bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukemia
Authors: Te Loo D. M. , van Schie R. M. , Hoogerbrugge P. M. 
Published: August 2020

10049 Background: Vincristine is one of the corner stitches in the treatment of children with acute lymphoblastic leukemia (ALL). Constipation and other peripheral and central neurotoxicities are the most common side effects. Drugs interfering with the metabolism of vincristine might potentiate these side effects. A group of drugs that interact with the metabolism of vincristine are azoles. Several case reports suggest that co-administration of azoles and vincristine lead to increased toxicity. A comparative study exploring toxicity in patients receiving vincristine with and without azoles, is lacking. For this reason, we retrospectively analyzed neurotoxicity induced by vincristine with (n = 20) and without (n = 20) co-administration of azoles in the same patient group. Methods: In total, twenty pediatric patients with de novo ALL were included in this study. Vincristine toxicity was graded retrospectively according to the National Cancer Institute toxicity scale without information considering comedication. Statistical analysis was performed using the Wilcoxon Signed Rank test and McNemar test. Results: Patients receiving vincristine in combination with prophylactic azole treatment experienced significantly more complaints of constipation and peripheral neurotoxicity (P = 0.001 and P< 0.001, respectively). Three patients (15%) treated with azole therapy developed severe toxicity and needed treatment at the pediatric intensive care unit. Vincristine induced CNS toxicity (convulsions, toxic encephalopathy and SIADH) was seen in 6 patients (30%). All these patients were treated with vincristine in combination with an azole. CNS toxicity was not observed in patients receiving vincristine alone (P = 0 .014). Because of severe toxicities, vincristine treatment was significantly reduced (50% of normal dose) in several patients. Conclusions: This study shows that vincristine toxicity is significantly increased when combined with azole treatment and even can be life threatening. Therefore we advise to avoid the combination of azole and vincristine treatment in patients with ALL. No significant financial relationships to disclose.
The role of 131-I-metaiodobenzylguanidine (13II-MIBG) therapy in irresectable and compromising localized neuroblastoma
Authors: Schoot R. A. , Bleeker G. , Heij H. A. , van Eck B. L. , Caron H. N. , de Kraker J. 
Published: August 2020

10053 Background: According to current practice, observation only is justified in patients with localized, irresectable neuroblastoma with favorable biologic features. However, when organ or life threatening symptoms arise, therapy is required. Side effects of treatment should be minimal, since outcome is good. The aim of this study was to evaluate the response and outcome of neuroblastoma under these circumstances, when treated with 131-I-metaiodobenzylguanidine (131I-MIBG). Methods: Between 1989 and 2008, 21 patients (8 boys/13 girls) with localized neuroblastoma were included. Median age was 1.6 years (range of 0–5.5 years). Patients were eligible when the primary tumour was irresectable and organ or life threatening. Diagnosis and staging were performed according to the International Neuroblastoma Staging System (INSS). Fixed dosages of 131I-MIBG (50–200 mCi) were given with an interval of four weeks. The median number of infusions was two (range 1 to 7).131I-MIBG was given according to standard directions for targeted therapy. Response was graded according to the International Neuroblastoma Response Criteria (INRC). Results: Four patients were classified as stage I, three as stage II, and fourteen as stage III. Three tumors were NMYC amplified and two had loss of heterozygosity of 1p. Minimal pretreatment was given to nine patients, because of organ or life threatening symptoms. These patients responded insufficiently or showed return of tumor growth. After 131I-MIBG treatment, 8/21 regressed. Resection became possible in 13/21 patients. In 10/13 patients resection was macroscopically complete. Three other patients had incomplete resection of their tumor. They had longterm progression free survival. At the end of treatment 16/21 patients achieved complete response (CR) and 3/21 had stable disease (2 very good partial response (VGPR), 1 partial response (PR)). Two patients died, one of progressive disease, one due to complications of surgery (CR). One patient was lost to follow-up. Ten years OS was 90.5%, 10 years EFS was 72.4%. Median follow-up was 7.5 years (range 1 to 17.4). Conclusions: 131I-MIBG treatment is an effective treatment modality in irresectable, localized neuroblastoma, in case of organ or life threatening situations. No significant financial relationships to disclose.
Resistance of stem-like cells from neuroblastoma cell lines to commonly used anticancer drugs
Authors: Vangipuram S. D. , Wang Z. J. , Lyman W. D. 
Published: August 2020

10054 Background: Neuroblastoma is the most common extra-cranial solid tumor of childhood. Recent studies have shown that most cancers contain a small number of stem-like cells which may be responsible for cancer progression and relapse. For this study, we investigated the cytotoxicity of 4 commonly used anti-cancer drugs on stem-like cells isolated from neuroblastoma cell lines. Methods: Cell surface marker CD133 positivity was used to define stem-like cells. Three neuroblastoma lines were screened for the expression of stem cell marker CD133 by FACS analysis. CD 133+ cells were isolated by positive selection using magnetic micro-beads. The cytotoxicity of four cancer drugs Cisplatin (0–50μg/ml), Etopside (0–200μg/ml), Doxorubicin (0–200ng/ml), and Carboplatin (0–200μMl) was studied on CD133+ and CD133- populations, by MTT and PI/Annexin binding assays. Results: Neuroblastoma lines SK-N-BE and SK-N-SH had 2% and 8% cells expressing CD133 respectively, while SH-SY-5Y had no CD133 expressing cells. CD133 + cells showed significant resistance to all four drugs in the MTT assay as well as the PI/Annexin binding assay compared to CD 133 - cells. Conclusions: This study suggests that CD133+ cells in neuroblastoma cell lines are more resistant to conventional anti-cancer drugs compared to CD133- cells. Targeting these stem-like cell populations could lead to development of more effective treatment for neuroblastoma. [Table: see text] No significant financial relationships to disclose.
Neuroblastoma: A spectrum of cells isolated from bone marrow of patients
Authors: Saulnier Sholler G. , Illenye S. , Warzynski M. , Brown R. E. , Lescault P. J. , Koto K. , Dorf L. , Bond J. 
Published: August 2020

10055 Background: Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, portends a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant and radiation, long-term survival remains at 30%. Better detection of the 70% of patients who will relapse is essential. One possibility may be in the better detection of minimal residual disease and improved classification of the heterogeneous populations of cells present in the bone marrow with respect to risk. Methods: Bone marrow aspirates of patients with neuroblastoma were harvested and placed in neurobasal culture media and heparinized vacutainer tubes. They were analyzed by 6-color flow cytometry (CD56+, GD2+, CD81+, CD45−, CD9+, CD34+or−). Neuroblastoma cells and neurospheres were grown. mRNA expression analysis using U133 chips, immunofluorescence, and immunohistochemistry were performed. Mouse xenograft models were used to evaluate tumorigenicity of patient cells injected subcutaneously. Results: Flow cytometry can detect neuroblastoma cells as low as 0.001% within the heparinized samples and used to characterize the cultured cells. Cell culture showed a spectrum of neuronal morphology. Neurospheres express lower levels of GD2, TrkB, and CD56 compared to adherent neuroblastoma (consistent results were obtained using flow cytometry, immunofluoresence, immunohistochemistry, and mRNA expression analysis). Tumorigenicity was confirmed using mice injected subcutaneously with patient neurospheres tumors were present at the injection site and metastasized. Conclusions: Bone marrow aspirates of patients with neuroblastoma can be analyzed for the presence of neuroblastoma initiating cells which can be further characterized. This may play an important role in clinical decision making for therapeutic end points in a cancer that is likely to relapse. No significant financial relationships to disclose.
A clinical trial to study the effect of adding cis-retinoic acid during and after conventional treatment for pediatric neuroblastoma patient
Authors: Arafat W. , Abdelghany A. , Awad N. 
Published: August 2020

10057 Background: Neuroblastoma is predominantly a tumor of early childhood, with two thirds of the cases presenting in children younger than 5 years. Cis-retinoic acid has been used as maintenance therapy for treatment of advanced neuroblastoma after BMT. Patients who received cis-retinoic acid had significantly better 3-year event-free survival than patients receiving no maintenance therapy. However, there is no data available about usingcis-retinoic acid during induction phase of chemotherapy. The aim of this study is to evaluate the efficacy of cis-retinoic acid when used in combination with conventional chemotherapy in pediatric patient who is newly diagnosed with locally advanced neuroblastoma. Methods: Seventeen newly diagnosed children with locally advanced neuroblastoma who is candidate to receive chemotherapy were also received cis-retinoic acid starting at a dose of 160 /m2 day (day 2–15 of chemotherapy) first the 3 patients, 20% dose reduction were allowed if toxicity occurred in first cohort of patient. . Patients were giving the drugs for at least 4 cycles. RT-PCR analysis of several related genes was done from tumor, sample after treatment. Results: Median age 2.4. Male:Female ratio was 1.4:1. Patients were stage III, IV (70%), II (30%). 88% of patients were presented with abdominal mass .Most patient received at least 6 cycles of OPEC/OJEC regimen. N Myc was done to 12 of patients. Median follow up was 6 months. Maximum tolerated dose were 130mg/m2, response was seen as CR 30%VGR 40, PR 12%, and PD 18%. Median event free survival was 12 months. Toxicity: Hypercalcemia mucositis, rash, and elevated liver enzymes were the main dose limiting effect of cis-retinoic acid. Preliminary collaborative analysis showed that down regulation of N-MYC is related to response rate. Conclusions: Cis-retinoic acid at dose 130mg/m2 is a well tolerated drug with chemotherapy. Response to treatment is better than historical control. Randomized phase III trial is warranted. No significant financial relationships to disclose.
ATM gene analysis in neuroblastoma: A report from the COG
Authors: Gumy-Pause F. , Ozsahin H. , Khoshbeen-Boudal M. , Pardo B. , Betts D. , Maillet P. , Sappino A. 
Published: August 2020

10058 Background: Neuroblastoma (NB) is the most common malignant disease of infancy and accounts for approximately 8% of all childhood cancers. The clinical hallmark of this tumor is the marked variability in prognosis depending of the age, stage, and biological characteristics. There is evidence to suggest that the long arm of chromosome 11 (11q) plays a role in NB biology. The ATM gene is located at 11q22–23 and hereditary mutations of this gene cause ataxia-telangiectasia, a recessive disorder associated with a high incidence of neoplasia. The aim of this project was to determine the prevalence of ATM gene mutation and ATM methylation status in 50 NB samples. Methods: Following DNA extraction, PCR products of the 65 exons of the ATM gene and its promoter were screened by DHPLC. This screening was also performed on DNA from 60 blood donors. Alterations detected were analyzed by direct sequencing. Direct and indirect criteria were used to classify the observed nucleotide alterations as mutation (if pathogenic), rare variant (if the allelic frequency in controls was < or = 1%), variant (1.1–2.4%) or polymorphism (> or = 2.5%). The ATM methylation status was analyzed by MS-MLPA (Methylation-Specific Multiplex Ligation-dependent Probe Amplification). Results: Except polymorphisms, 17 different sequence alterations were found in 17 NB samples (34%). Ten of these 17 alterations, found in 11 NB (22%), were rare variants (RV). In 5 NB (10%), RV were found homozygous. At the same time, we found 20 different sequence alterations in 19 controls (32%). Sixteen of these 20 alterations were RV and one was a heterozygous pathogenic mutation. These 17 alterations concern 15 controls (25%). No homozygous RV was found in controls. We found no evidence of ATM promoter hypermethylation in the 48 NB samples analyzed. Conclusions: We found no difference in ATMvariant and RV frequency between NB and control samples. However, as ATM deletion is a frequent event in NB, we found a high frequency of homozygous RV (10%). At present, we are completing this study by screening ATMlarge genomic deletion/duplication using MLPA. Finally, our observations indicate that epigenetic ATM silencing by methylation is uncommon in neuroblastoma. No significant financial relationships to disclose.
Multimodality treatment on long-term outcome of intracranial germ cell tumors in children: A single institution study
Authors: Kebudi R. , Darendeliler E. , Ayan I. , Gorgun O. , Yaman Agaoglu F. , Dizdar Y. , Darendeliler F. , Emiroglu H. 
Published: August 2020

10063 Background: Intracranial germ cell tumors (iGCT) constitute 1% of all malignant neoplasms in children. The aim of this study is to evaluate the demographic characteristics, therapy, and long term outcome of children with iGCT in a single institution. Methods: 16 children (9 female, 7 male) with a median age of 11 years (10 months-18 yrs) treated for iGCT between 1990 and 2008 were evaluated retrospectively. They were treated according to our institutional protocol. Patients > 13 years old with germinomas recieved radiotherapy alone (2520 cGy craniospinal/1980 cGy local boost), patients <13 yrs old recieved 2 courses of etoposide, cisplatinum followed with cranial radiotherapy. Nongerminoma patients recieved 3 courses of bleomycine, etoposide, cisplatinum followed by 3600 cGy craniospinal / 1980 cGy local boost RT. Results: Presenting clinical features were diabetes insipidus (7), raised intracranial pressure (12), visual changes-oculomotor palsies (6), hypopituitarism (4). 8 had germinomas and 8 nongeminomatous GCT. Ten were suprasellar and 6 pineal. AFP and BHCG were evaluated at diagnosis and during therapy both in serum and CSF. Three had seeding in the spinal axis in MRI. One had widespead systemic metastasis. Three had a total resection, 12 had a biopsy, 1 was clinically/radiologically diagnosed, 5 had a shunt. Two nongerminamatous iGCT patients died: 1 of widespread disease in the intensive care unit at diagnosis, the other with progressive disease 18 months after diagnosis. Fourteen patients are alive at a median follow-up of 12 years (1–17 years) from diagnosis. One that had motor and mental retardation before diagnosis needs special care. All others have a moderate/good quality of life. One is married and has a child. Six are at school (2 in university). Five are employed. The patients are also followed up in the endocrinology clinic. One is recieving growth hormone. Conclusions: Cisplatin based chemotherapy and radiotherapy is successful and well tolerated in children with iGCT. The possibility of an early clinical diagnosis based on MRI and tumor markers and the use of modern neurosurgical techniques increases the chance of cure, gives a chance to reduce acute morbidity and further decrease late effects. No significant financial relationships to disclose.
Preliminary safety and activity results of trabectedin in a phase II trial dedicated to triple-negative (ER-, PR-, HER2-), HER2+++, or BRCA1/2 germ-line-mutated metastatic breast cancer (MBC) patients (pts)
Authors: Delaloge S. , Tedesco K. L. , Blum J. , Gonçalves A. , Lubinski J. , Efrat N. , Osborne C. , Lebedinsky C. , Tercero J. C. , Holmes F. A. 
Published: August 2020

1010 Background: Trabectedin ([T]; Yondelis) binds to the minor groove of DNA; its cytotoxicity is determined by the synergistic action of two DNA repair mechanisms, the efficient nucleotide excision repair (NER) and deficient homologous recombination repair (HRR) machinery. T has EMEA authorization in soft tissue sarcoma after failure of standard treatment. Preliminary data have shown activity of T as single agent in MBC. Clinical and preclinical data suggested T may display specific activity among certain NER-intact or HRR-deficient MBC, and prompted this phase II trial dedicated to 3 subgroups: triple-negative (TN), HER-2-overexpressed, and BRCA1/2 germline-mutated MBC. Methods: T was given at 1.3 mg/m2 as a 3- hour iv infusion every 3 weeks to pts with pretreated progressive MBC: Group A: TN; Group B: HER-2+++; Group C: BRCA1/2 mutation carriers. Endpoints were objective response (OR) rate by RECIST, duration of response, progression free survival (PFS), tumor volume changes, safety and exploratory pharmacogenomics (PGx). Results: A total of 95 women (median [med] age 52, ECOG 0/1 48/52%) have been enrolled (A:50, B:24, C:21) with data available for 72 pts. Med number of prior chemotherapy regimens: 4 (1–10). Med number of T cycles administered: 2 (1–12) for all groups. The most commonly reported grade 3/4 AEs are neutropenia (29/21%), ALT (28/2%) and AST (13/0). Alopecia/stomatitis, only G1, was reported in <2% each. Long-lasting disease stabilizations were described in all groups. While OR were rare among TN MBC pts (2PR/43 evaluable), preliminary analysis by investigator shows efficacy in group C (4PR/11 evaluable). Tissue samples from 36 pts were collected for RNA expression analysis (XPG + ERCC1 + BRCA1). Preliminary results show high XPG is associated with longer PFS: 4.1 months (95% CI 2.6-not reached) versus 1.3 months (95% CI 1.2–3.7), p = 0.01. Analyses are ongoing. Conclusions: Trabectedin shows a manageable safety profile in the 3 groups of MBC with promising efficacy in certain DNA-repair machinery sub-categories defined molecularly. TN group was closed due to low response. More mature PGx results will be discussed to help selecting the patients who are at highest chance for response. [Table: see text]
Dasatinib in advanced HER2/neu amplified and ER/PR-positive breast cancer: Phase II study CA180088
Authors: Mayer E. , Baurain J. , Sparano J. , Strauss L. , Campone M. , Fumoleau P. , Rugo H. , Awada A. , Sy O. , Llombart A. 
Published: August 2020

1011 Background: SRC family kinases (SFKs) are involved in numerous signaling pathways including from ER and HER-2 receptors, as well as osteoclast function. Dasatinib is a potent oral inhibitor of SFKs. A phase II trial was performed in patients (pts) with ER+ and/or PR+ and/or HER-2-amplified progressive advanced breast cancer. Subsequent to study initiation, dasatinib demonstrated similar efficacy with a lower incidence of key side-effects at 100 mg once daily in CML and prostate cancer. Methods: Pts with measurable disease and progression after chemotherapy and other targeted agents were treated with dasatinib on a continuous twice-daily (BID) schedule; RECIST-defined response rate was primary endpoint. Results: Sixty-eight pts, 24 with HER-2-amplified and 44 with HER-2-normal, ER+ and/or PR+ disease, were treated. Original starting dose of 100 mg BID (23 pts) was reduced to 70 mg BID (45 pts) due to fluid retention, fatigue, or GI toxicity. Median age was 55 years; nearly all pts (93%) had prior therapy in advanced setting. 59 were radiographically-evaluable (8 discontinued for toxicity and 1 inevaluable). We observed 3 partial responses lasting 9, 9 and 8+ mos plus 6 stable disease ≥16 weeks (range 24–33 wks). All 9 controlled tumors were ER/PR+, 2 were also HER-2-amplified; thus, disease control rate was 19% in the 47 radiographically-evaluable pts with ER/PR+ disease. Median dose intensity was 136 mg/day at 70 mg BID and 175 mg/day at 100 mg BID; median duration of therapy was 1.8 mos in both dose groups. Most pts (75%) discontinued for disease progression. The most common drug-related AEs were diarrhea (49%), headache (34%), nausea (34%), asthenia (32%), pleural effusion (31%), musculoskeletal pain (25%), and vomiting (24%). Drug-related grade 3–4 AEs were reported in 37% of pts and comparable between doses, but related serious AEs were less frequent at 70 mg BID than 100 mg BID (16% vs 26%). Grade 3–4 laboratory abnormalities were uncommon. PK and biomarker analyses will be presented. Conclusions: Encouraging single-agent activity was observed with dasatinib in pts with advanced ER+ breast cancers. Future studies will address the combination of dasatinib with hormonal therapies using a better-tolerated once daily schedule. [Table: see text]
Quantitative measurement of HER3 total protein (H3T) and association with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab
Authors: Goodman L. J. , Weston J. K. , Mukherjee A. , Sperinde J. , Paquet A. , Williams S. , Parry G. , Bates M. , Koestler W. , Lipton A. 
Published: August 2020

1021 Background: The heterodimerization of HER3, with HER2 and the subsequent activation of the AKT pathway, has been implicated in both regulation of tumor cell growth and in resistance to HER2 targeted therapies such as trastuzumab. Currently available methods of measuring H3T in formalin-fixed, paraffin-embedded (FFPE) samples are insufficiently sensitive or specific; thus the impact of quantitative measurement of H3T expression on clinical response to trastuzumab has not been evaluated. Methods: We have developed a highly quantitative, accurate, precise, sensitive, and reproducible H3T assay in FFPE samples based on the VeraTag technology platform. Consequently, the H3T assay displays ∼5-fold greater sensitivity than conventional IHC measurements. Additionally, the rank order and accuracy of the H3T measurements were preserved over a wide dynamic range in well-characterized cell line panels. Intra- and inter-assay reproducibility measurements demonstrated 7–11 %CV and 8–16 % CV, respectively. Results: Quantitative levels of HER2 total protein (H2T) and H3T expression were determined by the VeraTag technology in 81 tumors from patients with trastuzumab-treated metastatic breast cancer. A previously reported H2T cutoff was used to sub-divide the patients into HER2-normal (N = 26, median TTP = 4.1 mos) and HER2-overexpressing (N = 55, median TTP = 11.1 mos, HR = 0.43, p = 0.0002) groups. In the HER2-overexpressing group, high H3T expression, as defined by a positional scanning cutoff analysis, predicted shorter median time to progression (N = 25, median TTP = 6.1 mos) compared with low H3T expression (N = 30, median TTP = 13.1 mos, HR = 2.7, p = 0.0002). Univariate Cox proportional hazards analyses examining the HER2-overexpressing subgroup identified H3T (high vs. low) as the most significant predictor of TTP (HR = 2.98, p = 0.0004). Conclusions: These results demonstrate that the accurate and sensitive measurement of H3T in a cohort of patients with HER-2 positive breast cancer predicts TTP in response to trastuzumab and could indicate a population of patients with worse outcome requiring additional therapeutic intervention. [Table: see text]