Standard Therapy Research Articles

Clinical Effectiveness of Biological Immunomodulators in SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children: A Systematic Review.

Although there is consensus to use immunoglobulins and corticosteroids as first-line treatments for multisystem inflammatory syndrome in children (MIS-C), the effectiveness of biological immunomodulators in patients refractory to standard therapy remains unclear. We aimed to outline real-world data on biological immunomodulators. A literature search using Ovid-Medline, EMBASE, Cochrane CDSR, and KMBASE was conducted from September 2021 to August 2022; certainty of evidence was assessed via GRADE. Among 258 studies, 10 were selected for analysis, of which 2 were observational studies (with control groups receiving standard therapy of either intravenous immunoglobulins and/or glucocorticoids) and 8 were single-arm studies. In all, 145 patients were treated with biological immunomodulators (anakinra (72; 49%) or infliximab (65; 44%)). In the first observational study, patients in the anakinra group initially exhibited a lower left ventricular ejection fraction than those in the control group. In the second study, patients in the infliximab group required less additional therapy and showed lower newly developed left ventricular dysfunction rate and reduced C-reactive protein levels. The clinical outcomes associated with each biological agent in single-arm studies were not reported individually. Biological immunomodulators are feasible therapeutic options for refractory MIS-C. Nevertheless, further research is warranted to demonstrate clinical efficacy.

Response to induction chemotherapy modifies the effect of conventional prognostic factors in high-risk neuroblastoma: A report from the Children’s Oncology Group

BackgroundResponse to induction chemotherapy has been shown to predict outcome in patients with high-risk neuroblastoma (HR-NB), with those achieving a complete response (CR) having superior outcomes. MethodsWe evaluated whether conventional prognostic factors remain prognostic in subsets of patients defined by response to induction. 1244 Patients from four COG high-risk trials were included. End-induction response was coded as CR, partial response (PR) or better, less than PR without progressive disease (PD), and PD. Cox regression models were performed to calculate event-free and overall survival (EFS, OS) hazard ratios, including interaction terms between induction response and prognostic factors including sex, age, stage, primary tumor location, LDH, ferritin, ploidy, MYCN status, ALK status, histology, MKI, grade, and study era. ResultsAmong patients who achieved a CR after induction, INSS stage 4 disease and trial era were the only factors that remained significantly associated with inferior OS. For those who achieved less than a PR, adrenal primary site, MYCN amplification, and 1p LOH were associated with inferior outcomes. Multivariable models showed that end-induction response remained prognostic of EFS and OS even after controlling for other factors. Multiple significant statistical interactions were observed between end-induction response and other prognostic factors. ConclusionThe impact of conventional prognostic factors is not static in patients with HR-NB. Instead, response to induction chemotherapy modifies the effect of conventional prognostic factors. These data can help to further refine prognosis for patients with variable responses to induction and help to identify candidates who might benefit from treatment other than standard post-induction therapy.

Cognitive training and physical therapy for fibromyalgia : Results of the KogTraP pilot study

The effectiveness of additive cognitive training in groups to the standard physical-medical therapy for primary and secondary fibromyalgia syndrome (p/sFMS) and asubsequent home-based self-training phase (STP) was analyzed. In the prospective controlled randomized study, 32people with confirmed p/sFMS were included, whereby 4patients could not be evaluated. During 2weeks of acute inpatient therapy, the control group (CG; n = 12) received standard physical-medical therapy and the intervention group (IG, n = 16) also received social-communicative cognitive group training (once/day, 60 min). In thesubsequent 3‑months, STP training was continued by both groups. Outcome parameters at baseline (U1), at discharge (U2), and after a quarteryear (U3) were pain, well-being/depressive mood, general health, and cognitive parameters (memory functions, cognitive speed). Both groups showed significant pain relief (U2 vs. U1), which was 10% more in the IG. Asignificant improvement in mood could be seen in both groups, but only the IG no longer achieved depressive values in the follow-up (U3). An improvement in the general state of health was also detected in both groups, which was only maintained in the IG until the end of the STP. Cognitive performance remained the same in the IG at U2, while there was areduction in the CG; cognitive speed could only be further improved in the IG during the STP. Adding cognitive training to astandard physical-medical clinical therapy resulted in significant pain relief and improvement of depression in patients during ahospital stay.

Lenvatinib for the Treatment of Hepatocellular Carcinoma After Liver Transplant

What Is the Issue? Liver transplant is 1 of the main curative therapies for liver cancer; however, hepatocellular carcinoma (HCC) recurrence presents in 10% to 20% of patients after liver transplant. Lenvatinib, an oral multikinase inhibitor drug, was approved for use in Canada as a first-line standard therapy for unresectable HCC, based on a pivotal trial that excluded patients who underwent a prior liver transplant. Data were scarce on the efficacy and safety of lenvatinib for treatment of HCC recurrence in patients who received a liver transplant, and were limited to a few case series and case reports. What Did We Do? We identified and summarized the literature on the evidence of the clinical effectiveness and safety of lenvatinib for the first-line treatment of patients with unresectable HCC recurrence after liver transplant. We searched key resources, including journal citation databases and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? We identified a multinational, multicentre, retrospective, single-arm chart review study evaluating the efficacy and safety of lenvatinib in patients with HCC recurrence after liver transplant. Lenvatinib was primarily used as a first-line treatment for most patients (n = 42; 93.3%) and as a second-line treatment for 3 patients (6.7%). The single-arm chart review study showed lenvatinib treatment had an overall response rate (ORR) of 20.0%, a median overall survival of 14.5 months, and a median progression-free survival (PFS) of 7.6 months. These findings were similar to those randomized to lenvatinib in the pivotal phase III REFLECT trial, which excluded patients who had a prior liver transplant. What Does This Mean? The findings of this report suggest that lenvatinib has a potential role as a first-line treatment of patients with HCC recurrence after liver transplant. As the current evidence is limited to a retrospective single-arm chart review study, which had several limitations (e.g., lack of sample size calculation, noncomparative, and retrospective design), further investigations are needed to establish the clinical efficacy and safety of lenvatinib as a first-line treatment for unresectable HCC recurrence after liver transplant.

Clinical and immunological efficacy of complex therapy for bronchial asthma in children with the inclusion of components of far eastern brown algae

Classical basic therapy for asthma is aimed at stopping inflammation, primarily atopic, and has achieved significant positive results in the treatment of the disease, which has led to a decrease in the severity of asthma. The proportion of patients in whom asthma control is achieved does not exceed 30%; complete control is achieved in 5%, that is associated with the influence non-atopic factors on the pathogenesis of BA, leading to the search for additional methods of correction. Despite the identified biological, immunomodulatory properties of the components of brown algae, the mechanisms of their action, in asthma, are not sufficiently illuminated, which became the purpose of this study: to determine the possible immunomodulatory effect of a functional food product in children with asthma based on brown algae (Far Eastern kelp) and its use in addition to standard therapy to improve control of the course of this disease. Children with asthma (n = 56) aged from 5 to 17 years were comprehensively examined and divided into 2 groups: those who received a functional food product in addition to standard therapy (n = 20) and those who received only standard therapy (n = 36). Laboratory tests included CBC, immunogram, cytokines (IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL-18, TNFá), blood ICC MPM, and herpesvirus DNA. Against the background of complex treatment, changes in the interleukin profile (IL-6, IL-10, IL-18) were noted, characteristic of a decrease in the intensity of inflammatory processes, including nonspecific ones, expressed in a tendency towards a decrease in the total number of lymphocytes, an increase in the immunoregulatory index both due to an increase in the number of T helper cells and and reduction of killer T cells. This was confirmed by a decrease in monocytes and ESR. Improved energy supply of immunocompetent blood cells (granulocytes and monocytes), a decrease in the number of patients with active replication of EBV and herpes virus type 6 indicate its immunomodulatory effect. The result of these changes was the positive clinical dynamics of asthma control indicators, which allows us to recommend the inclusion of a functional food product based on Far Eastern brown algae in addition to standard therapy for children with asthma aged 5-17 years.

An inhalable nanoparticle enabling virulence factor elimination and antibiotics delivery for pneumococcal pneumonia therapy

Streptococcus pneumoniae (S. pneumoniae) is a major cause of community-acquired pneumonia. Current standard clinical therapies mainly focus on combating S. pneumoniae through antibiotics. However, the limited delivery of antibiotics and the undetoxified hydrogen peroxide (H2O2) virulence factor secreted by S. pneumoniae impede the therapeutic outcomes. Here we report an inhalable catalase (CAT)-tannic acid (TA) nanoassembly for local antibiotic (levofloxacin) delivery and simultaneously neutralizing the secreted H2O2 virulence factors to treat pneumococcal pneumonia. After aerosol inhalation, the inhalable formulation (denoted as CT@LVX) effectively accumulates in lung tissues through TA-mediated mucoadhesion. CAT can reduce alveolar epithelial cells apoptosis by catalyzing the decomposition of accumulated H2O2 in the infected lung tissues. In synergy with antibiotic LVX-mediated S. pneumoniae elimination, CT@LVX significantly decreases lung injury companied with reduced inflammatory, resulting in 100 % survival of mice with pneumonia. In a clinically isolated S. pneumoniae strain-induced pneumonia mouse model, CT@LVX also shows superior outcomes compared to the traditional antibiotic treatment, highlighting its potential clinical application prospects.

5-Fluorouracil metabolic pathway genes predict recurrence risk following adjuvant S-1 therapy: Results of an ancillary analysis from a phase III trial of resected biliary tract cancer (JCOG1202A1).

S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy for resected biliary tract cancer (BTC), based on the results of the JCOG1202, a phase III trial evaluating the survival benefit with adjuvant S-1 following curative resection for BTC compared to surgery alone. This multicenter ancillary study of the JCOG1202 aimed to evaluate the prognostic impact of the 5-fluorouracil (5-FU) metabolic pathway genes including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). The 5-FU metabolic pathway genes were measured in tumor cells from formalin-fixed paraffin-embedded resected specimens from 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89). We randomly divided them into training (n = 96) and validation sets (n = 87) for evaluating the interaction between gene levels and RFS benefits in the treatment arm. RFS benefits of adjuvant S-1 were observed in the low DPD (HR = 0.440 and 0.748, respectively in the training and validation sets) and the low TP groups (HR = 0.709 and 0.602, respectively). Clinicopathological characteristics were well balanced between low and high DPD populations. More advanced stage tumors were observed in high TP populations as compared to those in low TP populations (p = .0332). The results suggest the RFS benefit of adjuvant S-1 in resected BTC patients with low DPD and low TP gene expressions.

An Approach to Development and In-vivo Evaluation of Beta Sitosterol Phytosomes by Taguchi Orthogonal Array Design.

The research mainly focused on developing and optimizing beta-sitosterol phytosomes through a systematic Taguchi orthogonal array design and assessment of their performance in both beta-sitosterol phytosomes. The fabrication of phytosomes containing β-sitosterol was carried out using the rotary evaporation technique. An orthogonal array design was employed in the study to precisely optimize the phytosomes. In this two responses and three independent variables were analyzed. The data was analyzed by using statistical modeling. Characterization of these phytosomes involves Fourier transform infrared spectroscopy, entrapment efficiency, differential scanning calorimetry compatibility study, zeta potential and particle size. Based on the findings, an optimized phytsome formulation was developed to achieve the best results. The results indicated that beta-sitosterol phytosomes responses are significant. It effectively reduced body weight as well as levels of total cholesterol (126.120 ± 0.98 mg/dl), triglycerides (104.23 ± 2.8 mg/dl), HDL (39.31 ± 0.45 mg/dl), VLDL (21.67 ± 0.34 mg/dl), and LDL (76.43 ± 0.34 mg/dl) in rats compared to the other groups. The orthogonal array design study observed that the anti-hyperlipidemic activity of β-sitosterol was nearly as potent as that achieved with standard drug therapy.

High dose cotrimoxazole treatment in patients with severe COVID-19: A randomised controlled trial

Background: Cotrimoxazole for severe COVID-19 may have a better prognosis because of its antibacterial, immunomodulatory, and anti-inflammatory activities. We examined the efficacy of high-dose cotrimoxazole therapy in terms of duration of hospital stays and reduction in mortality in severe COVID-19 infections. Methods: From May to November 2021, we conducted a double blind randomised controlled trial with two parallel groups in the COVID units of Bangabandhu Sheikh Mujib Medical University and Anwar Khan Modern Medical College Hospital, Dhaka. One group received standard therapy in addition to an oral dose of 960 mg of cotrimoxazole twice daily for 7 days (intervention group), while the other group received standard treatment and a placebo (standard group). Pre-protocol analysis was done. Results: A total of 188 patients were enrolled, but 166 completed the study. Of them, 93 were in the intervention group and 73 were in standard group. The mean ages of the groups were similar (intervention, 56.2 and standard, 59.2 years) (P=0.10). The mortality at 28 days between groups was also similar (11.8% in the intervention group and 15.0% in the standard group) (P=0.56). The hospital stay was 13.7 days for the intervention group and 13.5 days for the standard group (P=0.86). However, the reduction in C-reactive protein was statistically significant in the intervention group, with a mean decline of 23.6 mg/L (95% confidence interval, 0.5–46.7 mg/L). Conclusion: High-dose cotrimoxazole did not benefit in shortening in-hospital stay or reducing mortality at day 28 in patients with severe COVID-19. However, the decline in the C-reactive protein level was significant, necessitating further research.

Transformative Impact of Islamic Spiritual Care (ISC) Enriched with Murottal: Alleviating Anxiety and Depression among Coronary Heart Disease Patients through Pre- and Post-Intervention Analysis

Background:Spiritual care is a vital component of comprehensive nursing, especially for patients in palliative care, such as those with coronary heart disease. While pharmacological and medical interventions remain the primary approach for heart-related conditions, the substantial success rate observed with spiritual therapy incorporating Murottal recitations highlights its significant impact on improving patients' quality of life, particularly in managing anxiety and depression. Objective:This study aimed to assess the differences in anxiety and depression scores among cardiovascular patients diagnosed with coronary heart disease before and after the application of Islamic spiritual care interventions using Murottal, in both intervention and control groups. Method:Using a quasi-experimental pretest-posttest design with a control group, the study involved a population of 156 coronary heart disease patients undergoing treatment. Simple random sampling produced a sample size of 110 patients at Muhammadiyah Hospital in Palembang, South Sumatra, Indonesia. Respondents were divided into two groups of 55 participants each. The intervention group received spiritual care through Murottal, while the control group received standard hospital therapy. Levels of anxiety and depression were measured using the Depression Anxiety Stress Scale (DASS). Results:The Wilcoxon test results for anxiety and depression variables in the intervention group showed a p-value of <0.005, indicating a significant difference in anxiety and depression scores before and after receiving the spiritual care intervention with Murottal. Conclusion:Islamic spiritual care (ISC) services incorporating Murottal recitations have the potential to reduce anxiety and depression among coronary heart disease patients at Muhammadiyah Hospital in Palembang, South Sumatra, Indonesia. Keywords: Anxiety, Coronary Heart Disease, Depression, Murottal, Spiritual Care, Patient.

Laser Photocoagulation Treatment for Candida Chorioretinitis.

The purpose of this article is to describe the novel surgical technique utilizing laser photocoagulation for the management of Candida chorioretinal lesions that are refractory to medical therapy. This report presents the use of laser photocoagulation applied to a Candida chorioretinal lesion that was refractory to extensive systemic and intravitreal antifungal medications. The presenting lesion was in an immunosuppressed patient. Argon laser photocoagulation was applied onto and surrounding the Candida chorioretinal lesion. Following laser photocoagulation, the Candida chorioretinal lesion has remained resolved for over one year with no further reactivation, extensions, or satellites. Candida chorioretinitis can be extremely therapeutically resistant. Current treatment involves systemic and intravitreal antifungals. There are currently limited options for chorioretinal lesions refractory to standard medical therapy. The authors report the novel application of laser photocoagulation as a potential treatment option in refractory cases of Candida chorioretinitis.

Efficacy of early use of Percutaneous Stellate Ganglion Block for electrical storms.

Electrical Storm (ES) is a life-threatening condition requiring a rapid management. Percutaneous Stellate Ganglion Block (PSGB) proved to be safe and effective on top of standard therapy, but no data are available about its early use. We considered all patients enrolled from 1st July 2017 to 30th April 2024 in the STAR registry (STellate ganglion block for Arrhythmic stoRm), a multicentre, international, observational, prospective registry. We aimed to assess the effectiveness of the first PSGB only. Patients were divided into two groups depending on whether they received PSGB before (Early-PSGB, often due to AAD contraindication) or after (Delayed-PSGB) intravenous antiarrhythmic drugs (AADs other than beta-blockers). We considered 180 PSGB (26 Early-PSGB and 154 AAD-first). In the early-PSGB group we observed a statistically significant reduction of treated arrhythmic events in the hour after PSGB compared to the hour before: 0 (0-0) vs 4.5 (1-10), p<0.001 and the extent of the reduction was similar in the Early-PSGB and delayed-PSGB group [-4.5 (-7 to -2) vs. -2.5 (-3.5 to -1.5), p=ns]. The percentage of patients free from arrhythmias was similar in the two groups up to 12 hours after PSGB (81%vs 84%, p=0.6 after one hour; 77% vs 79%, p=0.8 at three hours and 65% vs 69%, p= 0.7 after 12 hours). PSGB proved to be effective also when used early in the treatment of ES. Due to its rapidity of action, our results may suggest its early use to reduce the number of defibrillations and possibly to reduce the likelihood of a refractory ES.

The Impact of Antidepressants on COVID-19 and Post-Acute COVID-19 Syndrome: A Scoping-Review Update

On May 20, 2024, this systematic scoping review in PUBMED identified 1016 articles related to AD and COVID-19, Long COVID and SARS-COV-2. These included 10 retrospective "large scale" studies (> 20000 chart reviews), 8 prospective clinical trials (plus 4 regarding Long COVID), 11 placebo-controlled randomized (RCT) (plus 2 regarding Long COVID) and 15 meta-analyses. COVID-19: Retrospective studies with cohorts taking AD primarily for psychiatric comorbidities or chronic pain conditions directly prior to SARS-COV-2 infection described that this substance class (most studied: Selective Serotonin Re-Uptake Inhibitors (SSRI) and Selective Serotonin Noradrenaline Re-Uptake Inhibitors (SSNRI)) were associated with (i) significantly fewer SARS-COV-2 infections and (ii) a milder course of COVID-19 ("COVID-19 protection"). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared suitable as a prophylactic agent against severe COVID-19, taking into account its in vitro potency against the progression of intracellular sepsis cascades. Therefore, most (12 out of 15) meta-analyses also referred to fluvoxamine. They found (iii) a significant (40-70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. When this AD was used in the early stages of the disease, it was more successful than when it was given later in advanced, severe COVID-19 (e.g. severe pneumonia, final sepsis stages). A dose dependency was observed: 2x50 mg fluvoxamine over 15 days was less effective than 2x100 or even 3x100 mg with an adverse event profile still at the placebo level. Direct comparisons with drugs approved for COVID-19 do not yet exist. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: risk reduction of 95% (I2 = N/A, but only one study) or 78% (I2=0) versus 5+-5% (I2=48). However, an add-on of fluvoxamine was still significantly more efficacious than symptom-oriented standard therapy alone. Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds to AD, relaxation therapy and/or psychotherapy, has now been identified. Casuistics report positive effects of AD on fatigue, cognitive and autonomic dysfunctions. A first large prospective open-label RCT has just shown significantly more favourable courses, less viral load and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary Long COVID or fatigue. Overall, there is promising evidence of a preventive effect of AD (especially fluvoxamine) against progression to severe COVID-19 and against the development of Long COVID. It is likely, that the entire AD substance class could be effective here. This assumption is based on the results of retrospective large scale studies, but awaits verification by better controlled studies. The potential effectiveness/efficacy (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of fluvoxamine as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to pose a lasting threat to the health of those affected. We consider the evidence to date to be sufficient to be able to emphasize a possible positive effect of these substances in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other conditions - especially also against the symptoms associated with the viral disease or its consequences. In regions where neither vaccines nor antiviral agents currently approved for the prevention or treatment of COVID-19 are available, AD and in particular fluvoxamine would be a cost-effective alternative to protect against a severe course, even if this AD appears to have a smaller effect against COVID-19 than the currently approved antiviral agents, but with presumably better tolerability. A direct comparative clinical trial with approved antiviral agents is still pending and should be positive to further open the door for a guideline-based recommendation of fluvoxamine (or perhaps even AD) for COVID-19 or its aftermath.

Treatment opportunities for refractory immune thrombocytopenia

Background. Primary immune thrombocytopenia (ITP) is an orphan disease characterized by decreased platelet count in the peripheral blood which in some cases can cause bleeding of varying severity. Currently, the use of thrombopoietin receptor agonists (TPO-RAs) is recommended as the second line therapy for ITP as it allows to achieve high platelet response (PR), including complete, in 73 % of cases of chronic ITP and in 87 % of cases of newly diagnosed disease. The mechanism of action differs for different TPO-RAs. Given this fact, in cases of resistance or intolerance to therapy with one TPO-RA, attempts are made to switch to another. The effectiveness of this approach for overcoming ITP resistance varies from 50 to 93 % according to various publications. Aim. To assess the ability to achieve and maintain PR by switching from one TPO-RA to another in cases of resistance to the previous TPO-RA used in the second or subsequent lines of therapy. Materials and methods. The analysis included 59 patients who were resistant (in 2 cases intolerance was also noted) to TPO-RA therapy (received after standard therapy) who were prescribed TPO-RA treatment with a different mechanism of action: switch from romiplostim to eltrombopag (25 patients) or vice versa (34 patients). Both groups were comparable in terms of demographic characteristics and median platelet level at the time of TPO-RA switching. Results. PR was obtained in 76 % of cases, including complete response in 54 %, as a result of switching from one TPO-RA to another in 59 patients. Among 34 patients switched from eltrombopag to romiplostim, PR was achieved in 31 (91 %) patients, including complete response in 22 (65 %). Romiplostim was switched to eltrombopag in 25 patients, PR was achieved in 14 (56 %) with complete response in 10 (40 %). Conclusion. The study showed that PR can be achieved and maintained through switching from one TPO-RA to an alternative.

Synchronous Head and Neck Squamous Cell Carcinoma and Hematologic Malignancies

Synchronous occurrence of solid tumors and hematological malignancy is a rare condition. There is no standard management or therapy for this complicated situation. The authors systematically reviewed articles searched using online databases. The patients are predominantly male, and the average age is similar to each malignancy. According to these studies, most patients are treated in order of aggressiveness. However, when a patient has multiple primary malignancies, all of which are aggressive, the treatment decision is challenging. Due to the limited number of cases, it is hard to have a firm conclusion about an optimal treatment policy. It appears that poor outcomes are mostly related to less adequate therapy. Because the condition is complicated in such cases and there is no standardized treatment, patients should be treated on an individual basis with treatments customized to a given patient’s particular circumstances. In addition, multidisciplinary communication and cooperation are crucial in the management of these patients. More in-depth research is still needed to reach a more conclusive treatment strategy and predictable outcomes.

Identification of Immune-Related Gene Pair Signature to Predict Prognosis of Diffuse Large B-Cell Lymphoma Based on Bioinformatics Analyses

Since over one-third of DLBCL patients experience relapse or refractory after standard therapy, high-risk patients must be predicted. We developed a prognostic immune-related gene pairs (IRGPs) signature for DLBCL patients using bioinformatics analyses. This signature can predict the prognosis of these patients adequately, either alone or in combination with other clinical parameters. It hopes to improve the stratification and management of these patients for broad clinical applications.

Vorasidenib- A Paradigm Shift in IDH1- or IDH2-Mutant Low-Grade Glioma Treatment.

Low-grade gliomas (LGGs) pose significant challenges in cancer research and treatment due to their infiltrative nature and tendency for recurrence, making them the most common brain tumour in adults. Most of the LGGs have the propensity to cause notable alterations in the microenvironment of the tumour thus making them difficult to treat. These alterations can be attributed to the prevalent mutations in the genes that produce isocitrate dehydrogenase (IDH) enzymes, especially in grade 2 diffuse gliomas. [1] Despite its inability to provide a complete cure, chemoradiation has been adopted as the standard therapy in grade 3 gliomas since it can lead to long-lasting remission. Chemoradiotherapy, when administered promptly, can help prevent tumour progression, and recurrence after surgery and improve long-term outcomes. Nevertheless, immediate adjuvant chemoradiotherapy is not administered in patients afflicted with tumours containing IDH mutant grade 2 gliomas. This decision is often made to circumvent potential harm such as radiation-induced cognitive problems, chemotherapy-related DNA mutations, and other negative effects on their health. [2] Due to the intricacies associated with the treatment decisions and the inclination to delay aggressive therapies to avoid adverse events, creates a necessity for a novel therapeutic strategy that is both effective and well tolerated. Vorasidenib, an oral medication specifically designed to deal with IDH mutations has displayed promise despite existing challenges. By aiming to specifically target aberrant metabolic pathways triggered by mutant IDH enzymes, Vorasidenib offers a potential treatment capable of interrupting tumour growth and could subsequently result in better patient outcomes. Among the many reasons that make Vorasadenib an appealing option are its capability to penetrate the blood-brain barrier and its promising safety profile, resulting in effective treatment while alleviating potential side effects. [3] Vorasidenib’s efficacy is derived from its ability to halt the metabolic cascades driven by mutant IDH enzymes thus leading to decreased progression of the gliomas. Clinical studies elicit the substantial value Vorasadenib has to offer by enhancing progression-free survival and postponing the advancement of the illness in patients with grade 2 IDH-mutant gliomas. This offers an optimistic prospect for delaying the need for more aggressive treatments in these patients. [2,4] Hence, to conclude Vorasadenib can transform treatment norms and enhance outcomes for those suffering from IDH-mutant LGG. Furthermore, it is crucial to investigate different treatment combinations, finding markers that would help assess clinical response to treatment, which in turn would be an important milestone in the treatment journey.

Cyanocobalamin-loaded dissolving microneedles diminish skin inflammation in vivo

Inflammatory diseases of the skin have a considerable high prevalence worldwide and negatively impact the patients' quality of life. First-line standard therapies for these conditions inherently entail important side effects when used long-term, particularly complicating the management of chronic cases. Therefore, there is a need to develop novel therapeutic strategies to offer reliable alternative treatments. Abnormally high reactive oxygen species (ROS) levels are characteristic of this kind of illnesses, and therefore a reasonable therapeutic goal. Cyanocobalamin, also known as Vitamin B12, possesses notable antioxidant and ROS-scavenging properties which could make it a possible therapeutic alternative. However, its considerable molecular weight restricts passive diffusion through the skin and forces the use of an advanced transdermal delivery system. Here, we present several prototypes of Cyanocobalamin-loaded Dissolving Microarray Patches (B12@DMAPs) with adequate mechanical properties to effectively penetrate the stratum corneum barrier, allowing drug deposition into the skin structure. Ex vivo penetration and permeability studies noted an effective drug presence within the dermal skin layers; in vitro compatibility studies in representative cell skin cell lines such as L929 fibroblasts and HaCaT keratinocytes ensured their safe use. The in vivo efficacy of the selected prototype was tested in a delayed-type hypersensitivity murine model that mimics an inflammatory skin process. Several findings such as a reduction of MPO-related photon emission in a bioluminescence study, protection against histological damage, and decrease of inflammatory cytokines levels point out the effectivity of B12@DMAPs to downregulate the skin inflammatory environment. Overall, B12@DMAPs offer a cost-effective translational alternative for improving patients' skin healthcare.

The effect of local injections of a vitamin d receptor activator into the parathyroid glands on the level of parathyroid hormone and mineral metabolism in patients with secondary hyperparathyroidism in chronic kidney disease

Aim: to assess the dynamics of laboratory parameters (total calcium, inorganic phosphorus, albumin, and alkaline phosphatase levels) and parathyroid hormone (PTH) concentrations after administrating local injections of vitamin D receptor activators into the parathyroid glands of patients with secondary hyperparathyroidism in chronic kidney disease. The intial PTH concentration ranged from 300 to 600 pg/ml. This range was chosen to explore a more active strategy for managing the disease at its early stages and preventing the induction and progression of cardiovascular complications associated with secondary hyperparathyroidism.Methods: the study included 48 patients diagnosed with end-stage of chronic kidney disease, who were treated in the nephrology and dialysis department. The main group consisted of 34 patients who received two consecutive injections of a vitamin D receptor activator (Paricalcitol) into the most enlarged and technically accessible parathyroid gland under ultrasound guidance. The control group included 14 patients who continued with conservative treatment due to technical infeasibility of performing the injections. Effectiveness was assessed by comparing laboratory parameters before the intervention and six months after the injections in the main group, and among patients continuing standard medical therapy for secondary hyperparathyroidism.Results: the results showed a statistically significant reduction in parathyroid hormone levels after 3 and 6 months of treatment. In the control group, which continued to receive standard drug therapy, PTH and blood phosphate levels continued to rise. No undesirable effects or complications, such as hypocalcemia, bleeding, allergic reactions, and recurrent laryngeal nerve paralysis, were not observed throughout the observation period.Conclusion: this research confirms the efficacy of local injections of vitamin D receptor activators (Paricalcitol) in reducing PTH levels without significant complications or changes in calcium levels. This method could be employed to correct and prevent secondary hyperparathyroidism complications in early stages among patients with end-stage chronic kidney disease, offering a safer and more effective treatment option.

A joint-threshold Filippov model describing the effect of intermittent androgen-deprivation therapy in controlling prostate cancer

Intermittent androgen-deprivation therapy (IADT) can be beneficial to delay the occurrence of treatment resistance and cancer relapse compared to the standard continuous therapy. To study the effect of IADT in controlling prostate cancer, we developed a Filippov prostate cancer model with a joint threshold function: therapy is implemented once the total population of androgen-dependent cells (AC-Ds) and androgen-independent cells (AC-Is) is greater than the threshold value ET, and it is suspended once the population is less than ET. As the parameters vary, our model undergoes a series of sliding bifurcations, including boundary node, focus, saddle, saddle-node and tangency bifurcations. We also obtained the coexistence of one, two or three real equilibria and the bistability of two equilibria. Our results demonstrate that the population of AC-Is can be contained at a predetermined level if the initial population of AC-Is is less than this level, and we choose a suitable threshold value.