Annual Meeting Proceedings Part 1 - American Society of Clinical ...

9569 General Poster Session (Board #42H), Sun, 8:00 AM-12:00 PM
Long-term outcomes of children with Xp11.2 translocation renal cell
carcinoma. Presenting Author: Hiroshi Asanuma, Department of Urology,
Keio University School of Medicine, Tokyo, Japan
Background: We aimed to assess the clinico-pathological characteristics
and the long-term prognosis of Xp11.2 translocation renal cell carcinoma
(Xp-RCC) in children. Methods: A total of 52 Japanese children with renal
tumors were presented to our institutions. Of these, 5 (10%) had RCC, and
all RCCs were Xp11.2 translocation subtype with positive nuclear transcription
factor E3 immunostaining. We retrospectively reviewed the pathological
and hospital records of these 5 patients. Results: In the 1 boy and 4 girls
with an average age of 9 years 7 months at diagnosis, the most common
presenting complains were gross hematuria (60%) and palpable abdominal
mass (40%). All patients had unilateral disease and there was no special
family or medical history in any children. Computerized tomography
revealed characteristic calcification within the tumor in 4 of the 5 patients
(80%). In the remaining case, the lesion had high density areas with
microcalcification, as confirmed by histopathological study. In 3 patients
with regional lymph node metastasis, calcification was also observed in the
metastatic lesions. Stage of the disease were stage I in 1 patient, II in 1, IV
without and with distant metastasis in 2 and 1, respectively. All patients
underwent transabdominal nephrectomy with regional lymphadenectomy.
One patient with stage I disease had multiple metastases 15 months after
surgery and died of disease in spite of interferon and chemotherapy 4 years
postoperatively. Three patients received adjuvant interferon therapy and 2
of them are without evidence of recurrence postoperative 19 and 14 years,
respectively. One of them had lymph node and lung metastases 12 years
postoperatively. The remaining one patient had multiple lymph node, lung,
bone, and dura mater metastases at diagnosis. The latter 2 patients have
received targeted therapy (sunitinib, temsirolimus) without their progression
for 6 and 12 months, respectively. Conclusions: Calcification within
the tumor and/or metastatic lesions is characteristic findings suggestive of
Xp-RCC in children. Regional lymphadenectomy or targeted therapy may
provide some benefit in selected pediatric patients. Long-term follow-up is
essential in pediatric patients with RCC.
9571 General Poster Session (Board #43B), Sun, 8:00 AM-12:00 PM
Substitution of cisplatin for etoposide in 2 of 3 induction cycles of CAV/IE
with subsequent irinotecan and vincristine for relapse in adults with Ewing
sarcoma (ES) and primitive neuroectodermal tumor (PNET). Presenting
Author: Daniel A. Rushing, Indiana University Melvin and Bren Simon
Cancer Center, Indianapolis, IN
Background: Treatment for adults with cyclophosphamide, doxorubicin and
vincristine alternating with ifosfamide and etoposide (CAV/IE) for ES/PNET
is based on the success reported in children however the same treatment in
adults is less effective. 50% of relapsed disease is expected to occur in the
lungs with median survival of 12.5 months (mo) after relapse. Since
Cisplatin is used for relapse, we initially substituted cisplatin for etoposide
in courses#2and#3ofIEfor2patients (pts) who were not responding to
IE as determined by serial CT scanning and then used it for all pts.
Relapsed pts were treated with irinotecan � vincristine (IRI-V) for at least 2
cycles as salvage therapy. We report the effect of cisplatin on influencing
the relapse pattern and the effect of IRI-V on survival for pts after relapse
Methods: A retrospective chart review of 19 consecutive adult pts (July
2004 to June 2011), with newly diagnosed ES /PNET were treated with
CAV/IE as per H. Grier NEJM 2003 and modified as a 14 day cycle.
Cisplatin 20 mg/m2 I.V.qdX4wassubstituted for etoposide for courses #
2 and 3 of IE and combined with ifosfamide as above (IC) followed by
surgery or RT. For pts with relapse Irinotecan was given I.V. 20mg/m2 days
1-5 & 8-12 � vcr I.V. 2mg days1&8q21days for 2 or more cycles. Repeat
treatment with CAV, IE or IC was also utilized for relapse. We evaluated the
toxicities, the pattern of relapse and the survival after relapse with these
treatments Results: Grade IV hematologic toxicity occurred in 11 of 19 pts
treated with CAV vs. 7of 19 pts treated with IE vs. 7 of 19 pts treated with
IC and 1 of 11 pts treated with IRI-V but 3 of those 11 pts had Grade IV
diarrhea. Median survival was 44.8� mo for 10 pts with non- metastatic
and 23 mo for 9 pts with metastatic disease respectively. More importantly
median survival from the time of relapse was 22.5� mo, (range 12.7 to
31� mo). 11 pts relapsed: 2 pts only in bone, 9 pts Local only, 0 pts had
distant lung recurrence Conclusions: Cisplatin appears to markedly alter the
relapse pattern in adults with ES/PNET and Irinotecan �vcr appears to
prolong survival in relapsed pts previously treated with cisplatin.
Pediatric Oncology
623s
9570 General Poster Session (Board #43A), Sun, 8:00 AM-12:00 PM
Preclinical study of a PARP inhibitor in neuroblastoma. Presenting Author:
Anissa Addioui, Research Center CHU Sainte Justine, Montreal, QC,
Canada
Background: Neuroblastoma (NB) is the most common extracranial solid
tumor of childhood. In spite of many therapeutic improvements, only 60%
survive long term despite aggressive combinations of multi-agent chemotherapy.
In previous studies, we have demonstrated that tumor initiating
cells (TIC) expressing CD133 (CD133high ) in NB are more resistant to
chemotherapy. Moreover, these cells express higher levels of PARP-1, a
central protein involved in DNA repair. PARP-1 expression is significantly
lower in NB usually showing spontaneous regression than in standard NB,
suggesting an implication of PARP-1 in NB progression. The objective of
this study is to determine the efficacy in vitro of AG-014699 (AG), a PARPinhibitor,
used in monotherapy or in combination to cisplatine (CP) and
doxorubicine (DR), classical chemotherapeutic agents used in NB treatment,
on NB cell survival. Methods: Six NB cell lines (parental or CD133high purified by flow cytometry (FACS)) were treated with AG alone or in
association to CP or DR. PARP-1 ELISA protein assay was used to
determine the optimal drug concentration needed to inhibit the protein.
Cell survival was measured by MTT test. Western Blots were done to
evaluate any apoptotic or autophagic pathway modulations. Quantification
of DNA damage in treated cell was done by immunofluorescence of H2A-X
protein. Results: We showed that a 4�M concentration of AG is sufficient for
PARP-1 inhibition. One third of celllines presented a sensitivity to AG when
used in monotherapy with an IC50 lower than 5�M. However, AG
demonstrated synergistic effects when associated to DR, decreasing the
IC50 by half, although none is observed when combined to CP. Sentitivity
of the TIC did not appear to be more important than the bulk cells. With
increasing concentration of AG, our WB showed no increase in cleaved
Caspase-3 suggesting no modulation of the apoptotic pathway. However,
autophagy seemed to be upregulated confirmed by an increase in cleaved
LC3 II protein. Double strand breaks increased 2.5 folds when 4�M AGis
added to the IC50 of DR. Conclusions: AG used in combination at
potentially therapeutic doses shows promising results in NB. These results
will allow for the improvement of NB treatments by introducing a new
therapeutic strategy.
9572 General Poster Session (Board #43C), Sun, 8:00 AM-12:00 PM
High-dose thiotepa: Neurotoxicity and risk factors in children with solid
tumors. Presenting Author: Christophe Maritaz, Institut Gustave Roussy,
Clinical Pharmacy Department, Villejuif, France
Background: Thiotepa (TTP) is a cytotoxic agent used in children with solid
tumors at high doses followed by autologous stem cell transplantation
(ASCT). During these treatments, neurological adverse events (NAE) were
observed. Causal relationships and risk factors were investigated. Methods:
Patients with solid tumors treated with high-dose thiotepa with ASCT
between May 1987 and March 2011 were retrospectively identified.
Clinico-biological data were collected and NAE were identified from
medical and nursing records. Toxicity was graded according to the NCI
CTCAE v4.03 classification. Imputability of thiotepa was assessed according
to Begaud et al. method. Analysis of risk factors was assessed with
Fisher’s exact test (alpha 0.05) and relative risk was estimated by
calculating odds ratios with their 95% confidence interval. Results: 251
patients received 307 courses (56 patients received twice) of high-dose
thiotepa (600 mg/m²: 82 courses; 720 mg/m²: 76 courses; 900 mg/m²:
149 courses) with ASCT. The median age was 8.33 years (range, 1 - 31.2
years). 81 NAE (26.4%) were described. NAE were considered “possibly”
related to TTP in 9 courses, “likely” related to TTP in 35 courses and “very
likely” related to TTP in 13 courses. Other NAE were assessed “doubtful”
or “incompatible”. In these 57 NAE, neurological symptoms appeared at a
median time of 2 days (range, 0-4days) after the introduction of TTP.
Symptoms were headache, tremor, dizziness and confusion, blurred vision,
seizure, pyramidal tract syndrome, cerebellar syndrome, opsoclonusmyoclonus
syndrome and coma. These events disappeared without sequelea
in a median time of 3 days (range, 1-8days). TTP was reintroduced in
21 cases. NAE reappeared in 12 cases. For 3 patients with seizure during
the first course, premedication with clonazepam prevented NAE during the
second course. The use of analgesic for moderate to severe pain, such as
tramadol or codeine, increased the probabiblity to have NAE (OR 5.6467;
95CI [1.5523-21.2786]; p 0.037). Conclusions: In our study, the incidence
of NAE related to TTP was 18.6%. The outcome was favorable
without sequelea in all cases. TTP could be reintroduced after NAE. The
association of TTP with tramadol increases the risk of neurotoxicity.
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