Search Results (574)

Natural killer cell large granular lymphocytic leukemia (NK-LGLL) is a rare and heterogenous lymphoproliferative disorder. This study retrospectively evaluated 35 consecutive Chinese patients (median age 58 years) to evaluate their unique clinical–biological profiles and treatment responses. Our Chinese population exhibited a distinct comorbidity spectrum, characterized by a lower prevalence of concurrent arthritis (2.9%) and secondary malignancies, compared with Western cohorts. At diagnosis, 31.4% of the cohort had neutropenia, 42.9% had anemia, and 31.4% had thrombocytopenia. The median large granular lymphocyte count was 3.9 × 10⁹/L (range 0.11–114.8 × 10⁹/L; IQR 1.9 × 10⁹/L, 5.9 × 10⁹/L). Immunophenotyping consistently identified as a CD3 CD56+ clone. Notably, genomic profiling via NGS revealed a STAT3 mutation rate of 14.3%. Regarding therapeutic efficacy, frontline immunosuppressive therapy with cyclophosphamide or cyclosporine was associated with favorable clinical responses (best overall response, complete remission rate 66.7% for both). Additionally, sirolimus emerged as a potentially highly effective salvage option, yielding an overall response rate of 85.7% (95%CI 42.1–99.6%) and complete remission rate of 57.1%. With an estimated 3-year overall survival rate of 85.6% (95%CI 73.3%, 99.8%), our findings suggest a generally indolent clinical course of NK-LGLL in this Chinese cohort and highlight the potential of mTOR inhibition in refractory cases, warranting further prospective investigation. Full article

Background: Acute rejection (AR) is an established risk factor for kidney allograft loss, but whether the timing of the first AR episode adds prognostic information independent of secular changes in immunosuppression remains incompletely defined. We re-examined this question in a cohort restricted to the contemporary calcineurin-inhibitor (CNI) era and explicitly accounted for the maintenance CNI (tacrolimus vs. cyclosporine). Methods: We studied 2470 recipients of an isolated kidney transplant performed between 2000 and 2018 at a single academic center. Recipients were classified by the timing of the first AR episode as AR-free, Early AR (≤6 months), Intermediate AR (6–12 months), or Late AR (>12 months). Co-primary outcomes were estimated glomerular filtration rate (eGFR) and death-censored graft survival. Multivariable Cox regression adjusted for recipient and donor age, recipient sex, HLA mismatch, donor type, ABO incompatibility, diabetes, retransplantation, transplant year, and maintenance CNI. A pre-specified secondary analysis evaluated whether the observed AR-timing association was explained by the maintenance CNI. Results: AR occurred in 294 of 2470 recipients (11.9%): 253 Early, 10 Intermediate, and 31 Late. Median follow-up was 105 months. Mean 5-year eGFR was 67.1 (AR-free), 56.5 (Early), 47.5 (Intermediate), and 47.2 mL/min/1.73 m² (Late) (p < 0.001). Kaplan–Meier 10-year death-censored graft survival was 90.5%, 80.7%, 77.8%, and 52.2%, respectively (log-rank p < 0.001). After adjustment, the hazard of graft failure relative to AR-free recipients was 2.25 (95% CI 1.68–3.01) for Early AR and 7.03 (4.28–11.54) for Late AR (both p < 0.001). The Intermediate AR estimate was directionally consistent but imprecise because of the small number of cases. Tacrolimus use was associated with a lower observed incidence of AR (8.5% vs. 20.0%, p < 0.001), but the observational CNI comparison was confounded by era and follow-up duration and did not explain the AR-timing gradient. Conclusions: Within a contemporary CNI-era cohort and after adjustment for maintenance immunosuppression and transplant year, late-onset AR—particularly onset beyond the first post-transplant year—provided strong prognostic information for long-term graft dysfunction and graft failure. Full article

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). The remission rate of MN remains limited, and effective strategies for refractory MN are not established. We present the case of a 49-year-old Japanese woman with severe NS caused by MN. Kidney biopsy revealed glomerular basement membrane thickening with granular deposition of immunoglobulin G (IgG) and complement component 3. IgG subclass analysis showed predominant IgG1 deposition, with weak IgG2 and IgG3 deposition. Phospholipase A2 receptor (PLA2R) deposition was equivocal in the first kidney biopsy and negative in the second. Serum anti-PLA2R antibody was not detected. Electron microscopy revealed subepithelial, subendothelial, and mesangial electron-dense deposits. Detailed screening revealed no significant abnormalities other than appendiceal findings, suggesting secondary MN associated with appendiceal infection. Although combined therapy with prednisolone, cyclosporine, rituximab, and low-density lipoprotein apheresis was administered during the first 6 months, remission of MN was not achieved. During dialysis, initiated because of kidney failure, long-term multidisciplinary management, including control of appendiceal infection and inflammation and initiation of angiotensin II receptor blocker therapy, ultimately led to remission of MN and discontinuation of dialysis. Overall, even refractory MN requiring dialysis may have a reversible clinical course with careful conservative management and long-term follow-up. Full article

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with extraintestinal manifestations, including primary sclerosing cholangitis (PSC). Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that rarely coexists with UC or PSC. The concurrent occurrence of UC, PSC, and SLE in a single individual represents a unique diagnostic and therapeutic challenge. Vedolizumab, a gut-selective biologic agent, is effective for managing UC; however, its utility in patients presenting with this triad of conditions has not yet been explored. Case summary: A 32-year-old man presented with a 10-year history of recurrent upper abdominal pain, frequently accompanied by high-grade fever, along with recent onset of jaundice, diarrhea, hematochezia, and chronic rashes. Diagnostic evaluation confirmed PSC, SLE, and severe UC. During hospitalization, the patient also developed bacteremia. Initial management of UC with mesalazine and immunosuppressants (azathioprine followed by cyclosporine) resulted in limited clinical improvement. Vedolizumab was subsequently initiated, resulting in marked clinical improvements and near-complete endoscopic remission of UC. PSC and SLE remained clinically stable with ongoing therapies; however, the patient is currently awaiting liver transplantation for PSC. Conclusions: This case highlights the potential utility of vedolizumab in the treatment of UC in patients with concurrent PSC and SLE. Full article

Background/Objectives: Therapeutic drug monitoring (TDM) of cyclosporine is essential due to its narrow therapeutic index and pronounced pharmacokinetic variability. Long-term surveillance of patient results may provide insight into analytical stability and clinical practice patterns beyond conventional quality control approaches. Methods: This retrospective observational study included 48,835 routine whole blood cyclosporine concentrations analyzed at a tertiary university hospital laboratory between January 2006 and December 2025. Yearly patient percentiles (10th, 25th, 50th, 75th and 90th percentiles) were calculated to assess longitudinal trends, variability, and potential effects of analytical platform transitions. Results were analyzed overall and by sex. Results: The yearly number of reported cyclosporine results declined modestly over the study period. The overall median cyclosporine concentration was 134.4 µg/L, with negligible differences between female and male patients. The 10th, 25th, and 50th percentiles remained highly stable across the 20-year period, with coefficients of variation between 6.1% and 6.8%. Upper percentiles exhibited greater variability, but the total coefficient of variation for the 90th percentile remained below 8%. No systematic shifts associated with analytical platform transitions were observed. Conclusions: Long-term patient median and percentile analysis demonstrated remarkable temporal stability of cyclosporine concentrations over two decades, despite changes in analytical platforms and clinical practice. Continuous monitoring of patient medians and percentiles may serve as a valuable complementary quality indicator, particularly for assays with limited commutable quality control materials. Full article

Everolimus is approved for the treatment of advanced renal cell carcinoma after VEGF-targeted therapy, metastatic HR-positive/HER2-negative breast cancer in combination with exemestane, and other oncologic indications. However, an intravenous option has not been developed, largely due to its pronounced hydrophobicity and limited oral bioavailability of approximately 15–20%. In this study, we report the development of Sapu003, a novel intravenous Everolimus formulation enabled through the Deciparticle™ platform. A diverse library of mPEG-based block copolymers was evaluated for their ability to encapsulate Everolimus and self-assemble into stable nanoparticle structures. mPEG-Chol was ultimately selected based on its favorable biocompatibility characteristics. In addition to Everolimus, mPEG-Chol and related analogs demonstrated broad formulation compatibility with multiple hydrophobic therapeutics, including Sirolimus, Tacrolimus, Cyclosporine, as well as representative peptides and polyketides. Clinical manufacturing was conducted in a cGMP environment over a 7-day production cycle. Production was carried out under amber light using light-protective vials to reduce drug degradation. The bulk material was sterile-filtered, and subsequent fill/finish/lyophilization operations were performed under temperature-controlled conditions with high precision in fill accuracy (≥98%). After reconstitution, the final product yielding uniform Deciparticles™ that met predefined sterility and particle size criteria. Stability studies demonstrated that the formulation remained stable for at least one month at 5 °C and retained acceptable in-use stability for at least 24 h at room temperature. The process was successfully scaled beyond 10 g, supporting an ongoing Phase 1b open-label dose escalation clinical study of Sapu003 in combination with exemestane in patients with advanced mTOR-sensitive solid tumors (NCT07369505). In vivo evaluation demonstrated strong antitumor efficacy following intravenous administration (QW × 3), with tumor growth inhibition reaching 97–98% in the U-87MG glioblastoma xenograft model. No evidence of phlebitis was observed with repeated tail vein dosing. In this model, Sapu003 dosed weekly showed superior tumor suppression compared with oral Everolimus. Collectively, screening of a mPEG-block copolymer library identified mPEG-Chol as a lead excipient capable of consistently forming stable Deciparticles™ with sub-20 nm mean particle size. The resulting intravenous Everolimus formulation demonstrated scalable manufacturing, favorable stability, and potent antitumor activity in preclinical models, supporting further clinical evaluation of Sapu003 in advanced solid tumors. Full article

Background/Objectives: To investigate the relationship between lacrimal punctum size and the severity of dry eye disease (DED) in a clinically refractory, real-world patient cohort from a tertiary ophthalmology center in Lebanon. Methods: A retrospective observational study was conducted at Advanced Eye Care Center, Beirut, Lebanon (2016–2024). A total of 312 eyes from 156 patients with moderate-to-severe DED unresponsive to topical artificial tears, loteprednol etabonate, and cyclosporine (0.05% ophthalmic emulsion) were included. All eyes subsequently underwent lower lacrimal punctum plug insertion as part of clinical management. Lacrimal punctal diameter was estimated by the largest silicone plug (0.5 mm, 0.6 mm, or 0.7 mm) inserted nonforcefully into the lower punctum under slit-lamp visualization. Tear film stability was assessed by Tear Break-Up Time (TBUT). Group differences were analyzed using the Kruskal–Wallis H test with post hoc Mann–Whitney U tests (Bonferroni correction), and Spearman’s rank correlation was calculated to quantify the monotonic association. Results: Eyes were distributed across punctal diameter categories as follows: 0.5 mm (n = 15, 4.8%), 0.6 mm (n = 204, 65.4%), and 0.7 mm (n = 93, 29.8%). Median TBUT values were 5.55 s [IQR 5.51–5.77], 5.06 s [IQR 4.80–5.37], and 4.51 s [IQR 4.23–4.71] for the 0.5 mm, 0.6 mm, and 0.7 mm groups, respectively. Kruskal–Wallis analysis confirmed significant inter-group differences (H = 140.1, p < 0.001). All post hoc pairwise comparisons remained significant after Bonferroni correction (p < 0.001). Spearman’s rank correlation demonstrated a significant negative association between lacrimal punctal diameter and TBUT (ρ = −0.70, p < 0.000001). All analyses were conducted at the eye level and do not account for within-patient correlation (bilateral design, 156 patients); p-values should be interpreted accordingly. Conclusions: In this treatment-refractory cohort, larger lacrimal punctal diameter was significantly associated with greater tear film instability. These findings suggest that lacrimal punctal diameter estimation during therapeutic plug insertion may serve as a practical, cost-free adjunct to standard DED evaluation. Prospective multimodal studies are needed to validate punctal diameter as an independent clinical indicator of DED severity. Full article

Background and Clinical Significanc: Neuropathic corneal pain is a debilitating condition characterized by ocular pain disproportionate to clinical signs, often resulting from peripheral and central sensitization of the corneal somatosensory pathway. Emerging evidence suggests that chronic involuntary muscle contraction in blepharospasm may lead to irritation of trigeminal afferents and corneal neurogenic inflammation, potentially predisposing patients to neuropathic corneal pain. Given its debilitating nature, early recognition can prevent the progression of neuropathic sequelae. This study examines the potential role of blepharospasm as a predisposing factor contributing to neuropathic corneal pain. Case Presentation: This retrospective case series describes three cases (median age: 50 years) of neuropathic corneal pain in association with blepharospasm and their clinical course following multimodal treatment over a median follow-up period of one year. Ocular surface was evaluated using slit-lamp biomicroscopy, while corneal nerve structure and morphology were assessed with in vivo confocal microscopy. All the three subjects presented with minimal ocular surface staining but disproportionate ocular pain characterized by burning sensation and photophobia. Proparacaine challenge testing was performed to determine the subtype of neuropathic corneal pain. Pain symptoms and quality of life were evaluated using the Ocular Pain Assessment Survey and Ocular Surface Disease Index questionnaires. In vivo confocal microscopy demonstrated characteristic corneal nerve abnormalities including reduced corneal nerve density, increased nerve tortuosity, and the presence of microneuromas. Treatment included oral Pregabalin or Gabapentin, topical lubricants, Cyclosporine 0.05% (1 case), and 20% autologous serum eye drops (1 case). Two of the three cases received four to five injections of botulinum toxin for blepharospasm, whereas one had undergone a single injection prior to review. All patients also received weekly periorbital quantum molecular resonance electrotherapy for two months. Improvements were observed across multiple domains of the Ocular Pain Assessment Survey and Ocular Surface Disease Index evaluation, including ocular pain, photophobia, non-ocular pain, and quality-of-life measures following multimodal treatment. The co-existence of blepharospasm and neuropathic corneal pain observed in our cases supports a possible association between chronic periocular muscle hyperactivity and corneal nociceptor sensitization. Proposed mechanisms include chronic trigeminal nerve irritation, neurogenic inflammation, and sensitization mediated by pro-inflammatory neuropeptides. Multimodal treatment targeting both motor hyperactivity and neuropathic pain pathways appeared to provide symptomatic relief, including the use of quantum molecular resonance electrotherapy, which might modulate pain pathways, block nociceptor neurotransmission, and accelerate corneal nerve regeneration. Given the complexity of the neural pathways responsible for ocular discomfort, further studies are required to elucidate the relationship between neuropathic corneal pain and blepharospasm in larger cohorts, as well as refine existing therapeutic approaches, including evaluating the therapeutic role of electrotherapy. Conclusions: Blepharospasm may represent a potential predisposing factor of neuropathic corneal pain. Early recognition and concurrent treatment of blepharospasm and neuropathic corneal pain can effectively relieve symptoms and improve quality of life. Adopting a multimodal treatment approach is therefore recommended. Full article

Background: Dry Eye Disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability and inflammation. Cyclosporine A, an immunomodulator, and Diquafosol sodium, a mucin secretagogue, represent two distinct therapeutic pathways. However, current evidence directly comparing their clinical efficacy is inconsistent. This meta-analysis aimed to compare treatment outcomes and efficacy between 0.05% Cyclosporine A and 3% Diquafosol sodium in patients with moderate-to-severe DED. Methods: In January 2026, we conducted a systematic search of PubMed, Scopus, Web of Science, and the Cochrane Library for randomized controlled trials directly comparing 0.05% Cyclosporine A to 3% Diquafosol sodium in adult patients with moderate-to-severe DED. For the meta-analysis, we used R 4.5.0 with R Studio 2024.12.1+563. Results: We included six RCTs with a total of 859 patients. No significant differences were found between Cyclosporine A and Diquafosol sodium in Tear Break-Up Time (TBUT) at 4, 8, or 12 weeks. Cyclosporine A showed a suggestive greater improvement in Schirmer test scores at 4 weeks (SMD = 0.35, 95% CI 0.07 to 0.63). A modest benefit in symptom scores favoring Diquafosol sodium was observed at 12 weeks (SMD = 0.23, 95% CI 0.06 to 0.41). Subgroup analysis suggested this symptomatic benefit may be more pronounced in patients with severe disease, although subgroup interaction tests were not statistically significant. There were no significant differences in corneal or conjunctival staining at any time point. The risk of adverse events did not differ significantly between treatments. Conclusions: Early improvement in tear production showed a potential benefit for Cyclosporine A, while longer-term symptomatic relief showed a potential benefit for Diquafosol sodium, with suggestive evidence in severe disease. However, these findings should be interpreted cautiously, given the methodological limitations and inconclusive TSA evidence for several outcomes. Future large-scale, standardized trials with extended follow-up are warranted to confirm these findings. Full article

Background/Objectives Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases involved in collagen cross-linking, has emerged as a key mediator of pathological extracellular matrix remodeling and tissue fibrosis. Dysregulated LOXL2 activity has been implicated in various fibrotic diseases; however, its role in fibrosis-driven chronic kidney injury, particularly in the context of calcineurin inhibitor-induced kidney toxicity, remains incompletely defined. Methods To investigate the contribution of LOXL2 inhibitor to cyclosporine A (CsA)-induced nephropathy, a well-established model of progressive tubulointerstitial fibrosis, male CD-1 mice were administered either saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. After 4 weeks of CsA exposure, CsA-treated mice were further divided into two groups and received either vehicle or a LOXL2 inhibitor (10 mg/kg/day, oral gavage) for an additional 4 weeks. Kidney function, albuminuria, histological fibrosis, inflammatory cell infiltration, and profibrotic gene expression were assessed. Results In a murine model of CsA-induced nephropathy, pharmacological inhibition of LOXL2 markedly improved kidney outcomes. LOXL2 inhibition significantly reduced albuminuria and ameliorated kidney dysfunction. In parallel, tubulointerstitial fibrosis was substantially attenuated, accompanied by reduced myofibroblast activation and extracellular matrix accumulation. These protective effects were associated with downregulation of profibrotic and inflammatory mediators and inhibition of TGF-β-related downstream signaling pathways activated by CsA. Conclusions The present preclinical findings suggest that Compound #765-mediated LOXL2 inhibition may offer a potential therapeutic benefit in CsA-induced fibrosis, though further validation is warranted. Full article

Nasal alar arteriopathy (NAA) is a rare dermatologic condition in dogs characterized by ulcerative and potentially severe hemorrhagic lesions of the nasal alar fold. This condition has only previously been reported in German Shepherd Dogs. Achieving clinical remission can be challenging and typically involves a combination of surgical resection of the diseased tissue and immunosuppressive therapies. This report is the first to describe two cases of NAA in which clinical remission was initially achieved with oclacitinib alone. Both cases were presented to the Internal Medicine service with a complaint of unilateral recurrent epistaxis. The first case involved a 7-year-old German Shepherd dog. Clinical remission was first achieved with oclacitinib monotherapy. Relapse occurred following dose tapering, and remission was ultimately regained with dose reescalation of oclacitinib and the addition of cyclosporine. The second case involved a 3-year-old Poodle mix that achieved and maintained clinical remission with oclacitinib alone. These cases suggest that oclacitinib may be an effective and well-tolerated treatment option for NAA, offering an alternative to traditional systemic immunosuppressive therapies. However, additional treatment may be required in severe cases or during oclacitinib dose reduction. Further studies are needed to evaluate long-term outcomes and broader applicability. Full article

Background/Objectives: The Systemic Immune–Inflammation Index (SII), derived from routine blood counts, has emerged as a potential marker of systemic inflammation in psoriasis. However, its longitudinal behavior across different systemic and biologic therapies remains poorly characterized. This study aimed to evaluate changes in SII over time, assess its relationship with Psoriasis Area and Severity Index (PASI) scores, and compare SII trajectories among different treatment classes. Methods: A retrospective single-center study included 210 adults with psoriasis treated for 12 months with cyclosporine, anti-TNF-α, anti-IL-17, or anti-IL-23 agents. SII and PASI were recorded at baseline, 16, 36, and 52 weeks. Correlations between SII and PASI were assessed using Spearman’s analysis. Longitudinal changes were evaluated using the Friedman test, and treatment-group differences were assessed using Kruskal–Wallis analysis. An adjusted multivariable linear regression model including age, sex, body mass index, psoriatic arthritis, baseline PASI, and treatment group was performed to identify factors associated with Δ%SII. Results: SII correlated with PASI at baseline (ρ = 0.406, p < 0.001) and at 52 weeks (ρ = 0.186, p = 0.007), whereas no significant associations were observed at intermediate timepoints. Longitudinal analyses demonstrated significant differences in SII trajectories among treatment groups (p < 0.001). SII increased over time in the cyclosporine and anti-TNF-α groups, while anti-IL-17 and anti-IL-23 therapies were associated with marked and sustained reductions. In the adjusted model, anti-IL-17 (β = −90.7, 95% CI −119.6 to −61.8, p < 0.001) and anti-IL-23 therapies (β = −97.9, 95% CI −126.2 to −69.6, p < 0.001) remained independently associated with greater reductions in SII compared with cyclosporine, whereas anti-TNF therapy showed no significant difference. Conclusions: SII is a dynamic marker of systemic inflammatory changes in psoriasis and exhibits distinct longitudinal patterns according to treatment class. The pronounced reductions observed with IL-17 and IL-23 inhibitors support the potential value of SII as an adjunctive measure of systemic inflammation. However, prospective studies are required to clarify its clinical utility and determine its role in routine patient management. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article

Background: Cyclosporine is widely used to prevent transplant rejection; however, its systemic administration is associated with low bioavailability and a risk of severe adverse side effects. In the context of lung transplantation, local pulmonary delivery represents a promising strategy to reduce the required dose while enhancing local anti-inflammatory efficacy and limiting systemic toxicity. Methods: In this study, cyclosporine was encapsulated in liposomes coated with calcium phosphate to improve cellular uptake. The liposomal formulation was subsequently converted into a dry powder for inhalation to enable pulmonary administration, combining cyclosporine-loaded liposomes with a calcium phosphate coating, extending prior work on inhaled liposomal cyclosporine and mineral-coated liposomes into a single platform. The cyclosporine loading was optimised to achieve an efficient drug content in the final formulation. Results: The presence of the calcium phosphate coating on the liposomal surface was confirmed by the shift in zeta potential and by cryo-transmission electron microscopy. The resulting dry powder exhibited suitable aerodynamic properties for pulmonary delivery with a fine particle fraction of 33.6 ± 1.6%. In vitro biocompatibility studies performed on A549 epithelial cells and THP-1 monocytic cells demonstrated that the formulation did not affect cell viability. Furthermore, the formulation containing calcium phosphate-coated liposomes showed a stronger anti-inflammatory effect compared with both uncoated liposomal formulations and the corresponding raw material, consisting of a physical mixture of phospholipids and cyclosporine. Conclusions: Overall, despite limitations on respirability and efficacy that will require further in vivo studies, this calcium phosphate-coated liposomal dry powder could represent a promising strategy for targeted pulmonary delivery of cyclosporine, with potential to improve the prevention of lung transplant rejection while minimising systemic side effects. Full article

Background: Immunosuppressive drugs (ISDs) are essential for preventing organ rejection but have been reported to increase cancer risk with prolonged use. This study compares cancer risk between ISDs used for long-term maintenance after transplantation (T-ISDs) and those prescribed for non-transplant chronic conditions including cell-mediated (C-ISDs) and receptor-mediated (R-ISDs) ISDs. We hypothesized that cancer risk would differ between T-ISDs and both C-ISD and R-ISD groups. Methods: Using the TriNetX database, solid organ transplant recipients treated with tacrolimus (TAC), cyclosporine (CY), rapamycin (RAPA), or mycophenolate (MMF) were compared to propensity-matched R-ISDs (adalimumab, infliximab, etc.) or C-ISDs (methotrexate, azathioprine, etc.) for at least 24 encounters to determine risk of malignancy. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the three-year cancer risk. Results: After matching, T-ISDs were associated with higher malignancy risk compared to both R-ISDs (n = 29,748; HR 2.616, 95% CI 2.427–2.820) and C-ISDs (n = 31,704; HR 1.271, 95% CI 1.195–1.351). Each individual immunosuppressant in the T-ISD cohort was associated with increased cancer risk compared to R-ISDs, while only TAC and CY showed higher risk than C-ISDs (TAC: n = 9846, HR 1.354, 95% CI 1.228–1.492; CY: n = 1801, HR 1.234, 95% CI 1.007–1.512). Organ-specific analyses showed consistent patterns across systems. Conclusions: Overall, T-ISDs are associated with increased malignancy risk compared to R-ISDs and modestly compared to C-ISDs. TAC and CY confer the greatest risk, while MMF demonstrates relatively lower relative risk. These findings underscore the need to individualize ISD regimens to minimize long-term cancer risk. Full article