Browsing by Author "Schroeder, Kristin"
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Item Open Access A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.(PLoS One, 2015) Halvorson, Kyle G; Barton, Kelly L; Schroeder, Kristin; Misuraca, Katherine L; Hoeman, Christine; Chung, Alex; Crabtree, Donna M; Cordero, Francisco J; Singh, Raj; Spasojevic, Ivan; Berlow, Noah; Pal, Ranadip; Becher, Oren JDiffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.Item Embargo Adaptation and Translation of Cancer Stigma Scale to Evaluate Perceived and Experienced Stigma among Pediatric Cancer Patients in Mwanza, Tanzania(2024) Pham, HongBackground: The Cataldo Cancer Stigma Scale (CASS) was developed to measure patient experienced and perceived stigma and was further modified for use in the pediatric patient population. This study aimed to adapt and translate a Swahili version of the CASS for use in the Tanzanian pediatric patient population to measure cancer stigma and identify the types of stigma pediatric cancer patients face. Methods: Approximately 40 items were extracted from two prior developmental and validation studies of the CASS that assessed stigma in adult patients and non-patient cohorts. The survey items, developed initially in English, underwent translation into Swahili, back-translated, reconciled, and screened for duplications. The translated items were refined using concurrent cognitive interviewing. Results: After three rounds of cognitive interviews with 15 respondents, comprehension of the survey questions was assessed and improved with all items reaching at least 80% comprehension. Additional reviews included grammar and specific Swahili word selection changes to clarify the question’s meaning. Duplications or repetition of sentences were also considered to remove questions from the survey. The final survey comprised 25 survey items with 7 stigma sub-categories. Conclusions: This study sheds light on the complex nature of cancer-related stigma in pediatric patients. For future purposes, research is needed to validate the CASS survey with a larger sample of the population, including a comparison stigma assessment to establish validity.
Item Open Access CTIM-21. PEPTIDE VACCINE DIRECTED TO CMV pp65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL(Neuro-Oncology, 2020-11-09) Thompson, Eric; Landi, Daniel; Lipp, Eric; Balajonda, Bea; Herndon, James; Buckley, Evan; Flahiff, Charlene; Jaggers, Denise; Schroeder, Kristin; Randazzo, Dina; Desjardins, Annick; Johnson, Maggie; Peters, Katherine; Khasraw, Mustafa; Malinzak, Michael; Mitchell, Duane; Ashley, David; Sampson, JohnAbstract INTRODUCTION The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma. METHODS Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly. RESULTS To date, 17 patients have been enrolled. Diagnoses include medulloblastoma (n=1), glioblastoma (n=9), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=2), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 41% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 0.8, not estimable) and median OS is 6.5 months (95% CI 1.8, not estimable). Interim analysis of immune monitoring bloodwork and perfusion MRI to quantify responses to PEP-CMV has been delayed due to COVID-19. However, adults with GBM who received PEP-CMV (NCT02864368) had significant (p≤0.05) increases in GCSF, GM-CSF, IFN-γ, IL-10, IL-2, IL-8, MIP1-α, and TNF-α levels. CONCLUSIONS Preliminary results demonstrate that PEP-CMV is feasible and well-tolerated in heavily pretreated, multiply recurrent patients.Item Open Access Molecular variants and mutations in medulloblastoma.(Pharmgenomics Pers Med, 2014) Schroeder, Kristin; Gururangan, SriMedulloblastoma is the commonest malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved outcomes in recent years, but patients are frequently left with devastating neurocognitive and other sequelae following such therapy. While the prognosis has traditionally been based on conventional histopathology and clinical staging (based on age, extent of resection, and presence or absence of metastasis), it has become apparent in recent years that the inherent biology of the tumor plays a significant part in predicting survival and sometimes supersedes clinical or pathologic risk factors. The advent of deep sequencing gene technology has provided invaluable clues to the molecular makeup of this tumor and allowed neuro-oncologists to understand that medulloblastoma is an amalgamation of several distinct disease entities with unique clinical associations and behavior. This review is a concise summary of the pathology, genetic syndromes, recent advances in molecular subgrouping, and the associated gene mutations and copy number variations in medulloblastoma. The association of molecular alterations with patient prognosis is also discussed, but it should be remembered that further validation is required in prospective clinical trials utilizing uniform treatment approaches.Item Open Access Validation and Quality Assessment of the Kilimanjaro Cancer Registry.(J Glob Oncol, 2016-12) Zullig, Leah L; Schroeder, Kristin; Nyindo, Pilli; Namwai, Theresia; Silayo, Elvis; Msomba, Angelah; Munishi, Michael Oresto; Karia, Francis; Muiruri, Charles; Bartlett, John; Maro, Venance; Zafar, S YousufPURPOSE: Global cancer burden has increasingly shifted to low- and middle-income countries and is particularly pronounced in Africa. There remains a lack of comprehensive cancer information as a result of limited cancer registry development. In Moshi, Tanzania, a regional cancer registry exists at Kilimanjaro Christian Medical Center. Data quality is unknown. Our objective was to evaluate the completeness and quality of the Kilimanjaro Cancer Registry (KCR). METHODS: In October 2015, we conducted a retrospective review of KCR by validating the internal consistency of registry records with medical and pathology records. We randomly sampled approximately 100 total registry cases. Four reviewers not associated with the KCR manually collected data elements from medical records and compared them with KCR data. RESULTS: All 100 reviewed registry cases had complete cancer site and morphology included in the registry. Six had a recorded stage. For the majority (n = 92), the basis of diagnosis was pathology. Pathology reports were found in the medical record for 40% of patients; for the remainder, these were stored separately in the pathology department. Of sampled registry cases, the KCR and medical records were 98% and 94% concordant for primary cancer site and morphology, respectively. For 28%, recorded diagnosis dates were within 14 days of what was found in the medical record, and for 32%, they were within 30 days. CONCLUSION: The KCR has a high level of concordance for classification and coding when data are retrieved for validation. This parameter is one of the most important for measuring data quality in a regional cancer registry.