Oncological Treatment Research Articles

Beyond hazard ratios: appropriate statistical methods for quantifying the clinical effectiveness of immune-oncology therapies – the example of the Netherlands

BackgroundThe Dutch Committee for the Evaluation of Oncological Drugs evaluates the effectiveness of new oncological treatments. The committee compares survival endpoints to the so-called PASKWIL-2023 criteria for palliative treatments, which define if treatment effects are considered clinically relevant. A positive recommendation depends on whether the median overall survival (OS) is below or above 12 months in the comparator arm. If the former applies, an OS benefit of at least 12 weeks, and a hazard ratio (HR) smaller than 0.7 are required. If the latter applies, an OS or progression free survival (PFS) benefit of at least 16 weeks, and an HR smaller than 0.7 are required. Nonetheless, the median survival time may not be reached and the proportional hazards (PH) assumption, quantified by the HR, is likely violated for immuno-oncology (IO) therapies, deeming these criteria inappropriate.MethodsWe conducted a systematic literature review to identify statistical methods used to represent the clinical effectiveness of IO therapies based on trial data. We searched MEDLINE and EMBASE databases from inception to August 31, 2022, limited to English papers. Methodological studies, randomized controlled trials, and discussion papers recognising key issues of survival data analysis of IO therapies were eligible for inclusion.ResultsA total of 1,035 unique references were identified. After full paper screening, 17 publications were included in the review. Additionally, 43 papers were identified through ‘snowballing’. We conclude that the current PASKWIL-2023 criteria are methodologically incorrect under non-PH. In that case, single summary statistics fail to capture the treatment effect and any measure should be interpreted in combination with the Kaplan-Meier curves. We recommend ’parameter-free’ measures, such as the difference in restricted mean survival time, avoiding assumptions on the underlying survival.ConclusionsThe HR is commonly used to assess treatment effectiveness, without investigating the validity of the PH assumption. This happens with the application of the PASKWIL-2023 criteria for palliative oncology treatments, which can only be valid under a PH setting. Under non-PH, alternative treatment effect measures are suggested. We propose a step-by-step approach supporting the choice of the most appropriate methods to quantify treatment effectiveness that can be used to redefine the PASKWIL-2023 criteria, or similar criteria in other clinical areas.

Disfunção Cardíaca Associada À Quimioterapia Em Paciente Pediátrico: Relato De Caso

Introduction: Due to advances in antineoplastic treatments, there has been a notable improvement in the outlook of cancer patients. However, it is crucial to highlight that the cardiotoxicity associated with these therapeutic approaches is recognized as one of the most significant adverse effects. This phenomenon is characterized by the ability of chemical agents or therapeutic procedures to induce damage to the heart muscle, resulting in compromised cardiac function. Objectives: To present a case report of a patient suffering from Non-Hodgkin's Lymphoma (NHL), with impaired cardiac function due to cardiotoxicity. Methods: This is a descriptive observational study, of the case report type, which describes the clinical manifestations and management of a patient with cardiac dysfunction associated with chemotherapy. The research data used were collected through medical records made available by the public health service reference in pediatric oncology in the city of João Pessoa-PB. Results: Report the case of an 18-year-old pediatric patient, diagnosed with non-Hodgkin's Lymphoma, presenting with underlying heart disease, who underwent chemotherapy treatment, developing cardiotoxicity that led to death. Conclusion: Therefore, it is essential that continuous monitoring is implemented throughout the entire cancer treatment. Additionally, it is necessary to ensure that patients have broad access to diagnostic tests and chemotherapy with a cardioprotective profile, aiming to minimize the risk of cardiotoxicity. These measures are essential to reduce the incidence of adverse effects on the myocardium and improve the safety and effectiveness of oncological treatment.

Status of and Challenges in Therapy of Mucinous Ovarian Cancer Associated with Pseudomyxoma Peritonei Syndrome: Review of Current Options and Future Treatment Trends

Objective: Pseudomyxoma peritonei (PP) is a rare condition, and differentiating between primary and secondary ovarian causes is crucial for determining the appropriate oncological therapy. Given the resistance of ovarian mucinous carcinoma to standard platinum-based chemotherapy, the objective of this review is to present the current therapeutic approaches and summarize the emerging trends in the treatment of this disease. Methods: The authors conducted an exhaustive evaluation of studies published over a 14-year period (June 2010–May 2024) concerning pseudomyxoma peritonei, mucinous ovarian carcinoma, ovarian causes of PP, and ovarian cancer using the following databases: PubMed, Scopus, and Science Direct. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The results were organized into seven subchapters and analyzed. Results: The analyzed studies present surgery followed by HIPEC as the current therapy with the best long-term survival results. However, the oncological treatment is unsatisfactory, and the choice of therapy depending on the primary origin of the tumor becomes particularly important. For the differential diagnosis between pseudomyxoma due to a gastrointestinal cause and that of ovarian origin, genetic analyses are recommended; these include the characteristics of the mucin present in the lesion, as the therapeutic response can have contradictory results depending on the primary origin of the tumor. Conclusions: Surgery followed by HIPEC remains the standard for resectable cases. However, oncological treatment has controversial results in the case of mucinous ovarian carcinoma compared to other types of ovarian cancer and to metastatic ovarian tumors associated with pseudomyxoma of the peritoneum. Based on the articles included in this review, it was found that the current trend is the study of mucin as a resistance factor against chemotherapy based on platinum products and the targeting of oncological therapy according to the tumor’s genetic characteristics.

Metastatic Adenoid Cystic Carcinoma at the Base of the Tongue and Duplicate Breast Cancer Diagnosed During Restaging.

Adenoid cystic carcinoma (AdCC) is a rare malignant tumor that primarily affects the salivary glands but can also occur in other organs. Low incidence and unpredictable clinical behavior make AdCC one of the most difficult head and neck tumors to treat. We present the case of a 54-year-old woman with AdCC localized at the base of the tongue, following radical surgical and oncological therapy. Due to advances in palliative oncological treatment, there is a more than five-year survival period before the progression of metastatic disease. Considering the rare occurrence of this disease, a literature search was also conducted, and therapy options are discussed. Ensuring a sufficient extent of the surgical procedure is still a challenge, and most specialists agree that subsequent postoperative radiotherapy reduces the risk of local recurrence. The effective dose of radiotherapy to the area of the primary tumor and lymph nodes is not clearly defined. The distinct biological behavior of AdCC results in varying sensitivity to chemotherapy or radiotherapy compared to treatments commonly used for head and neck squamous cell carcinomas. Treatment recommendations for these rarer tumors are based mainly on case reports and small clinical trials. The acquired therapeutic experience can contribute to prolonging the survival period of patients and improving their prognosis and quality of life.

Adverse Myocardial and vascular side effects of Immune Checkpoint Inhibitors: a prospective multimodal cardiovascular assessment (AMICI study)

Abstract Background Immune checkpoint inhibitors (ICIs) are transformative treatments in oncology, yet they are also associated with a range of cardiovascular (CV) events. Purpose To identify the incidence of CV events (including subclinical) in patients receiving ICIs for solid cancer, either alone or in association with other cancer therapies (e.g., chemotherapies, target therapies). Objectives and methods The Adverse Myocardial and vascular side effects of Immune Checkpoint Inhibitors(AMICI) study prospectively assessed the incidence of CV changes by means of a thorough multimodal assessment. This included repeated CV imaging (transthoracic echocardiograms (TTE), cardiac magnetic resonance imaging (CMR)), serum biomarkers (troponin, brain natriuretic peptides in a single laboratory), and ambulatory ECG monitoring, before and during (at 6 weeks and at 6 months) ICI therapy (Figure). Cardiovascular events included myocarditis, pericarditis, acute coronary syndrome, heart failure (HF), high degree conduction abnormalities (defined as new grade 2 or 3 atrioventricular block) or sustained ventricular arrhythmias (defined as 3 or more ventricular beats at a rate ≥ 120/min), CV death as a composite endpoint, validated by an independent expert panel Results Out of 130 solid cancer patients considered for ICI therapy, 49 patients (38 (77.6%) male; mean age 64.3 (­SD 11.0) years old) were included (June 2020 -December 2021). 22 (55.1%) suffered from kidney or bladder cancer; 7 (14.3%) had CV disease prior to cancer diagnosis; 4 (8.2%) received PD1 and CTLA4 inhibitors. Early CV events were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P=0.035) predicted early CV events at 6 weeks (Table). At 6 months follow-up, 18 CV events were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias or conduction disorders and 4 (8.2%) AF. There was a significant decline in LVEF (P<0.001) in patients even in the absence of CV event (P=0.003) or HF (P=0.003). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P=0.006) predicted HF. Conclusions Cardiovascular complications arising during cancer treatment with ICIs are primarily due to the exacerbation of pre-existing HF or the onset of non-inflammatory heart rhythm disorders. The majority of these CV changes manifest shortly after starting ICIs and do not need hospital admission. Our results suggest that more close follow-up may be needed in patients with underlying CV conditions when starting ICI therapy, by means of CMR and ambulatory ECG holter monitoring.

Cardiovascular outcomes in acute coronary syndrome patients with cancer: a statewide population-linkage study

Abstract Background Advances in oncology treatment have led to an increase in the number of cancer survivors. As a result, the number of acute coronary syndrome (ACS) patients with cancer is increasing and the outcomes of these patients are not well described. Purpose This study aimed to examine revascularisation strategies and all cause and cardiovascular death in ACS patients with and without cancer. Methods Hospitalised patients in New South Wales, Australia, from July 2006 to December 2020 with a primary diagnosis of ACS were identified from the statewide Admitted Patient Data Collection database. Patients were stratified into those with or without a history of cancer (non-melanoma skin cancers excluded). Propensity scoring matching (PSM) for the variables of age, gender and cardiovascular risk factors was performed with each cancer patient matched to two non-cancer patients. Cox proportional hazards regression model was used to evaluate the hazard ratios of all-cause mortality between individuals with a history of cancer in the 5 years preceding their hospital admission, and those without. Additionally, Fine-Gray competing risk analysis was performed for cardiovascular death with non-cardiovascular mortality as the competing event. Results During the study period, 193,848 patients were admitted with ACS. 12,543 patients had a history of cancer and were PSM to 25,085 patients without cancer. The median age was 75 (Q1-Q3 67-82) years with 69% male and hypertension the most prevalent risk factor (55%) (Table 1). ACS patients with cancer had clinically comparable, rates of percutaneous revascularisation (36 vs 37%, p=0.07) and coronary artery bypass grafting (11 vs 13%, p<0.001) with ACS patients without cancer. During a median follow up of 8.6 (95% CI 8.4-8.8) years, ACS patients with a history of cancer had a significant higher risk of all cause death (HR 1.42 95% CI [1.38-1.46]) and cardiovascular death (SHR 1.14 [1.11-1.18]). The cumulative incidence function demonstrated cardiovascular death in those with a cancer history occurred in 20% by approximately 1.4 years follow up compared to 2.5 years in those without cancer (Figure 1). Conclusion ACS patients with cancer have a higher risk of all cause death and cardiovascular death compared to those without a history of cancer with clinically comparably revascularisation rates. Further studies to determine the cause of increased cardiovascular death in ACS patients with cancer are required.Figure 1

Spontaneous recovery of postsurgical progressive cervical spine kyphosis following intramedullary spinal cord tumor resection in a 4-year-old boy: illustrative case.

Postsurgical kyphosis is relatively common in children who have undergone resection of intramedullary spinal cord tumors. Progressive kyphosis almost always requires instrumentation and fusion surgery, which can delay or interfere with adjuvant oncological treatments and can deleteriously impact the long-term performance status of the patient. Here, the authors report a case of near-complete spontaneous recovery (i.e., without spinal fusion surgery) of postsurgical progressive cervical spine kyphosis following intramedullary spinal cord tumor resection and discuss the potential factors that may have contributed to this positive outcome. This case serves as a reminder that spontaneous recovery from postsurgical progressive cervical spine kyphosis can occur and that some patients (i.e., those without neurological deficits) can be monitored closely, with a watch-and-wait approach, before subjecting them to additional surgical risks, delays in other treatments, and potential morbidity. https://thejns.org/doi/10.3171/CASE24187.

Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment

Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al 's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis , enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.

Oncogenic Alterations, Race, and Survival in US Veterans with Metastatic Prostate Cancer Undergoing Somatic Tumor Next Generation Sequencing.

National guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans. This retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival. 5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations in SPOP (OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]). Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes including TP53 were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]). In the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.

A Multiple Targeting Genome Editing System for Remodulation of Circulating Malignant Cells to Eliminate Cancer Immunosuppression and Restore Immune Responses.

Cancer immunotherapy, which aims to eliminate cancer immunosuppression and reactivate anticancer immunity, holds great promise in oncology treatments. However, it is challenging to accurately study the efficacy of immunotherapy based on human-derived cells through animal experiments due to xenogeneic immune rejection. Herein, a personalized and precise strategy to evaluate the effectiveness of immunotherapy using the blood samples of cancer patients is presented. Through the utilization of multiple cancer-targeting delivery system decorated with the epidermal growth factor receptor (EGFR)-specific aptamer CL4 and the AXL-specific aptamer GL21.T to achieve superior efficiency in delivering the genome editing plasmid for MUC1 knockout, effective modulation on the behavior of circulating malignant cells (CMCs) is realized. After genome editing, both mucin 1 (MUC1) and programmed death-ligand 1 (PD-L1) are significantly downregulated in CMCs. The elimination of immunosuppression results in markedly enhanced secretion of pro-inflammatory anticancer cytokines encompassing interleukins 2, 12, and 15 and interferon-γ by immune cells. The study not only provides a strategy to overcome immunosuppression but also yields critical insights for personalized immunotherapy approaches.

A causal network model to estimate the cardiotoxic effect of oncological treatments in young breast cancer survivors

A causal network model to estimate the cardiotoxic effect of oncological treatments in young breast cancer survivors

Towards verifiable cancer digital twins: tissue level modeling protocol for precision medicine.

Cancer exhibits substantial heterogeneity, manifesting as distinct morphological and molecular variations across tumors, which frequently undermines the efficacy of conventional oncological treatments. Developments in multiomics and sequencing technologies have paved the way for unraveling this heterogeneity. Nevertheless, the complexity of the data gathered from these methods cannot be fully interpreted through multimodal data analysis alone. Mathematical modeling plays a crucial role in delineating the underlying mechanisms to explain sources of heterogeneity using patient-specific data. Intra-tumoral diversity necessitates the development of precision oncology therapies utilizing multiphysics, multiscale mathematical models for cancer. This review discusses recent advancements in computational methodologies for precision oncology, highlighting the potential of cancer digital twins to enhance patient-specific decision-making in clinical settings. We review computational efforts in building patient-informed cellular and tissue-level models for cancer and propose a computational framework that utilizes agent-based modeling as an effective conduit to integrate cancer systems models that encode signaling at the cellular scale with digital twin models that predict tissue-level response in a tumor microenvironment customized to patient information. Furthermore, we discuss machine learning approaches to building surrogates for these complex mathematical models. These surrogates can potentially be used to conduct sensitivity analysis, verification, validation, and uncertainty quantification, which is especially important for tumor studies due to their dynamic nature.

Cancer Therapy-Induced Encephalitis

Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients’ quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy—particularly immune checkpoint inhibitors—has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies. The widespread adoption of immunotherapy has led to improved survival rates and long-term remissions, even in patients with advanced metastatic disease. However, as immune modulators, these therapies can trigger a range of immune-related adverse events, including a variety of novel neurological toxicities. Among these, encephalitis is of particular concern due to its potential severity, which can compromise treatment outcomes. This review aims to provide a comprehensive overview of the literature on this condition, highlighting optimal diagnostic strategies and management approaches to mitigate the risk of significant morbidity, while also comparing encephalitis induced by immunotherapy with that caused by traditional chemotherapies and targeted oncologic treatments.

Treatment sequencing in gastroenteropancreatic neuroendocrine tumors

SummaryThe oncological treatment of neuroendocrine tumors (NET) has improved significantly in the last few years. Several informative clinical studies on NET have been conducted recently and updated NET guidelines have been published by the European Neuroendocrine Tumor Society (ENETS) in 2023 and 2024. With the growing number of positive phase III trials in NET, the main difficulty today is selecting the most appropriate treatment for a patient at the right time. The purpose of this short review is to delineate the main concepts and important changes in the therapy sequences for gastroenteropancreatic NET (gepNET) outlined in current European guidelines. In clinical practice, more individualized treatment decisions are often required that go beyond these general recommendations.

A month of diagnostic imaging studies in an acute supportive/palliative care unit.

The aim was to assess the characteristics of patients who required imaging studies during admission to an acute supportive palliative care unit (ASPCU). A consecutive number of patients who performed imaging studies during ASPCU admission in a month period were assessed. Epidemiological data, ongoing anticancer treatment, cancer diagnosis, reasons for admission, referral, and type of imaging study were recorded. Indications, findings, consequent actions for treatment, prognosis, and discharge were also collected. Twenty-one of 56 patients admitted to ASPCU in the period taken into consideration were assessed. Pain and deterioration of the general condition were the most frequent indications for admission. Computed tomography (CT) was the most frequent imaging study performed. Indications for performing imaging studies depended on individual clinical needs. Findings suggested different clinical decisions, after a comprehensive oncological and palliative care assessment and family conference, the most frequent of which was to withdraw oncological treatments. The majority of patients underwent transition to palliative care and were discharged home or to hospice. Imaging studies were of paramount importance for clinical treatment and decision-making process in an intensive ASPCU. There is the need to explore the need and the possible outcomes of imaging studies, as well cost-effectiveness in any ASPCU.

Differences Between Intravenous and Subcutaneous Modes of Administration in Oncology from the Patient, Healthcare Provider, and Healthcare System Perspectives: A Systematic Review.

While patients with cancer have traditionally received oncology treatments through intravenous (IV) administration, some therapies are becoming available via alternative modes of administration, such as subcutaneous (SC). This study aimed to evaluate IV versus SC therapy administration from the perspectives of the patient, healthcare provider (HCP), and healthcare system. A systematic review was conducted, searching MEDLINE and Embase databases from 2000 to 2022. This was supplemented with grey literature searches of additional sources such as conference proceedings. Observational studies and clinical trials were included if they assessed adult patients with any cancer type who were treated with pharmacologic therapies administered via IV or SC and included patient- or HCP-reported outcomes or healthcare system perspectives on the mode of administration. Records identified by the literature search were screened by two independent reviewers. Included studies were data extracted by a single reviewer and validated by a second reviewer and synthesized using a narrative approach. After screening, 33 unique studies were included in the systematic review. Patients and HCPs reported substantially more favorable preference rates for SC over IV treatment. Additionally, from the patient perspective there were reductions in treatment time and economic burden for SC compared with IV therapy. From the HCP's perspective, treatment time was consistently reduced by SC compared with IV treatment administration. Although information on the impact of SC and IV treatments for oncology on healthcare systems was limited, the use of SC formulations showed consistent cost savings (direct costs) and time savings from this perspective considering various uptake scenarios compared with IV administration. Compared with IV administration, SC oncology treatment is a preferred option by patients and HCPs, increasing optionality and reducing treatment time while simultaneously increasing capacity and reducing the financial burden on healthcare systems.

In vitro maturation of oocytes: what is already known?

Assisted reproductive technologies (ARTs) involve the laboratory manipulation of gametes and embryos to help couples with fertility problems become pregnant. One of these procedures controlled ovarian stimulation uses pharmacological agents to induce ovarian and follicular maturation in vivo. Despite the effectiveness in achieving pregnancy and live births, some patients may have complications due to over-response to gonadotropins and develop ovarian hyperstimulation syndrome (OHSS). In vitro maturation of oocytes (IVM) has emerged as a technique to reduce the risk of OHSS, particularly in women with polycystic ovary syndrome (PCOS), and for fertility preservation in women undergoing oncological treatment. Although there are some limitations, primarily due to oocyte quality, recent advances have improved pregnancy success rates and neonatal and infant outcomes. Different terms have been coined to describe variations of IVM, and the technique has evolved with the introduction of hormones to optimize results. This review we provide a comprehensive overview of IVM and its reproductive outcomes during ARTs.

Large Scale Comparative Analysis of Canine and Human Osteosarcomas Uncovers Conserved Clinically Relevant Tumor Microenvironment Subtypes.

Osteosarcoma is an aggressive bone cancer lacking robust biomarkers for personalized treatment. Despite its scarcity in humans, it is relatively common in adult pet dogs. This study aimed to analyze clinically annotated bulk tumor transcriptomic datasets of canine and human osteosarcoma patients to identify potentially conserved patterns of disease progression. Bulk transcriptomic data from 245 pet dogs with treatment-naïve appendicular osteosarcoma were analyzed using deconvolution to characterize the tumor microenvironment (TME). The TME of both primary and metastatic tumors derived from the same dog was compared, and its impact on canine survival was assessed. A machine learning model was developed to classify the TME based on its inferred composition using canine tumor data. This model was applied to 8 independent human osteosarcoma datasets to assess its generalizability and prognostic value. This study found three distinct TME subtypes of canine osteosarcoma based on cell type composition of bulk tumor samples: Immune Enriched (IE), Immune Enriched Dense Extra-Cellular Matrix-like (IE-ECM), and Immune Desert (ID). These three TME-based subtypes of canine osteosarcomas were conserved in humans and could predict progression-free survival outcomes of human patients, independent of conventional prognostic factors such as percent tumor necrosis post standard of care chemotherapy treatment and disease stage at diagnosis. These findings demonstrate the potential of leveraging data from naturally occurring cancers in canines to model the complexity of the human osteosarcoma TME, offering a promising avenue for the discovery of novel biomarkers and developing more effective precision oncology treatments.

MANAGEMENT OF THE OLDER PATIENT WITH GLIOBLASTOMA IN THE UK: AN INITIAL REPORT FROM THE HISTO-MOL GBM COLLABORATIVE

Abstract AIMS The management of older (>70 years old) patients with glioblastoma is challenging with significant variation in practice. Using the Histo-Mol GBM database we analysed the variation in practice across 11 UK centres. METHOD Biopsy confirmed glioblastoma patients diagnosed between 01/01-31/12/2021 were identified. Descriptive statistics were used to compare demographic, tumour and treatment characteristics, and the Kaplan-Meier method was used to analyse survival, assessed from surgery date. Differences in treatment between centres were assessed using one way ANOVA. RESULTS In 2021, 81/330 (24.5%) patients with glioblastoma were >70. Compared to younger patients, the older cohort had a greater proportion of males (79.0% vs 59.0%, p<0.001), a worse performance status (66.7% vs 79.5% ECOG PS 0-1, p<0.001), and more likely to have MGMT promoter methylation (30.9% vs 22.9%, p=0.027). Most patients received biopsy only (31/81, 38.3%), followed by subtotal resection (85-94% tumour resection) (26/81, 32.1%), whilst 8/81 (9.9%) underwent debulking, 8/81 near-total resection (95-99% tumour resection), and 8/81 gross total resection, with statistically significant variation in resection extent between centres (p=0.031). Adjuvant radiotherapy was used in 56/81 patients (69.1%) with no difference between centres (p=0.220). However, there was a statistically significant difference in radiotherapy regime between centres (p=0.041). 6/81 (7.4%) received conventional chemoradiotherapy, 28/81 (34.6%) hypofractionated chemoradiotherapy, 16/81 (19.8%) hypofractionated radiotherapy alone, 2/81 (2.5%) temozolomide alone both with MGMT promoter methylation, and 21/81 (25.9%) received no oncological treatment. Median progression free survival was 5.9 months and median overall survival (OS) was 7.1 months with no difference between centres (p=0.199 and p=0.083 respectively). Median OS was 8.4 months with conventional fractionation chemoradiotherapy, 11.2 months with hypofractionated chemoradiotherapy, 7.3 months with hypofractionated radiotherapy alone, 1.8 months with temozolomide alone, and 2.5 months with no oncological treatment. CONCLUSION We identify variations in the treatment of elderly glioblastoma patients across the UK, although these do not significantly impact survival.

GLIOBLASTOMA IN THE UK POST WHO CNS 5: INITIAL fiNDINGS FROM THE HISTO-MOL GBM COLLABORATIVE

Abstract AIMS The 2021 World Health Organisation Classification (WHO CNS5) incorporated molecular diagnostic features for glioblastoma for the first time. The Histo-Mol GBM collaborative is conducting a retrospective cohort study evaluating the outcomes of patients prospectively diagnosed with WHO CNS5 IDH wild type glioblastoma. METHOD Biopsy confirmed glioblastoma patients diagnosed between 01/01-31/12/2021 were identified. Demographic, tumour, treatment, and survival data were collected. Descriptive statistics and Kaplan-Meier method were used to describe the cohort and for survival analysis respectively, assessed from surgery date. RESULTS So far, 363 glioblastoma patients were included from 13 centres (range: 11-61 patients/centre). Median age was 63.0, 65.8% were male, 77.4% had an ECOG performance status of 0-1 at diagnosis, and 28/333 had a molecular glioblastoma (8.4%). Biopsy was performed in 106/363 patients (29.2%), and gross total resection in 50/363 (13.8%). Adjuvant radiotherapy was performed in 290/363 (79.9%), and 71/290 (24.5%) had an additional pre-radiotherapy MRI with rapid early progression identified in 30/71 patients (42.3%). 128/269 (47.6%) patients received 2nd line treatment; most commonly systemic therapy (91/128, 71.1%) followed by re-resection (27/128, 21.1%). Second line systemic therapy was primarily lomustine (48/81, 52.7%). Median progression free survival was 7.7 months and median overall survival (OS) was 11.6 months. Median OS was 16.9 months with conventional fractionation chemoradiotherapy (n=169/363, 46.6%), 10.4 months with hypofractionated chemoradiotherapy (n=64/363, 17.6%), and 2.3 months with no oncological treatment (n=57/363, 15.7%). On univariate analysis age, gender, performance status, multifocality, MGMT promoter methylation, surgery extent, radiotherapy type (none, palliative, hypofractionated, conventional fractionation), larger planning target volume (PTV), receiving concurrent temozolomide, and receiving adjuvant temozolomide were statistically significant. On multivariate analysis age, and receiving concurrent temozolomide remained significant. CONCLUSION We describe the initial findings from a large real-world cohort of glioblastoma patients prospectively diagnosed according to WHO CNS5. Survival compares favourably with the practice changing phase 3 clinical trial outcomes.