Cancer
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21728
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Browsing Cancer by Author "Bowman, W. Paul"
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Item Reproductive Health in Female Members of Cook Children's Life After Cancer Program(2015-03) Chitturi, Kalyan R.; Prendergast, Christina; Bashore, Lisa; Shah, Deep; Paxton, Raheem; Bowman, W. PaulReproductive Health in Female Members of Cook Children’s Life After Cancer Program Purpose: Late effects from cancer treatment have been a topic of growing interest in pediatric oncology. In this study, we assessed the relationship between cancer treatment modalities (radiation therapy and chemotherapeutic drugs) on spontaneous primary ovarian insufficiency (POI) and hormone replacement therapy (HRT) among female pediatric cancer survivors enrolled in the Life After Cancer Program (LACP) at Cook Children’s Medical Center. Reproductive ability is an important quality of life issue in pediatric cancer survivors. Oncologists can utilize this information to minimize risks during treatment and recommend fertility-preserving steps such as removal and cryopreservation of oocytes and ovarian tissues prior to treatment. Female pediatric patients benefit from being more informed of reproductive late effects as fertility-preserving measures can be pursued prior to initiation of cancer treatment. Methods: Chart review (n = 194) was conducted of LACP cancer survivors from 1/1/2011 to 6/30/2013. POI was defined clinically as females <40 years old with metrorrhagia or amenorrhea in association with elevated serum FSH levels as determined by individual lab assay method. Bivariate and stepwise logistic regression models assessed associations between treatment-related factors and both POI and HRT. Two-sided statistical tests (significance = 0.10) were performed in the model. Inclusion criteria as follows: Females who are currently ≥12 years of age, Females who completed last cancer treatment ≥2 years ago, Females who were seen at least once in LACP clinic between 1/1/2011 to 6/30/2013. Results: Mean age of diagnosis = 6.69 years. 25 subjects required HRT. Age at diagnosis, busulfan, ifosfamide, carboplatin, radiation therapy affecting ovaries/uterus, and total body irradiation (TBI) were found to be significantly associated (p < .05) with HRT in stepwise model. Twenty-three patients developed POI. Age at diagnosis, busulfan, carboplatin, radiation therapy affecting ovaries/uterus, and total body irradiation (TBI) were found to be significantly associated (p < .05) with POI in stepwise model Conclusions: Findings show certain alkylating agents (busulfan, ifosfamide), heavy metals (carboplatin), and radiation therapy increased odds of HRT and POI among LACP pediatric and young adult cancer survivors. Future analyses are ongoing with an expanded cohort (n = 449).Item Small Molecule, Tolfenamic Acid Induces the Apoptotic Response of Cis-Retinoic Acid in High-Risk Neuroblastoma Cells(2015-03) Shelake, Sagar; Sankpal, Umesh; Wadhwani, Anmol; Tabor-Simecka, Leslie; Bowman, W. Paul; Basha, RiyazNeuroblastoma (NB) is an aggressive and highly heterogeneous extra-cranial solid tumor found in children. NB accounts for 15% deaths among pediatric cancer patients. 13-cis-retinoic acid (RA) is commonly used as adjuvant therapy during the remission maintenance phase of NB treatment. There is, however, a greater than 50% risk of relapse in high-risk neuroblastoma (HRNB) that necessitates the development of an alternative therapeutic strategy. Specificity protein 1 (Sp1) is a transcription factor that is involved in the regulation of various cellular functions including cell growth, differentiation, and apoptosis. The present study is aimed at investigating the effect of a small molecule and Sp1 inhibitor, Tolfenamic Acid (TA) for enhancing the anti-proliferative effect of RA in HRNB cell lines, LA1-55n and SH-SY5Y. The optimized doses obtained from dose/time-dependent response of individual agents were used for the combination treatment experiments. LA1-55n and SH-SY5Y cells were treated with TA (30 µM) or RA (20 µM) or both for 48 h and tested to assess the effect on cell viability, apoptosis and selected molecular markers- Sp1, survivin, AKT and ERK1/2. Cell viability and caspase activity were measured using the CellTiter-Glo and Caspase-Glo kits. The apoptotic cell population was determined by flow cytometry with Annexin-V staining. The expression of Sp1, survivin, AKT, ERK1/2 and c-PARP were evaluated by western blot analysis. Treatment with TA and RA resulted in significant inhibition of cell viability in dose/time- dependent manner in tested cell lines. Even though the individual agents showed anti-proliferative response, the combination of both agents increased cell growth inhibition in LA1-55n (91.8%), SH-SY5Y (78.2%) as compared to TA alone (LA1-55n: 65%; SH-SY5Y: 51%) and RA alone (LA1-55n: 50%; SH-SY5Y: 33.5%). This anti-proliferative effect is accompanied by a decline in Sp1 and survivin expression. Furthermore, TA and RA combination treatment resulted in a significant increase in apoptotic (Annexin-V positive) cells, caspase 3/7 activation (LA1-55n: 12 fold and SH-SY5Y: 9 fold; pItem Therapeutic Leukapheresis in Pediatric Leukemia: The Cook Children’s Experience(2015-03) Thapa, Namisha; Cole, Charles; Ray, Anish; Bowman, W. PaulPurpose (a): In Pediatrics, acute leukemia is the most common cause of hyperleukocytosis, as defined by WBC above 100K. In children, hyperleukocytosis is associated with early morbidity and mortality due to leukastasis-related complications such as intracranial hemorrhage and pulmonary distress. Additionally, tumor lysis syndrome, a dreaded complication due to high rate of cell turnover, can especially occur if chemotherapy is initiated without leukoreduction. Currently, therapeutic leukapheresis (LK) serves as an adjunctive therapy for select population presenting with hyperleukocytosis and/or leukastasis-related symptoms. Although LK is commonly used for this purpose, specific guidelines regarding when to use LK are not well-established. The purpose of this study is to evaluate the efficacy of LK and to determine the specific patient population that will benefit the most from this procedure. To our knowledge, this is the largest study conducted on efficacy of LK and its clinical outcome in pediatric leukemia patients. Methods (b): After obtaining institutional IRB approval, a retrospective chart review was conducted on 20 pediatric leukemia patients (14 ALL, 5 AML, and 1 CML) who underwent LK at Cook Children’s Medical Center from 2000 to 2014. Data on white blood cell count (WBC), platelets, chemistry, complications due to leukastasis at presentation, complete remission (CR), and overall survival rate were collected. Results (c): At presentation, 15% children had CNS symptoms, 15% had respiratory symptoms, and 5% had both. First round of LK showed 61.6% reduction in WBC from median value of 474.2 (233 – 910 x 109/L) to 182.5 (99.2 – 845 x 109/L). Six patients underwent second LK that reduced WBC by another 28.9% with a final median WBC of 139.35 (27.1 – 725 x 109/L). Overall, 19 out of 20 patients were alive immediately post LK, and 15 patients achieved complete remission. Conclusions (d): LK significantly reduces WBC in pediatric leukemia in patients as young as 22 day old presenting with WBC > 250 9/L; 250 9/L and leukastasis-related complications. LK procedure itself has no significant complications and is concluded to be a safe adjunctive procedure in pediatric leukemia prior to initiation of induction chemotherapy.Item Tolfenamic Acid Induces Therapeutic Efficacy of Chemotherapeutic Agents in Medulloblastoma Cells(2015-03) Jones, Michelle; Shelake, Sagar; Hernandez, Yazmin; Wadhwani, Anmol; Sankpal, Umesh; Bowman, W. Paul; Murray, Jeffrey; Basha, RiyazMedulloblastoma (MB) is the most common malignant brain tumor of childhood. Currently, MB is treated using a multimodal approach consisting of surgery, craniospinal irradiation, and chemotherapy. Among the most commonly used chemotherapeutic agents are vincristine (Vinc), etoposide (Etop) and Cisplatin (Cis), while doxorubicin (Dox) is also used rarely. All of these agents carry significant delayed consequences for the patients including cognitive deficits. It is imperative that the strategies to improve the therapeutic efficacy of standard chemotherapy will include reduction of side effects in order to have a significant impact for treating MB patients. The primary objective of this study is to determine the effectiveness of a combination treatment to enhance the therapeutic efficacy of chemotherapeutic agents using MB cell lines. We have tested the combination of Tolfenamic Acid (TA), a small molecule and non-steroidal anti-inflammatory drug along with Vinc or Etop or Cis or Dox using MB cell lines, DAOY and D283. These cell lines were purchased from American Type Culture Collection (ATCC), Manassas, VA. TA has been shown to inhibit cell proliferation, induce apoptosis, and decrease the expression of Sp1 and Survivin which play roles in growth and cell survival in MB cells. Our results show that each drug together with TA causes a time and dose dependent decrease of MB cell viability which is more than that of single drug treatment. The cell growth inhibition is accompanied by an induction of apoptotic markers and the decrease in expression of Sp1 and survivin. The preliminary results of this preclinical model are in favor of combining TA with Vinc or Etop or Cis or Dox to achieve maximum therapeutic benefit while limiting the duration of treatment. Further studies are under investigation to precisely understand the underlying mechanisms and to confirm these results via in vivo assays. Addition of TA to current chemotherapy regimen for MB may reduce the dose and amount of time necessary for chemotherapy and therefore potentially reduce the toxicity and side-effects in children.