The Dejour classification for trochlear dysplasia shows slight interobserver and substantial intraobserver reliability.

PURPOSE: Trochlear dysplasia is one of the main risk factors for recurrent patellar dislocation. The Dejour classification identifies four categories that can be used to classify trochlear dysplasia. The purpose of this study is to evaluate the inter- and intraobserver reliability of the Dejour classification for trochlear dysplasia. The hypothesis was that both intra- and interobserver reliability would be at least moderate. METHODS: This is a cross-sectional, reliability study. Twenty-eight examiners from the International Patellofemoral Study Group 2022 meeting evaluated lateral radiographs of the knee and axial magnetic resonance images from 15 cases of patellofemoral instability with trochlear dysplasia. They classified each case according to Dejour's classification for trochlear dysplasia (A-D). There were three rounds: one with only computed radiograph (CR), one with only magnetic resonance imaging (MRI) and one with both. Inter- and intraobserver reliability were calculated using κ coefficient (0-1). RESULTS: The mean age of patients was: 14.6 years; 60% were female and 53% had open physis. The interobserver reliability κ probabilities were 0.2 (CR), 0.13 (MRI) and 0.12 (CR and MRI). The intraobserver reliability κ probabilities were 0.45 (CR), 0.44 (MRI) and 0.65 (CR and MRI). CONCLUSION: The Dejour classification for trochlear dysplasia has slight interobserver reliability and substantial intraobserver reliability. LEVEL OF EVIDENCE: Level I.

Prospective study of predictors for anxiety, depression, and somatization in a sample of 1807 cancer patients.

In cancer patients, psychological distress, which encompasses anxiety, depression, and somatization, arises from the complex interplay of emotional and behavioral reactions to the diagnosis and treatment, significantly influencing their functionality and quality of life. The aim was to investigate factors associated with psychological distress in cancer patients. This prospective and multicenter study, conducted by the Spanish Society of Medical Oncology (SEOM), included two cohorts of patients with cancer (localized resected or advanced unresectable). They completed surveys assessing psychological distress (BSI-18) before and after cancer treatment and coping (MINI-MAC) and spirituality (FACIT-sp) prior to therapy. A multivariable logistic regression analysis and a Structural Equation Modeling (SEM) were conducted. Between 2019 and 2022, 1807 patients were evaluated, mostly women (54%), average age 64 years. The most frequent cancers were colorectal (30%), breast (25%) and lung (18%). Men had lower levels of anxiety and depression (OR 0.66, 95% CI 0.52-0.84; OR 0.72, 95% CI 0.56-0.93). Colorectal cancer patients experienced less anxiety (OR 0.63, 95% CI 0.43-0.92), depression (OR 0.55, 95% CI 0.37-0.81), and somatization (OR 0.59, 95% CI 0.42-0.83). Patients with localized cancer and spiritual beliefs had reduced psychological distress, whereas those with anxious preoccupation had higher level. SEM revealed a relationship between psychological distress and coping strategies, emphasizing how baseline anxious preoccupation exacerbates post-treatment distress. This study suggests that age, sex, extension and location of cancer, coping and spirituality influence psychological distress in cancer patients.

Prevalence and Distribution of MUTYH Pathogenic Variants, Is There a Relation with an Increased Risk of Breast Cancer?

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.

Evaluation of Immune Infiltrates in Ovarian Endometriosis and Endometriosis-Associated Ovarian Cancer: Relationship with Histological and Clinical Features.

BACKGROUND: the association between ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC) is extensively documented, and misfunction of the immune system might be involved. The primary objective of this study was to identify and compare the spatial distribution of tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) in OE and EAOC. Secondary objectives included the analysis of the relationship between immunosuppressive populations and T-cell exhaustion markers in both groups. METHODS: TILs (CD3, CD4, and CD8) and macrophages (CD163) were assessed by immunochemistry. Exhaustion markers (PD-1, TIM3, CD39, and FOXP3) and their relationship with tumour-associated macrophages (CD163) were assessed by immunofluorescence on paraffin-embedded samples from n = 43 OE and n = 54 EAOC patients. RESULTS: we observed a predominantly intraepithelial CD3+ distribution in OE but both an intraepithelial and stromal pattern in EAOC (p < 0.001). TILs were more abundant in OE (p < 0.001), but higher TILs significantly correlated with a longer overall survival and disease-free survival in EAOC (p < 0.05). CD39 and FOXP3 significantly correlated with each other and CD163 (p < 0.05) at the epithelial level in moderate/intense CD4 EAOC, whereas in moderate/intense CD8+, PD-1+ and TIM3+ significantly correlated (p = 0.009). Finally, T-cell exhaustion markers FOXP3-CD39 were decreased and PD-1-TIM3 were significantly increased in EAOC (p < 0.05). CONCLUSIONS: the dysregulation of TILs, TAMs, and T-cell exhaustion might play a role in the malignization of OE to EAOC.

Efficacy of second and third lines of treatment in advanced soft tissue sarcomas: a real-world study.

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.

The Scarface Score: Deciphering Response to DNA Damage Agents in High-Grade Serous Ovarian Cancer-A GEICO Study.

Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87-159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p < 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC.

Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme.

AIM: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. PATIENTS AND METHODS: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. RESULTS: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. CONCLUSION: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. GOV REGISTRATION: NCT04546373.

Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study.

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.

Comparative Effects of Neuromuscular- and Strength-Training Protocols on Pathomechanical, Sensory-Perceptual, and Motor-Behavioral Impairments in Patients with Chronic Ankle Instability: Randomized Controlled Trial.

(1) Background: Chronic ankle instability (CAI) is a complex condition that includes limited mobility, perceived instability, and recurrent ankle sprains are common characteristics that reduce the quality of life in subjects who suffer from CAI. Neuromuscular training and strength training have been recommended in CAI management interventions. However, there are contradictory findings on results when comparing neuromuscular training, strength training, and the control group. The objective of this study was to compare the effectiveness of 8 weeks of neuromuscular intervention training, strength training, and no intervention in a sporting population with reported CAI. (2) Methods: Sixty-seven athletes with CAI were randomly assigned to a neuromuscular training group (NG), strength training group (SG), or control group (CG). Participants completed 8 weeks of neuromuscular training (a combination of static and dynamic exercises), strength training (resistance band exercises), or no training. Outcome measures were assessed at baseline and after 8 weeks and included selfs-reported instability feeling (CAIT), dynamic balance (SEBT), ankle dorsiflexion range of motion (WBLT), and functional status (FAAM and FAAM-SPORT). (3) Results: There were significant differences between strength and control groups in the posteromedial direction of SEBT, FAAM, and FAAM-SPORT after 8 weeks of intervention. (4) Conclusions: Neuromuscular training and strength training based on resistance bands exercises showed significant improvements in ankle dorsiflexion, subjective feeling of instability, functional status, and dynamic balance in patients with CAI.

Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network.

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

Prognostic markers of inflammation in endometrioid and clear cell ovarian cancer.

OBJECTIVES: Cancer-related systemic inflammation has been associated with prognosis in multiple cancer types. Conversely, local inflammation, which is characterized by dense intratumoral immune infiltrates, is a favorable predictor of survival outcome. However, these survival associations are not well established in ovarian cancer, particularly in the less frequent endometrioid and clear cell endometriosis associated histotypes. METHODS: This retrospective study included 119 patients (63 endometrioid and 56 clear cell ovarian carcinomas). We performed a comprehensive survival association analysis of both systemic (neutrophil-to-lymphocyte ratio or presence of endometriosis) and local inflammation markers (CD3+ and CD8+ tumor infiltrating lymphocytes) using multivariate Cox proportional hazards models that account for confounding factors. RESULTS: Medium to high levels of intraepithelial CD8+ tumor infiltrating lymphocytes are associated with longer survival in endometrioid ovarian cancer (p=0.04). In addition, we found that intraepithelial CD8+ tumor infiltrating lymphocytes are prognostic in clear cell ovarian cancer (p=0.02), and that intraepithelial CD3+ tumor infiltrating lymphocytes are also associated with improved outcome (p=0.02). Furthermore, intratumoral CD3+ and CD8+ tumor infiltrating lymphocytes showed improved prognosis in the endometrioid subtype (p<0.1). No prognostic value was observed for systemic immune markers. CONCLUSIONS: In this study, patients with endometrioid and clear cell ovarian cancer with moderate to high CD8+ and CD3+ intraepithelial tumor infiltrating lymphocytes had longer overall survival. Higher expression of intratumoral CD3+ and CD8+ tumor infiltrating lymphocytes also showed an improved outcome in endometrioid ovarian cancer. In contrast, systemic inflammation, evaluated by neutrophil-to-lymphocyte ratio or presence of endometriosis, did not have a prognostic impact in these histologic subtypes.

Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models.

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.

Dostarlimab for the treatment of advanced endometrial cancer.

INTRODUCTION: Between 20% and 30% of the endometrial cancers (EC) are associated with a deficiency of a mismatch repair (MMRd) protein or high microsatellite instability (MSI-H), characteristics that render the tumor more sensitive to immune checkpoint inhibitors. There is no standard treatment for advanced EC after progression to a platinum-containing regimen. AREAS COVERED: The phase I GARNET clinical trial assessed the safety, tolerability, and antitumor activity of anti-PD1 dostarlimab in patients with advanced solid tumors. The A1 cohort of this trial enrolled patients with MMRd or MSI-H recurrent or advanced EC who had previously received a platinum-containing regimen. The results of this cohort showed significant clinical activity, durable responses, and a favorable safety profile, without reducing quality of life. Based on these data, dostarlimab achieved accelerated approval. EXPERT OPINION: Although a randomized study has not yet been conducted, dostarlimab monotherapy should be the treatment of choice for patients with advanced MMRd EC in progression after a platinum-containing regimen. Selecting patients with EC for immune checkpoint inhibitors using the MMRd predictive biomarker could facilitate more efficient and sustainable health systems and avoid the use of more toxic combinations, leading to personalized medicine.

Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

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.

Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study.

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1-5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0-5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3-4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.

Prognostic implications of tumor-infiltrating T cells in early-stage endometrial cancer.

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.

Effects of global postural reeducation on postural control, dynamic balance, and ankle range of motion in patients with hallux abducto valgus. A randomized controlled trial.

Hallux abducto valgus (HAV) is a common musculoskeletal disorder that has been addressed surgically. Nevertheless, the manual therapy approach may play an important role in the management of this condition. The present study aimed to determine the effectiveness of global postural reeducation (GPR) in subjects with symptomatic mild to moderate HAV in static postural control, dynamic stability, and ankle dorsiflexion range of motion (DFROM). A total of 80 patients with mild to moderate symptomatic HAV were allocated to the intervention group (GPR) or control group (CG) (no treatment) for 8 weeks. Outcome measures were assessed at baseline at 4 and 8 weeks including static postural control (Romberg test), dynamic balance (Star Excursion Balance Test [SEBT]), and ankle DFROM (Weight-Bearing Lunge Test [WBLT]). No improvements were observed at 4 weeks, but there were improvements at 8 weeks in: static postural control mediolateral displacement (X) of center of pressure (CoP) in both eyes open (EO) and eyes closed (EC): XEO (t(36) = 2.892, p = .006, d = 0.67); XEC (t(68) = 2.280, p = .026, d = 054); and velocity (V) of CoP displacement: VEO (t(68) = 2.380, p = .020, d = 0.57); VEC (t(36) = 2.057, p = .047, d = 0.37). It were also improvements in: WBLT (t(36) = -2.869, p = .007, d = 0.54) and SEBT at three directions (anterior, ANT; posteromedial, PM; and posterolateral, PL): SEBT.ANT (t(36) = -2.292, p = .028, d = 0.23); SEBT.PM (t(36) = -4.075, p < .001, d = 0.43); SEBT.PL (t(62) = -3.506, p = .001, d = 0.34). The present study showed that GPR compared to the CG might be effective in enhancing ankle function including postural control, dynamic balance, and DFROM.

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

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.

Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma.

Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumours.