bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib/IIa study of sustained release lipid inhalation targeting cisplatin by inhalation in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung
Authors: Chou A. J. , Bell M. D. , Mackinson C. , Gupta R. , Meyers P. A. , Gorlick R. 
Published: March 2020

9525 Background: Pulmonary relapse is the most common site of relapse for patients with osteosarcoma (OS). Few therapeutic options are available for these patients. By encapsulating the drug within liposomes, sustained release lipid inhalation targeting (SLIT) cisplatin is a novel sustained-release formulation of cisplatin designed for administration via inhalation, thereby targeting the lungs with little systemic exposure. Methods: A two-center, open-label, phase Ib/IIa study was designed to characterize the safety and efficacy of SLIT cisplatin in patients with OS metastatic to the lung. Two dose levels were utilized: 24 mg/m2/dose, and 36 mg/m2/dose. Study drug was administered via nebulizer once every two weeks. OS patients with only pulmonary relapse were eligible. Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Response was evaluated radiographically according to the World Health Organization criteria after every 2 cycles. When clinically indicated, metastasectomy was undertaken in patients on study after 2 cycles, and levels of SLIT cisplatin were measured in tumor samples upon metastasectomy. Results: Fourteen patients have been treated on study. SLIT cisplatin has been well tolerated in heavily pre-treated patients who have received multiple cycles of therapy, including one patient, approaching cumulative doses of 840 mg of SLIT cisplatin over one year and a second patient receiving 1,020 mg. Specifically, no patients have experienced hematologic toxicity, nephrotoxicity or peripheral neuropathy. Nausea (= grade 3) was attributed to study drug in 5 patients. Respiratory symptoms (= grade 3) were attributable to study drug in 4 patients. No adverse events required discontinuation of study drug. Two patients are pulmonary disease free one year after initiation of therapy. Conclusions: SLIT cisplatin is well tolerated in patients with pulmonary relapse of OS. Two of 14 patients are pulmonary disease free one year after initiation of therapy. SLIT cisplatin provides a novel therapeutic modality for patients with pulmonary relapse of OS, and warrants further study. No significant financial relationships to disclose.
Vancomycin-resistant enterococcus (VRE) in pediatric oncology patients: An analysis of potential consequences of colonization and infection
Authors: Dunkel I. J. , Kosack A. , Riedel E. , Kiehn T. E. , Small T. N. , Wexler L. H. 
Published: March 2020

9537 Background: VRE colonization and infection have emerged as an issue for pediatric oncology patients, but little is known about the long-term risks following initial VRE positivity in this population. The purpose of this study was to determine the risk of subsequent VRE infection in colonized or infected pediatric oncology patients and to try to identify risk factors. Methods: A retrospective analysis was performed of the 57 pediatric oncology patients who had a positive VRE culture at MSKCC from 1996–2000 and subsequently received chemotherapy and/or radiation therapy. Patients whose only subsequent treatment was allogeneic stem cell transplantation were excluded. The incidence of subsequent VRE infection was calculated using a competing risk analysis accounting for death from non-VRE causes as a competing risk. Data regarding hypothesized risk factors for subsequent VRE infections were collected. Results: Ten of the 57 patients had subsequent VRE infection, but none was the primary cause of death. The cumulative incidence of subsequent infection was 14% (7–27%, 95% confidence interval) at 1 year and 16% (9–29%, 95% confidence interval) at 2 years. Eight developed their subsequent infection within 3 months; the other 2 occurred at 15 and 30 months. A formal analysis of risk factors was not attempted due to the small number of events; however, none of the hypothesized risk factors (initial VRE colonization versus infection, number of chemotherapy or radiation therapy regimens, number of neutropenic or mucositis episodes, number of hospitalizations, number of abdominal surgeries or stem cell transplantations) appeared to differ between those who developed a subsequent infection and those who did not. Conclusions: Pediatric oncology patients with VRE colonization or initial infection are at risk for subsequent VRE infection, particularly within the first 3 months of initial diagnosis of VRE positivity. No significant financial relationships to disclose.
Cloning and characterization of the sympathetic nervous system mutant, Sym3, in zebrafish
Authors: George R. , Lee J. , Stewart R. , Bayul T. , Campisi N. , Olale F. , Schier A. , Kanki J. , Look A. T. 
Published: March 2020

9541 Background: Neuroblastoma (NB) is a neural crest tumor manifesting in the adrenal gland and the sympathetic ganglia. The goal of this project was to use the zebrafish model to identify genes involved in the development of the peripheral sympathetic nervous system (PSNS). We used the expression of tyrosine hydroxylase (TH) in the cervical sympathetic ganglion (cervical complex, CC), as a marker for PSNS development. TH expression can be observed by whole-mount RNA in situ hybridization in 2–3-day zebrafish embryos in the CC. Methods: In an ethyl nitrosourea mutagenesis screen for mutations that affect PSNS development, we identified a putative mutant, Sym3, showing a change in modeling of the TH staining cells in the region of the CC. Results and Conclusion: The TH-positive cells were scattered rather than conglomerated together as is typical of cells in the normal CC. The mutant was also characterized by a “curly-tail” phenotype. After the mutation was recovered from the F3 generation, heterozygous pairs harboring the mutation were identified. Using genome wide scanning PCR assay, linkage of the Sym3 mutation to microsatellite markers z9704 and z1351, located on Linkage Group 1, was established. Complementation assays were performed with other known “curly tail” mutants in the genetic interval, which revealed that Sym3 and a previously described vic mutant were in the same complementation group. The vic mutant is characterized by curved body axis, left to right asymmetry and kidney cysts and results from a mutation in the ARL13b gene, a protein of the Ras superfamily involved in intracellular trafficking and cilial motility. The vic mutation is a C to A transition at position 104 in the second exon of the open reading frame (T35L). The ARL13b gene in Sym3 has a four aa insertion at the 5’ end of the 4th exon of the coding region.The mutant Sym3 phenotype can be rescued by overexpression of the normal ARL13b gene. The vic mutant showed defective cilia formation in the kidney. However, immunocytochemistry showed normal cilia in the Sym3 mutant, suggesting that the Sym3 allele of ARL13b affects the development of alternative tissues during development, such as the aggregation of sympathetic neurons into discrete ganglia. Further functional characterization of the Sym3 mutation is ongoing. No significant financial relationships to disclose.
Long-term complications of neuroblastoma: A report from the Childhood Cancer Survivor Study
Authors: Laverdiere C. , Liu Q. , Yasui Y. , Nathan P. C. , Gurney J. , Stovall M. , Diller L. , Cheung N. K. , Wolden S. , Robison L. L. , Sklar C. A. 
Published: March 2020

9544 Background: Neuroblastoma (NB) survivors can develop many complications from their treatment. We evaluated long-term morbidity and mortality in a large cohort of NB survivors. Procedures: Late effects data from 5-year NB survivors diagnosed between 1970–1986 enrolled in the Childhood Cancer Survivor Study (CCSS) were collected from self-administered questionnaires. 832 survivors and 3,899 siblings were included. Treatment data were abstracted from the medical records of all survivors. Late mortality, second malignant neoplasm (SMN), and chronic health conditions were analyzed in relation to treatment factors. Results: 42 survivors (6%) died more than 5 years after their diagnosis (standardized mortality ratio [SMR]:4.8; 95% CI 3.5–6.5). Causes of death included: disease recurrence (n=23), SMN (n=6) (SMR: 8.5; 95% CI 3.1–18.4), cardiac (n=1) (SMR 2.9; 95% CI 0.04–16.0), pulmonary (n=1) (SMR 4.8; 95% CI 0.1–26.5), external causes (n=4), other and unknown (n=11). 33 developed a SMN (standardized incidence ratio [SIR] 8.6; 95% CI 5.9–12.1): thyroid (n=7), renal (n=6), soft tissue sarcomas (n=3), acute myeloid leukemia (n=2), breast cancer (n=2) and other (n=13). Exposure to radiation therapy (RT) (p=0.003) and to VP-16 (p=0.04) were significant risk factors for SMN. 38% of the survivors reported at least one chronic health condition. Compared to siblings, they were more likely to report any chronic condition (risk ratio [RR] 14.7; 95% CI, 12.4–17.6). The most common prevalent conditions included: musculoskeletal (RR 49.8; 95% CI, 27.9–88.8), endocrine (RR 36.2; 95%CI 24.1–54.5), sensory (RR 21.5; 95%CI, 14.6–31.7) and neurological (RR 13.1; 95% CI 10.8–16). A multivariable Poisson regression analysis revealed the following associations: laminectomy (RR 8.6; 95% CI 3.5- 21) and chest RT (RR 2.8; 95% CI 1.3–6.5) as risk factors for scoliosis; age < 1 year at diagnosis (RR 1.9; 95% CI 1.4–2.6) and laminectomy (RR 3.5; 95% CI 2.4–5.3) for neurological complications; for hearing loss, increasing cumulative dose of cisplatin (for ≥ 600 mg/m2 RR 52.8; 95% CI 10.2–272.5); and RT to the neck (RR 6.6; 95% CI 2.4–18) for hypothyroidism. Conclusions: NB survivors are at risk of developing chronic conditions. Long-term surveillance is required for early detection of these complications. No significant financial relationships to disclose.
Both age and location predict survival in childhood ependymoma: A SEER study
Authors: McGuire C. S. , Cobb K. L. , Fisher P. G. 
Published: March 2020

9545 Background: Supratentorial (SUP) ependymoma in childhood has been reported in studies with limited samples to carry improved overall survival (OS) compared to infratentorial (INF) tumors, with spinal (SPI) ependymoma having the best outcome. Moreover, radiation therapy (XRT) for INF tumors has been considered standard of care, though there have been case reports of children treated successfully without XRT. Thus, we aimed to examine how age, gender, location, XRT and race influence OS in childhood ependymoma by rigorous analysis of a large registry. Methods: We queried the Surveillance Epidemiology End Results (SEER) registry from 1973 to 2003, strictly defining ependymomas by histology (ICD-O-3: 9391–9394). ICD-0–2 site codes, when available, were used to distinguish SUP, INF, and SPI tumors. OS was compared by age, gender, race, location, and XRT, using Kaplan-Meier analysis with logrank tests in SPSS 12.0 (Chicago, IL). Cox regression incorporated all significant covariates from univariate analysis. A similar analysis was conducted to determine whether findings differed in adults. Results: 635 children <18 years at diagnosis were identified (265 females; 510 whites, 77 blacks; 106 SUP, 193 INF, 55 SPI) with 5-year OS 57.1% ± standard error 2.3%. With univariate analysis, OS did not differ by gender or race. For location, 5-year OS did not differ between SUP 59.5% ± 5.4% and INF 57.1% ± 4.1%, but was significantly better for SPI 86.7% ± 5.2%. With multivariate analysis, location and age remained significant predictors for OS, with younger children having worse outcome. A similar multivariate analysis in 1388 adults again showed age and location to be significant. Adults fared better than children (logrank p <0.0001). XRT of INF tumors was associated with significantly improved OS in children (logrank p <0.018), but did not lead to an OS difference among adults. Conclusions: Age and location directly influence OS in childhood ependymoma. SPI tumors are associated with a significantly better prognosis than other ependymomas. This study could not show a difference in OS between SUP and INF tumors, proposed recently to have different stem cell origins. SPI tumors may represent a distinct biological entity. Curiously, XRT is associated with improved OS in pediatric, but not adult, INF ependymomas. No significant financial relationships to disclose.
Characteristics and outcome of patients (pts) enrolled on phase I trials: A report from the Pediatric Oncology Branch, NCI
Authors: Kim A. , Fox E. , Warren K. , Blaney S. , Berg S. , Adamson P. , Libucha M. , Byrley E. , Balis F. , Widemann B. 
Published: March 2020

9550 Background: Knowledge of the characteristics and outcomes of pts enrolled on pediatric phase I trials may aid in the design of future phase I trials and selection of pts. Methods: Pre-enrollment characteristics and treatment outcomes (toxicity, response, survival) were retrospectively analyzed from pts with refractory solid tumors enrolled in 16 phase I trials with similar eligibility criteria from 1992 to 2005. The relationship between patient characteristics and dose-limiting toxicity (DLT) was evaluated using multivariate analysis. Results: Of 262 pts (62% M, 38% F) eligible for analysis, 147 were on trials of myelosuppressive drugs (MS) and 115 were enrolled on trials of non-MS. 50 pts (19%) participated in =2 separate trials. Median (range) or (frequency) entry characteristics were: age 13.5 yrs (1–24); ECOG performance score 0 (30%), 1 (50%), 2 (19%); prior regimens 2 (0–9); prior stem cell transplant (20%); prior radiation (66%); concomitant medications 1 (0–12); and presence of metastatic disease (65%). 94% of pts were evaluable for the primary trial outcome, and 92% participated in pharmacokinetic (PK) studies. 17% of pts had grade 3 as their highest-grade toxicity. 22% of pts had grade 4 as their highest-grade toxicity, of which 91% were hematological. DLT rate was 18%. 5% of pts came off study due to toxicity, and treatment related death occurred in 0.3%. Age, prior radiation, medications, prior regimens, performance status, gender, transplant history, and drug dose expressed as a fraction of the maximum tolerated dose were included in the multivariate analysis. Only drug dose (OR 14.2, 95% CI 3.0–67.8) and prior radiation (OR 3.4, 95% CI 1.1–10.7) were statistically significantly associated with increased risk of developing DLT after adjusting for all other variables. The median number of cycles was 1 (range 0–31). Complete and partial response rate was 3%, however, 18% of pts had stable disease (received = 3 cycles). The median survival (Kaplan Meier analysis) from time of enrollment was 5 months. Conclusion: Standard phase I eligibility criteria selected a population of pts who tolerated the investigational agents well and >90% were evaluable for the toxicity and PK endpoints. Prior radiation was associated with a greater risk for DLT. No significant financial relationships to disclose.
Long-term evaluation of ifosfamide-related nephrotoxicity in children: The French experience
Authors: Fawaz O. , Rey A. , Niaudet P. , Orbach D. , Bergeron C. , Gentet J. , Corradini N. , Munzer M. , Rubie H. , Oberlin O. 
Published: March 2020

9551 Background: Ifosfamide-induced nephrotoxicity is a significant issue in patients treated for tumours during childhood. This study aimed at documenting incidence of late renal toxicity of ifosfamide and its risk factors. Methods: 183 patients have been investigated. 100 were male. Median age at treatment was 9.3 years (0.4–18 years). Median dose of ifosfamide was 54 g/m2 (18–77 g/m2). No patients received cisplatin and/or carboplatinum. Diagnoses included rhabdomyosarcoma (77), other soft tissue sarcoma (39), Ewing (39), and osteosarcoma (28). Investigations were performed at a median interval of 10.3 years (5–20.7) after the end of the treatment, at a median age of 21.6 years (7.1–44.2). No patient had electrolyte or vitamine supplementation. Glomerular and tubular functions were graded according to the Skinner's system. Results: After 5 year minimal follow-up 55% had normal tubular and 79% had normal glomerular functions. Natraemia, kalaemia, serum HCO3 and calcaemia were normal in all patients. Hypomagnesaemia was observed in 4, hypophosphaetemia in 8 %. The tubular threshold for phosphate was reduced in 44% of the patients (grade 2 or 3 in 15%, grade 3 in 1 pt). Significant glycosuria (> 0.5 g/24h) was detected in 5 % of the patients but it was clearly abnormal only in 5 patients. 34% of the patients had beta2 microglobulinuria, however, proteinuria was observed in only 12%. Cumulative dose of ifosfamide, older age at treatment and follow-up since treatment were predictor for tubulopathy in univariate and multivariate analyse. The glomerular filtration rate was normal in 79% of the patients. 21% had a grade 1 toxicity and 1 patient a grade 2. Univariate analysis did not find any prognostic factor for glomerular toxicity apart from the association with tubular toxicity. Conclusions: Since ifosfamide-induced renal toxicity can be severe, long term evaluation is important and this risk should be balanced carefully against efficacy. No significant financial relationships to disclose.
The pharmacokinetics (PK) and pharmacodynamics (PD) of ABT-751 in children with recurrent neuroblastoma or other solid tumors
Authors: Fox E. , Widemann B. C. , Maris J. M. , Cohn S. L. , Xiong H. , Krivoshik A. P. , Hagey A. E. , Adamson P. C. , Balis F. M. 
Published: March 2020

9557 Background: ABT-751 is an orally administered agent that binds to the colchicine site on β-tubulin and blocks microtubule formation. We studied the PK and PD of ABT-751 and its sulfate and glucuronide conjugates in children enrolled on a phase 1 trial in solid tumors and a pilot study in neuroblastoma. Methods: Seventy-two children (2–18 yrs) received ABT-751 on a once, daily × 7d or daily × 21d schedule. Sixty had PK plasma sampling (53 sets analyzed), and 41 had a 24h urine collection after the first dose. Drug concentrations were quantified with a LC/MS/MS assay. Results: Median (range) plasma PK parameters are shown in the table . ABT-751 was rapidly absorbed (Tmax , 2h), and the Cmax and AUC0-8 increased in proportion to dose. The median molar ratio of the sulfate plasma AUC0-8 to glucuronide plasma AUC0-8 was 1.5. The median (range) percent of the administered dose excreted in urine as ABT-751, glucuronide, or sulfate conjugates was 0.09 (0–0.4)%, 10.2 (1.0–38.5)%, and 12.6 (2.3–50.9)%, respectively. The median ABT-751 AUC0-8 was higher in patients with dose-limiting toxicity (DLT) compared to those without DLT on the 7d (118 vs. 74.5 μg·h/mL; P=0.014) and 21d (73.8 vs 49.3 μg·h/mL; P=0.049) schedules. In 28 patients with neuroblastoma, the AUC0-8 did not correlate with time to progression. Apparent clearance (CL/F) did not correlate with age or gender. Conclusions: PK samples were obtained from 83% (60/72) of children enrolled. The ABT-751 AUC0-8 was dose proportional; inter- and intra-patient variability was low. Patients who experienced DLT had higher ABT-751 AUC0-8. The mean CL/F of ABT-751 was similar to that observed in adults (40 mL/min/m2) but did not correlate with age or gender. The sulfate conjugate was the primary metabolite in plasma and urine. Urinary excretion was not a major route of elimination of the parent drug. [Table: see text] No significant financial relationships to disclose.
A retropective analysis of colorectal cancer in adolescents and young adults: A report from the Surgical Committee of the Children's Oncology Group
Authors: La Quaglia M. P. , Morris M. , Shia J. , Idrees K. , Rosenberg S. , Ishill N. , Shamberger R. C. , Doski J. J. , Heller G. , Paty P. B. 
Published: March 2020

9568 Background: The genetic origin, clinical features, and prognosis of early onset colorectal carcinomas (CRC diagnosed ≤ 30 years of age) are poorly understood. To evaluate these parameters, we performed a multi-institutional review. Methods: This is a retrospective review accomplished through a survey of Children's Oncology Group Institutions. 167 patients (median age=21yrs., range 10–30 yrs.) with adequate material were reviewed. Immunostaining for mismatch repair (MMR) proteins (MSH2, MLH1, MSH6, PMS1) was performed for 119 cases with sufficient archival tumor. Survival estimates were computed using Kaplan Meier methodology and associations assessed using a log-rank test or Cox proportional hazards. Results: The overall stage of disease at presentation: 9% stage I, 16% stage II, 34% stage III, 38% stage IV, and 4% unknown. Site of origin in the colon included: 17% right, 8% transverse, 14% left, 15% sigmoid, 37% rectosigmoid or rectum, and 9% unknown. 37% of cancers were poorly differentiated and 23% had signet ring cell features. A family history of CRC was reported in 46 (40%) of 114 patients for whom data were available. HNPCC criteria (Amsterdam II) were met in only 10 of these cases. MMR protein expression was deficient in 20 of 119 evaluable cases (17%) and was correlated to HNPCC status (P<0.0001) but not to other clinical features. R0 resection was accomplished in 115 patients. Of 159 patients with follow-up data the median survival was 44 mos. (95% CI: 31–65mos.). The 1, 3, and 5-year overall survival were 81%, 54%, and 42% respectively. Variables associated with overall survival in univariate analysis included: age (p=0.02), family history of CRC (P=0.03), HNPCC status (P=0.03), stage (P<0.0001), grade (P=0.0003), and R0 status (P<0.0001). Conclusions: CRC in this age group is associated with clinical features distinct from adult CRC, including advanced stage, high grade pathology, and poor survival. The majority of cases occur sporadically, and less than 25% can be associated with HNPCC either by clinical criteria or by MMR immunostaining. Future studies should pursue more detailed molecular characterization, improved detection strategies, and better treatment to improve outcome for these aggressive cancers. No significant financial relationships to disclose.