bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of palbociclib based therapy in hormone receptor positive metastatic breast cancer patients after treatment with everolimus.
Authors: Dhakal Ajay , Matthews Christina , Zhang Fan , Levine Ellis Glenn , Edge Stephen B. , Salerno Kilian Elizabeth , O'Connor Tracy , Early Amy P. , Khoury Thaer , Takabe Kazuaki , Young Jessica S. , Opyrchal Mateusz 
Published: September 2018

1054 Background: Resistance mechanisms to CDK 4/6 inhibition are not well defined. Outcome data on hormone receptor positive (HR+) metastatic breast cancer patients (MBCP) treated with palbociclib (PA) after treatment with everolimus (EV) are lacking. The PALOMA 3 trial (P3) showing benefit of PA plus fulvestrant (FU) compared to FU in HR+ MBCP after progression on endocrine therapy excluded women previously treated with EV. The aim of our study was to investigate the outcomes of HR+ MBCP with prior EV treatment on PA based therapy. Methods: This is a retrospective, single institute review of HR+, HER 2 nonamplified MBCP from Jan 2014 - Nov 2016 treated with PA after treatment with EV. Women who received EV for < 1 month or PA < 14 days were excluded. Progression free survival (PFS) was defined as the time from the initiation of PA to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Response rates were determined based on available radiological data. Clinical benefit was defined as a complete response (CR), partial response (PR) or stable disease of at least 24 weeks. Results: 23 patients with mean age 67 years (42 to 81) were identified. 95% were postmenopausal, 81% had ECOG performance status 0 or 1, 83% had visceral metastases, 95% had > 2 lines of prior endocrine therapy (ET), 82% shown prior sensitivity to ET, 82% received prior chemotherapy, of which 84% were in metastatic setting. Kaplan Meier estimate showed median PFS of 2.9 months (95% CI 2.0-4.2); median PFS of P3 PA cohort was 9.5 months (95% CI 9.2-11.0). Fisher’s exact test comparing study cohort with P3 PA cohort showed statistically significant differences in objective response (CR or PR) rates of 0/23 (0%) vs. 66/347 (19%, p = 0.02) & clinical benefit ratio of 4/23 (17.4%) vs. 231/347 (66.5%, p = 0.00). Conclusions: Outcomes with PA in HR+ EV treated MBCP were worse when compared to the P3 PA cohort data. Treatment with EV may lead to resistance to CDK inhibition. Though limited by size, our data suggests that use of PA after EV is associated with low response & clinical benefit rates. Further studies are necessary to confirm the findings to determine sequencing of targeted therapies.
A curative approach to central nervous system metastases of neuroblastoma.
Authors: Kramer Kim , Kushner Brian H. , Modak Shakeel , Pandit-Taskar Neeta , Tomlinson Ursula , Wolden Suzanne L. , Zanzonico Pat , John Humm L. , Haque Sofia , Souweidane Mark M. , Greenfield Jeffrey , Basu Ellen M. , Roberts Stephen S. , Carrasquillo Jorge A. , Lewis Jason Stuart , Lyashchenko Serge K. , Larson Steven M. , Cheung Nai-Kong V. 
Published: September 2018

10545 Background: Neuroblastoma metastatic to the central nervous system (CNS NB) is associated with significant mortality (median survival < 6 months, < 10% survival at 36 months). Intraventricular compartmental radioimmunotherapy (cRIT) with radio-iodinated murine IgG1 monoclonal antibody 131I-8H9 targeting tumor cell-surface glycoprotein B7-H3 offers a therapeutic strategy. We analyzed overall survival of patients with CNS NB treated with intraventricular 131I-8H9 cRIT at Memorial Sloan Kettering Cancer Center (MSK) since 2003. Methods: After radiographic and/or pathologic confirmation of CNS NB, and assessment of adequate CSF flow, cRIT eligible patients underwent treatment on an IRB-approved protocol with either temozolomide/irinotecan-based CNS salvage regimen incorporating craniospinal radiation therapy, 131I-8H9 cRIT plus systemic immunotherapy (group 1), or non-regimen therapies with 131I-8H9 cRIT (group 2). cRIT administration involved a 2mCi tracer of 124I- or 131I-8H9 with nuclear imaging and CSF sampling for dosimetry followed by 1 or 2 therapeutic injections up to 70 mCi 131I-8H9. Disease surveillance included serial MR brain/spine, MIBG, CT, and bone marrow evaluation. Data are presented as overall survival after detection of CNS metastasis. Results: 105 patients with CNS NB were evaluated;80 patients (76%) were treated (57 group 1, 23 group 2). Of the 25 patients who were not eligible for cRIT, survival averaged 8.6 months. Of 19 patients with radiographic evidence of disease at the time of cRIT, 7 (36%) demonstrated post cRIT radiographic improvement. At analysis, 45/80 (56%) patients were alive 4.8–152 months (median 58 months) after CNS metastasis, including 36 (45%) at 36 months and 23 (29%) > 60 months. Subgroup analyses of 131I-8H9–treated patients identified age at NB diagnosis (≤18 months), relapse restricted to CNS and group 1 status as factors positively correlated with survival. Conclusions: 76% of patients with CNS NB treated at MSK received 131I-8H9 cRIT, and approximately half completed multimodality CNS salvage regimen with 131I-8H9 cRIT. Despite advanced CNS involvement, over 50% of patients treated with 131I-8H9 cRIT are still alive and nearly 50% have survived at least 36 months. Clinical trial information: NCT00089245.
Pazopanib therapy for adolescent and young adult desmoid tumors.
Authors: Agresta Laura , Nagarajan Rajaram , Szabo Sara , Turpin Brian , Kim Hee , Sorger Joel , Pressey Joseph Gerald 
Published: September 2018

10547 Background: There is a lack of reliably effective medical therapies for desmoid tumors (DT). Surgical resection may be morbid, and even a complete resection does not preclude recurrence. Radiotherapy is associated with potentially severe late-effects, a risk that may be particularly detrimental in young patients. In a previous review of our single institution DT experience, we found that objective treatment responses to medical therapies were rare.However,we have recently observed promising effect from therapy with the tyrosine kinase inhibitor pazopanib in adolescent and young adult (AYA) patients with DT. Methods: Retrospective single institution chart review evaluating all pazopanib treatment in AYA patients with DT. Results: Five AYA patients, ages 15-21 years, with previously treated DT received pazopanib. Four patients with sporadic DT were documented by next generation sequencing to have mutations of CTNNB1, and 1 patient with intra-abdominal tumors following colectomy was known to carry a large germline interstitial chromosomal deletion (5q21.2q23.1) including the APC locus. The median duration of pazopanib treatment was 6 months at the time of analysis (range: 5-21), with treatment ongoing for 4 patients. None of the patients demonstrated progressive disease while on treatment. Best responses by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) were partial response in 3 of 5 and stable disease in 2 of 5 cases. One response was nearly complete. In one case of stable disease, tumor necrosis was evident on magnetic resonance imaging after 2 months on pazopanib. Four patients reported pain relief while on pazopanib, including one patient with stable disease. Pazopanib was discontinued in 1 patient after 18 months due to recurrent facial edema. Other grade 1-2 adverse effects responded to dose reduction. The only grade 3 adverse effect was increasing weakness in a patient with pre-existing myopathy; this patient tolerated pazopanib at a reduced dose. Conclusions: This is the first report of objective responses to pazopanib by RECIST criteria in AYA patients with DT. Given these benefits and relatively mild toxicity, we conclude that pazopanib therapy should be considered in this patient population.
A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric solid tumors.
Authors: Shelat Anang , Tinkle Christopher , Stewart Elizabeth , Federico Sara Michele , Bianski Brandon , Mellado-Lagarde Marcia 
Published: September 2018

10556 Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric solid tumors and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included: talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric solid tumor lines, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2Gy IR and 1-10nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations < 10nM in tumor cells expressing detectable levels of SLFN11. Conclusions: SLFN11 is present in select pediatric solid tumors and may induce a DNA repair defect that is best exploited by combining low-doses of TAL and irinotecan with IR.
Diabetes risk in childhood cancer survivors: A population-based study.
Authors: Lega Iliana Carolina , Pole Jason D , Austin Peter , Lau Cindy , Nathan Paul C. , Baxter Nancy N. 
Published: September 2018

10558 Background: Cure rates for childhood cancer have improved significantly over the last three decades. Diabetes has emerged as a delayed side-effect of treatment for childhood cancer. Methodologic limitations may have led to underestimation of the risk for diabetes in previous studies. Understanding the extent of diabetes risk and identifying risk factors for diabetes is imperative for improving screening and prevention strategies in this population. Methods: We used the Ontario population-based cancer registry and administrative health databases to evaluate the risk of diabetes in adult survivors of childhood cancer. Diabetes was measured using a validated algorithm. Survivors were compared to age and sex-matched controls from the general population using a multivariable, cause-specific hazard regression model where death and development of another cancer was treated as a competing risk. Results: We identified 10,438 1-year survivors of childhood cancer diagnosed prior to age 21 years between January 1st, 1990 and December 31st, 2010. Mean age at cancer diagnosis was 10.7 years (standard deviation [SD] 6.8) and the mean follow up was 11.2 years (SD 6.9). In multivariable models adjusted for rurality and income status, cancer survivors had a 55% increased rate of developing diabetes compared to matched controls (HR 1.55, 95% CI 1.31-1.83). Individuals treated for cancer between age 6-10 years (HR 4.01, 2.33-6.91) had the highest increased rate for diabetes among age categories. Leukemia (HR 2.39, 1.74-3.27) and lymphoma (HR 1.61, 1.12-2.31) was also associated with an increased risk for diabetes compared to the general population. Conclusions: Our study provides evidence of an increased risk for diabetes in adult survivors of childhood cancer. The increased risk is highest among those treated at younger ages, and after treatment for leukemia and lymphoma. Future research is warranted to identify optimal ways for diabetes screening and prevention in this population. Given the burden of cardiovascular disease in survivors, identifying and treating diabetes early may help improve overall morbidity and mortality.
Prospective study of UDP-glucuronosyltransferase (UGT) 2B17 genotype and exemestane (Exe) pharmacokinetics (PK) and pharmacodynamics (PD) in Asian, hormone receptor (HR) positive, metastatic breast cancer (MBC) patients.
Authors: Walsh Robert John , Lee Soo Chin , Seng Kok Yong , Wang Ling-Zhi , Ho Gwo Fuang , Ow Samuel Guan Wei , Kumarakulasinghe Nesaretnam Barr , Sundar Raghav , Lee Xiao Wen , Yap Hui-Ling , Jeyasekharan Anand Devaprasath , Pang Angela , Ho Jingshan , Tan Chee Seng , Lim Yi Wan , Malik Rozita Abdul , Wan Ishak Wan Zamaniah , Goh Boon Cher , Tai Bee Choo , Wong Andrea Li Ann 
Published: September 2018

1056 Background: The active metabolite of Exe, 17-dihydroexemestane (17DhExe), is glucuronidated by UGT2B17 to inactive exemestane-17-O-glucuronide (Exe17- O-glu). UGT2B17*2/*2null genotype is 7 times more common in Asians than Caucasians and leads to reduced Exe glucuronidation in vitro. We studied Exe PK and PD in MBC patients genotyped for UGT2B17. Methods: Eligible patients (HR+ MBC; ≥1 line of endocrine therapy) received Exe 25mg OD till progression. UGBT2B17 genotype was correlated with day 29 (D29) steady-state PK (Exe and metabolites), change in PD biomarkers (estrone and androstenedione) at D29 vs baseline (BL), objective response rate (ORR) [sum of complete and partial responses], and clinical benefit rate (CBR) [response or stable disease ≥ 24 weeks]. Results: In 64 patients enrolled, CBR was 25%; ORR was 3%. Frequencies of UGT2B17*2/*2, UGT2B17*1/*2 and UGT2B17*1/*1 were 72%, 26% and 2%, respectively. PD and PK data were available for 54 and 53 patients respectively. Mean Exe17- O-glu AUC and Cmax were significantly lower, and mean 17DhExe Cmax numerically higher in patients with UGT2B17*2/*2 vs other genotypes (Table 1). 17DhExe Cmax was higher in patients with clinical benefit vs none (5.6 vs 3.8 ng/ml, p=0.02). Frequency of desired PD effect (rise in androstenedione and fall in estrone at D29 vs BL) was 22%. Exe plasma active index (PAI) [Table 1] was higher in patients with a fall in D29 estrone vs those without (14.7 vs 9.5, p=0.05). Conclusions: UGT2B17 genotype affects Exe PK and may have significant PD correlates. Larger studies to examine effects on clinical treatment efficacy are needed. Clinical trial information: NCT01655004. [Table: see text]
Late complications among adult survivors of neuroblastoma in the St. Jude Lifetime Cohort Study (SJLIFE).
Authors: Wilson Carmen Louise , Cook Cathleen Marie , Brinkman Tara M. , Huang Sujuan , Furman Wayne Lee , Bhakta Nickhill , Robison Leslie L. , Ness Kirsten K. , Hudson Melissa M. 
Published: September 2018

10561 Background: Assessment of late outcomes in neuroblastoma survivors has generally consisted of self-reported health events within retrospective cohorts. We aimed to characterize the health outcomes of a clinically-assessed cohort of long-term survivors of neuroblastoma diagnosed between 1963-2003. Methods: In a cohort of 239 ten-year survivors of neuroblastoma, of whom 137 (57%) underwent comprehensive clinical assessments, chronic conditions were graded using a modified version of the Common Terminology Criteria of Adverse Events, version 4.03. Comparisons were made using 272 clinically assessed community controls. Log-binomial regression was used to compare the prevalence of chronic conditions (grade 1-5) between survivors and controls and to calculate prevalence ratio (PR) and 95% confidence intervals (CI). Mean cumulative count (treating death as a competing risk) of chronic conditions by age was used to estimate cumulative burden with imputation of outcomes for non-clinically assessed survivors. Results: The median age at diagnosis was 0.9 (range: 0.0-14.4) and the median age at follow-up was 31.9 (range: 20.2-54.6) years for clinically assessed survivors. Median age of controls was 34.7 (range: 18.3-70.2). Treatment consisted of chemotherapy (75%), radiation (23%) and surgery (91%). Survivors were more likely than controls to have hearing loss (31.4% vs. 2.9%, PR = 10.7, 95% CI = 5.2-22.0), cardiomyopathy (8.8% vs. 0.7%, PR = 11.9, 95% CI = 2.7-52.5), hypothyroidism (10.9% vs. 5.2%, PR = 2.1, 95% CI = 1.1-4.3) or neurological disorders (56.9% vs. 32.4%, PR = 1.8, 95% CI = 1.4-2.2). At 35 years of age, the cumulative incidence of survivors experiencing at least one grade 3-5 condition was 67.3% (95% CI = 58.3-76.0%). By age 35 survivors experienced, on average, 8.5 (95% CI = 7.6-9.3) grade 1-5 and 2.4 (95% CI = 2.0-2.8) grade 3-5 conditions per 100 survivors, which was higher than the burden of grade 1-5 (3.3 [95%CI = 2.9-3.7]) and grade 3-5 (0.9 [95%CI = 0.7-1.0]) conditions identified among controls. Conclusions: Two-thirds of survivors are affected by severe or life-threatening health conditions. Continued follow-up, screening and intervention provide opportunities to optimize health.
Infection related late mortality in survivors of childhood cancer with asplenia or radiation-induced hyposplenism: A report from the Childhood Cancer Survivor Study.
Authors: Weil Brent , Madenci Arin L , Liu Qi , Gibson Todd M. , Yasui Yutaka , Neglia Joseph Philip , Leisenring Wendy M. , Howell Rebecca M. , Tonorezos Emily S. , Friedman Danielle Novetsky , Tinkle Christopher , Diller Lisa , Armstrong Gregory T. , Oeffinger Kevin C. , Weldon Christopher Bertero 
Published: September 2018

10563 Background: Asplenia or hyposplenism can develop in survivors of childhood cancer following splenectomy or radiotherapy exposure to the left upper quadrant of the abdomen (LUQ). Knowledge regarding long-term infection related outcomes for these survivors is limited. Methods: Infection related late mortality (sepsis, meningitis or pneumonia) was evaluated in 20,805 5-year survivors (diagnosed <21 years of age from 1970-1999, median follow-up 26 years, range 5-44) using cumulative incidence and Poisson regression models to calculate adjusted relative risk (RR) and 95% confidence intervals (CI). Average LUQ radiation was calculated as a surrogate for splenic radiation. Results: Treatment included splenectomy for 1328 survivors (6%). An additional 10,295 (49%) were exposed to LUQ radiotherapy without splenectomy. The cumulative incidence of infection related late mortality was 1.4% (95%CI: 0.7%-2.2%) at 35 years after splenectomy and 0.6% (95%CI: 0.4%-0.8%) after LUQ radiotherapy, with a total of 78 deaths attributable to infectious causes (25 sepsis, 1 meningitis, 52 pneumonia). Splenectomy (RR=8.4, p<0.001) and increasing LUQ radiotherapy dose (p<0.001) were independently associated with infection related late mortality (Table). Conclusions: Splenectomy and LUQ radiotherapy increased risk for infection related late mortality. While infectious mortality increased with increasing LUQ radiation dose, even lower dose exposure (<10Gy) increased risk substantially. Accordingly, cancer survivors exposed to LUQ radiotherapy should be considered at risk for functional asplenia and managed similarly to asplenic individuals with respect to vaccinations and febrile illnesses. [Table: see text]
Hepatic injury 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 , Fernandez-Pineda Israel , Pui Ching-Hon , Jeha Sima , Bishop Michael William , Furman Wayne Lee , Robison Leslie L. , Hudson Melissa M. 
Published: September 2018

10567 Background: We assessed hepatic injury (HI) in a large cohort of childhood cancer survivors (CCS). Methods: We measured aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 2751 SJLIFE CCS ( > 10 years (yrs) post-diagnosis, age ≥18 yrs), and graded using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Multivariable log binomial regression was used to estimate associations between demographic and clinical factors and grades 1–4 ALT and AST. Variables with a p < 0.1 were examined in multivariable models. Results: 1339 (48.7%) CCS were female. 2271 (82.6%) were non-Hispanic white (NHW). Median age at diagnosis - 7.4 yrs, median age at evaluation - 31.4 yrs, and median time from diagnosis to evaluation - 23.2 yrs. 177 (6.4%) had grades 1-4 AST (grade 1 = 164, grade 2 = 9, grade 3 = 4), and 421 (15.3%) had grades 1-4 ALT (grade 1 = 394, grade 2 = 18, grade 3 = 8). The multivariable results are shown in the table below. Conclusions: Male gender, obesity, hepatitis C virus infection, and treatment with busulfan are risk factors for increased AST and ALT. V10 is an additional risk factor for increased ALT. These results may guide future treatment designs and lifestyle interventions. [Table: see text]
Prevalence of attention-deficit/hyperactivity disorder in pediatric brain tumor survivors.
Authors: Shabason Emily Kauvar , Brodsky Cole , Baran Julie , Hobbie Wendy , Minturn Jane E. , Blum Nathan , Hocking Matthew 
Published: September 2018

10572 Background: Pediatric brain tumor survivors (PBTS) often have neurodevelopmental late effects, including attention and concentration deficits, which may impact cognitive and academic functioning. Such symptoms are also seen in attention-deficit/hyperactivity disorder (ADHD), which affects ~5-8% of children and adolescents. This study examined the prevalence of ADHD diagnosis and ADHD medication use in PBTS and identified higher risk subsets of patients. Methods: A retrospective chart review was completed of PBTS (n = 106), diagnosed from 1999-2013, who were at least 2 years from the end of tumor-directed therapy (surgery, chemotherapy and/or radiation therapy) and without a multi-system genetic disorder or severe developmental delay prior to brain tumor diagnosis. Subjects were already screened for or enrolled in 3 other studies of PBTS late effects. Statistical analysis involved chi-squared analysis. Results: Among the 106 patients, 55.7% were male, with an average age at time of brain tumor diagnosis of 5.9 years (0-12.2 years). The most common tumor types were glioma (51.9% with 47.2% low grade, 4.7% high grade), medulloblastoma (13.2%) and ependymoma (11.3%), with 50% of tumors supratentorial, 46.2% infratentorial and 3.8% either extending or multifocal across the tentorium. Of the patients, 42.5% received radiation therapy, 38.7% chemotherapy and 86.8% surgery. Nineteen patients (17.9%) had ADHD diagnoses, and 20 (18.9%) had been on ADHD medications. Clinical factors associated with an ADHD diagnosis were supratentorial vs. infratentorial tumors (28.3% vs. 6.1%, p = 0.013), no radiation therapy vs. radiation therapy (27.9% vs. 4.4%, p = 0.002) and no chemotherapy vs. chemotherapy (24.6% vs. 7.3%, p = 0.024). ADHD diagnosis was not associated with age of brain tumor diagnosis or surgical treatment. Conclusions: Our study suggests that PBTS have over twice the ADHD prevalence as the general population, most notably in patients with supratentorial tumors or without a history of radiation therapy or chemotherapy. The results suggest that a closer look at this population is warranted and that select patients may benefit from behavioral or pharmacologic ADHD treatments to optimize functioning.