Melanoma is a highly aggressive skin cancer with poor prognosis, often linked to excessive UV exposure. Despite advancements in immunotherapy and targeted treatments, melanoma's invasiveness and metastatic potential remain significant challenges. This study aimed to identify novel molecular targets associated with melanoma progression. Consensus clustering analysis revealed three melanoma subtypes, with the C3 subtype exhibiting the worst prognosis. Weighted gene co-expression network analysis (WGCNA) identified FOXQ1 as a key driver in this subtype. FOXQ1 expression was elevated in clinical melanoma tissues and cell lines, and silencing FOXQ1 in vitro reduced melanoma cell proliferation, migration, and induced apoptosis. To explore its downstream targets, FOXQ1 was found to repress the expression of SSBP2, a gene inversely correlated with FOXQ1. Functional assays demonstrated that silencing SSBP2 promoted melanoma malignancy. Rescue experiments showed that knockdown of SSBP2 reversed the tumor-suppressive effects of FOXQ1 silencing. These results suggest that the FOXQ1/SSBP2 regulatory axis plays a critical role in melanoma progression and may serve as a potential therapeutic target to improve melanoma treatment outcomes.

Introduction Metastatic uterine sarcomas are aggressive malignancies with poor outcomes and a scarcity of real-world data. Methods This retrospective study collected data from patients treated over eight years, from January 2018 to December 2025. The included patients had histopathologically confirmed sarcoma arising from the uterus who were deemed unresectable or were metastatic and treated with palliative intent. Results Twenty-eight patients were included in the final analysis, and 23 received first-line treatment. High-grade endometrial stromal sarcomas (HG-ESS) and uterine leiomyosarcomas (ULMS) were the most common histologies. The most common metastatic sites were the pelvis/peritoneum (60.7%) and lungs (57.1%). Anthracycline-based regimens, with or without ifosfamide and gemcitabine, plus docetaxel, were the most common first-line regimens. Disease control rate (DCR) was 13/23 (56.52%). Overall survival (OS) for the whole cohort was five months (95% confidence interval (CI): 0.8-9.2 months). By histologic subtype, HG-ESS had the shortest median OS at four months (95% CI: 1.84-6.12 months), whereas ULMS had the best prognosis, with a median OS of 11 months (95% CI: 2.35-19.65 months). Patients on best supportive care had a median OS of one month, whereas those receiving any treatment had a median OS of 10 months (95% CI: 5.9-14 months) (p<0.001). Patients with a maximum tumor dimension of less than 10 cm had significantly better OS than those with more than 10 cm (10 months (95% CI: 4.8-15.2 months) versus five months (95% CI: 2.6-7.4 months); p=0.031). Conclusion The prognosis of metastatic uterine sarcomas remains dismal. Further studies are needed to identify the optimal treatment and sequencing while incorporating molecular classification, especially for HG-ESS.

The liver and kidneys are essential for drug metabolism and clearance and are highly sensitive to toxicity. Most in vitro models assess these organs in isolation, limiting the study of inter-organ interactions. Here, an induced pluripotent stem cell (iPSC)-derived kidney-liver organ-on-a-chip model was developed that co-cultured hepatocyte-like cell (HLC) organobodies and proximal tubular-like cells (PTL) under microfluidic flow. In parallel, a PTL-HepaRG spheroid co-culture model was established to investigate bioactivation of the prodrug ifosfamide. Co-culture induced distinct transcriptional responses in PTL and HLC, as revealed by gene set enrichment analysis. In PTL, co-culture with HepaRG enriched signaling and cell polarity pathways, while co-culture with HLC enhanced metabolic and transport-related programs. In HLC, co-culture with PTL affected intermediary metabolism, lipid processing, redox regulation, and plasma protein synthesis. The PTL-HepaRG model demonstrated bioactivation of ifosfamide into metabolite chloroacetaldehyde, highlighting the utility of these systems for studying human-relevant kidney-liver interactions and drug metabolism in vitro. However, the concentration of chloroacetaldehyde was too low to cause adverse effects in the renal tissue in the current setup.

Microscopically positive surgical margins (R1) complicate 15-30% of soft tissue sarcoma (STS) resections and independently worsen local recurrence and overall survival, yet no randomised trial has targeted the R1 population; we recommend risk-adapted management directed by a multidisciplinary team at a specialist sarcoma centre. Decision-making should integrate histological subtype, tumour grade, anatomical site, margin context, and individualised prognostic risk estimated by validated nomograms such as Sarculator and PERSARC. Planned positive margins on critical anatomical structures, most often encountered in retroperitoneal sarcoma, do not mandate re-excision, as local recurrence rates approximate those of R0 resection, and management should proceed directly to histotype-tailored adjuvant radiotherapy where indicated. Inadvertent positive margins after unplanned or non-specialist excision carry a substantially higher local recurrence risk and warrant re-excision whenever secondary R0 is achievable without prohibitive morbidity, followed by adjuvant radiotherapy in high-grade or deep tumours. When further surgery is not feasible, adjuvant radiotherapy alone remains the standard adjunct and substantially reduces local recurrence in extremity STS. Adjuvant anthracycline-ifosfamide chemotherapy should be considered in patients identified as high-risk by validated nomograms, in whom R1 status is the strongest predictor of survival benefit. Active surveillance with structured imaging follow-up is a reasonable option for small, low-grade R1 tumours at sites of prohibitive re-excision morbidity. Referral to a specialist sarcoma centre before any initial intervention remains the single most impactful measure to reduce R1 incidence and optimise oncological outcomes and should be regarded as the overarching standard of care.

Ifosfamide is a chemotherapeutic agent used to treat aggressive solid tumors, but nephrotoxicity is a serious adverse effect and a risk factor for chronic kidney disease. Isophosphoramide mustard is the therapeutically active metabolite, whereas chloroacetaldehyde (CAA) is considered the nephrotoxic metabolite. The kidney injury predominantly affects the proximal tubule and has been linked to mitochondrial defects, although the cellular mechanisms remain incompletely understood. Here, we review the evidence for mitochondrial involvement and discuss potential therapeutic interventions. CAA is thought to disrupt oxidative phosphorylation, leading to ATP depletion and increased reactive oxygen species formation, which ultimately contributes to mitochondrial dysfunction. Additionally, CAA has been shown to interact with essential thiols such as glutathione and coenzyme A, and has been reported to impair lipid, protein metabolism and glucose synthesis. Collectively, these processes might contribute to tubulointerstitial nephritis, cellular senescence, and necrosis. Preclinical therapeutic interventions to prevent ifosfamide-induced nephrotoxicity have focused on protecting mitochondrial function and mitigating oxidative stress. These data indicate that antioxidants and glutathione precursors may reduce toxicity markers and preserve kidney histological structure. Ifosfamide-induced nephrotoxicity remains a clinical challenge as its mitochondrial mechanisms are not fully understood. To address this, we recommend investigating genetic susceptibility, and determining mitochondrial pathways, such as disrupted mitochondrial dynamics, mitochondrial DNA damage, and dysregulated energy signaling, through integrated molecular, functional, and metabolomic analyses in human-derived in vitro models. Additionally, we recommend evaluating nephroprotective strategies, including antioxidants, mitochondrial transplantation, and therapies that stimulate mitochondrial biogenesis, to identify interventions that prevent kidney injury while preserving antitumor efficacy.

Bleomycin, etoposide, and cisplatin (BEP) remains the cornerstone of curative first-line treatment for metastatic germ cell tumors (GCTs) across all prognostic risk groups. Although etoposide-cisplatin (EP) and etoposide-ifosfamide-cisplatin (VIP) are validated alternatives in selected clinical scenarios, oncologic efficacy among standard first-line cisplatin-based regimens is largely comparable within their respective indications. Consequently, treatment selection is increasingly driven by differences in toxicity profiles rather than antitumor effectiveness. Bleomycin exposure distinguishes BEP from other cisplatin-based regimens and underlies its distinct spectrum of adverse effects. Among these, pulmonary toxicity is the most clinically consequential and potentially irreversible complication. Bleomycin-induced pulmonary toxicity is characterized by marked interindividual variability, clinically significant toxicity occurring even at relatively low cumulative exposure despite cumulative dose remaining an important risk factor, and clinically meaningful morbidity and mortality in a predominantly young and otherwise curable population. Accumulating evidence indicates that bleomycin lung injury represents an immune-mediated process driven by dysregulated alveolar-immune crosstalk, innate immune activation, and profibrotic signaling. This review provides a toxicity-focused comparison of standard first-line cisplatin-based regimens used in the curative treatment of metastatic GCTs, particularly BEP, EP, and VIP regimens within the framework of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification and repositions bleomycin pulmonary toxicity as a model of immune-mediated chemotherapy toxicity. We integrate clinical and experimental data on immunopathogenesis and discuss emerging biomarkers of alveolar injury and immune activation, as promising investigational tools that require prospective validation before routine implementation in first-line treatment selection or pulmonary toxicity monitoring.

Objective: To evaluate the efficacy and safety of brentuximab vedotin (BV) combined with the IGE regimen (ifosfamide, gemcitabine) in the treatment of children's relapsed or refractory classic Hodgkin lymphoma (cHL). Methods: In this case series study, clinical data including age, sex, symptoms, pathological sub-type, clinical stage, previous clinical stage and treatment of the relapsed or refractory cHL children diagnosed and treated at Beijing Children's Hospital Affiliated to Capital Medical University from June 2022 to August 2025 were collected. All 23 children received 1 to 4 cycles of chemotherapy with BV plus the IGE regimen. Children were followed up until December 31[st], 2025, and infusion reactions during treatment and adverse reactions after administration were recorded. Results: Among 23 children, there were 16 males and 7 females, the age was 14.8 (12.1, 16.7) years, and there were 3 children of refractory and 20 children of relapsed cHL. Pathological sub-types included 13 children of nodular sclerosis, 1 child of lymphocyte depletion, 7 children of mixed cellularity, and 2 children of lymphocyte-rich type. At initial diagnosis, 3 children presented with stage Ⅱ, 8 with stage Ⅲ, and 12 with stage Ⅳ. All 23 children received chemotherapy, among whom 14 had prior radiotherapy, 3 had programmed death 1 inhibitor treatment (1 of whom underwent autologous hematopoietic stem cell transplantation). At relapse or refractory disease, clinical stage was stage Ⅱ in 5 children, stage Ⅲ in 4 children, and stage Ⅳ in 14 children. A total of 84 cycles of BV combined with IGE regimen chemotherapy were administered. All children received involved-field radiotherapy after chemotherapy. Twenty-one children avoided hematopoietic stem cell transplantation, and 3 received single-agent BV maintenance therapy. All 22 evaluable children achieved a treatment response after 2 cycles of chemotherapy, and 14 (64%) achieved complete metabolic response (CMR). The follow-up time was 15 (9, 24) months; all 23 children achieved event-free survival, with an overall CMR rate of 91% (21/23). A total of 144 cases of grade 3 or above adverse events were recorded, predominantly myelosuppression, and none of which affected subsequent sequential treatment. Serum immunoglobulin levels (IgA, IgG, IgM) in children remained within the normal range before and after treatment. The pre-treatment total B-cell count was 166×10[6] (38×10[6], 259×10[6])/L, which decreased to 17×10[6] (5×10[6], 21×10[6])/L during treatment and recovered to 214×10[6] (142×10[6], 266×10[6])/L at 3 months post-chemotherapy. Both natural killer cells and total T-cell counts were reduced at baseline, declined further during therapy, and returned to pre-treatment baseline levels at 6 months and 9 months after chemotherapy, respectively. Conclusion: BV combined with the IGE regimen has demonstrated marked efficacy and a favorable tolerable safety profile in the treatment of relapsed or refractory cHL in children while reducing the proportion of patients requiring hematopoietic stem cell transplantation.

Objective: To evaluate the efficacy of different chemotherapy regimens in children with high-risk hepatoblastoma (HB). Methods: A retrospective cohort study was conducted on 99 patients under 18 years old with high-risk HB treated at Sun Yat-sen University Cancer Center between December 2004 and July 2024. The patients were divided into three groups: the PLADO regimen (cisplatin in combination with doxorubicin, n=27), the C5VD/IIV regimen (alternating cycles of cisplatin/5-flourouracil/vincristine/doxorubicin with irinotecan/ifosfamide/vincristine, n=29), and the modified SIOPEL-4 regimen (the original SIOPEL-4 regimen with omitted high-dose cisplatin on day15, n=43). Short-term efficacy, adverse effects, and long-term survival were compared among the three groups. Results: The objective response rates for the PLADO, C5VD/IIV, and modified SIOPEL-4 groups were 73.9% (17/23), 70.8% (17/24), and 88.6% (31/35), respectively, with no statistically significant difference among the three groups (P=0.190). The disease control rates were 82.6% (19/23), 83.3% (20/24), and 100.0% (35/35), the 3-year progression-free survival (PFS) rates were 19.2%, 37.0%, and 56.7%, and the 3-year overall survival (OS) rates were 69.2%, 55.6%, and 79.0%, respectively. The modified SIOPEL-4 group showed significantly better disease control rate and PFS rate compared withthe other two groups (both P＜0.05). After merging the PLADO and C5VD/IIV groups, the modified SIOPEL-4 group demonstrated significantly superior PFS and OS rates (both P＜0.05). Conclusions: The efficacy of modified SIOPEL-4 regimen in treating high-risk HB is superior compared with those of PLADO and C5VD/IIV regimens, but there remains room for further improvement in efficacy. Intensifying supportive care and pursuing aggressive local therapies, especially upfront liver transplantation for locally inoperable tumors, may further improve outcomes.