EClinicalMedicine最新文献

Background: Renal sarcomas arise rarely in children and adolescents and represent a histologically and biologically diverse disease category. Consequently, standardizing optimal therapies for pediatric renal sarcomas remains challenging. Leveraging a large North American research collaborative, the purposes of this study were to evaluate the current state of patient, disease, and survival characteristics among pediatric renal sarcomas and to expose knowledge gaps that will inform future discovery.

Methods: Patients 21 years or younger and treated for a primary renal sarcoma between January 1st, 2000 and November 30th, 2022 were identified through the Pediatric Surgical Oncology Research Collaborative. Patient (e.g., demographics) and disease (e.g., histology, stage, molecular alterations) characteristics were abstracted from contributing institutions. Descriptive statistics, Pearson-Chi square (categorical variables), Kruskal-Wallis (continuous variables), Cox regression (Hazard ratios), and Kaplan-Meier 4-year event-free and overall survival (OS) analyses were completed.

Findings: Among 158 patients, clear cell sarcoma of the kidney (CCSK; n = 94), Ewing sarcoma (EWS; n = 33), and undifferentiated sarcoma (n = 8) predominated. Sarcoma type correlated significantly with age at diagnosis (p < 0.0001), with infantile fibrosarcoma (IFS) and CCSK occurring in the youngest patients, whereas EWS and synovial sarcoma presented in the oldest. Predisposition syndromes were identified in 11/155 (7.1%) patients, most commonly DICER1 and Li-Fraumeni. Multimodal therapies varied significantly across sarcoma types (p = 0.0008), although nephrectomy was uniform. Tumor thrombectomy was performed in 9 patients (6 with EWS). When tested, somatic molecular alterations were observed principally in CCSK (17/38; 45%) and EWS (26/26; 100%; p = 0.001). At 4 years, OS differed significantly by sarcoma type, ranging from highest to lowest as follows: CCSK 0.927 (95% CI 0.845-0.967), EWS 0.901 (95% CI 0.723-0.967), undifferentiated sarcoma 0.833 (95% CI 0.273-0.975), IFS 0.667 (95% CI 0.054-0.945), and rhabdomyosarcoma 0.500 (95% CI 0.111-0.804; p = 0.036). Hematogenous metastases occurred most in the lungs (n = 19 total; 10 with EWS), followed by bone (n = 12), which occurred only with CCSK (n = 9) and EWS (n = 3). Two patients developed brain metastases (one each with CCSK and rhabdomyosarcoma). At 4 years, OS was 0.957 (95% CI 0.888-0.984) for patients presenting without metastases and 0.717 (95% CI 0.545-0.833) for those with metastases (p = 0.00015).

Interpretation: Renal sarcomas presenting in children and adolescents comprise a heterogeneous disease category with unique patient, clinical, and molecular characteristics that complicate standardizing therapeutic strategies beyond CCSK and EWS.

Funding: None.

Background: Higher pre-pregnancy body mass index (BMI) has been associated with obstetric complications and proposed as a psychosocial risk factor for postpartum depression (PPD). However, its relationship with postpartum post-traumatic stress disorder (PP-PTSD) and perceived obstetric violence has not been sufficiently investigated. We aimed to examine the association between pre-pregnancy BMI and perinatal mental health outcomes.

Methods: We conducted a retrospective cohort study in Spain in 2023 using a self-administered online questionnaire completed by 2363 women between one and six months postpartum. Outcomes included high perception of obstetric violence (CARE-MQ > p90), risk of PP-PTSD (PPQ ≥ p90), and PPD (EPDS ≥12). Pre-pregnancy BMI was categorized according to WHO criteria. Multivariable logistic regression models adjusted for sociodemographic, clinical, and obstetric confounders were used.

Findings: Women with higher pre-pregnancy BMI had a higher frequency of medical interventions (induction of labor, oxytocin, regional analgesia) and more birth complications (aOR 1.69, 95% CI 1.21-2.34). Higher pre-pregnancy BMI was independently associated with increased risk of PPD (aOR 1.44, 95% CI 1.05-1.97), but not with PP-PTSD or perceived obstetric violence. Protective factors included older maternal age, higher income, attendance at childbirth preparation classes, adherence to the birth plan, skin-to-skin contact, and early initiation of breastfeeding. Complicated births and failure to adhere to the birth plan were associated with increased risk of experiencing at least one postpartum mental health problem.

Interpretation: Higher pre-pregnancy BMI may be linked to increased vulnerability to postpartum depression. This relationship appears influenced by obstetric characteristics and care practices, underscoring the need for further research and for preventive strategies to improve respectful, stigma-free perinatal care for women with higher pre-pregnancy BMI.

Funding: This study was funded by Instituto de Salud Carlos III (project PI22/00541) and co-funded by the European Union.

Background: People from socioeconomically deprived backgrounds are at greater risk of developing lung disease and having a higher symptom burden. It remains unclear whether they have equitable access to and experience of palliative care. Therefore, we aimed to synthesise evidence on socioeconomic inequalities in access, receipt of, preference for, and experience of palliative care among people with advanced lung disease.

Methods: Mixed-methods systematic review, searching four databases (MEDLINE, Embase, PsychINFO, CINAHL) from inception to March 28, 2025. We included studies that reported on socioeconomic position and palliative care in advanced lung disease (lung cancer, mesothelioma, chronic obstructive pulmonary disease, interstitial lung disease). Study quality was assessed using the Mixed Methods Appraisal Tool. Both meta-analysis (using a random effects model with I² to assess heterogeneity, sensitivity analysis and GRADE of evidence) and narrative synthesis were performed. PROSPERO CRD42024546502.

Findings: Of 10,572 records, 54 studies met inclusion criteria (4.2 million participants). Meta-analysis of six studies showed people with lung cancer in the lowest SEP group were 18% less likely to receive palliative care than those in the highest (OR 0.82, 95% CI 0.75-0.90, I² = 93.9%). GRADE of evidence was assessed as moderate. Qualitative findings identified financial hardship and insurance barriers limited access to pain relief and oxygen. Few studies considered multiple demographic characteristics, but those that did reported worse access among ethnic minorities and rural populations.

Interpretation: This review provides novel evidence of how the inverse care law operates in advanced lung disease. People from lower socioeconomic groups are significantly less likely to access palliative care, despite greater need. There is an urgent need for equity-focused research and policy interventions, co-produced with underserved communities that account for intersecting social disadvantages.

Funding: National Institute for Health and Care Research.

Background: For chronic lymphocytic leukaemia (CLL) and intermediate risk factors (unmutated IGHV and/or 11q deletion and/or complex karyotype; no TP53 alteration), the best first-line treatment is unclear. We compared an MRD-guided, fixed-duration ibrutinib-venetoclax (IV) regimen to fludarabine-cyclophosphamide-rituximab (FCR) in this population.

Methods: The ERADIC randomised, phase 2 trial (NCT04010968), conducted at 35 French hospitals, recruited previously untreated, fit adults with intermediate-risk CLL. Randomisation was 1:1 to: 6x4-weekly cycles of FCR (Months 1-6); or ibrutinib 420 mg/day from Month 1 plus venetoclax (ramp-up to 400 mg/day from Month 4) for a duration depending on the bone marrow measurable residual disease level at Month 9 (if undetectable at a threshold of <0·01% [BM uMRD4] to Month 15; otherwise to Month 27). Primary outcome was the BM uMRD4 rate at Month 27, by assessment oligocentrally (intent-to-treat, worst-case scenario method).

Findings: Between 27 September 2019 and 31 January 2021, 120 patients were enrolled (73% male). At Month 27, the BM uMRD4 rate was 37% (22/59; 95% confidence interval [CI] 25, 51) with IV versus 13% (8/61; 95% CI 6, 24) with FCR. The high amount of missing BM MRD data, along with imbalance in missing data between arms, meant that no confirmatory statistics were performed. Best rate of BM uMRD4 plus peripheral blood uMRD5 was 47% (22/47) with IV versus 19% (8/43) with FCR (p = 0·0090). With median 43 months' follow-up, progression-free survival was longer with IV versus FCR (estimated hazard ratio 0·35, 95% CI 0·16, 0·80, p = 0·012). By Month 27, six deaths had occurred (FCR: acute myeloid leukaemia, septic shock, myelodysplastic syndrome; IV: 2 sudden deaths, COVID-19). By the time of follow-up, the most common serious grade 3/4 events were infections and haematological toxicities with FCR, and infections and cardiovascular/metabolic toxicities with IV.

Interpretation: Due to the high amount of missing BM MRD data at Month 27, the primary outcome statistical analysis was not deemed feasible. The outcomes reported are secondary and exploratory, and were not been powered for in the study design. A patient profile suitable for an MRD-guided, fixed-duration IV regimen requires consideration of potential toxicities.

Funding: Abbvie and Janssen France.

Background: Obesity increases the risk of developing chronic kidney disease and progression to kidney failure (KF) and precludes kidney transplantation (KT). Challenges exist in people with KF losing weight to access KT, therefore understanding patients' and clinicians lived experiences of obesity management is crucial to improving equitable access to KT. This review aimed to synthesise qualitative and quantitative evidence to better understand patients' and clinicians' experiences of obesity management in KF prior to transplantation.

Methods: This mixed-methods systematic review followed the integrated methodological framework by the Joanna Briggs Institute. MEDLINE, Embase, and Web of Sciences were searched from 1st January 1980 to 16th April 2025 for studies investigating patients' and clinicians' perspectives on obesity management in KF. Qualitative, quantitative and mixed methods studies published in English in which patients or clinicians reported on their experiences of obesity management in kidney failure were included. Two investigators independently screened studies, extracted data, and assessed the risk of bias. Summary data were extracted from published reports and quantitative data underwent transformation into 'qualitised' data, Qualitative findings and qualitised survey results were analysed inductively using thematic synthesis. The study was registered with PROSPERO, CRD42024510237. The Mixed Methods Appraisal Tool version 2018 was used to evaluate the quality of selected studies.

Findings: Of 6525 records identified, 5203 remained after de-duplication and 7 studies met inclusion criteria with a total of 738 participants The overall quality of the studies was low and only one study scored highly on the quality assessment. Four main themes were constructed 1) Hungry and exhausted: The impact of dialysis on eating behaviour and activity (six studies [n = 339]) 2) Weight stigma-lack of support, trust and open communication (five studies [n = 212]) 3) Lack of resources as a barrier for weight loss (six studies [n = 339]) 4) Who gets a transplant? Moving beyond BMI to improve equity in transplantation (four studies [n = 631]).

Interpretation: Significant barriers to accessing and delivering obesity management were identified. When interpreting the results it should be appreciated that the overall quality of the studies was low. and clinician perspectives were limited to dietitians, nephrologists and transplant surgeons. To address these barriers, targeted strategies are recommended, such as enhanced training for health professional on obesity and communication about weight and weight stigma. There is an urgent paradigm shift needed to ensure equitable access to obesity management for people with obesity and KF.

Funding: National Institute for Health and Care Research.

Background: To investigate the efficacy and safety of adding tislelizumab to neoadjuvant chemotherapy with nab-paclitaxel and carboplatin (TP) followed by adjuvant tislelizumab for early TNBC to explore the optimal neoadjuvant chemotherapy backbone and courses.

Methods: The cTRIO study (ChiCTR2100041675) is a multicenter, prospective, open-label phase II trial across 8 sites in China, evaluating the efficacy and safety of neoadjuvant tislelizumab plus TP followed by adjuvant tislelizumab in patients with early triple-negative breast cancer (TNBC). We included women aged ≥18 years with histologically confirmed early TNBC defined by estrogen receptor immunohistochemistry (IHC) with T1 N1-3 or T2-4 N0-3 stage. Participants received six cycles of neoadjuvant tislelizumab (200 mg on day 1) plus nab-paclitaxel and carboplatin (TP; 125 mg/m² on days 1 and 8), definitive surgery 3-6 weeks after completion of neoadjuvant therapy, followed by adjuvant tislelizumab every 3 weeks for 1 year. The primary endpoint was pathologic complete response (pCR).

Findings: Sixty-two patients were enrolled from March 2021 to October 2022, including 44 cases with programmed cell death ligand 1 (PD-L1) positive and 9 cases at N3. At final analysis, 35/62 patients had achieved pathologic complete response (pCR, 56%; 95% confidence interval [CI], 43%-69%), with 33% (3/9) of N3 cases achieving pCR. The 3-year EFS and OS rates were 82.2% (95% CI, 70.2%-89.7%) and 87.7% (95% CI, 75.6%-94.0%), respectively. The incidence rates of grade ≥3 treatment-related adverse events (TRAEs) and grade ≥3 immune-related adverse events (irAEs) were 53% (33/62) and 5% (3/62), respectively. Patients with a higher PD-L1 combined positive score were less likely to experience relapse (P = 0.0090).

Interpretation: Despite being a de-escalating and anthracycline-free neoadjuvant treatment approach, the triplet combination therapy showed promising efficacy and safety, signifying a crucial step toward the optimization of chemoimmunotherapy for early TNBC.

Funding: This study was supported by BeOne Medicines, Ltd.

Background: Pharmacogenetics (PGx) aims to revolutionize healthcare by individualizing drug doses and medication choices. However, clinical uptake will require positive evaluation evidence of both clinical utility and cost-effectiveness. We have recently demonstrated the clinical utility of this approach, using a panel-based PGx-guided treatment of patients from various indications recruited in seven countries (PREPARE study).

Methods: Here, we provide economic evidence from a multinational cost-utility analysis of PGx-guided treatment in 6930 patients participating in the PREPARE study. The study was conducted from March 2017 to June 2020. We used the national healthcare system's perspective in each participating country, including only direct medical costs that budget holders cover. A Visual Analog Scale was used to measure utility and the quality of life was estimated by averaging the Visual Analog Scale scores of participants over four specific time points in the study, namely baseline visit (day 1), week 4, week 12, and 18 months from the baseline visit.

Findings: Our analysis showed that the PGx-guided treatment is marginally cost-effective at the threshold of €11,000 QALYs. Cost drivers were hospitalization and ADRs costs, accounting for most of the resources used in both groups (46% and 37.5% in the PGx-guided group versus 49% and 48% in the control group, respectively), as a result of the average duration of hospitalization [1.51 days (95% CI: 1.23-1.82) for the PGx-guided group and 2.37 days (95% CI: 1.95-2.89) for the control group, resulting in a mean difference of 0.86 days (95% CI: 0.37-1.44). The difference in QALYs gained was 0.00178 (95% CI: 0.00176-0.00180). The ICER was €12,020 (95% CI: €10,957-€13,356) per QALY on average (SD: €116). When comparing cost and effectiveness of actionable PGx-guided versus actionable control patients, the total cost for the PGx-guided group was €491 (95% CI: €384-€613), versus €767 (95% CI: €583-€982) in the control group, with an incremental cost difference of €276 (95% CI: €62-€511), favoring the PGx-guided group. Also, the difference in effectiveness was 0.007 QALYs (95% CI: -0.021 to 0.033). Lastly, the difference in the mean total cost was estimated to be €21.4 (95% CI: €19.5-€23.8), while without considering the PGx test cost, indicative of a pre-emptive genetic testing approach, the PGx-guided treatment becomes a cost-saving option, with an estimated savings of approximately €103.6 (€124-€21.4) per patient.

Interpretation: These data suggest that panel-based PGx testing is cost-effective, which, together with the clinically beneficial outcomes already demonstrated in the PREPARE study, provides additional evidence of the need to implement PGx into clinical practice.

Funding: European Union Horizon 2020.