Survival Outcomes and Relapse Patterns in High-Risk Metastatic Neuroblastoma Treated with Radiotherapy-Only Consolidation in a Resource-Limited Setting: A Retrospective Study from a Lower-Middle-Income Country

Survival Outcomes and Relapse Patterns in High-Risk Metastatic Neuroblastoma Treated with Radiotherapy-Only Consolidation in a Resource-Limited Setting: A Retrospective Study from a Lower-Middle-Income Country | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 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Data may be preliminary. 12 July 2025 V1 Latest version Share on Survival Outcomes and Relapse Patterns in High-Risk Metastatic Neuroblastoma Treated with Radiotherapy-Only Consolidation in a Resource-Limited Setting: A Retrospective Study from a Lower-Middle-Income Country Authors : Haydar Hamza Alabedi , Noor Muhammed Abdulrahman , and Ali Al-Rudayni 0009-0005-9432-881X [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175231296.63600690/v1 Published Frontiers in Oncology Version of record Peer review timeline 274 views 114 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background : High-risk metastatic neuroblastoma (HR-MNB) requires intensive multimodal therapy for durable remission. In many low- and middle-income countries (LMICs), access to autologous stem cell transplantation (ASCT) and maintenance immunotherapy remains limited. This study evaluated survival outcomes and relapse patterns among patients with HR-MNB treated with radiotherapy-only consolidation after achieving a complete or near-complete response to induction chemotherapy in Iraq. Methods : We conducted a retrospective cohort study of children with HR-MNB treated between December 2023 and March 2024 at a national radiotherapy center. Eligible patients received standard induction chemotherapy and consolidation radiotherapy with curative intent, without ASCT. Relapse-free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Relapse patterns were classified as local, distant, new-site, or combined failures. Subgroup analyses examined associations between survival outcomes and radiotherapy dose, age, and metastasis sites. Results : Twenty-five patients (median age, 48 months) were included. The median RFS from diagnosis was 18 months (95% CI, 14.4–21.6), and the median OS was 20.1 months (95% CI, 16.2–23.9). From radiotherapy initiation, the median RFS was 5.8 months and OS was 11.4 months. Relapse occurred in 84% of patients, most frequently at new anatomical sites (56%). Subgroup analyses did not identify significant differences in survival by radiotherapy dose or baseline characteristics. Conclusions : Radiotherapy-only consolidation following induction chemotherapy provided limited systemic disease control, reflected in early relapses and modest survival. These findings highlight the urgent need to expand access to ASCT, immunotherapy, and integrated care pathways to improve outcomes for HR-MNB in LMICs. Reporting real-world data from resource-constrained settings contributes essential evidence to guide equitable neuroblastoma treatment strategies globally. Introduction Neuroblastoma is the most common extracranial solid tumor in childhood and arises from the neural crest elements of the sympathetic nervous system. It primarily affects infants and young children and is characterized by substantial clinical and biological heterogeneity. Prognosis varies considerably according to the age at diagnosis, stage, histopathological features, and molecular markers such as MYCN amplification and segmental chromosomal aberrations. 1 Globally, an estimated 5,560 new cases of neuroblastoma occur annually in children aged < 15 years, resulting in approximately 1,977 deaths. In the Middle East and North Africa region, where comprehensive pediatric cancer registries are limited, neuroblastoma remains underreported. However, regional estimates for 2021 indicate approximately 247 incident cases and 354 deaths. 2,3 The Children’s Oncology Group (COG) and the International Society of Pediatric Oncology European Neuroblastoma Group (SIOPEN) classify neuroblastoma into low-, intermediate-, and high-risk categories based on age, International Neuroblastoma Risk Group (INRG) staging, histology, MYCN amplification, DNA ploidy, and segmental chromosomal aberrations. High-risk neuroblastoma (HR-NB) is frequently metastatic at diagnosis, with common sites including the bone marrow, bone, liver, and lymph nodes, and is associated with poor overall survival (OS). 4,5 The current standard of care for HR-NB includes induction chemotherapy to achieve maximal tumor reduction followed by consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT). Data from the ANBL0532 randomized trial demonstrated superior event-free survival (EFS) with tandem versus single ASCT, leading to the current COG recommendation in favor of tandem ASCT for most patients with HR-NB. 6,7 The SIOPEN HR-NBL1 protocol favors single ASCT with busulfan–melphalan as the preferred conditioning regimen, based on phase 3 evidence supporting its efficacy. 8 Radiotherapy plays a central role in the consolidation phase by eradicating the residual disease at the primary tumor site and metastatic foci in selected cases. Despite surgical resection and intensive chemotherapy, the risk of microscopic residual disease remains high, necessitating the routine use of consolidative radiotherapy, regardless of surgical completeness. 9,10 Radiation doses ranging from 21 to 36 Gy are typically administered and tailored according to the extent of resection, residual disease burden, and surrounding organ sensitivity. 8 Radiotherapy is frequently used as the sole form of consolidation in resource-limited settings where access to ASCT is limited. Although this approach cannot replace the systemic disease control provided by ASCT, followed by a maintenance regimen containing anti-GD2 immunotherapy, it may still provide meaningful local control, particularly in patients who achieve a complete or near-complete response to induction chemotherapy. Nevertheless, long-term survival in this context remains suboptimal because of the high risk of systemic relapse. 11-13 This retrospective study evaluated the relapse-free survival (RFS), OS, and recurrence patterns in patients with high-risk metastatic neuroblastoma (HR-MNB) who achieved a complete or near-complete response to induction chemotherapy and subsequently received radiotherapy as the sole consolidation modality. By emphasizing outcomes in a context where ASCT is not yet widely available, we aimed to highlight the importance of equitable access to comprehensive neuroblastoma treatment options. Methods Study Design and Setting This retrospective cohort study assessed RFS, OS, and recurrence patterns in patients with HR-MNB who achieved a complete or near-complete response to induction chemotherapy and received consolidation radiotherapy. This study was conducted at the Baghdad Radiotherapy and Nuclear Medicine Center located within the Baghdad Medical City Complex in Iraq. The data were collected between December 2023 and March 2024. Ethics Approval The Institutional Review Board of the Department of Surgery, College of Medicine, University of Baghdad approved this study (Approval No. 1674; December 26, 2023). All data were collected and analyzed in accordance with the ethical standards and institutional guidelines. Eligibility Criteria Cases with confirmed HR-MNB who received standard induction chemotherapy (with or without surgery), achieved complete or near-complete response post-induction, and received consolidation radiotherapy with curative intent were included in this study. Patients who received palliative radiotherapy, had an unfavorable response to induction therapy, did not undergo radiotherapy, had incomplete data, or were lost to follow-up were excluded from the study. Data Collection Data were extracted from paper-based medical records. Variables included demographic information such as sex, age, and diagnosis date; clinical information such as tumor location and metastatic sites; and treatment-related information such as chemotherapy regimen, response, surgery status, and radiotherapy site/dose/fractionations. Outcomes included relapse site and date, survival, and last follow-up date (mortality status). Data entries were verified for consistency. Only patients treated with curative-intent radiotherapy were included. Statistical Analysis Descriptive statistics were used to summarize patient data, and Kaplan–Meier survival analysis was performed to estimate OS and RFS. RFS was calculated separately from both the date of diagnosis and the initiation of consolidation radiotherapy. Patients who did not experience relapse or death were censored at the date of last follow-up or, if unavailable, at the study end date. (radiotherapy dose, age, and metastasis site). Statistical significance was set at p < 0.05. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, N.Y., USA). Relapse Pattern Classification Relapse pattern classification was determined according to the COG/SIOPEN/MSKCC model and included local, distant, or new-site relapses. The site-specific model was classified as predefined (original sites) vs. new anatomical sites. Limitations The retrospective design, small sample size, and paper-based records may have introduced classification and selection biases. Despite this, the uniform treatment approach and data from a national referral center ensure a degree of internal consistency. These findings provide a novel perspective on previously undocumented LMIC settings. Results Patient Characteristics Overall 25 patients with HR-MNB who achieved a complete response to induction chemotherapy and subsequently received consolidation radiotherapy with curative intent were included. The median age at diagnosis was 48 months (range, 20.4–84 months); 56% were male. The most common primary tumor site was the suprarenal region (84%), followed by the paravertebral (8%), carotid (4%), and mediastinal (4%) sites. At the time of diagnosis, the most frequent site of metastasis was the bone marrow (48%), followed by bone (28%), brain (12%), and other locations (28%). All patients received systemic induction chemotherapy and 80% underwent surgical resection. Consolidation radiotherapy was delivered to the primary tumor bed in all patients, with two (8%) also receiving radiotherapy for metastatic lesions (vertebrae and femur) (Table 1) . Radiotherapy Dose and Classification Radiotherapy dosing varied among the patients. Ten (40%) patients received high-dose radiotherapy (36 Gy in 20 fractions), whereas 14 (56%) received standard-intermediate doses ranging from 21 to 25.2 Gy. One patient received undocumented radiotherapy. For analytical purposes, the doses were grouped into the following two categories: standard intermediate (<36 Gy) and high (36 Gy) doses (Table 1) . RFS The median RFS from diagnosis was 18 months (95% confidence interval [CI], 14.4–21.6months) (Fig. 1A) . The median RFS from the start of radiotherapy was 5.8 months (95% CI, 2.55 – 7.45) (Fig. 1B) . A steep decline in RFS was observed during the first year post-radiotherapy, with fewer than 20% of the patients remaining relapse-free at 18 months. Stratification based on radiotherapy dose, age at diagnosis, sex, and metastasis patterns revealed no statistically significant differences in RFS. Relapse Patterns During follow-up, disease relapse occurred in 21 of the 25 patients (84%). Relapse patterns were analyzed using both anatomical and international classification frameworks. Based on anatomical distribution, relapse at predefined sites (either the original primary tumor or known metastatic sites) was observed in 10 (48%) patients. Relapses at new sites (anatomical locations not involved in the initial diagnosis) occurred in 11 (52%) patients. Relapses were further subclassified to align with the classification model employed by the COG, SIOPEN, and the Memorial Sloan Kettering Cancer Center. Local relapse only (primary tumor site) occurred in one (4%) patient, distant relapse only (initial metastatic sites) occurred in six patients (24%), new site relapse only occurred in 14 (56%), and combined relapse (involving >1 category, such as local + distant or distant + new) occurred in seven (28%). OS The median OS was 20.1 months (95% CI, 16.2–23.9 months) (Fig. 2A) . The median OS from the start of radiotherapy was 11.4 months (95% CI, 6.8–15.9 months) (Fig. 2B) . No statistically significant differences in OS based on the radiotherapy dose, sex, age, or metastatic pattern at diagnosis. Subgroup Analyses Exploratory subgroup analyses demonstrated no statistically significant survival differences when stratified based on radiotherapy dose (standard-intermediate vs high), age (<60 months vs. ≥60 months), metastasis site (bone vs. bone marrow vs. central nervous system), or pattern of relapse (predefined vs. new site); given the sample size, these results should be cautiously interpreted. Discussion This study evaluated survival outcomes and relapse patterns in patients with HR-MNB treated with consolidation radiotherapy as the sole post-induction modality following a complete or near-complete response to chemotherapy. Conducted in a resource-limited setting, this retrospective analysis provides real-world insights from a country with limited access to standard-of-care consolidation such as ASCT and maintenance modalities, including anti-GD2 immunotherapy. The survival outcomes in our cohort were notably inferior to those reported for standard multimodal regimens. Median OS and RFS were 20.1 and 18 months, respectively, from diagnosis. Post-radiotherapy OS and RFS were as low as 11.4 and 5.8 months, respectively. These outcomes underscore the limited durability of radiotherapy as a stand-alone consolidation approach for HR-MNB. In contrast, in high-income countries, integrating ASCT followed by a maintenance regimen containing anti-GD2 monoclonal antibodies and isotretinoin into post-induction therapy has significantly improved long-term outcomes. For example, the ANBL0032 trial demonstrated that patients receiving this comprehensive consolidation strategy had a 5-year OS exceeding 60%. 14 Similarly, the HR-NBL1/SIOPEN phase 3 trial, which used a single ASCT, reported a 3-year OS and EFS of 60% and 50%, respectively. 8 Tandem ASCT, currently endorsed by the COG, has been shown to further improve EFS over single-transplant approaches. 6 Our findings align more closely with those observed in LMICs, where access to optimal systemic consolidation and maintenance modalities is constrained. As reported by van Heerden and Kruger, the absence of ASCT and anti-GD2 immunotherapy in LMICs is associated with poorer survival outcomes than those achieved in high-income settings. 13 An Indian cohort treated with a non-myeloablative TVD-based regimen (topotecan, vincristine, and doxorubicin) and radiotherapy, but without ASCT or immunotherapy, achieved a 4-year EFS of 29.3%. 15 While inferior to outcomes achieved with ASCT or anti-GD2 immunotherapy protocols, these results exceeded those observed with radiotherapy alone, highlighting the critical role of systemic therapy in prolonging remission and survival. 8,14 Although direct comparison across studies should be approached with caution, given differences in patient demographics, treatment infrastructure, and supportive care, the findings by Jain et al. offer a relevant point of reference for evaluating alternative consolidation approaches in resource-constrained settings. Their experience underscores the potential role of intensive chemotherapy consolidation in the absence of ASCT. Building on this evidence, further studies are needed to guide the development of context-adapted treatment strategies that balance efficacy and feasibility in LMICs. Our findings support the consideration of interim consolidation strategies using accessible chemotherapeutic agents in contexts where ASCT is not feasible. In our cohort, it was unclear why chemotherapy-based consolidation regimens were not employed, although fragmented documentation and limited post-treatment follow-up constrained our ability to explore this further. Subgroup analyses stratified based on age, sex, metastasis site, and radiotherapy dose yieled no statistically significant differences in OS or RFS. These uniformly poor outcomes across the strata emphasize the limitations of radiotherapy-only consolidation and reflect the modest statistical power of our sample size (n = 25). In our retrospective analysis, 84% of the patients experienced relapse, most commonly at new anatomical sites (56%), followed by distant relapse at the initial metastatic sites (24%) and local recurrence at the primary tumor site (4%). Combined patterns involving multiple relapse categories were observed in 28% of the cases. These dynamics align with the relapse patterns reported by the COG, SIOPEN, and the Memorial Sloan Kettering Cancer Center, where systemic and new-site failures remain predominant despite favorable local control rates. This reinforces the principle that effective post-remission therapy targets systemic micrometastatic diseases and not solely the primary tumor site. Our study reflects the broader systemic challenges faced by pediatric oncology programmes in Iraq and is likely relevant to other LMICs. During the study period, MYCN amplification testing, which is a cornerstone of neuroblastoma risk stratification, was not performed. Anti-GD2 immunotherapy was not accessible through the national formulary, and documentation on the use of isotretinoin for maintenance therapy was inconsistent. Radiotherapy is frequently delayed, with median intervals exceeding 6 months from diagnosis, reflecting limited infrastructure, fragmented referral pathways, and the absence of integrated, timely treatment coordination. Furthermore, owing to scattered and incomplete documentation, it is difficult to assess the quality and consistency of supportive care measures, which are important determinants of outcomes in high-risk neuroblastoma. We included this observation for transparency because these limitations may have influenced the observed survival and relapse outcomes. Additionally, structured posttreatment surveillance and digital patient tracking systems are lacking, hindering the early detection of relapse and long-term outcome monitoring. Public awareness of the importance of completing all treatment phases, including consolidation and maintenance, remains limited. These systemic gaps mirror those described in other LMIC contexts, including sub-Saharan Africa and the Middle East, where delayed radiotherapy, poor integration of services, and treatment abandonment are common. 12,13,16,17 Notably, Iraq has recently made significant progress in expanding its ASCT capacity across public and private hospitals. This development may reduce the burden of cross-border treatment and represent a vital step toward aligning national practices with international standards. This study had some limitations. The small sample size reduces the power required to detect meaningful subgroup differences and limits generalizability. As this was a single-center retrospective study, the findings were subject to selection and information bias, particularly due to the reliance on handwritten medical records. Nonetheless, the cohort’s clinical homogeneity and treatment within a centralized national cancer center conferred internal consistency and underscored the need for broader prospective data collection in the region. In this retrospective analysis, radiotherapy-alone consolidation therapy following a complete or near-complete response to induction chemotherapy offered modest local control but did not sufficiently prevent systemic relapse in children with HR-MNB treated in a resource-limited setting. These findings underscore the significance of multimodal consolidation, including ASCT, in attaining a durable remission. Our results reflect the real-world limitations of care delivery in LMICs and underscore the urgent need to expand access to comprehensive risk-adapted treatment strategies. By documenting survival outcomes and relapse patterns in an underrepresented LMIC context, this study contributes to the growing call for the equitable implementation of evidence-based protocols and capacity-building initiatives in global pediatric oncology. Conflict of Interest statement The authors have no conflict of interest to disclose Acknowledgment Statistical support and assistance with manuscript preparation were provided by the Scientific Department of Warith International Cancer Institute. Language editing was performed by Editage (www.editage.com). References 1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet 2007;369:2106–2120. https://doi.org/10.1016/S0140-6736(07)60983-02. Howard SC, Zaidi A, Cao X, et al. The My Child Matters programme: effect of public-private partnerships on paediatric cancer care in low-income and middle-income countries. Lancet Oncol 2018;19:e252–e266. https://doi.org/10.1016/S1470-2045(18)30123-23. Nong J, Su C, Li C, et al. Global, regional, and national epidemiology of childhood neuroblastoma (1990–2021): a statistical analysis of incidence, mortality, and DALYs. EClinicalmedicine 2025;79:102964. https://doi.org/10.1016/j.eclinm.2024.1029644. Irwin MS, Naranjo A, Zhang FF, et al. Revised neuroblastoma risk classification system: a report from the Children’s Oncology Group. J Clin Oncol 2021;39:3229–3241. https://doi.org/10.1200/JCO.21.002785. Pinto NR, Applebaum MA, Volchenboum SL, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33:3008–3017. https://doi.org/10.1200/JCO.2014.59.46486. Park JR, Kreissman SG, London WB, et al. Effect of tandem autologous stem cell transplant vs single transplant on event-free survival in patients with high-risk neuroblastoma: a randomized clinical trial. JAMA 2019;322:746–755. https://doi.org/10.1001/jama.2019.116427. Updates in the Management of Neuroblastoma. J Natl Compr Canc Netw 2024;22:e245018.8. Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol 2017;18:500–514. https://doi.org/10.1016/S1470-2045(17)30070-09. Gatcombe HG, Marcus RB Jr, Katzenstein HM, Tighiouart M, Esiashvili N. “Excellent local control from radiation therapy for high-risk neuroblastoma.” Int J Radiat Oncol Biol Phys 2009;74:1549–1554. https://doi.org/10.1016/j.ijrobp.2008.10.06910. National Comprehensive Cancer Network Neuroblastoma. version 2.2024. J Natl Compr Canc Netw 2024;22:413–433.11. Parikh NS, Howard SC, Chantada G, et al. “SIOP-PODC adapted risk stratification and treatment guidelines: recommendations for neuroblastoma in low- and middle-income settings.” Pediatr Blood Cancer 2015;62:1305–1316. https://doi.org/10.1002/pbc.2550112. Magrath I, Steliarova-Foucher E, Epelman S, et al. Paediatric cancer in low-income and middle-income countries. Lancet Oncol 2013;14:e104–e116. https://doi.org/10.1016/S1470-2045(13)70008-113. van Heerden J, Kruger M. Management of neuroblastoma in limited-resource settings. World J Clin Oncol 2020;11:629–643. https://doi.org/10.5306/wjco.v11.i8.62914. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010;363:1324–1334. https://doi.org/10.1056/NEJMoa091112315. Jain R, Trehan A, Menon P, et al. Survival in patients with high-risk neuroblastoma treated without autologous stem cell transplant and dinutuximab beta. Pediatr Hematol Oncol 2021;38:291–304. https://doi.org/10.1080/08880018.2020.185095516. Israels T, Ribeiro RC, Molyneux EM. Strategies to improve care for children with cancer in sub-Saharan Africa. Eur J Cancer 2010;46:1960–1966. https://doi.org/10.1016/j.ejca.2010.03.02717. Ward ZJ, Yeh JM, Bhakta N, Frazier AL, Atun R. Estimating the total incidence of global childhood cancer: a simulation-based analysis. Lancet Oncol 2019;20:483–493. https://doi.org/10.1016/S1470-2045(18)30909-4 Legends FIGURE 1. Kaplan-Meier curves for relapse-free survival (RFS) in patients with high-risk metastatic neuroblastoma treated with consolidation radiotherapy after achieving complete or near-complete response to induction chemotherapy. (A) RFS calculated from the date of diagnosis (B) RFS calculated from the date of starting consolidation radiotherapy. FIGURE 2. Kaplan-Meier curves for overall survival (OS) in patients with high-risk metastatic neuroblastoma treated with consolidation radiotherapy after achieving complete or near-complete response to induction chemotherapy. (A) OS calculated from the date of diagnosis. (B) OS calculated from the start of consolidation radiotherapy. TABLE 1 Baseline clinical and treatment characteristics of patients with high-risk metastatic neuroblastoma treated with consolidation radiotherapy after achieving complete or near-complete response to induction chemotherapy. Sex Male 14 (56) Female 11 (44) Age (months) Median (range) 48 (20.4–84) <60 months 17 (68) ≥60 months 8 (32) Primary Tumor Site Suprarenal 21 (84) Paravertebral 2 (8) Carotid space 1 (4) Mediastinal 1 (4) Site of Metastasis Bone marrow 12 (48) Bone 7 (28) Brain 3 (12) Other 7 (28) Induction Chemotherapy 25 (100) Surgery 20 (80) Consolidation Radiotherapy 25 (100) Tumor bed treated 25 (100) Secondary site irradiated 2 (8) Femur 1 (4) Vertebrae 1 (4) Radiotherapy Dose (Gy/Fx) 22 Gy / 12 Fx 8 (32) 23 Gy / 13 Fx 7 (28) 25.2 Gy / 14 Fx 1 (4) 36 Gy / 20 Fx 9 (36) Response to Treatment Complete response (CR) 23 (92) Stable disease 2 (8) Relapse Status No relapse 4 (16) Relapse 21 (84) Site of Relapse Primary tumor site 4 (16) Distant relapse 6 (28) New sites 14 (56) Abbreviations: RT, radiotherapy; Gy, Gray; Fx, fractions; CR, complete response Information & Authors Information Version history V1 Version 1 12 July 2025 Peer review timeline Published Frontiers in Oncology Version of Record 12 Mar 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords neuroblastoma outcomes research pediatric oncology radiation therapy Authors Affiliations Haydar Hamza Alabedi University of Baghdad College of Medicine View all articles by this author Noor Muhammed Abdulrahman Pediatric Teaching Hospital View all articles by this author Ali Al-Rudayni 0009-0005-9432-881X [email protected] Warith International Cancer Institute View all articles by this author Metrics & Citations Metrics Article Usage 274 views 114 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Haydar Hamza Alabedi, Noor Muhammed Abdulrahman, Ali Al-Rudayni. Survival Outcomes and Relapse Patterns in High-Risk Metastatic Neuroblastoma Treated with Radiotherapy-Only Consolidation in a Resource-Limited Setting: A Retrospective Study from a Lower-Middle-Income Country. Authorea . 12 July 2025. 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