bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of children and young adults with localized extremity rhabdomyosarcoma treated on Children's Oncology Group trials.
Authors: Oberoi Sapna , Xue Wei , Qumseya Amira , Scharschmidt Thomas , Binitie Odion , Sorger Joel , Kumar Kiran , Wong Kenneth , Donaldson Sarah S. , Teot Lisa A. , Rudzinski Erin R. , Venkatramani Rajkumar 
Published: June 2024

10006 Background: Extremity rhabdomyosarcoma (RMS) accounts for 15-20% of patients with localized RMS. The long-term survival and associated prognostic factors of extremity RMS patients treated on the contemporary Children’s Oncology Group (COG) trials have not been reported. Methods: Patients with localized extremity RMS enrolled on the D9602, D9803, ARST0331 and ARST0531 COG trials were analyzed. The Kaplan-Meyer method estimated event-free (EFS) and overall survival (OS). The Log-rank test and Cox regression were used to estimate the prognostic significance of age at diagnosis, sex, race, tumor site & size, IRS group, stage, histology, FOXO1 fusion status, anaplasia, lymph node involvement, delayed primary excision (DPE) and radiation on survival. Results: We identified 159 patients with localized extremity RMS; 108 (68%) were < 10 years at diagnosis, 84(53%) had primary tumor > 5 cm, and 35 (22%) and 98 (62%) had IRS group II and III disease. Histology was alveolar in 106 (67%), and 43 (27%) had regional lymph node involvement on imaging or pathology. Seventeen were treated on low-risk (LR) studies D9602 (N = 10) and ARST0331 (N = 7), whereas 142 were treated on intermediate-risk (IR) trials D9803 (N = 85) and ARST0531 (N = 57). Eighty patients (50%) underwent primary surgical excision and 121 (76%) received radiotherapy. DPE was attempted in 60 patients (38%), resulting in an R0 (microscopically negative) margin in 48 (80%). Relapse/progression occurred in 52 patients: metastatic 26 (50%), local 22 (42%), and combined 3(6%). The 5-year EFS and OS of the whole cohort were 62.6% (95% CI: 54%-71.2%) and 78.7%% (95%CI: 71.4%-85.9%). LR patients treated on D9602 and ARST0331 trials had comparable 5-year EFS (70% vs. 71.4%, p-0.90) and OS (90% vs. 85.7%, p-0.54), respectively, while IR patients had significantly better 5-year EFS (68.9% vs. 51%, p-0.023) and OS (86.2% vs. 64.4%, p-0.007) on D9803 trial than ARST0531 trial. The 5-year EFS and OS of IRS group III patients with DPE with R0 margins were comparable to IRS group II patients (70.4% vs. 66.6%) & (86.5% vs. 84.6%), respectively. On univariable analysis, age at diagnosis and sex were associated with EFS, while age at diagnosis, sex, tumor size, IRS group, stage and fusion status were associated with OS (p < 0.05). None of the analyzed factors demonstrated independent statistical association with EFS, whereas female sex was the only factor independently associated with OS [Hazard ratio (HR): 0.4, 95% CI 0.20-0.85)]. Conclusions: IR localized extremity RMS patients treated on ARST0531 had suboptimal outcome. Survival of IRS group III patients with R0 DPE was comparable to IRS group II patients. Females with localized extremity RMS had better OS than males. Clinical trial information: NCT00354835 ; NCT00003958 ; NCT00075582 ; NCT00002995 .
Access for adolescents and young adults with hard-to-cure cancer to PROFYLE: The pan-Canadian precision oncology pipeline.
Authors: Abbott Lesleigh S. , Grover Stephanie , Henning Jan-Willem , Oberoi Sapna , Malkin David 
Published: June 2024

10012 Background: Cancer is the most common cause of disease-related death in children, adolescents and young adults (CAYA). Approximately, 1.5% of patients with cancer in Canada are adolescents and young adults (AYAs) (age 15-29). AYAs often present with advanced disease and limited access to clinical trials including genomic testing. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options for CAYA with hard-to-cure cancers. The AYA node of PROFYLE aims to enhance the inclusion of AYAs across Canada at pediatric and adult centers while raising awareness of improving cancer outcomes of this underserved population. Methods: Building upon 3 pre-existing regional precision oncology programs, PROFYLE was implemented as the first pan-Canadian precision oncology pipeline. The PROFYLE study is multi-centred, non-randomized, interventional, and qualitative. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. It includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples. Actionable findings, potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations are provided to the clinical care team. Results: To date, > 1,200 CAYA are included from all provinces. Of these, 33% were AYAs. Cancer diagnoses included: 47% sarcoma, 15% leukemia/lymphoma, 13% CNS tumor, 25% other. Of the AYAs enrolled, 53% had ≥1 significant tumour profiling finding (48% specific mutations/fusions; 6% DNA repair defect signature, hypermutation, microsatellite instability, chromosomal instability; 3% predictors of therapeutic resistance; 5% outliers in gene expression). 71% had potentially useful findings (15% diagnostic; 9% prognostic; 59% therapeutic; 2% etiologic; 15% cancer predisposition; 2% secondary germline; 0.5% pharmacogenetic). 23% had a pathogenic/likely pathogenic germline variant. 60% had ≥1 potentially actionable somatic alteration. 64% of clinicians indicated that molecular findings impacted clinical management (12% diagnostic; 6% prognostic, 60% therapeutic; 16% germline genetic). 24% indicated a change in treatment planning in response to these findings. Conclusions: The goal of developing a national precision oncology pipeline that provides equitable access to molecular profiling in a clinically relevant timeframe has been realized through the establishment of PROFYLE. Findings demonstrate that the sequencing platform provided medically informative results in the majority of enrolled AYAs. The success of PROFYLE underscores the importance of the continuing efforts to increase the access to this precision oncology initiative for all AYAs with cancer in Canada.
A multi-assay liquid biopsy approach to improve detection of bone and soft tissue sarcomas.
Authors: Najjar Deena , Lui LeeAnna , Battle Lauren , Dubin Robert , Zeldin Elizabeth , Applebaum Mark A. , Hayashi Masanori , Weiser Daniel A. 
Published: June 2024

10019 Background: Bone and soft tissue sarcomas are among the most common extra-cranial solid tumors of childhood, yet advances in liquid biopsies lag behind what has been achieved across adult cancers. Solid tumors that lack recurrent genetic mutations or translocations, such as bone and soft tissue sarcomas, are more difficult to detect in circulation using established assays, such as ddPCR. We have developed a pipeline to analyze cell-free DNA (cfDNA) using two molecular profiling techniques that we hypothesized would improve detection of circulating tumor DNA at diagnosis for patients with bone and soft tissue sarcomas. Methods: cfDNA was isolated from plasma of patients with osteosarcoma (OS) (n = 36) and fusion-negative rhabdomyosarcoma (FN-RMS) (n = 7) at multiple timepoints. Methods for detecting tumor DNA in cfDNA included ultra-low coverage whole genome sequencing (ULC-WGS, 0.5x) and ultra-deep targeted sequencing (UDP, ~1000x) using a panel of 11 and 22 tumor-associated genes for OS and FN-RMS, respectively. ULC-WGS data underwent ichorCNA analysis to define percent tumor content of each sample. UDP analysis identified somatic variants through variant callers, Mutect2, Lancet, strelka, and DELLY2, with ClinVar to annotate and define tumor-specific variants in each sample. Combining ULC-WGS and UDP data, an integrated tumor score was developed and assessed in diagnostic samples. Results: 136 OS and 30 FN-RMS cfDNA samples were collected during the patients’ disease courses. Circulating tumor material was detected in 18/23 (78%) OS and7/7 (100%) FN-RMS samples at diagnosis. The most frequent copy number aberrations were seen in the region of chromosome 8q containing the cMYC gene. cMYC amplification was found in 11/23 (48%) of diagnostic OS samples and 2/7 (29%) of diagnostic FN-RMS samples. UDP analysis identified variants in 17/23 (73%) and 7/7 (100%) of diagnostic OS and FN-RMS samples respectively. The most commonly detected variants included TP53, BRCA2, MET, and BRAF. Of the 23 diagnostic OS samples, four had TP53 translocations. The integrated tumor score detected the presence of tumor associated material within diagnostic samples with a sensitivity of 25/30 (83%), compared to the sensitivity of ULC-WGS or UDP alone, which was 15/30 (50%) and 24/30 (80%) respectively. Conclusions: A multi-assay liquid biopsy has promise to improve disease detection and monitoring for patients with solid tumors that lack recurrent driver mutations. We plan to integrate additional molecular profiling technologies to improve the sensitivity and specificity of our cfDNA assays and aim to adapt our pipeline across additional cancers.
Phase I dose escalation and pharmacokinetics clinical trial of mitoxantrone hydrochloride liposome in children with relapsed and refractory solid tumors.
Authors: Huang Junting , Ji Mingqing , Li Hui , Wu Yanpeng , Cai Ruiqing , Wang Juan , Lu Suying , Zhu Jia , Sun Feifei , Zhen Zijun , Zhang Yizhuo 
Published: June 2024

10047 Background: Compared with solvent-based mitoxantrone, mitoxantrone hydrochloride liposome has been found to reduce bone marrow toxicity. This open-label, muti-center, single-arm phase I clinical trial aims to evaluate the safety and efficacy of mitoxantrone hydrochloride liposome in pediatric with solid tumors. Methods: The study was divided into Phase Ia and Ib. Phase Ia was the dose escalation study, with a "3+3" design. Patients received mitoxantrone hydrochloride liposome at three dose levels (16 mg/m2, 20mg/m2, 24mg/m2, d1) in combination with irinotecan (50mg/m2, d1-5) and vincristine (1.5mg/m2, d1) every 3 weeks. Pharmacokinetic studies were conducted simultaneously. The primary endpoint of Phase Ia was the maximum tolerated dose (MTD). In phase Ib, patients received the combination therapy of mitoxantrone hydrochloride liposome at the MTD dose. The primary endpoint of Phase Ib was the incidence and severity of hematological adverse events. Secondary endpoints in both phases included objective response rate (ORR), pharmacokinetic (PK) parameters, and others. Results: From October 2022 to January 2024, a total of 51 pediatric patients with relapsed and refractory solid tumors were enrolled, 28 patients in Phase Ia and 23 patients in Phase Ib. The median age was 10.0 years (range: 3, 21). All Patients could be evaluated for toxicity and 40 for efficacy. The MTD of mitoxantrone hydrochloride liposome was determined to be 24mg/m2. The results of pharmacokinetic analysis were not returned. Highest incidence of hematological and non-hematological adverse events (AEs) were anaemia (88.2%), diarrhea (84.3%). The newly found or aggravated TnIUtra, BNP value abnormality and lower LV function after medication were 4 (11.8%), 5 (14.3%) and 0 (0.0%), respectively. The overall ORR and DCR were 50.0% (95% CI: 33.8% - 66.2%) and 90.0% (95% CI: 76.3% -97.2%). 13 patients (25.0%) treated with mitoxantrone hydrochloride liposome combination regimen received the opportunity of surgery. Conclusions: The mitoxantrone hydrochloride liposome combination regimen has demonstrated an acceptable toxicity profile and promising clinical efficacy in pediatric patients with solid tumors, especially in sarcomas. Clinical trial information: NCT05620862 .
Central pathological review and molecular classification of medulloblastoma in countries with limited resources: A commitment to equitable access.
Authors: Epelman Sidnei , Carvalho Filho Neviçolino Pereira de , Purificação Filho Antonio Fernando da , Souza Filho Ronaldo Modesto de , Oliveira Renato de Paula Guedes de , Vieira Ana Glenda Santarosa , Rehder Roberta , Opazo Carlos Eduardo 
Published: June 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.
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: Green Daniel M. , Li Kendrick , Ke Raymond W. , Delaney Angela , Yu Christine , Xie Lu , Srivastava Deokumar , Kutteh Wiliam H , Ware Megan Elizabeth , Shelton Kyla C. , Taneja Siddhant , Ness Kirsten K. , Lucas John Thomas , Armstrong Gregory T. , Robison Leslie L. , Hudson Melissa M. 
Published: June 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 > 0 and < 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/m2 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/m2 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/m2 is the optimal cutoff for differentiating risk for oligo- or azoospermia from normospermia. [Table: see text]
AMH levels after initial cycles of chemotherapy in female adolescents with Ewing sarcoma and implications for preservation of fertility.
Authors: Xu Jie , Sun Xin , Liu Kuisheng , Xie Lu , Shi Jingtian , Tang Xiaodong 
Published: June 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.
The frequency of HER2-low breast cancer among BRCA1, BRCA2, and PALB2 mutation carriers.
Authors: Goldblatt Lindsay , Coutifaris Paulina , Shah Payal Deepak 
Published: June 2024

10509 Background: Human epidermal growth factor 2 (HER2) expression in breast cancer (BC) has historically been characterized as negative (0 or 1+ by immunohistochemistry (IHC); 2+ by IHC and not amplified by in-situ hybridization, ISH) or positive (2+ by IHC and amplified by ISH or 3+ by IHC). Recently developed therapies highlight the importance of identifying tumors that are HER2-low (IHC 1+, or 2+ with negative ISH). A minority of BC associated with germline BRCA1, BRCA2( BRCA1/2) or PALB2pathogenic variants (PV) are HER2-positive, but the proportion of BRCA1/2- and PALB2-associated HER2-negative BC that are HER2-low and may benefit from novel HER2-low therapies is unknown.This study aims to retrospectively identify the frequency of HER2-low BC in BRCA1/2 and PALB2 mutation carriers whose cancers were identified as HER2-negative. Methods: We conducted a retrospective chart review of 170 patients diagnosed with HER2-negative BC in the context of a BRCA1/2or PALB2PV at the University of Pennsylvania from 2003 to 2023. Genomic and cancer-specific characteristics including variant classification and receptor status were collected and are descriptively reported. Results: 170 individuals with BRCA1/2 or PALB2 PV developed 190 HER2-negative BC. Forty-seven percent of primary tumors that had been identified as HER2-negative were HER2-low (39% of BRCA1-, 56% of BRCA2-,60% of PALB2-associated BC; see Table). 17 individuals had 17 metastatic site biopsy reports available for review. Of these, 10 (59%) were HER2-low (1 BRCA1-, 8 BRCA2-, and 1 PALB2-associated). 6 of 17 (35%) individuals had discordant HER2 status in primary and metastatic samples; in all cases, the primary tumor was HER2 IHC 0 and the metastatic site was HER2-low. Conclusions: Despite the lower frequency of conventionally HER2-positive BC among individuals with BRCA1/ 2and PALB2PVs, the proportion of these BC that have low HER2 expression is substantial and similar to that of sporadic breast cancer. Discordance in HER2 status between primary and metastatic samples is observed. Individuals with BRCA1/2and PALB2HER2-negative BC may benefit from therapies for HER2-low BC; reevaluation of HER2 status on metastatic samples may identify additional candidates for such therapies. [Table: see text]