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How One Company Added Carbon Estimates to Its Customer Invoices

• Robert S. Kaplan
• Timmy Melotte

A four-step playbook to help businesses increase transparency and reduce emissions.

Soprema is an international building materials supplier, producing millions of square meters of waterproofing, insulating, and roofing products each year. In 2022, Pierre-Etienne Bindschedler, the company’s president and third-generation owner, committed to reporting the carbon footprint of each product on every customer invoice, and to help customers reduce the embedded GHG emissions in the products they purchased. Paper co-author Melotte, an experienced operations director, was selected to lead a pilot project to measure and subsequently lower the carbon embedded in its products. Melotte decided to follow the E-Liability Pilot Playbook, which divides a pilot project into four stages: Project Design, Data Collection; Data Analysis, and Action. This article describes how the pilot, which focused on the company’s bitumen waterproofing systems, unfolded at Soprema. The company estimates a potential carbon footprint reduction of 34% from the project.

In 2022, Pierre-Etienne Bindschedler, the president and third-generation owner of Soprema, set a goal to develop sustainable solutions for customers. Soprema is a multi-product, family-owned business in the middle of the building materials value chain and produces millions of square meters of waterproofing, insulating, and roofing products each year.  Bindschedler wanted to report the carbon footprint of each product on every customer invoice, and to help customers reduce the embedded GHG emissions in the products they purchased.

• Robert S. Kaplan is a senior fellow and the Marvin Bower Professor of Leadership Development emeritus at Harvard Business School. He coauthored the McKinsey Award–winning HBR article “ Accounting for Climate Change ” (November–December 2021).
• TM Timmy Melotte is an Operational Excellence Director for Soprema International, a building materials supplier based in Limburg, Belgium

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Prognostic Factors of Pediatric Acute Myeloid Leukemia Patients with t(8;21) (q22;q22): A Single-Center Retrospective Study

Associated data.

Data are provided within the manuscript or Supplementary Information files.

This retrospective study aimed to analyze the treatment effect and prognostic factors of pediatric acute myeloid leukemia (AML) patients with t(8;21). A total of 268 newly diagnosed pediatric AML (pAML) enrolled from 1 January 2005 to 31 December 2022 were retrospectively reviewed, and 50 (18.7%) patients harbored t(8;21) translocation. CR rate, OS, EFS, and RFS were assessed by multivariate Logistic and Cox regression models in these patients. Of the 50 patients, 2 patients abandoned treatment during the first induction course. Of the remaining 48 patients who received double-induction therapy and were included in the final analyses, CR1 and CR2 were 75.0% (36/48) and 95.8% (46/48), respectively. The overall three-year OS, EFS, and RFS were 68.4% (95% CI, 55.0–85.1), 64.2% (95% CI, 50.7–81.4), and 65.5% (95% CI, 51.9–82.8), respectively. The presence of loss of sex chromosome (LOS) at diagnosis (n = 21) was associated with a better 3-year OS [87.5% (95% CI, 72.7–100) vs. 52.7% (95% CI, 35.1–79.3), p = 0.0089], 3-year EFS [81.6% (95% CI, 64.7–100) vs. 49.7% (95% CI, 32.4–76.4), p = 0.023], and 3-year RFS [81.6% (95% CI, 64.7–100) vs. 51.7% (95% CI, 33.9–78.9), p = 0.036] than those without LOS (n = 27), and it was also an independent good prognostic factor of OS (HR, 0.08 [95% CI, 0.01–0.48], p = 0.005), EFS (HR, 0.22 [95% CI, 0.05–0.85], p = 0.029), and RFS (HR, 0.21 [95% CI, 0.05–0.90], p = 0.035). However, extramedullary leukemia (EML) featured the independent risk factors of inferior OS (HR, 10.99 [95% CI, 2.08–58.12], p = 0.005), EFS (HR, 4.75 [95% CI, 1.10–20.61], p = 0.037), and RFS (HR, 6.55 [95% CI, 1.40–30.63], p = 0.017) in pediatric individuals with t(8;21) AML. Further analysis of combining LOS with EML indicated that the EML+LOS− subgroup had significantly inferior OS (92.9%, [95% CI, 80.3–100]), EFS (86.2%, [95% CI, 70.0–100]), and RFS (86.2%, [95% CI, 80.3–100]) compared to the other three subgroups (all p < 0.001). LOS and EML are independent prognostic factors of OS, EFS, and RFS with t(8;21) pAML patients. LOS combined with EML may help improve risk stratification.

1. Introduction

Acute myeloid leukemia (AML) constitutes 20% of pediatric leukemias, with 5.1% of AML patients being diagnosed at an age younger than 20 years [ 1 , 2 , 3 ]. AML1::ETO (also known as RUNX1::RUNX1T1 ) resulting from t(8;21) (q22;q22) is one of the most frequent genetic aberrations, with a incidence of 20% in newly diagnosed pAML patients [ 4 , 5 , 6 , 7 ]. Although t(8;21) AML is generally categorized as a favorable subgroup, 20%–35% of patients with this genotype experience relapse, and the outcomes of this genotype are heterogeneous [ 8 , 9 , 10 ]. We conducted a single-center retrospective study of children with this genotype from 1 January 2005 to 31 December 2022 to search for prognostic factors that could potentially be useful to further improve outcomes and update therapy strategies.

2. Materials and Methods

2.1. study design and patients.

Individuals aged ≤eighteen years with a confirmed diagnosis of AML were enrolled in the retrospective study. Data from individuals without proof of t(8;21) presence and individuals without treatment during the first induction course were excluded from analyses. All patients were treated in the Children’s Hospital of Fudan University between 2005 and 2023, receiving risk-stratified therapy without prophylactic cranial irradiation. Patients treated in our institution from 2005 to 2014 received the CHFU-AML 2005 regimen, and CCLG-AML-2015 and CALSIII-AML18 regimens were used in 2015–2018 and 2018–2023, respectively [ 11 , 12 ]. The study was approved by the institutional review board of the Children’s Hospital of Fudan University, and informed consent was obtained from all patients or their legal guardians. Outcome data reported here were updated on 21 March 2023.

2.2. Morphology, Cytogenetics and Immunophenotyping

The morphologic assessment was founded on May-Grünwald–Giemsa stains, myeloperoxidase reactions, and nonspecific esterases utilizing α-naphthyl acetate following the FAB and WHO classifications [ 13 , 14 , 15 ]. A chromosome G-banding analysis was conducted on all cases according to standard procedures [ 16 , 17 ]. The description of karyotypes followed the ISCN [ 18 ]. Loss of sex chromosomes (LOS) was defined as the presence of a -X/-Y clone in more than 3 of the 20 cells analyzed [ 19 ]. Complex karyotype (CK) was defined as ≥3 chromosomal aberrations [ 20 ]. Monosomal karyotype (MK) was defined as ≥2 separate autosomal monosomies or 1 monosomy plus ≥ 1 structural aberrations [ 21 , 22 ]. Immunophenotyping was conducted in bone marrow (BM) specimens of all cases following previous descriptions [ 23 , 24 ]. Quantification of minimal residual disease (MRD) in the BM (after induction therapy I and II, or other later timepoint) using multiparameter flow cytometry (MFCM) commenced in June 2018.

2.3. Molecular Biology Analysis

Molecular studies were performed from June 2018, and the results for 20 patients are available. Mononuclear cells were isolated, and both DNA and mRNA were extracted from BM and peripheral blood samples. Additionally, random-primed cDNA synthesis was conducted according to the protocols [ 25 ]. As for fusion genes, interphase fluorescence in situ hybridization (FISH) with probes for RUNX1 and RUNX1T1 was conducted using commercially available probes. Investigations for FLT3-ITD , C-KIT/D816 , NPM1 (Exon12), and CEBPA were carried out in these patients [ 26 ].

2.4. Statistical Analysis

Each statistical assessment was performed utilizing R software (version 4.1.0). Outcomes were evaluated by using complete remission (CR), overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) ( Table S1 ) [ 27 ]. Categorical variables were compared between groups utilizing the χ2 test and continuous variables by the Mann–Whitney U test. To identify factors associated with CR and prognosis, variables with p < 0.2 [ 28 ] in univariate analyses entered a multivariate Logistic regression model and a multivariate Cox regression model, respectively. Results were presented as OR or HR and 95% CI. Survival outcomes were determined utilizing the Kaplan–Meier method, and comparisons between groups were conducted utilizing the logrank test. Statistical importance was denoted by two-sided p < 0.05.

3.1. Clinical Characteristics

From 1 January 2005 to 31 December 2022, 268 evaluable individuals were enrolled from a Chinese children’s medical center. Data from 218 individuals without proven t(8;21) presence and two individuals without treatment during the first induction course were excluded ( Figure 1 ). An amount of 48 individuals with t(8;21) AML were included in the final analyses, with a male-to-female ratio of 1.8:1. The median age at diagnosis was 8.6 years (range, 2.5–16.7), with 46 patients (95.8%) aged between 3 and 14 years and only one patient (2.1%) in each age group younger than three years and older than fourteen years, respectively. The median white blood cell (WBC) count was 15.9 × 10 9 /L (range, 1.7–123.0). The median platelet count was 28.5 × 10 9 /L (range, 4–265). The median hemoglobin (Hb) count was 78.6 g/L (38.2–122.0). The median follow-up time was 35.5 months (IQR, 12.8–74.8). According to MFCM, the sums of the percentage of positive cells for CD34 plus CD117 or HLA-DR were greater than 95% in these cases. CD19 antigen and CD56 antigen were detected in 23 (47.9%) and 21 (43.6%) of these cases, respectively. As for additional chromosome abnormality (ACA), t(8;21) was the sole cytogenetic aberration in 13 patients (27.1%), while 35 (72.9%) harbored other ACAs, 21 (43.8%) had loss of sex chromosome (LOS), 7 (14.6%) had CK, 11 (22.9%) had MK, 3 (6.3%) had deletion of chromosome 9q [del(9q)], only one (2.1%) had trisomy 4, and no one had trisomy 8. Of the 20 patients analyzed for genetic mutation, two (10.0%) were FLT3-ITD positive, 12 (60.0%) were C-KIT positive, and none of them had CEBPA and NPM1 mutations. Within the same cohort evaluable for MRD analysis, 7 (35%) and 18 (90%) had a negative MRD status (defined by <0.1%) after induction therapy I and II, respectively ( Table 1 ).

Flow diagram.

Baseline features of 48 pediatric acute myeloid leukemia (pAML) patients with t(8;21).

Abbreviations: WBC: white blood cell counts; MRD: minimal residual disease; BM blast: bone marrow leukemic blast percentage; PLT: platelets; LOS: loss of sex chromosome; CR1: first complete remission; HB: hemoglobin; MK: monosomal karvotype; EML: extramedullary leukemia; PR: partial remission; NR: no remission; PB blast: peripheral blast percentage; del(9q), Deletion of chromosome 9q; M: median; CR2: second complete remission; CK: complex karyotype. 1 Missing data are due to being not submitted to the statistics center. N = 46. 2 Genetic mutation detection has been available since June 2018. N = 20. 3 MRD detection has been available since June 2018. N = 20. 4 EML was defined as the process whereby malignant leukemic cells from the BM infiltrate into tissues outside the BM at diagnosis, including the central nervous system, cutis, and periosteum, leading to the formation of an extramedullary mass.

3.2. Treatment Outcome

Overall, first complete remission (CR1) and second complete remission (CR2) were achieved by 75.0% (n = 36) and 95.8% (n = 46) of the patients, respectively. CR was achieved in 20 (100.0%) patients treated with the CALSIII-AML18 protocol, of whom 18 (90.0%) had a negative MRD status at the end of induction therapy. The 3-year OS, EFS, and RFS were 68.4% (95% CI, 55.0–85.1), 64.2% (95% CI, 50.7–81.4), and 65.5% (95% CI, 51.9–82.8), respectively ( Figure 2 a–c). The 3-year OS, EFS, and RFS of 18 cases treated with the CHFU-AML 2005 protocol were 72.2% (95% CI, 54.2–96.2), 61.1% (95% CI, 42.3–88.3), and 64.7% (95% CI, 45.5–91.9), respectively. The 3-year OS, EFS, and RFS of 10 cases treated with the CCLG-AML 2015 protocol were 60.0% (95% CI, 36.2–99.5), 60.0% (95% CI, 36.2–99.5), and 60.0% (95% CI, 36.2–99.5), respectively. The 3-year OS, EFS, and RFS of 20 cases treated with the CALSIII-AML18 protocol were 68.2% (95% CI, 43.8–100), 71.1% (95% CI, 47.5–100), and 71.1% (95% CI, 47.5–100), respectively. No significant differences were found in the outcomes ( Figure S1 ) and CR rate among these protocols ( Tables S2 and S3 ).

Outcomes of t(8;21) pAML patients. Kaplan–Meier analysis of overall survival (OS) ( a ), event-free survival (EFS) ( b ) and relapse-free survival (RFS) ( c ) for all patients. Three-year OS, EFS and RFS: 0.68 ± 0.08, 0.64 ± 0.08, 0.66 ± 0.08, respectively.

Of note, patients with LOS (n = 21) had significantly better 3-year OS [87.5% (95% CI, 72.7–100) vs. 52.7% (95% CI, 35.1–79.3), p = 0.0089], 3-year EFS [81.6% (95% CI, 64.7–100) vs. 49.7% (95% CI, 32.4–76.4), p = 0.023], and 3-year RFS [81.6% (95% CI, 64.7–100) vs. 51.7% (95% CI, 33.9–78.9), p = 0.036] than those without LOS (n = 27, Figure 3 a–c). Additionally, the OS, EFS, and RFS of patients with EML did not have any significant differences to those without EML ( p > 0.05, Figure 4 a–c), which may be associated with the limited quantity of individuals with EML (n = 8). For the 20 patients treated under the CALSIII-AML18 regimen, there was no significant difference in prognosis between those with and without C-KIT /negative MRD status, respectively (all p > 0.05, Figures S2–S4 ).

Outcomes depending on the loss of sex chromosomes (LOS) in t(8;21) AML. Kaplan–Meier analysis of OS ( a ), EFS ( b ) and RFS ( c ) for patients stratified by LOS.

Outcomes depending on the extramedullary leukemia (EML) in t(8;21) AML. Kaplan–Meier analysis of OS ( a ), EFS ( b ) and RFS ( c ) for patients stratified by EML.

3.3. Impact of Clinical and Biological Characteristics on CR Achievement

We assessed the association of clinical and biological features with CR achievement in a logistic regression model. As shown in Table 2 , age at diagnosis, WBC, PB blast, FAB, CD19, MK, and Year of diagnosis were significantly linked to CR achievement of those patients. We then included these seven variables in the multivariate logistic analysis and revealed that none of these values remained significantly different for CR achievement.

Univariate and multivariate logistic analyses of first complete remission (CR1) in 48 patients with t(8;21) AML.

Abbreviations: WBC: white blood cell counts; LOS: loss of sex chromosome; HB: hemoglobin; MK: monosomal karvotype; PB_blast: peripheral blast percentage; EML: extramedullary leukemia; BM blast: bone marrow leukemic blast percentage; CRR: complete remission rate; PLT: platelets; CI: confidence interval; CK: complex karyotype; OR: odds ratio.

3.4. Prognostic Factors for OS, EFS, and RFS

To assess the significant prognostic factors, Cox regression modeling was performed. As shown in Table 3 and Tables S4–S8 , EML and LOS were significantly correlated with the OS, EFS, and RFS of t(8;21) pAML patients. Individuals with EML had lower OS ( p = 0.071), EFS ( p = 0.164), and RFS ( p = 0.108), while those with LOS had higher OS ( p = 0.022), EFS ( p = 0.036), and RFS ( p = 0.051). We then included the two covariates in the multivariate analyses and demonstrated that EML was an independent risk factor for inferior OS (hazard ratio [HR], 10.99 [95% CI, 2.08–58.12], p = 0.005), EFS (HR, 4.75 [95% CI, 1.10–20.61], p = 0.037), and RFS (HR, 6.55 [95% CI, 1.40–30.63], p = 0.017), while LOS was an independent good prognostic factor that influenced OS (HR, 0.08 [95% CI, 0.01–0.48], p = 0.005), EFS (HR, 0.22 [95% CI, 0.05–0.85], p = 0.029), and RFS (HR, 0.21 [95% CI, 0.05–0.90], p = 0.035).

Univariate and multivariate COX analyses of event-free survival (EFS) in 48 patients with t(8;21) AML.

Abbreviations: WBC: white blood cell counts; MK: monosomal karvotype; BM blast: bone marrow leukemic blast percentage; CK: complex karyotype; PLT: platelets; LOS: loss of sex chromosome; HB: hemoglobin; CR1: first complete remission; PB blast: peripheral blast percentage; EML: extramedullary leukemia; HR: hazard ratio; CR2: second complete remission; CI: confidence interval.

3.5. Risk Stratification

To provide an estimation of prognostic stratification, we classified individuals into four risk groups based on EML and LOS: the EML+LOS+ (n = 4), EML+LOS− (n = 4), EML−LOS+ (n = 17), and EML−LOS− (n = 23) subgroups. As for other secondary ACAs that accompany t(8;21), one out of four individuals in the EML+LOS− subgroup had trisomy 4, 1 out of 23 individuals in the EML−LOS− group and 2 out of 17 patients in the EML−LOS+ subgroup had del(9q), and no patients had trisomy 8. Kaplan–Meier survival analysis unveiled that t(8;21) pAML patients with EML+LOS− had the most inferior outcome, while those with EML−LOS+ had the best prognosis, showing the following statistically significant survivals: the 3-year OS [0 vs. 92.9% (95% CI, 80.3–100), p < 0.001], the 3-year EFS [0 vs. 86.2% (95% CI, 70.0–100), p < 0.001], and the 3-year RFS [0 vs. 86.2% (95% CI, 80.3–100), p < 0.001] ( Figure 5 a–c). Given that the number of patients in the EML+LOS− and EML+LOS− subgroups was too small, we need to exercise caution when explaining the impact of risk stratification on prognosis. The observation of distinct prognostic effects between the two groups based on risk stratification suggested that EML+LOS− should be differentiated from EML−LOS+ in future research.

Kaplan–Meier curves for risk stratification. Kaplan–Meier analysis of OS ( a ), EFS ( b ) and RFS ( c ) for patients stratified by risk levels depending on EML and LOS.

4. Discussion

This study demonstrated that, among a large cohort of 268 pAML individuals, 50 (18.7%) harbored t(8;21) translocation. This finding aligns with the range reported in other studies [ 29 , 30 ]. We explored the prognostic factors of t(8;21) pAML patients at a single Chinese children’s medical center. Previous studies demonstrated that t(8;21) pAML individuals likely benefit from regimens incorporating high doses of Ara-C during induction therapy [ 29 ]. In this study, the three-year OS, EFS, and RFS were 68.4% (95% CI, 55.0–85.1), 64.2% (95% CI, 50.7–81.4), and 65.5% (95% CI, 51.9–82.8), respectively, which were greater than that in the research by Wu et al. [ 31 ], comparable with the research by Che et al. [ 32 ], and obviously lower than that reported by a Japanese team [ 8 ]. Their better therapeutic effect may be attributed to a higher cumulative dose of Ara-C (59.4–78.4 g/m 2 ) and adequate supportive care.

There was no difference in CR rate among different induction protocols [ 33 , 34 ]. In accordance with these studies, our cohort showed that patients treated with CHFU-AML 2005, CCLG-AML 2015, and CALSIII-AML18 regimens also showed no significant difference in CR rate ( p > 0.05). Walter et al. [ 35 ] demonstrated that CR is a unique clinical significance factor in trials of de novo AML. Fang et al. [ 34 ] observed that AML individuals achieving CR1 showed better prognoses than those without CR1. In our study, however, we did not verify their finding that the clinical and biological features of individuals between CR1 and PR/NR groups were compared, but there was no statistical difference in CR rate among all factors ( p > 0.05). Our results were slightly different from previous studies, considering that the sample size included in our study was small and needs to be further expanded in future studies.

In line with prior reports, the prevalence of ACAs was high (72.9%), and the most common cytogenetic aberration was LOS [ 36 , 37 , 38 , 39 , 40 , 41 ]. According to the Cox model, EML and LOS were independent prognostic factors for t(8;21) pAML individuals. Previous studies found that loss of Y chromosome (LOY) was linked to a high relapse risk and shorter OS [ 42 , 43 ]. However, some studies demonstrated that LOS had no significant associations with survival probabilities [ 19 , 36 , 44 , 45 ]. Mitterbauer et al. [ 46 ] suggested that LOS was linked to a significantly better EFS outcome. In our study, LOS was correlated with significantly better OS, EFS, and RFS, aligning with the research by Chen et al. [ 47 ].

The prognostic values of EML remain controversial across studies. Previous studies found that t(8;21) pAML patients with EML were linked to a low CR rate and poor RFS and OS [ 48 , 49 , 50 ]. However, Bisschop et al. [ 51 ] did not find significant associations with survival outcomes. The differences in results between studies may relate to the small-scale cohort, differences in race, and the wide range of case cohorts. In our study, EML was identified as an independent prognostic factor that is correlated with worse OS, EFS, and RFS, in line with the findings reported by Stove et al. [ 49 ] In addition, some reports claimed that patients with EML involving different sites had different survival outcomes [ 52 , 53 ]. In our study, subgroup analysis for the prognosis effect of EML at different sites could not be conducted due to the insufficient number of cases. Furthermore, individuals were categorized into four risk groups based on the two independent prognostic factors, LOS and EML, enabling the refinement of patients with different survival outcomes and suggesting that MRD should be closely monitored, as well as that HSCT should be considered in time among those subgroups with worse outcomes. To enhance the robustness of the findings, a larger cohort involving multiple medical centers is required for further verification of the results.

C-KIT mutations are reported to occur in 12−46% of adult t(8;21) AML patients [ 52 , 53 , 54 , 55 ], whereas they account for approximately 17−43% in pediatric t(8;21) patients [ 29 , 53 , 56 , 57 , 58 , 59 ]. The frequency of C-KIT in this study reached 60.0% (12/20), surpassing previous pediatric series [ 30 , 60 ]. This discrepancy could be owing to factors such as the small-sized sample from a single center, as well as the variations in the detection method and sequencing depth and coverage. Although C-KIT mutations mediate an adverse prognostic impact on the prognosis of adults with AML [ 61 , 62 ], the impact of C-KIT on pAML is still inconclusive [ 57 , 63 ]. Chen et al. [ 30 ] observed that C-KIT mutations are genetic markers linked to inferior prognoses in pAML patients. Another study indicated that C-KIT mutations were strongly correlated with poor outcome in t(8;21) pAML individuals [ 58 ]. In our study, despite the high frequency of C-KIT in t(8;21) pAML, it did not impact long-term prognosis, in line with previous pediatric reports [ 29 , 34 ]. This suggests potential differences in prognostic factors between pediatric and adult individuals diagnosed with this disease.

MRD is a pivotal marker in modern studies of pAML, with a commonly accepted threshold set at 0.1% [ 64 ]. MRD levels exceeding this threshold are linked to an elevated risk of relapse and unfavorable prognosis. In our study, MRD levels were quantified using MFCM following the first and second induction therapy phases in the CALSIII-AML18 protocol. However, the definitive prognostic value of MRD status derived from our findings may be inconclusive, likely due to the limited sample size.

The primary limitation of our study stems from its retrospective design, which may lead to missing data and an unavoidable bias. The power of the subsequent stratified analysis is constrained by the relatively small size of the subgroups and prospective research with a large-scale sample size is warranted to be practicable.

5. Conclusions

In conclusion, LOS is prognostically favorable, whereas EML is deemed to be strongly correlated with adverse prognoses in pediatric patients with t(8;21) AML. LOS combined with EML may help improve risk stratification and potentially facilitate the customization of future therapies.

Acknowledgments

We thank the pediatricians, patients and their guardians for participation in the study. This work was supported by the Medical Science Data Center in Shanghai Medical College of Fudan University.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/children11050605/s1 . Figure S1. Probability of survival for patients with t(8;21) AML in the protocols. Figure S2. Probability of survival depending on the C-KIT mutation in t(8;21) AML. Kaplan–Meier survival curves of OS (a), EFS (b) and RFS (c) for patients stratified by C-KIT mutation. Figure S3. Probability of survival depending on the Induction I MRD status in t(8;21) AML. Kaplan–Meier survival curves of OS (a), EFS (b) and RFS (c) for patients stratified by Induction I MRD status. Figure S4. Probability of survival depending on the Induction II MRD status in t(8;21) AML. Kaplan–Meier survival curves of OS (a), EFS (b) and RFS (c) for patients stratified by Induction II MRD status. Table S1. Definitions of end points. Table S2. Comparison of characteristics for patients with t(8;21) AML in differrent consecutive protocols. Table S3. Univariate and multivariate COX analyses of OS in 48 patients with t(8;21) AML. Table S4. Univariate and multivariate COX analyses of RFS in 48 patients with t(8;21) AML. Table S5. Univariate and multivariate COX analyses of overall survival (OS) in 48 patients with t(8;21) AML. Table S6. Univariate and multivariate COX analyses of overall survival (OS) in 20 t(8;21) AML patients who enrolled after 2018. Table S7. Univariate and multivariate COX analyses of relapse-free survival (RFS) in 48 patients with t(8;21) AML. Table S8. Univariate and multivariate COX analyses of relapse-free survival (RFS) in 20 t(8;21) AML patients who enrolled after 2018.

Funding Statement

The work was supported by the National Key Research and Development Program of China (2022YFC2705003, 2023YFC2706301); the National Natural Science Foundation of China (82141125); Shanghai Municipal Committee of Science and Technology (21Y31900302); Shanghai Hospital Development Center (SHDC12019121); the Cyrus Tang Foundation (ZSBK0070).

Author Contributions

Conceptualization, J.Y. and X.Z. (Xiaowen Zhai); methodology, J.Y. and H.W.; validation, J.Y., X.Z. (Xiaohua Zhu) and H.Z.; formal analysis, J.Y.; investigation, J.Y., X.Z. (Xiaohua Zhu) and H.Z.; resources, Y.F., Z.L. and Z.X.; data curation, Y.Y., P.C., J.L. (Jun Le), J.L. (Jun Li) and J.J.; writing—original draft preparation, J.Y.; writing—review and editing, J.Y., X.Z. (Xiaohua Zhu) and H.Z.; visualization, J.Y.; supervision, X.Z. (Xiaowen Zhai) and H.W.; project administration, X.Z. (Xiaohua Zhu) and H.Z.; funding acquisition, X.Z. (Xiaowen Zhai). All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Children’s Hospital of Fudan University (9 December 2021; 2021-436).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Conflicts of interest.

The authors declare no conflicts of interest.

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• About Adverse Childhood Experiences
• Risk and Protective Factors
• Program: Essentials for Childhood: Preventing Adverse Childhood Experiences through Data to Action
• Adverse childhood experiences can have long-term impacts on health, opportunity and well-being.
• Adverse childhood experiences are common and some groups experience them more than others.

What are adverse childhood experiences?

Adverse childhood experiences, or ACEs, are potentially traumatic events that occur in childhood (0-17 years). Examples include: 1

• Experiencing violence, abuse, or neglect.
• Witnessing violence in the home or community.
• Having a family member attempt or die by suicide.

Also included are aspects of the child’s environment that can undermine their sense of safety, stability, and bonding. Examples can include growing up in a household with: 1

• Substance use problems.
• Mental health problems.
• Instability due to parental separation.
• Instability due to household members being in jail or prison.

The examples above are not a complete list of adverse experiences. Many other traumatic experiences could impact health and well-being. This can include not having enough food to eat, experiencing homelessness or unstable housing, or experiencing discrimination. 2 3 4 5 6

Quick facts and stats

ACEs are common. About 64% of adults in the United States reported they had experienced at least one type of ACE before age 18. Nearly one in six (17.3%) adults reported they had experienced four or more types of ACEs. 7

Preventing ACEs could potentially reduce many health conditions. Estimates show up to 1.9 million heart disease cases and 21 million depression cases potentially could have been avoided by preventing ACEs. 1

Some people are at greater risk of experiencing one or more ACEs than others. While all children are at risk of ACEs, numerous studies show inequities in such experiences. These inequalities are linked to the historical, social, and economic environments in which some families live. 5 6 ACEs were highest among females, non-Hispanic American Indian or Alaska Native adults, and adults who are unemployed or unable to work. 7

ACEs are costly. ACEs-related health consequences cost an estimated economic burden of $748 billion annually in Bermuda, Canada, and the United States. 8

ACEs can have lasting effects on health and well-being in childhood and life opportunities well into adulthood. 9 Life opportunities include things like education and job potential. These experiences can increase the risks of injury, sexually transmitted infections, and involvement in sex trafficking. They can also increase risks for maternal and child health problems including teen pregnancy, pregnancy complications, and fetal death. Also included are a range of chronic diseases and leading causes of death, such as cancer, diabetes, heart disease, and suicide. 1 10 11 12 13 14 15 16 17

ACEs and associated social determinants of health, such as living in under-resourced or racially segregated neighborhoods, can cause toxic stress. Toxic stress, or extended or prolonged stress, from ACEs can negatively affect children’s brain development, immune systems, and stress-response systems. These changes can affect children’s attention, decision-making, and learning. 18

Children growing up with toxic stress may have difficulty forming healthy and stable relationships. They may also have unstable work histories as adults and struggle with finances, jobs, and depression throughout life. 18 These effects can also be passed on to their own children. 19 20 21 Some children may face further exposure to toxic stress from historical and ongoing traumas. These historical and ongoing traumas refer to experiences of racial discrimination or the impacts of poverty resulting from limited educational and economic opportunities. 1 6

Adverse childhood experiences can be prevented. Certain factors may increase or decrease the risk of experiencing adverse childhood experiences.

Preventing adverse childhood experiences requires understanding and addressing the factors that put people at risk for or protect them from violence.

Creating safe, stable, nurturing relationships and environments for all children can prevent ACEs and help all children reach their full potential. We all have a role to play.

• Merrick MT, Ford DC, Ports KA, et al. Vital Signs: Estimated Proportion of Adult Health Problems Attributable to Adverse Childhood Experiences and Implications for Prevention — 25 States, 2015–2017. MMWR Morb Mortal Wkly Rep 2019;68:999-1005. DOI: http://dx.doi.org/10.15585/mmwr.mm6844e1 .
• Cain KS, Meyer SC, Cummer E, Patel KK, Casacchia NJ, Montez K, Palakshappa D, Brown CL. Association of Food Insecurity with Mental Health Outcomes in Parents and Children. Science Direct. 2022; 22:7; 1105-1114. DOI: https://doi.org/10.1016/j.acap.2022.04.010 .
• Smith-Grant J, Kilmer G, Brener N, Robin L, Underwood M. Risk Behaviors and Experiences Among Youth Experiencing Homelessness—Youth Risk Behavior Survey, 23 U.S. States and 11 Local School Districts. Journal of Community Health. 2022; 47: 324-333.
• Experiencing discrimination: Early Childhood Adversity, Toxic Stress, and the Impacts of Racism on the Foundations of Health | Annual Review of Public Health https://doi.org/10.1146/annurev-publhealth-090419-101940 .
• Sedlak A, Mettenburg J, Basena M, et al. Fourth national incidence study of child abuse and neglect (NIS-4): Report to Congress. Executive Summary. Washington, DC: U.S. Department of Health an Human Services, Administration for Children and Families.; 2010.
• Font S, Maguire-Jack K. Pathways from childhood abuse and other adversities to adult health risks: The role of adult socioeconomic conditions. Child Abuse Negl. 2016;51:390-399.
• Swedo EA, Aslam MV, Dahlberg LL, et al. Prevalence of Adverse Childhood Experiences Among U.S. Adults — Behavioral Risk Factor Surveillance System, 2011–2020. MMWR Morb Mortal Wkly Rep 2023;72:707–715. DOI: http://dx.doi.org/10.15585/mmwr.mm7226a2 .
• Bellis, MA, et al. Life Course Health Consequences and Associated Annual Costs of Adverse Childhood Experiences Across Europe and North America: A Systematic Review and Meta-Analysis. Lancet Public Health 2019.
• Adverse Childhood Experiences During the COVID-19 Pandemic and Associations with Poor Mental Health and Suicidal Behaviors Among High School Students — Adolescent Behaviors and Experiences Survey, United States, January–June 2021 | MMWR
• Hillis SD, Anda RF, Dube SR, Felitti VJ, Marchbanks PA, Marks JS. The association between adverse childhood experiences and adolescent pregnancy, long-term psychosocial consequences, and fetal death. Pediatrics. 2004 Feb;113(2):320-7.
• Miller ES, Fleming O, Ekpe EE, Grobman WA, Heard-Garris N. Association Between Adverse Childhood Experiences and Adverse Pregnancy Outcomes. Obstetrics & Gynecology . 2021;138(5):770-776. https://doi.org/10.1097/AOG.0000000000004570 .
• Sulaiman S, Premji SS, Tavangar F, et al. Total Adverse Childhood Experiences and Preterm Birth: A Systematic Review. Matern Child Health J . 2021;25(10):1581-1594. https://doi.org/10.1007/s10995-021-03176-6 .
• Ciciolla L, Shreffler KM, Tiemeyer S. Maternal Childhood Adversity as a Risk for Perinatal Complications and NICU Hospitalization. Journal of Pediatric Psychology . 2021;46(7):801-813. https://doi.org/10.1093/jpepsy/jsab027 .
• Mersky JP, Lee CP. Adverse childhood experiences and poor birth outcomes in a diverse, low-income sample. BMC pregnancy and childbirth. 2019;19(1). https://doi.org/10.1186/s12884-019-2560-8 .
• Reid JA, Baglivio MT, Piquero AR, Greenwald MA, Epps N. No youth left behind to human trafficking: Exploring profiles of risk. American journal of orthopsychiatry. 2019;89(6):704.
• Diamond-Welch B, Kosloski AE. Adverse childhood experiences and propensity to participate in the commercialized sex market. Child Abuse & Neglect. 2020 Jun 1;104:104468.
• Shonkoff, J. P., Garner, A. S., Committee on Psychosocial Aspects of Child and Family Health, Committee on Early Childhood, Adoption, and Dependent Care, & Section on Developmental and Behavioral Pediatrics (2012). The lifelong effects of early childhood adversity and toxic stress. Pediatrics, 129(1), e232–e246. https://doi.org/10.1542/peds.2011-2663
• Narayan AJ, Kalstabakken AW, Labella MH, Nerenberg LS, Monn AR, Masten AS. Intergenerational continuity of adverse childhood experiences in homeless families: unpacking exposure to maltreatment versus family dysfunction. Am J Orthopsych. 2017;87(1):3. https://doi.org/10.1037/ort0000133 .
• Schofield TJ, Donnellan MB, Merrick MT, Ports KA, Klevens J, Leeb R. Intergenerational continuity in adverse childhood experiences and rural community environments. Am J Public Health. 2018;108(9):1148-1152. https://doi.org/10.2105/AJPH.2018.304598 .
• Schofield TJ, Lee RD, Merrick MT. Safe, stable, nurturing relationships as a moderator of intergenerational continuity of child maltreatment: a meta-analysis. J Adolesc Health. 2013;53(4 Suppl):S32-38. https://doi.org/10.1016/j.jadohealth.2013.05.004 .

Adverse Childhood Experiences (ACEs)

ACEs can have a tremendous impact on lifelong health and opportunity. CDC works to understand ACEs and prevent them.

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• Volume 10, Issue 2
• Untangling the relationship between smoking and systemic sclerosis: an analysis of the EUSTAR cohort
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• http://orcid.org/0000-0002-9446-7351 Jacopo Ciaffi 1 , 2 ,
• http://orcid.org/0000-0003-0328-7062 Sophie I E Liem 3 ,
• Suzanne Cannegieter 4 , 5 ,
• Saad Ahmed 3 ,
• Eva M Hoekstra 3 ,
• Piotr Wiland 6 ,
• http://orcid.org/0000-0001-5657-962X Tatsuya Atsumi 7 ,
• Gabriella Szücs 8 ,
• Alexandra Balbir Gurman 9 ,
• László Czirják 10 ,
• http://orcid.org/0000-0002-4845-5413 Elisabetta Zanatta 11 ,
• Ina Koetter 12 ,
• http://orcid.org/0000-0002-8385-6861 Joerg C Henes 13 ,
• http://orcid.org/0000-0002-9324-3161 Marco Matucci-Cerinic 14 ,
• Paolo Airò 15 ,
• http://orcid.org/0000-0001-8194-8642 Francesco Ursini 1 , 2 ,
• http://orcid.org/0000-0001-7033-7520 Tom W J Huizinga 3 ,
• http://orcid.org/0000-0002-5624-1415 Jeska De Vries-Bouwstra 3 and
• EUSTAR Collaborators 16
• 1 Medicine and Rheumatology Unit , IRCCS Istituto Ortopedico Rizzoli , Bologna , Italy
• 2 Department of Biomedical and Neuromotor Sciences (DIBINEM) , Alma Mater Studiorum University of Bologna , Bologna , Italy
• 3 Department of Rheumatology , Leiden University Medical Centre (LUMC) , Leiden , The Netherlands
• 4 Department of Clinical Epidemiology , Leiden University Medical Center (LUMC) , Leiden , The Netherlands
• 5 Department of Internal Medicine, Division of Thrombosis and Haemostasis , Leiden University Medical Center (LUMC) , Leiden , The Netherlands
• 6 Department of Rheumatology and Internal Medicine , Wroclaw Medical University , Wroclaw , Poland
• 7 Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine , Hokkaido University , Sapporo , Japan
• 8 Department of Rheumatology, Faculty of Medicine , University of Debrecen , Debrecen , Hungary
• 9 Rheumatology Department, Rambam Health Care Campus , Rappaport Faculty of Medicine, Technion , Haifa , Israel
• 10 Department of Rheumatology and Immunology, Medical School , University of Pécs , Pécs , Hungary
• 11 Department of Medicine-DIMED, Unit of Rheumatology , Padova University Hospital , Padova , Italy
• 12 Medical Department 4, Rheumatology, Immunology, Nephrology , Asklepios Klinik Altona , Hamburg , Germany
• 13 Internal Medicine II - Oncology, haematology, clinical immunology and rheumatology , University Hospital and Faculty of Medicine, University of Tübingen , Tubingen , Germany
• 14 Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) , IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University , Milan , Italy
• 15 Rheumatology and Clinical Immunology Service , Spedali Civili di Brescia , Brescia , Italy
• 16 EUropean Scleroderma Trials And Research group , None , UK
• Correspondence to Dr. Jacopo Ciaffi; jacopo.ciaffi{at}ior.it

Objectives To untangle the association between smoking and systemic sclerosis (SSc).

Methods In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA).

Results Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for ‘any organ progression’ (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and ‘any organ progression’ (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and ‘any organ progression’ (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently.

Conclusions Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and ‘any organ progression’.

• Systemic Sclerosis
• Autoantibodies
• Risk Factors

Data availability statement

Data are available on reasonable request.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/rmdopen-2024-004101

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Data about the association between smoking and systemic sclerosis (SSc) are limited.

Smoking has been hypothesised to contribute to the increased mortality observed in male SSc patients compared with females.

The available literature suggests a negative association between smoking and positivity of anti-topoisomerase antibodies (ATA).

WHAT THIS STUDY ADDS

This study confirms that smoking is associated with reduced survival in men with SSc, partially explaining their worse prognosis.

Smoking is associated with a lower prevalence of ATA in women with SSc and this association is dose-dependent.

Both in anti-centromere-positive and ATA-positive patients, smoking might increase the risk of mortality, skin progression and ‘any organ progression’.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Our study highlights the importance of considering smoking as a risk factor for disease progression and mortality in SSc and underlines that smoking cessation programmes should be implemented in the care pathways for all patients.

For the first time, we describe a negative dose–response relationship between cumulative smoking exposure and the presence of ATA, pointing at a possible etiopathogenetic link between smoking and ATA. This antibody–environment interaction might provide important clues for a better understanding of the SSc pathogenesis.

Introduction

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterised by vasculopathy and fibrosis of skin and internal organs. 1 2 The pathogenesis is elusive and incompletely understood. 3 A multifactorial background is postulated in which different endogenous and exogenous triggers contribute to the development of the disease in genetically predisposed individuals. 3–5 With the exception of silica, which is an established risk factor for SSc, 5–7 the nature of these triggers and their effects on the evolution of the disease remain unclear.

With regard to smoking, previous cross-sectional studies showed a correlation between smoking and vascular, gastrointestinal or respiratory symptoms in SSc, 8 but these findings were not confirmed in other cohorts. 9 10 In a longitudinal study on 3319 SSc patients, Jaeger et al did not observe a role of smoking on disease-specific cutaneous and pulmonary outcomes. 10 Whether smoking confers a risk for disease progression in SSc is thus debated. 11

The prevalence of SSc is higher in women, but men have more severe disease and worse outcomes, including the excess mortality observed in male SSc patients compared with females. 12–15 Since men with SSc are more frequently ever-smokers than women, 16 previous studies have hypothesised a role of cigarette smoking as a contributor to this excess mortality. 12 17 Notwithstanding the availability of new treatment strategies 18 19 and of accurate and reliable methods to assess disease-specific manifestations, 20 21 caring for patients with SSc is challenging. Several clinical practice guidelines exist, but a multidisciplinary approach for holistic SSc management is advocated. 22 Elucidating the extent of the impact of smoking on SSc and whether smoking exerts distinct effects in men and women or in patients with different disease characteristics, would have important implications for risk stratification.

Interestingly, two independent groups described a higher proportion of anti-topoisomerase antibodies (ATA) positivity in never-smokers than in ever-smokers in, respectively, 621 and 3319 patients. 10 23 In an analysis of the autoantibody profile of 361 patients of the Leiden Combined Care in SSc cohort, we reported the same finding, but we also showed that smoking might have different effects on autoantibodies in men and women, with never-smoking women being more frequently ATA-positive than ever-smoking women. 24

In rheumatoid arthritis (RA), smoking has a well-established impact on disease susceptibility and confers a risk for the development of anti-citrullinated peptide antibodies (ACPA) and rheumatoid factor, in particular in patients carrying specific HLA-DRB1 variants. 25 These observations have fuelled the hypothesis that, in a susceptible individual, chronic exposure to specific antigens, for example, in the lungs, can trigger a targeted chronic autoimmune response. 26 Considering that ATA have been traditionally related to aggressive SSc with a higher risk of interstitial lung disease (ILD) and increased mortality, 27 28 the negative association between smoking and ATA is highly intriguing and needs to be further elucidated.

To shed light on the complex interaction between smoking, autoantibodies, sex and disease outcomes in SSc, we performed an in-depth analysis of the EUSTAR cohort, in which we evaluated (1) the impact of smoking exposure on disease progression and mortality in the whole cohort, in men and women; (2) the association between smoking and presence of specific autoantibodies and (3) the intricate interactions among smoking habits and the presence of specific autoantibodies, and their collective impact on the progression of the disease.

This comprehensive approach not only aims to advance our understanding of SSc but also introduces a novel perspective on how lifestyle factors like smoking intersect with autoantibodies to influence disease dynamics.

Study design and patients

The research questions were addressed analysing the multinational prospective European Scleroderma Trials and Research (EUSTAR) database. The structure of the EUSTAR database, the definition of each clinical variable and the description of the collected data have been reported elsewhere. 29 30 All patients included in our study fulfilled either the American College of Rheumatology (ACR) 1980 or the ACR/European League Against Rheumatism (EULAR) 2013 classification criteria for SSc 31 32 at the baseline visit (ie, the first visit registered in the database) or during follow-up. Patients were included if they were aged 18 years or older at the baseline visit.

In the EUSTAR database, data have been collected since 2004 and the smoking module was added in 2013. This module assesses patient-reported information about ever smoking, current smoking, number of pack-years and dates of smoking start and cessation. Since the main focus of our study was laid on smoking, patients without any information about smoking status or with inconsistent smoking data during follow-up were excluded. Patients with a first visit before 2013 in which information about baseline smoking status could be derived from data collected during follow-up, were included and categorised as ‘never-smokers’ or ‘ever-smokers’ at the baseline visit. Cases in whom multiple autoantibody positivity for both anticentromere antibodies (ACA) and ATA was recorded during the available follow-up were excluded from the analysis.

Definitions of disease progression

Mortality: death from all causes.

SSc-related mortality: death attributed to SSc.

Development of ILD: evidence, after the baseline visit, of lung fibrosis on standard X-ray or high-resolution CT (HRCT) of the thorax.

Progression of ILD: forced vital capacity decline>10% or DLCO decline >15% compared with the baseline visit 33 in patients with X-ray or HRCT evidence of ILD.

Progression of skin involvement: 5-unit and 25% increase in modified Rodnan skin score (mRSS) from the baseline visit 34 or progression of disease subset (from sine scleroderma to limited SSc (lcSSc) or diffuse SSc (dcSSc), or from lcSSc to dcSSc).

Development of pulmonary hypertension (PH): evidence, after the baseline visit, of pulmonary hypertension confirmed by mean pulmonary arterial pressure (PAP)≥25 mmHg on right heart catheterisation.

Development of gastrointestinal involvement: onset, after the baseline visit, of gastrointestinal symptoms such as dysphagia, reflux, early satiety, vomiting, diarrhoea, bloating, constipation, paralytic ileus or malabsorption syndrome.

Development of renal involvement: onset, after the baseline visit, of scleroderma renal crisis or requirement of dialysis.

Development of cardiac involvement: onset, after the baseline visit, of conduction blocks, arrhythmias, pericardial effusion, diastolic dysfunction, myocarditis, left ventricular ejection fraction <50% or need for cardiac pacemaker implantation.

Development of digital ulcers or digital ischaemia.

‘Any organ progression’: a composite variable encompassing all of the above organ-specific domains.

Statistical analysis

Data are expressed as mean±SD or median (25th– 75th percentile) for continuous variables or number (percentage) for categorical variables.

To investigate the effects of smoking on disease progression in the whole cohort and, separately, in men and women, Kaplan-Meier estimates were used to assess the time until the first diagnosis of the event of interest in ever-smokers and never-smokers. Disease progression was defined as the occurrence of death or disease-specific outcomes within a follow-up period of 15 years since baseline. The starting point was the baseline visit. End time was set at the date of the visit at which the event was first recorded or at the end of follow-up when the event was never observed. Follow-up time was censored at 15 years from the first visit. Kaplan-Meier curves were compared between ever-smokers and never-smokers using a log-rank test. Incidence rates of mortality and 95% CI were calculated in men and women according to their smoking habit, considering never-smoking women as the reference category to determine the relative risk (RR). Additionally, univariable and multivariable Cox regression models, adjusted for age, were used to express the risk of mortality and progression in each disease domain as an HR with its 95% CI.

To assess whether the antibody profile in SSc was different in ever-smokers compared with never-smokers, χ 2 test and univariable logistic regression were applied, with smoking being the independent variable. To investigate a potential role of the intensity of exposure to tobacco on autoantibody occurrence, in the subgroup of ever-smokers, binary logistic regression was used to estimate the association between the number of pack-years or the years of smoking duration (both entered as continuous variables) and the autoantibody positivity, expressed through OR and their 95% CI.

To evaluate how cigarette exposure and ATA or ACA interact and are associated with disease outcomes and mortality, Kaplan-Meier curves were used to compare the time until progression in ever-smokers and never-smokers stratified by autoantibody profile assuming three categories, namely ACA positivity, ATA positivity or negativity of both autoantibodies. Cox regression models were built, adjusted for age and sex after stratification for ACA positivity, ATA positivity or negativity of both autoantibodies. Cox proportional hazards regression analysis was thus used to assess the risk of mortality and disease progression in each category according to the smoking status, expressing the event risk as an HR with its 95% CI.

All analyses were performed by using SPSS Statistics V.28 (IBM) and Stata version V.16 (StataCorp). A p<0.05 was considered statistically significant. Forest plots were created using R statistical software, ‘ggplot2’ package (V.4.3.0; R Foundation for Statistical Computing, Vienna, Austria).

EUSTAR population

At the time of data export from EUSTAR (5 July 2022), 21 349 patients were extracted from the database ( online supplemental figure S1 ). Of these, 7 were excluded because sex was unknown and 7640 because information about smoking was either missing (n=7077) or inconsistent during follow-up (n=563). Additionally, of the 14 702 patients with consistent smoking data, 1388 were excluded due to one or more of the following reasons: positivity for both ACA and ATA (n=377), not fulfilling classification criteria (n=1011), age below 18 years at the baseline visit (n=32). Finally, 12 314 patients met the inclusion criteria ( online supplemental figure S1 ). Of these, 4271 (35%) were ever-smokers. Compared with the excluded patients, included patients were more often males (16% vs 14%) and had shorter median disease duration (7.6 (3.0–16.0) vs 8.4 (3.3–16.7) years). Age (55.5±13.8 vs 55.3±14.5 years), prevalence of ACA (38% vs 38%) and limited cutaneous disease subset (56% vs 54%) were similar, whereas included patients were less often ATA-positive (32% vs 33%) and less often had diffuse cutaneous SSc (29% vs 31%). Median follow-up time of the included patients was 30 months (IQR 5–83). For 2848 (23%) included patients, only the baseline visit was available. Demographic and clinical features of the included and excluded patients are shown, respectively, in table 1 and in online supplemental table S3 .

Supplemental material

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Kaplan-Meier curves of ever-smokers and never-smokers showing mortality rate in the total cohort of EUSTAR patients (A) and after stratification based on sex (B). EUSTAR, European Scleroderma Trials and Research.

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Baseline characteristics of the 12 314 patients in the EUSTAR registry included in the study

Smoking, mortality and disease progression

In females, 807 deaths were observed during 47 162 patient-years of follow-up. In males, 241 deaths were observed over 6878 patient-years. Patients’ deaths were attributed to SSc in 448 cases (43%), were not SSc-related in 407 (39%), and the information was missing in 193 (18%). All-cause mortality was slightly higher in ever-smokers compared with never-smokers in the whole cohort (32% vs 30%, p=0.001) ( figure 1A ) and in male patients (50% vs 40%, p<0.001) ( figure 1B ), but not in female patients (26% vs 29%, p=0.207) ( figure 1B ). Incidence rate for mortality was 1.77/100 patient-years in never-smoking women (reference category), 1.56/100 patient-years in ever-smoking women (RR=0.88), 2.53/100 person-years in never-smoking men (RR=1.43), 4.10/100 person-years in ever-smoking men (RR=2.32). Thus, our results outline an increased mortality associated with smoking in men but not in women.

For disease progression in the whole cohort, Kaplan-Meier curves did not show significant differences between ever-smokers and never-smokers in any of the organ domains evaluated, with the exception of skin progression, that occurred in 69% of ever-smokers and 62% of never-smokers (p<0.001) ( figure 2A–H ).

Kaplan-Meier curves of ever-smokers and never-smokers showing development of interstitial lung disease (ILD) (A), progression of ILD (B), development of cardiac involvement (C), progression of skin involvement (D), development of pulmonary hypertension (PH) (E), development of digital ulcers (DU) or digital ischaemia (F), development of gastrointestinal involvement (G) and development of renal involvement (H) in the total cohort of EUSTAR patients. EUSTAR, European Scleroderma Trials and Research.

The same analyses were performed stratified by sex. Here, we observed a higher frequency of development of cardiac involvement among ever-smoking males compared with never-smoking males (78% vs 72%, p=0.025). In ever-smoking females, we found a lower risk of developing ILD (74% vs 78%, p<0.001) and a higher risk of skin progression (66% vs 61%, p=0.020). For all the other outcomes, we did not see an effect of smoking on disease progression in males or females ( online supplemental figure S2A–H ).

Combining all the above-mentioned domains in a composite ‘any organ progression’ variable, we noticed a significantly higher progression rate among ever-smokers compared with never-smokers across the entire cohort ( figure 3A ) and throughout the entire observation period (p<0.001), while no difference was observed in men and women ( figure 3B ). However, the estimates at the end of follow-up were numerically comparable with 100% of patients showing progression in at least one organ domain.

Kaplan-Meier curves of ever-smokers and never-smokers showing ‘any organ progression’ in the total cohort of EUSTAR patients (A) and after stratification based on sex (B). EUSTAR, European Scleroderma Trials and Research.

In multivariable Cox regression models, after adjusting for age, smoking was associated with increased risk of mortality (HR 1.50, 95% CI 1.32 to 1.71, p<0.001), cardiac involvement (HR 1.13, 95% CI 1.04 to 1.23, p=0.003), skin progression (HR 1.22, 95% CI 1.12 to 1.32, p<0.001) and ‘any organ progression’ (HR 1.10, 95% CI 1.05 to 1.16, p<0.001) in the whole cohort ( figure 4A ). In women, smoking was associated with a lower risk of developing ILD (HR 0.89, 95% CI 0.82 to 0.96, p<0.001) and with a higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for ‘any organ progression’ (HR 1.07, 95% CI 1.00 to 1.13, p=0.036) ( figure 4B ). In men, smoking was associated with increased all-cause mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001) ( figure 4C ). The increased mortality risk in ever-smokers was confirmed also analysing only patients who died due to SSc. Having a history of smoking was associated with an increased risk of SSc-related mortality in the whole cohort (HR 1.30, 95% CI 1.06 to 1.59, p=0.011) and in male patients (HR 1.60, 95% CI 1.03 to 2.49, p=0.038).

Forest plot of HRs and 95% CIs based on multivariable Cox regression analysis of the effect of cigarette smoking on different systemic sclerosis progression outcomes in the total cohort of EUSTAR patients (A) and after stratification in female patients (B) and male patients (C). All models were adjusted for age. Forest plots were created using R statistical software, ‘ggplot2’ package (V.4.3.0; R Foundation for Statistical Computing, Vienna, Austria). EUSTAR, European Scleroderma Trials and Research; ILD, interstitial lung disease.

Smoking and autoantibody profile

Of 12 314 included patients, 4637 were ACA-positive (38%) and 3919 were ATA-positive (32%). We observed a significantly different prevalence of autoantibodies in ever-smokers compared with never-smokers ( table 2 ). Among never-smokers, 35% of patients were ATA-positive, compared with 27% among ever-smokers (p<0.001). When stratified by sex, this difference was accounted for by female patients: 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). Additionally, 39% of never-smoking women were ACA-positive compared with 46% of ever-smoking women (p<0.001). In men, no statistically significant difference in the occurrence of ATA or ACA was observed. No significant difference was found in the prevalence of anti-RNA polymerase III, anti-U1RNP, anti-SSA and anti-PM/Scl antibodies ( table 2 ).

Positivity of anti-centromere antibodies (ACA), anti-topoisomerase I antibodies (ATAs), anti-RNA polymerase III antibodies (anti-RNAP-III), anti-U1 ribonucleoprotein antibodies (anti-U1RNP), anti-SSA antibodies and anti-PM/Scl antibodies in the whole EUSTAR cohort, and in men and women according to the smoking status

In univariable analysis, being a never-smoker was associated with ATA positivity in the whole cohort (OR 1.46, 95% CI 1.35 to 1.59, p<0.001) and in female patients (OR 1.91, 95% CI 1.73 to 2.11, p<0.001). Moreover, within the group of ever-smoking women, higher exposure rates as reflected by number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) or by years of smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), decreased the risk of being ATA-positive.

Smoking and disease progression in ACA and ATA patients

Kaplan-Meier curves stratified for autoantibody profile assuming three categories (ACA positivity, ATA positivity or ACA and ATA negativity) demonstrated that mortality rate was higher in ever-smokers compared with never-smokers for ATA-positive patients (38% vs 30%, p<0.001) and for ACA and ATA-negative patients (36% vs 32%, p=0.041) but not for ACA-positive patients ( figure 5A ).

Kaplan-Meier curves of ever-smokers and never-smokers showing mortality rate (A), development of interstitial lung disease (ILD) (B), progression of ILD (C), development of cardiac involvement (D), progression of skin involvement (E), development of digital ulcers (DU) or digital ischaemia (F), development of pulmonary hypertension (PH) (G), development of gastrointestinal involvement (H), development of renal involvement (I) and ‘any organ progression’ (L) in the cohort of EUSTAR patients stratified by positivity of anti-centromere antibodies (ACA+), positivity of anti-topoisomerase I antibodies (ATA+) or negativity for both antibodies (ACA- ATA-). EUSTAR, European Scleroderma Trials and Research.

The risk of ILD development between ever-smokers and never-smokers was comparable in each autoantibody category ( figure 5B ). Among patients with ILD at baseline, the risk of decline in lung function during follow-up was higher in ever-smoking than in never-smoking ATA-positive patients (88% vs 77%, p=0.050) ( figure 5C ).

In ACA-positive patients, development of cardiac involvement (66% vs 61%, p=0.020) ( figure 5D ) was more frequent in ever-smokers as compared with never-smokers. Skin progression was more common among ever-smokers in both ACA-positive (55% vs 48%, p=0.010), ATA-positive (78% vs 73%, p<0.001) and ACA and ATA-negative patients (75% vs 69%, p=0.014) patients ( figure 5E ). In ATA-positive smokers, digital ulcers or digital ischaemia occurred more frequently during follow-up (94% vs 90%, p=0.004) ( figure 5F ). No difference was found in the risk of developing PH ( figure 5G ), gastrointestinal involvement ( figure 5H ) or renal complications ( figure 5I ).

Combining all the above-mentioned organ-specific manifestations in a composite ‘any organ progression’ variable, we found that 100% of patients were progressors at the end of the follow-up period. However, ever-smokers had a higher progression rate compared with never-smokers for ACA-positive (p=0.007), ATA-positive (p=0.002) and ACA and ATA-negative patients (p=0.014) ( figure 5L ).

Multivariable Cox regression showed that, after adjusting for age and sex, in ACA-positive patients ( figure 6A ), smoking was associated with increased risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and ‘any organ progression’ (HR 1.14, 95% CI 1.05 to 1.24, p=0.002). In ATA-positive patients ( figure 6B ), smoking was associated with mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), with skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020), with development of digital ulcers or digital ischaemia (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and with ‘any organ progression’ (HR 1.11, 95% CI 1.00 to 1.22, p=0.048). Analysing the cases of death attributable to SSc, ever-smoking was associated with an increased risk of SSc-related mortality in ATA-positive patients (HR 1.40, 95% CI 1.00 to 1.96, p=0.047). Cox regression did not demonstrate associations between smoking and any outcome in ACA and ATA-negative patients ( figure 6C ).

Forest plot of HRs and 95% CIs based on multivariable Cox regression analysis of the effect of cigarette smoking on different systemic sclerosis progression outcomes in the cohort of EUSTAR patients stratified by positivity of anti-centromere antibodies (ACA, A), positivity of anti-topoisomerase I antibodies (ATA, B) or negativity for both antibodies (C). All models were adjusted for age and sex. Forest plots were created using R statistical software, ‘ggplot2’ package (V.4.3.0; R Foundation for Statistical Computing, Vienna, Austria). EUSTAR, European Scleroderma Trials and Research; ILD, interstitial lung disease.

In this study, we aimed to evaluate the interplay between smoking, sex, autoantibodies and disease outcomes in patients with SSc. We found that a never-smoking female patient with SSc has an almost twofold higher probability of being ATA-positive. Intriguingly, we observed a negative dose-response effect between smoking exposure and ATA. We demonstrated, for the first time, that smoking is associated with increased mortality in male patients but not in female patients. Ever-smoking women, however, have a higher risk for disease progression. Stratifying the analysis according to the autoantibody status, both ACA-positive and ATA-positive patients have an increased risk for mortality, skin involvement and ‘any organ progression’ if they are ever-smokers. Additionally, the risk for cardiac involvement is higher in ever-smoking ACA-positive patients while ATA-positive ever-smokers have a higher risk for digital ulcers.

Previous meta-analyses have showed that male sex is associated with increased mortality in SSc (HR of 1.9 for males compared with females). 13 14 In our analysis, smoking was associated with a relative mortality risk of 1.6 in men. Thus, our data suggest that smoking is a factor potentially accounting for the reduced survival of male SSc patients described in the literature. 27 35 36

Consistent with the findings from the prospective study by Jaeger et al , our observations reveal no link between smoking and SSc-specific pulmonary outcomes. 10 Nevertheless, a significant correlation was noted with the advancement of skin involvement, manifesting as either an elevation in mRSS or the progression of the disease subset. Furthermore, we conducted a stratified analysis dissecting the different effects of smoking in males and females and individuals with distinct autoantibody profile.

Interestingly, we observed a lower risk of developing ILD in ever-smoking women than in never-smoking women. This result should be interpreted in the light of the close association between ATA and ILD 37 and of the lower proportion of ATA positivity in ever-smoking women compared with never-smoking women identified by our analysis. Indeed, the apparently higher risk of developing ILD in never-smoking women is entirely mediated by ATA positivity. When ATA positivity is included in the model, smoking loses significance.

In accordance with earlier literature, our study shows that a history of smoking is associated with a lower prevalence of ATA 10 23 and we confirm that this imbalance is found typically in female patients. 24 Additionally, we notice that this association is dose-dependent (ie, the higher the exposure rate, the lower the chance to be ATA-positive), which underlines the hypothesis that, indeed, exposure to cigarette smoke might impact the ATA-specific B cell responses. This finding is unexpected if we consider what happens in other autoimmune diseases such as RA or systemic lupus erythematosus (SLE).

In RA, smoking promotes citrullination in the lung tissue, initiating autoimmunity within the respiratory system and contributing to the formation not only of ACPA, but of multiple autoantibodies involved in the pathophysiological mechanisms of the disease. 38 In SLE, smoking is strongly associated with the risk of anti-dsDNA positivity and with more severe disease manifestations. 39 Smoking can thus impair the immune homeostasis and elicit a broad autoimmune response through different biological pathways. 40 However, in SSc, the apparently protective influence of smoking on the presence of ATA does not correspond to any beneficial clinical outcome for ever-smokers.

The strength of our study is intrinsic to the use of the EUSTAR database, which is the largest available real-life multinational registry of longitudinally collected data on SSc. We were able to comprehensively characterise the disease course of SSc patients according to their smoking habit, investigating the development of multiple clinical outcomes over a follow-up period of 15 years and contributing unique insights into the controversial relationship between smoking and SSc. In addition, we have applied a hypothesis-driven approach to elucidate how smoking interacts with disease progression in SSc, both in different autoantibody groups and in males and females.

Some potential limitations should be acknowledged. The major concern regards the assessment of smoking status, self-reported, and therefore, susceptible to bias. Nevertheless, patients were categorised as never-smokers and ever-smokers to yield the analysis robust against overestimation or underestimation of the smoking exposure. We also recognise that, in the models for disease progression, we were unable to control for factors such as educational level, socioeconomic status and alcohol consumption that might act as confounders in the association between smoking and the evolution of SSc. 41 42 In discussing SSc-related mortality, it is important to note the complexities in determining the exact cause of death, which often relies on the assessment of the attending physician. More than one-third of the patients extracted from the EUSTAR database had to be excluded from the analysis due to missing or inconsistent smoking information, potentially representing a selection bias. Similarly, data about positivity of autoantibodies different from ACA or ATA were missing in a considerable proportion of patients, precluding the possibility to perform exhaustive analyses on less-prevalent autoantibodies. We recognise the complexity of discerning the impact of smoking on the progression of cardiac involvement in SSc, given smoking’s established adverse effects on the cardiovascular system. Our analysis did not encompass coronary artery disease or myocardial infarction in defining cardiac involvement. However, it is important to note that conditions such as heart failure, arrhythmias and diastolic dysfunction, which may stem from SSc-related myocardial damage and fibrosis, are prevalent among smokers in the general population. 43 44 To accurately separate the cardiovascular consequences of smoking from the cardiac manifestations intrinsic to SSc, targeted research would be essential. Finally, smoking data were collected at the baseline visit only, blurring the interpretation of a time-dependent association between smoking exposure and the development of the assessed outcomes. Since genome-wide association studies have been conducted in SSc, 45 46 it would be interesting to use a Mendelian randomisation method, based on genetic variants, and therefore, robust against bias or confounders, to investigate the association between liability to smoking and risk of SSc, similar to the approach used for other diseases. 47

In conclusion, we have investigated for the first time the interplay between sex, autoantibodies and smoking on the progression of SSc. Our results corroborate the association between smoking and a reduced prevalence of ATA positivity among SSc patients, particularly notable in females. The impact of smoking on SSc outcomes is heterogeneous and can be modified by factors like sex and autoantibody status. Given the poor prognosis of ATA-positive patients, the negative relationship between smoking and ATA introduces an additional layer of complexity. In males, our data indicate that smoking significantly compromises survival. Additionally, our findings suggest that smoking may influence mortality risk, skin progression and overall organ progression in ACA-positive and ATA-positive individuals, cardiac involvement in ACA-positive patients and the emergence of new digital ulcers in ATA-positive patients.

This study underscores the importance of identifying potential triggers to mitigate disease progression through more precise risk stratification. Nevertheless, the advantages of smoking cessation are unquestionable. We strongly advocate for the implementation of targeted smoking cessation counselling and effective interventions for all individuals with SSc.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study involves human participants and each EUSTAR site obtained approval from the respective local ethics committee prior to data inclusion in the registry. All patients included in the EUSTAR database gave written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the EUSTAR board (project number CP 126). Participants gave informed consent to participate in the study before taking part.

• Distler JHW ,
• Allanore Y ,
• Avouac J , et al
• Denton CP ,
• Truchetet ME ,
• Brembilla NC ,
• Chizzolini C
• Györfi AH ,
• Ramanujam M , et al
• Ouchene L ,
• Muntyanu A ,
• Lavoué J , et al
• Sighinolfi GL , et al
• Rahme E , et al
• Lu Y , et al
• Hissaria P ,
• Roberts-Thomson PJ ,
• Lester S , et al
• Jaeger VK ,
• Valentini G ,
• Hachulla E , et al
• Zhang Y-J ,
• Huang X-L , et al
• Peoples C ,
• Medsger TA ,
• Lucas M , et al
• Rubio-Rivas M ,
• Simeón CP , et al
• Pokeerbux MR ,
• Giovannelli J ,
• Dauchet L , et al
• De Almeida Chaves S ,
• Mounié M , et al
• Sopeña B , et al
• Pauling JD ,
• Armstrong-James L , et al
• Campochiaro C ,
• De Luca G ,
• Lazzaroni M-G , et al
• Elhai M , et al
• Santiago T ,
• Santos EJF ,
• Ruaro B , et al
• Ye T , et al
• Talarico R , et al
• Chaudhary P ,
• Assassi S , et al
• van Leeuwen NM ,
• Huizinga TWJ , et al
• Hedström AK ,
• Rönnelid J ,
• Klareskog L , et al
• Eggleton P , et al
• Cavazzana I ,
• Vojinovic T ,
• Airo’ P , et al
• Meier FMP ,
• Frommer KW ,
• Dinser R , et al
• Benvenuti F ,
• Zanatta E ,
• van den Hoogen F ,
• Fransen J , et al
• Volkmann ER ,
• Tashkin DP ,
• Sim M , et al
• Ledoult E ,
• Béhal H , et al
• De Angelis R ,
• Giuggioli D ,
• Bajocchi G , et al
• Carreira PE ,
• Carmona L ,
• Joven BE , et al
• van Wesemael TJ ,
• Ajeganova S ,
• Humphreys J , et al
• Speyer CB ,
• Costenbader KH
• Perricone C ,
• Versini M ,
• Ben-Ami D , et al
• Chapman B ,
• Fiscella K ,
• Duberstein P , et al
• Haldorsen T ,
• Martinsen JI ,
• Kjærheim K , et al
• Schlesinger S ,
• Norat T , et al
• D’Alessandro A ,
• Boeckelmann I ,
• Hammwhöner M , et al
• López-Isac E ,
• Acosta-Herrera M ,
• Kerick M , et al
• Larsson SC ,

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

JC and SIEL contributed equally.

Presented at Preliminary results of this study were presented at the EULAR 2023 Congress in Milan (Italy) and at the ACR Convergence 2023 in San Diego (USA).

Contributors All authors were involved in drafting and/or critical review of the manuscript and approved the final version for submission. All authors agreed to attest to the accuracy and integrity of the work. Conceptualisation (JC, SIEL, SC and JDV-B), data curation (JC, SIEL, SC and JDV-B), formal analysis (JC, SIEL and JDV-B), investigation (JC, SIEL, SC and JDV-B), methodology (JC, SIEL, SC, JDV-B and TWJH), resources (JC, SC, JDV-B, MM-C), supervision (MM-C, FU, TWJH and JDV-B), validation (SC, JDV-B and TWJH), writing–original draft preparation (JC, SIEL, SA and EMH), writing–review and editing (JC, SIEL, SC, SA, EMH, PW, TA, GS, ABG, LC, EZ, IK, JCH, MM-C, PA, FU, TWJH and JDV-B). Author JC is responsible for the overall content as guarantor.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Electrospinning Approach for Preparing Nanostructured Scaffolds for Stem Cell Seeding and/or Implantation in Neurotrauma

• First Online: 23 May 2024

Cite this protocol

• Eldar F. Davletshin 1 ,
• Albert A. Rizvanov 1 , 2 , 3 &
• Yana O. Mukhamedshina 1 , 2  

Part of the book series: Methods in Molecular Biology

Preparation of highly porous biocompatible and bioresorbable nerve conduit or scaffold by electrospinning based on synthetic polycaprolactone with a molecular weight of 80 kDa (PCL 80 kDa) has significance in the context of regenerative medicine with special emphasis on their application in neurotrauma. PCL conduits/scaffolds serving as a support structure for seeded stem cells show promising regenerative potential to promote functional recovery and tissue regeneration in models of neurotrauma. Here we describe a standard protocol for the production of conduits by electrospinning at high field-forming voltages (24kB) using a 6% solution of PCL 80 kDa in a chloroform/methanol mixture.

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Libro R, Bramanti P, Mazzon E (2017) The combined strategy of mesenchymal stem cells and tissue-engineered scaffolds for spinal cord injury regeneration. Exp Ther Med 14(4):3355–3368. https://doi.org/10.3892/etm.2017.4939

Article   Google Scholar  

Kaplan B, Levenberg S (2022) The role of biomaterials in peripheral nerve and spinal cord injury: a review. Int J Mol Sci 23(3):1244. https://doi.org/10.3390/ijms23031244

de Assis ACC, Reis ALS, Nunes LV, Ferreira LFR, Bilal M, Iqbal HMN, Soriano RN (2023) Stem cells and tissue engineering-based therapeutic interventions: promising strategies to improve peripheral nerve regeneration. Cell Mol Neurobiol 43(2):433–454. https://doi.org/10.1007/s10571-022-01199-3

Hackett JM, Dang TT, Tsai EC, Cao X (2010) Electrospun biocomposite Polycaprolactone/collagen tubes as scaffolds for neural stem cell differentiation. Materials 3(6):3714–3728. https://doi.org/10.3390/ma3063714

Mukhamedshina YO, Masgutov RF, Masgutova GA, Zuravleva MN, Shulman AP, Galieva LR, Rogozin AF, Chelyshev YA, Rizvanov AA (2015) Conduit based on poly(ε-caprolactone) filled with fibrin-based hydrogel with mesenchymal stromal cells for peripheral nerve defect reconstitution. Genes Cells 10(3):83–87. https://doi.org/10.23868/gc120496

Zhou X, Shi G, Fan B, Cheng X, Zhang X, Wang X, Liu S, Hao Y, Wei Z, Wang L, Feng S (2018) Polycaprolactone electrospun fiber scaffold loaded with iPSCs-NSCs and ASCs as a novel tissue engineering scaffold for the treatment of spinal cord injury. Int J Nanomedicine 13:6265–6277. https://doi.org/10.2147/IJN.S175914

Lu N, Wang X, Li X, Shi W, Wang X, Zou Y, Weng Y (2023) EMSCs-seeded micro-stripe patterned Polycaprolactone promoting sciatic nerve regeneration. Adv Mater Interfaces 10(5):2201929. https://doi.org/10.1002/admi.202201929

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Acknowledgments

This study was funded by the subsidy allocated to Kazan Federal University for the state assignment № FZSM-2023-0011 in the sphere of scientific activities.

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Kazan (Volga Region) Federal University, Kazan, Russia

Eldar F. Davletshin, Albert A. Rizvanov & Yana O. Mukhamedshina

Republic Clinical Hospital of the Ministry of Health of the Republic of Tatarstan, Kazan, Russia

Albert A. Rizvanov & Yana O. Mukhamedshina

Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, Kazan, Russia

Albert A. Rizvanov

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© 2024 Springer Science+Business Media, LLC

About this protocol

Davletshin, E.F., Rizvanov, A.A., Mukhamedshina, Y.O. (2024). Electrospinning Approach for Preparing Nanostructured Scaffolds for Stem Cell Seeding and/or Implantation in Neurotrauma. In: Methods in Molecular Biology. Springer, New York, NY. https://doi.org/10.1007/7651_2024_547

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DOI : https://doi.org/10.1007/7651_2024_547

Published : 23 May 2024

Publisher Name : Springer, New York, NY

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