Ultrasound-Based Monitoring in Unilateral Wilms Tumor: Treatment Response Assessment and Early Relapse Dynamics (2012–2020, Single-Center Cohort)

Ultrasound-Based Monitoring in Unilateral Wilms Tumor: Treatment Response Assessment and Early Relapse Dynamics (2012–2020, Single-Center Cohort) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Ultrasound-Based Monitoring in Unilateral Wilms Tumor: Treatment Response Assessment and Early Relapse Dynamics (2012–2020, Single-Center Cohort) Ramin Malikov This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8961303/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background: Ultrasound-first (US-first) monitoring is commonly used in resource-variable settings to reduce radiation exposure; however, the prognostic value of neoadjuvant ultrasound response in unilateral Wilms tumor is not well defined in real-world cohorts. We assessed whether a simple dichotomized ultrasound response (regression vs non-regression) can stratify relapse and survival risk in children treated under SIOP principles. Methods: This retrospective single-center cohort included consecutive patients aged 0–18 years with unilateral Wilms tumor treated with SIOP-based protocols between 2012 and 2020 at the National Center of Oncology, Baku, Azerbaijan (n=59). Neoadjuvant response was assessed by abdominal ultrasonography using the largest axial tumor diameter and categorized as regression, stable disease, or progression (chemoresistance). For primary analyses, response was dichotomized as regression vs non-regression (stable+progression). Outcomes were relapse, overall survival (OS), and disease-free survival (DFS). Survival was estimated by the Kaplan–Meier method, and hazard ratios (HRs) were estimated using Cox regression. Results: Neoadjuvant USM response was regression in 50/59 (84.7%), stable disease in 5/59 (8.5%), and progression/chemoresistance in 4/59 (6.8%). Non-regression occurred only in stage III–IV disease (p=0.038). Over a median follow-up of 94 months, relapse occurred in 11/59 (18.6%) and death in 7/59 (11.9%); 81.8% of relapses occurred within 24 months. Relapse and death were markedly higher in the non-regression group than in the regression group (relapse 66.7% vs 10.0%; death 55.6% vs 4.0%; both p<0.001). At 60 months, OS was 96.0% vs 44.4% (p<0.001) and DFS was 90.0% vs 33.3% (p<0.001) for regression vs non-regression, respectively. In univariable Cox models, non-regression was strongly associated with worse outcomes (OS HR 16.89, 95% CI 3.27–87.20, p<0.001; DFS HR 8.90, 95% CI 2.70–29.36, p<0.001). Conclusions: In this real-world SIOP-treated unilateral Wilms tumor cohort, a simple US-first neoadjuvant response classification strongly stratified relapse and long-term survival risk. Ultrasound non-regression identifies a high-risk subgroup that may warrant closer early monitoring in radiation-sparing follow-up strategies. Wilms tumor ultrasonography neoadjuvant response SIOP chemoresistance relapse overall survival disease-free survival Figures Figure 1 Figure 2 1 | Introduction Wilms tumor (nephroblastoma) is the most common malignant renal tumor of childhood, and with modern multimodal treatment, long-term survival in advanced centers often exceeds 85–90%. Nevertheless, relapse remains one of the main problems in clinical practice, and early recognition of risk using practical markers is essential for selecting the appropriate intensity of follow-up. [1] A key feature of the SIOP approach is that many patients receive neoadjuvant chemotherapy before surgery, and subsequent treatment is built in a risk-adapted manner based on stage, histological risk, and response indicators. Within the UMBRELLA framework, the aim is not only to improve survival but also, through more precise risk stratification, to justify intensification in high-risk patients while reducing toxicity and late complications in low-risk patients. [2] The prognostic role of imaging response to neoadjuvant treatment has long been debated; although tumor growth/progression during the preoperative chemotherapy period is rare, it may be associated with worse outcomes and is considered a “red flag” in clinical decision-making. [3] The choice of imaging is critical in terms of diagnosis, response monitoring, and relapse surveillance. Consensus recommendations for pediatric renal tumors support the broad use of ultrasound (US), while CT/MRI plays a complementary role in selected cases. [4] One of the key arguments supporting the widespread use of US is the radiation burden and long-term risks associated with CT in children. [5,6] However, US can be operator-dependent, and diameter-based measurements may not fully reflect components such as volume/necrosis. Still, classical data indicate that sonographic changes during chemotherapy in Wilms tumor may correlate with histopathological findings and can be used in practical follow-up. [7] In response assessment, the widely accepted concept of a “measurable target” in oncology (e.g., the principles of RECIST 1.1) provides a standardized approach based on changes in diameter. [8] Regarding the timing of relapse, large series show that a substantial proportion of relapses are detected within the first 2 years, and abdominal US lung imaging are considered the main tools in SIOP follow-up. [9] The SIOP-PODC recommendations developed for lower-resource settings also place particular emphasis on the accessibility of US. [10,11] The study design and reporting of results were structured in accordance with the STROBE recommendations accepted for observational studies. [12] The aim of this study is to evaluate, in children with unilateral Wilms tumor treated at a single center between 2012 and 2020 using the SIOP approach, the association of a US-first neoadjuvant response with relapse and survival outcomes, and to test whether a simple binary grouping of response as regression vs non-regression is useful for clinical risk stratification. 2 | Materials and Methods 2.1. Study design and setting This retrospective, single-center cohort study was conducted at the Department of Pediatric Oncology of the National Center of Oncology in Baku. Consecutive patients with unilateral Wilms tumor treated according to the SIOP approach between January 1, 2012 and December 31, 2020 were reviewed, and 59 children who met the eligibility criteria were included in the study. To minimize selection bias, all eligible consecutive patients were included without exception. To improve data accuracy, data were collected using a standardized form, and key clinical and pathological variables were cross-checked against medical records, operative notes, and pathology reports. 2.2. Patients and eligibility criteria Inclusion criteria: age 0–18 years at diagnosis; histologically confirmed unilateral Wilms tumor; SIOP stage I–IV; completion of protocol-based treatment at the center; and availability of essential clinical-pathological data. Exclusion criteria: bilateral (stage V) Wilms tumor; presentation with relapse (patients treated at another center and referred after recurrence); incomplete histopathological data; follow-up duration <6 months; treatment outside a SIOP-based approach; and cases in which standard evaluation was not possible due to incomplete treatment performed abroad. 2.3. Diagnostic approach, “US-first” imaging strategy, and assessment of response to treatment A distinguishing feature of this cohort is that tumor measurement, monitoring of response to neoadjuvant therapy, and surveillance examinations were performed primarily using ultrasound (US). The initial evaluation included clinical examination, laboratory tests, abdominal US, and contrast-enhanced CT for diagnostic purposes. To reduce radiation exposure, CT was used only at the diagnostic stage, whereas assessment of treatment response and follow-up abdominal imaging were based on US. Evaluation of pulmonary metastases was performed with chest radiography and/or CT depending on clinical need. Staging (I–IV) and histological risk group were determined according to SIOP criteria based on pathological evaluation of the surgical specimen (including blastemal component, degree of necrosis, and histological subtype). During the neoadjuvant phase, response to treatment was assessed based on US measurements. US measurements were obtained in standard projections and, whenever possible, were performed by the same radiologist and/or a trained specialist. The largest axial tumor diameter was used as the reference for response assessment, and the following categories were applied: Complete regression: complete disappearance of measurable tumor tissue Partial regression: ≥30% decrease in tumor size Stable disease: <30% decrease and <20% increase Progression: ≥20% increase in tumor size and/or emergence of new lesions For the main analyses, to improve statistical stability, responses were merged into two groups: regression (complete + partial) and non-regression (stable + progression) . Progression during the neoadjuvant period was considered chemoresistance (treatment resistance). 2.4. Treatment approach and stratification of intensity (0/1/2/3/4 agents) All patients were treated according to SIOP principles with neoadjuvant (preoperative) chemotherapy followed by radical nephrectomy. Postoperative (adjuvant) chemotherapy was selected according to stage and histological risk group. Radiotherapy (RT) was administered only when indicated by the postoperative protocol (locally advanced disease, residual disease, and/or metastatic involvement). In this study, treatment intensity was additionally stratified based on the “number of active drugs,” reflecting real-world clinical practice (this stratification is not identical to SIOP protocol names and was used to describe the spectrum of clinical intensity): 0-drug: no postoperative chemotherapy in selected very low-risk cases 1-drug (single agent): Vincristine (VCR) – additional/bridging doses in selected clinical situations 2-drug (doublet): Vincristine (VCR) + Actinomycin-D/Dactinomycin (ACT-D) 3-drug (triplet): Vincristine (VCR) + Actinomycin-D (ACT-D) + Doxorubicin (DOX) 4-drug (quadruplet, intensive): Etoposide (VP-16) + Carboplatin (CARBO) + Cyclophosphamide (CPM) + Doxorubicin (DOX) 2.5. Data collection and variables Data were extracted from electronic and paper medical records using a standardized form. The following variables were recorded: Demographics: age group, sex Tumor characteristics: laterality, stage, histological subtype, risk group, blastemal component, metastasis Treatment variables: neoadjuvant/adjuvant regimen, surgical details, lymph node sampling (if available), RT, US response Toxicity: thrombocytopenia and neutropenia (CTCAE v5.0) Outcomes: date of diagnosis, date of last follow-up, relapse, death, and cause of death When available, relapse type (local, pulmonary, combined) was recorded separately. Missingness in key variables was assessed, and analyses were performed using a complete-case approach whenever possible. 2.6. Endpoints, definitions, and ethical considerations The primary endpoints were overall survival (OS) and disease-free survival (DFS): OS: time from date of diagnosis to death from any cause or to the date of last follow-up DFS: time from date of diagnosis to relapse, death, or the date of last follow-up Relapse was defined as radiologically and/or histologically confirmed recurrence. As a secondary outcome, early relapse (≤24 months) was evaluated separately. Ethical approval: The study was approved by the Ethics Committee of the National Center of Oncology (Protocol No. MOM-2025/47, approval date: 07.10.2024). Due to the retrospective design, data were anonymized, the requirement for written informed consent was waived, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Statistical analysis: Categorical variables were presented as frequency and percentage, and continuous variables as median (IQR) or, when appropriate, mean ± SD. Group comparisons were performed using the χ² test or Fisher’s exact test. Survival outcomes were estimated using the Kaplan–Meier method, and between-group differences were assessed using the appropriate survival comparison test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression, and p<0.05 was considered statistically significant. 2.7. Statistical analysis Analyses were performed using IBM SPSS Statistics for Windows (version 29.0; IBM Corp., Armonk, NY, USA). Continuous variables were reported as median (IQR) or, where appropriate, mean ± SD, and categorical variables as n (%). Distribution of continuous variables was assessed using the Shapiro–Wilk test and graphical methods. For between-group comparisons, χ² or Fisher’s exact test was used for categorical variables, and Student’s t-test or the Mann–Whitney U test was used for continuous variables depending on distribution (ANOVA/Kruskal–Wallis for multi-group comparisons). Neoadjuvant response was assessed by US (largest axial diameter) and classified as complete/partial regression, stable disease, and progression (chemoresistance). For the main analyses, response was merged a priori into two groups: regression (complete + partial) and non-regression (stable + progression). Survival endpoints were defined as OS (diagnosis to death/last follow-up) and DFS (diagnosis to relapse/death/last follow-up); patients without relapse/death were censored. Survival probabilities were calculated using the Kaplan–Meier method, and differences between groups were compared using the log-rank test. Median follow-up duration was estimated using the reverse Kaplan–Meier method. A Cox proportional hazards model was constructed to identify prognostic factors associated with OS and DFS, and results were presented as HR (95% CI). The multivariable model was built based on clinical relevance and variables showing a trend in univariable analysis (p<0.10), and the proportional hazards assumption was assessed using graphical methods. Because the amount of missing data was low, no imputation was performed, and analyses were conducted using a complete-case approach whenever possible. All tests were two-sided, with p<0.05 considered significant (p<0.001 reported separately). 3 | Results Between 2012 and 2020, 59 children with unilateral Wilms tumor treated according to SIOP-based protocols were included in the study. Of these, 33 were boys (55.9%) and 26 were girls (44.1%). The age distribution was as follows: 0–24 months: 23 (39.0%), 24–60 months: 29 (49.2%), and >60 months: 7 (11.9%). Tumor laterality was left-sided in 31 (52.5%) and right-sided in 28 (47.5%). Stage distribution was I: 3 (5.1%), II: 23 (39.0%), III: 19 (32.2%), and IV: 14 (23.7%). In the database, one patient had been erroneously coded as “VI” and was standardized as stage IV for all analyses. Histological risk groups were low: 3 (5.1%), intermediate: 33 (55.9%), and high: 23 (39.0%). Postoperative radiotherapy was administered in 28 (47.5%) patients. Protocol distribution was as follows: SIOP-2001: 28 (47.5%), SIOP-2016: 27 (45.8%), SIOP-2016 ICE: 3 (5.1%), and other: 1 (1.7%) (baseline characteristics are summarized in Table 1). Neoadjuvant US response (US-first) When neoadjuvant response was assessed by ultrasound, regression was observed in 50/59 (84.7%), stable disease in 5/59 (8.5%), and progression/chemoresistancein 4/59 (6.8%); no complete regression was recorded (0%). For the primary analyses, response was categorized into two groups: regression (n=50) and non-regression (stable + progression, n=9; 15.3%). Non-regression occurred only in stage III–IV disease (p=0.038). The association between US response (binary categorization) and histological risk group did not reach statistical significance (p=0.166). When evaluated by protocol categories (excluding the “other” group, n=1, from inferential comparisons), non-regression was observed as follows: SIOP-2001: 6/28 (21.4%), SIOP-2016: 2/27 (7.4%), and SIOP-2016 ICE: 1/3 (33.3%); the difference was not statistically significant (p=0.243). These associations are summarized in Table 2. Timing of relapse and documented relapse sites During follow-up, relapse was recorded in 11/59 (18.6%) and death in 7/59 (11.9%). The median follow-up time was 94 months (reverse Kaplan–Meier). Relapse timing showed a strong early “clustering”: 9 of 11 relapses (81.8%) occurred within the first 24 months after diagnosis. The relapse site was documented in 7 of 11 relapses (63.6%), while data were missing in 4 (36.4%); documented relapse locations are summarized in Supplementary Table S1. Clinical outcomes by US response US response showed a pronounced separation in outcomes. In the regression group, relapse occurred in 5/50 (10.0%) and death in 2/50 (4.0%), whereas in the non-regression group, relapse was recorded in 6/9 (66.7%) and death in 5/9 (55.6%) (both p<0.001). Kaplan–Meier analyses also confirmed large survival differences. At 60 months, overall survival (OS) was 96.0% in the regression group and 44.4% in the non-regression group (p<0.001); disease-free survival (DFS) was 90.0% and 33.3%, respectively (p<0.001). In univariable Cox models, non-regression was strongly associated with worse outcomes: HR for OS 16.89 (95% CI 3.27–87.20), p<0.001, and HR for DFS 8.84 (95% CI 2.68–29.16), p<0.001 (summarized in Table 3). Kaplan–Meier curves for OS and DFS by US response are presented in Figure 1 and Figure 2. Contextual comparisons (protocols, stage, RT, toxicity) In contextual (non-causal) comparisons, relapse rates differed across protocols (excluding the “other” group, n=1): SIOP-2001: 7/28 (25.0%), SIOP-2016: 2/27 (7.4%), and SIOP-2016 ICE: 2/3 (66.7%) (p=0.024). Mortality also differed by protocol (p=0.006), noting that the ICE subgroup was very small. Relapse and death increased with higher stage (relapse p=0.005; death p=0.011); in stage IV, relapse was 7/14 (50.0%). Relapse was more frequent among patients who received radiotherapy (p=0.018, Fisher’s exact test), consistent with expected confounding by indication. Regarding hematologic toxicity, thrombocytopenia (any grade) was associated with relapse (p=0.009) and death (p=0.018); neutropenia (any grade) was associated with relapse (p=0.002) and showed a borderline association with death (p=0.052). Overall, the strongest prognostic separation within the cohort was observed according to neoadjuvant US response. 4 | Discussion In this single-center cohort study covering 2012–2020, the main finding is that, in children with unilateral Wilms tumor treated according to SIOP principles, a simple binary classification of neoadjuvant ultrasound response (regression vs non-regression) within a US-first surveillance strategy provides a strong prognostic signal in real-world clinical practice and clearly stratifies the risk of both relapse and long-term survival. This finding offers a practical answer to the question of “which patients require closer and earlier follow-up?”, even in a disease where overall survival is known to be high. [13] The rationale of the SIOP approach is to reduce surgical risks through preoperative chemotherapy and to tailor subsequent treatment in a risk-adapted manner based on stage and histological risk indicators; the UMBRELLA SIOP–RTSG 2016 framework systematizes this principle further by promoting more precise risk separation and a “treatment as needed” balance (de-escalation vs intensification). In our real-world cohort, the distribution of protocol strata (SIOP-2001/SIOP-2016/ICE) and their associations with outcomes should be interpreted not as causal effects but within the context of “clinical stratification and indication,” given that protocol selection is inherently linked to baseline risk profile. [14] A distinguishing aspect of this work is that response assessment and abdominal surveillance imaging were performed primarily by ultrasound. This represents an accessible and “radiation-sparing” strategy in systems with variable resources: considering the long-term risks of CT exposure in children and the cumulative radiation burden from repeated imaging, a US-first strategy appears to be a rational choice. However, the operator dependence of ultrasound and the limitation of diameter-based measurements in fully capturing volume, necrosis, and heterogeneity are well-recognized; therefore, standardization of US measurement protocols and, where feasible, verification of inter-center reproducibility should be prioritized in future work. [16–18] The observation that non-regression during the neoadjuvant period occurred only in stage III–IV groups is an expected pattern in terms of biology and clinical course: in more advanced stages, tumor burden and heterogeneity increase, and the likelihood of treatment-resistant subclones is higher. Within SIOP experience, progression during preoperative therapy is rare but has been described as a “red flag” marker that may be associated with poorer outcomes; our real-world results support the practical early identification of this signal using ultrasound. [19] The fact that most relapses occurred within the first 24 months carries an additional important clinical message. SIOP series have also shown that relapse tends to cluster early and that detection modalities (abdominal imaging plus chest assessment) form the core of surveillance strategies. In this context, within a US-first approach, closer abdominal US monitoring—especially during the first two years (with lung imaging when clinically indicated)—appears more rational when combined with risk stratification. [15] The marked increase in relapse and mortality in the non-regression group, together with the large separation in 60-month OS/DFS on Kaplan–Meier analysis, highlights neoadjuvant US response not only as a surveillance “tool” but also as a simple marker that can inform clinical decision-making (follow-up intensity, early warning, multidisciplinary discussion). This aligns with the risk-adapted treatment philosophy in Wilms tumor and suggests a stratification approach that can be implemented in real-world practice with minimal additional burden. [14,15] The higher relapse rate observed among patients who received radiotherapy should most plausibly be explained by confounding by indication: RT is typically administered to patients with locally advanced disease, suspected residual disease, and/or high-risk features. Therefore, presenting RT as an independent risk-increasing factor would be inappropriate; a more accurate interpretation is that RT reflects high-risk clinical scenarios. The same logic applies to hematologic toxicities: toxicity may serve as a proxy for treatment intensity and/or for overall clinical burden, and in a retrospective design, confounding is substantial; thus, these associations should be treated as hypothesis-generating observations. [21] Finally, the retrospective, single-center design, incomplete documentation for some variables, and small numbers in certain subgroups (particularly non-regression and ICE) warrant caution in interpretation. Nevertheless, structuring the report in accordance with STROBE principles and the long follow-up duration increase real-world value. Future prospective, multicenter validation, stricter standardization of US measurement protocols, and—where feasible—the development of integrated risk models incorporating histological/molecular determinants could further strengthen the clinical utility of this simple ultrasound response marker. [12,16,22] 5 | Limitations This study has several key limitations. First, because the design is retrospective and single-center, the risk of selection and information bias remains, and direct generalization of the findings to other centers may be limited. Second, although the overall sample size is acceptable for a real-world cohort, the number of patients is small in certain subgroups, particularly non-regression and ICE; therefore, inferential interpretations related to these subgroups should be made with caution. Third, although ultrasound-based response assessment has radiation-sparing advantages, it is operator-dependent; while measurement using standard projections and a consistent examiner reduces this risk, more formal standardization may be required to ensure inter-center reproducibility. Fourth, the protocol/agent strata in this study serve only as an indirect proxy for “treatment intensity,” and because protocol selection is linked to baseline risk, confounding by indication remains likely; therefore, protocol–outcome associations cannot be interpreted causally. Fifth, because centralized pathology review and molecular markers were not available, certain modern risk determinants could not be assessed in this analysis. Finally, although reporting was structured in accordance with accepted principles for observational studies, future studies using a prospective design and multicenter validation would improve the external validity of the results. 6 | Conclusion This real-world, single-center cohort study (2012–2020) demonstrated that, in unilateral Wilms tumor treated with the SIOP approach, a US-first assessment of neoadjuvant response is an accessible indicator with high prognostic value for clinical decision-making. In particular, a practical binary grouping of response (regression vs non-regression [stable/progression]) sharply separates the risks of relapse and death and is accompanied by clinically large differences in 5-year OS/DFS outcomes. This highlights the role of ultrasound not only as a surveillance modality but also as a “simple marker” that enables early risk stratification during the neoadjuvant phase. The fact that most relapses occurred within the first 24 months also provides an important practical message regarding the optimal surveillance time window: prioritizing abdominal US-based monitoring (and lung imaging according to clinical need) appears rational, especially during the first two years. In settings with variable resources, a US-first strategy can be considered both feasible and advantageous from a safety perspective by aiming to reduce radiation exposure in the pediatric population. Two directions are particularly appropriate for future research: (i) more formal standardization of the US response measurement protocol and assessment of reproducibility through prospective, multicenter validation; and (ii) combining US response with histological risk indicators (and, where available, molecular markers) to develop an integrated risk stratification model usable in clinical practice. Thus, ultrasound-based response assessment may serve as a valuable tool for both risk stratification and personalized surveillance/treatment planning in real-world settings. Declarations Author contributions R.M. developed the study concept and design, performed data collection and management, conducted the clinical interpretation, drafted the initial version of the manuscript, scientifically edited the content, and approved the final text. Statistical support Statistical analyses and independent verification of the results (statistical verification) were performed by Prof. Dr. Kenan Köse (Ankara University Faculty of Medicine, Department of Biostatistics). Ethical approval The study protocol was approved by the Ethics Committee of the National Center of Oncology (Ethics Protocol No.: MOM-2025/47, approval date: 07.06.2025) and was conducted in accordance with the principles of the Declaration of Helsinki. Because the study was retrospective in nature and data were used in anonymized form, written informed consent was not required. Conflict of interest The author declares no competing interests or financial conflicts of interest. Funding This study received no financial support. Data availability The data used in this study were obtained from the database of the National Center of Oncology. Although the data are not publicly available, anonymized core datasets may be shared upon reasonable request, after the relevant ethical and institutional approvals have been obtained, through the corresponding author. Acknowledgements The author thanks the pediatric surgery and pediatric oncology teams at the National Center of Oncology, as well as the clinical and administrative staff who supported data collection and archiving. The author also expresses special thanks to Prof. Dr. Kenan Köse (Ankara University Faculty of Medicine, Department of Biostatistics) for his support in conducting the statistical analyses and independently verifying the results. References Wang, J., Li, M., Tang, D., & Shu, Q. (2019). Current treatment for Wilms tumor: COG and SIOP standards. World Journal of Pediatric Surgery, 2(3), e000038. https://doi.org/10.1136/wjps-2019-000038 Godzinski, J. (2015). The current status of treatment of Wilms’ tumor as per the SIOP trials. 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The Lancet, 380(9840), 499–505. https://doi.org/10.1016/S0140-6736(12)60815-0 Ora, I., van Tinteren, H., de Kraker, J., & Vujanić, G. M. (2007). Tumor progression during preoperative chemotherapy in Wilms tumor: A report from the SIOP 93-01 nephroblastoma trial and study. Pediatric Blood & Cancer, 49(5), 682–686. https://doi.org/10.1002/pbc.21205 Pritchard-Jones, K., Bergeron, C., de Camargo, B., et al. (2015). Omission of doxorubicin from the treatment of stage II–III, intermediate-risk Wilms’ tumour (SIOP WT 2001): An open-label, non-inferiority, randomised controlled trial. The Lancet, 386(9999), 1156–1164. https://doi.org/10.1016/S0140-6736(14)62395-3 Janssens, G. O., Timmermann, B., Sulman, E. P., et al. (2020). The SIOP-Renal Tumour Study Group consensus statement on flank target volume delineation for highly conformal radiotherapy. The Lancet Child & Adolescent Health, 4(11), 829–838. https://doi.org/10.1016/S2352-4642(20)30183-8 Children’s Oncology Group (COG). (2018). Outcome and prognostic factors in stage III favorable histology Wilms tumor: Report from COG study AREN0532. (Conference abstract/video entry, ASCO). https://www.asco.org/abstracts-presentations/107584/video Tables Table 1. Baseline characteristics and treatment summary (N=59) Characteristic Category n (%) Sex Male 33 (55.9) Female 26 (44.1) Age group 0–24 months 23 (39.0) 24–60 months 29 (49.2) >60 months 7 (11.9) Laterality Left 31 (52.5) Right 28 (47.5) Stage (SIOP) I 3 (5.1) II 23 (39.0) III 19 (32.2) IV* 14 (23.7) Histologic risk group Low 3 (5.1) Intermediate 33 (55.9) High 23 (39.0) Postoperative radiotherapy Yes 28 (47.5) No 31 (52.5) Protocol (as recorded) SIOP-2001 28 (47.5) SIOP-2016 27 (45.8) SIOP-2016 ICE 3 (5.1) Other 1 (1.7) Neoadjuvant US response Regression 50 (84.7) Stable disease 5 (8.5) Progression / chemoresistance 4 (6.8) Complete response 0 (0.0) Any-grade thrombocytopenia Yes 6 (10.2) Any-grade neutropenia Yes 29 (49.2) Outcomes Relapse 11 (18.6) Death 7 (11.9) Table 2.Association of dichotomized neoadjuvant USM response with clinical variables Variable Regression (n=50) Non-regression (n=9) p-value Stage 0.038 I–II 26 0 III–IV 24 9 Histologic risk group 0.166 Low 3 0 Intermediate 29 4 High 18 5 Protocol category* 0.243 SIOP-2001 22 6 SIOP-2016 25 2 SIOP-2016 ICE 2 1 Table 3. Survival endpoints and univariable effect of non-regression Outcome Regression (n=50) Non-regression (n=9) p-value Relapse, n (%) 5 (10.0) 6 (66.7) <0.001 Death, n (%) 2 (4.0) 5 (55.6) <0.001 60-month OS, % 96.0 44.4 <0.001 60-month DFS, % 90.0 33.3 <0.001 Univariable Cox regression (reference = regression): OS: HR 16.89 (95% CI 3.27–87.20), p<0.001 DFS: HR 8.84 (95% CI 2.68–29.16), p<0.001 Additional Declarations No competing interests reported. Supplementary Files TabloS1.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 06 Apr, 2026 Reviewers agreed at journal 25 Mar, 2026 Reviewers invited by journal 18 Mar, 2026 Editor assigned by journal 25 Feb, 2026 Submission checks completed at journal 25 Feb, 2026 First submitted to journal 24 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8961303","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":609854800,"identity":"c5566176-b5c3-4edd-bb91-e49c21299308","order_by":0,"name":"Ramin Malikov","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYJCCA0Asw8YDJD9U2ABJxsYDxGjhAWlhnHEmDaSlgaAWEOABQgZm3rbDcENwAvP204mHC3PsePh4Dh+TnMF23m5t+2GgLTU20bi0yJzJ3XB45rZkHjbetjSJDzy3k7edSQRqOZaW24BDiwQDUAvvNmYeNn4eY8MZEreTzQ4AtTA2HMathf8tSEs9WIsxj8G5ZLPzDwlokQDbchjosB7DxzwJB+zMbhCyRQJsy3FgIB9LfDjjQHKC2Q2gLQn4/MKfu/kz77ZqOfme5AMHPv6zszc7n/7wwYcaG5xaMEAiWGUCscpBwJ4UxaNgFIyCUTAyAABZH2EhFXX8bQAAAABJRU5ErkJggg==","orcid":"","institution":"National Center of Oncology","correspondingAuthor":true,"prefix":"","firstName":"Ramin","middleName":"","lastName":"Malikov","suffix":""}],"badges":[],"createdAt":"2026-02-24 22:08:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8961303/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8961303/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105230166,"identity":"1f0b5bb3-a459-456e-bd80-e84050b449bf","added_by":"auto","created_at":"2026-03-23 17:50:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":50760,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDisease-free survival by neoadjuvant USM response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier curves for disease-free survival (DFS) stratified by neoadjuvant ultrasound (USM) response assessed within a US-first monitoring strategy in children with unilateral Wilms tumor (2012–2020). Patients were grouped as regression (partial/complete regression; \u003cem\u003en\u003c/em\u003e=50) versus non-regression (stable disease or progression/chemoresistance; \u003cem\u003en\u003c/em\u003e=9). DFS was defined as time from diagnosis to relapse or death; patients without an event were censored at last follow-up. Tick marks indicate censored observations. Survival differences were compared using the log-rank test (\u003cstrong\u003ep\u003c/strong\u003e\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8961303/v1/c9db4208acf02882f2a26fee.png"},{"id":105230164,"identity":"d3f69f40-b105-42ab-a93b-b4344263307d","added_by":"auto","created_at":"2026-03-23 17:50:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51270,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival by neoadjuvant USM response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier curves for overall survival (OS) stratified by neoadjuvant ultrasound (USM) response assessed within a US-first monitoring strategy in children with unilateral Wilms tumor (2012–2020). Patients were grouped as regression (partial/complete regression; \u003cem\u003en\u003c/em\u003e=50) versus non-regression (stable disease or progression/chemoresistance; \u003cem\u003en\u003c/em\u003e=9). OS was defined as time from diagnosis to death from any cause; patients alive at last follow-up were censored. Tick marks indicate censored observations. Survival differences were compared using the log-rank test (p\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8961303/v1/02ffc0ae4b3eb9a5c979ee57.png"},{"id":105564521,"identity":"3c196c2d-d8c2-42ea-8204-210b6d2515cf","added_by":"auto","created_at":"2026-03-27 12:49:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1405481,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8961303/v1/b8084a14-4713-4426-8a97-ddf8e3dbd2da.pdf"},{"id":105230165,"identity":"309b091b-2a3c-4702-a104-f18fb86acec8","added_by":"auto","created_at":"2026-03-23 17:50:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17771,"visible":true,"origin":"","legend":"","description":"","filename":"TabloS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8961303/v1/e9311b64cc6d6cc46f6fcb92.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eUltrasound-Based Monitoring in Unilateral Wilms Tumor: Treatment Response Assessment and Early Relapse Dynamics (2012–2020, Single-Center Cohort)\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1 | Introduction","content":"\u003cp\u003eWilms tumor (nephroblastoma) is the most common malignant renal tumor of childhood, and with modern multimodal treatment, long-term survival in advanced centers often exceeds 85\u0026ndash;90%. Nevertheless, relapse remains one of the main problems in clinical practice, and early recognition of risk using practical markers is essential for selecting the appropriate intensity of follow-up. [1]\u003c/p\u003e \u003cp\u003eA key feature of the SIOP approach is that many patients receive neoadjuvant chemotherapy before surgery, and subsequent treatment is built in a risk-adapted manner based on stage, histological risk, and response indicators. Within the UMBRELLA framework, the aim is not only to improve survival but also, through more precise risk stratification, to justify intensification in high-risk patients while reducing toxicity and late complications in low-risk patients. [2]\u003c/p\u003e \u003cp\u003eThe prognostic role of imaging response to neoadjuvant treatment has long been debated; although tumor growth/progression during the preoperative chemotherapy period is rare, it may be associated with worse outcomes and is considered a \u0026ldquo;red flag\u0026rdquo; in clinical decision-making. [3]\u003c/p\u003e \u003cp\u003eThe choice of imaging is critical in terms of diagnosis, response monitoring, and relapse surveillance. Consensus recommendations for pediatric renal tumors support the broad use of ultrasound (US), while CT/MRI plays a complementary role in selected cases. [4] One of the key arguments supporting the widespread use of US is the radiation burden and long-term risks associated with CT in children. [5,6]\u003c/p\u003e \u003cp\u003eHowever, US can be operator-dependent, and diameter-based measurements may not fully reflect components such as volume/necrosis. Still, classical data indicate that sonographic changes during chemotherapy in Wilms tumor may correlate with histopathological findings and can be used in practical follow-up. [7] In response assessment, the widely accepted concept of a \u0026ldquo;measurable target\u0026rdquo; in oncology (e.g., the principles of RECIST 1.1) provides a standardized approach based on changes in diameter. [8]\u003c/p\u003e \u003cp\u003eRegarding the timing of relapse, large series show that a substantial proportion of relapses are detected within the first 2 years, and abdominal US lung imaging are considered the main tools in SIOP follow-up. [9] The SIOP-PODC recommendations developed for lower-resource settings also place particular emphasis on the accessibility of US. [10,11]\u003c/p\u003e \u003cp\u003e The study design and reporting of results were structured in accordance with the STROBE recommendations accepted for observational studies. [12]\u003c/p\u003e \u003cp\u003eThe aim of this study is to evaluate, in children with unilateral Wilms tumor treated at a single center between 2012 and 2020 using the SIOP approach, the association of a US-first neoadjuvant response with relapse and survival outcomes, and to test whether a simple binary grouping of response as regression vs non-regression is useful for clinical risk stratification.\u003c/p\u003e"},{"header":"2 | Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1. Study design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective, single-center cohort study was conducted at the Department of Pediatric Oncology of the National Center of Oncology in Baku. Consecutive patients with unilateral Wilms tumor treated according to the SIOP approach between January 1, 2012 and December 31, 2020 were reviewed, and 59 children who met the eligibility criteria were included in the study. To minimize selection bias, all eligible consecutive patients were included without exception. To improve data accuracy, data were collected using a standardized form, and key clinical and pathological variables were cross-checked against medical records, operative notes, and pathology reports.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2. Patients and eligibility criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria:\u003c/strong\u003e age 0–18 years at diagnosis; histologically confirmed unilateral Wilms tumor; SIOP stage I–IV; completion of protocol-based treatment at the center; and availability of essential clinical-pathological data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria:\u003c/strong\u003e bilateral (stage V) Wilms tumor; presentation with relapse (patients treated at another center and referred after recurrence); incomplete histopathological data; follow-up duration \u0026lt;6 months; treatment outside a SIOP-based approach; and cases in which standard evaluation was not possible due to incomplete treatment performed abroad.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3. Diagnostic approach, “US-first” imaging strategy, and assessment of response to treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA distinguishing feature of this cohort is that tumor measurement, monitoring of response to neoadjuvant therapy, and surveillance examinations were performed primarily using ultrasound (US). The initial evaluation included clinical examination, laboratory tests, abdominal US, and contrast-enhanced CT for diagnostic purposes. To reduce radiation exposure, CT was used only at the diagnostic stage, whereas assessment of treatment response and follow-up abdominal imaging were based on US. Evaluation of pulmonary metastases was performed with chest radiography and/or CT depending on clinical need.\u003c/p\u003e\n\u003cp\u003eStaging (I–IV) and histological risk group were determined according to SIOP criteria based on pathological evaluation of the surgical specimen (including blastemal component, degree of necrosis, and histological subtype).\u003c/p\u003e\n\u003cp\u003eDuring the neoadjuvant phase, response to treatment was assessed based on US measurements. US measurements were obtained in standard projections and, whenever possible, were performed by the same radiologist and/or a trained specialist. The largest axial tumor diameter was used as the reference for response assessment, and the following categories were applied:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eComplete regression:\u003c/strong\u003e complete disappearance of measurable tumor tissue\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePartial regression:\u003c/strong\u003e ≥30% decrease in tumor size\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eStable disease:\u003c/strong\u003e \u0026lt;30% decrease and \u0026lt;20% increase\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eProgression:\u003c/strong\u003e ≥20% increase in tumor size and/or emergence of new lesions\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eFor the main analyses, to improve statistical stability, responses were merged into two groups: \u003cstrong\u003eregression (complete + partial)\u003c/strong\u003e and \u003cstrong\u003enon-regression (stable + progression)\u003c/strong\u003e. Progression during the neoadjuvant period was considered \u003cstrong\u003echemoresistance\u003c/strong\u003e (treatment resistance).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4. Treatment approach and stratification of intensity (0/1/2/3/4 agents)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were treated according to SIOP principles with neoadjuvant (preoperative) chemotherapy followed by radical nephrectomy. Postoperative (adjuvant) chemotherapy was selected according to stage and histological risk group. Radiotherapy (RT) was administered only when indicated by the postoperative protocol (locally advanced disease, residual disease, and/or metastatic involvement).\u003c/p\u003e\n\u003cp\u003eIn this study, treatment intensity was additionally stratified based on the “number of active drugs,” reflecting real-world clinical practice (this stratification is not identical to SIOP protocol names and was used to describe the spectrum of clinical intensity):\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003e0-drug:\u003c/strong\u003e no postoperative chemotherapy in selected very low-risk cases\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e1-drug (single agent):\u003c/strong\u003e Vincristine (VCR) – additional/bridging doses in selected clinical situations\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e2-drug (doublet):\u003c/strong\u003e Vincristine (VCR) + Actinomycin-D/Dactinomycin (ACT-D)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e3-drug (triplet):\u003c/strong\u003e Vincristine (VCR) + Actinomycin-D (ACT-D) + Doxorubicin (DOX)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003e4-drug (quadruplet, intensive):\u003c/strong\u003e Etoposide (VP-16) + Carboplatin (CARBO) + Cyclophosphamide (CPM) + Doxorubicin (DOX)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e2.5. Data collection and variables\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were extracted from electronic and paper medical records using a standardized form. The following variables were recorded:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eDemographics:\u003c/strong\u003e age group, sex\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTumor characteristics:\u003c/strong\u003e laterality, stage, histological subtype, risk group, blastemal component, metastasis\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTreatment variables:\u003c/strong\u003e neoadjuvant/adjuvant regimen, surgical details, lymph node sampling (if available), RT, US response\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eToxicity:\u003c/strong\u003e thrombocytopenia and neutropenia (CTCAE v5.0)\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOutcomes:\u003c/strong\u003e date of diagnosis, date of last follow-up, relapse, death, and cause of death\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eWhen available, relapse type (local, pulmonary, combined) was recorded separately. Missingness in key variables was assessed, and analyses were performed using a complete-case approach whenever possible.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6. Endpoints, definitions, and ethical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoints were overall survival (OS) and disease-free survival (DFS):\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eOS:\u003c/strong\u003e time from date of diagnosis to death from any cause or to the date of last follow-up\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDFS:\u003c/strong\u003e time from date of diagnosis to relapse, death, or the date of last follow-up\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eRelapse was defined as radiologically and/or histologically confirmed recurrence. As a secondary outcome, early relapse (≤24 months) was evaluated separately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u003c/strong\u003e The study was approved by the Ethics Committee of the National Center of Oncology (Protocol No. MOM-2025/47, approval date: 07.10.2024). Due to the retrospective design, data were anonymized, the requirement for written informed consent was waived, and the study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e Categorical variables were presented as frequency and percentage, and continuous variables as median (IQR) or, when appropriate, mean ± SD. Group comparisons were performed using the χ² test or Fisher’s exact test. Survival outcomes were estimated using the Kaplan–Meier method, and between-group differences were assessed using the appropriate survival comparison test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression, and p\u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.7. Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were performed using IBM SPSS Statistics for Windows (version 29.0; IBM Corp., Armonk, NY, USA). Continuous variables were reported as median (IQR) or, where appropriate, mean ± SD, and categorical variables as n (%). Distribution of continuous variables was assessed using the Shapiro–Wilk test and graphical methods.\u003c/p\u003e\n\u003cp\u003eFor between-group comparisons, χ² or Fisher’s exact test was used for categorical variables, and Student’s t-test or the Mann–Whitney U test was used for continuous variables depending on distribution (ANOVA/Kruskal–Wallis for multi-group comparisons).\u003c/p\u003e\n\u003cp\u003eNeoadjuvant response was assessed by US (largest axial diameter) and classified as complete/partial regression, stable disease, and progression (chemoresistance). For the main analyses, response was merged a priori into two groups: regression (complete + partial) and non-regression (stable + progression).\u003c/p\u003e\n\u003cp\u003eSurvival endpoints were defined as OS (diagnosis to death/last follow-up) and DFS (diagnosis to relapse/death/last follow-up); patients without relapse/death were censored. Survival probabilities were calculated using the Kaplan–Meier method, and differences between groups were compared using the log-rank test. Median follow-up duration was estimated using the reverse Kaplan–Meier method.\u003c/p\u003e\n\u003cp\u003eA Cox proportional hazards model was constructed to identify prognostic factors associated with OS and DFS, and results were presented as HR (95% CI). The multivariable model was built based on clinical relevance and variables showing a trend in univariable analysis (p\u0026lt;0.10), and the proportional hazards assumption was assessed using graphical methods. Because the amount of missing data was low, no imputation was performed, and analyses were conducted using a complete-case approach whenever possible. All tests were two-sided, with p\u0026lt;0.05 considered significant (p\u0026lt;0.001 reported separately).\u003c/p\u003e"},{"header":"3 | Results","content":"\u003cp\u003eBetween 2012 and 2020, 59 children with unilateral Wilms tumor treated according to SIOP-based protocols were included in the study. Of these, 33 were boys (55.9%) and 26 were girls (44.1%). The age distribution was as follows: 0–24 months: 23 (39.0%), 24–60 months: 29 (49.2%), and \u0026gt;60 months: 7 (11.9%). Tumor laterality was left-sided in 31 (52.5%) and right-sided in 28 (47.5%). Stage distribution was I: 3 (5.1%), II: 23 (39.0%), III: 19 (32.2%), and IV: 14 (23.7%). In the database, one patient had been erroneously coded as “VI” and was standardized as stage IV for all analyses. Histological risk groups were low: 3 (5.1%), intermediate: 33 (55.9%), and high: 23 (39.0%). Postoperative radiotherapy was administered in 28 (47.5%) patients. Protocol distribution was as follows: SIOP-2001: 28 (47.5%), SIOP-2016: 27 (45.8%), SIOP-2016 ICE: 3 (5.1%), and other: 1 (1.7%) (baseline characteristics are summarized in Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNeoadjuvant US response (US-first)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhen neoadjuvant response was assessed by ultrasound, regression was observed in 50/59 (84.7%), stable disease in 5/59 (8.5%), and progression/chemoresistancein 4/59 (6.8%); no complete regression was recorded (0%). For the primary analyses, response was categorized into two groups: regression (n=50) and non-regression (stable + progression, n=9; 15.3%).\u003c/p\u003e\n\u003cp\u003eNon-regression occurred only in stage III–IV disease (p=0.038). The association between US response (binary categorization) and histological risk group did not reach statistical significance (p=0.166). When evaluated by protocol categories (excluding the “other” group, n=1, from inferential comparisons), non-regression was observed as follows: SIOP-2001: 6/28 (21.4%), SIOP-2016: 2/27 (7.4%), and SIOP-2016 ICE: 1/3 (33.3%); the difference was not statistically significant (p=0.243). These associations are summarized in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTiming of relapse and documented relapse sites\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring follow-up, relapse was recorded in 11/59 (18.6%) and death in 7/59 (11.9%). The median follow-up time was 94 months (reverse Kaplan–Meier). Relapse timing showed a strong early “clustering”: 9 of 11 relapses (81.8%) occurred within the first 24 months after diagnosis. The relapse site was documented in 7 of 11 relapses (63.6%), while data were missing in 4 (36.4%); documented relapse locations are summarized in Supplementary Table S1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical outcomes by US response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUS response showed a pronounced separation in outcomes. In the regression group, relapse occurred in 5/50 (10.0%) and death in 2/50 (4.0%), whereas in the non-regression group, relapse was recorded in 6/9 (66.7%) and death in 5/9 (55.6%) (both p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eKaplan–Meier analyses also confirmed large survival differences. At 60 months, overall survival (OS) was 96.0% in the regression group and 44.4% in the non-regression group (p\u0026lt;0.001); disease-free survival (DFS) was 90.0% and 33.3%, respectively (p\u0026lt;0.001). In univariable Cox models, non-regression was strongly associated with worse outcomes: HR for OS 16.89 (95% CI 3.27–87.20), p\u0026lt;0.001, and HR for DFS 8.84 (95% CI 2.68–29.16), p\u0026lt;0.001 (summarized in Table 3). Kaplan–Meier curves for OS and DFS by US response are presented in Figure 1 and Figure 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContextual comparisons (protocols, stage, RT, toxicity)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn contextual (non-causal) comparisons, relapse rates differed across protocols (excluding the “other” group, n=1): SIOP-2001: 7/28 (25.0%), SIOP-2016: 2/27 (7.4%), and SIOP-2016 ICE: 2/3 (66.7%) (p=0.024). Mortality also differed by protocol (p=0.006), noting that the ICE subgroup was very small. Relapse and death increased with higher stage (relapse p=0.005; death p=0.011); in stage IV, relapse was 7/14 (50.0%). Relapse was more frequent among patients who received radiotherapy (p=0.018, Fisher’s exact test), consistent with expected confounding by indication. Regarding hematologic toxicity, thrombocytopenia (any grade) was associated with relapse (p=0.009) and death (p=0.018); neutropenia (any grade) was associated with relapse (p=0.002) and showed a borderline association with death (p=0.052). Overall, the strongest prognostic separation within the cohort was observed according to neoadjuvant US response.\u003c/p\u003e"},{"header":"4 | Discussion","content":"\u003cp\u003eIn this single-center cohort study covering 2012–2020, the main finding is that, in children with unilateral Wilms tumor treated according to SIOP principles, a simple binary classification of neoadjuvant ultrasound response (regression vs non-regression) within a US-first surveillance strategy provides a strong prognostic signal in real-world clinical practice and clearly stratifies the risk of both relapse and long-term survival. This finding offers a practical answer to the question of “which patients require closer and earlier follow-up?”, even in a disease where overall survival is known to be high. [13]\u003c/p\u003e\n\u003cp\u003eThe rationale of the SIOP approach is to reduce surgical risks through preoperative chemotherapy and to tailor subsequent treatment in a risk-adapted manner based on stage and histological risk indicators; the UMBRELLA SIOP–RTSG 2016 framework systematizes this principle further by promoting more precise risk separation and a “treatment as needed” balance (de-escalation vs intensification). In our real-world cohort, the distribution of protocol strata (SIOP-2001/SIOP-2016/ICE) and their associations with outcomes should be interpreted not as causal effects but within the context of “clinical stratification and indication,” given that protocol selection is inherently linked to baseline risk profile. [14]\u003c/p\u003e\n\u003cp\u003eA distinguishing aspect of this work is that response assessment and abdominal surveillance imaging were performed primarily by ultrasound. This represents an accessible and “radiation-sparing” strategy in systems with variable resources: considering the long-term risks of CT exposure in children and the cumulative radiation burden from repeated imaging, a US-first strategy appears to be a rational choice. However, the operator dependence of ultrasound and the limitation of diameter-based measurements in fully capturing volume, necrosis, and heterogeneity are well-recognized; therefore, standardization of US measurement protocols and, where feasible, verification of inter-center reproducibility should be prioritized in future work. [16–18]\u003c/p\u003e\n\u003cp\u003eThe observation that non-regression during the neoadjuvant period occurred only in stage III–IV groups is an expected pattern in terms of biology and clinical course: in more advanced stages, tumor burden and heterogeneity increase, and the likelihood of treatment-resistant subclones is higher. Within SIOP experience, progression during preoperative therapy is rare but has been described as a “red flag” marker that may be associated with poorer outcomes; our real-world results support the practical early identification of this signal using ultrasound. [19]\u003c/p\u003e\n\u003cp\u003eThe fact that most relapses occurred within the first 24 months carries an additional important clinical message. SIOP series have also shown that relapse tends to cluster early and that detection modalities (abdominal imaging plus chest assessment) form the core of surveillance strategies. In this context, within a US-first approach, closer abdominal US monitoring—especially during the first two years (with lung imaging when clinically indicated)—appears more rational when combined with risk stratification. [15]\u003c/p\u003e\n\u003cp\u003eThe marked increase in relapse and mortality in the non-regression group, together with the large separation in 60-month OS/DFS on Kaplan–Meier analysis, highlights neoadjuvant US response not only as a surveillance “tool” but also as a simple marker that can inform clinical decision-making (follow-up intensity, early warning, multidisciplinary discussion). This aligns with the risk-adapted treatment philosophy in Wilms tumor and suggests a stratification approach that can be implemented in real-world practice with minimal additional burden. [14,15]\u003c/p\u003e\n\u003cp\u003eThe higher relapse rate observed among patients who received radiotherapy should most plausibly be explained by confounding by indication: RT is typically administered to patients with locally advanced disease, suspected residual disease, and/or high-risk features. Therefore, presenting RT as an independent risk-increasing factor would be inappropriate; a more accurate interpretation is that RT reflects high-risk clinical scenarios. The same logic applies to hematologic toxicities: toxicity may serve as a proxy for treatment intensity and/or for overall clinical burden, and in a retrospective design, confounding is substantial; thus, these associations should be treated as hypothesis-generating observations. [21]\u003c/p\u003e\n\u003cp\u003eFinally, the retrospective, single-center design, incomplete documentation for some variables, and small numbers in certain subgroups (particularly non-regression and ICE) warrant caution in interpretation. Nevertheless, structuring the report in accordance with STROBE principles and the long follow-up duration increase real-world value. Future prospective, multicenter validation, stricter standardization of US measurement protocols, and—where feasible—the development of integrated risk models incorporating histological/molecular determinants could further strengthen the clinical utility of this simple ultrasound response marker. [12,16,22]\u003c/p\u003e"},{"header":"5 | Limitations","content":"\u003cp\u003eThis study has several key limitations. First, because the design is retrospective and single-center, the risk of selection and information bias remains, and direct generalization of the findings to other centers may be limited. Second, although the overall sample size is acceptable for a real-world cohort, the number of patients is small in certain subgroups, particularly non-regression and ICE; therefore, inferential interpretations related to these subgroups should be made with caution. Third, although ultrasound-based response assessment has radiation-sparing advantages, it is operator-dependent; while measurement using standard projections and a consistent examiner reduces this risk, more formal standardization may be required to ensure inter-center reproducibility. Fourth, the protocol/agent strata in this study serve only as an indirect proxy for “treatment intensity,” and because protocol selection is linked to baseline risk, confounding by indication remains likely; therefore, protocol–outcome associations cannot be interpreted causally. Fifth, because centralized pathology review and molecular markers were not available, certain modern risk determinants could not be assessed in this analysis. Finally, although reporting was structured in accordance with accepted principles for observational studies, future studies using a prospective design and multicenter validation would improve the external validity of the results.\u003c/p\u003e"},{"header":"6 | Conclusion","content":"\u003cp\u003eThis real-world, single-center cohort study (2012–2020) demonstrated that, in unilateral Wilms tumor treated with the SIOP approach, a US-first assessment of neoadjuvant response is an accessible indicator with high prognostic value for clinical decision-making. In particular, a practical binary grouping of response (regression vs non-regression [stable/progression]) sharply separates the risks of relapse and death and is accompanied by clinically large differences in 5-year OS/DFS outcomes. This highlights the role of ultrasound not only as a surveillance modality but also as a “simple marker” that enables early risk stratification during the neoadjuvant phase.\u003c/p\u003e\n\u003cp\u003eThe fact that most relapses occurred within the first 24 months also provides an important practical message regarding the optimal surveillance time window: prioritizing abdominal US-based monitoring (and lung imaging according to clinical need) appears rational, especially during the first two years. In settings with variable resources, a US-first strategy can be considered both feasible and advantageous from a safety perspective by aiming to reduce radiation exposure in the pediatric population.\u003c/p\u003e\n\u003cp\u003eTwo directions are particularly appropriate for future research: (i) more formal standardization of the US response measurement protocol and assessment of reproducibility through prospective, multicenter validation; and (ii) combining US response with histological risk indicators (and, where available, molecular markers) to develop an integrated risk stratification model usable in clinical practice. Thus, ultrasound-based response assessment may serve as a valuable tool for both risk stratification and personalized surveillance/treatment planning in real-world settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eR.M. developed the study concept and design, performed data collection and management, conducted the clinical interpretation, drafted the initial version of the manuscript, scientifically edited the content, and approved the final text.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses and independent verification of the results (statistical verification) were performed by Prof. Dr. Kenan Köse (Ankara University Faculty of Medicine, Department of Biostatistics).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Committee of the National Center of Oncology (Ethics Protocol No.: MOM-2025/47, approval date: 07.06.2025) and was conducted in accordance with the principles of the Declaration of Helsinki. Because the study was retrospective in nature and data were used in anonymized form, written informed consent was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no competing interests or financial conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received no financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study were obtained from the database of the National Center of Oncology. Although the data are not publicly available, anonymized core datasets may be shared upon reasonable request, after the relevant ethical and institutional approvals have been obtained, through the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author thanks the pediatric surgery and pediatric oncology teams at the National Center of Oncology, as well as the clinical and administrative staff who supported data collection and archiving. The author also expresses special thanks to \u003cstrong\u003eProf. Dr. Kenan Köse\u003c/strong\u003e (Ankara University Faculty of Medicine, Department of Biostatistics) for his support in conducting the statistical analyses and independently verifying the results.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWang, J., Li, M., Tang, D., \u0026amp; Shu, Q. (2019). Current treatment for Wilms tumor: COG and SIOP standards. World Journal of Pediatric Surgery, 2(3), e000038. https://doi.org/10.1136/wjps-2019-000038 \u003c/li\u003e\n\u003cli\u003eGodzinski, J. (2015). The current status of treatment of Wilms\u0026rsquo; tumor as per the SIOP trials. Journal of Indian Association of Pediatric Surgeons, 20(1), 16\u0026ndash;20. https://doi.org/10.4103/0971-9261.145438 \u003c/li\u003e\n\u003cli\u003eGraf, N., van Tinteren, H., Bergeron, C., et al. (2015). Treatment of renal tumours: A summary of the SIOP-RTSG clinical practice recommendations (ESCP document). SIOPE (PDF). https://siope.eu/media/documents/escp-treatment-of-renal-tumours.pdf \u003c/li\u003e\n\u003cli\u003eMathews, J. D., Forsythe, A. V., Brady, Z., et al. (2013). Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: Data linkage study of 11 million Australians. BMJ, 346, f2360. https://doi.org/10.1136/bmj.f2360 \u003c/li\u003e\n\u003cli\u003eEisenhauer, E. A., Therasse, P., Bogaerts, J., et al. (2009). New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer, 45(2), 228\u0026ndash;247. https://doi.org/10.1016/j.ejca.2008.10.026 \u003c/li\u003e\n\u003cli\u003eNational Cancer Institute. (2017). Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. (PDF). https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm\u003c/li\u003e\n\u003cli\u003eShyirambere, C., Renner, L., \u0026amp; Howard, S. C. (2016). Treating nephroblastoma (Wilms tumour) in Rwanda: Using international protocols in a resource-limited setting. JCO Global Oncology, 2, 354\u0026ndash;361. https://doi.org/10.1200/JGO.2015.000067\u003c/li\u003e\n\u003cli\u003ePatel, H., Mahboubi, S., Sherman, S., \u0026amp; Rosenberg, H. K. (1991). Diagnosis and follow-up of children with Wilms\u0026rsquo; tumor: Correlative study of ultrasound and computed tomography. Annales de Radiologie (Paris), 34, 376\u0026ndash;382. (No DOI indexed; PubMed/Library search by title)\u003c/li\u003e\n\u003cli\u003eNational Cancer Institute. (2025, April 15). Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ\u0026reg;)\u0026ndash;Health Professional Version. https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq\u003c/li\u003e\n\u003cli\u003eIsraels, T., Moreira, C., Scanlan, T., et al. (2013). SIOP PODC: Clinical guidelines for the management of children with Wilms tumour in a low income setting. Pediatric Blood \u0026amp; Cancer, 60(1), 5\u0026ndash;11. https://doi.org/10.1002/pbc.24321\u003c/li\u003e\n\u003cli\u003eIsraels, T., Chagaluka, G., Pidini, D., et al. (2012). The efficacy and toxicity of SIOP preoperative chemotherapy in Malawian children with a Wilms tumour. Pediatric Blood \u0026amp; Cancer, 59(4), 636\u0026ndash;641. https://doi.org/10.1002/pbc.24088\u003c/li\u003e\n\u003cli\u003evon Elm, E., Altman, D. G., Egger, M., Pocock, S. J., G\u0026oslash;tzsche, P. C., \u0026amp; Vandenbroucke, J. P. (2007). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. PLoS Medicine, 4(10), e296. https://doi.org/10.1371/journal.pmed.0040296 \u003c/li\u003e\n\u003cli\u003eAmerican Cancer Society. (2025, January 21). Survival Rates for Wilms Tumors. https://www.cancer.org/cancer/types/wilms-tumor/detection-diagnosis-staging/survival-rates.html\u003c/li\u003e\n\u003cli\u003eVujanić, G. M., Gessler, M., Ooms, A. H. A. G., et al. (2018). The UMBRELLA SIOP\u0026ndash;RTSG 2016 Wilms tumour protocol: A multidisciplinary approach to treatment. Nature Reviews Urology, 15, 693\u0026ndash;701. https://doi.org/10.1038/s41585-018-0100-3\u003c/li\u003e\n\u003cli\u003eBrok, J., Treger, T. D., Gooskens, S. L., et al. (2018). Relapse of Wilms\u0026rsquo; tumour and detection methods: A retrospective analysis from SIOP trials. The Lancet Oncology, 19(8), 1072\u0026ndash;1081. https://doi.org/10.1016/S1470-2045(18)30343-1\u003c/li\u003e\n\u003cli\u003eArtunduaga, M., McCarville, M. B., Federico, S. M., et al. (2022). Imaging of pediatric renal tumors: Consensus and practical recommendations. Pediatric Radiology, 52, 1678\u0026ndash;1696. https://doi.org/10.1007/s00247-022-05352-7\u003c/li\u003e\n\u003cli\u003eBrenner, D. J., \u0026amp; Hall, E. J. (2007). Computed tomography\u0026mdash;An increasing source of radiation exposure. New England Journal of Medicine, 357(22), 2277\u0026ndash;2284. https://doi.org/10.1056/NEJMra072149\u003c/li\u003e\n\u003cli\u003ePearce, M. S., Salotti, J. A., Little, M. P., et al. (2012). Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: A retrospective cohort study. The Lancet, 380(9840), 499\u0026ndash;505. https://doi.org/10.1016/S0140-6736(12)60815-0\u003c/li\u003e\n\u003cli\u003eOra, I., van Tinteren, H., de Kraker, J., \u0026amp; Vujanić, G. M. (2007). Tumor progression during preoperative chemotherapy in Wilms tumor: A report from the SIOP 93-01 nephroblastoma trial and study. Pediatric Blood \u0026amp; Cancer, 49(5), 682\u0026ndash;686. https://doi.org/10.1002/pbc.21205\u003c/li\u003e\n\u003cli\u003ePritchard-Jones, K., Bergeron, C., de Camargo, B., et al. (2015). Omission of doxorubicin from the treatment of stage II\u0026ndash;III, intermediate-risk Wilms\u0026rsquo; tumour (SIOP WT 2001): An open-label, non-inferiority, randomised controlled trial. The Lancet, 386(9999), 1156\u0026ndash;1164. https://doi.org/10.1016/S0140-6736(14)62395-3\u003c/li\u003e\n\u003cli\u003eJanssens, G. O., Timmermann, B., Sulman, E. P., et al. (2020). The SIOP-Renal Tumour Study Group consensus statement on flank target volume delineation for highly conformal radiotherapy. The Lancet Child \u0026amp; Adolescent Health, 4(11), 829\u0026ndash;838. https://doi.org/10.1016/S2352-4642(20)30183-8\u003c/li\u003e\n\u003cli\u003eChildren\u0026rsquo;s Oncology Group (COG). (2018). Outcome and prognostic factors in stage III favorable histology Wilms tumor: Report from COG study AREN0532. (Conference abstract/video entry, ASCO). https://www.asco.org/abstracts-presentations/107584/video\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"513\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" colspan=\"3\" valign=\"top\" style=\"width: 513px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics and treatment summary (N=59)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e33 (55.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e26 (44.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e0\u0026ndash;24 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e23 (39.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e24\u0026ndash;60 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e29 (49.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u0026gt;60 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e7 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaterality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e31 (52.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e28 (47.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage (SIOP)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e3 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e23 (39.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e19 (32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eIV*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e14 (23.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistologic risk group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e3 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e33 (55.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e23 (39.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostoperative radiotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e28 (47.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e31 (52.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtocol (as recorded)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eSIOP-2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e28 (47.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eSIOP-2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e27 (45.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eSIOP-2016 ICE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e3 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeoadjuvant US response\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e50 (84.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e5 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eProgression / chemoresistance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e4 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny-grade thrombocytopenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e6 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny-grade neutropenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e29 (49.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e11 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 171px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 185px;\"\u003e\n \u003cp\u003e7 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"612\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" colspan=\"4\" valign=\"top\" style=\"width: 612px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2.Association of dichotomized neoadjuvant USM response with clinical variables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegression (n=50)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-regression (n=9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.038\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eI\u0026ndash;II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIII\u0026ndash;IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistologic risk group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.166\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntermediate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtocol category*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIOP-2001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIOP-2016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 199px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSIOP-2016 ICE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"547\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" colspan=\"3\" valign=\"top\" style=\"width: 449px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3. Survival endpoints and univariable effect of non-regression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegression (n=50)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-regression (n=9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e5 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e6 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e2 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e5 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e60-month OS, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e96.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e44.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e60-month DFS, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e90.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 177px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 153px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 119px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" colspan=\"3\" valign=\"top\" style=\"width: 449px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable Cox regression (reference = regression):\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 177px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 153px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 119px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" colspan=\"2\" valign=\"top\" style=\"width: 331px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS: HR 16.89 (95% CI 3.27\u0026ndash;87.20), p\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 119px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 177px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 153px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 119px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" colspan=\"2\" valign=\"top\" style=\"width: 331px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDFS: HR 8.84 (95% CI 2.68\u0026ndash;29.16), p\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 119px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd nowrap=\"\" valign=\"top\" style=\"width: 97px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Wilms tumor, ultrasonography, neoadjuvant response, SIOP, chemoresistance, relapse, overall survival, disease-free survival","lastPublishedDoi":"10.21203/rs.3.rs-8961303/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8961303/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eUltrasound-first (US-first) monitoring is commonly used in resource-variable settings to reduce radiation exposure; however, the prognostic value of neoadjuvant ultrasound response in unilateral Wilms tumor is not well defined in real-world cohorts. We assessed whether a simple dichotomized ultrasound response (regression vs non-regression) can stratify relapse and survival risk in children treated under SIOP principles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective single-center cohort included consecutive patients aged 0–18 years with unilateral Wilms tumor treated with SIOP-based protocols between 2012 and 2020 at the National Center of Oncology, Baku, Azerbaijan (n=59). Neoadjuvant response was assessed by abdominal ultrasonography using the largest axial tumor diameter and categorized as regression, stable disease, or progression (chemoresistance). For primary analyses, response was dichotomized as regression vs non-regression (stable+progression). Outcomes were relapse, overall survival (OS), and disease-free survival (DFS). Survival was estimated by the Kaplan–Meier method, and hazard ratios (HRs) were estimated using Cox regression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eNeoadjuvant USM response was regression in 50/59 (84.7%), stable disease in 5/59 (8.5%), and progression/chemoresistance in 4/59 (6.8%). Non-regression occurred only in stage III–IV disease (p=0.038). Over a median follow-up of 94 months, relapse occurred in 11/59 (18.6%) and death in 7/59 (11.9%); 81.8% of relapses occurred within 24 months. Relapse and death were markedly higher in the non-regression group than in the regression group (relapse 66.7% vs 10.0%; death 55.6% vs 4.0%; both p\u0026lt;0.001). At 60 months, OS was 96.0% vs 44.4% (p\u0026lt;0.001) and DFS was 90.0% vs 33.3% (p\u0026lt;0.001) for regression vs non-regression, respectively. In univariable Cox models, non-regression was strongly associated with worse outcomes (OS HR 16.89, 95% CI 3.27–87.20, p\u0026lt;0.001; DFS HR 8.90, 95% CI\u003c/p\u003e\n\u003cp\u003e2.70–29.36, p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eIn this real-world SIOP-treated unilateral Wilms tumor cohort, a simple US-first neoadjuvant response classification strongly stratified relapse and long-term survival risk. Ultrasound non-regression identifies a high-risk subgroup that may warrant closer early monitoring in radiation-sparing follow-up strategies.\u003c/p\u003e","manuscriptTitle":"Ultrasound-Based Monitoring in Unilateral Wilms Tumor: Treatment Response Assessment and Early Relapse Dynamics (2012–2020, Single-Center Cohort)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-23 17:49:55","doi":"10.21203/rs.3.rs-8961303/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-06T19:16:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"195746467854858336074896788425051630460","date":"2026-03-25T11:00:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-19T00:58:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-25T06:13:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-25T06:13:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-02-24T21:52:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4e5268f6-2b39-4700-9f53-ace76a5de40e","owner":[],"postedDate":"March 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-23T17:49:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-23 17:49:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8961303","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8961303","identity":"rs-8961303","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}