tbuckley/cabot-search huggingface dataset:
Effect of oncolytic herpes simplex virus on fusion-positive rhabdomyosarcoma to radiotherapy.
Authors: Maryam G. Shaikh, Nazia Nazam, Swatika Butey, Michael H Erwin, Jerry E. Stewart, Jamie Aye, Elizabeth A Beierle
Journal: Journal of Clinical Oncology (2024)

10063 Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite multimodal interventions including surgery, chemotherapy, and radiotherapy, nearly a third of patients with localized disease will experience tumor recurrence. Patients with tumors harboring an oncogenic FOXO1 fusion are at greater risk of relapse and are most in need of novel therapies. Oncolytic viruses are being explored as treatments for pediatric tumors, and data suggest that oncolytic viruses may enhance responses to chemoradiotherapy. M002 is a genetically engineered oncolytic herpes simplex virus (oHSV) that exhibits aneurovirulence in normal cells. M002 selectively replicates in malignant cells, eliminating these cells through cellular burst during the lytic cycle. In the present study, we explored the efficacy of the M002 virus alone and in combination with low-dose ionizing radiotherapy in a human patient-derived xenograft (PDX) model of fusion-positive RMS (FP-RMS). Methods: A human FP-RMS PDX was established and maintained by injection into the quadriceps femoris muscle of athymic nude mice under Institutional Animal Care and Use Committee guidelines (IACUC-09363). Tumors were dissociated and cells were treated with increasing multiplicity of infection (MOI) of either the oHSV, R3659 or its genetically engineered variant, M002. A colorimetric assay evaluated the cytotoxicity of oHSV treatments on the RMS PDX cells after 24, 48, and 72 hours of infection. In separate experiments, cells treated with vehicle (control) or infected with M002 were exposed to irradiation (2 Gy), and viability was determined at 24, 48, 72, and 96 hours. Results: Treatment with M002 or its parent construct, R3659, significantly reduced RMS PDX cell viability in a dose-dependent manner at all time points. M002 showed slightly higher cytotoxicity than R3659 as measured by lethal dose 50% (LD50, 37±1.25 vs 44±0.95 PFU/cell, M002 vs R3659, at 24 hours, p=0.02). When sub-lethal doses of M002 were combined with low-dose irradiation, RMS PDX cell viability was significantly decreased compared to cells treated with either M002 or irradiation alone (26% decrease at 10 PFU/cell). Conclusions: Our preliminary data highlight that M002 exhibits cytotoxicity in a PDX model of FP-RMS. Treatment with M002 further increased the cytotoxicity of ionizing radiation compared to individual treatments, suggesting that oHSV sensitized the cells to radiotherapy. Future studies in vivo may provide more pre-clinical evidence for the radio-sensitizing and therapeutic potential of M002 in FP-RMS.
PP2A activation as a new therapeutic strategy in neuroblastoma: Making sense out of senescence.
Authors: Nazia Nazam, Maryam G. Shaikh, Swatika Butey, Michael H Erwin, Jerry E. Stewart, Michael Ohlmeyer, Elizabeth A Beierle
Journal: Journal of Clinical Oncology (2024)

10055 Background: Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for 15% of all pediatric cancer deaths. The five-year survival rate for children with high-risk disease is less than 50%, with the primary reasons for mortality being refractory and relapsed disease. One hypothesis for the poor response to therapy and propensity for recurrent disease in high-risk patients is treatment-induced senescence (TIS). Protein phosphatase 2A (PP2A) is a known tumor suppressor that is downregulated in NBL. PP2A activation has been shown to reverse cellular senescence in non-cancerous pathologies, therefore we hypothesized that reactivation of PP2A using novel small molecule activators would function as a novel senotherapeutic in NBL. Methods: We employed MYCNamplified, SK-N-BE(2), and non-amplified, SK-N-AS, established human NBL cell lines. Topotecan, a common NBL chemotherapeutic, known to induce senescence, and ATUX-1215, a small molecule PP2A activator, were utilized. NBL cells were treated with topotecan and ATUX-1215 alone, as well as in combination. Colorimetric assays detected cell viability and proliferation. Immunoblotting identified proteins of interest including γ-H2AX and CCL2. TIS was detected by S-β galactosidase (Sβgal) assay. Results: We found increased expression of the senescence marker, histone γ-H2AX, and increased Sβgal-positive tumor cells supporting the ability of topotecan to generate TIS in NBL. Following treatment with PP2A activator in combination with topotecan, markers of TIS are decreased in both MYCN amplified and non-amplified NBL cells. Further, and importantly, PP2A activation reversed the effects of topotecan TIS and acted in a synergistic fashion to decrease NBL cell viability. Conclusions: Activation of PP2A with a novel small molecule ameliorates topotecan-induced TIS in NBL cells irrespective of MYCN status. These results are promising, providing a potential novel therapeutic adjunct to children who are most in need of innovative interventions.
Cost-effectiveness of single-day intravenous fosaprepitant versus three-day oral aprepitant anti-emetic regimen in pediatric patients receiving highly-emetogenic chemotherapy.
Authors: Manraj Singh Sra, Azgar Abdul Rasheed, Shuvadeep Ganguly, Santosh Kumar, Priya Sharma, Ashwati S Pillai, Swetambri Sharma, DEEPAM PUSHPAM, Sameer Bakhshi
Journal: Journal of Clinical Oncology (2024)

10075 Background: The non-inferiority of single-dose fosaprepitant to a three-day oral aprepitant-based anti-emetic regimen for pediatric patients receiving high emetogenic chemotherapy (HEC) has not been demonstrated. The cost-effectiveness of these regimens with respect to each other in India and the United States (US) is unknown. Methods: Individual patient data from an investigator-initiated, open-label, non-inferiority randomized control trial was used to estimate health states. The total costs and quality-adjusted life years (QALY) were calculated from the patient's perspective in India and the US. The incremental-cost utility ratio (ICUR) and net-monetary benefit (NMB) were calculated. One-way sensitivity analysis was done by varying the cost of medications, hospitalization and utility values by ±25%. Results: The fosaprepitant arm had a total QALY of 0.0116 compared to 0.0118 in the aprepitant arm. The use of fosaprepitant led to an incremental cost of $14.21 in India and a cost reduction of $193.81 in the US. The total cost of medication in the fosaprepitant arm was higher in India and lower in the US compared to the aprepitant arm. The cost of hospitalisation was lower in the fosaprepitant in both India and the US. The ICUR was -$59,974.86/QALY in India and $817,737.23/QALY in the US. The ICUR for India was located in the north-west quadrant of the cost-effectiveness plane, for the US it was located in the south-west quadrant below the willingness the pay threshold for the US. The ICUR estimate was most sensitive to the cost of fosaprepitant in India and the utility value of the complete protection health state in the US. Conclusions: Fosaprepitant was not found to be cost-effective versus aprepitant in India, comparatively it was cost-saving and cost-effective in the US. These findings highlight the necessity of region-specific considerations when evaluating the cost-effectiveness of anti-emetic regimens. [Table: see text]
Mapping aging phenotypes in childhood cancer survivors: A report from the St. Jude Lifetime Cohort.
Authors: Kirsten K. Ness, Sedigheh Mirzaei Salehabadi, Rachel T Webster, Lisa M Jacola, Elizabeth A Salerno, I-Chan Huang, Tara M. Brinkman, Matthew J. Ehrhardt, Kevin R. Krull, Motomi Mori, Deokumar Srivastava, Gregory T. Armstrong, Zhaoming Wang, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2024)

10069 Background: Childhood cancer survivors experience accelerated aging manifest as physical, cognitive and/or emotional impairments. Aging populations respond to behavioral interventions that address impairment combinations. We aimed to identify and characterize phenotypes (classes) of physical, cognitive and emotional impairments in childhood cancer survivors to inform targets for future intervention. Methods: Factor analysis using St. Jude Lifetime Cohort data (N=4051, 52.2% male, mean [SD] age at diagnosis 8.7 [5.7], assessment 33.9 [10.1] years) generated 9 impairment domains (Table) using 40 items from the Neurocognitive Questionnaire, Brief Symptom Inventory 18 and NHIS Health Status/Limitation of Activities. Latent class analysis estimated impairment patterns and class membership probabilities. Descriptive statistics characterized survivors by class for deficit accumulation index (DAI) score (range 0-1, &gt;0.25 frail), Fried Frailty (FF) score (range 0-5, ≥3 frail), diagnosis and treatment exposures. Logistic regression comparing emotional or cognitive impairment class to the physical impairment class examined associations between survivor characteristics and class membership, adjusting for diagnosis and assessment ages, sex and race/ethnicity. Results: Three classes (phenotypes) differentiated survivors reporting only physical from those reporting both physical and cognitive or emotional impairments. Mean [SD] DAI (cognitive 0.40 [0.10], emotional 0.56 [0.16], physical 0.16 [0.11]) and FF scores (cognitive 1.5 [1.0], emotional 1.8 [1.0], physical 0.9 [0.9]) were highest in the emotional impairment class. Compared to solid tumor survivors (17.1%), brain tumor (33.7%, OR 3.5; 95% CI 2.7-4.4) and leukemia (21.7%, OR 1.5; 95% CI 1.2-1.8) survivors were more likely to be in the cognitive impairment class. Leukemia (OR 1.4; 95% CI 1.1-1.7) and lymphoma (OR 1.4; 95% CI 1.1-1.9) diagnoses increased risk for emotional impairment class membership. Cranial radiation was associated with cognitive (OR 1.8; 95% CI 1.5-2.2) or emotional (OR 1.3; 95% CI 1.1-1.6) impairment class membership. Chest radiation (1.4; 95% CI 1.2-1.7) was associated with emotional impairment class membership. Conclusions: These data provide foundational information for development and testing of targeted behavioral interventions to remediate accelerated aging in survivors. [Table: see text]
A pilot study of post-consolidation chemoimmunotherapy for high-risk neuroblastoma (ANBL19P1): A report from the Children’s Oncology Group.
Authors: Ami V. Desai, Arlene Naranjo, Brian LaBarre, Kelly C. Goldsmith, Meaghan P. Granger, Lisa States, Sean Green, Mariel Trunzo, Wendy Fitzgerald, Steven G. DuBois, Rochelle Bagatell, Julie R. Park, Araz Marachelian
Journal: Journal of Clinical Oncology (2024)

10004 Background: Post-consolidation anti-GD2 antibody-based immunotherapy has improved survival for newly diagnosed patients (pts) with high-risk neuroblastoma (HRNBL). However, nearly half of newly diagnosed pts relapse. Based upon the efficacy of anti-GD2 antibody dinutuximab given with chemotherapy (chemoimmunotherapy) in the relapse setting, we hypothesized that post-consolidation chemoimmunotherapy may further improve frontline outcomes. ANBL19P1 first assessed the feasibility of delivering chemoimmunotherapy after tandem high-dose chemotherapy with autologous stem cell transplant (ASCT). Methods: Pts &lt;31 years old with HRNBL who received 4-6 cycles of Induction chemotherapy +/- up to 4 cycles of post-Induction chemotherapy or chemoimmunotherapy, underwent tandem ASCT, had no evidence of progressive disease (PD), and met organ function criteria were eligible. Therapy, administered every 28 days, consisted of temozolomide and irinotecan on Days 1-5, dinutuximab on Days 2-5, and sargramostim on Days 6-12 during Cycles 1-5; isotretinoin on Days 8-21 during Cycles 1-6. Therapy was deemed feasible if the 95% confidence interval (CI) placed on the percentage of pts that completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks contained 75%, and if the interim monitoring rules for feasibility and excessive toxicity were not triggered. Event-free (EFS) and overall survival (OS) were determined from time of enrollment. Results: From 11/30/20-6/30/23, 40 eligible pts enrolled and started protocol therapy. 87.5% (n=35) were ≥18 months old and 97.5% (n=39) had INRG Stage M disease, at diagnosis. 87.5% (95% CI 73.9%, 94.5%) completed 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks, exceeding the feasibility benchmark of 75%. Feasibility and monitoring rules were not triggered. Five pts were removed from protocol therapy prior to Cycle 4 [physician determination (n=2), pt/parent refusal of further therapy (n=2), and PD (n=1)]. No unacceptable toxicities or deaths on protocol therapy were reported. Toxicities of interest are summarized (Table). One-year EFS and OS were 90.0±5.0% and 97.5±2.7%, respectively (median follow-up time for pts without event=1.2 years). Conclusions: Administration of post-consolidation chemoimmunotherapy in pts who underwent tandem ASCT is tolerable and met pre-defined feasibility criteria. The impact of this approach on survival outcomes will be studied in a future COG trial. Clinical trial information: NCT04385277 . [Table: see text]
AMH levels after initial cycles of chemotherapy in female adolescents with Ewing sarcoma and implications for preservation of fertility.
Authors: Jie Xu, Xin Sun, Kuisheng Liu, Lu Xie, Jingtian Shi, Xiaodong Tang
Journal: Journal of Clinical Oncology (2024)

10067 Background: Anti-Müllerian hormone (AMH) has been recommended as the primary surveillance modality for evaluation of ovarian insufficiency in females. Patients with Ewing sarcoma receive VDC-IE chemotherapy which is estimated high risk of gonadotoxic injury. Previous studies have shown that only a small part of female patients with Ewing sarcoma show signs of ovarian recovery during long-term follow-up, similar to those treated with SCT or abdominal radiotherapy. Time to start preservation of fertility should be defined in this group of patients. Methods: In this observational study, we prospectively investigated AMH as a measure of ovarian function in female adolescents (less than 18 years old) with Ewing sarcoma who received initial chemotherapy in our hospital. Patients previously treated with systemic treatment were excluded. Serum levels of AMH were measured at the laboratory of Peking University People’s Hospital. Blood samples were collected at the first day of the initial two cycles of VDC-IE treatment, before local therapy including surgical resection and radial radiation, and at the end of chemotherapy. All statistical analyses were performed using SPSS 19.0 version. Results: A total of 53 female adolescents with Ewing sarcoma who received initial chemotherapy in our hospital were analyzed from February 1, 2021 to December 31, 2023, including 35 patients aging from 6 to 12 (group 1), 18 patients aging from 12 to 18 (group 2). 255 blood samples from unique time points were measured. The baseline mean AMH were 4.16 (90% CI, 1.88 – 9.42) ng/mL in all patients, 3.58 (90% CI, 1.40 – 6.91) ng/mL for group1 and 5.28 (90% CI, 3.10 – 9.48) ng/mL for group 2. The mean AMH level after first cycle of chemotherapy was 0.43 (90% CI, 0.03 – 0.81) ng/mL in all patients, 0.40 (90% CI, 0.03 – 0.69) ng/mL and 0.47 (90% CI, 0.12 – 1.09) ng/mL for each group at a mean time of 16.5 days after initial chemotherapy. The mean AMH level before local therapy was 0.17 (90% CI, 0.03 – 0.37) ng/mL and 0.07 (90% CI, 0.01 – 0.32) ng/mL at the end of chemotherapy. Conclusions: Female adolescents with Ewing sarcoma treated by VDC-IE regimen showed a rapid reduction of AMH after initial cycles. Methods for preservation of fertility should be implemented as soon as possible but not at the same time of local therapy.
Central pathological review and molecular classification of medulloblastoma in countries with limited resources: A commitment to equitable access.
Authors: Sidnei Epelman, Neviçolino Pereira de Carvalho Filho, Antonio Fernando da Purificação Filho, Ronaldo Modesto de Souza Filho, Renato de Paula Guedes de Oliveira, Ana Glenda Santarosa Vieira, Roberta Rehder, Carlos Eduardo Opazo
Journal: Journal of Clinical Oncology (2024)

10062 Background: Medulloblastoma, the most common malignant pediatric brain tumor, exhibits molecular heterogeneity influencing prognosis and treatment decisions. This study focuses on feasibility the pathological review and molecular classification with cost-effective methods. Methods: From December 2018 to November 2023, we analysed samples of patients referred to our laboratory. Data were collected on patient demographics (age, gender, origin), pathological review and specific medulloblastoma subtypes identified. The study was performed without costs for parents or institutions. Results: During the study period, 146 patients were included. The predominant age groups being 0 to 4 years (20.1%) and 5 to 9 years (36.1%) The mean age was 10.2 years. 55.6% of patients were female and 43.8% were male. Ninety-three patients were from Brazil and 7% from Latin America. Of the 117 samples that could be analyzed, 43% was classified as group 4, 37% were sonic hedgehog (SHH) group, 10% were group 3 and 4% were WNT group. Five percent of the samples had inconclusive results, with two patients had diagnoses other than medulloblastoma. Seventy percent of samples had a turnaround time for molecular classification results around 30 days. Conclusions: This study highlights the importance of central review pathology and molecular classification in medulloblastoma management. Our results emphasize the feasibility of centralized pathology review and molecular classification in countries with limited resources and provide equity for all patients. Based on this experience, we have expanded for other brain and pediatric tumors. Our effort contributes to ensuring that every patient benefits from the advancements in personalized medicine and this represents a real step to offer the same chances of cure for everyone.
Joint effects of long-term exposure to multiple air pollutants and breast cancer risk.
Authors: Béatrice Fervers, Camille Giampiccolo, Thomas Coudon, Delphine Praud, Lény Grassot, Elodie Faure, Gianluca Severi, Francesca Romana Mancini, Amina Amadou, Pascal Roy
Journal: Journal of Clinical Oncology (2024)

10572 Background: Human exposure to air pollution involves complex mixtures of multiple correlated air pollutants. To date, very few studies have assessed the combined effect of exposure to multiple air pollutants on breast cancer risk. We assessed the joint effects of multiple air pollutants and breast cancer risk. Methods: The study was based on a case-control study nested within the French E3N cohort, involving 5222 incident breast cancer cases and 5222 matched controls. For each woman, the average of the mean annual concentration estimates for eight air pollutants ((benzo(a)pyrene, cadmium, dioxins, polychlorinated biphenyls (PCB153), nitrogen dioxide (NO 2 ), particulate matters (PM 2.5 , PM 10 ), ozone) was estimated from cohort inclusion (in 1990) to the index date. We used Bayesian Profile Regression, which groups individuals according to their exposure profile and risk levels, and assigns a risk to each of these clusters. Odds ratios (OR) and their 95% credible intervals (CrI) were estimated. Results: Overall, 21 clusters were identified. The cluster characterized by low exposures to all pollutants, except ozone was taken as reference. A significant increase in breast cancer risk compared to the reference cluster was observed for 3 clusters, with the OR of 1.61 (CrI: 1.13;2.26), OR (1.00; 1.88), and OR 1.38 (1.00; 1.88) respectively. These three clusters share quite similar exposure profiles characterized by women in urban settings with high exposure to most pollutants, particularly to NO 2 , PM and PCB153. Conclusions: Overall, there is evidence of a positive joint effect of high level exposures to air several pollutants, namely NO 2 , PM and PCB153 and increased risk of breast cancer.
Risk of subsequent primary cancers among adult cancer survivors.
Authors: Matthew T. Warkentin, Winson Y Cheung, Darren R Brenner, Dylan E. O'Sullivan
Journal: Journal of Clinical Oncology (2024)

10554 Background: Improvements in early detection and clinical management of cancers have led to a significant increase in long-term cancer survivors who may be at an elevated risk of developing a subsequent primary cancer (SPC). As the largest and most comprehensive analysis in Canada, we assessed the risks and patterns of SPC development among 134,693 adult cancer survivors with 852,661 person-years of follow-up. Methods: We used data from the Alberta Cancer Registry (ACR) to identify all first primary cancers (FPC) occurring between 2004 and 2015 to allow for adequate follow-up until December 31, 2020. A SPC was considered as the next primary cancer occurring in a different organ/site. We estimated incidence rates (IR) and standardized incidence ratios (SIR) for SPC development with 95% confidence intervals (CI). IRs were estimated as the observed number of SPC divided by the person-years of follow-up. SIRs were estimated as the observed number of SPC (O) divided by the expected number of SPC (E), where E is a weighted-sum of the general population-based year-age-sex-specific incidence rates and the corresponding person-years of follow-up among the adult cancer survivors. Results: The risk of developing a SPC up to fifteen years after an initial cancer was 16.1% for males and 12.3% for females. These risk estimates varied considerably by initial cancer site. Survivors of initial head and neck cancers had a fifteen-year cumulative incidence of 21.3% and a 2.5-fold relative risk of SPC development. Overall, both males (SIR=1.50) and females (SIR=1.64) had an increased risk of developing a SPC. Both male and female survivors of a FPC were at a significantly increased relative risk of developing a screen-detectable SPC (breast, cervical, colorectal, lung). There were significant increases in SPC risk for nearly all age groups, with a greater than 5-fold increase for survivors of early-onset cancers diagnosed between ages 18 to 39. Conclusions: Cancer survivors of nearly every FPC site had substantially increased risk of a SPC, compared to the cancer risk in the general population. Screen-detectable cancers were common SPC sites and this highlights the need to develop evidence-based guidelines for cancer screening in the growing population of long-term cancer survivors.[Table: see text]