Monitoring pediatric CNS non-germinomatous germ cell tumors via cerebrospinal fluid circulating tumor DNA.

BACKGROUND: Accurate molecular and clinical stratification of patients with central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) remains challenging, impeding the development of personalized therapeutic approaches. Herein, we investigated the translational significance of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) in pediatric NGGCTs to identify characteristic features of CNS NGGCTs and to identify a subset of patients for whom the presence of residual disease is a risk factor and an indicator of shorter progression-free survival (PFS) and overall survival (OS). METHODS: Medical records of patients with CNS NGGCTs between January 1, 2018 and December 31, 2022 were reviewed retrospectively. RESULTS: The cohort consisted of 11 male and six female patients. Tumor markers were elevated in four of the five people who underwent surgery. The remaining 12 patients were diagnosed with malignant NGGCTs according to elevated tumor markers. Among them, ctDNA before chemotherapy as well as ctDNA clearance were consistently associated with PFS and OS (p < .05). By setting a ctDNA positivity threshold of 6%, patients with high ctDNA (above the threshold) levels, which had limitation due to the selection based on optimal statistic from the survival analysis, had significantly inferior 5-year PFS and OS compared to those with low levels (below the threshold). ctDNA or ctDNA clearance combined with the presence of residual disease predicted significantly worse OS and PFS (p < .05). CONCLUSIONS: CSF ctDNA might allow the study of genomic evolution and the characterization of tumors in pediatric NGGCTs. CSF ctDNA analysis may facilitate the clinical management of pediatric NGGCT patients, and aid in designing personalized therapeutic strategies.

Efficacy of intrathecal methotrexate in children with high-risk medulloblastoma over three years: a retrospective study from a single center.

PURPOSE: Chemotherapy is commonly used for treatment in children over three years old with high-risk medulloblastoma(MB). However, little is currently known about the therapeutic benefits and side effects of intrathecal methotrexate(MTX), warranting further research. METHODS: In this retrospective study, patients who received intrathecal MTX during chemotherapy were included in the MTX group (n = 32), and patients that only underwent cerebrospinal fluid (CSF) cytology analysis were assigned to the control group (n = 14). RESULTS: In the MTX group, 27(84.38%) patients had metastatic disease, 3(9.38%) had diffuse anaplasia, and 3(9.38%) had residual disease greater than 1.5 cm2. Molecular subgroup classification was available for 28(87.5%) patients. In the control group, 8(57.14%) patients had metastatic disease, 3(27.27%) had diffuse anaplasia, and 6(42.86%) had residual disease greater than 1.5 cm2. Molecular subgroup classification was available for 6(42.86%) patients. The 5-year progression-free survival was 70.99% and the 5-year overall survival was 72.99% for the MTX group, and the corresponding values were 41.67% and 50% for the control group, respectively. 6 (18.75%) patients in the MTX group with group 4 disease developed MTX-related acute leukoencephalopathy and one of them died. CONCLUSIONS: Our findings support the addition of intrathecal MTX during chemotherapy as the optimal management for children with group 3 and SHH high-risk MB. However, it is not recommended for group 4 MB patients, especially in resource-limited regions. TRIAL REGISTRATION NUMBER: Retrospective registered No.(2020 - 117).

The role of lysine-specific demethylase 6A (KDM6A) in tumorigenesis and its therapeutic potentials in cancer therapy.

Histone demethylation is a key post-translational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Lysine specific demethylase 6A (KDM6A, also known as UTX) is an Fe2+- and α-ketoglutarate- dependent oxidase which belongs to KDM6 Jumonji histone demethylase subfamily, and it can remove mono-, di- and tri-methyl groups from methylated lysine 27 of histone H3 (H3K27me1/2/3). Mounting studies indicate that KDM6A is responsible for driving multiple human diseases, particularly cancers and pharmacological inhibition of KDM6A is an effective strategy to treat varieties of KDM6A-amplified cancers in cellulo and in vivo. Although there are several reviews on the roles of KDM6 subfamily in cancer development and therapy, all of them only simply introduce the roles of KDM6A in cancer without systematically summarizing the specific mechanisms of KDM6A in tumorigenesis, which greatly limits the advances on the understanding of roles KDM6A in varieties of cancers, discovering targeting selective KDM6A inhibitors, and exploring the adaptive profiles of KDM6A antagonists. Herein, we present the structure and functions of KDM6A, simply outline the functions of KDM6A in homeostasis and non-cancer diseases, summarize the role of KDM6A and its distinct target genes/ligand proteins in development of varieties of cancers, systematically classify KDM6A inhibitors, sum up the difficulties encountered in the research of KDM6A and the discovery of related drugs, and provide the corresponding solutions, which will contribute to understanding the roles of KDM6A in carcinogenesis and advancing the progression of KDM6A as a drug target in cancer therapy.

Evaluation of IL-2 and Dexamethasone intracavitary injection on the management of malignant effusion in children with solid tumors or lymphoma.

BACKGROUND: Currently, no available coherent management protocol exists for pediatric cancers associated with pleural effusion, ascites, and pericardial effusion. This study aimed to retrospectively present our experience in treating pediatric cancer patients with pleural effusion, ascites, and pericardial effusion using interleukin-2 (IL-2) and dexamethasone (DEX) intracavitary injections. METHODS: Between January 1st, 2008 and December 31st, 2020, medical reports of patients diagnosed with solid tumors or lymphoma were checked to identify patients diagnosed with > 2 cm pleural effusion, and/or more than grade 1 ascites, and/or more than small pericardial effusion. Patients diagnosed with effusions and treated with IL-2 and DEX were identified as being in the effusion group. Meanwhile, patients with the same primary tumors and effusions but did not receive interleukin 2 and DEX injection were reviewed and classified as the control group. RESULTS: Forty patients with solid tumors and 66 patients with lymphoma were further diagnosed with pleural effusion, ascites, or pericardial effusion. A total of 85 patients received IL-2 and DEX injection while the remaining 21 did not. The Kaplan Meier analysis revealed a significant difference between the two groups, with p < 0.01 for event free survival (EFS) and p < 0.01 for overall survival (OS), both of which had p < 0.01. Hazard ratio was found to be 0.344 for OS and 0.352 for EFS. CONCLUSIONS: This retrospective study illustrates that thoracic, intraperitoneal, or pericardial intracavitary injection of DEX plus IL-2 can be an effective and safe treatment for pediatric cancers with pleural effusion, ascites, and pericardial effusion.

Novel treatment of refractory / recurrent pulmonary hepatoblastoma.

BACKGROUND: There is no consensus about how to manage pulmonary metastasis in patients with hepatoblastoma. We reviewed a treatment with a combination of oxaliplatin, vincristine, and topotecan (OVT) paired with radiofrequency ablation (RFA) of 12 patients with multiple refractory / recurrent pulmonary hepatoblastoma. METHODS: The medical records from patients with ≤21 years of age presenting with multiple deposits (≥2) of refractory / recurrent pulmonary hepatoblastoma were reviewed. The following data were extracted from each patient: age, gender, histological subtyping, cycles of OVT, tumor size, biomarkers, chemotherapy regimen and dosage, RFA details, treatment response, follow up, and patient outcomes. The primary outcome measure was the complete response (CR) of pulmonary diseases, and secondary outcomes were event-free survival rate and overall survival rate. RESULTS: Of 12 assessable patients, three (25%) (95% CI, 46.3-104) patients achieved PR (partial resopnse) after they finished OVT. After RFA, five (41.7%) (95% CI, 8.95-74.4) patients achieved CR (complete response). The 2 year event-free survival rate was 33% (95% CI, 20.5-64.6). The 2 year overall survival for the study group was 41.7% (95% CI, 8.9-74.4). All toxicity events were handled satisfactorily and no toxic related deaths were observed. CONCLUSIONS: Our review report shows that OVT combined with RFA can be a successful treatment modality for previously heavily treated refractory / recurrent pulmonary metastatic lesions from hepatoblastoma.

Unexpected vincristine-induced systemic capillary leak syndrome in patients with Wilm's tumor: A single institution experience.

Capillary leak syndrome (CLS) is a rare but fatal disease, which has been reported following the infusions of interleukin-2, tumor necrosis factor, granulocyte-colony stimulating factor, certain monoclonal antibodies, and gemcitabine, suggesting that drugs can also cause CLS. In this study, seven Wilm's tumor cases with CLS had been presented, which was suggested to be caused following administration of vincristine (VCR). From January 1st, 2014 to December 31st, 2016, medical records from Wilm's tumor patients were reviewed to identify those diagnosed with CLS. Moreover, the following data were extracted for each patient, including age, gender, histological subtyping, tumor stage, risk group, biomarkers, chemotherapy regimen and dosage, surgery details, clinical manifestation of CLS, treatment regimen of CLS, and patient outcomes. From January 1st, 2014 to December 31st, 2016, a total of seven patients with Wilms tumor were identified with a diagnosis of VCR-associated CLS. Typically, for these seven cases in our study, the predominant features of CLS included interstitial pneumonia and pulmonary edema. Moreover, steroid therapy was demonstrated as the most effective therapy in our study. The clinical features of VCR-induced CLS are distinct, and pediatric oncologists should be aware of CLS that manifests as interstitial pneumonia and pulmonary edema during the VCR treatment for patients with Wilm's tumor.

Vincristine and irinotecan in children with relapsed hepatoblastoma: a single-institution experience.

PURPOSE: This study was to determine the efficacy of vincristine and irinotecan in children with relapsed hepatoblastoma (HB). METHODS: A total of 10 patients with relapsed HB were enrolled. Three patients were excluded. Patients received irinotecan 50 mg/m(2)/day, day 1-5 and vincristine 1.5 mg/m(2)/day, day 1, repeated every 3 weeks. The maximum cycles were eight. Reevaluation of tumor was performed every two cycles. The primary outcome was the rate of complete resection. Secondary outcomes were event-free survival (EFS) and overall survival (OS). RESULTS: Of the seven patients assessable for response, one patient with normal AFP level showed a progressive disease and withdrew. He finally died 6 months later. Four had PR, all of them underwent a second surgery and achieved complete resection. Two patients had SD, one patient relapsed 6 months after orthotopic liver transplantation and died, the other one undergoing surgery had micro margin positive, he relapsed again but alive. The rate of complete resection was 71.4% (including orthotopic liver transplantation). The 2-year EFS and OS for the whole group were 57.1% (95% CI, 12.7% to 34.2%) and 71.4% (95% CI, 16.39% to 37.4%), respectively. CONCLUSIONS: The combination of irinotecan and vincristine has a significant antitumor activity and acceptable toxicity in children with relapsed HB.

Single-agent cisplatin treatment of children with high-risk hepatoblastoma.

PURPOSE: The use of neoadjuvant chemotherapy has improved the survival of patients with hepatoblastoma (HB). However, an increased number of treatment complications and toxic deaths, particularly from heart failure, have been observed with doxorubicin treatment. We have applied cisplatin as a single agent to treat children with high-risk HB to improve event-free survival (EFS). METHODS: Between 2007 and 2009, 14 patients with untreated high-risk HB were enrolled in this study. All the patients received a single-agent treatment of cisplatin. The initial cisplatin cycle was administered in a continuous intravenous 24-hour infusion of 80 mg/m/24 h. The primary outcome was the rate of complete resection. Secondary outcomes were EFS and overall survival (OS). RESULTS: Eleven patients (78.6%) had an overall partial response. Two patients (14.3%) had stable disease. One patient experienced (7.1%) progression. Of the 4 patients who presented with lung metastases initially, 1 patient achieved complete response, 2 patients achieved partial response, and 1 patient experienced progression during preoperative chemotherapy. The complete resection rate was 78.6% (95% CI, 49%-95%). The Kaplan-Meier estimates of 2-year EFS and OS for the whole group were 64.3% (95% CI, 35%-87%) and 85.7% (95% CI, 57%-98%), respectively. The 2-year EFS and OS rates of patients who achieved complete resection were 81.8% (95% CI, 48%-98%) and 100% (95% CI, 62%-100%), respectively. CONCLUSIONS: The single-agent cisplatin had less toxicity than cisplatin plus doxorubicin and achieved an equal rate of complete resection in high-risk HB compared with conventional multiagent chemotherapy.

Diffuse lung metastases in a child with blastic plasmacytoid dendritic cell neoplasm and review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, highly aggressive hematopoietic malignancy, characterized by cutaneous and bone marrow involvement and leukemic spread. Cutaneous involvement is the most common presentation in BPDCN. At present, the diagnosis and management of BPDCN are still challenging. Due to its rarity, the pediatric experience with BPDCN is especially limited. Herein, we report a special case of BPDCN with diffuse nodular lung metastases and a cutaneous lesion, which achieved a dramatic response to non-Hodgkin lymphoma regimen and remained with complete remission for 2 years. To date, acute lymphoblastic leukemia (ALL)-type chemotherapy followed by hematopoietic stem cell transplantation (SCT) is commonly thought to be related to a favorable outcome in adults with BPDCN. In contrast to it, ALL or non-Hodgkin lymphoma-type therapy alone seems enough in children with BPDCN with or without cutaneous lesions. SCT should only be performed for children who relapse and achieve a second remission. For pediatric BPDCN, further study of larger numbers of cases is needed to better define prognostic factors and optimal treatment strategy, and understand the underling differences in pathogenesis between children and adults.

Paeoniflorin Coordinates Macrophage Polarization and Mitigates Liver Inflammation and Fibrogenesis by Targeting the NF-[Formula: see text]B/HIF-1α Pathway in CCl4-Induced Liver Fibrosis.

Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl4. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl2 to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200[Formula: see text]mg/kg) or YC-1 (2[Formula: see text]mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl4-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF-[Formula: see text]B/HIF-1[Formula: see text] signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway.

SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the most common mood disturbances worldwide. The Si-ni-san formula (SNS) is a famous classic Traditional Chinese Medicine (TCM) widely used to treat depression for thousands of years in clinics. However, the mechanism underlying the therapeutic effect of SNS in improving depression-like behaviors following chronic unpredictable mild stress (CUMS) remains unknown. AIM OF THE STUDY: This study aimed to investigate whether SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy in vitro and in vivo. STUDY DESIGN AND METHODS: In vivo, mice were exposed to CUMS for 42 days, and SNS (4.9, 9.8, 19.6 g/kg/d), fluoxetine (10 mg/kg/d), 3-methyladenine (3-MA) (30 mg/kg/d), rapamycin(1 mg/kg/d), and deferoxamine (DFO) (200 mg/kg/d) were conducted once daily during the last 3 weeks of the CUMS procedure. In vitro, a depressive model was established by culture of SH-SY5Y cells with corticosterone, followed by treatment with different concentrations of freeze-dried SNS (0.001, 0.01, 0.1 mg/mL) and rapamycin (10 nM), NCOA4-overexpression, Si-NCOA4. After the behavioral test (open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST), dendritic spines, GluR2 protein expression, iron concentration, and ferritinophagy-related protein levels (P62, FTH, NCOA4, LC3-II/LC3-I) were tested in vitro and in vivo using immunohistochemistry, golgi staining, immunofluorescence, and Western blot assays. Finally, HEK-293T cells were transfected by si-NCOA4 or GluR2-and NCOA4-overexpression plasmid and treated with corticosterone(100 µM), freeze-dried SNS(0.01 mg/mL), rapamycin(25 nM), and 3-MA(5 mM). The binding amount of GluR2, NCOA4, and LC3 was assessed by the co-immunoprecipitation (CO-IP) assay. RESULTS: 3-MA, SNS, and DFO promoted depressive-like behaviors in CUMS mice during OFT, SPT, FST and TST, improved the amount of the total, thin, mushroom spine density and enhanced GluR2 protein expression in the hippocampus. Meanwhile, treatment with SNS decreased iron concentrations and inhibited NCOA4-mediated ferritinophagy activation in vitro and in vivo. Importantly, 3-MA and SNS could prevent the binding of GluR2, NCOA4 and LC3 in corticosterone-treated HEK-293T, and rapamycin reversed this phenomenon after treatment with SNS. CONCLUSION: SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy.

Berberine as a potential agent for breast cancer therapy.

Breast cancer (BC) is a common malignancy that mainly occurred in women and it has become the most diagnosed cancer annually since 2020. Berberine (BBR), an alkaloid extracted from the Berberidacea family, has been found with broad pharmacological bioactivities including anti-inflammatory, anti-diabetic, anti-hypertensive, anti-obesity, antidepressant, and anticancer effects. Mounting evidence shows that BBR is a safe and effective agent with good anticancer activity against BC. However, its detailed underlying mechanism in BC treatment remains unclear. Here, we will provide the evidence for BBR in BC therapy and summarize its potential mechanisms. This review briefly introduces the source, metabolism, and biological function of BBR and emphasizes the therapeutic effects of BBR against BC via directly interacting with effector proteins, transcriptional regulatory elements, miRNA, and several BBR-mediated signaling pathways. Moreover, the novel BBR-based therapeutic strategies against BC improve biocompatibility and water solubility, and the efficacies of BBR are also briefly discussed. Finally, the status of BBR in BC treatment and future research directions is also prospected.

Treatment of Neuroblastoma with a Novel Delayed Intensification Chemotherapy.

OBJECTIVES: To test the feasibility of adding a novel delayed intensification chemotherapy to a dose-intensive induction regimen chemotherapy for high-risk neuroblastoma. METHODS: Patients enrolled in this study received chemotherapy in accordance with the design of the NB97 trial. At the end of the therapy, patients received three cycles of delayed intensification chemotherapy. The delayed intensification chemotherapy consists of two A1 and one A2 cycle. The A1 cycle consists of 1.5 mg/m2 of vincristine on day 1, 1.2 g/m2 of cyclophosphamide on day 2, 100 mg/m2 of cisplatin on day 3, and 160 mg/m2 of etoposide on day 4. The A2 cycle is similar to the A1 cycle, however the only difference is that on day 4, 30 mg/m2 of doxorubicin is substituted for etoposide. RESULTS: Between 2007 to 2011, a total of thirty-six patients were enrolled, sixteen patients were long term event-free survivors. Three patients were alive with tumor whilst fifteen patients died. The 3-year Event free survival (EFS) and Overall survival (OS) were 44.4% (95%CI, 27.4 to 61.5%) and 50% (95%CI, 32.8 to 67.2%) respectively. CONCLUSIONS: A high rate of survival among patients with high-risk neuroblastoma was achieved with delayed intensification chemotherapy without the occurrence of a second malignancy.

Different Kinds of Paraneoplastic Syndromes in Childhood Neuroblastoma.

BACKGROUND: Clinical presentations of paraneoplastic syndromes in neuroblastoma may multiply. Review of the clinical data and the literature on this syndrome may help in the diagnosis of neuroblastoma. OBJECTIVES: In order to make more accurate diagnosis, we reviewed the clinical data and the literature on this syndrome. PATIENTS AND METHODS: Between April 2007 and April 2012, 68 children were diagnosed with neuroblastoma or ganglioneuroblastoma in our institution, 9 of which presented exclusively with paraneoplastic syndromes and were not treated with chemotherapy prior to diagnosis. After the diagnosis, all patients received chemotherapy and operation on NB97 protocol. RESULTS: Among 68 pediatric patients with neuroblastoma or ganglioneuroblastoma, 4 (5.9%) patients suffered from neurological complications at diagnosis, 2 (2.9%) patients had digestive tract disorders, 2 (2.9%) patients had immune diseases, and 1 (1.5%) suffered from hematological disorder (without bone marrow involvement). All paraneoplastic syndrome patients achieved complete remission on paraneoplastic syndrome before completion of chemotherapy. CONCLUSIONS: Neuroblastoma may present with a range of non-specific neurologic symptoms in addition to the well-known opsoclonus-myoclonus syndrome and cerebellar ataxia. In any case, the presence of unexplained neurologic manifestations and other common clinical presentations such as rash, constipation, diarrhea, and especially immune disorders in an otherwise healthy child had raised the possibility of paraneoplastic syndrome due to the presence of an undiagnosed tumor.