tbuckley/cabot-search huggingface dataset:
Feasibility of tumor-informed circulating tumor DNA (ctDNA) for molecular residual disease (MRD) assessment in pediatric patients with solid tumors.
Authors: Michael Mitchell
Journal: Journal of Clinical Oncology (2024)

10058 Background: Circulating Tumor DNA (ctDNA) is a noninvasive biomarker which has been validated as a prognostic tool in multiple adult cancers. There is evolving evidence that ctDNA may be prognostic in pediatric solid tumors, but experience with commercially available assays in pediatric patients is scarce. Signatera is a ctDNA assay which utilizes whole exome sequencing of tumor and whole blood to identify 16 tumor-specific, clonal, somatic variants. These variants are then monitored in plasma as a molecular residual disease (MRD) assessment. Methods: From November 2021 through August 2023, 30 patients were enrolled on a single center study evaluating the feasibility and utility of Signatera MRD monitoring in pediatric patients with solid tumors. Patients 6 months to 25 years of age with any malignant extracranial solid tumor including lymphoma were eligible. Peripheral blood has been collected every 3 weeks to 3 months while on therapy and every 3 to 6 months while off therapy for up to 2 years. A minimum of 22mL of blood was required for the first draw, and 16mL for subsequent draws. Timing of blood draws was aligned with standard of care blood draws when possible. Results of ctDNA MRD were compared with imaging obtained for disease response and surveillance as standard of care. Results: The cohort consisted of 6 cases of neuroblastoma, 6 osteosarcomas, 4 Wilms tumors, 4 carcinomas, 3 soft tissue sarcomas, 2 Ewing sarcomas, 2 germ cell tumors, 2 lymphomas, and one hepatoblastoma. Of 30 patients enrolled, a tumor-informed ctDNA assay was successfully created for 27 (90%). Of 25 patients who had radiographic evidence of disease at any time of monitoring, 23 (92%) had simultaneous detectable ctDNA. Seven patients have had disease recurrence, of whom all seven had detectable ctDNA at or preceding time of recurrence. Conclusions: Signatera tumor-informed ctDNA assay is a feasible noninvasive tool which may be utilized in parallel with standard of care imaging to monitor for disease recurrence in pediatric patients with extracranial solid tumors. Additional analysis of a larger patient cohort is needed to identify tumor types and clinical scenarios for which its application is most useful.
Interpretable artificial intelligence-based analysis for morphologic classification of neuroblastic tumors.
Authors: Siddhi Ramesh, Monica Pomaville, Kristina Doytcheva, James M Dolezal, Sara Kochanny, Rachel TerHaar, Jacob Brewer, Benjamin Kusswurm, Hiroyuki Shimada, Arlene Naranjo, Peter Pytel, Susan Lerner Cohn, Rani George, Alexander T. Pearson, Mark A. Applebaum
Journal: Journal of Clinical Oncology (2024)

10023 Background: Rapid and accurate identification of morphologic features of neuroblastic tumors (NTs) is critical for risk stratification and therapeutic decision making. The prognostic value of features like neuroblast differentiation, mitosis-karyorrhexis index (MKI), and Schwannian stromal presence is well established. Deep learning permits objective histopathological analysis, streamlining workflows for pathologists, notably in rare cancers. In rare cancers, our method minimizes bias and optimizes limited data using transfer and self-supervised learning (SSL) for feature extraction, with improved explainability. Here, we used an artificial intelligence-based model to morphologically classify NT tumors and MYCN-amplification. Methods: Annotated H&amp;E-stained slides of diagnostic NT tumor biopsies from the University of Chicago and the Children’s Oncology Group were digitalized. Pathologists defined three binarized measures including diagnostic category (ganglioneuroblastoma/neuroblastoma), grade (differentiating/poorly differentiating), and MKI (low and intermediate/high). MYCN status was abstracted from patient records (amplified/non-amplified). Using Slideflow, our open-source pipeline, we developed an attention-based multiple instance learning model with features extracted by CTransPath, a SSL model pretrained on pan-cancer images from The Cancer Genome Atlas. For each measure, model performance was evaluated using 5-fold cross validation by aggregating k-fold model predictions across multiple metrics. Patients were excluded from a model if the measure of interest was unknown. Feature significance was assessed visually using Class Activation Mapping (Grad-CAM). Results: The mean age of the study cohort (n = 172) was 3.66 years. Of patients with clinical information, 84 of 138 (60.2%) had metastatic disease and 94 of 133 (70.7%) were high-risk. Of the 148 tumors with a diagnostic category of neuroblastoma, 93.2% were poorly differentiated and 25% had high MKI. Of the 135 tumors with known MYCN status, 40 were amplified (29.6%). The final models excelled across all outcomes, performing best for diagnostic category, grade, and MYCN status (Table 1). Physician review of the attention-based heatmaps for all measures highlighted biologically relevant regions such as neuropil. Conclusions: We created a deep learning pipeline for auto-characterization of digitized H&amp;E-stained NT pathology slides. Our approach may also aid in identifying molecular features including MYCN-amplification. Review of heatmaps showed pertinent biological tissue, boosting model reliability.[Table: see text]
Social support dynamics within parent-AYA cancer survivor dyads in a rural, socioeconomically disadvantaged, majority Hispanic/Latino region.
Authors: Rebecca M. Lewinsohn, Catherine Benedict, Mary Smith, Heidi Boynton, Lidia Schapira, Stephanie M Smith
Journal: Journal of Clinical Oncology (2024)

10071 Background: Childhood cancer survivors and their parents often face psychological, financial, and informational challenges as survivors transition to adolescent/young adult (AYA) age, which can be exacerbated by socioeconomic disparities. Social support can positively impact the trajectory of AYA survivors and their parents by facilitating post-traumatic growth and wellbeing and reducing psychological distress. The aim of this study was to examine social support dynamics within AYA-parent dyads by comparing their support needs and gaps. Methods: This qualitative study was conducted in collaboration with a community-based organization (CBO) serving a predominately socioeconomically disadvantaged, Hispanic/Latino (H/L), and rural population of families affected by childhood cancer in California. English- and Spanish-speaking AYA childhood cancer survivors (≥15 years old, ≥5 years from diagnosis) and parents were interviewed. Transcripts were analyzed qualitatively using applied thematic analysis. Results: Seven AYA-parent dyads (6 H/L) participated in the study. AYAs (6 male, 1 female) were median (min-max) age 19 (16-23) and 14 years post diagnosis (6-17). Parents (1 male, 6 female) were predominantly Spanish-speaking (5/7). Forms of social support fell into emotional, instrumental (i.e. tangible assistance such as financial help), and informational domains. Although family and faith were shared sources of emotional support for parents and AYAs, parents were more likely to discuss fractured family support structures and unmet emotional needs. In contrast AYAs universally identified their parents as consistent sources of emotional support. Parents also more commonly discussed gaps in instrumental support, which were exacerbated by being a single parent and lacking a local extended family network after immigrating to the United States. Parents were frequently the primary source of informational support for their children and AYAs often lacked knowledge regarding their cancer diagnosis and treatment course. Two AYAs expressed ambivalence about receiving more survivorship-focused information due to it bringing up negative emotions around fear of recurrence. Parents frequently expressed worry about their child’s readiness to transition to adult care. Conclusions: Parents experienced gaps in emotional and instrumental social support that were not noted by AYAs, suggesting that parents protected their children from these experiences. Parents continued to serve as primary sources of informational support for AYAs even as they transitioned out of pediatric care. Our findings demonstrate the opportunity to build upon supportive parent-AYA relationships through dyad-focused education and counseling, which may improve readiness to transition to adult-focused survivorship care.
Overall survival prediction and risk stratification in patients with neuroblastoma through machine learning in the large multi-institutional PRIMAGE cohort.
Authors: Jose Lozano-Montoya, Ana Jiménez Pastor, Glen J. Weiss, Leonor Cerdá-Alberich, Diana Veiga-Canuto, Blanca Martínez de Las Heras, Barbara Hero, Ruth Lydia Ladenstein, Luis Martí-Bonmatí, Angel Alberich-Bayarri
Journal: Journal of Clinical Oncology (2024)

10054 Background: Neuroblastoma (NB) is the most prevalent solid cancer in childhood in which imaging plays a pivotal role at every step of the patient's journey. This investigation aimed to develop a machine learning model using clinical, molecular (MycN amplification), and magnetic resonance (MR) radiomics features at diagnosis to predict patient’s overall survival (OS) and improve their risk stratification. Methods: A database comprising clinical, molecular, and International Neuroblastoma Risk Group (INRG) staging on 513 patients with accessible MR imaging (discovery cohort) was employed for model training, validation, and testing. An additional 22 patients from non-discovery cohort hospitals served as an external validation group. Tumor segmentations of NB were manually and semi-automatically performed on corresponding T2-weighted MR images by an experienced radiologist. In total, 107 radiomics features were extracted and harmonized across MR scan manufacturers and magnetic field strengths using the nested ComBat methodology to correct both batch effects. These radiomics features, combined with clinical and molecular data, were utilized as input for the models. A nested cross-validation approach was employed for model development to determine the optimal preprocessing, machine learning algorithm, and model configuration. Results: The discovery cohort yielded a C-index of 0.788 ± 0.049 in the test partitions, with a random survival forest (RSF) exhibiting the best performance. In the validation cohort, a C-index of 0.934 was achieved. Interpretability analysis identified lesion heterogeneity, size, and molecular variables as crucial factors in OS prediction. The model demonstrated superior predictive performance and patient stratification compared to conventional staging systems in both cohorts. Conclusions: The RSF predictive model exhibited high performance, emphasizing the significant contribution of radiomics features and alignment with established clinical and molecular variables. The model stratified NB patients into low-, intermediate-, and high-risk categories and suggests that radiomics features potentially could improve current risk stratification systems. Additional external validation is warranted as this may present new evidence for enhancing patient care and clinical decision-making for NB patients.
Survival outcomes in patients with high-risk neuroblastoma (HRNB) in remission after relapsed or refractory treatment receiving eflornithine (DFMO) maintenance.
Authors: Giselle Linda Saulnier Sholler, William Ferguson, Genevieve Bergendahl, Thomas Clinch, Jacqueline M. Kraveka
Journal: Journal of Clinical Oncology (2024)

10060 Background: Five-year overall survival in newly diagnosed HRNB patients is around 50%, with relapse as the primary cause of mortality. While survival for newly diagnosed HRNB has improved with new treatment advances, relapsed or refractory (R/R) patients continue to have poor outcomes, with a high risk of subsequent relapse even among those who achieve remission, underscoring the need for treatments to improve EFS in this group. DFMO has been evaluated as a chemopreventative therapy in a single arm phase 2 study designed to compare Event Free Survival (EFS) and Overall Survival (OS) outcomes with published data for HRNB. The results of patients treated after standard therapy have been previously published. We now present an analysis of EFS/OS for patients with R/R disease, who historically have had a two-year EFS of approximately 10%. Methods: A total of 140 HRNB patients were enrolled, prospectively divided into two strata. S1 included patients in initial remission after upfront therapy, whereas S2 included patients who had either relapsed or had disease refractory to standard induction chemotherapy but achieved remission with additional therapy. Patients received 2 years of continuous treatment with oral DFMO 750 ±250 mg/m 2 BID and were followed for up to 7 years. Results: A total of 35 patients withR/R disease who had achieved remission after additional therapy were enrolled onto S2, including 28 patients in remission after one or more prior relapses and 7 refractory patients in remission after subsequent therapies. Of the relapsed patients, 23 had one prior relapse, while 5 patients had two or more relapses prior to enrollment; only one previously relapsed patient had received chemoimmunotherapy prior to enrollment in the study. For the entireS2 cohort, two-year EFS was 46% (95% CI 29%, 61%) with the lower confidence interval above the 10% historical control estimate. Four-year EFS was 46% (95% CI 29%, 61%) and OS 62% (95% CI 44%, 76%), with no relapses occurring after 18 months. For patients enrolled with refractory disease only (n=7) the four-year EFS was 85.7%. In the 28 relapsed patients, the four-year EFS was 35.7%, with single relapse patients (n=23) having an EFS rate of 39.1% and multiple relapsed patients (n=5) 20.0%. Conclusions: Patients in remission after chemotherapy for relapsed or refractory HRNB and treated with DFMO had improved EFS compared to the best historical estimate available at the time of the study. Although the number of patients is too small to support clear conclusions, the subgroup of refractory patients had outcomes that trended better than the relapsed subgroup with an EFS rate that was unexpectedly similar to prior reports of DFMO-treated S1 patients in remission after standard upfront therapy. Clinical trial information: NCT02395666 , NCT00026312 .
The dose-response relationship between cumulative alkylating agent exposure and sperm concentration in adult survivors of childhood cancer: A report from the St. Jude Lifetime (SJLIFE) cohort study.
Authors: Daniel M. Green, Kendrick Li, Raymond W. Ke, Angela Delaney, Christine Yu, Lu Xie, Deokumar Srivastava, Wiliam H Kutteh, Megan Elizabeth Ware, Kyla C. Shelton, Siddhant Taneja, Kirsten K. Ness, John Thomas Lucas, Gregory T. Armstrong, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2024)

10066 Background: Male survivors of childhood cancer treated with alkylating agents (AA) are at risk for azoospermia; however, the long-term dose-response relationship is unknown. Methods: Of the 685 male SJLIFE participants treated with AA but no radiation therapy, 387 (56.5%) provided an evaluable semen sample (mean age at diagnosis: 8.3 years, mean age at evaluation: 28.6 years, and mean years from diagnosis to evaluation: 20.3 years). 73 had one or more subsequent semen analyses (median interval between semen analyses 5.4 years; interquartile range 4.2 – 6.6 years). Survivors were categorized as azoospermia, oligospermia (sperm concentration &gt; 0 and &lt; 15 million/ml), or normospermia (sperm concentration ≥ 15 million/ml). AA exposure was estimated using the cyclophosphamide equivalent dose (CED). Risks were estimated using the odds ratio (OR) and 95% confidence intervals (CI) from multinomial logistic regression analyses. Results: Among survivors 22.5% had azoospermia, 26.6% oligospermia, and 50.9% normospermia (Table). Motility and progressive motility were not associated with increasing CED categories among normospermic or oligospermic participants. Multinomial logistic regression including CED, age at diagnosis and at follow-up demonstrated that, for each 1,000 mg/m 2 increase in CED, the odds of azoospermia increased by 1.14 (95% CI 1.09, 1.20), and the odds of azoospermia and oligospermia increased by 1.22 (95% CI, 1.14, 1.30). Azoospermia and oligospermia were best distinguished from normospermia using a CED cutoff of 7,000 mg/m 2 based on the Youden Index. Nearly all participants initially identified with azoospermia (24 out of 25) maintained this diagnosis upon later evaluation. Conclusions: Nearly half of adult childhood cancer survivors who received alkylating agents without radiation therapy experience impaired sperm production, either low sperm count (oligospermia) or no sperm at all (azoospermia). The association increases with increasing CED. Recovery of spermatogenesis is unlikely among those who present azoospermic. CED = 7,000 mg/m 2 is the optimal cutoff for differentiating risk for oligo- or azoospermia from normospermia. [Table: see text]
Analytical and clinical validation of a circulating tumor DNA–based assay for multicancer early detection.
Authors: Le Son Tran, Luu Hong Dang Nguyen, Hanh Thi-Hue Nguyen, Duy Sinh Nguyen, Hung Sang Tang, Hoa Giang, Hoai-Nghia Nguyen, Minh-Duy Phan
Journal: Journal of Clinical Oncology (2024)

10548 Background: The development of multi-cancer early detection (MCED) through a single blood test has emerged as a promising method for improving the efficiency of early cancer detection and benefiting population health. However, the lack of analytical validation and clinical evidence for their utility in diverse populations have prevented their use in clinical practice. To address these challenges, we conducted a comprehensive analytical and clinical validation for an MCED test, SPOT-MAS (Screening for the Presence of Tumor by DNA Methylation and Size). Methods: A prospective cohort study (ClinicalTrials.gov identifier: NCT05227261) was conducted at 13 major hospitals and one research institute in Vietnam. Our study recruited asymptomatic participants aged 40 years or older and followed up for 6 and 12 months. Analytical sensitivity of our assay was assessed by using our healthy and cancer-standard samples with known tumor fraction. The clinical performance was assessed by computing the positive predictive value (PPV), the negative predictive value (NPV) and accuracy in detecting tumor tissue-of-origin (TOO). Results: SPOT-MAS demonstrates the capability to detect at least 50% of cancer samples with a specificity of 98% when the samples have a tumor fraction of 0.049 (95% CI: 0.043-0.059). These results were consistently reproduced in both intra- and inter-batch analyses. Furthermore, our test maintains robustness even in the presence of hemoglobin contamination up to 500 mg/dL and genomic DNA contamination of up to 100%. Our analysis of 10,027 eligible participants demonstrated its ability to detect cancers in asymptomatic individuals with a positive predictive value of 58.14% (95%CI: 43.33- 71.62), an accuracy of 84.00% (95%CI: 65.35-93.60) in predicting tumor location and a negative predictive value of 99.92% (95%CI: 99.83-99.96). Conclusions: To our knowledge, this is the first and largest prospective validation study in Asia supporting the utility of SPOT-MAS as a multi-cancer blood test for early detection in a low- and middle-income country, where a nationwide cancer screening program is urgently needed but currently not available. Clinical trial information: NCT05227261 .
Impact of pathogenic germline variants in HRR genes on gastroesophageal cancer in a large real-world Chinese population: A comprehensive study.
Authors: Jian Li, Zhe Zhang, Liangjun Zhu, Jun Shi, Ting Hou, Lan Su, Xinze Lv, Zhou Zhang, Lin Shen
Journal: Journal of Clinical Oncology (2024)

10588 Background: Genetic testing in gastroesophageal cancer has been limited to those with hereditary cancer syndromes, restricting understanding of the impact of germline variants in sporadic cancers. Our study expands this by exploring germline and somatic characteristics in a broad Chinese cohort, enhancing risk assessment and guiding treatment strategies in a wider population. Methods: From October 2017 to April 2023, we retrospectively analyzed 2596 Chinese gastroesophageal cancer (GEC) patients, including 2003 with gastric cancer (GC), 196 with gastroesophageal junction cancer (GEJC), and 397 with esophageal cancer (EC). A 520-gene panel including 62 genes associated with cancer predisposition, was employed for genomic profiling of paired tumor and white blood cell samples. The pathogenicity of germline variants was determined according to ACMG guidelines. Results: In this retrospective cohort, the proportion of patients carrying pathogenic/likely pathogenic (P/LP) germline variants was 5.3% in GC, 5.6% in GEJC, and 5.0% in EC, respectively. Notably, genes associated with HRR exhibited the highest rates of P/LP germline mutations in GEC (94, 3.7%), with the majority occurring in non-BRCA HRR genes (77, 3.0%). The top five genes with the highest mutation rates were ATM, PALB2, FANCA, CHEK2, and RAD54L. Compared to the East Asian population without cancer in the genomAD database, a higher proportion of P/LP germline mutations were found in the CDH1(Inf [6.46-Inf], p &lt; 0.001), PALB2 (5.60 [1.61-13.09], p = 0.002), SDHA (8.99 [1.29-99.42], p = 0.012), ATM (2.15 [1.08-4.09], p = 0.02), and CHEK2 (3.83 [1.06-13.32], p = 0.02) genes in GC. Similarly, significant increases in PALB2 (10.36 [2.32-37.28], p = 0.002) and ATM (4.42 [0.86-14.33], p = 0.036) were also observed in EC and GEJC. The HRR P/LP variant group exhibited a higher incidence of biallelic inactivation (loss of wildtype allele) compared to the B/LB variant group (24.7% vs 6.6%, p&lt;0.001). Moreover, the similar trend was observed for the moderately/uncertainly penetrant gene ATM and FANCA (38.5% vs 0.6%, p &lt; 0.001; 42.9% vs 9.8%, p = 0.025), which suggests that ATM and FANCA may be associated with a high risk. The HRR genes ATM(56 vs 61, p = 0.052), CDH1(33 vs 61, p = 0.003), and FANCI(48 vs 61, p = 0.041) with P/LP variants were associated with a younger age of onset. Carriers of HRR P/LP variants had less prevalent somatic TP53 variants in GC and GEC and higher HRD score compared to non-carriers (p=0.005). Conclusions: Our research delineates the germline P/LP variant landscape in Chinese GEC, revealing the significant role of HRR P/LP variants. The presence of P/LP variants in HRR genes in GEC is linked to distinct disease characteristics and progression, underscoring their importance in guiding personalized treatment approaches and risk evaluation.