Oral vinorelbine and continuous low doses of cyclophosphamide in pediatric rhabdomyosarcoma: a real-world study.

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations. Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25-40 mg/m2 for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25-50 mg/m2 daily for 48 consecutive weeks. Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9-117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively. Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients.

Risk factors for totally implantable access ports-associated thrombosis in pediatric oncology patients.

The application of totally implantable access ports (TIAPs) reduces treatment-related discomfort; however, the existence of catheter may cause side effects, with the most common one being the occurrence of TIAPs-associated thrombosis. The risk factors for TIAPs-associated thrombosis in pediatric oncology patients have not been fully described. A total of 587 pediatric oncology patients undergoing TIAPs implantation at a single center over a 5-year period were retrospectively analyzed in the present study. We investigated the risk factors for thrombosis, emphasizing the internal jugular vein distance, by measuring the vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae on chest X-ray images. Among 587 patients, 143 (24.4%) had thrombosis. Platelet count, C-reactive protein, and the vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae were demonstrated to be the main risk factors for the development of TIAPs-associated thrombosis. TIAPs-associated thrombosis, especially asymptomatic events, is common in pediatric cancer patients. The vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae was a risk factor for TIAPs-associated thrombosis, which deserved additional attention.

Occurrence of bisphenol diglycidyl ethers and bisphenol analogs, and their associations with DNA oxidative damage in pregnant women.

Bisphenol diglycidyl ethers (BDGEs) and Bisphenol A and its analogs (bisphenols) may have the same exposure routes and coexposure phenomenon in sensitive populations such as pregnant women. Previous biomonitoring studies on BDGEs are limited. Levels of fifteen bisphenols, six BDGEs and the DNA oxidative damage biomarker 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured in the urine of pregnant women recruited in south China (n = 358). We aimed to provide the occurrence of bisphenols and BDGEs in pregnant women, and to investigate the potential relationship between their exposure and oxidative stress. Bisphenol A, bisphenol S, bisphenol F, bisphenol AP and all BDGEs (except for BADGE·2HCl) were frequently detected. The total concentrations of all bisphenols and BDGEs were 0.402-338 and 0.104-32.5 ng/mL, with geometric means of 2.87 and 2.48 ng/mL, respectively. BFDGE was the most abundant chemical of BDGEs, with a median concentration of 0.872 ng/mL, followed by BADGE·H2O·HCl (0.297 ng/mL). Except for pre-pregnancy obesity, maternal age/height, employment, fasting in the morning and parity did not affect the urinary concentrations of BDGEs. Significant and weak correlations were observed between concentrations (unadjusted) of total bisphenols and BDGEs (r = 0.389, p < 0.01), indicating their similar sources and exposure routes. The biomarker 8-OHdG was detected in all samples, with concentrations ranging from 1.98 to 32.6 ng/mL (median: 9.96 ng/mL). Levels of 8-OHdG were positively correlated with urinary several bisphenol concentrations (adjusted ß range: 0.037-0.089, p < 0.05) but were not correlated with those of BDGEs. Further studies should focus on whether BDGEs and bisphenols exert combined effects on oxidative stress. Our study provided the first BDGEs exposure data in pregnant women and indicated that BDGEs exposure was highly prevalent in pregnant women as early as 2015 in south China.

The Efficacy and Safety of Anlotinib in Pediatric Patients With Refractory or Recurrent Solid Tumors.

Objective: Refractory or recurrent pediatric solid tumors lack effective treatments, and are associated with dismal outcomes. Hence, there is an urgent need for a novel therapeutic strategy. This study aimed to evaluate the efficacy and safety of anlotinib, a novel oral multi-kinase angiogenesis inhibitor, in pediatric patients with refractory or recurrent solid tumors. Methods: This single-institutional, observational retrospective study was conducted in Sun Yat-sen University Cancer Center, China. Refractory or recurrent pediatric solid tumor patients treated with anlotinib between 2018 and 2020 were evaluated. Results: Forty-one and 30 patients were enrolled to evaluate the efficacy and safety of anlotinib, respectively. There was partial response in five patients, stable disease in 22 patients, no patient with complete response, with an objective response ratio of 12.2% (5/41; 95% CI 1.7-22.7). The disease control rate was 65.9% (27/41; 95% CI 50.7-81) and the median progression-free survival was 2.87 months (95% CI 0.86-4.88). The incidence rates of any grade and grade 3-4 adverse events were 80% (24/30) and 23.3% (7/30), respectively. Bleeding (20%, 6/30), hand-foot syndrome (16.7%, 5/30), and diarrhea (13.3%, 4/30) were the most common adverse events. Grade 3-4 adverse events included hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There were no adverse events-related deaths. Conclusion: For heavily pretreated pediatric solid tumors, anlotinib monotherapy and its combination with chemotherapy may be an effective treatment option with tolerable adverse events. It is necessary to monitor blood pressure when using anlotinib in children.

Irinotecan Plus Doxorubicin Hydrochloride Liposomes for Relapsed or Refractory Wilms Tumor.

PURPOSE: The prognosis of relapsed or refractory pediatric Wilms tumor (WT) is dismal, and new salvage therapies are needed. This study aimed to evaluate the efficacy of the combination of irinotecan and a doxorubicin hydrochloride liposome regimen for relapsed or refractory pediatric WT. PATIENTS AND METHODS: The present study enrolled relapsed or refractory pediatric WT patients who were treated with the AI regimen (doxorubicin hydrochloride liposomes 40 mg/m2 per day, day 1, and irinotecan 50 mg/m2 per day with 90-min infusion, days 1-5; this regimen was repeated every 3 weeks) at Sun Yat-sen University Cancer Center from July 2018 to September 2020. The response was defined as the best-observed response after at least two cycles according to the Response Evaluation Criteria of Solid Tumors (RECIST 1.1), and toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03). RESULTS: A total of 16 patients (male:female, 8:8) with a median age of 4.2 years (0.5-11 years) with relapsed or refractory disease were enrolled in this study, including 14 patients with relapsed disease and two patients with refractory disease. These patients received 1-8 courses (median, 3 courses) of the AI regimen. Fourteen patients were assessable for response: two with complete response (CR), five with partial response (PR), two with stable disease (SD), and five with progressive disease (PD). The objective response rate was 50% (two CR, five PR), and the disease control rate was 64% (two CR, five PR, and two SD). Seven out of 14 patients (50%) were alive at the last follow-up, ranging from 2.6 to 32.4 months. The median progression-free survival and median overall survival were 3.5 months (range 0.5-12 months) and 8 months (range 1-28 months), respectively. Sixteen patients were assessable for toxicity, with the most common grade 3 or 4 adverse events being alopecia (62%), leukopenia (40%), abdominal pain (38%), diarrhea (23%), and mucositis (16%), etc. No fatal adverse events have been observed, and modest adverse effects can be administered. CONCLUSION: Irinotecan and doxorubicin hydrochloride liposome regimens have positive efficacy on relapsed or refractory pediatric WT with well-tolerated toxicity. A prospective clinical trial is warranted.

Quality of life and related demographic factors in long-term survivors of childhood non-Hodgkin's lymphoma. / å„¿ç«¥éžéœå¥‡é‡‘æ·‹å·´ç˜¤é•¿æœŸç”Ÿå­˜è€ ç”Ÿæ´»è´¨é‡åŠç›¸å ³äººå£å­¦å› ç´ ç ”ç©¶.

OBJECTIVES: To evaluate the quality of life and related demographic factors in long-term survivors of childhood non-Hodgkin's lymphoma (NHL). METHODS: A retrospective analysis was performed on the medical and demographic data of the NHL patients who received treatment in the Sun Yat-sen University Cancer Center and achieved long-term survival at follow-up, with an age of <18 years at initial diagnosis and a present age of ≥18 years. A questionnaire survey was performed using 36-Item Short-Form Health Survey (SF-36) and the symptom subscale of the Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30). The health status of long-term survivors of NHL was evaluated by comparing the scores of various dimensions of the SF-36 scale of general adult population in the United States (American norm) and those of the SF-36 scale of general adult population in Hong Kong, China (Hong Kong norm). The correlation between the score of each dimension of the scale and demographic characteristics was evaluated. The symptoms of long-term NHL survivors were evaluated according to the score of QLQ-C30 scale. RESULTS: A total of 23 patients with NHL with complete follow-up data were enrolled. The pathological types included diffuse large B-cell lymphoma in 10 patients, Burkitt lymphoma in 4 patients, T-cell lymphoblastoma in 5 patients, B-cell lymphoblastoma in 3 patients, and natural killer/T cell lymphoma in 1 patient. All patients received the chemotherapy regimen containing anthracyclines and alkylating agents. The median present age was 26.2 years (range: 16.9-55.8 years), and the median age at initial diagnosis was 10.4 years (range: 2.4-17.6 years). Among the 23 patients, 6 were married and had children and 2 had chronic diseases. There was no significant difference between the long-term survivors and the US norm in role physical, general health, role-emotional, and mental health (P>0.05), while the long-term survivors had significantly better scores of the other dimensions than the US norm (P<0.05). Similar results were obtained for the comparison between the long-term survivors and the China Hong Kong norm. Age at initial diagnosis was negatively correlated with the scores of social functioning, role physical, and general health in the SF-36 scale (P<0.05), and the present age of patients was positively correlated with the score of physical functioning and was negatively correlated with the score of general health (P<0.05). The urban and rural distribution of patients was related to the general health status (P<0.05). In addition, the long-term survivors of childhood NHL had relatively low scores of the symptom domain of QLQ-C30, and few moderate or severe symptoms were found. CONCLUSIONS: Long-term survivors of childhood NHL tend to have a good overall health status, with no significant differences compared with the general population. Age at initial diagnosis is the main demographic factor that affects patients' quality of life. Citation.

DNA oxidative damage in pregnant women upon exposure to conventional and alternative phthalates.

Exposure to alternative phthalates and related health effects in pregnant women are rarely reported. Nineteen phthalate metabolites and a DNA oxidative damage biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined in urine samples of pregnant women recruited in South China. The detection frequencies and concentration of selected alternative phthalates, i.e., diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP) and di-(2-propylheptyl) phthalate (DPHP) were lower than those of conventional phthalates. However, mono-(6-hydroxy-2-propylheptyl) phthalate, a metabolite of DPHP, was detected in 70% of urine samples (median: 0.13 ng/mL). The estimated daily intakes of conventional plasticizers, including dimethyl phthalate, di-n-butyl phthalate, diisobutyl phthalate and di-(2-ethylhexyl) phthalate (median range: 1.0-3.0 µg/kg_bw/day) were significantly higher than those of DiNP (0.08 µg/kg_bw/day) and DPHP (0.03 µg/kg_bw/day) (p < 0.05). Approximately 24% of pregnant women were at high risk when cumulative risk from exposure to several phthalates was considered. The concentrations of phthalate metabolites and urinary 8-OHdG were significantly correlated with each other (r = 0.206-0.772, p < 0.01), which were further conformed by multiple linear regression analysis (ß = 0.168-0.639, p < 0.01). In addition, conventional phthalates were more strongly correlated with 8-OHdG than alternative phthalates (i.e., DiNP, DPHP), partly suggesting the relatively smaller health effects of alternatives due to their low exposure doses and toxicities. These findings suggested that alternative phthalates have entered the human body from consumer products in the study area, and exposure-related risk of DNA oxidative stress was comparatively lower.

Bioinformatics Analysis and Validation Identify CDK1 and MAD2L1 as Prognostic Markers of Rhabdomyosarcoma.

PURPOSE: The goal of the current study was to identify potential prognostic biomarkers of rhabdomyosarcoma (RMS). MATERIALS AND METHODS: We screened chip sequencing datasets of RMS through the gene expression omnibus (GEO) database. A total of 74 RMS patient tissues and 39 normal muscle cell tissues were analyzed. Limma R software was used to identify the differentially expressed genes (DEGs) between RMS tissues and normal controls. The GO plot R package was used to visualize the results of the GO analysis. We screened for pathaffy package enrichment of DEGs by the Kyoto Encyclopedia of Genes and Genomes (KEGG). The cutoff criterion was a P-value <0.05. Immunohistochemistry (IHC) was applied to validate the expression of CDK1 (cyclin-dependent kinases 1) and MAD2L1 (Mitotic Arrest Deficient 2 Like 1) in RMS. RESULTS: We obtained a total of 498 up- and 480 down-regulated DEGs. The hub genes are mainly involved in the cell cycle and P53 singling pathway. CDK1 expression was associated with tumor size and COG-STS (Children's Oncology Group-soft tissue sarcoma) staging of RMS. For the low CDK1 expression group and high CDK1 expression group, the 5-year overall survival (OS) rate was 83.0% vs 63.5% (P = 0.004), and the 5-year event-free survival (EFS) rate was 47.5% vs 27.5% (P = 0.049) respectively. When compared low MAD2L1 expression group with high MAD2L1 expression group, the 5-year OS rate was 80.0% vs 43.2% (P = 0.001), and the 5-year EFS rate was 45.1% vs 21.8% (P = 0.038), respectively. If patients were divided into three groups: low CDK1 and low MAD2L1 expression group, high CDK1 or high MAD2L1 expression group, and high CDK1 and high MAD2L1 expression group, the 5-year OS rate was 87.1%, 58.6%, 39.6% (P = 0.001), while the 5-year EFS rate of RMS patients was 54.2%, 23.2%, 21.7% (P = 0.028), respectively. CONCLUSION: This study has identified that CDK1 and MAD2L1 were adverse prognostic factors of RMS.

The Efficacy and Safety of Apatinib in Refractory/Relapse Advanced Pediatric Solid Tumor: A Retrospective Study.

BACKGROUND: The prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients. PATIENTS AND METHODS: The study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019. RESULTS: Fifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15-41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65-90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6-5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p>0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related. CONCLUSION: Apatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.

Several environmental endocrine disruptors in beverages from South China: occurrence and human exposure.

Environmental endocrine disruptors (EEDs) in beverages may enter the human body by ingestion and thus may represent a potential health risk. In this study, phthalates, bisphenol A, and its analogues, parabens, benzophenone-type UV filters, and triclosan (TCS) were analyzed in beverage samples (n = 116) collected from local markets in Guangzhou, South China. Twelve of 30 target compounds were found in > 50% samples, and for the first time, TCS was found in a majority of beverages from China (~ 80%). Among all analytes, concentrations of total phthalates (median = 14.4 ng/mL) were generally two orders of magnitude higher than other target EEDs, and concentrations of total benzophenone-type UV filters (0.02 ng/mL) and TCS (0.01 ng/mL) were the lowest. Among all targets, phthalates were predominant, accounting for > 99% of the total EEDs, and dimethyl phthalate was frequently detected in beverages (> 60%). In addition, we estimated the daily intake (EDI) of EEDs for Chinese populations of different age groups based on the daily consumption of beverages. The EDIs of total EEDs were the highest for toddlers (mean = 14,200 ng/kg-bw/day) followed by children and teenagers (3420 ng/kg-bw/day), adults (1950 ng/kg-bw/day), the elderly (1740 ng/kg-bw/day), and infants (70 ng/kg-bw/day). Compared to all food categories, EEDs from beverage consumption accounted for ~ 0.1% (parabens) to 20% (phthalates) of total exposure from diet. However, intakes of phthalates, bisphenols, and TCS from beverages were comparable to those from other potential sources (food, dust, personal care products, cloth, and medicines). Furthermore, the cumulative risks of EEDs by beverage consumption were not high, which indicated that EEDs in beverages might not represent a potential human health risk for Chinese populations.

Occurrence and Ecological Risk Assessment of Eight Endocrine-Disrupting Chemicals in Urban River Water and Sediments of South China.

Chemicals in the water of urban areas are representative of the occurrence of these chemicals in the city surrounding water systems and reflect recent human or industrial usage of those chemicals in the sampling areas. In this study, the levels of eight endocrine-disrupting chemicals [including bisphenol analogues, parabens, and triclosan (TCS)] were determined in urban river water and sediments in Guangzhou, South China, and their related ecological risks were evaluated. The eight target chemicals were frequently detected in our samples, with concentrations ranging from not detected (ND) to 65,600 ng/L and from ND to 492 ng/g dw in river water and sediments, respectively. Among these chemicals, the three most abundant were bisphenol A (BPA) (accounting for 35% of the total amount), methyl paraben (MeP) (23%), and TCS (14%) in river water and BPA (43%), TCS (37%), and MeP (14%) in sediments. Significant correlations were found between most target EDCs, particularly MeP and TCS, in river water and sediments (both p < 0.01), indicating their similar sources and wide usage. The ecological risk assessment methods used suggested that TCS was the chemical of primary concern, with an average hazard quotient (HQ) = 1.57 (up to 11.5) in river water and an average HQ = 0.74 (up to 3.63) in sediments. In addition, the ecological risk assessment of different sampling sites indicated a suspected high-risk level for some sites in the study area.

Urinary phthalate metabolites and environmental phenols in university students in South China.

In China, university students have unique lifestyles compared with the rest of the youth population, as they are almost entirely isolated in campuses. The number of university students is large, and since students represent the future of human reproduction, exposure to environmental endocrine disruptors (EEDs) may have a large impact on society. In this study, levels of several EEDs, including phthalate metabolites, parabens, bisphenol A (BPA) and its analogues, triclosan (TCS), and benzophenone-3, were determined in 169 urine samples collected from university students in Guangzhou, South China. In addition, to further understand the potential sources of EEDs in their daily lives, a survey of students' lifestyles was conducted. Based on the urinary concentrations of EEDs and the survey results, daily exposure doses of target EEDs and their potential sources were investigated. Our results indicated that nine phthalate metabolites, three parabens, and BPA were ubiquitous (detection frequency > 60%) in the urine of university students. The concentrations of total phthalates (median: 99.4 µg L-1) were orders of magnitude higher than those of total parabens (7.30 µg L-1) and of other environmental phenols (0.40 µg L-1). Significantly higher concentrations of phthalates, parabens, and TCS were found in female versus male students, partly due to the higher usage of personal care products (PCPs) by female students (p < 0.05). The estimated daily intakes (EDIs) of phthalates, parabens, BPA, and TCS were 0.46-1.35, 3.29-10.3, 0.007, and 0.67 µg/kg-bw/day, respectively. The EDIs of phthalates and BPA were much lower than those suggested by the European Food Safety guidelines (10, 50, and 50 µg/kg-bw/day for dibutyl phthalate, diethylhexyl phthalate, and BPA, respectively). Our results indicated that university students were widely exposed to EEDs, but at relatively low doses. PCP usage was the main reason for differences in levels of phthalates (especially diethyl phthalate) and parabens between male and female students in South Chinese universities.

Occurrence of bisphenol S in the environment and implications for human exposure: A short review.

As a substitute of bisphenol A (BPA), bisphenol S (BPS) has been applied in consumer products present in our daily lives. With a similar chemical structure as BPA, BPS has also been demonstrated as an exogenous endocrine disrupting chemical. Compared with a large number of studies on BPA, investigation on BPS has remained limited. In this study, we reviewed the literature of BPS mainly published during 2010-2017, including its environmental distributions, toxicities, and human exposure. The data demonstrated that BPS is now ubiquitous in the environment and found worldwide, but generally with concentration levels lower than BPA in various environment media, including water, sediment, sludge, indoor dust and air, consumer products, and human urine. However, we found that the concentration levels of BPS in aquatic environments, especially water samples, were almost comparable or equal to that of BPA. Our summary also indicated that process speed of substituting BPA with BPS in consumer products in the U.S. was relatively faster than other countries. In addition, we summarized the toxicities of exposure to BPS both in vivo and in vitro experiments. The current data supports that exposure to BPS may have adverse effects on reproductive systems, endocrine systems, and nervous systems in animals and humans, and may trigger oxidative stress. The occurrence of BPS was frequently reported in human urine, but rarely in other human samples. The current research indicates that food is the dominant source for human exposure to BPS, and the contribution of personal care product usage is low. The occurrence of BPS and their metabolites in the human body and the guidelines for BPS exposure merit further investigation.