Extracranial Tumor Research Articles

Metronomic chemotherapy for paediatric extracranial solid tumours: a systematic review and meta-analysis of randomised clinical trials

BackgroundMetronomic chemotherapy (‘less is more, regularly’) could be an alternative to the maximum tolerated dose (‘the more, the better’) in the chemotherapeutic cancer treatment of high-risk malignant solid extracranial tumours...

Outcome of radiotherapy for metastatic neuroblastoma

Background. Neuroblastoma (NB) is a prevalent solid extracranial tumor that primarily affects children. It is the third most common type of cancer in children, following leukemia and brain tumors. Aim. The study aimed to discuss the clinical outcomes after adjuvant radiotherapy to the primary site in case of metastatic NB after good response to chemotherapy. Methods. A retrospective clinical-dosimetric study of 25 patients metastatic NB treated with radiotherapy at Baghdad Radiotherapy and Nuclear Medicine Center, at Baghdad Medical City Complex, Baghdad, Iraq. Data collection begin from December 2023 and March 2024. Data were collected retrospectively with review of records. The following variables were studied: sex, age, date of diagnosis, site of primary tumor, site of metastasis, chemotherapy, surgery, RT, RT sites, doses of RT, fractions of RT, recurrence sites, date of relapse and survival outcome for each patient. Follow-up period include look up to metastasis, site of metastasis, recurrence, site of recurrence and survival rates. Results. In relation to sex, males (14, 56%) were more than females (11, 44%). The mean age of NB cases was 45.64±17.6 months. In NB, suprarenal masses were the most common site of primary in 21 (84%) of patients. The most common site of metastasis of NB was bone marrow in 12 (48). The multi sites of recurrence was the commonest presentation in 48%. The relapse-free survival (RFS) was 22.38 months. 5 out of 25 patients were alive whereas 20 (80%) of cases were dead. The median follow-up time was 6 years, and the OS of NB in this study after optimal treatment was 2.46 years (95%CI= 1.705-3.21) for survivors. The MS was 4.84 years. The OS was 6 yrs for those diagnosed at 2017, 2 yrs for those diagnosed at 2018, 1.5 yrs for those diagnosed at 2019, 1.75 yrs for those diagnosed at 2020, 3 yrs for those diagnosed at 2021 and 1.5 yrs for those diagnosed at 2022. There was a significant difference among doses (Log Rank (Mantel-Cox)= 11.425, p=0.044). Conclusions. This study is the first study in Iraq that examines the clinical results of radiotherapy on the primary site in cases of metastatic neuroblastoma following induction chemotherapy. The suprarenal masses of neuroblastoma are the most often occurring main site. The primary sites of metastases for neuroblastoma (NB) are the bone marrow and bones. Timely detection and proactive treatment of NB can improve overall results. Reoccurrence of skeletal issues and the infiltration of bone marrow are frequently observed. There were no significant differences observed in terms of relapse-free survival and overall survival based on factors such as sex, age, location of the main tumor, chemotherapy, radiation treatment, surgery, and radiation therapy dosages.

Barriers to T Cell Functionality in the Glioblastoma Microenvironment.

Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic interventions. Currently, chemotherapy and radiation combined with surgical resection are the standard of care for GBM treatment. Although immune checkpoint blockade has revolutionized the treatment of solid tumors, its observed success in extracranial tumors has not translated into a significant survival benefit for GBM patients. To develop effective immunotherapies for GBM, it is vital to tailor treatments to overcome the numerous immunosuppressive barriers that inhibit T cell responses to these tumors. In this review, we address the unique physical and immunological barriers that make GBM challenging to treat. Additionally, we explore potential therapeutic mechanisms, studied in central nervous system (CNS) and non-CNS cancers, that may overcome these barriers. Furthermore, we examine current and promising immunotherapy clinical trials and immunotherapeutic interventions for GBM. By highlighting the array of challenges T cell-based therapies face in GBM, we hope this review can guide investigators as they develop future immunotherapies for this highly aggressive malignancy.

Clinical and Molecular Risk Factors in Extracranial Malignant Rhabdoid Tumors: Toward an Integrated Model of High-Risk Tumors.

Extracranial malignant rhabdoid tumors (eMRT) are a challenging entity. Despite the use of multimodal treatment approaches, therapy failure occurs in 55% to 67% of these. Molecular markers for identification of patients at increased risk for relapse or refractory (R/R) disease are not available. Clinical characteristics may only insufficiently predict the individual course of disease. Using the EU-RHAB database, we analyzed a cohort of 121 patients with eMRT clinically. For 81 patients, molecular and clinical data were available, which were further complemented with publicly available DNA molecular data from 92 eMRTs. We aimed to delineate molecular risk factors by dissecting the DNA methylome of these tumors. Moreover, we establish clinical characteristics and treatment details of R/R disease in a subcohort of 80 patients. Using consensus hierarchical clustering, we identified three distinct subgroups, one of which (eMRT standard risk) was associated with significantly improved survival, irrespective of germline status and/or localization. At the transcriptome level, this subgroup was characterized by an overexpression of genes involved in muscle development. A relevant proportion of patients developed distant relapses or progressions; the median time to the event was 4 months, underlining the need for early identification and risk stratification of R/R disease. The overall survival was significantly decreased in patients with progressive disease when compared with relapse cases, and reaching complete remission during salvage therapy provided a survival benefit. Our analysis of eMRT in this comprehensive cohort provides novel insights into the patterns of relapse and integrates molecular and clinical risk factors to guide clinical decision-making.

A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer.

For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS). In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%. Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.

Validating process mining in pediatric oncology: Demonstrating protocol adherence and variability in neuroblastoma treatment.

166 Background: Neuroblastoma is the most common extracranial tumor in children. The mortality rate for patients with metastatic disease is over 50%. In the Netherlands, 30 new patients are diagnosed annually. Current clinical treatment guidelines are complex and include multiple treatment arms consisting of chemotherapy, surgery, radiotherapy, and immunotherapy (IT). Although poor patient health and complications are known to cause adaptations to the otherwise standardized treatment regimen, the extent to which these variations occur is unknown. This study aimed to validate the use of process mining, a data-driven technique, to retrospectively examine protocol adherence and variability within current clinical guidelines based upon the GPOH-DCOG NBL2009 neuroblastoma treatment protocol. Methods: Data was extracted from electronic health records, as well as laboratory, pathology, and pharmaceutical databases, to create individual event logs for each patient. Process mining was performed using a fuzzy mining algorithm. The treatment courses for all neuroblastoma patients were mapped. Commonalities and variations were highlighted, and the throughput time for key treatment phases was calculated. Subsequently, conformance with protocol was determined. Results: Analysis of 70 patients treated between 2018-2022 showed 62 distinct treatment processes, revealing significant variations in patient care. Patients with high-risk disease showed the least variation (n=47, 42 variants). Notably, 17 variants were identified among 18 patients who died, indicating a highly personalized approach in the advanced stages of the disease. Subgroup analysis of 17 high-risk patients who received IT consisting of alternating cycles of anti-GD2 antibody and retinoic acid showed 6 variants. 12/17 patients (70.6%) completed the full IT regimen. Other treatment adjustments included shortened anti-GD2 infusions for two patients (5 and 8 days versus the prescribed 10 days, respectively), potentially indicating treatment toxicity. One patient received a 15-day infusion, exceeding the prescribed limit of 11 days. The recorded interval between the administration of anti-GD2 and retinoic acid was a median 5.5 hours (range: 60 seconds – 6.4 days), deviating from the prescribed interval of 24 hours and warranting further investigation. Conclusions: Process mining is a valuable tool for analyzing protocol performance and adherence in neuroblastoma treatment. Despite standardized treatment protocols, significant heterogeneity was observed in the treatment of neuroblastoma patients, especially those with poor prognosis. Throughput time analysis revealed variabilities in the IT regimen that warrant further investigation. This study underscores the potential of data-driven approaches to optimize treatment protocols and support evidence-based practices in clinical oncology.

Management and Outcomes of Children with Malignant Germ Cell Tumor.

To assess the clinico-pathological features, management and outcomes, amongst extracranial malignant germ cell tumors (MGCTs) in children treated primarily at a tertiary care center in a resource-challenged nation. The prospectively maintained data for children below 14 y of age treated for extracranial MGCT from May 1994 to January 2023 was analyzed for patient characteristics, management, event-free survival (EFS) and overall survival (OS) and factors effecting survival. Events was defined as death, recurrence and progression. Multivariate logistic regression analysis was performed to identify the factors independently predicting unfavorable outcomes. One hundred and seventy-seven children (37% males) with a median (IQR) age at presentation of 30 mo (range 2-168 mo) were included. The cohort consisted of 87 (49%) extra-gonadal and 90 (51%) gonadal cases. Disease was metastatic at presentation in 48 (27%) with lungs being the most common site. Neoadjuvant chemotherapy (NACT) was given to 119 (67%) and finally 162/177 (92%) had undergone resection of the primary tumor. Endodermal sinus tumor (EST) was the commonest histological subtype in 141 children (73%). Twenty-two (12%) patients had died giving a 5-y OS of 84.7% (95% CI 78.3- 91.1). Recurrence occurred in 25 patients, and an additional 5 patients had progression giving a 5-y EFS of 69.9% (95% CI 62.5- 77.3). Stage III (p = 0.05), Stage IV (p = 0.006) and extra-gonadal site (p = 0.05) were significantly associated with poorer EFS. Children with MGCT have a favorable outcome with 5-y OS of 84.7% and EFS of 69.9%. Stage III and IV disease and extra-gonadal sites were independent predictors of a poor outcome.

Current surgical approach: Extracranial malignant germ cell tumors.

Germ cell tumors (GCT) are a complex, heterogeneous collection of tumors that may present in either gonadal or extragonadal sites. They consist of a variety of benign and malignant histologies that can occur at several locations throughout the body. An important component of treatment is surgical resection, and while the key components of resection are site specific, the universal goals of GCT resection include the complete resection of tumor without violating the tumor capsule, while preserving function of surrounding organs, minimizing morbidity, and assessing for regional spread.

PET imaging of gliomas: Status quo and quo vadis?

PET imaging, particularly using amino acid tracers, has become a valuable adjunct to anatomical MRI in the clinical management of patients with glioma. Collaborative international efforts have led to the development of clinical and technical guidelines for PET imaging in gliomas. The increasing readiness of statutory health insurance agencies, especially in European countries, to reimburse amino acid PET underscores its growing importance in clinical practice. Integrating artificial intelligence and radiomics in PET imaging of patients with glioma may significantly improve tumor detection, segmentation, and response assessment. Efforts are ongoing to facilitate the clinical translation of these techniques. Considerable progress in computer technology developments (eg quantum computers) may be helpful to accelerate these efforts. Next-generation PET scanners, such as long-axial field-of-view PET/CT scanners, have improved image quality and body coverage and therefore expanded the spectrum of indications for PET imaging in Neuro-Oncology (eg PET imaging of the whole spine). Encouraging results of clinical trials in patients with glioma have prompted the development of PET tracers directing therapeutically relevant targets (eg the mutant isocitrate dehydrogenase) for novel anticancer agents in gliomas to improve response assessment. In addition, the success of theranostics for the treatment of extracranial neoplasms such as neuroendocrine tumors and prostate cancer has currently prompted efforts to translate this approach to patients with glioma. These advancements highlight the evolving role of PET imaging in Neuro-Oncology, offering insights into tumor biology and treatment response, thereby informing personalized patient care. Nevertheless, these innovations warrant further validation in the near future.

QOL-31. NEUROPSYCHOLOGICAL FUNCTIONING AND QUALITY OF LIFE IN INFANT AT/RT SURVIVORS: FOCUS ON FLUID INTELLIGENCE AND VISUAL PROCESSING

Abstract BACKGROUND Understanding the long-term cognitive sequelae in infant brain tumor survivors remains incomplete, particularly regarding the impact of tumor type, multimodal treatment, and other patient-related factors. This retrospective analysis explores neuropsychological and quality of survival (QoS) outcomes in survivors of atypical teratoid/rhabdoid tumors (AT/RT) and extracranial malignant rhabdoid tumors of soft tissues (eMRT) and kidneys (RTK), all treated within the same framework. Neuropsychological data from children with AT/RT were compared to data from children with non-irradiated low-grade glioma (LGG). METHODS Patients (0 - 36 months at diagnosis) underwent various treatments, including radio-chemotherapy for AT/RT (n = 13) and eMRT/RTK (n = 7), chemotherapy only for LGG (n = 4) and eMRT/RTK (n = 1), or observation for LGG (n = 11). Neuropsychological evaluations were conducted at a median of 6.8 years (AT/RT), 6.6 years (eMRT/RTK), and 5.2 years (LGG) post-diagnosis. RESULTS Impairments were observed for all tumour types. Patients with AT/RT exhibited impairments in fluid intelligence (p =.041; d = 1.11) and visual processing (p =.001; d = 2.09) when compared to LGG-patients. Both groups demonstrated deficits in psychomotor speed and attention abilities (p &amp;lt;.001–.019; d = 0.79–1.90). Diagnosis significantly predicted cognitive outcomes, whereas gender and age-related variables did not. QoS outcomes for all rhabdoid patients indicated lower scores in psychosocial functioning (p =.023; d = 0.78) and quality of life (p =.006; d = 0.79) compared to healthy controls. CONCLUSIONS Infant rhabdoid tumor survivors experience cognitive and quality-of-life sequelae. Patients with AT/RT are especially vulnerable to impairments in fluid intelligence and visual processing, while infant LGG-patients without radiotherapy demonstrated comparable deficits in psychomotor and attention abilities. Close monitoring of neuropsychological and quality of life outcomes is crucial for early onset and multimodal treatment.

BIOM-09. TOWARDS CLINICAL IMPLEMENTATION OF LIQUID BIOPSY ANALYSIS FOR PAEDIATRIC BRAIN TUMOUR PATIENTS – A PAN-EUROPEAN EFFORT FOR STANDARDIZATION

Abstract BACKGROUND Liquid biopsies (LBs) allow for analysis of tumour-derived molecules, such as cell-free DNA (cfDNA) and microRNAs (miRNAs), complementing cancer diagnostics, therapy monitoring, and minimal residual disease detection. While circulation-based LB has benefit for extracranial tumour entities, peripheral blood has not historically been a reliable source for diagnosis and disease-monitoring in brain tumours. For these tumours, cerebrospinal fluid (CSF) analysis is better suited for detection despite being a more invasive procedure. However, standardized protocols for sample collection and pre-analytical parameters for these LBs currently are limited. AIM We aim to establish an evidence-based gold standard protocol for cfDNA and miRNA analyses from CSF in paediatric brain tumour patients. In addition to higher compliance in trial-related CSF sampling, this initiative seeks to facilitate identification of clinically relevant indications and time-points for collection, thereby paving the way for well-informed, routine CSF molecular diagnostics. METHODS AND RESULTS We have initiated the Liquid Biopsy Working Group within the framework of the International Society of Paediatric Oncology Europe Brain Tumour Group (SIOPE-BTG). Available literature on LB in brain tumours was critically assessed regarding pre-analytical parameters, downstream analyses and LB assay performance. To directly evaluate confounding by pre-analytical factors, we experimentally compared the impact of CSF sampling sites, storage conditions, and different pre-processing protocols. cfDNA and miRNA yields, purity, and the fraction of tumour-derived material were selected as read-outs and correlated with tumour tissue information. To prepare for clinical translation, we consulted clinical paediatric brain tumour trial coordinators to identify major bottlenecks for CSF sampling in routine clinical practice. In addition, clinical practitioners and patient/ parent representatives have been consulted to comprehensively represent the perspectives and needs of all stakeholders. Together, results of this collaborative effort will be fundamental to the successful clinical integration of LBs to improve the future management of paediatric brain tumour patients.

IMMU-17. A PHASE I STUDY OF INTRATUMORAL/PERITUMORAL HERPES SIMPLEX VIRUS-1 MUTANT HSV1716 IN PATIENTS WITH REFRACTORY OF RECURRENT HIGH-GRADE GLIOMAS: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

Abstract BACKGROUND Immune-modulatory strategies, including checkpoint inhibition and tumor vaccines, have been tested in efforts to mitigate the pro-tumor microenvironment in pediatric high-grade glioma (pHGG). HSV1716 is a first-generation oncolytic virus that was previously reported safe with evidence of response in pediatric patients with relapsed or refractory extracranial tumors and in adults with high-grade glioma. METHODS PBTC-037 was a multicenter, phase I trial developed and performed by the Pediatric Brain Tumor Consortium (PBTC) to estimate the maximum tolerated dose or recommended phase II dose of HSV1716 administered during surgical resection. Patients aged 12 to 21 years with recurrent or refractory pHGG for whom surgical resection was clinically indicated were eligible. After maximal tumor resection, patients received one intraoperative dose of HSV1716. RESULTS Two patients were enrolled; one was later deemed ineligible (due to out-of-window screening evaluations) yet was continued in follow up for safety. Shortly after enrollment of the 2 patients, the study was closed to accrual due to a change in the sponsor’s investment focus. One patient completed the 8-week reporting period without toxicities. The only grade 3 or higher adverse event noted was grade 3 hyperglycemia at 2- and 3-months post injection. The second patient that was later deemed ineligible received the injection of HSV1716 and had no evidence of dose-limiting toxicity. The two patients had progressive disease 1.9 and 2.9 months after enrollment; both eventually died due to progressive disease at 7.5 months. CONCLUSIONS We describe the administration of HSV1716 to two pediatric patients with recurrent high-grade glioma, without evidence of dose-limiting toxicity. Oncolytic viruses are currently being tested in pediatric patients in larger trials and in combinatorial trials in other tumor types. Despite the limited numbers, the data presented here will hopefully provide incremental steps toward improved immunovirotherapy of pediatric brain tumors.

Interventional oncology in children: Where are we now?

Paediatric Interventional Oncology (IO) lags behind adult IO due to a scarcity of specific outcome data. The suboptimal way to evolve this field is relying heavily on adult experiences. The distinct tumour types prevalent in children, such as extracranial germ cell tumours, sarcomas, and neuroblastoma, differ strongly from those found in adults, presenting a completely different biological behaviour. Compounding this challenge, paediatric interventional radiology often employs adapted or off-label techniques, potentially compromising optimal outcomes. This review outlines the present indications for interventional radiology in paediatric cancer, from biopsy to supportive care, including complication management. It emphasises the role of locoregional approaches, and explores the status of common paediatric oncological diseases, highlighting areas where IO has made progress identifying potential opportunities for future advancements in this evolving field.

Factors predicting surgical receipt in extracranial rhabdoid tumors.

e23541 Background: Extracranial rhabdoid tumors (ERTs) are a very rare and aggressive carcinoma that grow in a wide range of tissues, including but not limited to the lungs, kidneys, muscles, skin, and other soft tissues. These tumors most commonly present in infants between 11-18 months old, with an estimated annual incidence of less than 1 per million in the United States. Metastasis is common, and average survival time after diagnosis is approximately 5 years. Though most patients appear to undergo tumor resection at the primary site, a standardized treatment protocol for ERTs has not yet been developed. This study aimed to analyze the factors predicting receipt of this surgery. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with SEF from 2004 to 2020 using histology code 8963 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Logistic Regression tests were performed, and data were analyzed using SPSS version 29. Statistical significance was set at α = 0.05. Results: 208 patients with extracranial rhabdoid tumors formed the initial sample. Of these patients, 128 patients (61.5%) received surgery at the primary site. 80 patients (38.5%) did not have tumor resection. Median overall survival of surgical patients was significantly higher than nonsurgical patients ( 91.6 months vs. 32.1 months, p &lt; 0.001). Head, neck, and face, were the most common primary tumor sites (25.4%). Wider surgical margins were associated with improved outcomes ( p &lt; 0.05). On nominal regression, stage I, II, and III disease, grade 1 and 2, and younger age were associated with increased likelihood of receiving surgery ( p &lt; 0.05). Metastasis to distant sites was associated with decreased likelihood of receiving surgery ( p &lt; 0.05). Treatment at an academic facility, income status, tumor size, insurance status, and race were not significant predictors of receiving surgery. 77 patients (37%) received adjuvant chemotherapy, 1 patient received adjuvant radiation, and 4 patients received adjuvant chemoradiation. 121 patients (58.2%) did not receive adjuvant therapy. Conclusions: Resection of the primary tumor in ERT is associated with improved overall survival. Younger age, stage I, II, or III disease, and grade 1 or 2 disease are factors predicting a higher likelihood of receiving surgery. Improved outcomes of tumor resection are associated with wider surgical margins. The presence of metastasis decreased likelihood of undergoing surgery. Treatment location, insurance, status, race, income, and tumor size did not affect surgery receipt. Interestingly, the majority of patients sampled did not receive any adjuvant therapies, such as chemotherapy or radiation. Future research should continue delineating what factors predict both receipt of surgery and improved surgical outcomes, as well as better understand what the role of adjuvant therapies is in managing ERT.

Impact of age on clinical trial availability for AYAs with cancer: A time-trend analysis.

1534 Background: Low participation of adolescents and young adults (AYAs, age 15-39 yrs at diagnosis) in cancer clinical trials (CCT) limits their access to novel therapies and hinders the ability to study disease biology and age-specific toxicities. Patient age may be an important barrier as younger and older AYAs may be excluded depending on the trial’s focus. In 2017, the American Society of Clinical Oncology and Friends of Cancer Research issued a joint statement encouraging removal of age as a CCT eligibility criterion unless there is specific biological rationale. To evaluate the impact of this statement, we undertook this analysis of CCT availability for AYAs. Our primary objective was to compare the number of CCT available for AYAs, overall and by tumor types, from 2019-2023 vs previously published data from 2007-2018. The availability of early phase trials and study sponsor was also assessed. Methods: We identified CCT registered on ClinicalTrials.gov from January 2019 to July 2023 enrolling patients with 10 malignancies relevant for AYAs (Hodgkin lymphoma, anaplastic large cell lymphoma, melanoma, extracranial germ cell tumors [GCT], medulloblastoma, thyroid cancer, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma [RMS], and synovial sarcoma). Trials were categorized as adult (≥18 yrs), transitional (patients &lt; or ≥18 yrs), or pediatric (&lt;18 yrs). Transitional trials with an age range 12-18 to &lt;40 yrs were defined as AYA specific trials. Early phase included phase 1 and 1/2 trials; late phase included phase 2/3 and 3 trials. Trial availability from 2007-2018 was identified from a prior analysis by deRojas et al in 2019 (PMID:32337483). The proportion of trials in each category was compared between 2007-2018 and 2019-2023 using z-tests. Results: There were 1071 eligible trials registered on Clinicaltrials.gov: 840 (78%) adult, 226 (21%) transitional, and 5 (0.5%) pediatric. Four trials were AYA-specific. Compared to the prior 10 years, the proportion of transitional trials did not change overall (19% vs 21%, p=0.24) or within any disease. Whereas the proportion of trials available at age 17 has not significantly changed overall (20% vs 21%; p=0.48) or within any disease, the proportion of trials available at age 18 significantly increased (95% vs 98%; p&lt;0.001) in aggregate and specifically for Ewing sarcoma (93% vs 100%; p=0.003), GCT (96% vs 99%; p=0.002), medulloblastoma (86% vs 98%; p=0.006), RMS (87% vs 98%; p=0.007) and thyroid cancer (92% vs 98%; p=0.01). Time trends for transitional trials by phase and sponsor are summarized (Table). Conclusions: Availability of transitional trials for AYAs has not increased, particularly for those &lt;18 yrs. The 18-yr-old age limit continues to be an obstacle in CCT availability and enrollment. [Table: see text]

Enrichment of glioblastoma tumor microenvironment in a GZMK+ T cell population.

2065 Background: Glioblastoma (GBM) bears a survival estimate below 10% at 5 years, despite standard chemoradiation treatment. Trials evaluating immune checkpoint blockade (ICB) in gliomas have been disappointing so far, dealing with the unique immunosuppressive tumor microenvironment (TME) of the brain. Nevertheless, we have clinical evidence of ICB efficacy for brain metastases (BrM) of immunosensitive tumors. Even if both GBMs and BrM share the same organ-specific microenvironment, it is clear that disease-specific immune characteristics instruct differential response to ICB. Methods: By using advanced deep learning algorithms to combine public and in-house-generated single-cell RNA sequencing profiles, we analyzed immune infiltrate characteristics of 602949 CD45+ cells from 76 GBM, 30 BrM from different types of extracranial tumors (13 NSCLC, 12 melanoma, 2 ovarian, 1 breast, 1 colorectal and 1 renal carcinoma) and 3 normal brain samples. The analysis was restricted to newly diagnosed GBM, excluding recurrent and pre-treated cases. CD8+ cells underwent segregation into clusters based on log2 normalized expression levels of CD3E and CD8A (with expression values greater than 0). The data integration utilized DESC, a deep learning model founded on autoencoders, and subsequent examination was conducted within the Scanpy framework. Cluster analysis was executed employing the Leiden algorithm. Differentially expressed genes (DEGs) were pinpointed across clusters using the Wilcoxon test, with False Discovery Rate (FDR) correction carried out through the Benjamini-Hochberg procedure. Results: From CD45+CD3+ cells, we isolated CD8+ T cells and identified 7 informative CD8+ T cells clusters. Based on DEGs, we could appreciate T cells clusters that were also recapitulated in other extracranial malignancies. The most abundant subset was composed of GZMK+ effector T cells (Cluster 0: GZMK, GZMM, CD44, KLRG1, IL7R, GZMA, CXCR3), followed by putative tumor-specific tissue-resident memory cells (Cluster 1: GZMB, LAG3, CTLA4, TIGIT, CXCL13, ITGAE, ENTPD1, PDCD1, CD27, HLA-DRB1), stem-cell memory-like T cells (Cluster 3: IL7R, CCR7, JUNB, KLF2, TCF7) and a less represented cluster characterized by high expression of genes belonging to the HSP family (Cluster 4: HSPA1, HSPH1, HSPE1, HSPD1, IFN). Interestingly, while the majority of the identified clusters was equally represented in the 3 different tissues, the GZMK+ effector T cells cluster (Cluster 0) was found to be more represented in GBM compared to BrM and normal brain tissue. Conclusions: A GZMK+ effector T cells subpopulation, specifically enriched in GBM, has been poorly characterized in its function and spatial localization. Our data highlight the importance of studying the composition of the immune infiltrate in GBM with multi-omics approaches in order to uncover deep mechanisms of resistance to ICB and eventually provide hints on potential therapeutic targets.

In vivo cisplatin-resistant neuroblastoma metastatic model reveals tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as an independent prognostic factor of survival in neuroblastoma.

Neuroblastoma is the most common solid extracranial tumour in children. Despite major advances in available therapies, children with drug-resistant and/or recurrent neuroblastoma have a dismal outlook with 5-year survival rates of less than 20%. Therefore, tackling relapsed tumour biology by developing and characterising clinically relevant models is a priority in finding targetable vulnerability in neuroblastoma. Using matched cisplatin-sensitive KellyLuc and resistant KellyCis83Luc cell lines, we developed a cisplatin-resistant metastatic MYCN-amplified neuroblastoma model. The average number of metastases per mouse was significantly higher in the KellyCis83Luc group than in the KellyLuc group. The vast majority of sites were confirmed as having lymph node metastasis. Their stiffness characteristics of lymph node metastasis values were within the range reported for the patient samples. Targeted transcriptomic profiling of immuno-oncology genes identified tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as a significantly dysregulated MYCN-independent gene. Importantly, differential TNFRSF4 expression was identified in tumour cells rather than lymphocytes. Low TNFRSF4 expression correlated with poor prognostic indicators in neuroblastoma, such as age at diagnosis, stage, and risk stratification and significantly associated with reduced probability of both event-free and overall survival in neuroblastoma. Therefore, TNFRSF4 Low expression is an independent prognostic factor of survival in neuroblastoma.

Comprehensive characterization of circulating tumor cells and cell-free DNA in patients with metastatic melanoma.

Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head-to-head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome-wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P < 0.001), whereas the presence of CTCs in peripheral blood was associated with number of lesions on radiological imaging (P < 0.001). In conclusion, DLA tended to increase the proportion of patients with detectable CTCs but was also associated with low recovery. Both cfDNA and CTCs were correlated with clinical parameters such as LDH levels and extracranial tumor burden.

Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Radioligand therapies in meningioma - evidence and future directions.

Meningiomas are the most common intracranial neoplasms in adults. While most meningiomas are cured by resection, further treatment by radiotherapy may be needed, particularly in WHO grade 2 and 3 tumors which have an increased risk of recurrence, even after conventional therapies. Still, there is an urgent need for novel therapeutic strategies after exhaustion of local treatment approaches. Radionuclide therapies combine the specificity of tumor-specific antibodies or ligands with the cytotoxic activity of radioactive emitters. Alongside, integrated molecular imaging allows for a non-invasive assessment of predictive biomarkers as treatment targets. Whereas the concept of "theranostics" has initially evolved in extracranial tumors such as thyroid diseases, neuroendocrine tumors, and prostate cancer, data from retrospective case series and early phase trials underscore the potential of this strategy in meningioma. This review aims to explore the available evidence of radionuclide treatments and ongoing clinical trial initiatives in meningioma. Moreover, we discuss optimal clinical trial design and future perspectives in the field, including compound- and host-specific determinants of the efficacy of "theranostic" treatment approaches.