bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of targeted treatments for the rare tumor syndrome infantile myofibromatosis.
Authors: Chen Ying , Das Srirupa , Pandya Deep , Billaud Jean-Noel , Reva Anna , Roth Annabel , Dottino Peter Remsen , Hakonarson Hakon , Martignetti John 
Published: May 2020

e22519 Background: Infantile myofibromatosis (IMF; MIM 228550) is an autosomal dominant disorder characterized by fibroblastic tumors of skin, muscles, viscera and bones. Tumor growth may begin during fetal development, where it may lead to early death, and/or can be present throughout adult life. We originally demonstrated that mutations in the platelet-derived growth factor receptor beta gene (PDGFRb) result in IMF. Currently, beyond surgical removal and chemotherapy, there is no effective treatment. Using an integrated genomic, bioinformatic and functional approach based on analysis of patient-derived IMF cells and mouse models, encapsulating multiple IMF-causing PDGFRb mutations, we sought to identify potentially druggable targets and validate them in preclinical models. Methods: Patient samples were genetically characterized by whole exome (WES) and RNA sequencing. Patient-derived cell lines from tumor and adjacent normal tissue (PDCL) were generated from a patient with a novel F864L mutation. This IMF-causing mutation along with two others, R561C and P660T, were stably expressed in BAF3 cells for functional characterization. PDCL-F864L were used to generate an orthotopic mouse IMF model. Results: WES of paired patient tumor, PDCL and germline samples confirmed a novel germline PDGFRb mutation (c.2590T > C, Phe864Leu). Using PDCL, the F864L mutation was shown to result in constitutive PDGFRb activation. Based on these findings, the tyrosine kinase inhibitors Imatinib and Sunitinib were chosen as candidate therapies. As predicted, they markedly inhibited cell proliferation and blocked PDGFRb activation and downstream signaling molecules AKT and ERK. Similar results were obtained in F864L, R561C and P660T mutant expressing BAF3 (natively PDGFRb null) cells when compared to WT PDGFRb expressing controls. Having established these findings using cultured cells, the effects of Imatinib and Sunitinib were next tested on an orthotopic mouse model. Given to IMF tumor mice as a single drug, both drugs markedly and sustainably decreased tumor size compared to control mice. Conclusions: Our findings demonstrate that IMF-associated PDGFRb mutations are gain-of-function mutations. Using patient-derived IMF models, Imatinib and Sunitinib effectively target these GOF mutations through PDGFRb signaling pathway inhibition. These findings provide preclinical data for targeted treatment of this rare cancer.
Primary care utilization and barriers among pediatric cancer and bone marrow transplant survivors.
Authors: Lipak Keagan , Gerhardt Cynthia , Olshefski Randal S. , Bajwa Rajinder , Skeens Micah 
Published: May 2020

e22523 Background: The Institute of Medicine (IOM) report on childhood cancer survivorship specified the need to create and evaluate standards and alternative models of care delivery, including collaborative practices between oncologists and primary care physicians (PCP).1 We aimed to examine the utilization of primary care physicians by childhood cancer and bone marrow transplant (BMT) survivors, as well as identify barriers to non-oncology follow-up care. Methods: Survivors and caregivers were recruited from a cancer and bone marrow transplant survivorship clinic at a large Midwestern pediatric hospital. Participants completed a demographic survey and an 8-item semi-structured interview in clinic or online. Results: A total of 472 participants (211 survivors, 259 caregivers, 2 left unanswered) completed the survey (Survivors Mage= 26.11, SD= 7.32). Most participants were Caucasian (89%) and female (58%). Only 57 (12.3%) survivors received a BMT. There were no significant differences in PCP utilization between BMT survivors and those who did not receive a BMT, t(448) = -.519, p = .604. In addition, there were no significant group differences in PCP utilization between oncological and hematologic survivors, t(387) = 1.144, p = .253. Most survivors (87%) had a PCP, but 43% sought care for ill visits only. Survivors most commonly chose their PCP through referral from family or friends (45%), with only 4% obtaining a recommendation from their oncology provider. Top reasons for not having a PCP included being unsure who to see (52%), lack of insurance (20%), and not perceiving a need for a PCP (18%). In a logistic regression, greater annual family income ( β= .209, p< .001) and having health insurance ( β= .161, p< .01) were predictive of having a PCP. The frequency of PCP visits was also positively correlated with annual family income ( r= .13, p= .014). Conclusions: While most survivors had a PCP, higher income and insurance coverage were important predictors of having a PCP. There is a clear need for education and formal transition programs to primary care, as survivors and their family identified the need for guidance in choosing a PCP. Stronger partnerships between oncology and primary care providers may improve surveillance and outcomes for these survivors. 1. Blaauwbrock R, Zwart, N., Bouma, M., Meyboom-de Jung, B., Kamps, W., & A. Postma. The willingness of general practitioners to be involved in the follow up of adult survivors of childhood cancer. Journal of Cancer Survivors. 2007;1:292-297.
Longitudinal evaluation of alanine aminotransferase after treatment for childhood cancer. A report from the St. Jude Lifetime Cohort Study.
Authors: Green Daniel M. , Wang Mingjuan , Krasin Matthew J. , Srivastava Deokumar , Relling Mary V. , Howell Carrie R. , Ness Kirsten K. , Kaste Sue C. , Greene William , Jay Dennis W. , Davidoff Andrew M. , Pui Ching-Hon , Jeha Sima , Bishop Michael William , Furman Wayne Lee , Robison Leslie L. , Hudson Melissa M. 
Published: May 2020

e22525 Background: Many childhood cancer survivors have been exposed to hepatotoxic agents. We assessed longitudinal hepatic injury, using alanine aminotransferase (ALT) elevation, and associated factors in a large cohort of long-term survivors. Methods: We evaluated SJLIFE participants ( > 10 years post-diagnosis, age ≥18 years) who had two or more determinations of ALT (T1 baseline, T2 last evaluation). Elevated ALT was defined as ALT > Upper Limit of Normal (ULN, 30 IU/mL for males and 19 IU/mL for females). Elastic net was used to perform model selection for elevated ALT at T2. Modified Poisson regression was used to identify risk factors for elevated ALT at T2. Results: Serial ALT assessments were available for 1941 survivors (49.6% female, 82.2% non-Hispanic white [NHW]). Their median age at diagnosis and T1 were 7.6 years (interquartile range [IQR] = 3.4-13.5) and 31.7 years (IQR = 26.1-38.1), respectively. Elapsed time from diagnosis to T1, and T1 to T2, were 23.3 years (IQR = 17.8-29.6) and 5.2 years (IQR = 4.4-5.7). ALT was normal at T1 and T2 in 45.7%, and persistently (25.9%) or newly (11.7%) abnormal in 37.6%. Compared to those with normal ALT at T1, those with elevated ALT at T2 were more likely to have NHW race/ethnicity, treatment with busulfan, increasing volume of the liver exposed to 10 Gray (Gy) or more (V10), body mass index (BMI) > 25 kg/m2, hepatitis C, metabolic syndrome, or treatment with atorvastatin, rosuvastatin or simvastatin at T2. History of hematopoietic stem cell transplantation (HSCT), but not busulfan, were additional risk factors included in the models for V15 and V20 (Table). Conclusions: Demographic, treatment, lifestyle, and non-oncologic interventions increase the risk for ALT elevation in survivors. These results may guide future treatment designs and lifestyle interventions. [Table: see text]
Prevalence of childhood growth hormone deficiency in survivors of pediatric intracranial germ cell tumors.
Authors: Lone Diana , Sadak Karim Thomas , Miller Bradley S , Roesler Michelle , Poynter Jenny N 
Published: May 2020

e22526 Background: Survival rates for childhood cancer continue to rise, and there are now greater than 420,000 survivors in the United States. However, high cure rates come at the cost of short and long-term treatment-related toxicities. Endocrine disorders are among the most common late effects and are associated with poor health outcomes and lower quality of life. Survivors of pediatric intracranial germ cell tumors (iGCTs) are at high risk for endocrine disorders, particularly for growth hormone deficiency (GHD), due to their exposures to cranial radiation, chemotherapy, and brain surgery. To date, no long-term follow-up studies have explored the late effects experienced by survivors of iGCTs. Methods: Study participants were enrolled in the Germ Cell Tumor Epidemiology Study, which is a case-parent triad study conducted using the resources of the Children’s Oncology Group’s Childhood Cancer Research Network. Eligibility criteria included diagnosis with a germ cell tumor in any location at age 0-19 years in the years 2008-2015. The study population included 233 cases with a diagnosis of iGCT. We are currently following the cohort to evaluate outcomes and late effects of treatment, including medical record review to extract data on treatment characteristics and hormone deficiencies. This interim analysis includes chart review for 57 iGCT cases. Results: Of the 57 cases reviewed, there was a male predominance (73.7%) with the highest prevalence in non-Hispanic whites (80.4%). Cases of iGCTs can be subdivided into two main histologic subtypes, germinomas (36 cases) and non-germinomatous GCTs (NGGCT, 21 cases). The median age at diagnosis was 14.6 years for the germinomas and 10.5 years for NGGCTs. Data on growth hormone deficiency (GHD) was available for 42 of the 57 cases with a median follow-up of 7.4 years. Twenty-eight of the 42 cases (66.7%) had GHD; 19 in the germinoma group and 9 in the NGGCT group (p = 0.47). 17 of those with GHD were males (p = 0.10). There was no significant difference in prevalence of GHD by age of tumor diagnosis (p = 0.20). Conclusions: Survivors of iGCTs are at high risk for growth hormone deficiency. Identifying specific risk factors for developing GHD amongst these survivors can enhance the current guidelines for screening and management.
lncRNA, PVT-1, controls tumorigenesis and cancer stem-like phenotypes in osteosarcoma through PI3K/TSC2.
Authors: Tsang Susan , Rainusso Nino Carlo , Yustein Jason Todd 
Published: May 2020

e23512 Background: Osteosarcoma is the most common pediatric bone cancer and a key genetic characteristic of this particular malignancy is its complex karyotype. Specifically it has been reported that 40% of osteosarcoma patients’ present with 8q24 amplification. The presence of this specific amplification has been previously associated with a high rate of relapse and poor prognosis for osteosarcoma patients. Within this amplicon resides, a long non-coding RNA gene, PVT-1. Prior studies indicates that PVT-1 has pro-oncogenic properties however the function of PVT-1 in osteosarcoma is not well characterized. Methods: To understand PVT-1 copy number, Fluorescent In Situ Hybridization was performed on both osteosarcoma cell lines and osteosarcoma patient-derived xenografts. In addition the PVT-1 RNA level is elevated in a majority of osteosarcoma samples compared to normal bone. To test PVT-1 pro-oncogenic role in osteosarcoma, several functional assays were performed. Results: Our studies demonstrated that overexpression of PVT-1 in osteosarcoma cell lines promotes multiple tumorigenic behaviors including enhanced proliferation, migration, invasion and chemotherapeutic resistance to cisplatin. PVT-1’s ability to mediate metastasis and contribute to chemotherapeutic sensitivity is a shared phenotype of cancer stem cells. Based on this observation, we hypothesize targeting PVT-1 will reduce cancer stem-cell properties. Osteosarcoma lines with increased levels of PVT-1 exhibited higher expression of cancer stem cell genes: Nanog, SOX2, c-Myc, and Oct4 at both the transcriptomic and proteomic level. In Vitro and In Vivo self-renewal capacity studies showed enhanced osteosarcoma cell self-renewal in the PVT-1 overexpression cohort. Additional molecular studies were performed in order to gain additional insights into potential mechanism of action for PVT-1 including Reverse Phase Protein Array. Initial analysis suggest a role for PVT-1 in regulating the PI3K-AKT-TSC2 pathway. Conclusions: This suggests a potential oncogenic pathway in which PVT-1 enhances cancer stem cell phenotypes. On-going investigations are addressing potential PI3K/TSC2 pathway inhibitors, BEZ-2335 and LY3023414, which could be utilized to regulate PVT-1 mediated tumorigenic roles and cancer stem-like properties.
Zinc finger E-box-binding homeobox 1 (ZEB1): A novel predictor for the prognosis in gastrointestinal tumors.
Authors: Yang Shenglan , Min Jiang 
Published: May 2020

e23515 Background: The gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcoma arising anywhere along gastrointestinal tract. The advanced and metastatic GISTs are the leading cause in GISTs inducing death. GISTs are the most commonly resulted from KIT or PDGFRA activation mutation. Currently adjuvant therapy with imatinib also targets the KIT and PDGFRA signals, which significantly increases the relapse-free survival and overall survival. However, KIT and PDGFRA mutation are not completely responsible for the progression of disease, especially metastasis of GISTs. So, there could be other molecular mechanism in GISTs progression. ZEB1 (zinc finger E-box-binding homeobox 1), as a member in zinc finger and homeodomain transcriptional factor family, plays a key role in metastasis of some epithelial carcinomas, such as colorectal cancer, breast cancer and NSCLC. We present that ZEB1, as a vital molecular in epithelial-mesenchymal transition, could be a promising marker in predicting the prognosis in GISTs. Methods: Immunohistochemistry staining for paraffin-embedding slices from 157 patients firstly diagnosed as GIST is applied for detecting the ZEB1 expression. Clinical, pathological, molecular and survival time were analyzed. All performances were approved by the Medical Ethics Committee in the First Affiliated Hospital of Chongqing Medical University. Results: In 157 patients, metastasis was found in 87 patients. In 87 patients with metastasis, high expression of ZEB1 almost exhibited (80 high/96 VS 7 non or low/96), while non or low expression was frequently detected in patients without metastasis (50 non or low/70 VS 20 high/70) (p < 0.0001). There was no significant difference between high and non/low expression patients in gender (48% VS 46% for male rate; 52% VS 54% for female rate), age (53 vs 54 years for median age), primary location (esophagus 2% VS 1.8%; stomach 57% VS 52.6%; duodenum and small intestine 31% VS 31.6%; colorectum and anus 10% VS 14.0%), tumor size (0.5-24cm, median 9.7cm VS 1-25.5cm, median 10.1cm), mitotic index (55.0% VS 58.6% for > 5/50HPF; 45.0% VS 41.4% for ≤5/50HPF), and risk stratification (low/intermediate risk 60.7% VS 63%; high risk 39.3% VS 37%). In addition, the 5-year OS rate was considerably lower in patients with ZEB1 high expression than those with ZEB1 none or low expression at baseline (37% vs 86%; p = 0.011). Conclusions: High expression of ZEB1 facilitates metastasis and indicates the poor prognosis in GISTs. ZEB1 could be a novel predictor for GIST’s prognosis.
Radiomic features for patients with primary soft tissue sarcomas: A prognostic study.
Authors: Pasquali Sandro , Bologna Marco , Infante Gabriele , Vigorito Raffaella , Messina Antonella , Morosi Carlo , Miceli Rosalba , Greco Gabriella , Casale Alessandra , Corino Valentina , Barretta Francesco , Mainardi Luca , Palassini Elena , Sanfilippo Roberta , Stacchiotti Silvia , Casali Paolo Giovanni , Callegaro Dario , Gronchi Alessandro 
Published: May 2020

e23532 Background: Prognosis of extremity soft tissue sarcomas (ESTS) and retroperitoneal sarcomas (RPS) is currently estimated on clinical-pathological features, as those incorporated in the Sarculator nomogram. This study investigated the added value of end-point specific radiomic signatures (RS) in patients with primary ESTS and RPS. Methods: We retrospectively analysed data from patients with a ESTS (N = 100) or a RPS (N = 116) who underwent surgery (Jan2011-Dec2015) at one sarcoma reference institute and had magnetic resonance imaging (MRI) or computed tomography (CT) scan, respectively. Radiomic features were extracted from DICOM files of MRI and CT scan for ESTS and RPS, respectively. The study end-points were incidence of distant metastases (DM) and overall survival (OS) for ESTS and disease-free survival (DFS) and OS for RPS. A RS was established for each end-point. Models discriminative ability was measured using the Harrell c-index (C). Results: ESTS histology was undifferentiated pleomorphic sarcoma, myxofibrosarcoma, myxoid liposarcoma, dedifferentiated/pleomorphic liposarcoma, and others in 28, 21, 18, 9, and 24 patients, respectively. At a median follow-up of 61 months, the 5-yr DM-free rate and OS were 73.6% (95%CI 64.2-82.2%) and 73.4% (95%CI 64.5-83.6), respectively. A prognostic model based on the Sarculator and a DM-RS achieved higher C (0.86, 95%CI 0.77-0.93) than the Sarculator alone (0.83, 95%CI 0.71-0.94). For OS, the RS was not able to increase the Sarculator discriminative ability (Sarculator and OS-RS: C = 0.73, 95%CI 0.62-0.82; Sarculator alone: C = 0.72, 95%CI 0.62-0.81). RPS histology was well differentiated liposarcoma, dedifferentiated liposarcoma, leiomyosarcoma, and other in 22 (19%), 60 (52%), 22 (19%), and 12 (10%) patients, respectively. At a median follow-up of 58 months, 5-yr DFS and OS were 46.7% (95%CI, 37.8-57.6%) and 68% (95% CI 59.9-79.0%), respectively. RS extracted from CT scan without contrast enhancement slightly improve the discriminative ability of the Sarculator for DFS (Sarculator and DFS-RS: C = 0.65, 95%CI 0.57-0-72; Sarculator alone: C = 0.63, 95%CI 0.55-0.70) but not for OS (0.70, 95%CI 0.60-0.80 and 0.69, 95%CI 0.59-0.79, respectively). Conclusions: RS did not improve the discriminative ability of the Sarculator for OS. The added value for RS in relapse prediction (DM incidence for ESTS and DFS for RPS) deserves further investigations.
Phase II trial using haploidentical hematopoietic cell transplantation (HCT) followed by donor natural killer (NK) cell infusion and sirolimus maintenance for patients with high-risk solid tumors.
Authors: Thakar Monica S. , Browning Meghen , Hari Parameswaran , Charlson John A. , Margolis David A. , Logan Brent , Schloemer Nathan , Kelly Michael E. , Newman Amy , Johnson Bryon , Keever-Taylor Carolyn Anne , Malarkannan Subramaniam 
Published: May 2020

e23551 Background: Patients with relapsed solid tumors have dismal predicted OS < 10-20% at 5 years with conventional salvage therapies. We hypothesized that a multi-faceted immunotherapy approach to optimize graft-versus-tumor (GVT) effects, in combination with a mammalian target of rapamycin (mTOR) inhibitor maintenance strategy, would enhance early disease-control rates (DCR), leading to improved progression-free survival (PFS) and OS for this high-risk population. Methods: Treatment consisted of HLA-haploidentical marrow (n = 12) or peripheral blood stem cell (n = 3) transplantation to optimize GVT effects, preceded by reduced-intensity conditioning (fludarabine, cyclophosphamide, and 3 Gy total body irradiation) to promote engraftment of these mismatched stem cells. Haplo-NK cells were given to boost this GVT effect. They were purified from non-mobilized donor mononuclear cells by CD3 depletion followed by CD56 selection using the Miltenyi CliniMACS system and were infused fresh on day +7 after HCT. Postgrafting immunosuppression included sirolimus maintenance, which continued until 6 months post-HCT. Results: Fifteen patients with relapsed Ewing sarcoma (EWS) (n = 9), rhabdomyosarcoma (n = 4), osteosarcoma (n = 1), and medulloblastoma (n = 1) having stable or undetectable gross disease were enrolled on this Phase II trial. Median age at HCT was 19 (4.5-37) years old and median performance status was 80%. Four patients underwent prior autologous transplants. Patients received a median NK dose of 6.5 (3.7-11.4) x 106/kg. NK cell products had a median log T cell depletion of 5.94 (5.18-6.75), median NK recovery of 62% (48-71%), and median NK purity of 92% (74%-97%). All donor NK infusions were well-tolerated without cytokine release syndrome. All patients engrafted, and all had sustained full donor chimerism ( > 95% CD3). Two patients developed grade II acute graft-versus-host disease (GVHD), and 2 patients developed chronic GVHD. No patients died from transplant-related causes. With a median follow-up of 1.3 years (range, 70 days – 5 years), 6-month DCR is 72%. 1- and 2-year OS for the entire cohort is estimated at 64% and 40%, respectively, while PFS is 29% and 22%, respectively. For patients with EWS,1- and 2- year -OS is estimated at 75% and 45%, and PFS is 38% and 25%, respectively. Conclusions: This dual immunotherapy approach followed by mTOR inhibition maintenance was well-tolerated, with better than expected OS for this high-risk set of diseases. Clinical trial information: NCT02100891 .
Prognostic and predictive factors for the outcomes of clear cell sarcoma (CCS) multidisciplinary treatment: The role of lymph node involvement.
Authors: Teterycz Pawel , Czarnecka Anna Malgorzata , Szmajdzinska Aleksandra , Kalejta Magdalena , Spalek Mateusz , Rosinska Magdalena , Poleszczuk Jan , Switaj Tomasz , Zdzienicki Marcin , Falkowski Slawomir , Rutkowski Piotr 
Published: May 2020

e23554 Background: CCS is a rare aggressive sarcoma with melanocytic differentiation and specific genetic background of EWSR1/ATF1 or EWSR1/CREB1 translocations. It typically localizes in the tendons, fascia, and aponeuroses. The role of lymph node dissection (LND) remains to be elucidated in this sarcoma, although it was indicated to have a high rate of clinically occult regional lymph node (LN) metastases. Methods: 23 consecutive patients (pts) (15 women and 8 men) were referred, diagnosed and underwent multidisciplinary treatment in our Institute between 07/2000 and 12/2019. Kaplan-Meier estimator was used in survival analysis and univariate Cox proportional hazard model was used to investigate prognostic and predictive factors. Cases for whom local relapsed were not noted or those not known to be dead were censored at last visit. OS was compared for nodal involvement, including both: clinically detected and treated with therapeutic LND and microscopic metastases evaluated in sentinel LN biopsy (SLNB). Local relapse and radiotherapy were analyzed. Results: The median age at diagnosis was 32y (range:20-72). The median tumor size was 3.5cm (2-15cm). 15 pts underwent surgery of the primary tumor and 8 - resection of local relapse after non-complete resection outside the reference center. In 11 cases SNLB was performed, while in 7 – therapeutic LND. SLNB was positive in 2 (18%) cases and was followed by completion LND. For pts treated due to primary tumor, R0 resection was achieved in 12 cases and R1 in 3. After median follow-up of 65.6 months (m) (95% confidence interval, CI 55.3–NR) 11 (48%) pts are alive. Median OS was 59m (95%CI: 39-NR). Clinically detectable LN were correlated with shorter DFS (HR: 6.6, 95%CI: 1.5-28.8, p = 0.01). The number of involved LN also correlated with DFS (HR 1.7 per 1 LN; 95%CI:1.1-2.6, p = 0.009). No such correlations were found for OS. 5-year LRFS rate was 72.5% (95%CI: 53.8-97.7). 15 pts underwent neoadjuvant radiotherapy and for these pts 5-year LRFS rate was 75.0% (95%CI: 50.3-100). There was no statistical difference for LRFS if radiation therapy was not applied, which may be due to the number of pts. Conclusions: CCS is a highly aggressive sarcoma with poor prognosis. High quality surgery remains the gold standard for these pts, with the increasing role of SLNB and LND. Multimodal treatment should be considered in all cases. There is unmet need for new therapies for advanced CCS pts.