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IntroductionChemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein.MethodsQOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale.ResultsAt the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change.ConclusionsPROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials.Trial registrationNCT00942357.

Following a period of slow progress, the completion of genome sequencing and the paradigm shift relative to the cell of origin for high grade serous ovarian cancer (HGSOC) led to a new perspective on the biology and therapeutic solutions for this deadly cancer. Experimental models were revisited to address old questions, and improved tools were generated. Additional pathways emerging as drivers of ovarian tumorigenesis and key dependencies for therapeutic targeting, in particular, VEGF-driven angiogenesis and homologous recombination deficiency, were discovered. Molecular profiling of histological subtypes of ovarian cancer defined distinct genetic events for each entity, enabling the first attempts toward personalized treatment. Armed with this knowledge, HGSOC treatment was revised to include new agents. Among them, PARP inhibitors (PARPis) were shown to induce unprecedented improvement in clinical benefit for selected subsets of patients. Research on mechanisms of resistance to PARPis is beginning to discover vulnerabilities and point to new treatment possibilities. This Review highlights these advances, the remaining challenges, and unsolved problems in the field., Epidemiology, risk factors, and histological subtypes Over the past 10 years, we have made progress in understanding the biology of and improving the therapeutic options for ovarian cancer (OC), a [...]

BACKGROUND: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. METHODS: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. RESULTS: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. CONCLUSIONS: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).

(1) Background: Cirrhosis is associated with frequent alterations in standard coagulation tests that do not adequately reflect hemostasis. Thromboelastography provides a global assessment of coagulation and evaluates the functional status of clotting factors, fibrinogen, platelets, and fibrinolysis. The study aimed to assess whether liver disease severity leads to progressive alterations in the thromboelastography-based assessment of coagulation. (2) Methods: Consecutive patients with cirrhosis and abnormal standard coagulation tests (at least one of International Normalized Ratio > 2, platelet count < 50 × 103/µL, fibrinogen < 200 mg/dL) were analyzed using native thromboelastography. (3) Results: A total of 106 patients were included, of whom 69 (65.1%) had a normal thromboelastography. While the standard coagulation tests were significantly worse in patients in the Child C group (n = 62, 58.5%) than in patients staged in Child A and B, no significant differences existed between any of the thromboelastography variables. Of the 50 patients (47.1%) with an International Normalized Ratio > 2, only two patients (4%) had features of hypocoagulation, while 26% had features of hypercoagulability on thromboelastography. Patients with a platelet count < 50 × 103/µL had significantly lower platelet function as assessed by thromboelastography, yet only eight patients (20%) met the criteria for platelet transfusion. A thromboelastography-based transfusion protocol might lead to a 94.6% reduction in blood product transfusion indications in a simulation where the included patients would require interventional procedures. (4) Conclusion: Standard coagulation tests showed a poor correlation with thromboelastography. Based on thromboelastography, patients with severe, decompensated liver disease have a preserved hemostasis balance despite abnormal standard coagulation tests. Therefore, standard coagulation tests should not be used to guide the administration of blood products in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Fibromyalgia (FM) affects up to 5% of the global population and is a leading cause of significant social and economic consequences. Higher health literacy leads to better understanding of treatment plans, improved self-care, and adherence to recommendations, enhancing overall quality of life. This study aims to determine whether different aspects of the disease are influenced by patients' education level and literacy when applying the same therapy and to assess how patients' perceptions of therapy outcomes vary over time based on their educational level. Methods: This study involved 140 fibromyalgia (FM) patients diagnosed using the 2016 ACR criteria, with 128 completing the study. Participants attended three visits over 28 weeks and were stratified into four groups based on educational level: Group 1—secondary school or less; Group 2—high school graduates; Group 3—college graduates; Group 4—university graduates. Patients were assigned to groups (n = 32, 32, 30, and 34, respectively) after the initial evaluation (T0). The treatment was assessed (T1) and followed up three months later (T2) to evaluate changes in functional status and quality of life. All patients underwent the same rehabilitation program, cognitive therapy, and kinesiotherapy. Results: Significant differences in disease impact on the patient's life (FIQ total score) were observed between groups from the initial evaluation (p = 0.000). The overall FIQ score was notably affected by non-pharmacological therapy in patients with higher education. These differences continued to be significant even three months after the treatment ended (p = 0.000). Functional limitations were evident from the start (p = 0.000) and improved significantly post-treatment in patients with higher education (p = 0.000). However, subjective evaluations of disease impact (assessed by the first item of FIQ) did not consistently align with objective findings (hand grip strength). Functional limitations did not significantly differ in subjective evaluations (F1Q1) across educational levels (p = 0.045), and inverse correlations were noted between functional status and SF-12 well-being components. Conclusions: This study underscores that higher education enhances fibromyalgia management and functional outcomes, particularly when combined with non-pharmacological therapies. However, subjective perceptions may not always align with objective improvements, indicating that factors beyond education, such as personal and external influences, also impact disease management. Thus, improving health literacy through educational interventions could further benefit FM patients' quality of life. [ABSTRACT FROM AUTHOR]

Introduction: The diseases number with a known inflammatory etiology is constantly increasing. Cardiovascular and neurodegenerative diseases, osteoporosis, cancer, asthma, atherosclerosis, type 2 diabetes and obesity are associated with chronic low-grade inflammation. There is evidence that individuals who engage in intense physical activity or who exercise regularly, shows changes in biomarkers associated with chronic inflammation. Physical exercise is useful in preventing many diseases, due to improved cardiorespiratory, metabolic, musculoskeletal function. All these improve the immunity and antioxidant capacity, thus reducing the incidence of acute and chronic inflammatory diseases. Materials and Methods: In this study were included 90 bibliographic sources, of which the title contains the following keywords: exercise - 23, inflammation - 27, anti-inflammatory - 6, IL-6 - 13, IL-10 - 4, myokine - 3, IL-15 - 3, irisin - 6, obesity - 11, chronic inflammation - 7. This study discussed aspects of exercise, pro- and anti-inflammatory cytokines, immunological mechanisms, the dual role of IL-6 cytokine, and the anti-inflammatory effects of physical exercise. Results: Physical exercise is an efficient clinical tool, that limits chronic inflammation activating the immune system that will increase the level of anti-inflammatory IL-6 myokine. There is a direct relationship between the volume and intensity of exercise and the amount of IL-6 myokine in the blood stream. Conclusions: These studies contribute significantly to the understanding of the mechanisms of the anti-inflammatory effect of exercise. More studies on chronic low-grade inflammatory diseases are needed to understand their pathophysiology, and that will inspire the specialists improve long-term treatment strategies.

The main objective of the research consists in providing evidence that a long-term rehabilitation protocol is favorable for the patient. In adult brachial plexus (BP) palsies, after several surgical attempts, the lack of results in the upper limb's functionality leads to less compliance to rehabilitation therapy. The upper limb's functionality of 22 patients with posttraumatic operated chronic BP paresis (either on the right or left, regardless the dominant limb) was assessed retrospectively. The patients were evaluated regarding MRC scaling, dynamometric tests and electroneuromyographic examination. All patients have gone through at least one rehabilitation interval (10 days) after an initial evaluation, and were evaluated again, by same methods, at a second session, at least 6 months later, but no more than one year. Mild and inconstant improvements were obtained in a total of 9 patients, especially in better dynamometric results and improved amplitudes of motor and sensory action potentials. The electrodiagnosis correlates with dynamometric parameters (muscle strength) and slight amelioration of the motor deficit. Given the small sample size as a limitation, as well as no standardized therapeutic protocol, it should be noted that the 9 patients were the only ones who either attended more than one interval or did more procedures as frequency in time (more often meaning 3 times weekly for 6 months, in 6 patients). Although the most frequent procedures were neuromuscular electrical stimulation (NMES) and proprioceptive neuromuscular facilitation (PNF), the results suggest that regardless of the techniques, the more active patients had better results. Proving the need for long-term rehabilitation, even contrary to the less visible results, can be the trigger point for future research and therapy strategies, as the results suggest central mechanisms involved, adding the cortical ongoing plasticity into the equation. [ABSTRACT FROM AUTHOR]

Significant gaps remain in the understanding of the etiology and pathogenesis of fibromyalgia (FM), and the COVID-19 pandemic has introduced even more unknowns. Social factors specific to that period, the viral infection itself, and/or vaccination are additional elements that can complicate the progression of the disease or the response to treatment. Aim: The primary hypothesis to be evaluated in this study is that an acute COVID-19 infection, even when considered recovered, may induce changes in the response to non-pharmacological treatment in FM patients, particularly concerning pain. Results: We included 128 patients diagnosed with FM before the pandemic began. The patients were divided based on their history of acute SARS-CoV-2 infection and COVID-19 vaccination status. All patients followed the same rehabilitation program (cognitive therapy, kinesitherapy). Perceived pain: The non-COVID-19 patient groups showed a statistically significant reduction in pain at the final evaluation compared to patients with a history of acute SARS-CoV-2 infection (p < 0.001). Algometric evaluation: Patients without COVID-19 infection and that were vaccinated exhibited the best improvement in pain threshold, both across evaluation times (p < 0.001) and compared to any of the other three groups studied (p < 0.001). Using the WHYMPI questionnaire, the same group of patients (those not having experienced acute COVID-19 and who were vaccinated) was the only group with a statistically significant improvement in pain severity (p = 0.009). In conclusion, to control and improve FM pain symptoms, in addition to appropriate medication, we propose paying additional attention to the history of acute SARS-CoV-2 infection and the COVID-19 vaccination status. [ABSTRACT FROM AUTHOR]

Nesfatin-1, deriving from a precursor protein, NUCB2, is a newly discovered molecule with anti-apoptotic, anti-inflammatory, antioxidant, and anorexigenic effects. It was initially identified in the central nervous system (CNS) and received increasing interest due to its energy-regulating properties. However, research showed that nesfatin-1 is also expressed in peripheral tissues, including the digestive system. The aim of this review is to give a résumé of the present state of knowledge regarding its structure, immunolocalization, and potential implications in diseases with inflammatory components. The main objective was to focus on its clinical importance as a diagnostic biomarker and potential therapeutic molecule in a variety of disorders, among which digestive disorders were of particular interest. Previous studies have shown that nesfatin-1 regulates the balance between pro- and antioxidant agents, which makes nesfatin-1 a promising therapeutic agent. Further in-depth research regarding the underlying mechanisms of action is needed for a better understanding of its effects. [ABSTRACT FROM AUTHOR]

Diabetic Neuropathy (DN) is a complication that affects at least half of the patients with Diabetes Mellitus. Unlike other symptoms and signs that may sooner alarm the patients, DN manifestations tend to be rather silent, and so usually neglected by the patient for a long period of time, which can last for years. Therefore it’s a “hidden complication of diabetes” label. Unfortunately, it is only when symptoms already affect the quality of life that the treatment becomes challenging when it comes to speaking of either etiological, symptomatic or rehabilitation strategies. Early diagnosis can also be tricky while aiming for lifestyle corrections and proper individualized treatment strategies. Rehabilitation methods for DN aim especially towards the improvement of articulation mobility and muscular strength amelioration, the suggested brief review of literature promoting this part of therapy essential for both prevention and amelioration of overall morbidity.

Limb-girdle muscular dystrophy (LGMD) is a burdensome progressive neuromuscular disease, with a great impact upon quality of life. Unlike other types of neuromuscular dystrophies, which have onset in early childhood and severely limit the life expectancy, LGMD is usually diagnosed at young adulthood age. Since no etiological treatment is currently available, physiotherapy and generally, rehabilitation therapy, are mandatory for preserving the functional capabilities of the muscles for as long as possible. Exercise therapy, electrical stimulation or novel therapies such as exoskeleton devices aim towards alleviating the impact of disability. It is ideal that muscular dystrophy should be assessed in interdisciplinary clinics (physical therapy, neurology, cardiology, pneumology, surgery and orthopedics) for proper long-term care.

BACKGROUND. Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study. METHODS. Eligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/[m.sup.2]) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment. RESULTS. Among 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory [CD4.sup.+] T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of [CD8.sup.+] T cells and [CD20.sup.+] B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR. CONCLUSION. Epigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC. TRIAL REGISTRATION. ClinicalTrials.gov NCT02901899. FUNDING. US Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553., Introduction Strategies targeting immune checkpoints have significantly altered the clinical outcomes of various malignancies and completely altered the standard-of-care approach (1). Ovarian cancer (OC) stands out as one of the [...]

ObjectiveTo determine the role of miR-378 as a biomarker for anti-angiogenic therapy response in ovarian cancer.MethodsExpression of miR-378 was analyzed in ovarian cancer cell lines and human tumors vs. normal ovarian epithelial cells by qRT-PCR. After miR-378 transfection in SKOV3 cells, dysregulated genes were identified using microarray. Data from The Cancer Genome Atlas (TCGA) was utilized to correlate miR-378 expression with progression-free survival (PFS) among patients treated with anti-angiogenic therapy by using Kaplan-Meier and Cox proportional hazards.ResultsMiR-378 was overexpressed in ovarian cancer cells and tumors vs. normal ovarian epithelial cells. Overexpressing miR-378 in ovarian cancer cells altered expression of genes associated with angiogenesis (ALCAM, EHD1, ELK3, TLN1), apoptosis (RPN2, HIPK3), and cell cycle regulation (SWAP-70, LSM14A, RDX). In the TCGA dataset, low vs. high miR-378 expression was associated with longer PFS in a subset of patients with recurrent ovarian cancer treated with bevacizumab (9.2 vs. 4.2months; p=0.04). On multivariate analysis, miR-378 expression was an independent predictor for PFS after anti-angiogenic treatment (HR=2.04, 95% CI: 1.12-3.72; p=0.02). Furthermore, expression levels of two miR-378 targets (ALCAM and EHD1) were associated with PFS in this subgroup of patients who received anti-angiogenic therapy (9.4 vs. 4.2months, p=0.04 for high vs. low ALCAM; 7.9 vs. 2.3months, p

Background. The perspective of ongoing electric signals within the motor cortex, conditioned by continuous rehabilitation strategies (doubled by adherence to the treatment protocol), is of interest related to understanding how cerebral plasticity is being modulated in adult traumatic brachial plexus (BP) lesions. Very often, patients with chronic BP lesions tend to be less compliant to rehabilitation therapy over time, since multiple reconstructive microsurgery interventions may not always offer a proper upper limb functionality, especially in severe, complex BP cases. Material and methods. In order to asses the ongoing psychomotric projection of the limb's representation among the motor cortex, in relation with long term rehabilitation protocol we followed up a group of 11 chronic patients, by transcranial magnetic stimulation (TMS) during a time-lapse of two years. Results. Although modest in relation with amelioration of the deficit on the MRC scale, the patients had mild improvements of the parameter latency, but more important, by assessing the amplitude of the motor evoked potential (MEP), we observed a dynamism of the motor area. This we consider suggestive for ongoing psychomotor components stimulated by rehabilitation: ideomotricity, perceptual-motor coordination, laterality and body representation, as a foundation in maintaining a proven measurable potential of continuous neuroplasticity. Conclusion. From clinical perspective, since psychomotricity actually means interdisciplinarity, this is the common denominator found in the collaboration between medical specialties: plastic surgery and reconstructive microsurgery, clinical neurology, electrodiagnostic and neuromotor rehabilitation. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) exerts a cortical modulating effect through its diffuse projections, especially involving cerebral structures related to autonomic regulation. The influence of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients is still debated. We aimed to evaluate the impact of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients, after three months of neurostimulation, using the heart rate variability (HRV) analysis.

Understanding the regulatory programs enabling cancer stem cells (CSCs) to self- renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1[alpha] (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1[alpha] transcription. At the molecular level, FOXK2-driven upregulation of IRE1[alpha] led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs., Introduction Cancer stem cells (CSCs) represent a small fraction of cells within tumors with self-renewal, differentiation, and tumor-initiation capacity (TIC). CSCs express high levels of stemness-associated transcription factors (TFs) SOX2, [...]

Studies show that the autonomic nervous system (ANS) has an important impact on health in general. In response to environmental demands, homeostatic processes are often compromised, therefore determining an increase in the sympathetic nervous system (SNS)’s functions and a decrease in the parasympathetic nervous system (PNS)’s functions. In modern societies, chronic stress associated with an unhealthy lifestyle contributes to ANS dysfunction. In this review, we provide a brief introduction to the ANS network, its connections to the HPA axis and its stress responses and give an overview of the critical implications of ANS in health and disease—focused specifically on the immune system, cardiovascular, oxidative stress and metabolic dysregulation. The hypothalamic–pituitary–adrenal axis (HPA), the SNS and more recently the PNS have been identified as regulating the immune system. The HPA axis and PNS have anti-inflammatory effects and the SNS has been shown to have both pro- and anti-inflammatory effects. The positive impact of physical exercise (PE) is well known and has been studied by many researchers, but its negative impact has been less studied. Depending on the type, duration and individual characteristics of the person doing the exercise (age, gender, disease status, etc.), PE can be considered a physiological stressor. The negative impact of PE seems to be connected with the oxidative stress induced by effort.