bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial dysfunction in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort study.
Authors: Mulrooney Daniel A. , Ness Kirsten K. , Huang Sujuan , Santucci Aimee , Hebbel Robert P. , Solovey Anna S. , Duprez Daniel , Ehrhardt Matthew J. , Green Daniel M. , Srivastava Deokumar , Robison Leslie L. , Hudson Melissa M. 
Published: September 2018

10564 Background: Endothelial dysfunction, as an indicator of vascular disease in childhood cancer survivors (CCS) has not been widely studied. Methods: Markers of vascular inflammation (high sensitivity C-reactive protein [hsCRP]), hemostasis (fibrinogen), activation (endothelial cell expression of vascular cell adhesion molecule [VCAM-1]) and functional testing (large/small artery elasticity [L/SAE], pulse wave velocity [PWV]) were assessed in 200 CCS, ≥10 years from diagnosis, and 192 age/gender matched healthy controls. Exclusion criteria included: inflammatory processes, use of anti-inflammatory or cardiovascular medications, or pregnancy. Differences were assessed by adjusted multivariable linear regression. Results: CCS (53% male) of leukemia/lymphoma (59%), central nervous system tumors (6%), sarcomas (11.5%), embryonal tumors (22.5%), and other (1%) had a mean age at diagnosis 7.3 years (SD ±5.7). CCS and controls did not differ in current age (mean 34.1 ±9.2 vs. 33.5 years ±9.8), body mass index, smoking, mean systolic (124 mm Hg ±11.7 vs. 123 ±11.9) or diastolic blood pressure (73 ±9.5 vs. 71 ±9.5). Fasting low- (110 mg/dl ±31 vs. 102 ±30) and high-density (52 ±16 vs. 56 ±18) cholesterol levels differed between survivors and controls (p<0.01). Endothelial expression of VCAM-1 and PWV were statistically significantly increased in CCS; arterial elasticity was significantly reduced (table). Therapeutic exposures (anthracyclines and radiation) were not significantly associated with endothelial dysfunction. Conclusions: Childhood cancer survivors have greater endothelial dysfunction, a sign of atherosclerosis, and preventive measures should be investigated. [Table: see text]
Intensity of end-of life-care in children with cancer: A population-based study.
Authors: Johnston Emily E. , Alvarez Elysia Marie , Saynina Olga , Sanders Lee , Bhatia Smita , Chamberlain Lisa J 
Published: September 2018

10574 Background: There is growing evidence that adult oncology patients who know they are dying choose less intense care. Further, high intensity care is associated with worse caregiver outcomes. Little is known about pediatric oncology end-of-life care intensity. Methods: Using the California Office of Statewide Health Planning and Development administrative database linked to death certificates, we performed a retrospective population based analysis of cancer patients aged 0-21 who died between 2000 and 2011. The frequency of previously defined end-of-life intensity markers (hospital death, intense medical interventions, IV chemotherapy, and gastrostomy and tracheostomy tube placement) were calculated and multivariable logistic regression was used to determine clinical and sociodemographic factors associated with > 2 intensity markers (as above), intense medical intervention (cardiopulmonary resuscitation, intubation, ICU admission, or hemodialysis), and hospital death. Results: The 3,732 pediatric cancer decedents were 34% non-Hispanic whites and 45% Hispanic; 41% had hematologic malignancies and 59% solid tumors. The most prevalent intensity markers included: hospital death (63%) and ICU admission (20%). 65% had > 1 intensity marker, 23% > 2, and 22% > 1 intense medical intervention. There was a bimodal association between age and intensity: the youngest patients (age < 5) and adolescent patients (age 15-21) were more likely to receive intense care: < 5y (intense medical intervention: OR = 1.42; 95% CI, 1.1-1.9; hospital death: OR = 1.72; 95% CI, 1.4-2.2; > 2 markers: OR = 1.37, 95% CI 1.1-1.8); 15-21y (intense medical: OR = 1.48; 95% CI, 1.2-1.9; hospital death: OR = 1.39; 95% CI, 1.1-1.7; > 2 markers: OR = 1.35, 1.1-1.7) (references: 5-9y). Other factors associated with intensity included, hematologic malignancies, minority status, and death between 2008 and 2011 vs. < 2008. Conclusions: Nearly two-thirds of the pediatric cancer decedents had ≥1 marker of intense care and disparities exist. Patients < 5 and adolescents were more likely to receive intense end-of-life care. Further research needs to determine if these rates and variation are consistent with patient goals and factors associated with goal concurrent care.
Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in combination with fulvestrant in treatment refractory advanced breast cancer patients.
Authors: Varghese Anna M. , Moore Kathleen N. , Hamilton Erika Paige , Hyman David Michael , Jhaveri Komal L. , Wang Xuejing Aimee , Callies Sophie , Fink Aaron Alan , Wacheck Volker , Bendell Johanna C. 
Published: September 2018

1064 Background: Thephosphatidylinositol 3-kinase (PI3K) /mammalian target of rapamycin (mTOR) pathway is frequently activated in breast cancer. LY3023414 (LY) is an oral ATP- competitive inhibitor that selectively and potently inhibits class I PI3K isoforms, mTOR, and DNA-PK. The recommended phase 2 dose (RP2D) of LY monotherapy was previously established to be 200 mg twice daily (BID). Here we present the safety and preliminary activity data of LY in combination with fulvestrant (F) for breast cancer patients (pts) as part of a multi-cohort Phase 1 study. Methods: Pts with advanced HR+, HER2- breast cancer refractory to standard treatment received 200 mg LY BID + 500 mg F (day 1 and 15, then once monthly). Eligible pts had measurable disease and baseline tumor tissue available. Primary objective was to determine a RP2D. Other objectives included assessment of pharmacokinetics (PK), antitumor activity, and biomarker analysis. Results: 9 pts received LY + F in the breast cancer expansion cohort. All pts had multiple lines of prior systemic therapy (range 3-12), including chemotherapy. Dose limiting toxicity was observed in one pt in the form of grade (Gr) 3 oral mucositis. Common possibly related adverse events included nausea (5 pts), vomiting (4 pts), oral mucositis (4 pts), decreased appetite (3 pts), fatigue (3 pts), mucosal inflammation (2 pts), and paresthesia (2 pts). No obvious impact of LY on F PK or of F on LY PK was observed. Median duration of treatment was 15 weeks (range 3-63). In the 6 pts evaluable for tumor response, there was 1 durable partial response according to RECIST (still on treatment for ≥11 months) and 4 further pts had a decrease in their target lesions for a disease control rate of 56%. The median progression-free survival for this cohort is 4.2 months (90% CI 1.8, NA). Of note, the partial response was observed in a pt harboring an activating PIK3CA mutation (H1047R). Further biomarker analysis is ongoing. Conclusions: The RP2D of LY in combination with F is 200mg BID and may cause tumor regression or stabilization in breast cancer pts. Clinical trial information: NCT01655225.
A phase II study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma.
Authors: Ott Patrick Alexander , Pavlick Anna C. , Johnson Douglas Buckner , Hart Lowell L. , Infante Jeffrey R. , Luke Jason John , Lutzky Jose , Rothschild Neal Evan , Spitler Lynn E. , Cowey Charles Lance , Alizadeh Aaron , Salama April K. , Yin Xiaoyan , Bagley Rebecca G. , Wang Ying , Hamid Omid 
Published: September 2018

109 Background: gpNMB is an internalizable transmembrane glycoprotein expressed in melanoma and multiple other tumor types. The ADC GV (CDX-011) delivers the potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in advanced melanoma and breast cancer. Methods: This Phase II study (CDX011-05) assessed the efficacy and safety of GV monotherapy (1.9 mg/kg q3w) for patients (pts) with advanced melanoma progressive after ≤1 chemotherapy, ≥1 checkpoint inhibitor (CPI) and if BRAFV600mutated, ≥1 BRAF/MEK inhibitor. Central IHC determined gpNMB expression in archival and/or pre-treatment tumor. Primary endpoint was objective response rate (ORR) (RECIST 1.1) with ≥6 responders out of 52 evaluable pts as threshold for antitumor activity. Additional endpoints: progression free survival (PFS), overall survival (OS), duration of response (DOR), safety, PK/PD and correlation of tumor gpNMB expression with efficacy. Results: 62 pts enrolled (all evaluable) had median age of 67 years; 55% male; 21% BRAFV600mutated; 63% with ≥3 lines prior therapy; 100% had prior CPI; 100% Stage IV; 89% M1c. One confirmed complete response (CR) and 6 confirmed partial responses (PR, including 1 unconfirmed CR) were seen (confirmed ORR = 11%, p = 0.035 comparing to reference ORR 5%); 33 pts had stable disease including 3 unconfirmed PR. Median DOR = 6.0 (range: 4.1, 14+) months (mos), median PFS = 4.3 mos and median OS = 9.8 mos; 26 pts continue to be followed for survival. All pts with available tissue (60/60) had gpNMB+ tumors; 47/60 had 100% gpNMB+ epithelial cells; no clear correlation with outcome was seen in this population with consistent high expression. Toxicities included alopecia, neuropathy, rash, fatigue and neutropenia. Treatment-related rash in cycle 1 was associated with improved ORR (rash = 22%; no rash = 7%), PFS (p = 0.007) and OS (p = 0.035). Conclusions: GV has promising activity (primary endpoint of ORR was met) with a manageable safety profile in heavily pre-treated melanoma pts. Additional cohorts evaluating GV with either varlilumab, an activating anti-CD27 monoclonal antibody, or PD-1 inhibitors are open to accrual to provide further insights into the synergy of ADC and immunotherapy. Clinical trial information: NCT02302339.
Dynamic relationship between cycling kinetics of triple-negative breast cancer and tumor infiltrating immune cells.
Authors: Choudhary Ishita , Klimov Sergey , Rida Padmashree C.G. , Ogden Angela , Green Andrew R. , Aleskandarany Mohammed A. , Rakha Emad A. , Ellis Ian O. , Biganzoli Elia , Sarkar Surojit , Kalia Vandana , Aneja Ritu 
Published: September 2018

1100 Background: Recent studies show strong correlation between tumor infiltrating lymphocytes (TILs) and triple-negative breast cancer (TNBC) patient survival. CD8+ T cells serve as a favorable prognostic marker for TNBC. In addition, other cells such as CD4+ T cells, macrophages, B cells, and Tregs also infiltrate tumors. In this study, we delineate a strong relationship between the cycling kinetics of proliferating cells in TNBCs and antitumor immune response. Methods: A multi-institutional study performed by our group has previously shown that KAMS (Ki67-Adjusted Mitotic Score) provides a measure of the cycling kinetics of proliferating tumor cells and robustly stratifies TNBC patients into slow cycling (low KAMS) cyclophosphamide-methotrexate-fluorouracil (CMF)-responsive and fast cycling (high KAMS) CMF-resistant subgroups. In this study, we reviewed clinical data from 124 CMF-treated TNBC patients from Nottingham Hospital and sought correlations between cycling kinetics (High/Low KAMS) and tumor infiltrating immune cells. Results: We found that slow cycling TNBCs had higher mean expression of tumor infiltrating immune cells than fast cycling TNBCs. Intratumoral CD68 (p = 0.003), CD3 (p = 0.006), CD20 (p = 0.01), FOXP3 (p = 0.01), and total numbers of intratumoral and stromal CD68 (p = 0.01) and CD3 (p = 0.03) expressing cells were found to be significantly higher in low KAMS tumors than in high KAMS tumors. Of these biomarkers, CD68 was significantly associated with patients’ breast cancer-specific survival (BCSS): (a) low KAMS, high CD68 TNBCs had better BCSS than low KAMS, low CD68 (p = 0.01) TNBCs, and (b) high KAMS, low CD68 cases had better BCSS than high KAMS, high CD68 cases. Conclusions: Our observation that there are more TILs in slow cycling TNBCs suggests that there may be a dynamic cross-regulation between cycling kinetics and antitumor immune response. From our surprising observation that CD68 exerts polar roles in low/high KAMS subgroups, we propose that distinctions in M1 and M2 macrophage subsets in slow and fast cycling TNBCs may correlate with distinct outcomes. In addition, metabolic competition between tumor and immune cells may determine the level and function of TILs.
Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas.
Authors: Chawla Sant P. , Ganjoo Kristen N. , Schuetze Scott , Papai Zsuzsanna , Van Tine Brian Andrew , Choy Edwin , Liebner David A. , Agulnik Mark , Chawla Shanta , Wieland Scott , Levitt Daniel J. 
Published: September 2018

11000 Background: Aldoxorubicin (A) is a novel drug that binds covalently to albumin in the circulation, accumulates in tumors and releases doxorubicin in the acidic tumor environment. It has demonstrated enhanced antitumor activity in several murine models and in a phase IIb STS study when compared with doxorubicin. Trial Design: Phase III open-label study evaluating efficacy and safety of A compared to investigators' choice (IC) of treatment in subjects with soft tissue sarcomas (STS) who have relapsed or were refractory to prior chemotherapy. Objectives: (1) Primary: Efficacy of A vs IC: progression-free survival (PFS); (2) Secondary: Efficacy of A vs IC: tumor response (ORR), disease control rate (DCR; CR+PR+SD > 4 months), overall survival (OS) and safety. Methods: A: 350 mg/m2 (260 mg/m2dox. equiv.) iv q3 wks. IC drugs: dacarbazine, doxorubicin, pazopanib, ifosfamide, gemcitabine/docetaxel administered per package insert or study site's standard practice; provided, with G-CSF, by the sponsor. AEs, serum chemistries, CBCs, EKG and ECHOs obtained frequently. CT scans every 6 weeks for 30 weeks, then every 12 weeks; analyzed using RECIST 1.1 by Blinded Independent Central Review. Results: Randomized 433 subjects; 79 countries; 313 (72%) in North America (NA) and 121 (28%) in Rest of World (ROW). Leiomyosarcoma 42.5%, liposarcoma 15%, synovial sarcoma 9%, others 33.5%, L-sarcomas (lipo+leiomyo) 57.5%. Median PFS Total Pop. (months): A= 4.06; IC= 2.96; p = 0.12; HR = 0.82 (0.64-1.06). Median PFS NA (months): A= 4.21; IC= 2.96; p = 0.027; HR = 0.71 (0.53-0.97). Median PFS L-sarcomas (months): A= 5.32; IC= 2.96; p = 0.007; HR = 0.62 (0.44-0.88). DCR Total Pop.(%): A= 30.3; IC= 20.9; p = 0.028; DCR NA (%): A= 32.9; IC= 19.2; p = 0.007; DCR L-Sarcomas (%): A= 37.5; IC= 23.0; p = 0.018. ORR and OS will be reported. TEAEs gr 3 or 4 (%): A= 61.0; IC= 46.4. Trtmt Rel. SAEs (%): A= 27.0; IC= 14.0. TEAEs leading to Drug Discontinue (%): A= 4.2; IC= 6.3. Trtmt Related Deaths (#); A= 3; IC= 0; LVEF < 50% expected (%): A= 2.8%;Dox = 12.8%. Conclusions: Aldox is an active, well-tolerated drug for treating relapsed or refractory STS and is significantly better than standard treatments for patients with L-sarcomas. Clinical trial information: NCT02049905.
Pathologic complete response and survival outcomes in patients with localized soft tissue sarcoma treated with neoadjuvant chemoradiotherapy or radiotherapy: Long-term update of NRG Oncology RTOG 9514 and 0630.
Authors: Wang Dian , Harris Jonathan , Kraybill William G. , Eisenberg Burton Larry , Kirsch David G. , Kane John Michael , Ettinger David S. , Spiro Ira J , Trotti Andy , Freeman Carolyn R. , Chen Yen-Lin , Hitchcock Ying J. , Bedi Manpreet , Salerno Kilian Elizabeth , Dundas George , Godette Karen D. , Larrier Nicole , Curran Walter John , Lucas David Robert 
Published: September 2018

11012 Background: We sought to determine the prognostic significance of pathologic complete response (pCR) in soft tissue sarcoma (STS) in patients (pts) receiving neoadjuvant chemoradiotherapy (RTOG 9514) or radiotherapy (RTOG 0630) with long-term outcomes. Methods: RTOG has completed two phase II trials (RTOG 9514 and RTOG 0630) for pts with localized STS. Pts with high-grade STS ≥8 cm of extremities or body wall were enrolled to 9514 from 1997-2000 and received 3 cycles neoadjuvant chemotherapy (CT), interdigitated with RT, and 3 cycles postop CT. Pts with STS of extremities were enrolled to 0630 from 2008-2010 and received preoperative RT without CT. One pathology expert (DL) assessed pts for pCR at time of surgery without knowledge of disease outcomes. Overall and disease-free survival (OS and DFS) were calculated from the date of surgery. Pts that did not have surgery or had an amputation were excluded. Hazard ratios (HR) and p-values were estimated by multivariate Cox model stratified by study, where possible (i.e., > 0 events in both groups); otherwise p-values were calculated by stratified log-rank test. Results: Of 135 who had surgery, 123 were evaluable for pCR: 14/51 (27.5%) on 9514 and 14/72 (19.4%) on 0630 had pCR. With median follow-up of > 5 years for surviving pts, OS is 100% for pts with pCR vs. 5-year 76.5% (95% confidence interval 62.3-90.8) and 56.4% (43.3-69.5) for pts with < pCR in 9514 and 0630, respectively. pCR is associated with improved OS (p = 0.01) and DFS [HR 4.91 (1.51-15.93); p = 0.008] relative to < pCR. Local failure rate was 0% in pts with pCR vs. 5-year 11.7% (3.6-25.1) and 9.1% (3.3-18.5) for pts with < pCR in 9514 and 0630, respectively. Leiomyosarcoma/liposarcoma/myxofibrosarcoma are associated with better OS [hazard ratio 2.24 (1.12 and 4.45)] while liposarcoma/myxofibrosarcoma are associated with better DFS [hazard ratio 2.42 (1.23-4.76)]. Conclusions: Results from this analysis have demonstrated that pCR is associated with improved survival outcomes in pts with STS treated with either neoadjuvant RT or CT-RT. pCR should be considered as a survival surrogate for future STS studies. Clinical trial information: RTOG 9514 and RTOG 0630.
Immune-infiltrate characterization in localized osteosarcoma patients treated within protocol ISG-OS1.
Authors: Palmerini Emanuela , Agostinelli Claudio , Picci Piero , Pileri Stefano A , Lollini Pier-Luigi , Scotlandi Katia , Benassi Maria Serena , Marafioti Teresa , Ferrari Stefano 
Published: September 2018

11025 Background: We hypothesized that immune-infiltrates were associated with survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. Methods: Biopsies of patients (pts) treated from 04/2001 to 11/2006 were analyzed. TMAs from representative areas were assembled. Clinical and pathological characteristics at diagnosis, expression of CD8, CD4, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage), Tia-1 (cytotoxic T cell), CD303 (plamacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immuno-cells (IC), and PD-L1 both on tumor cells (TC) and IC were correlated with patients outcome. A TMA of surgical specimens of the same cases also was assembled, and chemotherapy-induced changes analysis is ongoing. Results: 86 pts identified. Median age: 16 (range 4-39); high LDH: 36/86; high serum alkaline phosphatase (SAP): 18/86. All pts underwent neoadjuvant chemotherapy and surgery. A good pathologic response (≥90% necrosis) was achieved by 45/86 pts. IHC results are displayed in the Table. With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-yr OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-yr OS for: a) good responders (good 89% vs poor 57%, p=0.0001); b) pts with CD8/Tia1 tumoral infiltrates (+/+ 81% vs +/- 60% vs -/- 45% p=0.002); c) pts with normal SAP (normal 85% vs high 44%, p=0.04). A numerically lower 5-yr OS was found in PD-L1 (IC) positive (+ 58% vs - 77%, p=0.14) and CD163 negative (+ 81% vs - 56%, p=0.17) cases. After multivariate analysis, poor histologic response (p=0.007) and lack of CD8/Tia1 infiltration (p=0.02) were independently correlated with poorer survival. In the subset of CD8+ patients, poorer (p= 0.02) OS was observed for PD-L1 (IC) + cases. Conclusions: Our findings support the hypothesis that CD8/Tia1 (cytotoxic T cells) infiltrate in tumor microenvironment at diagnosis is associated with superior survival for patients with localized osteosarcoma, while PD-L1 expression is associated with poorer survival. [Table: see text]
A phase Ib study of BGJ398 in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST).
Authors: Kelly Ciara Marie , Shoushtari Alexander Noor , Qin Li-Xuan , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Sjoberg Ana , Mcfadyen Chloe , Hwang Sinchun , Heinemann M.H. , Francis Jasmine , Singer Samuel , DeMatteo Ronald P. , Antonescu Cristina R. , Chi Ping , Tap William D. 
Published: September 2018

11039 Background: Preclinical studies suggest that imatinib resistance (IR) in GIST can be mediated by MAP-kinase activation via FGF signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR inhibitor in combination with imatinib, is cytotoxic and superior to imatinib alone, or imatinib in combination with MEK-inhibition. In GIST with FGF signaling, the combination of BGJ398 and imatinib may provide a mechanism to overcome IR. Methods: This phase Ib study of BGJ398 in combination with imatinib was performed in patients (pts) with imatinib resistant advanced GIST. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose. Two treatment schedules were evaluated incorporating imatinib 400mg daily continuously in combination with (A) BGJ daily 3 wks on, 1 wk off or (B) BGJ daily 1 wk on, 3 wks off. Response was evaluated by RECIST and CHOI every 8 wks x4 and then every 12 wks. Results: 16 pts enrolled. Median age 54 (range: 44-77), 81% male, median prior therapy 4 [range: 2-6, 13/16 pts had ≥ 3 prior therapies (81%)]. 12 pts received treatment on schedule A [dose level (DL)1 (BGJ 75mg), n = 6; DL-1 (BGJ 50mg), n = 3; DL-2 (BGJ 25mg), n = 3]: 3 DLTs (myocardial infarction, grade (G)4 CPK elevation, G3 ALT elevation) were observed on schedule A at DL1, hyperphosphatemia (on target effect) was not observed raising concern for therapeutic efficacy at the maximum tolerated dose. Following protocol amendment that allowed an alternative dosing schedule, 4 pts enrolled on schedule B [DL1 (BGJ 75mg), n = 3; DL2 (BGJ 100mg), n = 1]: one DLT occurred (G3 intra-abdominal hemorrhage) at DL2. The most common non-DLT G3/4 toxicity was HTN (2/16pts) and G2 toxicity was prolonged QTc interval (3/16pts). Of the 12 pts with evaluable CT scans, stable disease (SD) was the best response observed in 7 pts by RECIST and 9 pts by CHOI. 3pts achieved SD for > 6 months. 2 pts remain on study at data cut-off (range: 1 – 67 wks). Median progression free survival is 8 weeks. Pharmacokinetic analysis of imatinib and BGJ is forthcoming. Conclusions: In heavily pre-treated pts, durable disease control was observed in 3/16 pts. This signal of efficacy suggests that further evaluation of FGF signaling in the development of IR is warranted. Clinical trial information: NCT02257541.