive therapeutic management of PC patients., Methods: A Spanish multidisciplinary group of specialists from the areas of Medical Oncology; Radiation Oncology; Endocrinology and Nutrition; and General Surgery agreed to assess the role of MNT as part of the best therapeutic management of PC patients., Results: The panel established different recommendations focused on nutritional screening and nutritional screening tools, MNT strategies according to PC status, and MNT in palliative treatment., Conclusions: There is an unmet need to integrate nutritional therapy as a crucial part of the multimodal care process in PC patients. Health authorities, health care professionals, cancer patients, and their families should be aware of the relevance of nutritional status and MNT on clinical outcomes and QoL of PC patients., (© 2021. The Author(s).)

Purpose: To identify risk factors for toxicity, unplanned hospitalization (UH) and early death (ED) in older patients with colorectal carcinoma (CRC) initiating chemotherapy., Methods: 215 patients over 70 years were prospectively included. Geriatric assessment was performed before treatment, and tumor and treatment variables were collected. The association between these factors and grade 3-5 toxicity, UH and ED (<6 months) was examined by using multivariable logistic regression. Score points were assigned to each risk factor., Results: During the first 6 months of treatment, 33% of patients developed grade 3-5 toxicity, 31% had UH and 23% died. Risk factors were, for toxicity, instrumental activities of daily living, creatinine clearance, weight loss and MAX2 index; for UH, Charlson Comorbidity Score, creatinine clearance, weight loss, serum albumin, and metastatic disease; and for ED, basic activities in daily living, weight loss, metastatic disease, and hemoglobin levels. Predictive scores were built with these variables. The areas under receiver operation characteristic (ROC) curves for toxicity, UH and ED were 0.70 (95% CI: 0.64-0.766), 0.726 (95% IC: 0.661-0.799) and 0.74 (95% IC: 0.678-0.809), respectively., Conclusion: Simple scores based on geriatric, tumor and laboratory characteristics predict severe toxicity, UH and ED, and may help in treatment planning.

The reasons for the sluggish kinetics of the hydrogen adsorption reaction in alkaline media remain a question still to be solved. This information is important to achieve a complete understanding of the mechanistic details that could lead to the production of key catalytic materials necessary for the development of a future hydrogen economy. For a better understanding of this reaction, it is important to acquire information about the thermodynamic parameters characteristic of the different steps in the reaction. Among these, the hydrogen adsorption is a key step in the process of hydrogen evolution. Although some debate still remains about the difference between adsorbed hydrogen in the underpotential deposition (UPD) region and at the overpotential deposition region, there is no doubt that understanding the former can help in the understanding of the latter. Making use of charge density measurements, we report on this paper a thermodynamic study of the hydrogen UPD process on Pt(111) in 0.05M NaOH over the range of temperatures from 283 ≤ T/K ≤ 313. The coulometric features corresponding to H UPD allow for the calculation of the hydrogen coverage and a fit to a Generalized Frumkin isotherm. From these values, different thermodynamic functions for the UPD reaction have been calculated: ΔG ads , ΔS ads , ΔH ads , and the Pt-H bond energy. From extrapolation, a value of ΔS ads ◦ =-7.5±4Jmol -1 K -1 was found, which is very close to 0, much lower than previously reported measurements both in acid and in alkaline solutions. Such value has an effect on the enthalpy and bond energy calculations, the latter having a decreasing tendency with pH and coverage. This tendency is completely different from the acidic systems and implies that the change in the thermodynamic functions due to the formation of the double layer and the reorganization of interfacial water has a strong influence on the process in high pH solutions.

Background: Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS)., Methods: In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity., Results: Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS., Conclusions: Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research., (© 2021. The Author(s).)

Purpose: Long-term cancer survivors (LTCS) are a vulnerable and continued growing population. To date, only few studies have been conducted in the Spanish population; none of them with a comprehensive analysis of the most common problems identified for cancer survivors in order to improve their care and quality of life., Methods: We conducted an observational descriptive study in 347 patients recruited between January 2015 and December 2016 from our newly created medical office for the specific care and follow-up of LTCS. Variables that describe the medical history were completed by the oncologist and measures on common problems previously reported for LTCS, related to cancer diagnosis and treatment, function, lifestyle, and emotional concerns, were collected from the patient., Results: The mean age of our patients was 65.1 years at the time of the study and a median time without any antitumor treatment of 5.7 years. At the time of cancer diagnosis, 298 patients (85.9%) had at least one related chronic disease and 184 patients (53%) were retired. In addition, in 17.9% of those who continued working, income had been reduced. The incidence of health problems showed an increase during follow-up, even after 5 years, and required evaluation in an emergency department in 157 cases (45.3%). Regardless of age or sex, 239 patients (68.9%) had a significant decrease in sexual activity and 120 (34.6%) were diagnosed with clinical depression., Conclusions: LTCS are patients with significantly high socioeconomic, labor, sexual, health, and psychological problems, 5 years after completion of cancer treatment, especially in older survivors., Implications for Cancer Survivor: Common concerns of LTCS were identified and are consistent across many countries. It is important to realize that even 5 or so years following treatment, both medical and non-medical problems can exist and may need attention by an expert., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

SARS-CoV-2 infection can be a life-threatening disease. The optimal treatment of patients is not yet standardized. We use a serology-based therapeutic strategy based on the presence of antibodies against the SARS-CoV-2 virus, in which patients with positive serology receive aggressive anti-inflammatory treatment with high-dose dexamethasone and/or tocilizumab and patients with negative serology receive early convalescent plasma therapy. We also analyze the immunological impact of this therapy in the recovery of T cells, B cells and NK cells during hospitalization in a COVID-19 infectious ward. Our results suggest that aggressive therapy with early administration of convalescent plasma and high-dose dexamethasone may be of benefit in patients with SARS-CoV-2 infection and might avoid progression of lung damage or need of admission in intensive care. This strategy did not impair immune responses against SARS-CoV-2, as 93% of the patients generated antibodies against the virus. Independently of previous immunological status of the patients, serology-guided therapy might benefit even patients with a high CIRS-G score, immunosuppressed or medically debilitated individuals and elderly patients. T cell disturbances were most frequent in patients who required high-dose dexamethasone, and B cell depletion was most frequent in patients who received tocilizumab. Early passive immunotherapy with convalescent plasma does not affect lymphoid recovery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with high lethality. Even with surgery, radiotherapy, chemotherapy, and other locoregional or systemic therapies, the survival rates for PDAC are low and have not significantly changed in the past decades. The special characteristics of the PDAC's microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease. PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells. The pancreatic microenvironment is a fibrotic, microvascularized stroma that isolates the tumor from systemic vascularization. Immunotherapy, a novel approach that has demonstrated effectiveness in certain solid tumors, has failed to show any practice-changing results in pancreatic cancer, with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden, which show prolonged survival rates with immunotherapy. Currently, numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell transfer, alone or in combination with other immunotherapeutic agents, chemoradiotherapy, and other targeted therapies. A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interest for this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC., Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability., Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen., Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease., (©2021 American Association for Cancer Research.)