bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of tailored exercise for improving sleep disruption in women with metastatic breast cancer
Authors: Mustian K. M. , Griggs J. , Palesh O. , Morrow G. 
Published: March 2020

9129 Background: Women diagnosed with metastatic breast cancer (MBC) live for months and years. Long-term effects of cancer and its treatment result in chronic symptoms, such as sleep disruption (SDN) that diminish quality of life (QOL). Exercise reduces SDN and minimizes QOL deficits in women with early stage breast cancer during adjuvant treatment, but the feasibility and efficacy of exercise for women with advanced disease is not well established. This phase I pilot study assessed the feasibility and efficacy of a tailored exercise intervention for reducing SDN in women with MBC. Methods: Women with MBC (N=12; mean age=50; disease-free interval 0–10yrs) participated in an 8-week, low to moderately intense, exercise intervention (3x's/wk). The program included flexibility, core stability, aerobic, and resistance training. Results: The intervention was safe, well-tolerated with no adverse events, and well-liked by patients and oncologists. The participants exercised an average of 3.5 days (SD=1.5) a week for 58 minutes (SD=12.9) per exercise session at a moderate intensity (RPE of 3.6; SD=1.2) during the 8-week intervention. Patients spent an average of 25 minutes (SD=7.8) in cardiovascular exercise, 21 minutes (SD=5.5) in resistance exercise, and 10 minutes (SD = 2.2) in flexibility and core stability exercise per exercise session. Paired t-tests showed statistically significant improvements in SDN (Pittsburgh Sleep Quality Index) from baseline to week 4 (mean change=2.56; SE=.96; t1,8 = 2.70, p ≤.05). SDN Also improved from baseline to week 8 (mean change=2.13; SE=1.22). Conclusion: Phase II and III randomized, controlled trials are warranted to substantiate the efficacy of this tailored exercise intervention for improving SDN and, ultimately, QOL and survival among women with MBC. Supported by Roche Biomedical and NCI grant 1R25CA102618 No significant financial relationships to disclose.
Antioxidants and toxicity of cancer chemotherapy: A systematic review of the evidence from randomized controlled trials
Authors: Block K. I. , Koch A. C. , Mead M. N. , Tothy P. , Newman R. A. , Gyllenhaal C. 
Published: March 2020

9130 Background: Much debate has focused on whether or not antioxidants interfere with the efficacy of cancer chemotherapy. The objective of this study is to systematically review the medical literature to compile results from randomized, controlled clinical trials evaluating the effects of concurrent use of antioxidants with chemotherapy on toxic side effects. Methods: We performed a search of literature from 1966-December 2006 using MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases. Randomized, controlled clinical trials reporting mitigation of chemotherapy toxicity were included in the final tally. The searches were performed in duplicate following a standardized protocol. No meta-analysis was performed due to heterogeneity of cancers and chemotherapy regimens. Results: Of 848 articles considered, 32 trials met the inclusion criteria. Antioxidants evaluated were: glutathione (9), melatonin (6), vitamin A (1), an antioxidant mixture (3), N-acetylcysteine (3), vitamin E (5), selenium (1), L-carnitine (1), Co-Q10 (2) and ellagic acid (1). Subjects of most studies had advanced or relapsed disease. Conclusions: One of the 32 studies included reported evidence of significant increase in toxicity from the concurrent use of antioxidants with chemotherapy. In 18 studies, antioxidant groups experienced significantly lower toxicity than control groups. Statistical power and poor study quality were concerns with some of the studies. We have reported elsewhere that randomized trials of various antioxidants given with chemotherapy did not demonstrate an adverse effect on treatment response or survival. Well-designed studies evaluating larger populations of patients given antioxidants concurrently with chemotherapy are thus warranted. No significant financial relationships to disclose.
Identification of genomic DNA signatures predicting relapse in low- and intermediate-risk neuroblastoma using a case control design and high-density SNP genotyping: A Children's Oncology Group (COG) study
Authors: Attiyeh E. F. , Mosse Y. P. , Diskin S. , Hou C. , Attiyeh M. A. , Baker D. , Strother D. , Schmidt M. , London W. B. , Maris J. M. 
Published: March 2020

9500 Background: Neuroblastoma (NB) is a childhood malignancy with a heterogeneous clinical course. Clinical and genomic markers are powerful predictors of outcome and are used to stratify cases for treatment intensity, but imprecision remains. Methods: We identified all disease recurrences from the recently closed COG low- (P9641: 903 eligible, 63 events) and intermediate-risk (A3961: 467 eligible, 40 events) NB phase III trials. To date, tumor DNA from 35 cases and 90 controls (P9641/A3961 patients without event) was used for whole genome copy number and genotype evaluation on the Illumina HumanHap550 (550K SNPs) array. An in-house algorithm was developed to assign genomic copy number and loss of heterozygosity based on probe intensity (log R ratio) and degree of allelic imbalance (B allele frequency). Results: A total of 988 chromosomal aberrations were identified; 231 (23.4%) were whole chromosome (WC) copy number aberrations (CNA). Unsupervised hierarchical clustering identified 10 tumor subsets, with 2 highly enriched with cases showing progression events (13/21; 61%), and 2 dominated by WC gains (chromosomes 2, 6, 7 and 18) with only 2/20 events. Regional aberrations most highly associated with EFS included loss of 11q14-qter (p=0.036), and gain of 11p (p=0.003), 11q13 (p=0.020), and 17q23-qter (p=0.005). Other regional CNAs at borderline univariate significance for EFS included partial gain at 2p, 2q, 6q, 7q, 12q and 13q. The pattern 11p and proximal 11q gain associated with loss of distal 11q was associated with relapse and death (p=0.006 and p=0.023). Conclusion: Whole genome SNP genotyping detects patterns of chromosomal CNAs predictive of EFS, even in situations where events are rare such as low- and intermediate- risk NB. These data support chromosomal 11 and 17 structural CNAs as being most highly predictive of relapse in otherwise favorable NBs, but also suggest that other CNAs likely cooperate and may improve precisions for risk prediction. These data can be used to identify patients eligible for chemotherapy reduction/elimination, and perhaps others for intensification. Ongoing analyses of the remaining samples will extend these conclusions. No significant financial relationships to disclose.
Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols: Final report
Authors: Dhall G. , Grodman H. , Ji L. , Sands S. , Gardner S. , Allen J. , Sposto R. , Finlay J. 
Published: March 2020

9507 Background: The use of dose-intensive chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach to the management of infants and young children with non-metastatic (M-0) medulloblastoma, with the additional benefit of avoiding the late effects of irradiation. We report the results of the “Head Start” I (1991 to 1997) and “Head Start” II (1997 to 2002) clinical trials, using this approach, to treat children with M-0 medulloblastoma, who were less than three years of age at diagnosis. Methods: Twenty one children were enrolled on these two serial studies. After surgery, patients received a uniform induction chemotherapy regimen consisting of five cycles of vincristine, cisplatin, cyclophosphamide and etoposide. Following completion of induction, all patients underwent myeloablative consolidation chemotherapy using carboplatin, thiotepa and etoposide followed by AuHCR, and did not receive irradiation. Irradiation was used only at relapse. Quality of life (QoL) and social and emotional behavior were evaluated on “Head Start” I, and cognitive functioning was evaluated on “Head Start” II survivors. Results: The five-year event-free (EFS) and overall survival (OS) rates (±SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 ± 11% and 70 ± 10%, 64 ± 13% and 79 ± 17%, and 29 ± 17% and 57 ± 19%, respectively. The five-year EFS and OS (±SE) for patients with desmoplastic and classical medulloblastoma were 67 ± 16% and 78 ± 14%, and 42 ± 14 and 67 ± 14%, respectively. Young age (<2 years versus 2 to 3 years) at diagnosis did not appear to impact adversely upon outcome. There were four treatment related deaths. A majority of survivors (71%) avoided irradiation altogether. Neuropsychological functioning in children surviving without irradiation was well within the normal range for most patients. Conclusions: The strategy of brief intensive chemotherapy without irradiation for young children with M-0 medulloblastoma has eliminated the need for craniospinal irradiation in over half (52%) of the patients, with preservation of QoL and cognitive functioning in the majority. No significant financial relationships to disclose.
Randomized phase III trial comparing vincristine, actinomycin, cyclophosphamide (VAC) with VAC/V topotecan/cyclophosphamide (TC) for intermediate risk rhabdomyosarcoma (IRRMS). D9803, COG study
Authors: Arndt C. A. , Hawkins D. S. , Stoner J. A. , Wharam M. D. , Rodeberg D. A. , Parham D. M. , Meyer W. H. ,   Children's Oncology Group
Published: March 2020

9509 Background: IRRMS was defined as nonmetastatic alveolar (A) RMS or undifferentiated sarcoma (UDS); stage (stg) 2 and 3, group (gr) III embryonal (E) RMS; stg 4 ERMS <10y. IRRMS had a 5 yr failure free survival (FFS) of 64% on IRS IV. Since T alone and with C has significant activity in RMS, we tested whether alternating VAC/VTC improved FFS for IRRMS compared with VAC alone. Methods: Patients (pts) < 50 y with IRRMS with adequate organ function were randomized to 39 wks of VAC (V=1.5 mg/m2, A=0.045 mg/kg, C=2.2 g/m2 q 3 wk) vs VAC alternating with VTC (T=0.75 mg/m2/d ×5, C=250 mg/m2/d ×5 q 3 wk), with additional wkly V; doses adjusted for age <3y; local therapy was after wk 12. Pts with parameningeal RMS/meningeal extension (PME) were nonrandomly treated with VAC and immediate XRT. Primary study endpoint was FFS. The study was designed with 80% power (5% 2-sided alpha level) to detect an increase in 5 yr FFS from 64% to 75%, a relative risk (RR) of 0.64, with VAC/VTC, requiring 518 randomized pts. Results reflect the 3rd of 4 planned analyses (75% information); O'Brien Fleming adjusted alpha level is 0.0166; and Cox PH model was used. Results: 620 eligible pts were entered from 9/99 to 8/05: 266 randomized to VAC, 253 to VAC/VTC, 101 PME patients were nonrandomly treated with VAC. Treatment strata were ERMS stg 2/3, gr III 37%; ERMS grp IV <10 y 6%; ARMS/UDS stg 1 or gr I 16%; ARMS/UDS other 25%; PME 16%. 3% of pts were <1 y, 69% 1–9 y, 28% ≥10 y; 13% of pts were stg 1; 26% stg 2; 54% stg 3; 7% stg 4. 77% pts had gr III tumors. Primary tumor sites were PM in 35% pts, extremity 15%, bladder/prostate 16%, retroperitoneal/perineal 15%, other 19%. Median follow up is 2.4 yrs. FFS at 2 yrs is 77% with VAC and 72% with VAC/VTC. Observed data are inconsistent with hypothesized improvement under VAC/VTC (RR=1.20, 98.34% CI: 0.78–1.85, p=0.3). Similar patients on IRS IV had 2 yr FFS of 77%. 2 yr survival (OS) with VAC: 91%; VAC/VTC: 87% (RR=0.94, CI: 0.55–1.59, p=0.8). There were 12 2nd malignancies and 10 deaths as first events. 4 of 10 deaths were from hepatopathy, which decreased in incidence following dose changes for A and C. Conclusions: In IRRMS, VAC/VTC does not significantly improve FFS nor OS versus VAC, and outcome is similar to IRS IV. No significant financial relationships to disclose.
Activation of the PI3K/Akt pathway in neuroblastoma
Authors: Sartelet H. , Castain M. , Fabre M. , Bosq J. , Rougemont A. , Michiels S. , Vassal G. 
Published: March 2020

9523 Background: Neuroblastoma is a pediatric malignant neurorectodermal tumor with still a poor survival in children over 1 year of age. In cancer, the PI3K/Akt pathway contributes to tumor aggressiveness (proliferation, metastasis). It is a major target for novel anti- cancer therapies. The objective was to study the activation of the PI3K/Akt pathway in NB. Methods: 101 patients (median age 2.5 years, range: 0–13) with a resected neuroblastoma (16 stage I; 7, II; 22, III; 48, IV and 8, IVS) were included. Tissue microarrays were constructed containing 101 primary tumors, 39 paired metastases and 56 paired normal tissues. Immunohistochemical staining was performed on sections using antibodies against PI3K, Akt and phosphoAkt (S-473). The expression of membrane receptors (EGFR, HER-2, VEGFR1, VEGFR2, PDGFRa, PDGFRβ, IGF1Rβ, TrkB), proteins directly interfering with AKT (PTEN, mTOR) and downstream proteins (phospho-p70S6 kinase, 4eBP1) was studied. The intensity was evaluated by a semi-quantitative score based on the percentage of positive cells. The Wilcoxon signed rank test was applied for the comparison of paired data and adjusted for multiple testing using the False Discovery Rate criterion. Spearman correlation values (rho) were used to compare the expression between genes in the primary tumors. Results: 60% of the tumors expressed PI3K, 80% AKT and 73% pAKT. In addition, phospho-p70S6 kinase and 4eBP1p were expressed in 95% and 85%. All these proteins had a higher expression in tumors as compared with paired normal tissues (fdr-adjusted p<0.001). Akt and pAkt showed a tendency for higher expression in metastases as compared to paired primary tumors (raw p<0.05 for both, but fdr-p=0.11 and fdr-p=0.17 respectively). While EGFR, IGF1Rβ, TrkB, PDGFRa and PDGFRβ were significantly more expressed in primary tumors as compared to normal tissues (fdr-p<0.05), only IGF1Rβ seemed more expressed in metastases (fdr-p=0.09). A significant positive correlation was found between pAkt and the following: VEGFR1, VEGFR2 and IGF1Rβ (rho>0.34, p<0.001), phospho-p70S6 kinase and mTOR(rho>0.26, p<0.01). Conclusions: The PI3K/Akt pathway is activated in neuroblastoma and could be an attractive target for novel therapies. In addition, the data suggested that VEGFR and IGF1R are preferentially committed to this pathway activation. No significant financial relationships to disclose.
Expression of the multidrug transporter genes ABCC1/MRP1, ABCC3/MRP3, and ABCC4/MRP4 are powerful predictors of clinical outcome in childhood neuroblastoma
Authors: Norris M. D. , Smith J. , Kwek A. , Flemming C. , Cohn S. L. , London W. B. , Buxton A. , Marshall G. M. , Haber M. 
Published: March 2020

9524 Background: We have previously shown, both retrospectively and prospectively, that high-level expression of the multidrug transporter gene ABCC1/MRP1, is strongly predictive of poor outcome in the childhood cancer neuroblastoma (NEJM, 334:231–8, 1996; JCO, 24:1546–53, 2006), and that ABCC1/MRP1 can be regulated by the MYCN oncogene. The contribution of other ABCC family genes to clinical outcome in this disease has now been examined. Methods: Real-time quantitative PCR was used to determine ABCC gene expression in a large prospectively accrued cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Results: Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in the cohort. Amongst the ABCC family, high levels of ABCC1 and ABCC4, but low levels of ABCC3, were strongly associated with reduced survival and event-free survival (P<0.005) in the overall study population, and also in subgroups of patients lacking MYCN amplification. Following adjustment for the effect of MYCN gene amplification and other prognostic indicators by multivariate analysis, expression of ABCC1 (HR=2.3; p=0.03), ABCC3 (HR=2.7; p=0.0141), ABCC4 (HR=3.4; p=0.002) retained significant prognostic value for outcome, whereas age and MYCN amplification lost all prognostic significance. By combining the expression of these three transporter genes, patients could be stratified into groups having excellent, intermediate or poor outcome (EFS=84%, 59%, 17%, respectively). Conclusions: These data, suggest that ABCC1, 3 and 4 are amongst the most powerful prognostic markers yet identified for childhood neuroblastoma and as such represent important targets for potential therapeutic intervention. No significant financial relationships to disclose.
My child matters program: A UICC-sanofi-aventis partnership to improve pediatric cancer care in developing countries
Authors: Ribeiro R. C. , Eden T. , Hartford J. , Lemerle J. , Magrath I. , Sancho-Garnier H. , Steliarova-Foucher E. , Thaxter G. , Tabah-Fisch I. M. , Cavalli F. 
Published: March 2020

9526 Background: Despite dramatic advances in curing childhood cancer in developed countries, most children with cancer live in low-income countries, where misdiagnosis, late diagnosis, lack of access to treatment and abandonment of treatment hinder progress. Methods: In 2004 the International Union against Cancer and sanofi-aventis initiated a campaign to improve childhood cancer care in developing countries through grants for local projects (up to 50,000 euros/year each), a survey of childhood cancer care (conducted by the public health consulting firm Sanisphere), and lobbying to increase political support. The projects focus on professional education, improved access to care, pain management, and psychosocial/educational support. Results: During 2006, 14 pilot projects in Bangladesh, Egypt, Honduras, Morocco, Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam were selected on the basis of feasibility, expected benefit, sustainability, and potential to serve as models. Only eight countries had pediatric hematology/oncology units, ranging from 20 (Tanzania) to 350 (Egypt) beds. These units manage 100 (Senegal) to 1,000 (Bangladesh) children with cancer per year (a small fraction of actual cases in these countries). One-year outcome analysis showed that various short-term objectives were met, including improved patient care infrastructure, public and professional education, earlier detection, improved access to care, the introduction of psychosocial support, decreased abandonment and better follow up. On the basis of these results, 12 additional projects have been funded in Bolivia, Indonesia, Kenya, Mali, Peru and Romania. Conclusions: Relatively small investments, accompanied by external mentoring, can help build sustainable capacity for the diagnosis and care of children with cancer in selected institutions in developing countries. No significant financial relationships to disclose.
Aberrant indoleamine 2,3 dioxygenase (IDO) expression is present in pediatric patients with Hodgkin's lymphoma
Authors: Shahlaee A. H. , Al-Quran S. Z. , Hou W. , Schwartz C. , Munn D. H. 
Published: March 2020

9531 Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme capable of inducing local immunosuppression and systemic tolerance. IDO activity, as measured by serum levels of tryptophan (TRP) and kynurenine (KYN), has been shown to portend a worse prognosis in several different malignancies. Additionally, IDO expression in tumor draining lymph nodes predicts a worst outcome in patients with malignant melanoma making IDO a potential target for therapeutic intervention. To date, no studies have evaluated the expression pattern of IDO in the setting of pediatric Hodgkin Disease. Methods: 20 cases of pediatric Hodgkin Disease (2 stage I, 11 stage II, 2 stage III and 5 stage IV), treated on Children's Oncology Group trials were studied. Paraffin-embedded tumor tissues and matching pre- and post-chemotherapy sera were obtained via the Cooperative Human Tissue Network (CHTN). Immunohistochemical studies were performed on sections of paraffin-embedded tissues to evaluate aberrant IDO expression and secondary serum KYN/TRP changes were analyzed. Results: Tumor tissues from 17/20 patients (85%) were positive for IDO. Two cases showed no expression and one was not evaluable due to tissue necrosis. Morphologically several cell types were noted to express IDO including eosinophils, dendritic cells and large cells, some of which are bi-nucleated, possibly consistent with Reed-Sternberg cells and variants. The mean serum KYN/TRP ratio was elevated pre-chemotherapy in comparison to post therapy levels (P value=0.0043 by Wilcoxon sign rank test). Conclusions: This pilot data demonstrates that aberrant IDO expression is a common finding in pediatric Hodgkin Disease, and that the potential immunomodulatory role of IDO expression in the context of Hodgkin Disease needs to be further studied. These data warrant further prospective evaluation in a larger cohort of patients to determine the clinical applicability of this observation. No significant financial relationships to disclose.
Rate of positive blood cultures after 3 days of empiric antibiotics in pediatric cancer
Authors: Kanathezhath B. , Feusner J. 
Published: March 2020

9535 Background: Infections continue to be a major cause of morbidity and mortality in pediatric oncology patients (pts) with febrile neutropenia (FN). The proportion of such pts who have bacteremia documented after 72 hours (hrs) of broad-spectrum antibiotics, in the absence of local or systemic signs of infection, has not been previously reported. Methods: We conducted a retrospective analysis of all FN oncology pts admitted to our hospital during the period of August 1999 to October 2006. Blood cultures (BCs) from pts who were persistently febrile more than 3 days after initiation of empiric broad-spectrum antibiotics (ceftazidime and tobramycin) were analyzed. Medical records of pts with positive late blood cultures (LBCs) after 72 hrs were reviewed for onset of new signs and symptoms of infection. Hematopoietic stem cell transplant and HIV pts were excluded. Results: Ninety-seven episodes of persistent fever occurred in 71 FN pts. The total number of positive BCs in the first 72 hours was 24 (33.8%). Three (4.2%) of the persistently febrile pts had positive LBC. Of these 3 pts, one had preceding new signs and symptoms. Another had a probable contaminant (only 1 positive BC for coagulase-negative staphylococcus). Only one pt (1.4%) had positive LBC without any new local or systemic signs of infection. The observed frequency of positive LBC was 4.2% for pts and 0.8% (3/391) for total cultures obtained after 72 hours. There were no changes made in the antibiotic regimen of pts with positive LBC and none of them suffered from sepsis related mortality. Conclusions: This is the first report of late blood culture results in FN pediatric oncology pts. The practice of obtaining daily blood culture in such pts who are stable after 72 hrs of broad- spectrum antibiotics has a low yield (<5%), and even lower (<2%) if pts with new signs or symptoms at the LBC are excluded. This observation, if confirmed by larger studies from other centers, could lead to a more efficient, risk based strategy for following these pts. No significant financial relationships to disclose.