bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of endocrine disorders in childhood brain tumor survivors in South Korea: A nationwide population-based, longitudinal study.
Authors: Heo Jaesung , Noh O Kyu , Park Jun Eun , Cho Minhyung , Choi Seonghye 
Published: March 2020

e21517 Background: Brain tumors are the most common solid cancers in child patients with a current expected 5-year overall survival rate of 73%. Also, patients with brain cancer tend to have a high rate of neuroendocrine disorders. These endocrine problems may have a significant negative effect on quality of life and treatment compliance. Methods: The aim of this longitudinal study was to analyze the prevalence of endocrine disorders in childhood brain tumor survivors using claims data in South Korea. We confirmed endocrine disorders in a nationwide cohort of 1,058 patients who were diagnosed with brain tumor between January 1, 2009 and March 29, 2016 and who survived > 2 years after diagnosis. Multivariable logistic regression was used to evaluate association between demographic and treatment related variables and the prevalence of endocrine disorders. Results: After a median follow-up of 60.0 months, a total of 393 (37.1%) patients were diagnosed with at least one endocrine disorder. The median follow-up time from primary brain tumor diagnosis to diagnosis of first endocrine disorders was 26.3 months (range, 0.06 to 96.7). Of those patients, 333 childhood brain tumor survivors were diagnosed with endocrine disorders during their first 5 years after diagnosis. The overall frequency of endocrine disorders peaked during 2 months after the cancer diagnosis. The most common endocrine disorders were pituitary dysfunction (21.9%), thyroidal disease (6.1%), precocious puberty (4.6%), and growth hormone deficiency (4.3%). Female patients were at a higher risk for endocrine disorders (odds ratio: 1.45, p = 0.005). The patients with radiotherapy were more likely to have endocrine disorders compared without radiotherapy (odds ratio: 1.79, p < 0.001). Conclusions: Endocrine disorders in childhood brain tumor survivors was high and showed different patterns of prevalence depending on the nature of disease and time sequence. In childhood brain tumor survivors who are risk of endocrine disorders, regular assessment of endocrine function and timely intervention were needed. [Table: see text]
A phase I/II trial of VX15/2503 in children, adolescents, and young adults with relapsed or refractory solid tumors (ADVL1614).
Authors: Greengard Emily Gustava , Williams Robin Lesley , Liu Xiaowei , Militano Olga , Fisher Terrence Lee , Evans Elizabeth E. , Minard Charles G. , Reid Joel M. , Voss Stephan D. , Berg Stacey L. , Fox Elizabeth , Weigel Brenda 
Published: March 2020

e21519 Background: Semaphorins regulate tumor progression, immune responses, and angiogenesis. SEMA4D was identified as a candidate proto-oncogene by a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice. SEMA4D is expressed on tumors, including osteosarcoma, and in the tumor microenvironment. VX15/2503, a humanized IgG4 monoclonal antibody, binds SEMA4D, blocks receptor interaction and enhances the anti-tumor immune response in preclinical studies. This trial aimed to determine the tolerability and recommended dose of VX15/2503 in patients with relapsed/refractory solid tumors and activity in patients with osteosarcoma. Methods: Part A enrolled patients age≤ 21y with refractory solid tumors to assess the tolerability of VX15/2503 (20 mg/kg) IV every 14 days x 2 doses/cycle. The recommended dose was one that was tolerated and achieved sustained target saturation. Up to 6 additional children were enrolled to assess pharmacokinetics (PK). In part B, a two-stage design was used to assess the activity of VX15/2503 in patients with measurable, relapsed /refractory osteosarcoma. In part B1 patients > 21-30y accrued concurrently with part A; Part B2 (patients £ 21y) was initiated after the pediatric recommended dose was determined. Correlative studies including target saturation by VX15/2503 were required. Results: 18 eligible patients enrolled, 16 evaluable for toxicity. In part A (n = 12) the median (range) age was 12.5 (1-20) y. Diagnoses included osteosarcoma (8), neuroblastoma (2), other (2). No dose limiting toxicities (DLTs) were observed. In Part B1, (n = 6) median (range) age was 22.5 (22-30) y; one patient had cycle 1 DLTs (grade 3 acute kidney injury, creatinine increase, arthralgia and myalgia); a second patient had a later cycle DLT (grade 4 pericardial effusion). Given only 1/18 had a cycle 1 DLT, this did not impact dose selection. T-cell saturation by VX15/2503 was adequate and sustained in all patients. Conclusions: VX15/2503 was well tolerated at 20 mg/kg IV every 2 weeks and is the recommended dose in children, adolescents and young adults. The activity in osteosarcoma is under evaluation. Future trials combining VX15/2503 with novel agents are in development. Clinical trial information: NCT03320330.
Phase 1 study of pevonedistat (MLN4924) in combination with temozolomide (TMZ) and irinotecan (IRN) in pediatric patients with recurrent or refractory solid tumors (ADVL1615).
Authors: Foster Jennifer , Muscal Jodi Ann , Minard Charles G. , Liu Xiaowei , Reid Joel M. , Berg Stacey L. , Fox Elizabeth , Weigel Brenda 
Published: March 2020

e21521 Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m2), 2 (20mg/m2), and 3 (25mg/m2). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.
Perceptions on good death among parents of pediatric patients with hematology-oncology disease in advance.
Authors: Kim Ji Yoon , Park Bu Kyung 
Published: March 2020

e21532 Background: It is difficult to perceive the preparation of a good death for children because of its social and cultural issues. Among the children with serious diseases, they can be alienated and the whole processes are done by the decision of the parent's proxy even when they have to prepare for death. The purpose of this study was to examine the perception of "Good Death" in advance among parents of pediatric patients with hematology-oncology diseases. Methods: We conducted a cross-sectional survey to parents of pediatric patients in Kyungpook National University Children’s Hospital. Participants were recruited from the outpatient department of pediatric hematology and oncology. The Good Death Inventory (GDI), a tool developed for the perspectives of end-of-life care from bereaved family members, has a total of 54 items, including 30 in 10 core domains and 24 in 8 optional domains. Higher GDI scores mean better quality of death. A total of 109 questionnaires were analyzed using SPSS 23.0. Results: Most patients were diagnosed with hematology (48%), followed by leukemia and lymphoma (31%), and solid oncology (21%). Patients had diagnosed with diseases 3.7 years ago. Among the characteristics of parents, parents who did religious activity had significantly higher optional GDI score (p = .048). Among the characteristics of patients, female patients had significantly higher optional GDI score (p = .041). Optional GDI score of middle school or higher patients was significantly higher than preschool patients (p = .010). Patients with good perceived health status patients had significantly higher scores in GDI core, optional, and total (p = .048, .044, .013). Patients who had discussed their end-of-life plan with parents or others had significantly higher GDI total scores (p = .045). Parents who agreed with having patients’ living will had significantly higher GDI optional and total scores (p = .012, .026). Patients who already had living will had significantly higher GDI total score (p = .036). Interestingly, parents who wanted to receive all possible treatments to prolong life for their children had higher GDI core score (p = .054). Conclusions: Discussing a living will as well as a willingness to treat would be important for care. To improve quality of life and decreasing the disease stress burden, individualized and multidisciplinary education should be performed regularly.
The effect of gastrectomy in regorafenib treated GIST patients on outcome and drug exposure.
Authors: Van Erp Nielka P. , Lubberman Floor , Van Der Graaf Winette T.A. , Xu Lei , Cleton Adriaan , Gelderblom Hans 
Published: March 2020

e22511 Background: Gastrointestinal stromal tumour (GIST) is one of the most common soft tissue sarcoma subtypes. Regorafenib is the approved third line treatment after imatinib and sunitinib. Often GIST patients have an altered gastro-intestinal tract due to resection of the primary tumour. Gastric surgery may influence the exposure of orally administered TKIs. We investigated whether major gastrectomy influences the plasma exposure of regorafenib and treatment outcome. Methods: Efficacy and pharmacokinetic data from 133 GIST patients included in a phase III trial were analysed. Patients were subdivided into two groups according to the extent of the gastrectomy (no/non-significant gastrectomy and major gastrectomy). Progression free survival (PFS) on regorafenib was measured and regorafenib and its pharmacological active metabolites plasma exposure (Cav) were measured. Results: A total of 133 patient were included of which 27 underwent major gastrectomy. In patients with no/non significant gastrectomy the median PFS was 145 (IQR 43-281) days. The PFS in patients with a major gastrectomy was 172 (IQR 57-280) days. Regorafenib pharmacokinetic samples were collected in 80 patients of which 19 patients with a major gastrectomy and 61 patients with no/ non-significant gastric surgery. The average free aggregate concentration of regorafenib including the metabolites M-2 and M-5 was 6.9 µmol/L (CV% 44.5) and 6.7 µmol/L (CV% 46.5) in patient with major gastrectomy and no or non significant gastrectomy respectively. Conclusions: Our study shows that major gastrectomy did not influence plasma exposure of regorafenib and metabolites. In addition, no difference in progression free survival between the subgroups was seen.
A novel HMGA2-YAP1 fusion gene in a patient with aggressive angiomyxoma.
Authors: Dasilva Brandon , Lee Mee-Young , Ramirez Daniel C. , Maki Robert G. 
Published: March 2020

e22514 Background: Aggressive angiomyxoma (AA) is a rare neoplasm typically found in the perineum or pelvis, often with a gelatinous consistency and a highly vascular nature that leads to surgical complications and a high recurrence rate following what otherwise are attempts at curative surgery. For patients with recurrent disease in whom surgery is not indicated or potentially mutilating, estrogen antagonism has been successfully employed. HMGA2 on chromosome 12 has been known to be translocated in this tumor for over a decade, but no partners have been identified for HMGA2 in this tumor type. Methods: A 44-year-old woman with a perineal mass underwent attempted resection, but this was halted due to extensive blood loss after removal of a portion of what proved to be an AA. She was referred for systemic treatment to the sarcoma clinic. A Foundation Medicine Heme test was conducted on the patient's tumor. Results: The patient was treated with leuprolide and anastrozole with a RECIST 1.1 partial response and loss of vascularity consistent with a radiological response. She underwent preoperative radiation therapy and a follow up operation with negative margins. The resection specimen showed evidence of a very good result from systemic therapy and radiation. Molecular testing demonstrated a HMGA2-YAP1 fusion, implying a t(11;12)(q22.1;q14.3) translocation. Conclusions: This is the first demonstration of a partner for the HMGA2 gene in AA. A variety of other translocations have been found in AA, some of which involve chromosome 12. Thus, as with benign lesions such as lipomas, myolipomas, osteochondrolipomas, leiomyomas, pleomorphic adenomas, as well as a smaller number of overt malignancies, there appears to be promiscuity in HMGA2 (or other translocation) fusion products that lead to development of AA. Not all patients with AA respond to estrogen antagonism, or will show evidence of benefit before getting worse, as shown in case series and reports of AA patients. Assessing HMGA2 partners and their outcomes may better stratify future patients with AA with respect to possible benefit of estrogen antagonism.
A novel approach to neoadjuvant chemoradiation for soft tissue sarcoma using cisplatin and adriamycin.
Authors: Brown Ashley , Henson Christina , Herman Terence S. , Dooley William C. , Schutz Alexis , Mirza Zeeshan , Hatoum Hassan , White Jeremy , Pareek Vipul , Pius Patricia 
Published: March 2020

e22515 Background: Soft tissue sarcomas (STS) are heterogeneous solid tumors of mesenchymal cell origin, often difficult to manage. Local recurrence of extremity STS with surgery alone ranges from 5-20% with amputation ; 40% with wide excision. Neoadjuvant therapies are used to improve surgical outcomes. There is currently no recognized optimal neoadjuvant chemoradiation regimen prior to resection of STS. At our institution, we have piloted a neoadjuvant regimen of daily Cisplatin with infusional Adriamycin concurrent with radiation to assess its impact on surgical outcomes and tumor control. Methods: Patients diagnosed with STS of any site were treated neoadjuvantly with Cisplatin 6mg/m2 IV over 3-5 mins given 20 to 30 minutes before radiation (5 days) for 6 weeks. Adriamycin was given in the inpatient setting at 12.5 mg/m2 IV over 24 hours on days 1-4, weeks 1 and 4. The radiation dose was 54 Gy in 30 fractions. More than 50% of patients were treated with IMRT planning. Results: Since 2011, 12 STS patients were treated preoperatively with this regimen. Of these patients, 9 underwent surgery. Six of the 9 surgical patients received this neoadjuvant protocol followed by resection in the upfront setting. All of the 6 upfront patients had negative surgical margins; all of these patients had grade 3 tumors. Necrosis was reported based on the FNCLCC grading system. The average percent of necrosis was 96.3% (95% confidence interval 50.4%, 99.8%). Toxicity: Reported according to the RTOG/EORTC Radiation toxicity grading system. Of all patients, grade 1-2 skin toxicity predominated (75%). No grade 4 toxicity reported. Hematologic toxicity: Of all patients, grade 2-3 hematologic toxicity during neoadjuvant chemotherapy was reported in 83% of patients; grade 4 in 1 patient. No febrile neutropenia occurred. Post-operative complications: Seroma/hematoma formation was the most common post-operative complication in the surgical patients. No severely delayed healing was noted. Survival:Nine of 12 patients were dead (6 of 9 surgical patients) at the time of this analysis, all of metastatic disease. Mean time to DM 7.4 months. Mean OS 10 months. Conclusions: Our novel regimen achieved high necrosis rates, and all surgical patients achieved negative margin status. These factors are prognostic and correlate with local control. The predominant pattern of failure was distant. With its acceptable toxicity, this regimen of neoadjuvant Cisplatin, Adriamycin and radiation should be examined in a randomized fashion versus neoadjuvant radiation alone to determine the long term outcomes.
Copy number variations of apoptosis-regulating genes and MKI67 gene in primary and recurrent soft tissues sarcomas.
Authors: Ausheva Tatiana V. , Kit Oleg I. , Novikova Inna A. , Nepomnyashchaya Evgeniya M. , Timoshkina Natalya N. , Vashchenko Larisa N. , Dashkova Irina , Kechedzhieva Emma , Andreiko Elena , Barashev Artem A. , Antonets Anna V. , Vladimirova Liubov Yu 
Published: March 2020

e22517 Background: Soft tissue sarcomas (STS) are relatively rare malignant tumors of mesenchymal origin, constituting about 1% of all solid human tumors. About 11% of STS cannot be classified. The relapses of STS are difficult to predict. So, the studying of molecular origin of STS remains to be an actual issue. We analyzed copy number variations (CNVs) of apoptosis-regulating genes and MKI67 gene in primary and recurrent STS. Methods: 32 patients with primary STS and 26 patients with relapses were investigated. Relative CNVs of bax, bcl2, casp3, casp8, casp9, p53, mdm2 and M kI67 were detected with the use of RT–qPCR in fresh frozen tumor and normal tissues obtained while surgical access. Relative Copy Quantitation (RCQ) was accounted with GAPDH and ACTB as reference genes. Results: The frequencies of CNVs of the studied genes in groups of primary and recurrent STS are presented in the table below. A significant change only in the group of primary STS sarcomas was observed for CNV of MDM2, whereas the amplification of the CASP3 and MKI67 genes was characteristic of recurrent sarcomas. CNVs of BAX and CASP8 were significantly more frequent in primary STS. Increased amplification of MDM2 gene, was observed only for liposarcomas among all the others STS. The literature describes amplification of chromosome 12q13-15 where MDM2 gene is localized as a diagnostic feature of liposarcoma which is consistent with our observations [Todorov SS, Kit OI Modern understanding of the morphogenetic features of liposarcomas // Archives of Pathology. 2012. T. 74. №6. p.59-61]. Conclusions: The study showed the potential role of CNV of the BAX, CASP3, CASP8 and MKI67 genes to develop an approach to predicting the course of STS and the effectiveness of the MDM2 gene amplification as an additional marker for liposarcoma molecular classification.[Table: see text]
Clinical outcomes from a retrospective registry of patients with locally advanced/metastatic synovial sarcoma and myxoid round cell liposarcoma.
Authors: Attia Steven , Pollack Seth , Van Tine Brian Andrew , Chawla Sant P. , Druta Mihaela , Burgess Melissa Amber , Bohac Gerry C. , Somaiah Neeta 
Published: March 2020

e22520 Background: Outcomes of patients (pts) with advanced synovial sarcoma (SS) and myxoid/round cell sarcoma (MRCL) is lacking. Current data is limited to single institution studies or post hoc analyses of clinical trials. To understand the natural history of these subtypes of soft tissue sarcoma we performed a systematic analysis of SS and MRCL patients from large medical institutions. Methods: Data was abstracted at 7 U.S. centers for pts treated from 2005 to 2015. Advanced SS or MRCL were eligible if they had received chemotherapy and were 18 years or older. The primary endpoint was overall survival, and secondary endpoints were progression free survival, time to next treatment, time to new distant metastasis. Results: 350 pts with locally advanced (LA), unresectable and/or or metastatic (Met) SS (n = 249) and MRCL (n = 101) were analyzed. The median age at diagnosis was 40 years for SS pts (58.2% male). The median age of MRCL pts was 50 years (67.3% male). 249 SS pts all had ≥ 1line of therapy, 74.7% had ≥2 lines of treatment. All MRCL pts received ≥1 line of treatment, 72.3% had ≥2 lines. The clinical outcomes (median overall survival (OS), progression free survival (PFS), time to next treatment (TTNT) and time to distant metastasis (TTDM)) from start of first-line chemotherapy are: The OS and PFS from second line chemotherapy decreased for all evaluable pts (n = 259) was 17.9 months (mos) [95% confidence interval (CI) (15.0, 22.3)]; 3.9 mos (3.4, 4.8), respectively. A similar trend toward shortened OS and PFS were seen with each subsequent line of chemotherapy. Conclusions: This registry analyzing real-world clinical outcomes among advanced SS and MRCL pts is the most comprehensive performed to date. It provides data on clinical outcomes depending on line of therapy and can provide the backbone for better patient management and design of future clinical trials.[Table: see text]