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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.).

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]

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.

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.

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]

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 [...]

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, [...]

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: Heart rate variability (HRV) is a parameter useful in monitoring post stroke cardiac dysautonomia. Our study is aimed at investigating HRV modifications in patients with stroke; (2) Methods: We investigated HRV parameters in 35 men and 35 women with stroke, data compared to 70 age and sex similar healthy subjects. We collected and interpreted HRV data related to resting state, deep breathing, and standing situations; (3) Results: The variables identified by classification methods to be discriminative in stroke groups for men and women classes are VLFms2, LFms2, LFnu, HFnu, and ApEn in resting state conditions, mean RR, HR, pNN50, VLFms2, LFnu, HFnu, ApEn and SampEn in deep breathing conditions, and mean RR, HR, HFnu, ApEn, and DFA1 in standing conditions; (4) Conclusions: Monitoring of HRV in patients who have suffered an ischemic stroke is essential, as it is known that stoke contributes to an increased risk of cardiac autonomic dysfunction and consequently to a second unwanted vascular event. [ABSTRACT FROM AUTHOR]

Heart rate variability (HRV) is a simple way to explore autonomic nervous activity. Current studies emphasize the need to identify a dependent relationship between smoking habit and HRV. The findings of these studies could demonstrate that smoking can have both an acute and a chronic effect on HRV. The aim of this study is to investigate the relationship between smoking and anthropometric data such as body weight, body fat distribution and heart rate variability. Our study involves measuring HRV parameters at rest and during two tests that are part of the Ewing test battery. Through the obtained data we can demonstrate that active smoking is associated with a reduction in HRV. At the same time, we can state that HRV is affected by different behavior patterns of the smoker.complex individualized rehabilitation treatment. [ABSTRACT FROM AUTHOR]

Background: Correlations of Transcranial magnetic stimulation (TMS) mapping of the cortical area and electromyography (EMG) + dynamometric testing may demonstrate active neuroplasticity events that are reliant on rehabilitation therapy (RT) compliance in adult postsurgical brachial plexus (BP) injuries. Material and Methods: On the right (dominant) arm of two patients with chronic operated BP lesions, we evaluated the progress of functional recovery. The traumatic event was dated more than 10 years ago for both patients. The first patient (male, 50 years old) and the second one (female, 58 years old) had a history of several microsurgical neurotiza-tion and muscle transfer procedures, with less amelioration of the motor deficit, especially re-lated to elbow flexion (MRC 1/5 and 2/5, respectively). We followed up their evolution by EMG parameters, dynamometry, MRC scaling, and TMS. The motor region of the limb was mapped using TMS to assess the amplitudes of the motor evoked potentials (MEP), on a 4-axis protocol. The patients were assessed twice, with the second examination performed after RT had just fin-ished. TMS findings were compared with EMG and dynamometric results. Results: Higher MEP amplitudes were associated with improved MEP latency during stimulation of the left cerebral hemisphere's cortical area, as well as at the cervical level. EMG findings, both nerve conduction and needle EMG studies showed nonsignificant improvements, as well as muscle strength (as measured by the hydraulic dynamometer). The best results for the first patient showed an in-crease in MEP's amplitude increase from 1.08 mV to 1.49 mV (in the hotspot), which correlated with measurable latencies, as compared to the first TMS (when no response was obtained at cer-vical stimulation). The second patient also had improvements in latencies: from 37.1 msec. to 36.3 msec. (cervical stimulation with recording at bicipital level) and from 39.2 msec. to 37.9 (cervical stimulation recording at the first interosseous), with a hotspot increase from 1.35 mV to 1.98 mV. The results demonstrate cortical region reactivity in regard to therapeutic techniques. Central modifications do not correlate with visible EMG and dynamometric improvements. Pa-tients with traumatic BP palsy may receive several microsurgical reconstructive procedures, nevertheless, the rehabilitation of the upper limb's functionality may sometimes still be limited. This increases the risk of discontinuity of the neuromotor RT. We aim to prove that in spite of little correlations with clinical and EMG findings, mapping the cortical area using TMS provides proof of ongoing neuroplasticity phenomena, dependent on adherence to RT. Conclusion: The evidence of continued brain activity supports the requirement for long-term adherence to treatment guidelines and long-term study protocols. [ABSTRACT FROM AUTHOR]

Background and Objectives: objective measures of disability and neurological impairmentare used to search for disease activity and monitor disease evolution in multiple sclerosis (MS). These are sometimes in disagreement with subjective quality-of-life measures. We aimed to establish the relations between the Multiple Sclerosis Quality of Life instrument (MSQOL-54) and objective measures of neurological impairment. Materials and Methods: 107 patients with MS were evaluated with the Single Digit Modalities Test (SDMT) for cognition, Nine Holes Peg Test (9HPT) for upper limb function, 25 Feet Walk Test (25FWT) for gait, and EDSS for global disability in a cohort study. Age and education level were recorded as sociodemographic factors. Results: the median EDSS was 3.5 (IQR 2.5); average SDMT score was 30.38 ± 13.54; and 9HPT speed was significantly higher for the dominant upper limb (0.3 ± 0.1 pegs/s versus 0.28 ± 0.11 pegs/s) (p = 0.016). The mental health composite score of the MSQOL-54 correlated with the SDMT, education level, and EDSS. Education level correlated with cognition and quality of life. The physical health composite score of the MSQOL-54 correlated with motor-function parameters and with SDMT. The motor-function parameters correlated well among themselves. A linear regression model found an important influence of SDMT and education level on the mental health composite score of the MSQOL-54. Although the linear regression model predicting the physical health composite score from physical disability parameters was statistically sound, none of the determinants had a significant individual influence. Conclusions: the subscores of the MSQOL-54 correlated well with the objective parameters. The strongest correlations were those with the cognitive function. Correlations with physical disability were less powerful, probably reflecting their indirect and more limited influence on quality of life compared to cognition and perception of disability. [ABSTRACT FROM AUTHOR]

Known as the degenerative disease of the knee with the highest prevalence, knee osteoarthritis (KOA) is characterized by a gradual destructive mechanism that, in severe cases, can provoke the need for total knee substitution. As the disease progresses, various enzymatic, immunological, and inflammatory processes abnormally degrade hyaluronic acid (HA), SF's main component, and affect the concentrations of specific proteins, with the final results seriously endangering synovial fluid (SF)'s rheological and tribological features and characteristics. No effective treatments have been found to stop the progression of KOA, but the injection of HA-based viscoelastic gels has been considered (alone or combined with physiotherapy (PT)) as an alternative to symptomatic therapies. In order to evaluate the effect of viscosupplementation and PT on the characteristics of SF, SF aspirated from groups treated for KOA (HA Kombihylan® and groups that received Kombihylan® and complex PT) was analyzed and compared from analytical, spectrophotometrical, and rheological perspectives. In the patients treated with PT, the SF extracted 6 weeks after viscosupplementation had a superior elastic modulus (G′) and viscous moduli (G″), as well as a homogeneous distribution of proteins and polysaccharides. The viscosupplementation fluid improved the bioadhesive properties of the SF, and the use of the viscosupplementation fluid in conjunction with PT was found to be favorable for the distribution of macromolecules and phospholipids, contributing to the lubrication process and the treatment of OA-affected joints. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (KOA) is a disease of wear and tear, leading to disability and ultimate surgical treatment. KOA has multiple etiologies and is considered a disorder of physiological processes that is manifested by progressive lesions of articular cartilage caused by chondrolysis, synovial membrane inflammation and subchondral osteophytes production. Modalities that limit the progression of the KOA and rehabilitation are a constant interest for clinicians and medical researchers. Various physical therapies and pharmacological strategies are currently used for pain management, with no clear benefit in terms of inhibiting disease progression. In this context, the use of exogenous hyaluronic acid (HA) (that is a vital component of the synovial fluid and involved in lubricating all synovial joints) has been explored as viable alternative to alleviate knee pain and temporarily restore knee function. In the following, we will review the use of HA injections associated with the physiotherapeutic recovery plan in the treatment of KOA. The therapeutic effects of the HA is still a matter of debate in the field, with no consensus being reached so far and thus, difficult to evaluate. However, much research has to be done to understand the therapeutic efficacy of HA alone or in combination with physical therapies and the role that other factors may play in unraveling its beneficial effects on the KOA.