bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary intake and metabolic syndrome in adult survivors of childhood cancer.
Authors: Smith Webb A , Li Chenghong , Nottage Kerri , Srivastava Deokumar , Lanctot Jennifer , Green Daniel M. , Nolan Vikki G , Laver Joseph H. , Gurney James G. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K.
Published: March 2020

9526

Background: Childhood cancer survivors (CCS) are at increased risk for metabolic syndrome (MetSyn) and increased morbidity and mortality from cardiovascular disease. Following a heart healthy diet may decrease this risk. The purpose of this investigation was to characterize dietary patterns and to evaluate the association between diet and MetSyn among CCS. Methods: CCS who were 10+ year survivors of childhood cancer, who were older than 18 years of age, and participating in the St. Jude Lifetime Cohort Study (SJLIFE). They completed a medical assessment based on Children’s Oncology Group screening guidelines, and a food frequency questionnaire (FFQ). Laboratory and physical measures were obtained to determine MetSyn status using the NCEP-ATPIII criteria. Participants were classified as having MetSyn if they met the criteria for ≥3 components of MetSyn. Data from the FFQ were used to score dietary patterns according to WCRF/AICR recommendations. Those who met ≥4 of the 7 recommendations were classified as following a “healthy diet.” A stratified analysis by sex using log-binomial regression models was undertaken to evaluate associations between diet and MetSyn, adjusted for age, age at diagnosis, cranial radiation, education, household income, and smoking status. Results: Among 1421 participating CCS (49.3% male, median age 33.0 years, range, 18.9-60.0 years), 31.5% met the criteria for MetSyn and 25.8 % followed a healthy diet according to the WCRF/AICR recommendations. In multiple regression models stratified by sex, females who followed a “healthy diet” were 2.1 (95% CI 1.5-2.9) times less likely and males who followed a “healthy diet” were 2.2 (95% CI 1.5-3.1) times less likely to have MetSyn than those who reported following a “healthy diet”. Conclusions: Heart healthy diets in CCS are associated with decreased risk for MetSyn. Dietary interventions may be warranted in CCS with MetSyn.
Effect of dexraoxane on impaired mitochondrial structure and function in doxorubicin-treated childhood ALL survivors.
Authors: Lipshultz Steven E. , Miller Tracie L. , Gerschenson Mariana , Neuberg Donna S. , Stevenson Kristen , Franco Vivian I , Anderson Lynn , LiButti Daniel , Silverman Lewis B. , Vrooman Lynda M. , Sallan Stephen E. ,   Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium
Published: March 2020

9530

Background: Cardiotoxicity in doxorubicin (DOX)-treated long-term childhood cancer survivors is characterized by impaired cardiac function which is partly mediated by mitochondrial (mt) energy production. Preclinical studies show irreversible DOX-associated cardiac mt dysfunction. A response to impaired mt function is to increase the mtDNA copies/cell (mtDNA). We examined mtDNA and function in peripheral blood mononuclear cells (PBMCs) in childhood survivors of high-risk ALL who received DOX alone or DOX plus dexrazoxane (DOX/DEX). Methods: Patients with HR ALL treated on DFCI Childhood ALL protocols from 1987-2005 were eligible for this study. PBMCs mtDNA and oxidative phosphorylation (OXPHOS) NADH dehydrogenase (CI) and cytochrome c oxidase (CIV) activities were measured by RT-PCR and immunoassays respectively. A Wilcoxon rank-sum test was used to compare continuous measures between groups. Models for mitochondrial parameters were based on maximum likelihood variance component estimation and were adjusted for patient characteristics. Results: 64 patients provided samples at a median follow-up of 7.8 (2.9-30.2) years. 58% received DOX/DEX. Median cumulative DOX dose was 300 mg/m2. A significant difference was detected between groups for mtDNA (p=0.001, adjusted p=0.015). MtDNA medians for the DOX and DOX/DEX groups were 1106.3 and 310.5. No significant differences were found between groups for CI or CIV activities. Conclusions: DOX-treated survivors have increased mtDNA consistent with impaired mt function, which is abrogated by concurrent use of DEX. The use of DOX/DEX is associated with lower mtDNA. Due to a compensatory increase in mtDNA to augment mt function, overall mt function is not different between groups. This compensatory mechanism in 7.8-year survivors at risk for cardiac dysfunction is concerning over their subsequent lifespan. [Table: see text]
Association of chromosome complexity with age and metastasis in synovial sarcomas: Validation of expression and genomic prognostic signatures.
Authors: Chibon Fred , Lagarde Pauline , Przybyl Joanna , Brulard Celine , Italiano Antoine , Orbach Daniel , Bui Nguyen Binh , Terrier Philippe , Sciot Raf , Debiec-Rychter Maria , Coindre Jean-Michel
Published: March 2020

9536

Background: Synovial sarcoma (SS) is one of the rare sarcomas that occurs in adolescents as well as in adults. Nevertheless, metastasis occurs with a lowest frequency in the former, 10 vs 50% respectively. In almost all cases, a characteristic translocation t(X;18)(p11.2;q11.2) exists and the importance of this translocation in SS oncogenesis is well established, but the genetic basis of SS metastasis is still poorly understood. We recently published expression (CINSARC) and genomic (GI) signatures related to chromosome integrity control that predict outcome in undifferentiated sarcomas and GIST and ask whether these signatures could also predict outcome in SS. Methods: To asses this issue we selected in the European sarcoma database CONTICABASE 92 primary untreated SS for expression and genomic profiling. Results: As demonstrated by metastasis-free survival, CINSARC and GI have strong and independent prognostic values (p = 1.6 x 10-5 and p = 4 x 10-6, respectively). Comparing expression profiles of tumors with or without metastasis in a training series of 58 SS, a 52-genes signature was identified and validated in an independent series of 34 SS. Fourteen of these genes are common with CINSARC and these 52 genes are involved the same pathways than CINSARC, mitosis checkpoints and chromosome integrity. Comparing genomic profiles of adult versus pediatric SS we show that in both situations metastasis is associated to genome complexity and that the adult genome is highly more frequently rearranged. In line with this, the pediatric good-prognosis patients, according to GI, do not develop metastasis. Conclusions: Results clearly indicate that SS metastasis development is strongly associated with chromosome complexity and that CINSARC and GI are powerful prognostic factors. Data also mean that the metastasis frequency difference between adult and children likely is associated to the genome instability which is highly more frequent in adults. Finally, among these tree signatures, GI is potentially the best overall and clearly the most clinically relevant considering that CGH from FFPE samples is already used in the daily practice of pathology.
A phase I trial of IMC A12 and temsirolimus in children with refractory solid tumors: A Children’s Oncology Group study.
Authors: Fouladi Maryam , Perentesis John Peter , Wagner Lars M. , Ingle Ashish M , Thomas George , Krueger Darcy A. , Houghton Peter , Vinks A.A. , Doyle L. Austin , Weigel Brenda , Blaney Susan
Published: March 2020

9541

Background: IMC-A12, a fully recombinant IgG1 monoclonal antibody that targets the human IGF-IR and inhibits downstream signaling of MAPK and PI3K/AKT, and temsirolimus, an mTOR inhibitor, have demonstrated preclinical single agent, antitumor activity against many pediatric tumors. A phase I and pharmacokinetic (PK) trial evaluating the combination of these agents was conducted in children with refractory solid and CNS tumors. Methods: Using a modified 3+3 design, IMC-A12 and temsirolimus were administered intravenously once every 7 days in 28 day cycles. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 15 and 28. Biology studies included assessment of IGFR and insulin receptor expression and phosphorylation in archival tumor samples and phosphorylation of IGFR and mTOR downstream targets in peripheral blood mononuclear cells (PBMC) pre and post therapy. Results: Thirty-nine patients [20 male, median age 11.8 years (range 1-21.5)] with rhabdomyosarcoma (n=10), osteosarcoma (n=6), Ewings sarcoma (n=5), astrocytoma (n=5), or other tumors (n=13) were enrolled; 33 were evaluable for toxicity. At dose level 1 [IMC-A12 (6 mg/kg); temsirolimus (15 mg/m2)], 2 DLTs (grade 3 hypercholestrolemia, mucositis) occurred among 6 evaluable patients. Six more patients were accrued and 3 additional DLTs were observed (grade 3 ALT, fatigue and prolonged thrombocytopenia > 14 days). At dose level 0 [IMC-A12 (6 mg/kg); temsirolimus (10 mg/m2)], dose-limiting mucositis occured in 2/6 patients. At dose level -1 [IMC-A12, (4 mg/kg) and temsirolimus at (8 mg/m2)], 0 of 3 patients experienced a DLT. At an intermediate dose level [IMC-A12 (6 mg/kg) and temsirolimus (8 mg/m2)], 1 of 6 patients experienced mucositis; among an expanded PK cohort for children <12 years, none of 6 patients experienced a DLT. Target inhibition (decreased S6K1 and PAkt) in PBMCS were noted at all dose levels. At 8 mg/m2, the median sirolimus AUC was 225 μg/ml · h (159-226), and median temsirolimus AUC was 3340 μg/ml · h (1894-4387), and median Cmax 1176 μg/ml (480-2231). Conclusions: The recommended pediatric phase II doses for the combination of IMC-A12 and temsorolimus are 6 mg/kg and 8 mg/m2, respectively.
Pharmacokinetic (PK) and pharmacodynamics (PD) properties of SC-PEG e. coli L-asparaginase (EZN-2285) in the treatment of patients with acute lymphoblastic leukemia (ALL): Results from Children's Oncology Group (COG) study AALL07P4.
Authors: Angiolillo Anne L. , Schore Reuven J. , Reaman Gregory H. , Winick Naomi Joan , Devidas Meenakshi , Zheng Hao W. , Wood Charlotte , Lane Ashley R. , Raetz Elizabeth A. , Carroll William L. , Hunger Stephen
Published: March 2020

9543

Background: Asparaginase is a critical therapeutic agent in the treatment of childhood ALL, and pegaspargase (Oncospar, ONC) is now the preferred product in COG frontline ALL trials. EZN-2285 replaces the succinimidyl succinate linker in ONC with a succinimidyl carbamate linker creating a more stable molecule. AALL07P4 was designed to determine the PK comparability of EZN-2285 to ONC when given intravenously in newly diagnosed patients with NCI high-risk (HR) B-precursor ALL. Methods: 162 eligible patients were randomized to receive EZN-2285 at 2100 (LD, n=66) or 2500 (HD, n=42) IU/m2 vs. 2500 IU/m2 of ONC (n=51) in a 2:1 manner based on the prednisone/Capizzi methotrexate arm of COG AALL0232. All groups were similar demographically with the exception of number of patients over the age of 16 years were 6, 5, and 19 in the ONC, HD and LD, respectively. Results: PK, PD and targeted AEs (Gr 3-5) after the first doses of study drug are presented in the table below. Adverse events in induction were not significantly different between arms with the exception of a higher incidence of hyperglycemia (p=0.042). Conclusions: Based on Cmax , AUC0-25d , and asparaginase activity 25 days post drug, EZN-2285 2500 IU/m2 appears to have an improved PK/PD profile compared to pegaspargase 2500 IU/m2 and a comparable toxicity profile in children with HR ALL. [Table: see text]
The application of radiotherapy to the pediatric preclinical testing program: Results of a pilot study.
Authors: Pelloski Christopher E. , Kaplon Rita , Hadziahmetovic Mersiha , Bondra Kathryn , Lu Lanchun , Sommerfeld James , Leasure Justin , Li Ning , Singh Mamta , Nguyen Phuoung , Chronowski Christopher , Kurmasheva Raushan , McHugh Kelsey , Sebastian Nikhil , Houghton Peter
Published: March 2020

9544

Background: The Pediatric Preclinical Testing Program (PPTP) has been successfully utilized to determine the efficacy of novel agents by testing via its mouse-flank in vivo model. We report on the feasibility and biologic outcomes of a pilot study using rhabdomyosarcoma (RMS) xenograft lines treated with radiotherapy (RT) alone and concurrently with the mTOR tyrosine kinase inhibitor, AZD8055, using the PPTP model. Methods: We developed a mouse flank irradiation device for daily delivery of RT in clinically relevant doses (2 Gy per fraction up to 40 Gy).Two RMS xenograft lines of the PPTP, Rh30 (alveolar) and Rh18 (embryonal), were implanted into SCID mice, grown to appropriate volumes and were subjected to fractionated RT. In a second study, daily co-administration of AZD8055 (5-20 mg/Kg, gavage) with RT was performed. Cure rates (durable complete response >12 weeks post-treatment) and RT dose densities (given dose / initial xenograft volume, Gy/cc) were compared between groups. Results: With RT alone at mean dose-densities of 59-60 Gy/cc, cure was achieved in only 4/18 (22%) of the Rh30-bearing mice and 9/12 (75%) of the Rh18-bearing mice (p=0.006). Profiling data revealed higher levels of Fanconi anemia pathway gene expression in Rh30 compared to the more sensitive Rh18. Since recent data showed conditional knockout of mTOR resulted in the loss of FANCD2 gene expression, we postulated that blockade of TORC1/TORC2 with AZD8055 would reduce FANCD2 and increase the RT-sensitivity of Rh30. The addition of AZD8055 to RT resulted in a selective sensitization of the Rh30 line. With a mean RT dose-density of 27 Gy/cc, the cure rate in Rh30-bearing mice improved to 11/15 (73%). For the Rh18 group, the cure rate was 7/15 (46%) at a mean dose density of 44 Gy/cc. Western blot analysis showed the co-administration of AZD8055 abrogated the brisk increase in mTOR signaling and FANCD2 expression after the first several 2 Gy fractions of RT; most strikingly in Rh30. Conclusions: This study demonstrates the feasibility of applying RT to the PPTP model. It recapitulated the expected clinical radiobiology and demonstrated its utility in preclinical testing and the discovery of novel mechanisms of RT resistance in pediatric tumors.
Fever at diagnosis of pediatric acute lymphoblastic leukemia (ALL): Are antibiotics really necessary?
Authors: Khurana Monica , Feusner James Henry , Lee Brian
Published: March 2020

9553

Background: Great variability exists in the management of suspected bacteremia in febrile, neutropenic pediatric ALL patients during chemotherapy. The National Comprehensive Cancer Network and Infectious Diseases Society of America encourage immediate, empiric antibiotics in patients with chemotherapy-induced fever and neutropenia to reduce infection-related mortality. No standard recommendation exists for patients with isolated fever at initial presentation of their ALL. This study evaluates bacteremic episodes in this subpopulation of pediatric patients. Methods: We retrospectively analyzed 245 consecutive patients with ALL at Children’s Hospital Oakland from 2000 through 2011. Using electronic medical records, we investigated each patient’s history and outcome. We surveyed bacteremic episodes up to 60 days after presentation per National Healthcare Safety Network’s guidelines. Inclusion criteria were patients with fever at presentation, which prompts a blood culture, and were started on antibiotics. We stratified bacteremic episodes into community-acquired (up to three days from admission) and nosocomial (four to 60 days). Results: Seventy-seven patients met the inclusion criteria, five of whom had positive cultures – four were contaminants (three coagulase-negative Staphylococcus and one non-anthracis Bacillus) and one was a true nosocomial bactermic episode (E coli). There were no infection-related deaths in the first 60 days of diagnosis in this cohort. Conclusions: Given our institution’s rarity of bacteremic episodes, we contemplate a more judicious use of antibiotics, including quicker narrowing of broad-spectrum antibiotics coverage and discontinuing all antibiotics sooner. These modifications may decrease bacterial resistance to antibiotics, reduce costs, and shorten patients’ hospitalization. We encourage other institutions to conduct a similar investigation.
YM155 sensitivity in pediatric acute lymphoblastic leukemia.
Authors: Chang Bill H. , Jemal Abdusebur , Tyner Jeffrey , Thayer Mathew , Muschen Markus , Druker Brian J.
Published: March 2020

9555

Background: Despite advances in treatment and outcomes in pediatric acute lymphoblastic leukemia, there continue to be subsets of patients that are refractory to standard intensive chemotherapy. Therefore, novel agents are needed to further advance treatment for this disease. YM155 (Astellas) is a selective suppressant of survivin expression. Survivin has been shown to be over-expressed in malignant cells and in relapsed ALL. Early adult phase I/II studies show promise in both tolerability and possible efficacy in B-cell malignancies. Methods: Fresh diagnostic leukemic patient samples, ALL cell lines, and xenograft samples were obtained and subjected to YM155 at doses ranging from 1nM to 10µM. Samples were then tested for viability using standard methane-thiosulfate, apoptosis using Guava nexin Annexin V binding, protein expression using immunoblot, and P53 activation with phospho-flow cytometry. Results: The median IC50 for viability and apoptosis for the samples are: NCI standard risk ALL 5.3nM ±3.47, NCI high risk ALL 91.76 nM ±93.42, T-ALL 336.6nM ±147.7, AML 333.6nM ±489, Ph+ALL xenografts 3.8nM ±1.04, and ALL cell lines 18.5nM ±135. Ph+ALL samples, including primary patient, xenograft, and dasatinib (BMS) resistant samples remain significantly sensitive to YM155. For dasatinib sensitive samples, combination therapy suggests an additive effect by isobologram analysis. Immunoblot and RT2-PCR Arrays (Qiagen) identify that multiple protein expression are decreased with YM155 treatment. Conclusions: Our data supports the model of the use of YM155 as a treatment for ALL including an added benefit in combination with dasatinib in Ph+ALL. Although initial studies suggested that YM155 is a selective suppressant of survivin, subsequent studies are beginning to identify off target effects. These off target effects may enhance the drugs potential for activating cell death. Finally, we show that screening primary samples with YM155 has the potential to select a target population that is more sensitive to YM155 treatment. Future studies will be designed to develop YM155 as an additional therapeutic agent for pediatric acute lymphoblastic leukemia.
Diffuse pontine gliomas in children: Do changing strategies change results?
Authors: Kebudi Rejin , Cakir Betul , Agaoglu Fulya Yaman , Darendeliler Emin , Gorgun Omer , Dagoglu Nergis , Ayan Inci , Dizdar Yavuz , Zulfikar Bulent , Koc Basak
Published: March 2020

9567

Background: The prognosis of children with diffuse intrinsic pontine gliomas (DIPG) is dismal. Despite various studies undertaken to improve outcome, radiotherapy (RT) remains the standard treatment, which is mostly palliative. This study aims to evaluate characteristics and treatment outcome of children with DIPG in a single center. Methods: We retrospectively reviewed the demographic, clinical characteristics and treatment outcome of children with DIPG treated at Istanbul University, Oncology Institute from 1999 to 2011. We also evaluated the group that prospectively recieved RT with concurrent and adjuvant temozolamide after 2004. Results: 47 children (24 female, 23 male) with the median age of 7 years (6 months-16 years) were analyzed. The median duration of symptoms was 30 days (2-630 days). The frequent clinical findings were ataxia, strabismus and motor weakness. All patients received RT, 54-60 Gy to the tumor site. 12 recieved only RT. 35 had concomitant and/or adjuvant chemotherapy with RT. 8 recieved cisplatinum, 7 vincristine. Since 2004, 20 patients recieved the institutional protocol consisting of temozolomide (TMZ) (75 mg/m2/day) for 6 weeks concurrent with RT, followed by TMZ (200 mg/m2/day) for 5 days every 28 days for 12 cycles or until progression. There was no major side effect due to TMZ, thrombocytopenia being the most frequent, but managable side effect. The median overall survival after diagnosis was 13 months (3-132 mo.) for the whole group. The median overall survival in 20 patients that received RT and TMZ [ 17 months (3-132 months)], was significantly superior than that in 12 patients that recieved only RT [ 12 months (3-20 months)] ( (p=0.03). Nimotuzumab was given to 4 patients that progressed after RT and TMZ. There was no major side effect due to nimotuzumab. One was stable for 1 year with significant clinical improvement, the others were stable for 5, 2 and 2 months after nimotuzumab. Conclusions: In our series, the median survival was significantly superior in patients who received RT with concurrent and adjuvant temozolamide in comparison to patients that recieved RT alone. Nimotuzumab may be promising in some progressive patients, its role as upfront treatment needs further investigation.
High-dose thiotepa: Neurotoxicity and risk factors in children with solid tumors.
Authors: Maritaz Christophe , Lemare Francois , Cherif Amani , Demirdjian Sylvie , Valteau Couanet Dominique , Dufour Christelle
Published: March 2020

9572

Background: Thiotepa (TTP) is a cytotoxic agent used in children with solid tumors at high doses followed by autologous stem cell transplantation (ASCT). During these treatments, neurological adverse events (NAE) were observed. Causal relationships and risk factors were investigated. Methods: Patients with solid tumors treated with high-dose thiotepa with ASCT between May 1987 and March 2011 were retrospectively identified. Clinico-biological data were collected and NAE were identified from medical and nursing records. Toxicity was graded according to the NCI CTCAE v4.03 classification. Imputability of thiotepa was assessed according to Begaud et al. method. Analysis of risk factors was assessed with Fisher's exact test (alpha 0.05) and relative risk was estimated by calculating odds ratios with their 95% confidence interval. Results: 251 patients received 307 courses (56 patients received twice) of high-dose thiotepa (600 mg/m²: 82 courses; 720 mg/m²: 76 courses; 900 mg/m²: 149 courses) with ASCT. The median age was 8.33 years (range, 1 - 31.2 years). 81 NAE (26.4%) were described. NAE were considered “possibly” related to TTP in 9 courses, “likely” related to TTP in 35 courses and “very likely” related to TTP in 13 courses. Other NAE were assessed “doubtful” or “incompatible”. In these 57 NAE, neurological symptoms appeared at a median time of 2 days (range, 0 - 4 days) after the introduction of TTP. Symptoms were headache, tremor, dizziness and confusion, blurred vision, seizure, pyramidal tract syndrome, cerebellar syndrome, opsoclonus-myoclonus syndrome and coma. These events disappeared without sequelea in a median time of 3 days (range, 1 - 8 days). TTP was reintroduced in 21 cases. NAE reappeared in 12 cases. For 3 patients with seizure during the first course, premedication with clonazepam prevented NAE during the second course. The use of analgesic for moderate to severe pain, such as tramadol or codeine, increased the probabiblity to have NAE (OR 5.6467; 95CI [1.5523-21.2786]; p 0.037). Conclusions: In our study, the incidence of NAE related to TTP was 18.6%. The outcome was favorable without sequelea in all cases. TTP could be reintroduced after NAE. The association of TTP with tramadol increases the risk of neurotoxicity.
Development of an open-source, flexible framework for interinstitutional data sharing and collaboration.
Authors: Kirby Chaim , Ambros Peter F , Billiter David , London Wendy B. , Mendonca Eneida , Monclair Tom , Pearson Andrew DJ , Cohn Susan Lerner , Volchenboum Samuel Louis
Published: March 2020

9583

Background: Clinical information, “-omic” datasets, and tissue samples are becoming more difficult to harmonize and manage for advanced data mining. We believe that clinical research data can be centralized and provide direct access to sample availability and associated data from a variety of information stores. Methods: We obtained a standardized set of anonymized patient data from the International Neuroblastoma Risk Group. The cohort consists of more than 11,000 children diagnosed worldwide between 1974 and 2002. The data consist of 34 metrics, such as age at diagnosis, stage of tumor, and other clinical and biological markers. We instantiated the dataset into a Postgres database, and using the Django web framework, created a data model for rapid development of tools and views and built a front-end interface for generating complex queries. To test the feasibility of accessing information on disparate and geographically distinct data samples, we have a formal agreement with the Children's Oncology Group Tumor Bank at The Research Institute at Nationwide Children's Hospital. Based on query results, we consume the Tumor Bank tissue inventory data through a web-facing application programming interface. The end-user is presented only with the number of patients who match their query search terms and for whom tissue samples are available. Results: We have completed our initial implementation and have agreements for collaboration with other international consortium groups. We have created a paradigm for statisticians to securely update and add data, and a verification system checks for internal validity and provides a report of the transaction. Our system can initiate queries and accept results in a variety of standards-compliant formats, and will be available in demonstration form by May 2012. Conclusions: Querying patient data while interrogating external sources allows researchers to observe which ancillary data and samples are available and to quickly download data or request any samples. While designed around a neuroblastoma dataset, our system can be applied to a variety of clinical scenarios and will be made available through an open-source license.
Patient-perceived facilitators in the transition of survivorship care from the pediatric to adult care setting.
Authors: Sadak Karim Thomas , DiNofia Amanda , Reaman Gregory H.
Published: March 2020

9587

Background: Survival rates in childhood cancer continue to rise. A new challenge has emerged in optimizing the transition of pediatric survivorship care to similarly focused programs that are age-appropriate. The purpose of this study is to identify components of a clinical survivorship program that facilitate the transition of care for adult survivors of childhood cancer from the pediatric to adult care-setting. Methods: A descriptive study of childhood cancer survivors was conducted using a cross-sectional study design. A questionnaire was used to identify which clinical components of a survivorship program most influenced the decision to transition care to an adult medical center. Primary data collection occurred through the mail. Secondary mechanisms included an online version of the questionnaire and in-person enrollment during survivorship clinic visits. 140 survivors were eligible but only 129 had valid addresses and received the questionnaire. The study endpoint was achieved when the response rate reached 80% (n=103). A descriptive review of clinical program components was performed using a frequency analysis. Results: Of 129 invited survivors, 103 participated (80%). Mean and median age-range was 20-24 years. There were 49 males (48%) and 54 females (52%). The most common diagnoses were leukemia (40/103), lymphoma (20/103), and CNS tumors (9/103). When asked if the participant was willing to transition their survivorship care to an adult facility, 97 (95%) responded affirmatively. The clinical components most frequently rated “Very Important” in the decision to transition survivorship care were the acceptance of insurance (80/103, 78%) followed by the presence of providers knowledgeable in childhood cancer (68/103, 66%). The clinical components most frequently rated “Very Important” or “Important” were flexible scheduling (102/103, 99%) followed by comprehensive care being offered (101/103, 98%). Conclusions: The decision to transition survivorship care to age-appropriate care-settings is complex and not well understood. Issues related to insurance, clinical team composition, and scheduling appear to be most important for young adult survivors making this decision.
Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response.
Authors: Topalian Suzanne Louise , Brahmer Julie R. , Hodi F. Stephen , McDermott David F. , Smith David C. , Gettinger Scott N. , Taube Janis M. , Drake Charles G. , Pardoll Drew M. , Antonia Scott , Spigel David R. , Atkins Michael B. , Lawrence Donald P. , McDonald Dan , Jure-Kunkel Maria , Korman Alan , Kollia Georgia , Gupta Ashok Kumar , Wigginton Jon , Sznol Mario
Published: March 2020

CRA2509

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Smith Ellen M. Lavoie , Pang Herbert , Cirrincione Constance , Fleishman Stewart Barry , Paskett Electra D. , Fadul Camilo E. , Knox Chetaye , Shapiro Charles L. , Gilman Paul ,   Cancer and Leukemia Group B
Published: March 2020

CRA9013

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Analysis of correlation between weight at diagnosis, weight gain after breast cancer treatment, and recurrence in women with early-stage breast cancer (EBC).
Authors: Fedele Palma , Lapolla Assunta Maria , Orlando Laura , Schiavone Paola , Nacci Angelo , Marino Antonella , Cinefra Margherita , Calvani Nicola , Ardizzone Antonino , De Pasquale Maria , Cinieri Saverio
Published: March 2020

e11001

Background: Overweight at the time of EBC diagnosis has been linked frequently to poorer survival in most studies and some evidence suggests that women who gain weight after breast cancer diagnosis are at increased risk of cancer recurrence and death. Most previous studies on this topic have relied on retrospective chart reviews. The aim of this prospective, observational, single-center study is to determine whether weight at diagnosis and weight gain after EBC treatment can be predictive of BC recurrence. Methods: From December 1990 to January 2012, the study included atotal of 311 EBC patients (stage I-IIIa).We assessed weight and body mass index (BMI=kg/m2) at baseline (≤ 1 month after surgery) and 24 months after completion of treatment (chemotherapy ± radiotherapy). The chi square test (X2) was conducted to determine if a significant correlation exists between BC recurrence and 3 categories of BMI at diagnosis (lean weight: BMI <25; overweight: BMI 25-30; obese: BMI >25) and BC recurrence and weight changes after EBC treatment (loss of <1 kg/m2; loss of ≥ 1 kg/m2; gain of <2kg/m2; gain of >2 kg/m2). Results: Median age was 56 years (range28-81); 68% of patients were postmenopausal, stage I-II in 88%; ER+/PGR+ in 66%; ER+/PGR- in 12%; HER2+ in 14%; 72% underwent conservative surgery+radiotherapy; 57% received chemotherapy (CT) and 78% received endocrine therapy alone or after CT. Median BMI at diagnosis was 27.03, after treatment 28.04. After a median follow-up of 13 years 104 patients recurred. Statistical analysis is reported in the table. Conclusions: Our findings show that EBC patients gain weight after treatment. No significant correlation was found between weight at diagnosis, weight changes after EBC treatment and recurrence. At ASCO meeting we will report results of the prognostic associations of baseline biological features, menopausal status and comorbid disease. [Table: see text]
Decline in physical functioning in first 2 years after breast cancer diagnosis to predict survival in older women.
Authors: Sehl Mary Elizabeth , Lu Xiang , Silliman Rebecca A , Ganz Patricia A.
Published: March 2020

e11003

Background: Breast cancer patients often experience a decline in physical functioning following cancer diagnosis. Although most patients recover after treatment, some patients do not. These changes may be magnified in older women with comorbid conditions and could impact survival outcomes. Methods: We used longitudinal data from a prospective cohort study of women 65+ years of age, recruited shortly after diagnosis of early stage breast cancer, to examine changes in self-reported physical functioning measured with the Physical Function Index (PF-10) of the Medical Outcomes Study Short Form-36 (SF-36). Outcomes were constructed for small (0.2 SD), medium (0.5 SD), and large (0.8 SD) decline in the PF-10 measurement over two intervals 1) 3 to 15 months following cancer diagnosis, encompassing treatment and early recovery, and 2) 3 to 27 months following cancer diagnosis, in order to detect sustained recovery versus persistent decline. Cox-proportional hazards regression was used to examine association between survival and decline in PF-10 scores. Results: A large (> 0.8 SD) decline in PF-10 scores from 3 to 27 months predicted shorter 10 year survival (HR=1.37, 95% CI 1.07-1.74). Persistent decline at 27 months was associated with less education, higher baseline PF-10, increased comorbidity, and lack of exercise at baseline. Conclusions: Older women with breast cancer who experience a large and persistent decline in PF-10 are at increased mortality risk. Future research should examine the value of clinical assessment of physical function as a marker for mortality and test interventions to prevent decline in physical function to improve post-treatment survival outcomes.
Standardization of Ki-67 assessment for breast cancer patients with preoperative endocrine therapy.
Authors: Mizuno Yoshio , Takayanagi Hiroyuki , Abe Hiroaki , Sato Kazuhiko
Published: March 2020

e11007

Background: Change in Ki-67 levels is a predictive marker of breast cancer, and it has been widely investigated in patients treated with preoperative endocrine therapy. Several studies have compared Ki-67 expression in untreated specimens obtained by core needle biopsy (CNB) and surgery. We conducted a retrospective study to assess Ki-67 expression between these two specimen types. Methods: 307 patients underwent primary operations for early breast cancer at Tokyo-West Tokushukai Hospital from August 2008 to October 2011. Among them, 193 patients who underwent CNB prior to the operation were enrolled. Patients with ductal carcinoma in situ and those undergoing neoadjuvant chemotherapy were excluded. A cutoff value of 20% was used as the Ki-67 positive criterion. We also examined ER, PgR, and HER2 expression and compared it with Ki-67 expression. Statistical significance for concordance rates between the two types of specimens was evaluated by Wilcoxon t-test. To evaluate the consequences of formalin and genetic heterogeneity, parameters such as operative method and tumor size were analyzed using chi-square test. We reexamined Ki-67 expression in the central laboratory among the Ki-67 discordant group to evaluate the discordance between the pathologist’s judgments. Results: The Ki-67 expression concordance rate between the two types of specimens was 77.7%, which was significantly lower than that for ER, PgR, and HER2 expression at 94.8%, 88%, and 91%, respectively. No significant differences in the operative method (mastectomy vs. breast conserving surgery) or tumor size (≤2cm vs. >2cm) were observed between the groups. We reexamined Ki-67 expression in the Ki-67 discordant group and found that the Ki-67 concordance rate had improved to 93.8%. Conclusions: The Ki-67 expression concordance rate between the two types of specimens was significantly lower than that of ER, PgR, and HER2 expression. However, a reexamination of Ki-67 expression in the central laboratory revealed no significant difference, suggesting the need for a standard pathological assessment of Ki-67 expression to clinically use Ki-67 as a predictive marker.
Retrospective analysis of octagenarian breast cancer patients: Multicenter retrospective study.
Authors: Dizdar Omer , Arslan Cagatay , Eren Tulay , Yalcin Selim , Kucukoztas Nadire , Aksoy Sercan , Rahatli Samed , Sener Dede Didem , Altundag Ozden , Zengin Nurullah , Ozyilkan Ozgur , Altundag Mustafa Kadri
Published: March 2020

e11011

Background: As life expectancy has steadily increased, more patients >80 yo are diagnosed with breast cancer. Data on the tumor biology, treatment choices, and outcomes are limited in this “oldest old” patient population. We herein present a multicenter retrospective analysis of octogenarian breast cancer patients including patient and tumor characteristics, treatment outcomes and survival. Methods: Patients >80 years of age who were diagnosed with breast cancer were retrospectively evaluated in 4 different cancer centers. Demographic features, tumor characteristics, treatment regimens and patient outcomes in terms of DFS and OS were analyzed. Results: A total of 83 patients were identified. Results were summarized in the table. Median age was 82. 69 (83%) had at least one co-morbid disease. Chemotherapy and radiotherapy were utilized in 15 (18%) and 21 (25%) of the patients, respectively, while endocrine treatment was given in 89% of the HR(+) patients. Median follow up was 22 months (range 1-181 months). Ten patients relapsed on follow up and 20 patients died. One of the relapses was locoregional and 9 were distant relapses. Median DFS was 68 months. Five-year OS was 61.9%. Conclusions: Breast cancer in octogenarian patients more likely seems to be low grade and hormone receptor positive. Adjuvant chemotherapy and radiotherapy were utilized infrequently. However, overall survival is fairly well with more than half of the patients alive for >5 years. [Table: see text]
Incidence of chemotherapy (CT)-induced amenorrhea in premenopausal patients (pts) with breast cancer (BC) following adjuvant anthracycline (A), cyclophosphamide (C), and taxane (T).
Authors: Basso Enrico , Rossi Luigi , Tomao Federica , Papa Anselmo , Zaccarelli Eleonora , Spinelli Gian Paolo , Lo Russo Giuseppe , Zoratto Federica , Giordani Erika , Alberti Antonio Maria , Verrico Monica , Strudel Martina , Pasciuti Giulia , Stati Valeria , Rinaldi Giulia , Tomao Silverio
Published: March 2020

e11039

Background: CT may induce amenorrhea or menopause to a variable extent. These side-effects may impair or impede fertility, cause sexual dysfunction, bone loss and menopausal symptoms in many women. We analyzed incidence of amenorrhea in premenopausal pts affected by BC treated with CT. Methods: In this retrospective study we evaluated the incidence of amenorrhea in 24 premenopausal BC pts (43 median age years) treated with adjuvant A + C +/- T based CT. Overall population (OP) had regular menstrual cycle and no pts began hormone therapy, at the same time. Results: 10 pts (42%) received only A + C, 6 pts (25%) received A + C + T, 8 pts (33%) received A + C and after T. In 22 pts (92%) amenorrhea appeared during CT; in particular, 9/10 pts (90%) treated with A + C , 5/6 pts (83%) with A + C + T and 8/8 pts (100%) with A + C and after T. In OP amenorrhea appeared during first three cycles of CT in 18 pts (82%) and particularly 7 pts (32%) after 1 cycle, 7 pts (32%) after 2 cycles, 4 pts (18%) after 3 cycles and 4 pts (18%) in subsequent doses. Amenorrhea occurred within the first two doses of treatment in 14/22 pts (64%); in 6/9 pts (66.7%) treated with A + C, in 4/5 pts (80%) with A + C + T and in 4/8 (50%) with A + C and after T. In 7 pts (32%), median age 40 years, at the end of CT reappeared menstrual cycle. Conclusions: In our small experience the incidence of amenorrhea during CT was extremely high and there are no differences between subgroups undergoing to CT with A + C alone or combined with T. In the group of pts in which T were given concomitant with A and C, amenorrhea occurred earlier than the other two groups. Menstrual cycle reappeared at the end of CT in younger pts.
An aggressive histologic phenotype in young breast cancers in India: A correlational study.
Authors: Hazarika Diganta , Nandini Marysingh , Prabhudesai Shilpa A. , Raghavendra Rao M. , Ajaikumar Basavalinga S
Published: March 2020

e11043

Background: Breast cancer patients younger than 40 years are known to have an aggressive disease than their older counterparts. In this correlational study involving Indian women with breast cancer; we analyzed if age is related to an aggressive histopathologic phenotype and biomarker expression. Methods: Paraffin embedded tissue blocks of hundred chemotherapy naive breast cancer patients with a diagnosis of invasive breast carcinoma were stratified for age group (less than forty and above forty years) equally from the hospital biorepository. Tissue samples were analyzed for pathological stage, histological type, ER, PR and Her2 Neu receptor status, and expression of biomarkers such as Ki67, EGFR and P53 using immunohistochemistry. Data were analyzed using Chisquare test for proportions. Results: Younger age group had significantly higher grade (p=0.03), higher incidence of solid (p=0.04) and micropapillary type DCIS (p=0.004), ER negativity (p=0.04), higher proliferation rate as indicated by over expression of Ki 67 (p=0.03) and triple negativity (p= 0.03) indicating an aggressive histological phenotype compared to older age group. Conclusions: Results suggest that younger breast cancer patients have an aggressive histological phenotype that may affect treatment response. Future studies should explore relationship of these biomarkers to survival and treatment outcomes.
Correlation of HER2/neu expression by real-time qRT-PCR in the peripheral blood of locoregional breast cancer patients with time to progression.
Authors: Kuniyoshi Renata Kelly , Vilas Boas Viviane , Alves Beatriz da Costa Aguiar , Maeda Patricia Hikari , Colo Anna Estela Luiza , Gehrke Flavia de Sousa , Fonseca Fernando L. A. , Del Giglio Auro
Published: March 2020

e11059

Background: HER2/neu is a membrane receptor overexpressed in about 20% of Breast Cancer (BC) patients which can be targeted by several agents. As an epithelial marker it can also be detected by qRT-PCR in the peripheral blood (PB) of BC patients reflecting the presence of circulating tumor cells (CTCs). Objectives: Evaluate the prognostic impact of Her2/neu expression detection in the PB of BC patients. Methods: We performed qRT-PCR for HER2/neu serially at entry into the study and at every 3 months intervals for up to 2 years in every patient. Our qRT-PCR used primers described in Ferreira et al, 2010. In our hands this method could detect 1 MCF-7 cell diluted in 1x104 mononuclear cells and had a specificity of 83% (4/22 normal women controls had a positive test). Results: from 02/20/08 to 02/09/10 we included 41 patients with a histopathological diagnosis of BC with a mean age of 54 years (range 29 to 83 years); 55% post-menopausal; stages I:12%, II:41% and III:46%; 58% and 51% were ER+, 64% PR+, and 25% cerb2 positive (+++). The patients were treated with adjuvant and 41% with neoadjuvant chemotherapy with anthracycline regimens including anthracyclines in 88% and taxanes in 75%. With a mean follow up of 28 months, only HER2/neu expression at study entry as a continuous variable (HR = 1.125 95% CI: 1.021 – 1.238) and disease stage (HR = 6.34 95% CI 1.30 – 30.82) correlated significantly with time to progression by multivariate analysis. HER2/neu expression did not correlate with HER2/neu tissue expression. Conclusions: HER2/neu expression by Real Time RT-PCR in the PB of BC patients is a potential new prognostic factor for BC patients with locorregional disease.
A retrospective study of inflammatory breast cancer patients from seven hospitals in the United Kingdom.
Authors: Rafii Saeed , Poole Christopher John , Francis Adele , Chaudhri Shalini , Rea Daniel
Published: March 2020

e11062

Background: Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer characterised by rapidly progressive breast erythema, pain and tenderness, oedema and paeu d’orange. It is estimated that between 1-4 % of all newly diagnosed breast cancer patients in the United Kingdom have IBC. Methods: We retrospectively identified 51 patients who were treated for IBC at 7 hospitals in the West midlands area of the United Kingdom between 1997 and 2011. Data including patients’ demographics, clinical, radiological and histopathological characteristics were collected from electronic clinical records. The test for HER-2 over-expression was not carried out routinely before 2002, therefore HER-2 status of such patients were assessed retrospectively on the archived tissues. A cox regression analysis was used for statistical assessment of survival and prognostic factors. Results: Median age at diagnosis was 55 years (range 34-83 yrs). Median overall (OS) and progression free survival (PFS) were 32 months (range 7-97 months) and 27 months (range 2-53 months) respectively. The 3–year survival rate for the entire cohort was 32%. Majority of patients were ER and HER-2 positive (49% and 52% respectively). The rate of complete pathological response (pCR) after neoadjuvant chemotherapy was 14%. All cases who had achieved pCR were HER-2 positive who had received anti HER-2 treatment during the neoadjuvant chemotherapy. The OS for the HER-2 positive patients with pCR was not statistically different from the whole cohort (49 vs 32 months, p=0.09) or from the patients with residual disease (49 vs 26 months, p=0.13). Although the triple negative IBC patients consisted 20% of the cohort, no patients in this group had achieved pCR. The OS and PFS for the triple negative patients were 20 and 14 months respectively. Although the rate of pCR was higher in patients treated with taxane compared to those treated with anthracycline containing chemotherapy (35% vs 7%), there was no significant difference in OS between either of these regimens (29 vs 27 months). Conclusions: HER-2 positive IBC patients had higher rate of achieving pCR after neo-adjuvant anti HER-2 therapy. However higher rate of pCR did not improve the OS.