bluuebunny/crossref_metadata_2025 huggingface dataset:
Percutaneous radiofrequency ablation of painful osseous metastases: A multicenter trial: American College of Radiology Imaging Network 6661
Authors: Dupuy D. E. , Liu D. , Hartfeil D. , Hanna L. , Blume J. , Ahrar K. , Lopez R. , Safran H. , DiPetrillo T. , Mayo-Smith W.
Published: March 2020

9101

Background: Radiofrequency Ablation (RFA) can destroy tissue in a defined area. Single institutions have reported that RFA can reduce pain from bone metastases. To confirm this, the American College of Radiology Imaging Network (ACRIN) completed a multicenter study of RFA for bone metastases. Methods: Eligible patients had bone pain in one dominant site: tumor size < 8 cm, and location > 1 cm from the spinal cord or cauda equina. RFA was performed under CT guidance. The Memorial Pain Assessment Card was used prior to RFA and repeated daily for two weeks, and at 1 and 3 months after RFA. AEs were recorded in addition to four different pain assessment measures: pain relief, patient mood, pain intensity, and pain severity. Results: Fifty-six patients had RFA at 9 centers. Metastatic sites were pelvis (24), chest wall (19), thoracolumbar spine (8), and extremities (5). Six out of 56 patients experienced at least one adverse event of grade 3 or higher, yielding an AE rate of 10.7% (95%CI is 2.6% to18.8%). AEs attributed directly to RFA were nerve injury in 2 patients. Of the 56 participants, 43 completed the 1 month follow-up and 33 completed the 3 month follow-up. At the time of this analysis, assuming that missing data were missing at random and after adjusting for all covariates, RFA showed significant effect in reducing pain at 1 and 3 month follow-up for all 4 pain assessment measures. The average increase in pain relief from pre-RFA to 1 month follow-up is 26.4 (P<0.0001) and the increase from pre-RFA to 3 month follow-up is 17.2 (P=0.003). The average increase in mood from pre-RFA to 1 month follow-up is 21.5 (P<0.0001) and the increase from pre-RFA to 3 month follow-up is 16.3 (P=0.001). The average decrease in pain intensity from pre-RFA to 1 month follow-up is 25.9 (P<0.0001) and the decrease from pre-RFA to 3 month follow-up is 13.0 (P=0.02). The odds of being in lower pain severity at 1 month follow-up is 12.6 (P<.0001) times higher than that at pre-RFA, and the odds at 3 month follow-up is 7.1 (P<0.0001) times higher than that at pre- RFA. Conclusions: This cooperative group trial confirms that RFA can safely palliate pain due to bone metastases. ACRIN receives funding from the National Cancer Institute through the grants U01 CA079778 and U01 CA080098.

No significant financial relationships to disclose.
Multivitamins do not improve radiation therapy related fatigue: Results of a double-blind randomized cross-over trial
Authors: Kaliks-Guendelmann R. , Oliveira Campos M. P. , Souza Fêde Â. B. , Bensi C. G. , Trufelli D. C. , Pecoroni P. G. , Ranzatti R. P. , del Giglio A.
Published: March 2020

9103

Background: Fatigue is a common symptom in cancer patients including those receiving radiation therapy. Multivitamins are broadly used by cancer patients to improve overall health and energy. Methods: We conducted a double blind randomized cross- over trial of multivitamins versus placebo in patients with breast cancer (BC) undergoing radiation therapy (Rxt) in order to evaluate if multivitamins would affect fatigue and quality of life. We randomized patients at the beginning of Rxt treatment to either placebo or Centrum Silver (Wyeth-Whitehall laboratory). At the middle of the radiation treatments patients were switched from placebo to multivitamins and vice versa. Patients answered to the EORTC QLQ C-30 quality of life (QOL) and Chalder fatigue questionnaires at the beginning, the time of switching and at the end of Rxt. Results: We randomized forty patients to either placebo or Centrum Silver. At the middle of the radiation treatments patients were switched from placebo to MVi and vice versa. Patients answered the EORTC QLQ C-30 quality of life (QOL) and Chalder fatigue questionnaires at the beginning, the middle and at the end of Rxt. Both groups experienced decreases in general (p = 0.009; p = 0.001) and physical fatigue scores (p = 0.031; p = 0.029) at the end of the course of placebo compared to the assessment prior to this treatment. We also observed significant improvements in functional (p = 0.026) and symptoms (p = 0.016) score scales of the QOL questionnaire in the patients on placebo. No significant changes were elicited with the use of MVi. We also observed significantly lower rates of fatigue in the patients who had just finished a course of placebo as compared to patients finishinga course of MVi (0 vs 25% p = 0.035). Conclusions: MVi do not improve radiation related fatigue in patients with BC.

No significant financial relationships to disclose.
Prophylaxis of chemotherapy-induced neutropenia: Patterns of care in U.S. community oncology practices
Authors: Naeim A. , Friedman L. , Pasta D. J. , Elkin E. P. , Malin J. , Viswanathan H. , Ozer H.
Published: March 2020

9123

Background: Adherence to neutropenia guidelines may improve patient outcomes and decrease costs associated with febrile neutropenia (FN). This analysis presents baseline data on patterns of colony-stimulating factor (CSF) use among community-based oncology practices prior to an educational intervention targeted to health care providers to improve adherence to CSF guidelines from the National Oncology Alliance (NOA). Methods: Medical records were identified from 47 participating sites. Abstractors collected data from a sequential sample of adult cancer patients receiving chemotherapy during the year prior to site randomization to an educational intervention (June and August 2006). A complex algorithm was developed to identify patients for whom the NOA guidelines recommend primary prophylaxis with a CSF including (1) patients receiving a chemotherapy regimen with a >20% expected risk of FN and (2) patients receiving chemotherapy with a 10–20% risk of FN and who have one of the following risk factors present: diminished performance status or non-Hodgkin's lymphoma with low serum albumin or high serum LDH or spread to bone marrow. Results: 2594 patients were evaluated for this analysis. Most were female (66%) and the mean age was 61.7 years (± 13.1). During this period (2005–06), 423 (16%) patients received chemotherapy regimens with an FN risk >20% and 143 (6%) received chemotherapy regimens with an FN risk of 10–20% and had a risk factor. Of patients receiving chemotherapy with a >20% risk of FN, 176 (42%) received CSF primary prophylaxis. Of patients receiving chemotherapy with a 10–20% risk FN with a risk factor present, 40 (28%) received CSF primary prophylaxis. Conclusions: Many patients for whom guidelines recommend treatment did not receive CSF primary prophylaxis. After the year-long educational intervention, we will re-evaluate CSF patterns of care and assess whether adherence to guidelines improved patient outcomes.

No significant financial relationships to disclose.
Influence of skin color in the development of erlotinib-induced rash: A report from the SERIES clinic
Authors: Lai S. E. , Minnelly L. , O'Keeffe P. , Rademaker A. , Patel J. , Bennett C. L. , Lacouture M. E.
Published: March 2020

9127

Background: A papulopustular reaction occurs in 68–75% of patients undergoing treatment with the epidermal growth factor receptor (EGFR) inhibitor erlotinib, necessitating dose modification or interruption in 14% and 12% of patients, respectively. Based on preclinical data showing that EGFR inhibition in the skin may potentiate the harmful effects of ultraviolet radiation (UVR) exposure, sun protection is generally advocated. Because the level of melanin, a biological pigment in the epidermis, correlates with increased intrinsic protection against the harmful effects of UVR, we hypothesized that lower levels of skin pigmentation would be associated with higher frequency and severity of erlotinib rash. Methods: We conducted a retrospective chart review of 42 patients undergoing erlotinib therapy to characterize the relationship between skin sensitivity to UVR and severity of EGFR inhibitor rash. Skin sensitivity to UVR was categorized using the Fitzpatrick skin phototype (SPT) classification scheme, and individuals were grouped in phototypes I/II, III/IV, and V/VI. Grading of rash was performed using the NCI-CTC criteria version 2.0 and 3.0. Results: Patients with SPT I/II developed rash grades 0 (6%), 1/2 (31%), and 3/4 (63%), whereas patients with skin phototype III/IV had rash grade 0 (26%), 1/2 (68%), and 3/4 (5%). Patients with SPT V/VI had rash grade 0 (43%), 1/2 (57%), and 3/4 (0%). Lower skin phototypes had higher grade rash (p=0.0006 by Fisher's exact test). Conclusions: Management of cutaneous side effects from EGFR inhibitors is important in order to achieve maximal patient compliance and anti-cancer therapeutic benefit, and the correlation between rash and survival underscores maintaining patients on therapy. The results of this study suggest that SPT may be an independent predictive factor for EGFR inhibitor-induced skin toxicities, thus impacting pre-therapy counseling and early intervention.

[Table: see text]
Factors associated with depressive symptoms in patients with metastases from prostate cancer
Authors: Domont J. , Fizazi K. , Zesnasni F. , Plantade A. , Massard C. , Escudier B. , Chauchereau A. , Dauchy S.
Published: March 2020

9131

Background: The purpose of this study was to identify predictive factors of depression in patients with metastases from prostate cancer. Methods: Patients with evidence of metastases from prostate cancer were prospectively screened for depression. Depressive symptoms were defined by the Beck Depression Inventory-Short Form (BDI-SF) with a low cut-off score of 4 to optimize sensitivity as a screening test (Lowe AW, 2004). Self-report questionnaires including BDI-SF were sent to pts through the mail and then given back to the oncologist. In case of a BDI-SF > 4, a consultation with a psychiatrist was proposed, so that the diagnosis of depression could be made and treatment be started. Characteristics including marital status, spiritual well-being, educational level, ongoing treatment for prostate cancer, and the presence of pain requiring analgesic therapy were registered. Results: 92 patients were prospectively enrolled of whom 54 (60%) completed the self-report questionnaires. Median age was 69 years (range: 50–84). 31 pts (54%) had castration-refractory disease, of whom 30 were receiving chemotherapy: docetaxel (n=22), carboplatin-etoposide (n=6) and doxorubicin (n=2). Eighteen patients (33%) had a BDI-SF score > 4, of whom 10 (18%) had a major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria. Logistic regression analysis showed that pain requiring analgesic therapy was the only predictive factor of depressive symptoms (OR=3.75; 95% confidence interval 1.1–12.4). In patients with pain requiring treatment, the incidence of depressive symptoms and MDD was 53% and 32%, respectively. In contrast to female with advanced breast cancer (Conforti R, 2004), marital status and belief in god were not predictive factors of depressive symptoms in this population of males. Conclusions: Pain requiring analgesic treatment was the only factor significantly associated with depressive symptoms in this sample of 54 patients with metastatic prostate cancer. A screening for depression should be systematically implemented at least in this subgroup of patients.

No significant financial relationships to disclose.
Anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) for primary refractory neuroblastoma (NB) in bone marrow (BM)
Authors: Kushner B. H. , Kramer K. , Modak S. , Cheung N. V.
Published: March 2020

9502

Background: Despite high-dose chemotherapy, NB in BM often persists and forebodes death. Methods: 3F8/GM- CSF was used in 63 patients (pts) with NB in BM by morphology and/or metaiodobenzylguanidine (MIBG) scan, no prior progressive disease or immunotherapy, and no soft tissue NB; 35 (56%) of the pts had received second-line therapy and 24 (38%) were post-transplant. Treatment was repeated if human anti-mouse antibody (HAMA) titer was low. Results: Of 30 pts with NB in BM but normal MIBG scans (Group 1), 25 (83%) had complete response (CR) after cycle 1 (n=17), cycle 2 (n=5), or cycle 3, 6, or 7 (one pt each), including 13/16 post-transplant pts. Among 15 pts with NB in BM and abnormal MIBG scans (Group 2), 12 (80%) had CR in BM after cycle 1 (n=5), cycle 2 (n=4), cycle 4 (n=2), or cycle 9 (n=1); MIBG scans normalized in 5/11 pts who had multiple abnormal MIBG(+) sites and in 4/4 pts who had one abnormal MIBG(+) site (irradiated in three pts). Of 18 pts who had abnormal MIBG scans but no NB seen in BM tests (Group 3), 14 (78%) had CR or near CR, including eight whose MIBG(+) sites were irradiated. Early HAMA limited treatment in 19 pts, but was prevented by high-dose cyclophosphamide. CR continues in 12 pts (five never transplanted) with long follow-up (20+ -to- 146+ months) and in 10 pts with short follow-up. The only common toxicities of this outpatient treatment were pain and hives; there were no long-term toxicities. Conclusions: 3F8/GM-CSF is well tolerated, achieves a high CR rate against primary refractory NB in BM (including post-transplant), and may prolong disease control in non- transplanted pts. Further experience will show whether it ought to be used for consolidative therapy in place of myeloablative cytoreduction.

No significant financial relationships to disclose.
A phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma
Authors: Baker D. L. , Schmidt M. , Cohn S. , London W. B. , Buxten A. , Sandler A. , Shimada H. , Matthay K.
Published: March 2020

9504

Background: Infants with advanced neuroblastoma (stage 3 and 4) and children >1 year with favorable biology stage 3 disease have had a survival exceeding 80% with aggressive chemotherapy. The primary objective of Childrens Oncology Group A3961 was to maintain a 3-year event-free and overall survival rate above 90% for intermediate risk (IR) neuroblastoma with a reduction in therapy compared to historical trials for similarly defined risk patients. Methods: IR patients were defined by selected clinical (age, INSS stage, histopathology) and biologic (MYCN status and DNA index) factors. All eligible IR patients were MYCN non-amplified and were divided into subcategories defined as favorable or unfavorable biology. Therapy consisted of 2 to 3 agent combinations of carboplatin, etoposide, cyclophosphamide and doxorubicin given every 3 weeks for a total of 4 cycles (favorable biology) or 8 cycles (unfavorable biology). Patients with favorable biology failing to achieve CR/VGPR after 4 cycles and surgery, received 8 cycles. All patients were required to enter a companion neuroblastoma biology study and to enroll on A3961 within 28 days of diagnosis. Results: Between March 1997 and May 2005, 467 eligible patients were enrolled on study. These included 261 stage 3 (105 children; 156 infants), 174 stage 4 infants, and 32 stage 4s infants. 362 (78%) were less than 12 months of age at diagnosis. 330 (71%) patients had favorable and 137 (29%) unfavorable biology. There were 40 (12.1%) of 330 favorable biology patients who went onto cycles 5–8. There were 52 events in 467 cases including 15 deaths and two secondary AML. Conclusions: The primary hypothesis of this study was confirmed and survival rates greater than 90% were maintained for IR neuroblastoma with reduced therapy compared to historical trials. The successor trial will prescribe duration of therapy based, in part, on loss of heterozygosity states at 1p36 and 11q23 as well as initial response to treatment in an endeavor to further reduce therapy for this group of patients.

[Table: see text]

No significant financial relationships to disclose.
Comparison of intermittent versus continuous methotrexate plus 6-mp in maintenance regimen for standard risk acute lymphoblastic leukemia in children (GBTLI ALL-99)
Authors: Brandalise S. R.
Published: March 2020

9512

Objectives: To compare by randomization the conventional use of 6-MP (50 mg/m2 daily) / MTX (25 mg/m2/wk) regimen with the intermittent use of MTX (200 mg/m2/IV 6 h infusion each 21 days)/ 6-MP (100 mg/m2/day × 10) in maintenance therapy. Methods: Newly diagnosed ALL children up to 18 yrs of age registered in the GBTLI ALL-99 Protocol. The eligibility criteria for standard-risk group were age >1 <9 years and WBC count at diagnosis <50,000/mm3 and good responders at D7/D14. Randomization was made after the late consolidation phase (week 42) prior to the maintenance treatment. Treatment Schedule: Induction: [DX(Pred), DNM, VCR, L-ASP, CICLO, Ara-C, 6-MP], Intensification: (MTX 2 g/m2 6 h inf. × 4, 6-MP) Late Consolidation: (DX, VCR, DOXO, L-ASP, CICLO, ARA-C, 6-TG) plus prolonged triple intratecal therapy, were done previously to maintenance therapy. Total treatment duration was two years. No CNS radiation was done. Toxicities were defined according to NCI-version 2001 criteria. Results: 560 pts were enrolled in the study. 22 slow responders pts (4.1%) moved to high risk group. The total number of analyzed pts was 512. Two hundred and thirty pts entered group 1 [continuous (conventional) 6MP-MTX] and 230 pts entered group 2 (Intermittent MTX/6-MP). Remission rate was 95.3%. 439 pts (87.9%) are in CCR. The mean follow up period is 2.2 years. The estimated 5 years OS rate for both groups is 88.1% ± 2.1%. The estimated 5 years EFS for both groups is 80% ± 2.9%. According to maintenance regimen, the 5 years EFS rate is 80.2% ± 4.5% and 88.3% ± 3.7% for group 1 and group 2, respectively (p=0.048). Grade 3 and 4 hepatic toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.019). Grade 3 CNS toxicities were 13 episodes (group 1) and 5 in group 2. Grade 4 hematological toxicities were 254 episodes for group 1 and 144 episodes for group 2 (p=0.003). Conclusions: Despite the short mean time follow-up (2.2 years) the patients with the intermittent regimen (Group 2) had better EFS rate (p = 0.048) and less hematological, CNS and hepatic toxicities, comparing with patients that received conventional maintenance treatment (group 1).

No significant financial relationships to disclose.
Chemoimmunotherapy reinduction with epratuzumab in children with ALL with marrow relapse: A Children's Oncology Group (COG) pilot study (ADVL04P2)
Authors: Raetz E. A. , Cairo M. S. , Borowitz M. J. , Blaney S. M. , Krailo M. D. , Leil T. A. , Goldenberg D. M. , Wegener W. A. , Carroll W. L. , Adamson P. C.
Published: March 2020

9513

Background: CD22, a 135kd protein restricted to B-cells, is expressed in > 90% of childhood B-precursor acute lymphoblastic leukemia (ALL). We conducted a feasibility/phase 2 study of epratuzumab, a humanized monoclonal antibody against CD22, with reinduction chemotherapy in children with relapsed CD22+ ALL. Methods: The feasibility portion (n=12) of the study is reported here. Patients with first or later ALL marrow relapse at any time following diagnosis, ± extramedullary disease, with = 25% blasts expressing CD22 and a presenting white blood cell count (WBC) of = 50,000/μl, were eligible. Therapy consisted of a 14-day single agent phase (epratuzumab 360 mg/m2 /dose IV twice weekly × 4 doses), followed by 4 weekly doses of epratuzumab in combination with standard reinduction chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin). Remission induction rates and minimal residual disease (MRD) by flow cytometry were determined at the end of this 6-week period. PK studies were performed by ELISA based immunoassay (prior + 30 minutes after infusions). Results: 12 evaluable patients, median age 10 years (range 3 - 18), were accrued. 9 pts were in 1st (n=5 early; n=4 late), and 3 pts in 2nd or later marrow relapse. The mean (±SD) trough epratuzumab concentration increased from 69±23 to 232±74 μg/ml during the initial 14 days. Surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration in all but one patient, indicating effective targeting of leukemic cells by epratuzumab. The most frequent toxicities were grade 1–2 infusion reactions (n=9). Two dose limiting toxicities occurred: one patient had a Grade 4 seizure of unclear etiology and one patient had asymptomatic Grade 3 ALT elevation. 9 patients achieved a complete remission following chemoimmunotherapy, of whom 7 were MRD-negative. Conclusions: Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and well tolerated in children with relapsed ALL, producing favorable early responses in the majority of patients. The phase II portion of the study is ongoing.

[Table: see text]
Hematopoietic stem cell transplant (HSCT) versus intensive chemotherapy in infant acute lymphoblastic leukemia (ALL)
Authors: Dreyer Z. E. , Dinndorf P. , Sather H. , Hilden J. M. , Devidas M. , Heerema N. A. , Smith F. O. , Carroll W. , Reaman G. , Camitta B. M.
Published: March 2020

9514

Background: Infants (<366 days) with ALL and an MLL rearrangement (MLL-R), have a dismal prognosis. Early relapse is common and event free survival (EFS) is poor. The Children's Oncology Group (COG) parallel pilot trials, 1953 and 9407, were designed to prospectively compare early HSCT to intensified chemotherapy in infants with MLL-R ALL. This is the largest prospective trial investigating the role of HSCT in such patients (pts) in first remission (CR-1). Methods: From 1997–2000, 186 pts were registered (132 MLL-R). Both trials were identical through Induction, Induction Intensification and Re-Induction (Re-I), then diverged. Pts with MLL-R ALL with matched/one antigen mismatched - related/unrelated donors were to undergo HSCT (mandated on 1953/optional on 9407) at completion of Re-I. The HSCT regimen was ara-c, cyclophosphamide, steroid and total body irradiation; graft vs. host prophylaxis was cyclosporine. Results: Compliance with protocol mandated conditioning for HSCT was poor and 28/53 HSCT pts received non-protocol preparative regimens. By life table comparisons, the 5 year HSCT EFS was 50.9% (SE=9.9%, RHR 1.13) vs. 48.7% (SE=10.1%) p=0.68 in 47 control pts (chemotherapy-treated, MLL-R), who survived 143 days (median time to HSCT = 143 days). By statistical regression analysis the RHR for HSCT was 1.454 (90% CI 0.911, 2.318), p-value = 0.19, showing a trend in favor of chemotherapy alone. Neither donor source nor preparative regimen affected HSCT outcome. Chemotherapy outcomes were similar on 1953 and 9407. Events for HSCT pts were most common in the first 6 months: 20 events (11 HSCT related deaths/9 relapses). In the control group, 7/9 events in this time period were due to relapse. Conclusion: These results show no advantage for HSCT in CR1 in infants with MLL-R ALL. These data do not support the routine use of HSCT in CR1 in MLL-R infants.

No significant financial relationships to disclose.
Obesity in adult survivors of childhood acute lymphoblastic leukemia: A follow-up report from the Childhood Cancer Survivor Study
Authors: Garmey E. G. , Liu Q. , Sklar C. A. , Meacham L. R. , Stovall M. , Yasui Y. , Robison L. L. , Oeffinger K. C.
Published: March 2020

9518

Background: We previously reported an association between ≥ 20 Gy cranial radiotherapy (CRT) and obesity in adult survivors of childhood ALL. This follow-up study aimed to determine if, with time, (1) the prevalence of obesity and (2) the rate of BMI change were increased in ALL survivors in comparison with sibling controls. Methods: A longitudinal cohort comparing 1,451 adult survivors of childhood ALL (mean age 32.3 years) to 2,167 siblings of childhood cancer survivors (mean age 35.9 years). BMI was calculated from self- reported heights and weights and used to determine the prevalence of being overweight (25.0 ≤ BMI < 30.0) or obese (BMI ≥ 30.0). Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for being overweight or obese among ALL survivors compared to sibling controls. BMIs at baseline and follow-up (with a mean interval of 7.8 years) were used to calculate mean BMI increases per year occurring between these timepoints. Results: Age- and race-adjusted ORs for obesity among survivors compared with siblings are shown in the table . Notably, 10–19 Gy CRT was associated with an increased likelihood of being obese in comparison with siblings. In longitudinal analysis, survivors who were treated with CRT had a significantly greater net increase in BMI/year in comparison with siblings. At follow-up, 69.7% of females treated with ≥ 20 Gy CRT prior to the age of 10 were overweight (31.1%) or obese (38.6%). Conclusion: Cranial radiotherapy ≥ 10 Gy employed in the treatment of childhood ALL is strongly associated among both male and female survivors with increases in the prevalence of obesity and average BMI gains over time. Female survivors who received CRT ≥ 20 Gy, particularly those treated at a younger age, were most affected.

[Table: see text]

No significant financial relationships to disclose.
Endogenous knock-down of survival genes improves chemotherapeutic response in a T-ALL cell line
Authors: Morrison D. , Moskowitz N. , Bhojwani D. , Lee H. , Patel B. , Horton T. , Raetz E. , Carroll W.
Published: March 2020

9522

Background: New targets for more effective, less toxic therapeutic approaches to childhood acute lymphoblastic leukemia (ALL) can be developed by discovering pathways unique to the blast. Using microarray technology, we identified potential target genes that are up-regulated at relapse compared to diagnosis (Blood 2006;108:711–7). Two genes, survivin and securin, were selected for analysis because they are involved in cell cycle regulation, apoptosis and cellular transformation. We hypothesized that decreasing endogenous expression of these genes would increase apoptosis and sensitize cells to chemotherapy. Methods: Short hairpin RNA constructs (shRNA) targeting both transcripts and a control shRNA were engineered. LSN2181295 (sodium salt of LY2181308), an antisense molecule targeting survivin developed by Eli Lilly and its mismatch control (LSN2293329) were also tested. The T- ALL cell line Molt4 was transiently transfected with shRNA constructs or antisense oligos. Western blot and qRT-PCR were performed to determine the time course of target knock-down while apoptosis was assessed by annexin-V labeling. Following transfection, cells were also treated with varying doses of etoposide and doxorubicin for 24 hrs prior to FACS analysis. Results: The survivin and securin shRNAs blocked endogenous gene expression by 80–90%, with maximal effect achieved at 48 hrs. Transfection of Molt4 cells with survivin and securin shRNAs induced ∼13% and 35% apoptosis, respectively, as compared to a control shRNA. When used in combination with chemotherapeutic agents, the shRNA constructs potentiated the effect of both doxorubicin and etoposide at low dosages (≤100 nM and ≤0.4 uM respectively, p values <0.01). The antisense survivin drug had a similar effect as the survivin shRNA and also potentiated the effect of vincristine. Conclusion: Targeting levels of survivin and securin in conjunction with standard chemotherapy maximizes leukemia cell kill and effectively lowers the amount of chemotherapy needed to achieve cell death. Such an approach may improve overall survival for patients at relapse and could also lead to the delivery of effective chemotherapy at less toxic doses.

No significant financial relationships to disclose.
In vitro evaluation of the PARP inhibitor ABT-888 in combination with temozolomide for the treatment of pediatric leukemia
Authors: Horton T. M. , Zhang L. , Jenkins G. N. , Berg S. L. , Blaney S. M.
Published: March 2020

9528

Background: The alkylating agent temozolomide exerts its primary cytotoxic activity through the addition to O6 methyl adducts to guanine residues in DNA, and temozolomide resistance results either from increased expression of methyl-guanine DNA methyltransferase (MGMT), which removes O6 adducts, or from mutations in the mismatch repair system (MRS), which lead to microsatellite instability (MSI). Temozolomide also creates N3 and N7 methyl adducts that are efficiently removed by the base excision repair (BER) system. PARP inhibitors block BER and may potentiate the cytotoxic effects of temozolomide. Methods: The cytotoxicity of temozolomide in combination with the PARP inhibitor ABT-888 was evaluated in vitro in leukemia cell lines and primary leukemia cells using the MTT assay. PARP activity was measured using a commercially available PARP assay. Results: ABT-888 effectively enhanced temozolomide cytotoxicity in cell lines with elevated MGMT (Jurkat and HSB2 T-cell ALL cell lines) or MRS deficiencies (Jurkat and Molt-4 T cell ALL). The temozolomide IC50 decreased from 450 μM to 35 μM at an ABT-888 concentration of 5 μM in the Jurkat T-cell ALL cell line and from 340 μM to 7.5 μM in the HSB2 T-cell line. ABT-888 also enhanced temozolomide cytotoxicity in non-T-cell leukemia subtypes, decreasing the IC50 in the JM1 pre-B ALL cell line from 51 μM to 7.7 μM and decreasing the IC50 from 316 μM to 22 μM in tumor cells obtained from a patient with pre-B ALL. PARP activity was also examined. In contrast, the sensitivity of U937 AML cells to temozolomide showed no effect of the addition of a PARP inhibitor. These results are consistent with the findings that these cells have low or undetectable MGMT and no MSI to suggest MRS mutations. Conclusion: These results suggest that ABT-888 may enhance the cytotoxic activity of temozolomide in leukemia patients whose tumors are resistant to temozolomide because of elevated MGMT expression and mismatch repair defects.

No significant financial relationships to disclose.
Targeted immunotherapy with gemtuzumab ozogamicin (GO) following reduced intensity allogeneic stem cell transplantation (RI AlloSCT) to reduce minimal residual disease (MRD) in children with acute myeloid leukemia (AML): MRD monitoring by Wilms tumor gene
Authors: Roman E. , Olszewski M. , Kletzel M. , Bhatia M. , Bradley B. , George D. , Garvin J. , Satwani P. , van de Ven C. , Cairo M. S.
Published: March 2020

9532

Background: RI vs myeloablative (MA) AlloSCT in adults with AML is associated with significantly less transplant related mortality but increased rate of relapse, presumably secondary to MRD (Alyea et al; Blood, 2005). Quantification of the WT1 has been used successfully to detect MRD in children with acute myeloid leukemia (AML) (Kletzel et al; Pediatr Dev Pathol, 2002). GO has induced ORR in >30% of patients with overt relapsed CD33+ AML and may have a better effect in the setting of MRD (Sievers et al; J Clin Oncol, 2001). We have shown that RI AlloSCT followed by 2 doses of GO in average risk AML has resulted in >94% donor chimerism (Roman/Cairo, Clin Can Res, 2005). We explored changes in MRD prior to and after consolidation with 2 doses of GO targeted immunotherapy in children with average risk AML post RI AlloSCT. Methods: 11 pts, 11 years (0.5–21) with CD33+ (8 CR1, 3 CR2) received fludarabine 30 mg/m2x6d and busulfan 3.2–4 mg/kgx2d. Donors: 7 6/6 HLA related peripheral blood stem cells (RPBSC), 1 5/6 RPBSC, 1 6/6 related cord blood (CB) and 2 4/6 unrelated CB. GOx2 was administered =60d post AlloSCTx2 (8wks apart), at 4.5–7.5 mg/m2 (dose escalation). Samples were collected for WT1 analysis prior to and after each dose of GO (n=5). WT1 levels were determined by quantitative RT-PCR and compared with WT1 expression in a K562 leukemia line. Positive MRD was a ratio of K562 WT/patient's WT1>0.5. Results: The MTD for GO post RI AlloSCT has not been reached. 8/11 are NED (3 deaths: 1 relapse, 1 graft failure, 1 cGVHD) Pre GO WT1–0.079±0.07 (n=5), pre GO-dose #2–0.012±0.016 (n=3). One of these patients had detectable MRD (WT1–1.56) prior to the GO-dose #2, no MRD at 1year and is alive and in remission at 2 years post GOx2. The fifth patient entered transplant with +MRD (WT-0.866), relapsed after the first dose of GO and died of relapse prior to receiving the second dose. Conclusions: Targeted therapy with GOx2 may be useful in eradicating MRD in patients post RI AlloSCT. A larger cohort is necessary to assess the impact of GO (at the MTD) on MRD post RI AlloSCT in children with AML.

No significant financial relationships to disclose.
Treatment of acute myeloid meukemia with a mrc aml 10 modified regime in Mexican children
Authors: Gallegos Castorena S. , Medina Sanson A. , Zapata Tarres M. , Dorantes Acosta E. , Martinez Avalos A.
Published: March 2020

9533

Background: The results of treatment in acute myeloid leukemia had been limited. We have obtained event free survival of 17% in patients treated in our Institution from 1990–2003. The availability of stem cell transplantation is limited in our country. The objective of the present study was to assessed the remission rate, event-free and overall survival obtained with and intense chemotherapy regime. Methods: We designed a prospective study using a MRC AML 10 modified protocol from February 2003 to September 2005 for patients diagnosed with de novo AML 0 to 18 years. Patients were classified as high risk if they presented with M4 or M5 morphology, >100,000 WBC/mm3, positive CSF, t(11;23) or > 1 cycle to achieve remission. Induction consisted on two cycles of daunorubicin 50 mg/m2/day 1, 3 and 5; cytarabine 100 mg/m2/dose twice days 1–10 and etoposide 100 mg/m2/day 1–5; in the second cycle cytarabine was scheduled for 8 days. Consolidation consisted on 4 alternating cycles of etoposide 100 mg/m2/day 1–5 and cytarabine 1 gr/m2/dose twice day 1–3 alternating with mitoxantrone 10 mg/m2/day 1–5 and cytarabine 1 gr/m2/dose twice day 1–3. All patients received triple intrathecal chemotherapy every cycle and craniospinal radiation was limited to patients with >100,000 WBC/mm3 o positive CSF at diagnosis. Remission rate, event-free and overall survival were assessed. Kaplan Meier curve for survival was used. Results: We included 37 patients, 21 male and 16 female, mean age was 8.3 years (11 months-16 years), M1, M2 and M4 subtypes were equally frequent with 21.6% each. Mean leukocyte count was 79,000 (2,100- 525,000). CSF was positive in one patient. 56.8% were classified as high risk patients. Remission was achieved in 91.6%, 75% after the first cycle, 13% after the second and 3% needed more than two cycles. An event free survival of 48.6% (50% for low risk and 47% for high risk) and overall survival of 59.4% were achieved. Relapse rate was high with 35% of patients. Conclusions: The evaluated treatment regime improved our results and was well tolerated.

No significant financial relationships to disclose.
Late recurrence in survivors of childhood and adolescent cancer: A report from the Childhood Cancer Survivor Study (CCSS)
Authors: Wasilewski-Masker K. , Leisenring W. , Meacham L. R. , Hammond S. , Meadows A. T. , Robison L. L. , Mertens A. C.
Published: March 2020

9534

Background: An increasing percentage of childhood cancer patients are surviving their disease, but limited research suggests that late recurrences may impact overall survival. The goal of this study is to estimate late recurrence rates for the most common pediatric cancers and to determine additional risk factors for late recurrence. Methods: CCSS is a retrospective cohort study of five-year survivors of childhood cancer diagnosed before 21 years of age, between 1970 and 1986 at one of 26 consortium centers. Late recurrence was defined as first recurrence occurring > five years post-diagnosis. Recurrences were determined by self-report questionnaire or by confirmation through medical record, death certificate or pathologic review. Probability of late recurrence was calculated using cumulative incidence. Adjusted hazard ratios (HR) were obtained using Cox proportional hazards regression. Results: In 12,948 survivors with no recurrence = five years from diagnosis, 670 (5.2%) subjects had a first recurrence > five years after their primary diagnosis. Late recurrences ranged from 5 to 28.9 years from diagnosis (median 7.9 years). Cumulative incidence varied by diagnosis ( table ). In multivariate analysis, significant risk factors for increased late recurrence included a primary diagnosis of Ewing's sarcoma or CNS tumors (HR of 2.3 and 2.7 respectively vs. leukemia survivors), age = 10 years at diagnosis (HR 1.4 vs. age < 10 years), chemotherapy exposure (HR 1.5 vs. none), and radiation exposure (HR 1.4 vs. none) (p < 0.001 for all). At the time of last follow-up, 51.6% of subjects with a late recurrence had died versus 6.4% of those with no history of recurrence. Conclusions: Late recurrences occur in survivors of childhood cancers with a significant risk of mortality. This emphasizes the importance of long-term survivor follow-up into adulthood, particularly for adolescents and patients with Ewing's sarcoma and CNS tumors.

[Table: see text]

No significant financial relationships to disclose.
The attainment of life goals by adult survivors of childhood cancer
Authors: Crom D. B. , Lensing S. , Rai S. , Snider M. , Hudson M. M.
Published: March 2020

9536

Background: Adult survivors of childhood cancer are at risk for disease- and therapy-related morbidity, which can adversely affect marriage and employment status, ability to obtain health insurance and access to care. Our aim was to identify factors associated with survivors’ ability to achieve these goals. Methods: We surveyed 1,437 survivors of different types of childhood cancer who were >18 years of age and >10 years from diagnosis. We compared our cohort's data to normative data in the Medical Expenditure Panel Survey and the Current Population Surveys of the U.S. Census Bureau. Survivors were categorized into 3 groups (hematological malignancy, solid tumors, or central nervous system tumors) and whether they had received radiation therapy. Results: The majority of respondents (response rate 65%) were survivors of hematological malignancies (71%), white (91%), and working full-time (62%); (43%) were married. When compared to age- and gender-adjusted national averages, only survivors of hematological malignancy who received radiation therapy were significantly less likely to be married than the general population (44% vs. 52%). Full-time employment among survivors was lower than national norms, except for survivors of hematological malignancy who had not received radiation therapy. The prevalence of having any health insurance, especially public insurance, was higher in all diagnostic groups than in the general population. Difficulty obtaining care was reported by 11% of all survivors; 12% reported not receiving needed health care. Additionally, 26.9% reported having been denied insurance. Current unemployment and lack of insurance were significantly associated with difficulty in obtaining care (p=0.049 and p<0.001, respectively). CNS tumor survivors reported greater difficulty in obtaining needed care (p=0.030). Current employment and solid tumor diagnosis were associated with lower rates of denial of insurance (p=0.018 and p=0.003, respectively). Conclusion: Subgroups of adult childhood cancer survivors are at risk of problems with attaining life goals, including access to care. This has serious implications given the known long-term secondary medical complications in this at- risk population.

No significant financial relationships to disclose.
Dominant negative Hes1 blocks osteosarcoma invasion driven by Notch pathway signaling
Authors: Hughes D. P. , Zhang P. , Yang Y. , Lee K. E. , Zweidler-McKay P. A.
Published: March 2020

9549

Background: Osteosarcoma (OS) is the most common bone cancer, with a peak incidence in mid-adolescence. OS outcome is poor for metastatic or recurrent disease (<30% and 10–20% survival respectively at 5 years). We investigated mechanisms regulating invasion and metastasis to identify new therapeutic targets for OS. One potential target is γ-secretase, required for activating Notch, Her-4 and β-catenin pathways. We have shown previously that Notch pathways genes are expressed in OS cells, and recently identified an association between Notch-mediated Hes1 expression and OS invasiveness. Here we sought to determine if OS invasiveness could be eliminated by direct blockade of Hes1 function. Methods: OS cell lines OS 187, COL, Saos-2 and Saos2-LM7 (a metastatic subline of Saos-2) were used for all studies. Functional analyses included proliferation, anchorage-independent growth, cell-cycle/apoptosis and matrigel invasion. Notch pathway signaling was genetically manipulated by transduction with constitutively active Notch 1 (ICN1), a dominant negative inhibitor of Notch signaling (dnMAM), normal Hes1, and dominant negative Hes1 (dnHes1). The efficacy of dnHes1 in blocking Hes1 was confirmed in Shep neuroblastoma cells by demonstrating upregulation of Hash1, a gene suppressed by Hes1. Comparisons were made to cells transduced with empty vector (negative control) and cells treated with γ-secretase inhibitor (positive control). Results: Notch pathway manipulation did not affect proliferation, cell cycle or in vitro tumorigenesis. Retroviral transduction with ICN1 or Hes1 increased invasion in all cell lines, and dnMAM reduced invasiveness in OS 187, Saos-2 and LM7, similar to γ-secretase inhibition. Hes1 expression in COL was constitutively active, did not suppress with dnMAM, but invasiveness was proportional to the Hes1 expression. dnHes1 suppressed invasiveness of all lines, indicating the importance of Hes1 expression in regulating invasion, an essential feature of metastasis in OS. Conclusions: Hes1 expression may be useful as a marker of increased metastatic risk. Therapies blocking Hes1 expression, including γ-secretase inhibitors, may have therapeutic potential for OS. Further preclinical and clinical trials are warranted.

No significant financial relationships to disclose.
Phase I study of erlotinib administered concurrently with and after irradiation (RT) in the treatment of children, adolescents, and young adults with newly diagnosed intracerebral high-grade glioma
Authors: Broniscer A. , Baker S. J. , Merchant T. E. , Laningham F. H. , Kocak M. , Krasin M. J. , Kun L. E. , Gajjar A. , Stewart C. F.
Published: March 2020

9553

Background: High-grade gliomas are uncommon neoplasms in childhood that portend a poor prognosis. Because of the promising activity of erlotinib in adults with high-grade glioma, we conducted this Phase I study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of erlotinib administered concurrently with and after RT. Methods: Patients between 3 and 25 years of age with newly diagnosed high-grade glioma received erlotinib continuously once daily during and after RT for a maximum of 52 weeks. Pharmacokinetic studies of erlotinib and its metabolite OSI-420, and genotyping were performed during course 1 in consenting patients. Use of enzyme-inducing anticonvulsants was an exclusion criterion. Dose escalation followed a typical Phase I design (dosage levels of 70, 90, and 120 mg/m2 per day). The DLT-evaluation period comprised the first 8 weeks of erlotinib. Results: Seventeen patients (median age 10.4 yrs; 10 males) were enrolled. Diagnoses consisted of glioblastoma (n=9), anaplastic astrocytoma (n=4), and other high-grade gliomas (n=4). Two of seven patients experienced reversible grade 3 hypokalemia / hypophosphatemia at the 70 mg/m2 level. Once electrolyte abnormalities were excluded as DLT, only one of seven patients at the 120 mg/m2 level has experienced grade 3 diarrhea so far. Pharmacokinetic studies were obtained in 14/17 patients. At the 70 mg/m2 dosage level, the median (range) erlotinib and OSI-420 Cmax and Tmax were 1,405 ng/ml (937–2,180) and 4.1 hr (2.2–8.2) and 158.5 ng/ml (45–203) and 4.1 hr (2.2–7.9), respectively. Three patients have received erlotinib for more than 1 year with disease stabilization. Six patients have already experienced disease progression. Conclusions: Erlotinib administered concurrently with RT on this schedule has been well tolerated. Preliminary pharmacokinetic results are comparable to those observed in adults. Rather than continue to escalate erlotinib dosages, we plan to complete this study and open a phase II study of erlotinib and RT for this same patient population.

No significant financial relationships to disclose.
Operating characteristics of two independent sample design in phase I trials in pediatric oncology
Authors: Raphael M. , Le Deley M. , Vassal G. , Paoletti X.
Published: March 2020

9555

Background: The European Medicine Agency (EMEA) stated that the degree of pre-treatments can modify the patient's tolerance to new treatments in pediatrics oncology, and then suggested that exploration of this potential difference should be considered. It is current practice to split a phase I trial in two groups to identify the Maximum Tolerated Dose (MTD) in each group. Yet how relevant such approach is, has not been investigated. In particular, role of baseline characteristics has not been explored. Methods: We reanalyze a large phase I trial of CPT11 in which 80 children had been included (32 heavily pre-treated pts and 48 less heavily pre-treated) to determine if baseline characteristics were associated with the heaviness of pre-treatment and could predict serious adverse events. To investigate robustness of conclusions in the context of small sample sizes, we performed an extended simulation study. We explored dose recommendations in scenarios with group difference, as measured by Odds Ratio (OR), ranging from 1 (absence of difference) to 8 (large difference) and sample size increasing from 2 * 20 to 2*40. Results: We did not find any relation between the degree and pre- treatment and neither the risk of DLT nor the baseline characteristics in this pediatric trial. However robustness appeared to be critical with high risk of misidentification of MTD in each of the two groups, whatever the prognostic value. With a group difference corresponding to OR=8 and balanced sample sizes (2*20 pts), the same MTD was identified in 10% of the simulations. Even with larger sample sizes (2*40pts), this figure reached 24% for OR=3. There is also a very high risk of identifying two different MTD although the risk is similar in the two groups (52% for 40 × 2 patients). Conclusions: Two independent sample designs in pediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data.

No significant financial relationships to disclose.