Search Results (620)

Objective: Chronic non-cervical-origin interscapular pain remains challenging to treat when refractory to conservative management and ultrasound-guided injections. This retrospective feasibility study aimed to assess the feasibility, procedural practicality, safety, and preliminary clinical outcomes of transarterial embolization (TAE) as a salvage therapy in this patient population. Methods: This single-center retrospective study included 20 patients with chronic interscapular pain (Numeric Rating Scale [NRS] score ≥5 for >3 months) who initially underwent ultrasound-guided injection therapy. Patients who experienced inadequate pain relief after 3 months (n = 10) proceeded to TAE, while the remaining 10 patients with sufficient relief formed the comparison group. TAE primarily targeted the transverse cervical artery using imipenem/cilastatin sodium as the embolic agent. Pain outcomes were assessed using NRS scores at 1, 3, and 6 months post-procedure. The primary outcome was pain reduction (≥50% decrease in NRS score), with secondary outcomes including technical success, medication use, and safety assessment. Results: The mean baseline NRS score for all patients was 6.5 ± 1.4, which decreased to 3.4 ± 2.0 at 1 month and 3.9 ± 2.5 at 3 months post-injection (p < 0.001). In the TAE group, the NRS score decreased from 7.4 ± 1.4 to 5.1 ± 1.1 at 1 month and 6.0 ± 1.4 at 3 months, indicating inadequate pain relief. In contrast, the injection-only group showed significant improvement, with NRS scores decreasing from 5.6 ± 0.5 to 1.6 ± 0.5 at 1 month and 1.7 ± 0.7 at 3 months (p < 0.001). The reduction in NRS scores was significantly less in the TAE group compared with the injection-only group (−2.2 vs. −4.0 and −28.7% vs. −71.4% at 1 month; −1.4 vs. −3.9 and −18.2% vs. −69.7% at 3 months; all p ≤ 0.001). Following TAE, the mean NRS score further decreased to 2.1 ± 0.7, 2.0 ± 1.1, and 1.9 ± 1.2 at 1, 3, and 6 months, respectively (p < 0.001), with clinical success rates of 90%, 100%, and 90% at these respective time points. At the final follow-up, the percentage of NRS score reduction was comparable between the TAE and injection-only groups (−74.8% vs. −69.7%, p = 0.397). No severe or life-threatening adverse events were observed; only self-limited adverse events were reported. Conclusions: In this retrospective feasibility study, TAE appeared safe and effective as a salvage therapy for patients with refractory non-cervical-origin interscapular pain unresponsive to injection therapy. Further prospective, randomized studies are needed to validate these findings, refine patient selection criteria, and optimize treatment outcomes. Full article

Background: Tendinopathy is a degenerative condition caused by mechanical overload, accounting for approximately 30% of musculoskeletal healthcare cases. It progresses through a process characterized by collagen disorganization, altered vascularization, and neuronal ingrowth. Traditional conservative treatments, such as therapeutic exercises, non-steroidal anti-inflammatory drugs, and physical therapies, are useful, but their effectiveness is sometimes only partial and there is a need to search for new potential solutions. Recent interest in oxygen–ozone (O₂-O₃) therapy stems from preliminary observations suggesting potential anti-inflammatory and regenerative effects. Nevertheless, its clinical role remains speculative and warrants thorough investigation beyond anecdotal evidence. Considering the heterogeneity of clinical presentations and treatment responses among patients, O₂-O₃ therapy has been proposed as a promising tool for tailoring personalized treatment strategies for tendinopathy. This review critically appraises the available literature concerning the mechanistic rationale and clinical applications of O₂-O₃ therapy in tendinopathy, with attention to both its theoretical underpinnings and the quality of empirical evidence. Methods: A literature search was conducted on O₂-O₃ therapy for tendinopathy using PubMed, Cochrane, and Embase, filtering for full-text articles published between 2004 and 2024. Recent clinical trials were included irrespective of evidence level, while excluding systematic reviews, duplicates, and irrelevant studies. Results: Ozone has been shown to modulate oxidative stress, promote neovascularization, and suppress pro-inflammatory cytokines. Both clinical and in vivo studies indicate that O₂-O₃ therapy relieves pain, enhances tendon healing, and improves biomechanical properties. Some comparative studies suggest that O₂-O₃ therapy might provide more sustained symptoms control than corticosteroids, but the heterogeneity of follow-up durations and outcome measures prevents definitive conclusions. Conclusions: O₂-O₃ therapy emerges as a potentially valuable adjunct in the management of chronic tendinopathy, particularly in cases unresponsive to conventional treatments. However, its clinical role remains to be clearly defined and its possible role in personalized medicine needs further exploration, particularly in relation to patient stratification and individualized treatment protocols. Further high-quality randomized controlled trials are warranted to validate its efficacy, determine long-term outcomes, and standardize treatment protocols to ensure safety and reproducibility. Full article

Background/Objectives: Diabetic neuropathy (DN) is a prevalent complication of diabetes mellitus, affecting up to 50% of long-term patients and causing significant pain, reduced quality of life, and healthcare burden. Conventional treatments, including anticonvulsants, antidepressants, and opioids, offer limited efficacy and are associated with adverse effects. Emerging evidence suggests that cannabis, acting via the endocannabinoid system, may provide analgesic and neuroprotective benefits. This study evaluates the long-term effects of inhaled cannabis as adjunctive therapy for refractory painful DN. Inhaled cannabis exhibits rapid onset pharmacokinetics (within minutes, lasting 2–4 h) due to pulmonary absorption, targeting CB1 and CB2 receptors to modulate pain and inflammation. Methods: In this prospective, observational study, 52 patients with confirmed painful DN, unresponsive to at least three prior analgesics plus non-pharmacological interventions, were recruited from a single clinic. Following a 1-month washout, patients initiated inhaled medical-grade cannabis (20% THC, <1% CBD), titrated individually. Assessments occurred at baseline and annually for 5 years, including the Brief Pain Inventory (BPI) for pain severity and interference; the degree of pain relief; Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score; HbA1c; and medication usage. Statistical analyses used repeated-measures ANOVA, Kruskal–Wallis tests, Welch’s t-tests, and Pearson’s correlations via Analyze-it for Excel. Results: Of 52 patients (mean age 45.3 ± 17.8 years; 71.2% male; diabetes duration 23.3 ± 17.8 years), 50 completed follow-up visits. Significant reductions occurred in BPI pain severity (9.0 ± 0.8 to 2.0 ± 0.7, p < 0.001), interference (7.5 ± 1.7 to 2.2 ± 0.9, p < 0.001), LANSS score (19.4 ± 3.8 to 10.2 ± 6.4, p < 0.001), and HbA1c (9.77% ± 1.50 to 7.79% ± 1.51, p < 0.001). Analgesic use decreased markedly (e.g., morphine equivalents: 66.8 ± 49.2 mg to 4.5 ± 9.6 mg). Cannabis dose correlated positively with pain relief (r = 0.74, p < 0.001) and negatively with narcotic use (r = −0.43, p < 0.001) and pain interference (r = −0.43, p < 0.001). No serious adverse events were reported; mild side effects (e.g., dry mouth or euphoria) occurred in 15.4% of patients. Conclusions: Inhaled cannabis showed sustained pain relief, improved glycemic control, and opioid-sparing effects in refractory DN over 5 years, with a favorable safety profile. These findings are associative due to the observational design, and randomized controlled trials (RCTs) are needed to confirm efficacy and determine optimal usage, addressing limitations such as single-center bias and small sample size (n = 52). Future studies incorporating biomarker analysis (e.g., endocannabinoid levels) could elucidate mechanisms and enhance precision in cannabis therapy. Full article

Introduction: Posterior tibial tendon dysfunction (PTTD) is a progressive degenerative tendinopathy often unresponsive to conservative care, necessitating surgical interventions with significant postoperative risks. Wharton’s jelly (WJ) tissue allograft from the human umbilical cord, with its collagen-rich matrix homologous to tendon tissue, presents a potential alternative intervention. This study aims to report preliminary findings on the safety and efficacy of WJ allografts for the supplementation of degenerated tissue in patients with PTTD. Material and Methods: Twenty-six patients from the observational repository were identified with PTTD (Stages II-IV) and failed at least three months of conservative care. Patients received one or two ultrasound-guided percutaneous applications of the WJ allograft. Outcomes were tracked using the Numeric Pain Rating Scale (NPRS), the Western Ontario and McMaster University Arthritis Index (WOMAC), and the Quality-of-Life Scale (QOLS) at the initial, 30, 90, and 120-day follow-ups. Results: The cohort was 62% male (n = 16) and 38% female (n = 10), with a mean age predominantly in the 70–89 range. From the initial to final visit (90 days for single applications, 120 days for double applications), the single-application group (n = 22) showed a 48.32% improvement in NPRS and a 22.73% improvement in total WOMAC. The double-application group (n = 8) showed a 50% improvement in NPRS and a 27.86% improvement in total WOMAC. A statistically significant improvement in NPRS was observed in the single-application group (p = 0.042). No adverse events were reported. Discussion: This study provides preliminary evidence that WJ tissue allografts may be a safe and effective minimally invasive application for degeneration of the PTT, which is associated with improvements in pain, function, and quality of life. Key limitations include a lack of a control group and a small cohort size. Conclusions: The positive findings of this study warrant further research through randomized controlled trials to confirm efficacy, establish optimal dosage, and compare WJ to other conservative interventions. Full article

Background/Objectives: Colorectal carcinoma (CRC) is among the most commonly diagnosed cancers in both men and women. Although CRC mortality is generally decreasing, new therapeutic options are needed for unresponsive subgroups of CRC patients. Methods: A series of known and new tyrphostin derivatives was tested for their efficacy against three CRC cell lines with varying KRAS, p53, and/or BRAF statuses. Growth inhibition, apoptosis induction, and inhibition of EGFR and VEGFR-2 were investigated. Results: Tyrphostin A9, the known RG13022-related tyrphostin 1a and its dichlorido(p-cymene)ruthenium(II) complex 1b, and the new SF₅-substituted compounds 2a and 2b showed selective antiproliferative activity against KRAS-mutant HCT-116 CRC cells expressing wildtype p53, while p53-knockout HCT-116 and KRAS-wildtype BRAF/p53-mutant HT-29 CRC cells were distinctly less sensitive. In HCT-116 cells, only tyrphostin A9 increased mRNA expression of caspases 3 and 8, as well as the kinases MEK1 and MEK2, whereas 2a reduced caspase 8 mRNA levels. Tyrphostin A9 increased caspase 3 activity and induced apoptosis in HCT-116 p53-wildtype cells while simultaneously inhibiting the receptor tyrosine kinases EGFR and VEGFR-2 at low nanomolar concentrations. Conclusions: Tyrphostin A9 could be a promising therapeutic option for the treatment of KRAS-mutant CRC that expresses wildtype p53. Full article

The Farnesoid-X-receptor (FXR) is a bile sensor involved in the regulation of bile acid homeostasis, fibrosis, inflammation, and metabolism. Obeticholic acid (OCA), a semisynthetic derivative of chenodeoxycholic acid (CDCA), initially named 6-ethyl-CDCA or INT-747, is the first in a class of FXR ligands that have been approved for clinical use for the treatment of patients with primary biliary cholangitis (PBC) who are unresponsive or intolerant to ursodeoxycholic acid. In this narrative review, we will examine the current status and future perspective of clinical use of OCA. Based on results from phase 2 and 3 clinical trials, OCA received a conditional market approval for its use as a second-line treatment for the management of PBC in 2016. However, concerns over drug (OCA)-induced liver injury (DILI), including hepatic decompensation in cirrhotic and non-cirrhotic PBC patients, have led to discontinuation of OCA commercialization in the EU, but not in North America and the UK, in 2024. Based on positive results from preclinical models, OCA has been investigated also for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Results from phase 2 and 3 trials, however, have shown that while OCA reduces liver fibrosis, the beneficial effects on steatosis are marginal, thus preventing its clinical approval under the current regulatory guidelines. Here, we review potential applications of OCA in PBC patients in the context of a highly competitive therapeutic landscape, generated by the approval for clinical use of safer and effective second-line therapies, including PPARs agonists such as elafibranor and seladelapar and increased off-label use of fibrates. The current status of development of second-generation FXR agonists such as cilofexor, tropifexor, and vonafexor and their potential in the treatment of liver fibrosis in MASH will be discussed and compared to recently approved therapies, resmetirom, and semaglutide, a GLP-1 agonist. Finally, since some of the novel candidates for treating MASH, have shown limited efficacy on liver fibrosis, we suggest that development of combinatorial therapies based on FXR ligands and agents acting on different molecular targets might offer the opportunity for the repositioning of drug candidates whose development has been abandoned for insufficient efficacy, minimizing/recovering costs linked to drug development. Full article

Background: Severe acute pancreatitis (SAP) presents with Multiple Organ Dysfunction Syndrome (MODS) in ~15% of cases, accounting for ~35% of early deaths within 48 h. Major complications—shock, renal failure, and respiratory insufficiency—arise from an overwhelming systemic inflammatory response driven by markedly elevated pro-inflammatory cytokines. Massive release of IL-2, IL-6, and TNF-α underlies the systemic inflammatory response syndrome (SIRS). Continuous veno-venous hemofiltration (CVVH) with the oXiris filter, adsorbing endotoxins and cytokines, has been used in sepsis and applied early in SAP to reduce cytokine load and organ injury. Aims: To evaluate the efficacy and safety of early CVVH with the oXiris filter in modulating the systemic inflammatory response by removing toxic cytokines from the bloodstream in patients with SAP complicated by organ dysfunction and refractory sepsis. Methods: This single-centre, retrospective, observational study was conducted at a tertiary university hospital between 2000 and 2022. Forty-eight consecutive patients with SAP at onset, defined according to the 2012 Atlanta Classification, with an APACHE II score ≥ 19 and persistent organ dysfunction (>48 h), were included. All patients were unresponsive to initial intensive care within the first 24 h and underwent urgent laparotomy with extensive peritoneal lavage, pancreatic necrosectomy, and placement of multiple abdominal drains, followed by transfer to the intensive care unit. CVVH (Prismax system) with the oXiris filter was initiated within 12 h post-surgery. IL-6 and TNF-α were selected as inflammatory markers and measured in both serum and ultrafiltrate at baseline (0 h) and at 24, 48, 72, and 96 h. These measurements were correlated with clinical parameters and prognostic scores (APACHE II, SOFA). Results: Treatment was well tolerated in all patients. The 28-day survival rate was 97.9%. There was a significant time-dependent decrease in IL-6 (p = 0.019) and TNF-α (p = 0.008) concentrations in the ultrafiltrate, consistent with high early adsorption followed by a reduced cytokine burden, whereas serum levels showed a non-significant downward trend (IL-6 p = 0.08; TNF-α p = 0.310). The APACHE II score decreased from 23 postoperatively to 8 by the second week (−65.2%; p = 0.013), with a statistically significant correlation between cytokine reduction and clinical improvement. Adverse events were rare and manageable. Conclusions: Early CVVH with the oXiris filter in SAP, complicated by MODS and refractory sepsis, proved safe, well-tolerated, and potentially effective in reducing cytokine burden and improving prognostic indices. These findings support the hypothesis of a relevant immunomodulatory effect, warranting prospective controlled trials to confirm its true impact on survival and organ recovery. Full article

Background and Objectives: Upadacitinib is a recently approved Janus kinase (JAK) inhibitor for the treatment of inflammatory bowel disease (IBD). Although it has been adopted for clinical use, there are limited real-world data regarding its efficacy and safety, as well as its effects on laboratory parameters. In our study, we aimed to evaluate these outcomes in patients with moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC) who had previously failed biologic agents. Materials and Methods: This retrospective cohort study included 22 UC and 19 CD patients who received Upadacitinib for at least six months, where efficacy was assessed at pretreatment and at 3 and 6 months. We used the Harvey–Bradshaw Index (HBI) for CD and the partial Mayo score (PMS) for UC to define clinical response and remission. Results: All patients were biologic-experienced, with a substantial portion (47%) having previously failed at least two different agents. At six months, the persistence rates were 78.3% for CD and 88% for UC. The clinical response rates were 72.7% for CD and 83.3% for UC, while the clinical remission rates were 50% and 58.3%, respectively. Fecal calprotectin and C-reactive protein levels significantly improved (p < 0.001). Total, LDL, and HDL cholesterol levels increased, but triglyceride levels and the LDL/HDL ratio remained unchanged. Biochemical parameters, including glucose, HbA1c, and thyroid, kidney, and liver function tests, remained within normal limits. No clinically significant changes were observed in hemogram parameters, and no serious adverse events, embolisms, major cardiovascular events (MACEs), or deaths occurred. Conclusions: Upadacitinib is effective in biologic-unresponsive IBD patients. While it increases cholesterol levels, it does not alter the LDL/HDL ratio and does not demonstrate a negative effect on glucose metabolism. Further multicenter, longer-term studies are needed on this topic. Full article

Bi-phasic (with a local minimum) response of fluorescence to scattering when probed by a single fiber (SF) was first observed in 2003. Subsequent experiments and Monte Carlo studies have shown the bi-phasic turning of SF fluorescence to occur at a dimensionless reduced scattering of ~1 and vary with absorption. The bi-phase of SF fluorescence received semi-empirical explanations; however, better understandings of the bi-phase and its dependence on absorption are necessary. This work demonstrates a quasi-analytical projection of a bi-phasic pattern comparable to that of SF fluorescence via photon-transport analyses of fluorescence in a center-illuminated-area-detection (CIAD) geometry. This model-approach is principled upon scaling of the diffuse fluorescence between CIAD and a SF of the same size of collection, which expands the scaling of diffuse reflectance between CIAD and a SF discovered for steady-state and time-domain cases. Analytical fluorescence for CIAD is then developed via radial-integration of radially resolved fluorescence. The radiance of excitation is decomposed to surface, collimated, and diffusive portions to account for the surface, near the point-of-entry, and diffuse portion of fluorescence associated with a centered illumination. Radiative or diffuse transport methods are then used to quasi-analytically deduce fluorescence excited by the three portions of radiance. The resulting model of fluorescence for CIAD, while limiting to iso-transport properties at the excitation and emission wavelengths, is compared against the semi-empirical model for SF, revealing bi-phasic turning [0.5~2.6] at various geometric sizes [0.2, 0.4, 0.6, 0.8, 1.0 mm] and a change of three orders of magnitude in the absorption of the background medium. This model projects a strong reduction in fluorescence versus strong absorption at high scattering, which differs from the semi-empirical SF model’s projection of a saturating pattern unresponsive to further increases in the absorption. This framework of modeling fluorescence may be useful to project frequency-domain and lifetime pattens of fluorescence in an SF and CIAD. Full article

Introduction: The elbow is a rare site for bone tumors, and for this reason, the literature provides little data on the epidemiology of metastatic lesions involving the distal humerus, proximal ulna, and radius. Before performing surgery of the metastatic bone, it is first necessary to consider both patients’ and metastatic lesions’ features in order to better choose the best possible treatment. This systematic review aims to collect data on elbow metastases, delineate primary tumors leading to such metastases, guide surgical treatment decisions, and evaluate reconstructive techniques and associated complications. Material and Methods: A systematic literature review was conducted in April 2024, searching the PubMed, MEDLINE, and Cochrane Library databases using specific search terms related to elbow metastases. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was followed. Eligible studies reported at least one patient with metastatic bone disease involving the elbow region and specified the undertaken treatment. For studies reporting multiple skeletal sites, only elbow-specific data were extracted. We excluded recurrences of primary elbow tumors. The methodological quality of included studies was assessed with the modified Coleman Methodology Score (mCMS). Results: In total, 28 articles (103 patients) were included. The studies were predominantly case reports (68%), with a mean mCMS of 31. Gender was reported for only 41 patients: 71% were male and 29% female. The mean age at diagnosis of elbow metastatic lesion was 55 years old. Renal cell carcinoma was the most common primary tumor (28%), followed by breast (9%) and lung cancer (6%). The distal humerus was the most frequently affected site (85%). A surgical approach was adopted in 90% of cases, whereas 10% of patients were managed conservatively. Forty-five patients underwent wide tumor resection followed by reconstructive surgery while forty-eight patients received a surgical treatment for either pathological fractures or impending fractures. Conclusions: When treating elbow metastasis, a thorough evaluation of the patient is crucial, considering the patient’s functional status, pain management needs, and overall prognosis; all these features influence the treatment of choice. The selected treatment should aim to provide optimal functional outcomes and minimize complications. For patients with pathological or impending fractures, single or double plate fixation is typically the preferred approach. For patients with severe, symptomatic lesions unresponsive to conservative therapy, resection followed by the implantation of a modular prosthesis usually offers the best clinical and functional outcomes. Full article

Cannabinoids have gained increasing attention as potential therapeutic agents in chronic pain management. Their mechanisms of action, mediated through CB1 and CB2 receptors, provide a pharmacological alternative to conventional analgesics. The evidence is strongest for neuropathic pain and multiple sclerosis-related spasticity, while the results for fibromyalgia, osteoarthritis, and musculoskeletal pain remain inconsistent. The average pain reduction is modest, often not exceeding 0.5–1.0 points on a 10-point scale, and therapeutic gains are offset by safety concerns. Quantitative data show that discontinuation rates range from 4.3% at low-dose CBD to 12.9% at high-dose CBD, compared with 3.5% on placebo, while nabiximols (THC + CBD spray) are associated with dizziness in 25% of patients, somnolence in 8%, and treatment discontinuation in 12%. High-dose CBD also carries a measurable risk of hepatotoxicity. Regulatory heterogeneity further constrains trial feasibility, scalability, and patient access, with disparities evident across the United States, Europe, Canada, and Australia. Overall, cannabinoids provide modest, condition-specific analgesia and should be considered adjunctive rather than first-line options, reserved for patients unresponsive to conventional therapy. Future progress requires standardized formulations, harmonized international regulations, long-term safety data, and large-scale randomized controlled trials to clarify their role in evidence-based pain management. Full article

Background/Objectives: A subset of children with monosymptomatic nocturnal enuresis (MNE) remains unresponsive to standard treatments such as desmopressin and alarm therapy. This study aimed to identify clinical predictors of response to biofeedback therapy in treatment-resistant MNE and to evaluate the role of bladder capacity as a stratification parameter. Methods: In this prospective study, 89 children with treatment-resistant MNE underwent six weekly sessions of biofeedback therapy involving visual pelvic floor feedback. Based on treatment outcomes, patients were classified as complete responders or partial/non-responders. Clinical characteristics including age-adjusted maximal voided volume (MVV), nocturnal polyuria, and wetting frequency were compared. Results: Patients with a complete response had significantly lower baseline MVV and age-adjusted MVV (p < 0.001). Nocturnal overactivity was more common among responders (60.6% vs. 33.9%, p = 0.017), whereas nocturnal polyuria was more frequent in non-responders (p = 0.027). Age-adjusted MVV emerged as the only independent predictor of treatment success in multivariate analysis (p = 0.045), with ROC analysis confirming its predictive value (AUC = 0.767, 95% CI: 0.667–0.866). Conclusions: These findings suggest that reduced bladder capacity and frequent night-time wetting may help identify patients who are more likely to benefit from biofeedback therapy. Bladder capacity assessment may thus serve as a useful tool in tailoring management strategies for refractory MNE. Full article

Deferasirox (DFX) is an oral iron chelator for thalassemia patients with iron overload. DFX was FDA-approved as a first-line treatment for chronic iron overload. In Thailand, DFX was indicated as second-line therapy for patients unresponsive to deferiprone. Objectives: This study aimed to investigate the efficacy and safety of DFX monotherapy. Methods: All transfusion-dependent thalassemia patients who received second-line DFX monotherapy were identified from the thalassemia registry between May 2007 and May 2022. The primary endpoint was the change in body iron stores, measured by serum ferritin at week 24. At treatment end, patients with a serum ferritin (SF) level < 1000 ng/mL in transfusion-dependent thalassemia (TDT) were categorized as the ferritin response group. Multivariate analysis identified factors driving group differences. Results: Forty-two patients were enrolled with a mean age of 35.5 (13–57) years. Of these, 73.81% had beta-thalassemia. The median initial DFX dose was 20.26 (17.85–22.22) mg/kg/day, with a median treatment follow-up of 2 (1.80–2.45) years. Median SF was decreased from 2516 (1712 to 3065) ng/mL to 1027.5 (598–1867) ng/mL (p < 0.001). Of 21 (50%) patients in the ferritin response group, independent factors were age > 15 years and lower initial SF, with OR = 7.13 (95% CI 1.05–48.49, p = 0.045) and OR = 0.93 (95% CI 0.87–1.00, p = 0.039). The most common adverse events were gastric irritation symptoms (11.90%). Conclusions: Deferasirox is an effective oral iron chelator for thalassemia, with manageable side effects. Half of patients reached target SF levels. Adults (>15 years) with lower initial SF levels had a better response to DFX. Full article

Targeted therapy with BRAFi has significantly improved outcomes for patients with BRAF-mutated metastatic melanoma. However, resistance mechanisms, particularly metabolic adaptations, such as increased glutaminolysis, present substantial clinical challenges. This study investigated the metabolic changes underlying BRAFi resistance in melanoma cells. Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. Our methodologies included cell culture, qPCR, polysome profiling, animal studies in nude mice, and analyses of patient samples to evaluate the therapeutic potential of targeting glutaminolysis. Our findings confirmed that melanoma cells, with resistance to targeted therapies, exhibit metabolic adaptations, including enhanced glutaminolysis, increased mitochondrial content, and elevated antioxidative capacities. We evaluated the efficacy of CB-839 and demonstrated its ability to reduce the proliferation of resistant melanoma cells both in vitro and in vivo. Mechanistic studies revealed that CB-839 suppressed ATP production and TCA cycle intermediates in resistant cells while inducing oxidative stress in sensitive cells, thereby inhibiting their proliferation. High glutaminase expression in primary patient tumor samples was associated with poor prognosis. We identified a metabolic signature in tumors from patients responsive or unresponsive to BRAFi prior to treatment, which could serve as a predictive factor for BRAFi response. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management. Full article