Background:Dental caries is a common oral health problem that affects people all over the world. To detect and treat it early on, it is important to have a thorough understanding of its genesis and potential biomarkers. Objective:The objective of this systematic review is to answer the question: "Is there any role of immune status in the development of dental caries among children and adults, and is there any potential in using immunological markers for diagnosis, prognosis, and treatment of this condition?" Design:From 2016 to 2024, a thorough search approach adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria was used across several datasets (PROSPERO: CRD42024612045). To find pertinent publications, a total of 2,723 articles were searched using keywords associated with dental caries, immunity, and interventions. The inclusion criteria included papers that addressed the connection between immunity and the development of caries, interventions, and results, including alterations in basal metabolic rate (BMR), weight gain in patients, improvements in quality of life, and recurrence of carious lesions. Two reviewers independently extracted the data, assessed its quality, and assessed the risk of bias using validated instruments such as the Cochrane Risk of Bias tool and the Newcastle-Ottawa Scale. Results:The evaluation encompassed 10 articles in all, demonstrating noteworthy correlations between immunological indicators and dental caries. Results point to a favorable correlation between salivary immunoglobulin A (IgA) levels and the number of carious teeth, as well as an increase in proinflammatory cytokine concentrations in dental caries patients. Furthermore, the pulp tissue of dental caries patients has different bacterial communities and higher expression of proinflammatory cytokines, suggesting a possible connection between immune activation and dysbiosis. Conclusion:The findings highlight the significance of immune status/immunological indicators in the diagnosis and treatment of dental caries, emphasizing the necessity for additional study to corroborate these conclusions and improve treatment and preventative dental care practices. Clinical relevance:This work has got great relevance to pediatric dentists. The current work highlights a possible link between the immune status and the development of caries in pediatric and adult patients as well as the potential of immunological markers in the diagnosis, prognosis, and treatment of dental caries in both pediatric and adult patients. Prospero registration number:CRD42024612045.

INTRODUCTION:CAR T therapy is used in various hematological malignancies that involve genetic modification of autologous T cells to target tumor cells. The aim of this meta-analysis was to evaluate the efficacy and safety of CAR T cell therapy in haematological malignancies with relation to response rates, survival outcomes, and treatment-related adverse events. METHODS:This meta-analysis followed PRISMA guidelines. 428 records were identified from Pub- Med, Embase, Web of Science, Scopus, Cochrane Library, and Google Scholar for studies between 2019 and 2024. Clinical trials and observational studies evaluating CAR T therapy in haematological malignancies were included. Study quality was assessed using the Newcastle Ottawa Scale and ROBINS I tool. Random effects models were used, and heterogeneity was measured with the I² statistic. RESULTS:Twelve studies met the inclusion criteria. CAR T therapy showed high ORR and CR in Bcell malignancies, with ORR reaching 90.5% in R/R B NHL and 81% remission in B ALL. CRS was common but mainly mild to moderate, while neurotoxicity and GvHD were less frequent. Metaanalysis demonstrated substantial heterogeneity for ORR, CR, and CRS. Most studies were rated good quality, though moderate bias related to missing data and design differences was observed. DISCUSSION:Meta-analysis shows CAR T therapy achieves high ORR and durable remission in B ALL and DLBCL. CD19-directed therapy was promising. Compared to myeloid cell malignancies, B-cell malignancies showed better response. These findings point towards optimisation of protocol and appropriate patient selection apart from the toxicity management, which is required to improve the outcomes. CONCLUSION:CAR T therapy shows high response rates in haematological malignancies with controllable toxicity, thus establishing its role in relapsed and refractory disease. It highlights the need for improved durability, access, and constant clinical application.

D, Swaminadhan; Veeraraghavan, Vishnu Priya; Surapaneni, Krishna Mohan; Prashar, Lavina MBChB., MD; Mony, Ullas Author Information

BACKGROUND:Tumor-infiltrating lymphocyte (TIL) treatment is an individualized method of treating different types of solid tumors by using the immune system of the body to target and destroy cancer cells. Although its usefulness has been shown in certain diseases, such as ovarian cancer and melanoma, research is still being done to see whether it is also beneficial against a wider variety of solid tumors. AIM:To methodically assess the safety, effectiveness, and clinical results of TIL therapy for various solid tumors. METHODOLOGY:A thorough search in various databases produced 218 papers on TIL treatment for various solid tumors (2018-2024). Nine of the ten papers that satisfied the requirements for inclusion in the quantitative analysis were also included in the systematic review. Two reviewers separately extracted the data and evaluated it. The Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool were used to evaluate the quality of the studies, and the I2 statistic in the meta-analysis was used to measure heterogeneity. RESULTS:Numerous studies that looked at the effectiveness of TIL treatment in different types of cancer showed different results. In NSCLC and melanoma, higher CD8+/CD4+ TIL ratios were associated with improved outcomes; in advanced melanoma, TIL therapy was superior to ipilimumab. Response rates differed, with NSCLC showing up at 23.1 % and melanoma up to 53.3 %. Most studies were of good quality and is confirmed by the Newcastle-Ottawa Scale, while some had problems with follow-up. The results' dependability was confirmed by the ROBINS-I and ROB2 tools, which showed low to moderate bias risk. CONCLUSION:According to the study's findings, TIL therapy is effective in treating solid tumors, especially melanoma, but its results vary according to the kind of cancer as well as tumour microenvironments. Therefore more research is needed to determine the best course of action.

Introduction: Serum B-cell maturation antigen (sBCMA) is an emerging non-invasive biomarker for assessing tumor burden and treatment response in multiple myeloma (MM). While several Western studies have established its diagnostic and prognostic utility, data from South Asian populations is limited. Differences in patient demographics, disease biology, and access to diagnostics may influence biomarker utility, making the validation of sBCMA in this population essential. This prospective study focuses on a South Indian cohort, evaluating sBCMA levels across the spectrum of plasma cell dyscrasias and healthy controls. It also explores correlations between sBCMA and established prognostic markers in newly diagnosed MM (NDMM). Methods: This single-center prospective study was conducted between July 2023 and February 2025, enrolling 219 individuals categorized into six subgroups: NDMM (n=60), smoldering MM (SMM, n=17), monoclonal gammopathy of undetermined significance (MGUS, n=32), relapsed MM (n=17), MM in remission (n=17), and age- and gender-matched controls (n=76). Serum samples were collected and stored at –80°C until analysis. sBCMA levels were quantified using ELISA (RayBio® Human TNFRSF17, Catalogue No: ELH-TNFRSF-17) with all samples run in triplicate and their mean values were taken to ensure analytical precision. Comparisons of median sBCMA levels across subgroups and ISS/RISS stages (I–III) were done using the Kruskal-Walli's test, followed by post hoc Dunn's test for pairwise comparisons. In the NDMM subgroup, Spearman's rank correlation was used to assess the relationship between sBCMA and established markers of tumor burden and disease severity. Risk stratification based on mSMART 4.0 was analysed using the Mann–Whitney U test. Results: The median age of the cohort was 62 years (range:58-69 years), with 54.8% males. A significant difference in sBCMA levels were observed across subgroups (p < 0.001). The highest median sBCMA levels were noted in NDMM (255 ng/mL) and relapsed MM (240 ng/mL), while markedly lower levels were observed in patients in remission (80 ng/mL, p<0.001) and those with MGUS (81 ng/mL, p<0.001), both comparable to controls (74 ng/mL). SMM exhibited significantly elevated levels (200 ng/mL, p <0.001) compared to controls, indicating that sBCMA may detect early disease activity. In NDMM, sBCMA showed strong positive correlations with bone marrow plasma cell percentage by morphology (ρ = 0.759, p < 0.001) and flow cytometry findings (ρ = 0.537, p = 0.001). Moderate correlations were observed with M-protein (ρ = 0.287, p = 0.026) and β₂-microglobulin (ρ = 0.396, p = 0.005). Significant negative correlations were seen with hemoglobin (ρ = –0.508, p < 0.001) and serum albumin (ρ = –0.408, p = 0.001). No significant association was found with age, serum creatinine, or involved free light chains. These findings suggest that sBCMA reflects tumor burden independently of renal function, age, and secretory output, making it particularly useful in assessing oligo-/non-secretory myeloma, especially in resource-limited settings.Patients with high-risk disease, by mSMART 4.0, had significantly higher median sBCMA (278 ng/mL) than standard-risk disease (245 ng/mL; p = 0.03). sBCMA levels also progressively increased in both ISS and R-ISS, with significant differences between R-ISS I and III (p = 0.032), II and III (p = 0.016), and ISS I and III (p = 0.015). Conclusions: This prospective study offers important real-world insights into sBCMA levels across the spectrum of plasma cell dyscrasias in a South Indian population, utilizing age- and gender-matched healthy controls. The findings validate sBCMA as a reliable, non-invasive biomarker that correlates strongly with tumor burden and established prognostic markers in multiple myeloma. Importantly, its utility appears independent of renal function and secretory phenotype, highlighting its relevance in routine clinical settings where access to advanced diagnostics may be constrained. These results support the potential integration of sBCMA into diagnostic and monitoring algorithms for plasma cell disorders, particularly in resource-limited or diverse healthcare environments. Ongoing longitudinal follow-up will further clarify its role in predicting treatment response and detecting relapse.

Background: Although Emicizumab has transformed prophylaxis in Hemophilia A management, standard-dose therapy remains inaccessible for most in resource-limited settings. Evidence on lower dose Emicizumab in real-world pediatric cohorts is limited. Objective: To assess clinical outcomes, thromboelastography (TEG) profiles, and cost-effectiveness in children receiving lower dose Emicizumab compared to prior treatment regimens. Methods: This was a hybrid observational study comprising a retrospective clinical audit and a prospectively designed laboratory substudy, conducted at a single tertiary care center in India of children with severe Hemophilia A who initiated lower-dose Emicizumab prophylaxis between June 2019 and May 2024. Eighteen pediatric patients were included: 15 without inhibitors (on low- to intermediate-dose clotting factor concentrate [CFC] prophylaxis) and 3 with inhibitors (previously on FEIBA on demand). Clinical Outcomes: Annualized bleed rates (ABR) and school absenteeism (days/year) were recorded for one year pre- and post-Emicizumab. Data were verified using clinical documentation and parental recall. Laboratory Evaluation: All 18 children underwent TEG while on Emicizumab. Parameters—R time, K time, α-angle, and maximum amplitude (MA)—were compared with age-matched Hemophilia A controls not on Emicizumab. Correlations with clinical bleeding outcomes were explored. Plasma Emicizumab concentrations were measured in a subset (n=9) using a modified ELISA assay. Cost-Effectiveness Analysis: A detailed healthcare system cost analysis compared treatment expenditures before and after Emicizumab initiation. Costs included prophylactic and episodic factor use, hospitalization, emergency transport, and Emicizumab acquisition. Cost per bleed avoided and cost per school day gained were calculated. Statistical Analysis: Paired t-tests or Wilcoxon signed-rank tests were used for continuous variables; chi-square test for categorical data. A p-value <0.05 was considered statistically significant. SPSS v25.0 was used for all analyses. Results: Mean age was 8.1 years (range 2–17). Three children (16.6%) were inhibitor-positive, previously managed with FEIBA. The mean monthly Emicizumab dose was 2.8 mg/kg (Range: 1.3-5.8 mg/kg/month, SD 1.45), yielding a mean plasma level of 25.16 µg/mL (Range: 6.01-48.42, SD 16). Prior to switching, average FVIII usage was 30 IU/kg/week (7.4 - 77.7 IU/kg/week).ABR dropped significantly from 6 (Range: 0-28, SD 8) to 0.6 (Range 0-2, SD 0.7) post-Emicizumab (p < 0.01). All 10 post-treatment bleeds were minor and trauma-related. No major bleeds occurred. The proportion with zero bleeds increased from 16.6% on FVIII to 44.4% on Emicizumab (p = 0.03).School absenteeism declined from a median of ~30 days/year to <10 days/year (p = 0.03), indicating improved quality of life.Plasma Emicizumab levels correlated strongly with administered dose (p < 0.01), confirming predictable pharmacokinetics at lower doses.TEG demonstrated significant improvements in global hemostasis: median R-time (5 vs 22 min, p < 0.001), K-time (1.3 vs 4.3 min, p < 0.001), α-angle (70° vs 45°, p < 0.001), MA (79 vs 66 mm, p < 0.001), coagulation index (4 vs –11, p < 0.001), and thrombin generation (950 vs 812, p < 0.001). However, TEG parameters did not predict individual bleeding phenotypes.Mean annual treatment cost increased from USD 5,790 (Range: 401 - 39279, SD 8,791) to USD 20,115 (Range: 8047.4 - 40220, SD 12,039). The incremental cost-effectiveness ratio (ICER) for avoiding one bleed per year was USD 7,308 (95% CI: 3,604–12,085), within accepted thresholds based on a willingness-to-pay of two times per capita GDP, per Health Technology Assessment (HTA) guidelines. Conclusion: Lower dose Emicizumab significantly reduces bleeding and school absenteeism in children with Hemophilia A, including those on prior low/intermediate-dose FVIII prophylaxis or bypassing agents. Despite higher costs, the clinical and functional benefits support its cost-effectiveness in resource-limited settings. TEG parameters improved post-therapy but did not correlate with bleeding phenotype. These findings support adoption of tailored, lower-dose Emicizumab regimens as a viable and sustainable prophylaxis option in low- and middle-income countries.

Background: CD19-directed CAR-T cell therapies have significantly improved outcomes in relapsed/refractory (R/R) B-cell malignancies, including acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (B-NHL). Despite their efficacy, these therapies are associated with serious early toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), driven by aberrant cytokine surges. Predictive biomarkers for these complications are urgently needed to enable early risk stratification and guide supportive care. While cytokine kinetics have been well-characterized in commercial CAR-T products such as tisagenlecleucel and axicabtagene ciloleucel, no published studies to date have described cytokine profiles in recipients of NexCAR19 (Actalycabtagene autoleucel), a novel CD19-directed CAR-T cell product developed in India. This is the first pilot study to conduct such an analysis. Aim: To evaluate whether early post-infusion cytokine profiling predicts toxicity and clinical outcomes in patients receiving NexCAR19 for R/R B-cell malignancies. Methods: This prospective, single-center study included 11 patients (8 B-ALL, 3 B-NHL) with complete cytokine data, selected from a larger cohort of 23 patients infused with NexCAR19 between January 2024 and July 2025. Disease burden was classified by marrow blast percentage in B-ALL and metabolic tumor volume (MTV) on baseline PET-CT in B-NHL (≥65 cc considered high). Cytokine analysis was performed only in patients who developed fever within the first 7 days post-infusion, targeting the window of peak inflammatory response. Plasma samples were analyzed using the Randox Evidence MultiSTAT platform, a fully automated biochip-based immunoassay system providing simultaneous quantification of IL-1β, IL-2, IL-6, IFN-γ, TNF-α, MCP-1, and ferritin. Results were available within 30 minutes. Clinical and laboratory toxicities were documented per ASTCT and CTCAE v5.0 guidelines. Associations between cytokine levels and outcomes were assessed using Spearman's rank correlation and exact permutation tests. Results: Median age was 26 years (range: 18–50); 7 patients were male. ECOG performance status >2 was noted in 3 patients. CRS occurred in all patients, with Grade ≥2 in 6 (55%). ICANS occurred in 1 patient (9.1%), HLH-like syndrome in 4 (36.3%), and documented infections in 4 (36.3%). Grade ≥3 cytopenias were universal (100% neutropenia), with 91% experiencing thrombocytopenia and 55% anemia. Median ANC <500 duration was 21 days (range: 12–35). Four patients (36.4%) died during follow-up (median: 5.6 months, range: 0.4–18 months). Key cytokine correlations: IL-1β Median value is 2pg/ml (IQR:1-2) : Strong correlation with mortality and overall toxicity (r = 0.78, p = 0.001) IL-2 2.7pg/ml (IQR:2.0-5.8): Strongly associated with HLH syndrome (r = 0.72, p = 0.001) IL-6 53pg/ml (IQR:29-456): Correlated with both adverse outcomes (r = 0.86, p = 0.001) and Grade ≥3 anemia (r = 0.62, p = 0.04) IFN-γ 12pg/ml (IQR:7-22) : Associated with infection and sepsis (r = 0.64, p = 0.04) TNF-α 16pg/ml (IQR:7-21) : Correlated with EASIX score (r = 0.74, p = 0.01); showed a trend with transaminitis (r = 0.58, p = 0.06) MCP-1 193pg/ml (IQR:136-489): Linked to HLH diagnosis and requirement of immunosuppressive therapy (r = 0.63, p = 0.04) Ferritin 794ng/ml (IQR:197-2045): Correlated with HLH status (r = 0.60, p = 0.05) Conclusion: Early post-infusion cytokine profiling in NexCAR19 recipients demonstrated predictive utility for key toxicities and adverse clinical outcomes. Elevated IL-1β, IL-2, IL-6, and MCP-1 levels were significantly associated with HLH, cytopenias, infections, and mortality. The rapid turnaround of the point-of-care cytokine panel supports its feasibility in real-time clinical decision-making. These findings suggest a potential role for cytokine-guided risk stratification and preemptive interventions in CAR-T programs. Validation with longitudinal anayses in larger, multicenter cohorts is warranted to confirm clinical applicability and optimize patient outcomes.

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells within the bone marrow. Traditionally, disease assessment has relied on bone marrow sampling and radiological imaging; however, the presence of circulating clonal plasma cells (CCPCs) in peripheral blood has emerged as a novel prognostic indicator, associated with aggressive disease biology and adverse outcomes. Although international studies have increasingly highlighted the significance of CCPCs, data on their prevalence and characteristics among South Asian MM patients remain scarce. This study aims to evaluate the frequency and phenotypic profile of CCPCs in newly diagnosed multiple myeloma (NDMM) patients at a tertiary care centre in India, and to assess their correlation with established clinical and biochemical risk parameters. Consecutive Patients newly diagnosed with multiple myeloma (NDMM) as per the IMWG criteria at Amrita Institute of Medical Sciences, who consented to the study (N=40) from August 2023 to June 2025, were included. CCPC was analysed by multiparametric flow cytometry from 2 mL of peripheral blood (PB) in EDTA tube before the initiation of treatment. The samples were processed within 24 hours by bulk lysis, surface/cytoplasmic staining and wash method. The cells were stained by Euro flow antibody panel - CD38 BV786, CD138 V450, CD45 V500c, CD19 PECy7, CD56 APC, CD27 PerCP Cy 5.5, CD81 APC H7, CD117 BV605, CD319 BV711 and kappa FITC, and Lambda PE. They were acquired and analysed either in FACS Canto (8 colour, two tube, 1.5 million events, LLOQ 0.003%) or Lyric (11 colour, single tube,4 million events, LLOQ 0.00125%). The clonality of circulating plasma cells was established by aberrant antigenic expression and light chain restriction. CCPCs were quantified both as a percentage of total CD45-positive viable events and as absolute counts per microliter. Associations between CCPC levels and patient characteristics (serum creatinine, calcium, β2-microglobulin, lactate dehydrogenase (LDH), presence of lytic lesions, Revised ISS (RISS), and mSMART 4.0) were assessed using Spearman's rank correlation. Median differences were assessed by the Wilcoxon signed-rank test. In our cohort of 40 newly diagnosed multiple myeloma (NDMM) patients (median age 63.5 years; 20 males, 20 females), circulating clonal plasma cells (CCPCs) were identified in 97.5% of cases, with a median CCPC percentage of 0.689% (5.83 cells/μL). Notably, female patients had a significantly higher median CCPC% compared to males (0.3% vs 0.035%; p = 0.035). Although not statistically significant, higher CCPC% was observed among patients aged <65 years (0.23% vs 0.03%; p = 0.076), those with serum calcium >11 mg/dL (0.2% vs 0.1%; p = 0.086), and those with >4 lytic lesions (0.3% vs 0.03%; p = 0.086). CCPC% did not correlate with serum creatinine, LDH, involved free light chain levels, heavy chain type, or hemoglobin. However, moderate correlations were observed with bone marrow plasma cell percentage by morphology (r = 0.36, p = 0.020) and flow cytometry (r = 0.33, p = 0.04), β2-microglobulin (r = 0.399, p = 0.019), and R-ISS stage (r = 0.443, p = 0.007). A strong correlation was found with mSMART 4.0 risk category (r = 0.7, p < 0.001), with high-risk patients showing significantly elevated median CCPC% compared to standard-risk (0.47% vs 0.039%; p < 0.001). Phenotypic analysis revealed a significantly lower expression of CD138 on circulating plasma cells compared to bone marrow plasma cells (p = 0.03). CCPCs were prevalent in a majority of Indian NDMM patients and correlated with advanced disease, as evident from its strong correlation with mSMART 4.0 risk stratification. Importantly, CCPCs demonstrated distinct phenotypic features compared to bone marrow plasma cells, including reduced CD138 expression, which may reflect biological heterogeneity and potential prognostic value. Given the limited data on CCPCs in South Asian populations, this study provides valuable insights into their prevalence and clinical relevance in newly diagnosed MM patients from India. Flow-based CCPC characterisation could be a practical, minimally invasive adjunct for disease assessment in resource-limited settings.

Background: AL (light-chain) amyloidosis, the common form of the complex spectrum of amyloidosis, poses significant diagnostic and therapeutic challenges even in well-resourced healthcare settings owing to non-specific symptoms, delayed diagnosis, limited therapeutic options and the need for specialised diagnostic techniques. In resource-limited settings such as India, these challenges are further compounded by constraints in healthcare infrastructure, limited access to advanced diagnostic tools and high costs of treatment. In 2023, our hospital established an Amyloid Centre (Amrita Amyloid Center) aimed at improving the diagnosis, treatment, and overall management of amyloidosis. This retrospective study analyses clinical data from the past two decades to identify the key challenges faced in the diagnosis and treatment of AL amyloidosis in a resource-limited setting. Methodology: Retrospective data was retrieved from in-house electronic records using keywords (amyloid, amyloidosis light chain, systemic, primary) from February 2002 to July 2024. All patients diagnosed during this period were included. Diagnosis was based on clinical, biochemical, cardiac imaging and histopathological criteria consistent with AL amyloidosis. Patient data included demographics, presenting symptoms, organ involved, diagnostic modalities and treatment regimens [chemotherapy, stem cell transplantation (SCT), supportive care] .Outcomes measured included time to diagnosis (TTD) (from symptom onset to confirmed diagnosis), diagnostic challenges , therapy outcomes and treatment-related challenges .Temporal trends and associations with time of diagnosis were examined for all variables using conditional density plots, linear regression model with a restricted cubic spline, Spearman rank correlation test and F-test. All statistical analyses were conducted using R version 4.3.0. Results : A total of 448 patient records were screened. The following were excluded- confirmatory report unavailable n=139(31.0%), biopsy proven congophilic amyloidosis but no further data available n=56 (12.5%), cutaneous amyloidosis (lichen, macular, amyloid angiopathy) n=84 (18.8%) and amyloidosis with other histologies (AA, ATTR, others)n=52(11.6%). Out of 117 patients with AL amyloid, 79 (67.5%) were males. Median age of the cohort was 67(40-94) years. Common presenting symptoms were dyspnoea on exertion (35, 29.9%), pedal edema (26, 22.2%), gastrointestinal(GI) symptoms (17,14.5%) and weakness of extremities (8, 06.4%). Serum free light chain assays confirmed light chain restriction . Biopsied tissues which demonstrated amyloid with apple green birefringence in Congo Red stain included renal n=26(22.2%), duodenal/rectal n=32(27.4%), fat pad n=19(16.2%), bone marrow n=15(12.3%) and other tissues n=10(8.5%). Median TTD was 5.5 (0-147) months. Most common organ-system involved was cardiac 40 (34.2%), followed by renal 34 ( 29.0%), Gastrointestinal 17(14.5%), liver 4(3.4%), skin 6 (5.1%), lungs and musculo-skeletal 1(0.9%) each. Median dFLC was 283 (51-6150)mg/dL. Unequivocal findings of amyloidosis were seen in echocardiogram n=30(25.6%) and cardiac magnetic resonance n=12(10.3%). Revised Mayo 2012 Staging revealed Stage I (n=37;31.6%), Stage II (n=33;28.2%), Stage III (n=15;13.5%), Stage IV (n=25;21.4%) and not classified (n=6;5.1%) patients. Amyloid typing by mass spectroscopy (MS) was done for 8 (6.4%) patients. Four (3.4%) patients died before treatment initiation. Induction therapy of the remaining 113 patients consisted of thalidomide n=16(14.2%), Mel-Pred n=15(13.27%), CyBorDex n=62(54.86%), BorLenDex n=13 (11.5%), pomalidomide n= 3 (2.6%). Autologous SCT was done in 6 (5.3%)cases. Daratumumab was used in 4 (3.5%) patients .The median follow up was 9.5 (0-150) months, with 21(17.9%) deaths registered [ most common: sudden cardiac death n=11(9.4%) followed by sepsis and AKI n=4(3.4% each)].Kaplan-Meier curves were used to predict the overall survival of patients. At the end of one year, the overall survival rate was 59.2%. Conclusion:This study highlights the diagnostic delays and limited access to advanced diagnostic and therapeutic options for AL amyloidosis in a resource-limited setting, underscoring the need for improved healthcare infrastructure and accessible, cost-effective treatments to enhance patient outcomes.

Background: CAR-T cell therapy, while revolutionary for treating relapsed or refractory hematologic malignancies, faces economic and logistical hurdles in low and middle-income countries (LMIC) such as India (per-capita income of $2,100 compared to US $81,000). With treatment costs ranging from $300,000 to $500,000 in the US and total costs exceeding $700,000, affordability of CAR-T therapy, infrastructure limitations, and insufficient insurance coverage are significant barriers in India. In October 2023, India's Central Drugs Standard Control Organization approved Acalycabtagene Autoleucel (NexCAR19) to treat relapsed or refractory B-cell leukaemia (B-ALL) and lymphoma. The central question we addressed in this study was whether it is feasible to establish a CAR T cell therapy centre in resource limited setting to deliver the treatment safely and effectively. Methods: A retrospective analysis was conducted from December 2023 to July 2024 at the haematology department of a tertiary care hospital in Kerala, South India. The department has a decade long running allogenic blood and marrow transplantation (BMT) program. Resources were limited, with most patients requiring to raise funds for their treatment through crowd funding. The core strategy involved leveraging the expertise of our existing BMT unit. This multidisciplinary team underwent comprehensive training in CAR therapy protocols and safety procedures. The existing infrastructure was optimized to meet the requirements for the therapy, ensuring compliance with necessary standards without new construction or major equipment purchases to optimize overall costs. Patients with relapsed or refractory B-cell malignancies who met regulator approved indications were selected. Leukapheresis was performed; CD3 and absolute lymphocyte counts were assessed. A cold chain was maintained for the leukapheresis product. Bridging therapy was given when deemed necessary. Patients underwent lymphodepletion five days before CAR-T infusion. Acalycabtagene Autoleucel was infused as per protocol, and patients were monitored for complications. Data on demographics, disease characteristics, adverse events, and responses were collected. Total costs, including CAR-T acquisition, administration, and inpatient care, were calculated. Variables were summarized by frequencies, or medians and ranges. Costs between patient subgroups were compared using t-tests. Results: We treated 8 patients (6 males, 2 females), with a median age of 38 years (range 18-63). There were an equal number of patients with B-ALL and B cell lymphoma. Five received more than three lines of prior therapy. The median CD3 count at leukapheresis was 735 (206-1398) cells/ml. The median apheresis dose was 7.5 (5-13) x 10^6/kg Bridging treatment was administered to all except one. All patients were hospitalized 5 days prior to the date of infusion for lymphodepletion. Seven (87.5%) patients received fludarabine plus cyclophosphamide, while one (0.12%) received bendamustine. The time from apheresis to infusion was 28 days (range 11 to 41). At CAR-T cell infusion, 4 patients had active disease. Post-CAR T. B-cell aplasia was documented in five patients (62.5%). Complications included cytokine release syndrome (CRS) grade 1-2 in 7 (87.5%) patients, hemophagocytic lymphohistiocytosis (HLH) in 3 (37.5%), and sepsis in 2 (25%). Six (75%) patients achieved complete remission by day 28 post-infusion. The median treatment cost was $64,055 ($46,674-$81,571), with CAR-T product costs accounting for 74% of the total. B-cell lymphoma patients had a significantly lower cost (p < 0.01). Costs were higher for patients with complications. In particular, patients who needed treatment for HLH had significantly higher costs (p < 0.01). Five (62.5%) patients paid out of pocket, supported by crowdfunding campaigns from our public education initiatives, while three (37.5%) were covered by insurance or reimbursement. Conclusions: Despite challenges such as high CAR-T costs, resource constraints, and patient affordability, the therapy was effectively implemented in an LMIC setting. Limitations included early-stage data, small sample sizes, and brief follow-up, yet the results highlight its potential for effective use in similar resource-constrained environments.

Neurodegenerative disorders (NDs) including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease are all incurable and can only be managed with drugs for the associated symptoms. Animal models of human illnesses help to advance our understanding of the pathogenic processes of diseases. Understanding the pathogenesis as well as drug screening using appropriate disease models of neurodegenerative diseases (NDs) are vital for identifying novel therapies. Human-derived induced pluripotent stem cell (iPSC) models can be an efficient model to create disease in a dish and thereby can proceed with drug screening and identifying appropriate drugs. This technology has many benefits, including efficient reprogramming and regeneration potential, multidirectional differentiation, and the lack of ethical concerns, which open up new avenues for studying neurological illnesses in greater depth. The review mainly focuses on the use of iPSC technology in neuronal disease modeling, drug screening, and cell therapy.

• Head and Neck Cancer. • Oncolytic Virotherapy. • Oncolytic Virotherapy in Oral Oncology. • Virus. • Targeting cancer.

• Studies reveal a significant association between air pollution, particularly fine particulate matter (PM2.5) and the prevalence and progression of oral cancer. • Understanding the mechanisms linking pollution to oral cancer development is vital for therapeutic and preventive strategies. Air pollutants induce oxidative stress, DNA damage, and disrupt biological pathways crucial for oral health.

Oral squamous cell carcinoma (OSCC) is a highly aggressive neoplasm of the surface epithelium that arises from the mucosal lining of the mouth. The poor prognosis can be attributed to the complex tumor microenvironment (TME) in OSCC, which is crucial for tumor progression, angiogenesis, invasion, metastasis, and therapeutic resistance. In recent years, three-dimensional (3D) in vitro models have emerged as powerful tools to study OSCC biology and evaluate targeted therapies in a more physiologically relevant context. Advanced models such as tumor spheroids, patient organoids and microfluidic devices offer unique possibilities to reconstitute intricate cellular interactions, ECM dynamics as well as physiological gradients found in the OSCC TME. The 3D OSCC model provides powerful preclinical tools for drug screening and mechanistic studies of this devastating malignancy. In this review, we discuss the role of the tumor-immune microenvironment (TIME) in tumorigenesis and the 3D in vitro cultures in recreating the tumor microenvironment paving the way for the development of personalized medicine in OSCC.

Introduction Paroxysmal Nocturnal Hemoglobinuria (PNH) is a chronic acquired disorder that can cause hemolysis, thrombosis and aplastic marrow , with an incidence of 1-10 cases per million people. Studies focusing on PNH in the Indian population are relatively sparse. Although C5 inhibitors are approved for the treatment of PNH by the FDA, their availability in low and middle-income countries like India is limited. We aimed to study the clinical characteristics and outcomes of patients diagnosed with PNH attending a tertiary care center in South India without access to C5 inhibitors. Methods Details of patients who have performed a PNH test by flow cytometry (FCM) were collected retrospectively from the electronic medical records and patients who were positive for PNH were selected. Specific gating markers used for flow cytometry analysis were CD15 for granulocytes and CD64 for monocytes along with GPI-AP markers, CD24 for granulocytes and CD14 for monocytes. The patients with either granulocyte clones or monocyte clones > 5% were included for analysis. Relevant clinical information including the onset of the first symptom, date of diagnosis, last follow-up date, blood investigation at the time of symptom onset and at the time of diagnosis, bone marrow cellularity as well as treatment received were recorded. Continuous variables were summarized using mean and standard deviation. Symptoms were catagorised and analysed using a contingency table. The p-value was calculated using Fisher's exact test. Laboratory measurements were summarized using median, interquartile range (IQR), and frequency percentages. The p-values were determined using the Wilcoxon rank-sum test and Pearson's chi-square test to evaluate the associations between laboratory measurements, and disease development. The average time to diagnosis was also calculated. The Kaplan-Meier curve was used to determine the overall survival(OS) of the patients. All statistical analyses were conducted in R version 4.3.0. Results PNH (FCM) tests were done in 468 patients between January 1st, 2018 and July 1st, 2024 of which 63 (%) tested positive . From this, those having either granulocyte clones or monocyte clones > 5% were further selected (n=45). The male: female ratio was 7:8. The median age at the onset of symptoms was 35 years (7-69). Most patients n=42(93%) were referred for symptomatic cytopenias while 6(13.3%) presented with thrombosis and another 5(11.1%) presented with hemoglobinuria. Mean duration between symptom onset and diagnosis was 1.88 years(0-17.8). The median follow-up period was 2.49 years(IQR 1.10 - 4.07). Out of the 39 evaluable reports, 29(74 %) had hypocellular marrow and 20(51.2%) had erythroid hyperplasia. The mean Hemoglobin was 7.3±2.3gm/dL, total count was 3770±1790 cells/mm3,and platelet count was 50300±70600 cells/mm3. Thirty (66.67%) patients had hemolytic picture (elevated LDH, raised retic count and indirect hyperbilirubinemia); the Mean LDH was 1046.8±1371.9 IU/mL, reticulocyte count 3.3±3.7% and the total bilirubin 1.3±1.2 mg/dL. The mean granulocyte and monocyte clones were 47±36.9% and 49.5±35.8 % respectively . The average number of admissions required per patient was 2.4 (0-16). Treatment received includes steroids 12(29 %), calcineurin inhibitors 18(42.5 %), danazol 27(64%), thrombopoetin receptor agonists (14,33%) and anti-thymocyte globulin 4 (9.5%). Thirty (66.67%) required transfusion after diagnosis. On followup,hemolytic manifestations were seen to be more common than thrombotic manifestations. 6/45(13.3%) developed venous thrombosis (5 mesenteric vein, 1 cerebral venous thrombosis) and 1/45(2%) developed arterial thrombosis. Out of 45 patients, 13 patients expired, and 3 patients were lost to follow up. 6/13 (46%) died due to bleeding (intracranial bleed and Upper GI bleed) while 6/13 (46%) died due to sepsis and 1 patient died due to unrelated cause.10-year OS was 33.4%, 95% CI(0.147,0.761). 2 patients underwent an allogenic stem cell transplant but both of them succumbed. Conclusion This study was limited by it's retrospective nature . However it underscores the significant morbidity and mortality associated with PNH in a resource-limited setting, highlighting the urgent need for access to advanced therapies such as C5 inhibitors to improve patient outcomes.

Background: Hemophilia, an X-linked recessive bleeding disorder, presents significant challenges in management but can be mitigated with appropriate clotting factor replacement therapy. Resource limited settings across the world face unique challenges in implementing prophylaxis as the standard of care. The objective of this study is to assess the improvement in prophylaxis and comprehensive care of children with Hemophilia(CwH) attached to a newly established Hemophilia Treatment Center (HTC) in India during the last decade. Methodology: Study was retrospective from January 2015 to June 2024. The HTC started functioning in a Government District Hospital in 2014. It had access to an accredited blood center. A coagulation laboratory doing factor and Bethesda assays was established and accredited. Educational sessions were conducted for patients , caregivers and healthcare workers. Fortnightly comprehensive care clinics were conducted with Hematologist , Paediatrician, Physiatrist , Physiotherapist and Laboratory Technologist. Cost of treatment was borne by local self-government and state. All patients <18 years with Hemophilia A and B registered in the center were included for analysis . Those staying near the center (< 50 km) were evaluated for access to prophylaxis. Clotting factor concentrate(CFC) are plasma-derived or recombinant CFCs and it provides convenient high doses of clotting factor for the treatment and prevention of bleeds. Standard half life CFCs need frequent venipunctures for prophylaxis as it has short half life when compared to Extended half life CFCs. Emicizumab is a chimeric bispecific antibody directed against the enzyme activated Factor IX and the zymogen FX that mimics the co-factor function of Factor VIII in patients with hemophilia A, with or without inhibitors. Proportion of adults and children on prophylaxis , age at initiation of prophylaxis , Annual bleed rates (ABR), Functional Independence Score in Hemophilia(FISH), Hemophilia Joint Health Score(HJHS) and Prevalence of inhibitors were measured. Patients on prophylaxis were regularly reviewed and treatment changes made to keep annual bleed rates 0-3. Outcomes of 2024 were compared against 2015. We used longitudinal mixed effects Poisson regression with a random intercept for patients and a fixed effect for time to model trends in the bleeding rate. Quantitative patient characteristics are summarised by means and standard deviations and categorical patient characteristics are summarized by frequencies and percentages. p values <0.05 is considered as statistically significant. Analysis were performed in R version 4.4.1. Results: Patients with Hemophilia(PwH) resgistered in the HTC were 441 in 2015 and increased to 874 in 2024, out of which 734(84%) had Hemophilia A(HA) ; 726(83.1%) had severe disease. Children with Hemophilia (CwH)in 2024 was 281(38.7%) against 128(38.3%) in 2015. CwH living in close proximity and eligible for prophylaxis from center were 37. No CwH were on prophylaxis in January 2015 and 32(86.5%) CwH received Prophylaxis in 2024. CFC use was 1894 IU/kg/year/person and 46.57 mg/kg/year/person for Emicizumab. ABR of 1.13(p=0.006) in 2024 vs 11 in 2015 and over the years, ABR has decreased significantly by a rate ratio of 0.8(95% CI: 0.76-0.85, p <0.001).The mean HJHS score was 1.43 (SD 2.06). There was a significant decrease in the average HJHS score per year by 0.84(95% CI: 0.71 - 1, p= 0.05). The mean FISH score was 31.7(SD 1.09) and FISH score did not change significantly over the years(p=0.83). Proportion of adults receiving prophylaxis were 7(12.7%). Conclusion: The establishment of HTC and its comprehensive approach, including prophylaxis, education, and financial support, has substantially improved the care of CwH in a resource-limited setting. Increased prophylaxis coverage, reduced ABR, improved HJHS and maintained FISH scores reflect improvement in care. Enhanced access to newer treatments like Emicizumab reflect significant progress in patient management and outcomes over the past decade. Limitations are retrospective, single center study.

• CDK5RAP2. • Head and Neck Cancer. • Prognostication. • Oral squamous cell carcinoma. • Centrosome-associated protein 215.