Variability In Treatment Response Research Articles

Variable treatment response to lumasiran in pediatric patients with primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH 1) is a rare genetic condition due to mutations in the AGXT gene. This leads to an overproduction of oxalate in the liver. Hyperoxaluria often causes kidney stones, nephrocalcinosis, and chronic kidney disease. Lumasiran is a recently approved drug that reduces the hepatic oxalate production by mRNA interference. In this multicenter study, we evaluated the response to lumasiran treatment in PH 1 patients (n = 8) with a median age of 10.9years (range 1.2-17.9years), including two patients on hemodialysis. We retrospectively analyzed the reduction of urinary and plasma oxalate levels as well as changes in kidney stone events, nephrocalcinosis, and kidney function. In patients without kidney failure, the median reduction of urinary oxalate was 64% (range 10-80%) and 71% (61-86%) at 6 and 12months, respectively. However, only one patient reached urinary oxalate levels within the age-specific normal range. Two patients did not respond to lumasiran and treatment was stopped. In one of the two patients on hemodialysis, the frequency of sessions could be reduced. The only notable side effects were injection site reactions. There was a variable response to lumasiran in PH 1. Despite a reduction of hyperoxaluria in many patients with PH 1, only one patient reached normal values and 2 of 8 patients did not respond. Regular monitoring of urinary oxalate values and registry data collection seems mandatory to monitor the efficacy and the long-term outcome of PH 1 treated with lumasiran.

P0604 Frequency and Analysis of Deep Remission in Patients with Ulcerative Colitis: A Single-Center Retrospective Study

Abstract Background Ulcerative Colitis (UC) is an inflammatory bowel disease affecting the colon and rectum, marked by periods of exacerbation and remission. Achieving deep remission is characterized by the absence of symptoms, normalized inflammatory markers, and endoscopic healing, which is linked to an improved long-term outcome. However, identifying the factors that contribute to deep remission remain important due to the variability in treatment responses and clinical presentations. The objective of this study was to assess the frequency of deep remission in patients with UC and to analyze the demographic and clinical factors associated with achieving this level of remission. Methods A retrospective study of 94 UC patients at the IBD Clinic of the General Hospital of Mexico analyzed medical records to assess demographic and clinical variables, including age, gender, disease extent, age at diagnosis, extraintestinal manifestations (EIMs), and treatments. Disease severity was evaluated using the Truelove and Witts scale (clinical), the Mayo sub-score (endoscopic), and the Riley index (histological). Patients were classified as being in deep remission if they achieved clinical, endoscopic, and histological remission, with normalized biochemical markers (C-reactive protein and fecal calprotectin). Statistical analyses, including chi-square tests and T-tests, were performed using SPSS version 29. Results Among the 94 patients studied, 18 (19.1%) achieved deep remission. In terms of gender, 38.9% of patients with deep remission were male and 61.1% were female, with no significant differences compared to patients without deep remission (p = 0.425). The mean age of patients with deep remission was higher (46.11 ± 13.26 years) compared to those without deep remission (40.66 ± 12.55 years), though this difference was not statistically significant (p = 0.091). Age at diagnosis was similar between both groups (35.83 ± 14.04 years vs. 34.76 ± 12.23 years, p = 0.785). Most patients in both groups were classified as E3 according to the Montreal classification, with no significant differences (p = 0.774). The use of conventional treatment was similar in both groups (77.7% vs. 64.4%, p = 0.423), while biological therapy was more common in patients without deep remission (35.5% vs. 22.2%, p = 0.217). Extraintestinal manifestations were more common in patients with deep remission (38.9% vs. 26.3%, p = 0.306). Conclusion In this study, 19.1% of patients with UC achieved deep remission. No significant differences were found in demographic or clinical factors. These results suggest that the factors evaluated were not significantly associated with deep remission in this cohort, underscoring the need to explore other potential determinants of remission in UC.

DOP093 ECCO Topical Review on predictive models for IBD disease course and treatment response

Abstract Background Inflammatory Bowel Disease (IBD) poses a clinical challenge due to its variable progression and treatment response. Despite the development of predictive models, their clinical application remains limited due to validation and methodological inconsistencies. This ECCO Topical Review examines existing predictive models, assesses their relevance, and discusses the barriers to their clinical implementation. Methods A panel formed by the European Crohn's and Colitis Organisation (ECCO), including gastroenterologists, surgeons, and methodologists, reviewed predictive models on IBD disease course and treatment response. Using the Medline, PubMed, EMBASE, and Scopus databases, they systematically identified relevant literature to evaluate clinical significance, performance, and barriers to clinical integration. Results The panel developed 21 statements on predictive models for IBD disease course and response, with supporting text. Predictive models for IBD disease course For ulcerative colitis (UC), models included clinical factors (e.g., age at diagnosis, male gender), biochemical markers (e.g., C-reactive protein [CRP], anemia), and treatment history. Crohn’s disease (CD) models incorporated disease characteristics like stricturing behavior, perianal disease, and imaging findings. Predictive models for treatment response UC models focused on severe flares and moderate-to-severe cases managed with biologics, with predictors like CRP, disease duration, and endoscopic severity. CD models emphasized predictors like body mass index, smoking status, and CRP levels. The utility of omics data remains inconsistent. Barriers to clinical implementation Models lacked generalizability across diverse populations and face barriers related to clinical integration, healthcare acceptance, regulatory factors, and economics. Methodological approaches Future models should use diverse datasets and adhere to TRIPOD guidelines (1). Validation through metrics like calibration and discrimination, as well as trials, will be essential for real-world effectiveness. Future directions Predictive models should identify treatment responders, aid in safe discontinuation, and support personalized strategies. Models need biomarkers that are cost-effective, reproducible, and adaptable to individual patient profiles. Conclusion Based on this ECCO Topical Review currently being finalized, predictive models for IBD hold promise, but challenges persist in clinical integration. Overcoming methodological issues, performing validation, improving biomarkers, and conducting impact studies are critical. Collaboration among researchers, clinicians, and regulators is pivotal to advance models that improve patient outcomes. References (1)Collins et al. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. The TRIPOD Group. Circulation 2015;131(2):211–9.

The Cell-Specific Effects of JAK1 Inhibitors in Ulcerative Colitis.

JAK1 inhibitors have become an important addition to the therapeutic options for ulcerative colitis (UC), targeting key inflammatory pathways mediated by cytokines such as the IL-6 family, interferons, IL-2 family, IL-10 family, and G-CSF. However, not all patients respond equally, and chronic inflammation persists in a subset of individuals. The variability in treatment response may reflect the heterogeneity of UC. Immune cells, epithelial cells, and stromal cells may have distinct contributions to disease pathogenesis. While JAK inhibitors were originally designed to target immune cells, their impact on non-immune cell types, such as epithelial and stromal cells, remains poorly understood. Investigating the mechanisms through which JAK1 inhibitors affect these diverse cellular populations and identifying the factors underlying differential responses is crucial to optimizing outcomes. This review explores the roles of immune, epithelial, and stromal cells in response to JAK1 inhibition and discusses potential strategies to improve treatment precision, such as predicting responders and identifying complementary therapeutic targets.

A Nomogram Built on Clinical Factors and CT Attenuation Scores for Predicting Treatment Response of Acute Myeloid Leukemia Patients.

Background: Acute myeloid leukemia (AML) is an aggressive cancer with variable treatment responses. While clinical factors such as age and genetic mutations contribute to prognosis, recent studies suggest that CT attenuation scores may also predict treatment outcomes. This study aims to develop a nomogram combining clinical and CT-based factors to predict treatment response and guide personalized therapy for AML patients. Methods: This retrospective study included 74 newly diagnosed AML patients who underwent unenhanced abdominal CT scans within one week before receiving their first induction chemotherapy. Clinical biomarkers of tumor burden were also collected. Patients were classified into two groups based on treatment response: complete remission (CR; n = 24) and non-complete remission (NCR; n = 50). Multivariable logistic regression was used to identify independent predictors of treatment response. Predictive performance was evaluated using receiver operating characteristic (ROC) curves, and model consistency was assessed through calibration and decision curve analysis (DCA). Results: Significant differences in hemoglobin (Hb), platelets (Plt), and CT attenuation scores were observed between the CR and NCR groups (all p < 0.05). Multivariable logistic regression identified Hb, Plt, and CT attenuation scores as independent predictors of treatment response. A nomogram incorporating these factors demonstrated excellent predictive performance, with an area under the curve (AUC) of 0.912 (95% CI: 0.842-0.983), accuracy of 0.865 (95% CI: 0.765-0.933), sensitivity of 0.880 (95% CI: 0.790-0.970), and specificity of 0.833 (95% CI: 0.684-0.982). The CR nomogram displayed significant clinical value and excellent goodness of fit. Conclusions: The nomogram, which incorporates Hb, Plt, and CT attenuation scores, provides valuable insights into predicting treatment response in AML patients. This model offers strong discriminatory ability and could enhance personalized treatment planning and prognosis prediction for AML.

Identifying factors associated with perfluorohexyloctane treatment response in dry eye disease patients with meibomian gland dysfunction: A post‐hoc analysis

Aims/Purpose: The heterogeneous nature of dry eye disease (DED) associated with meibomian gland dysfunction (MGD) poses challenges for effective treatment, necessitating a deeper understanding of associated factors. Perfluorohexyloctane eye drops (PED, SHR8058) have shown efficacy in DED treatment, yet variability in treatment response remains unclear. This post‐hoc analysis explores factors associated with PED treatment response to identify patient subgroups benefiting most.Methods: Using data from a phase 3, randomized, double‐blind, salinee‐controlled, multicenter clinical study (NCT05515471), this post hoc responder analysis aggregated data from 156 patients in the PED treatment group. Response outcomes for signs and symptoms were assessed using total corneal fluorescein staining (tCFS, ≥ 3 reductions from baseline) and eye dryness score (EDS, ≥ 30% reduction from baseline), respectively. Univariate and multivariate logistic regression using stepwise selection method, with the cutoff p‐value to enter of 0.1 and stay in the model set at 0.05 were applied to explore potential variables associated with response outcomes.Results: Among 156 patients treated with PED, the mean (SD) of tCFS and EDS was 6.2 (1.9), and 64.7 (15.1) at baseline. In both univariate and multivariate regression analysis for signs response, tCFS score and ametropia showed association with signs response (odds ratio [OR] 1.4; 95% confidence interval [CI], 1.08‐1.73 and OR 3.0; 95% CI, 1.27‐7.25 respectively in multivariate analyses). Regarding symptoms, EDS (OR 1.1; 95% CI, 1.02‐1.11), awareness of DED symptoms (OR 1.0; 95% CI, 0.93‐0.99), dryness frequency (OR 1.0; 95% CI, 0.93‐1.00), and tCFS (OR 1.4; 95% CI, 1.05‐1.77) were independent associated factor of EDS in multivariate analysis.Conclusions: These post hoc findings suggest that tCFS score, ametropia, EDS, awareness of DED symptoms and dryness frequency are associated with PED treatment response.

Multivariable prognostic prediction of efficacy and safety outcomes and response to fingolimod in people with relapsing-remitting multiple sclerosis.

The individual treatment response in people with relapsing-remitting multiple sclerosis (RRMS) remain unpredictable. In order to support medical decisions, we aimed to predict response to fingolimod compared to placebo, by developing and validating prognostic multivariable models. We included two-year follow-up from intention-to-treat populations of two multi-country placebo-controlled randomized controlled trials (RCT) of daily fingolimod 0.5 mg. The data was accessed via ClinicalStudyDataRequest.com (Proposal Number: 11223) The RCTs were in adult RRMS patients with active disease. We used four Cox proportional hazards based penalized (elastic net and grouped lasso) and tree methods (transformation tree and forest) to predict time-to relapse and other relevant efficacy and safety endpoints in data from the RCT FREEDOMS. Treatment arm, 80 baseline variables and their interaction with treatment were considered as candidate predictors in the models. A nested cross-validation scheme ensured independent tuning parameter optimization and internal model performance evaluation. The generalizability of the models with the highest cross-validated time-dependent area under the receiver operating curve (AUC) was further evaluated in terms of discrimination (AUC), calibration (plots, intercept, slope), clinical utility (decision curve analysis), and treatment response plots by external validation in data from the RCT FREEDOMS II. The best performing model predicting relapse risk (331 events) in the development sample (n=843) was an elastic net regression with main terms for four predictors alongside treatment: EDSS score, volume of Gadolinium enhanced T1 lesions, number of relapses in the last 2 years, and number of prior MS treatments. In external validation (n=713), it had an AUC of 0.68 (95% CI 0.63-0.72), but the predictions were overestimating the actual risk (358 events) with a calibration-in-the-large of -0.17 (-0.3 - -0.04) and a slope of 1.06 (0.78-1.35). Almost no heterogeneity (variability 0.001) was detected in the predicted relapse risk change in response to fingolimod. FREEDOMS II participants were predicted to have 0.21 to 0.31 absolute relapse risk reduction with fingolimod compared to placebo. The selected model predicting new or enlarging T2 magnetic resonance imaging (MRI) lesions had an AUC of 0.74 (0.70-0.78), moderate calibration, but no treatment response variability. The final model predicting confirmed disability progression had an AUC of 0.59 (0.54-0.64) and the predicted treatment response heterogeneity was not significant. The overall safety outcome could not be predicted with sufficient discrimination. However, the final model predicting infections or neoplasms had an AUC of 0.69 (0.63-0.74) and non-significant treatment response heterogeneity. For the efficacy outcomes, important predictors were related to (para)clinical disease activity or disability. Unexpected influential predictors included concomitant disorders. Relapse and new or enlarging T2 MRI lesions were moderately predictable in an independent sample with the developed prognostic models. Fingolimod was expected to decrease the risk of these events for all patients, with no predictable heterogeneity. Disability and safety outcomes could not be well-predicted and it is yet unresolved whether the change in their risk as response to fingolimod is heterogeneous or not.

DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia.

Inotuzumab Ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a primary driver of InO resistance. Mechanistically, DNTT downregulation attenuated InO-induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts, with substantial intra-leukemia heterogeneity as revealed by scRNA sequencing. In B-ALL patients enrolled in the COG trial AALL1621, we observed consistent DNTT downregulation in residual blasts post-InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.

Carrot-Derived Rhamnogalacturonan-I Consistently Increases the Microbial Production of Health-Promoting Indole-3-Propionic Acid Ex Vivo.

Using dietary interventions to steer the metabolic output of the gut microbiota towards specific health-promoting metabolites is often challenging due to interpersonal variation in treatment responses. In this study, we combined the ex vivo SIFR® (Systemic Intestinal Fermentation Research) technology with untargeted metabolite profiling to investigate the impact of carrot-derived rhamnogalacturonan-I (cRG-I) on ex vivo metabolite production by the gut microbiota of 24 human adults. The findings reveal that at a dose equivalent to 1.5 g/d, cRG-I consistently promoted indole-3-propionic acid (IPA) production (+45.8% increase) across all subjects. At a dose equivalent to 0.3 g/d, increased IPA production was also observed (+14.6%), which was comparable to the effect seen for 1.5 g/d inulin (10.6%). IPA has been shown to provide protection against diseases affecting the gut and multiple organs. The Pearson correlation analysis revealed a strong correlation (R = 0.65, padjusted = 6.1 × 10-16) between the increases in IPA levels and the absolute levels of Bifidobacterium longum, a producer of indole-3-lactic acid (ILA), an intermediate in IPA production. Finally, the community modulation score, a novel diversity index, demonstrated that cRG-I maintained a high α-diversity which has previously been linked to elevated IPA production. The results from the ex vivo SIFR® experiment mirrored clinical outcomes and provided novel insights into the impact of cRG-I on the gut microbiome function. Importantly, we demonstrated that cRG-I promotes tryptophan conversion into IPA via gut microbiome modulation, thus conferring benefits via amino acid derived metabolites extending beyond those previously reported for short chain fatty acids (SCFA) resulting from carbohydrate fermentation.

Autologous blood in the management of ocular surface disorders.

Autologous blood therapy has emerged as a promising modality in managing ocular surface disorders. This review provides a comprehensive overview of the current literature regarding the use of autologous blood in ocular surface disorders, encompassing its physiological basis, clinical applications, techniques, challenges, and future perspectives. The ocular surface, comprising the cornea, conjunctiva, and tear film, plays a critical role in maintaining visual function, and its disruption can lead to various pathological conditions. With its rich composition of growth factors, cytokines, and other bioactive molecules, autologous blood offers therapeutic potential in promoting corneal wound healing, reducing inflammation, and improving tear film stability. Clinical studies have demonstrated the efficacy and safety of autologous blood therapy in diverse ocular surface disorders, including persistent epithelial defects, neurotrophic keratopathy, and dry eye disease. However, challenges such as variability in treatment response, adverse effects, and optimal patient selection remain areas of concern. Further research is needed to elucidate the underlying mechanisms of action, refine treatment protocols, and explore synergistic approaches with other therapeutic modalities. Despite these challenges, autologous blood therapy holds promise as a valuable adjunctive treatment option for ocular surface disorders, offering new avenues for improving patient outcomes and quality of life. This review examines the mechanisms underlying ocular surface disorders while discussing existing autologous blood-based therapies for managing these disorders. Current clinical trials are also summarized, and a comparison between autologous blood therapy and conventional eyedrops is attempted. Finally, safe techniques and protocols for autologous blood medicine are elucidated, and adverse effects and future perspectives of this novel therapy are reviewed.

P117 Dose optimization of bimekizumab for adult patients with plaque psoriasis: an interim analysis of data from a real-world, multicentre, retrospective review

Abstract The standard bimekizumab dosing regimen for adult patients with plaque psoriasis is 320 mg administered as a subcutaneous injection at Weeks 0, 4, 8, 12, and 16, then every 8 weeks (Q8W) thereafter. However, dose optimization may be required due to variability in treatment response. We conducted a real-world, multicentre, retrospective review of bimekizumab dose optimization for plaque psoriasis in adults. From a total cohort of 91 patients, we identified 15 (16.5%) that underwent dose optimization from Q8W to every 4 weeks (Q4W; 93.3%, 14/15) or every 6 weeks (Q6W; 6.7%, 1/15) in the maintenance period. All patients underwent dose optimization due to lack of efficacy. Mean age was 47.7 (range: 23–74) years, with 60% (9/15) being female. Mean time to dose optimization was 42.4 (range: 15.6–99) weeks. At the time of dose escalation (n = 15), mean psoriasis area and severity index (PASI) score was 3.4 (mean improvement from baseline: 50.5%) and mean body surface area (BSA) was 3.2% (mean improvement from baseline: 51%), with Investigator Global Assessment (IGA) scores of 1 (33.3%, 5/15), 2 (46.7%, 7/15), 3 (13.3%, 2/15), and 4 (6.7%, 1/15). Prior to dose escalation, there were 33.3% (5/15), 46.7% (7/15), and 20% (3/15) of IGA 0/1, 75% improvement in PASI (PASI75), and 90% improvement in PASI (PASI90) responders. Following a mean follow-up period of 17.5 (range: 2.9–35.6) weeks after dose optimization, there were 86.7% (13/15), 66.7% (10/15), 66.7% (10/15), and 60% (9/15) responders in IGA 0/1, PASI75, PASI90, and PASI100. From the time of dose escalation, mean improvement in PASI and BSA were 79.2% (85.2% from baseline) and 81.2% (90.6% from baseline), respectively. There was 1 (6.7%) discontinuation due to persistent lack of efficacy following dose optimization. Five treatment-related adverse events (AEs) occurred, including candidiasis (13.3%, 2/15), folliculitis (6.7%, 1/15), recurrent cellulitis (6.7%, 1/15), and recurrent urinary tract infection (UTI; 6.7%, 1/15). Of these, only the UTI patient (6.7%, 1/15) experienced an AE following dose escalation. There were no safety-related treatment discontinuations, nor any serious infections, suicidal ideation/behaviour, malignancies, hypersensitivity reactions, major adverse cardiac events, or hepatic abnormalities. In Phase III clinical trials, while IGA 0/1 and PASI90 rates were comparable between dosing regimens, Q4W maintenance dosing of bimekizumab was associated with a higher PASI100 rate than Q8W dosing [73.5–83% (Q4W) vs. 66–70.8% (Q8W)] at 1-year. Furthermore, AEs were comparable between dosing regimens with slightly higher rates of oral candidiasis and UTI with Q4W dosing. Our real-world results show increased achievement of IGA 0/1, PASI90, and PASI100 with dose optimization and no new safety signals. Study limitations include its small sample and retrospective nature.

Single-cell RNA-seq reveals diverse molecular signatures associated with Methotrexate resistance in primary central nervous system lymphoma cells.

Methotrexate is one of the most essential single agents in patients with primary central nervous system lymphoma (PCNSL). However, 25-50% result in relapse with a poor prognosis. Therefore, studies on methotrexate resistance are warranted to explore salvage chemotherapy for recurrent PCNSL. Single-cell sequence analysis enables the characterization of novel cell types and provides a precise understanding of cancer biology. Single-cell sequence analysis of parental and methotrexate-resistant PCNSL cells was performed. We used a Weighted Gene Co-expression Network Analysis to identify groups of significantly connected genes. We identified consensus modules in both the HKBML and TK datasets. HLA-DRβ1, HLA-DQβ1,and SNRPG were hub genes those detected in both datasets revealed by network analysis. Cyclosporine A was selected as the candidate drug for treating methotrexate-resistant cells. The results of the present study characterized the methotrexate resistance-related signaling pathways in cultured PCNSL cells. Overall, these results may account for variations in treatment responses and lead potential novel therapeutic strategies for patients with PCNSL.

Intravenous immunoglobulin therapy: usage patterns and response to treatment in Qatar over ten years.

IVIg is a blood-derived antibody product initially designed as a replacement therapy in inborn errors of immunity (IEIs). However, over the last 50 years, IVIg has been used to treat a growing range of autoimmune, autoinflammatory, and secondary immunodeficiency disorders. The US FDA has licensed IVIg for use in the treatment of nine clinical indications; although, IVIg global usage extends to off-label indications with variable treatment responses. Data from Qatar on the use of IVIg is scarce; thus, hampering the formulation of local policies. This study aimed to examine the utilization patterns, clinical indications, and safety profile of IVIg usage in Qatar; a nation with a predominantly young population, and to investigate the response rates to short- and long-term IVIg treatment, as well as explore associations between age at first IVIg dose, clinical indication, and treatment response. A retrospective chart review was conducted of patients who received IVIg between March 2009, and March 2019, in Hamad General Hospital, Qatar. Demographics, immediate adverse effects of IVIg, and treatment response were collected. IVIg clinical indications were categorized into FDA- and/or EMA-approved, those supported by international guidelines; those approved as second-line therapy, and those with low or no supportive evidence. IVIg was used for 63 indications during the 10-years. The age of patients skewed towards a younger demographic (median (IQR) 24 (44-6) years); however, no significant differences in response to short- and long-term treatment between age groups were observed. Of the 841 patients, 62% received IVIg in concordance with international recommendations, while 14% bestowed the treatment for indications with low or no supportive evidence. Immediate IVIg adverse effects were documented in 4% of patients in all of the infusions received, with headaches being the most prevalent (1.8%). Variable treatment responses were observed, with the highest recovery reported in immune thrombocytopenic purpura (35%), followed by transverse myelitis (28%). This study provided crucial insights into IVIg utilization, safety, and treatment outcomes in Qatar's young population. Despite variability in treatment responses and off-label use, adherence to international recommendations remained eminent. Further research is warranted to inform local guidelines and optimize IVIg therapy outcomes.

Multiple gene therapy as a tool for regulating the expression of molecules involved in neovascular age-related macular degeneration.

Anti-vascular endothelial growth factor (VEGF) therapies have revolutionized the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. However, the necessity for repeated intravitreal injections and the observation of variable treatment responses calls for new treatment modalities where fewer and more effective interventions can result in a clinical effect. Gene therapy might be such an alternative, and therefore the development and clinical application of gene therapy aimed at modifying gene expression has received considerable attention. The article reviews current knowledge of the background, pathophysiological mechanisms, technologies, limitations, and future directions for gene therapy aimed at modifying the synthesis of compounds involved in acquired and senescent retinal disease. The authors have contributed to the field by developing gene therapy to reduce the expression of vascular endothelial growth factor (VEGF), as well as multiple gene therapy for simultaneous downregulation of the synthesis of VEGF and upregulation of pigment epithelium-derived factor (PEDF) using adeno-associated virus (AAV) vectors. It is suggested that such multi-target gene therapy might be included in future treatments of retinal diseases where the underlying mechanisms are complex and cannot be attributed to one specific mediator. Such diseases might include dry AMD (dAMD) with geographic atrophy, but also diabetic macular edema (DME) and retinal vein occlusion (RVO). Gene therapy can be expected to be most beneficial for the patients in need of multiple intra-vitreal injections and in whom the therapeutic response is insufficient. It is concluded, that in parallel with basic research, there is a need for clinical studies aimed at identifying factors that can be used to identify patients who will benefit from gene therapy already at the time of diagnosis of the retinal disease.

Clinical and genetic diversity in Iranian individuals with RAPSN-related congenital myasthenic syndrome.

Congenital myasthenic syndromes (CMSs) are genetic disorders affecting motor function with variable symptoms. RAPSN-related CMS, caused by mutations in the RAPSN gene, leads to muscle weakness. Accurate diagnosis is essential for proper management. This study aims to analyze six Iranian families affected by RAPSN-CMS, focusing on clinical manifestations, genetic variants, treatment response, and outcomes. Clinical assessments, genetic analysis, and whole-exome sequencing were performed on the six families to identify RAPSN gene mutations. The study examined symptoms, disease severity, age of onset, treatment response, and outcomes. Treatment with pyridostigmine and salbutamol was given to assess its effectiveness. Three homozygous known variants in RAPSN gene were identified: c.491G > A in three families, c.264C > A in two families, and c.-210A > G in one family. Clinical assessments showed diversity in symptoms and treatment responses. Pyridostigmine and salbutamol treatment improved symptoms and quality of life. This study highlights the significance of molecular diagnosis for RAPSN-related congenital myasthenic syndromes (CMS) in Iran, marking the first comprehensive genetic analysis in the region. The identification of specific pathogenic variants underscores the unique genetic landscape of local patients. Furthermore, our long-term follow-up revealed variable treatment responses, emphasizing the need for personalized care strategies. The clinical variability among patients with identical mutations necessitates a multidisciplinary approach for effective management. By enhancing genetic awareness and refining follow-up methods, we aim to improve diagnosis accuracy and interventions, fostering better outcomes for affected families in the Iranian population.

The Estrogen-Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection.

Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet to reach a consensus on the most effective approach to manipulating autophagy, with ongoing debates about whether its inhibition or stimulation is preferable for managing these complex conditions. One critical factor contributing to the variability in treatment responses for both cancers and infectious diseases is estrogen, a hormone known for its diverse biological effects. Given the strong correlations observed between estrogen signaling and autophagy, this review seeks to summarize the intricate molecular mechanisms that underlie the dual cytoprotective effects of estrogen signaling in conjunction with autophagy. We highlight recent findings from studies that involve various ligands, disease contexts, and cell types, including immune cells. Furthermore, we discuss several factors that regulate autophagy in the context of estrogen's influence. Ultimately, we propose a hypothetical model to elucidate the regulatory effects of the estrogen-autophagy axis on cell fate. Understanding these interactions is crucial for advancing our knowledge of related diseases and facilitating the development of innovative treatment strategies.

Immunotherapy in Oral Cancer

Abstract Squamous cell carcinoma of the head-and-neck (HNSCC) ranks sixth in global cancer incidence and poses significant challenges in terms of morbidity and mortality. The tumor microenvironment in HNSCC is a complex milieu involving immune cells, stromal elements, and cytokines, among other factors. Immunotherapy has emerged as a potent therapeutic avenue, particularly through immune checkpoint inhibitors (ICIs), for modulating this intricate environment. ICIs have garnered approval for first-line use in recurrent and metastatic HNSCC. However, recent clinical observations underscore the variability in treatment response to immunotherapy. This necessitates a thorough exploration of diverse ICI agents and combination strategies to optimize therapeutic outcomes. A comprehensive assessment and focused investigation of the immune contexture in HNSCC patients undergoing ICI therapy are pivotal for advancing treatment efficacy. Numerous innovative immunotherapeutic modalities, including chimeric antigen receptor-T-cell therapy, oncolytic virus therapy, and vaccination strategies, are actively under development. Furthermore, identifying robust biomarkers to guide patient selection for immunotherapy is of paramount importance. The quest for optimal combination regimens incorporating novel immunotherapies represents a recent paradigm shift in the management of HNSCC. This review is a concise summary of the clinical progress and ongoing trials in immunotherapy for HNSCC, highlighting the dynamic landscape of treatment approaches in this challenging disease context.

Detailed Pathophysiology of Minimal Change Disease: Insights into Podocyte Dysfunction, Immune Dysregulation, and Genetic Susceptibility.

Minimal Change Disease (MCD) is a predominant cause of idiopathic nephrotic syndrome in the pediatric population, yet presents significant clinical challenges due to its frequent relapses and steroid resistance. Despite its relatively benign histological appearance, MCD is characterized by severe proteinuria, hypoalbuminemia, and edema, which may affect patient outcomes. Current treatment strategies primarily rely on corticosteroids, which are effective in inducing remission but are associated with high relapse rates, steroid resistance, and numerous long-term side effects, underscoring the need for more targeted and effective therapeutic approaches. This narrative review synthesizes current knowledge on the pathophysiological mechanisms underlying MCD, focusing on the following three critical areas: podocyte dysfunction, immune dysregulation, and genetic susceptibility. Podocyte dysfunction, particularly involving alterations in nephrin, plays a central role in the breakdown of the glomerular filtration barrier, leading to the characteristic proteinuria observed in MCD. Immune dysregulation, including the presence of autoantibodies against nephrin and other podocyte components, exacerbates podocyte injury and contributes to disease progression, suggesting an autoimmune component to the disease. Genetic factors, particularly mutations in the NPHS1 and NPHS2 genes, have been identified as significant contributors to disease susceptibility, influencing the variability in treatment response and overall disease severity. Understanding these mechanisms is crucial for developing targeted therapies that address the underlying causes of MCD rather than merely managing its symptoms. This review highlights the need for further research into these pathophysiological processes to pave the way for more personalized and effective treatment strategies, ultimately improving patient outcomes and reducing reliance on corticosteroids.

Stimulant medication and symptom interrelations in children, adolescents and adults with attention-deficit/hyperactivity disorder.

Stimulant medication is effective in alleviating overall symptom severity of attention-deficit/hyperactivity disorder (ADHD), yet interindividual variability in treatment response and tolerability still exists. While network analysis has identified differences in ADHD symptom relations, the impact of stimulant medication remains unexplored. Increased understanding of this association could provide valuable insights for optimizing treatment approaches for individuals with ADHD. In this study, we compared and characterized ADHD symptom networks (including 18 ADHD symptoms) between stimulant-treated (n = 348) and untreated (n = 70) individuals with ADHD and non-ADHD controls (NACs; n = 444). Moreover, we compared symptom networks between subgroups defined by their stimulant treatment trajectory (early-and-intense use, late-and-moderate use). Stimulant-treated individuals with ADHD showed stronger associations between symptoms, compared with untreated individuals with ADHD and NACs. We found no differences in symptom networks between the stimulant treatment trajectory subgroups. Prospective longitudinal studies are needed to disentangle whether the identified differences stem from treatment or pre-existing factors.

RADT-41. RADIOSURGERY FOR GLOMUS TUMORS: IMPACT OF MRI-PET FUSION ON TREATMENT PLANNING AND OUTCOMES

Abstract Paragangliomas present a challenge for stereotactic radiosurgery (SRS) treatment planning, particularly regarding the delineation of tumor boundaries. We propose that integrating 68Ga-DOTATATE PET scans alongside MRI in SRS planning will facilitate superior target identification and tumor coverage compared to reliance on MRI alone. A retrospective analysis of 9 patients diagnosed with paraganglioma who underwent MRI and 68Ga-DOTATATE PET imaging over a 20-month period was conducted. Images were imported into GammaPlan treatment planning software, partitioned into separate sessions: one with MRI and another with MRI-PET fusion. A single evaluator contoured paragangliomas as gross tumor volume (GTV) initially using MRI alone and subsequently with PET/MRI fusion. The pre- and post-PET fusion GTV volumes were compared. The standard deviation of the percentage increases in volume was calculated to assess variability across the sample. Of included 9 patients, 7 were females and median age was 58.3 years. Four patients had prior surgery. Seven patients were treated with Gamma Knife, while 2 with LINAC. Two patients were treated with single fraction SRS while 7 with hypofractionated SRS. Across all treated patients (n=9), GTV volumes significantly increased with PET fusion, with an average volume increase of 26.02% (n=8). One patient reported dryness of throat after SRS. Significant PET avidity over structures like temporal bone, internal jugular vein, petrous internal carotid artery and sigmoid sinus-IJV junction were included in PET/MRI fusion GTVs, which were missed on isolated MRI contours. At median 6-month follow up, all patients had a stable radiological response. Integration of 68Ga-DOTATATE PET scans with MRI enhances the visualization of paragangliomas in patients undergoing SRS. Further extensive studies are warranted to validate this observation and to better understand the variability in treatment response observed across the patient population. Our practice has initiated routine utilization of DOTATATE-PET imaging in paraganglioma patients undergoing SRS planning.