Aggressive Multimodality Therapy Research Articles

Abstract PO5-06-03: Impact of curative-intent treatment on survival for metastatic breast cancer limited to distant lymph nodes

Abstract BACKGROUND: Metastatic breast cancer limited to distant lymph nodes is classified as stage IV but potentially represents an anatomically distinct entity amenable to curative treatment. Its optimal management is unclear, with existing studies limited by small sample sizes and short follow-up durations. We sought to investigate the impact of curative-intent treatment on breast cancer-specific survival (BCSS) and overall survival (OS) for patients with this diagnosis. METHODS: Three cohorts of patients diagnosed with breast cancer from 2010 to 2019 were identified from the Surveillance, Epidemiology, and End Results 17 registries database. The curative cohort consisted of patients with metastatic breast cancer involving only distant lymph nodes who received a combination of chemotherapy, surgery to the primary site, and radiotherapy (curative-intent treatment). The palliative cohort included patients who underwent chemotherapy but not curative-intent treatment. The N3c cohort was comprised of patients with ipsilateral supraclavicular lymph node metastases but no distant metastases who received curative-intent treatment. Weighting based on covariate balancing propensity scores was performed to balance age, sex, race, median household income, year of diagnosis, T stage, histology, pathological grade, and ER/PR/HER2 status between the cohorts. Weight-adjusted multivariable Cox regression models with the same covariates were then used to compare the BCSS and OS of the three cohorts. RESULTS: A total of 2,089 patients with a median follow-up of 37 months were eligible for analysis, of whom 577 (27.6%) were in the curative cohort, 905 (43.3%) were in the palliative cohort, and 607 (29.1%) were in the N3c cohort. After propensity score weighting, the maximal standardized mean difference for all covariates was less than 0.1. Five-year BCSS for patients in the weight-adjusted curative, palliative, and N3c cohorts were 63.0% (95% CI 58.1-68.3), 46.7% (42.4-51.4), and 66.4% (61.4-71.8), respectively; and five-year OS were 57.9% (53.0-63.2), 41.2% (37.2-45.7), and 62.2% (57.3-67.6), respectively. Compared to the palliative cohort, the curative cohort exhibited better BCSS (HR 0.47, 95% CI 0.38-0.57; P< 0.001) and OS (HR 0.48, 95% CI 0.40-0.58; P< 0.001). In contrast, the N3c cohort had similar BCSS (HR 0.93, 95% CI 0.73-1.17; P=0.53) and OS (HR 0.96, 95% CI 0.77-1.19; P=0.68) to the curative cohort. CONCLUSIONS: Patients treated curatively for metastatic breast cancer limited to distant lymph nodes had higher BCSS and OS than those receiving palliative chemotherapy and similar BCSS and OS to patients receiving curative-intent treatment for ipsilateral supraclavicular lymph node metastases. These results support the use of aggressive multimodal therapy for select stage IV breast cancer patients with only distant nodal metastases and, if confirmed, suggest that a substantial portion of such patients may be undertreated. Citation Format: Yang Xu. Impact of curative-intent treatment on survival for metastatic breast cancer limited to distant lymph nodes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-03.

Abstract LB310: Single-cell transcriptomics and TCR clonality reveal a role for immunotherapy in pediatric brain tumors

Abstract Central nervous system tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Outcomes remain dismal for a significant proportion of patients despite aggressive multimodal therapy and survivors suffer from treatment-related morbidity and neurological deficits. Despite their remarkable success in adult cancers, immunotherapies are not approved for pediatric brain tumors. Several factors like the relatively smaller patient population, a tumor location that makes them difficult to access through biopsies and poorly-studied tumor immune microenvironment (TME) have posed challenges in advancing immunotherapeutic options for these patients. Immune checkpoint blockers (ICB) tested in unstratified cohorts of children with brain tumors have not shown promising results; therefore, the role of immunotherapy remains unclear. Because the magnitude and nature of pre-existing T cell responses in the tumor has been shown to correlate with response to ICB, we asked if pediatric brain tumors show evidence of such favorable T cell responses. In the current study, we address this question using an unbiased approach to analyze the clonal relationship and transcriptional status of T cells present in tumor tissue of children with brain tumors using paired single-cell RNA-sequencing and TCR-sequencing. Our results demonstrate that a large fraction of T cells in the tumor tissue are clonally expanded with potential to recognize tumor antigens. Such clonally-expanded T cells display states linked to anti-tumor immunity, express higher levels of transcripts encoding for molecules linked to T cell activation, effector functions, immune cell recruitment, tissue-residency, immune checkpoints, and importantly, show significant enrichment of signatures linked to neoantigen-specific T cells and immunotherapy response. Notably, we identify several neoantigens in pediatric brain tumors, and show that neoantigen-specific T cell gene signatures are linked to better survival outcomes in high-grade glioma. We further show that PD1-expressing CD8+ T cells in pediatric brain tumors are indeed functional as evidenced by their capacity for cytotoxicity, cytokine production and proliferation. Among the patients in our cohort, we observe substantial heterogeneity in the degree of clonal expansion and expression of transcripts encoding immune checkpoints in tumor-infiltrating T cells. Overall, our findings suggest that accurate characterization of intra-tumoral T cell responses for features linked to immune check point therapy (ICB) response may enable selection of patients where immunotherapy is likely to be beneficial, an approach that requires prospective validation in future clinical trials. Citation Format: Anusha Preethi Ganesan, Aditi Upadhye, Kevin Meza Landeros, Ciro Ramírez-Suástegui1, Benjamin Schmiedel, Edwin Woo, Serena J. Chee, Denise Malicki, Nicole Coufal, David Gonda, Michael Levy, Jason Greenbaum, Gregory Seumois, John Crawford, William Roberts, Stephen Schoenberger, Hilde Cheroutre, Christian Ottensmeier, Pandurangan Vijayanand. Single-cell transcriptomics and TCR clonality reveal a role for immunotherapy in pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB310.

Clostridium perfringens-induced massive hemolysis treatment with blood purification to target toxins: a case report.

Clostridium perfringens can rarely cause severe systemic infections, usually from an abdominal source, associated with massive hemolysis, which is usually fatal. Hemolytic anemia and acute renal injury resulting from toxin action are critical for the development of multiple organ dysfunction syndrome (MODs), making this condition a real emergency, requiring multispecialty skills and aggressive multimodal therapies. We herein describe a case of septic shock from acute cholecystitis with massive hemolysis caused by C. perfringens in a 55year-old man that was successfully treated with early blood purification and continuous renal replacement therapy (CRRT) along with antibiotic therapy and surgery. The effect of the enormous amount of toxins produced by Clostridium which elicit a strong cytokine response and the damage caused by the hemolysis products are the main pathogenetic mechanisms of this rare but lethal clinical entity. The main goal of treatment is to remove toxins from plasma, block toxin action, and further production by achieving bacterial killing with antimicrobial agents and controlling the infectious focus, remove waste products and prevent or limit multiorgan damage. Blood purification techniques play an important role due to a strong pathophysiological rationale, as they can remove toxins and cytokines as well as cell-free products from plasma and also replace renal function. Although this condition is rare and robust data are lacking, blood purification techniques for C. perfringens-induced massive hemolysis are promising and should be further explored.

Abstract IA004: Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies

Abstract Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for the treatment of GBM. In this talk, we summarize recent clinical and pre-clinical efforts to develop immunotherapeutic and chimeric antigen receptor (CAR) T cell treatment strategies for GBM recurrence, including challenges in the form of fundamental mechanisms of therapy evasion by tumor cells, such as immense intratumoral heterogeneity, suppression of the tumor immune microenvironment, and low mutational burden. Insights from these advances and challenges have shaped our development of a translational research pipeline from initial target discovery, through target validation and exploration of mechanism, to building new biotherapeutics against novel cancer targets, and preclinical testing in our patient-derived animal models of treatment-resistant GBM. We have tracked GBM cell populations that undergo clonal evolution as a result of selective pressures exerted by standard treatments to identify the cellular composition of the recurrence, to allow us to determine the intracellular signaling pathways that drive GBM relapse. Ultimately, we will design rational combinations of therapeutics that can reignite the anti-tumor immune response, effectively and specifically target tumor cells, and reliably decrease tumor burden for GBM patients. Citation Format: Sheila K Singh. Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA004.

Nutritional status, body composition and diet quality in children with cancer.

During cancer treatment, nutritional status disorders such as malnutrition or obesity affect the tolerance of cancer treatment, quality of life, but also the pharmacokinetics of drugs. It is hypothesized that changes in fat and lean body mass can modify chemotherapy volume distribution, metabolism and clearance. In children with cancer, lean body mass decreases or remains low during treatment and fat mass increases. Body composition is influenced by the cancer itself, aggressive multimodal-therapies, changes in metabolism, unbalanced diet and reduced physical activity. Due to the side effects of treatment, including changes in the sense of taste and smell, nausea, vomiting, diarrhea, and stress, eating according to recommendation for macronutrients and micronutrients is difficult. Research indicates that throughout cancer treatment, the consumption of fruits, vegetables, and dairy products tends to be insufficient, whereas there is an elevated intake of sugar and unhealthy snacks. Children exhibit a preference for high-carbohydrate, salty, and strongly flavored products. This review revealed the importance of body composition and its changes during cancer treatment in children, as well as eating habits and diet quality.

EXTH-25. IN VIVO TWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL

Abstract BACKGROUND Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed. METHODS We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing B7-H3 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. B7-H3-directed CAR T-cells were injected into the adjacent brain parenchyma. RESULTS Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against B7-H3 are currently ongoing. CONCLUSIONS We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.

GLIOMA-12 GLIOSARCOMA: A SERIES OF FOUR CASES TREATED

Abstract INTRODUCTION Gliosarcoma is a rare central nervous system malignancy, characterized by classical biphasic histological pattern with both glial and sarcomatous component. It usually affects fifth and sixth decade of life with slight male preponderance. In this report, we reviewed the clinical and radiological presentation, pathologic diagnosis, and treatment outcomes for a series of 4 patients diagnosed with gliosarcoma. MATERIAL AND METHODS We carried out a retrospective analysis of four patients with gliosarcoma diagnosed between March 2019 and March 2023. Demographic data, clinicopathological data, treatment strategies employed, details of recurrence, and survival patterns are reviewed. RESULTS Four patients, males, respectively aged of 56, 39, 54 and 57 years, presented with signs and symptoms consistent with an expanding intracranial mass,including headache, seizure, hemiparesis. Median duration of presenting symptoms was 3.5 months. The tumor was located in temporo-parieto-occipital region, fronto-parietal region, fronto-temporal region, and temporal region. All patients underwent craniotomy with attempt to achieve gross total surgical resection. Unfortunately, total resection could be achieved in only two patients; remaining two patients underwent subtotal resection. Surgery was followed by adjuvant radiotherapy and temozolomide-based chemotherapy for three patients. All patients died at 1 week, 6 months, 7 months and 10 months. CONCLUSION As gliosarcoma is considered as a variant of glioblastoma, it is treated similarly to glioblastoma but optimum treatment recommendations are yet to be defined. In this series, we have reported four cases of gliosarcoma who have been treated on the lines of glioblastoma. The prognosis is still poor despite aggressive surgical resection and adjuvant multi-modality therapy is given.

Clinical characteristics and therapeutic outcomes of acromegalic patients with giant growth hormone-secreting pituitary adenomas: a single-center study of 67 cases.

Acromegalic patients with giant growth hormone-secreting pituitary adenomas (GHPAs) (≥ 40mm) are relatively rare, and their clinical characteristics and treatment outcome data are limited. This study aims to analyze the clinical practice experience of giant GHPAs. Sixty-seven acromegalic patients with giant GHPAs and 67 patients with macro GHPAs (10-39mm), matched for age and gender from the same hospital during the same period, were retrospectively recruited. The clinical characteristics, treatment, and outcomes were analyzed. Enlargement of the extremities and facial features were the most common symptoms in most patients (92.5%). Compared with the macroadenoma group, more frequent visual impairment (86.6% vs. 25.4%, P < 0.001) and gonadal axis dysfunction (49.3% vs. 34.3%, P = 0.008), higher preoperative fasting GH, nadir GH after OGTT and IGF-1 levels, and a higher proportion of extrasellar tumor invasion were seen in the giant adenoma group. As the adenoma size increases, the total resection rate decreases, and postoperative complications and multimodal treatment strategies increase significantly. Fasting and nadir GH levels remained higher at 1week postoperatively, and there were more surgical complications and cases of anterior hypopituitarism in the giant group. After a median follow-up of 36months, 12 patients (36.4%) in the giant GHPA group and 17 (36.2%) in the macro GHPA group achieved biochemical remission. Other factors such as age of onset, age of diagnosis, delayed diagnosis time, metabolic complications, p53 positive rate, and Ki-67 index showed no significant difference between the two groups. With aggressive multimodal therapy, the biochemical remission rate of acromegalic patients with giant GHPAs is comparable to that of patients with macro adenoma. However, postoperative complications and hypopituitarism need to be closely monitored.

Pain in Ewing Sarcoma: A Complex Case Report

Ewing sarcoma is a rare bone and tissue cancer which most commonly occurs in young adults and children. Survival rates are variable, recurrences common, and premature mortality a considerable burden despite aggressive multimodal cancer therapy. Pain is frequently experienced from the time of Ewing sarcoma diagnosis and even in favourable outcomes, chronic pain syndromes are not uncommon developments. However, the literature around the pain experience and pain-related distress, along with potential management strategies, is lacking. In this case report, we describe a patient with Ewing sarcoma of the right pelvis which was later complicated by developing secondary chondrosarcoma. This report will highlight the pain characteristics, syndromes, and challenges of pain management of a patient with Ewing sarcoma spanning multiple specialties and exploring key evolving concepts in cancer pain management.

OS09.1.AIN VIVOTWO-PHOTON TUMOR IMAGING IN AN ORTHOTOPIC MEDULLOBLASTOMA MOUSE MODEL

Abstract BACKGROUND Medulloblastoma represents the most common primary brain malignancy in pediatric patients and is associated with neuro-cognitive impairment and frequent relapses after aggressive multimodal therapy. Adoptive immunotherapies such as CAR T-cell therapy are currently being investigated, showing promising results in preclinical models but lacking efficacy in first-in-human trials. Refined in vivo models to investigate reasons for treatment failures are therefore urgently needed. METHODS We developed a xenogeneic orthotopic medulloblastoma (MB) model in mice by combining a chronic cerebellar window with repetitive intravital two-photon laser scanning microscopy. Red tdTomato-fluorescent DAOY (SHH MB) tumor cells expressing EphA2 were implanted intracranially into the cerebellum of immunodeficient mice (n = 7), and tumor cell formation was followed by in vivo-microscopy. Intravenous fluorescein isothiocyanate (FITC)-dextran was used for intravascular plasma staining. EphA-directed CAR T-cells were injected into the adjacent brain parenchyma. RESULTS Chronic cranial window implantation was well tolerated and allowed repetitive visualization of the mouse cerebellum. After intracranial tumor cell implantation, continuous tumor growth could be evaluated with epifluorescence as well as 2-photon laser scanning microscopy. Tumor formation was identified as early as day 5 in every mouse and could continuously be followed up to 35 days until mice succumbed due to tumor burden. Window quality and fluorescence intensity remained high until the end of the experiments. Studies on GFP-expressing CAR T-cell injection directed against EphA2 are currently ongoing. CONCLUSIONS We herein establish a robust orthotopic medulloblastoma mouse model that allows repetitive in vivo tracking of fluorescence-expressing tumor cells, CAR T-cells and blood vessels over weeks. Such models may be used to study medulloblastoma tumor growth under the influence of different immunotherapies and reveal interactions between tumor cells and CAR T-cell therapies on a single-cell level.

A multicenter, phase II trial of maintenance sirolimus in combination with metronomic chemotherapy in children and adolescents with high-risk solid tumors.

TPS10072 Background: Risk of relapse for children with high-risk solid tumors (ST) remains unacceptably high despite aggressive multimodal therapy. Maintenance therapy is an emerging option to improve outcomes. Sirolimus, an inhibitor of mammalian target of rapamycin, is a potent immunosuppressant with antiproliferative and antiangiogenic effects. Low-dose metronomic chemotherapy along with the cyclooxygenase-2 inhibitor celecoxib also decreases neovascularization in in vitro and in vivo systems. The maximum tolerated dose (MTD) of sirolimus in combination with celecoxib and etoposide alternating with cyclophosphamide was determined in a phase I study in pediatric patients with relapsed/refractory ST. The regimen was well-tolerated and showed best response of stable disease in 8/18 subjects and partial response in 1/18. The efficacy of this regimen in relapsed/refractory ST is being tested in a Phase II study (NCT02574728). We hypothesize that patients with high-risk ST administered a 12-month course of this maintenance regimen will have improved 2-year progression-free survival (PFS) when compared to matched historical patients who were observed following completion of upfront therapy. Methods: This is a phase II study of sirolimus in combination with celecoxib and alternating low-dose etoposide and cyclophosphamide delivered as maintenance therapy. Sirolimus will be given at the MTD of 2mg/m2/day with celecoxib 100mg twice daily and oral etoposide 50mg/m2/day (max 100mg) alternating every 21 days with oral cyclophosphamide 2.5mg/kg/day (max 100mg). This study includes: 1) a prospective cohort of patients with high-risk ST in first complete remission (CR), 2) a prospective cohort of patients with recurrent ST in second CR, and 3) a historical cohort matched 2:1 with cohort 1 on diagnosis, age, metastatic sites, and date of diagnosis treated with observation following upfront therapy. The study will enroll up to 38 patients in cohort 1. Eligible subjects are children (1-30 years) with a diagnosis of high-risk extracranial ST (metastatic sarcoma, desmoplastic small round cell tumor, malignant rhabdoid tumor) in first CR or any ST in second CR. Patients enrolled in upfront clinical trials are excluded. Primary endpoint is 2-year PFS of cohort 1 compared to the historical cohort. Secondary endpoints are median PFS of cohort 1, 2-year PFS and overall survival of cohorts 1 and 2, incidence of severe toxicities, and feasibility of completing the 12-month course following standard upfront therapy. Exploratory objectives include evaluation of circulating tumor DNA (ctDNA) in this population of patients in CR or with minimal disease burden and correlation of clinically obtained tumor molecular profiling with outcomes. As of January 2023, 12 subjects are enrolled, 9 in cohort 1 and 3 in cohort 2. Clinical trial information: NCT04469530 .

A phase 1 dose escalation trial of ex-vivo expanded allogeneic cord blood–derived natural killer cell immunotherapy for pediatric solid tumor malignancies.

2546 Background: Despite aggressive multimodality therapy, survival outcomes of most patients with recurrent/refractory solid tumors remain dismal. Preclinical data have shown that natural killer (NK) cells play a significant role in controlling cancer progression, metastasis, and survival. In this phase I dose escalation trial, we evaluated the safety and phase 2 recommended dose of cord blood derived NK cells in children and young adults with recurrent/refractory pediatric solid tumors. Methods: Eligible patients were 1-40 years old. Cord blood donors were 4, 5, or 6/6 HLA matched. Ex-vivo, antigen presenting cell-mediated expansion of human cord blood derived NK cells was performed over 14 days. All patients received lymphodepleting regimen with cyclophosphamide (500 mg/m2/day) and etoposide (100 mg/m2/day) for 5 days (days -7 to -3) followed by 2 days rest and a single infusion of NK cells on Day 0. The study evaluated two dose levels using a standard 3+3 phase I trial design with an expansion cohort at the maximum tolerated dose. Results: Twelve patients (median age 16 years) received NK cells infusions. Tumor types included osteosarcoma (n = 7), Ewing sarcoma (n = 4), and synovial sarcoma (n = 1). Three patients received NK cells at dose level 1 (5 X 107/Kg), and nine patients at dose level 2 (1 X108/Kg), which was determined to be the recommended Phase 2 dose. No dose-limiting toxicities were observed. Most adverse events were grade 1 and 2 (fatigue, dizziness, nausea and vomiting). Most frequently observed grade 3 and 4 adverse events were leukopenia, neutropenia, lymphopenia, and thrombocytopenia. No cytokine release syndrome or neurotoxicity was observed. Allogeneic NK cells were detected in recipients’ peripheral blood as high as 100% of all NK cell populations and as late as 9 days post infusion. Of the 9 patients evaluable for tumor response, 3 patients (with osteosarcoma) had stable disease and 6 had progressive disease. Conclusions: Allogeneic ex-vivo expanded NK cells immunotherapy demonstrated favorable safety profile in patients with advanced pediatric solid tumors. Strategies to improve efficacy are warranted including using adjuvant therapy to increase persistence, more stringent selection strategies and gene editing approaches to increase alloreactivity against recipient tumor cells. Clinical trial information: NCT03420963 .

Taming Glioblastoma in "Real Time": Integrating Multimodal Advanced Neuroimaging/AI Tools Towards Creating a Robust and Therapy Agnostic Model for Response Assessment in Neuro-Oncology.

The highly aggressive nature of glioblastoma carries a dismal prognosis despite aggressive multimodal therapy. Alternative treatment regimens, such as immunotherapies, are known to intensify the inflammatory response in the treatment field. Follow-up imaging in these scenarios often mimics disease progression on conventional MRI, making accurate evaluation extremely challenging. To this end, revised criteria for assessment of treatment response in high-grade gliomas were successfully proposed by the RANO Working Group to distinguish pseudoprogression from true progression, with intrinsic constraints related to the postcontrast T1-weighted MRI sequence. To address these existing limitations, our group proposes a more objective and quantifiable "treatment agnostic" model, integrating into the RANO criteria advanced multimodal neuroimaging techniques, such as diffusion tensor imaging (DTI), dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI), dynamic contrast enhanced (DCE)-MRI, MR spectroscopy, and amino acid-based positron emission tomography (PET) imaging tracers, along with artificial intelligence (AI) tools (radiomics, radiogenomics, and radiopathomics) and molecular information to address this complex issue of treatment-related changes versus tumor progression in "real-time", particularly in the early posttreatment window. Our perspective delineates the potential of incorporating multimodal neuroimaging techniques to improve consistency and automation for the assessment of early treatment response in neuro-oncology.

Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial)

BackgroundProstate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29–47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.MethodsThe PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617.DiscussionThis is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments.Trial registrationClinicalTrials, NCT05162573. Registered 7 October 2021.

Under recognition and treatment of lymphedema in head and neck cancer survivors – a database study

PurposeHead and neck cancer (HNC) will be diagnosed in approximately 54,000 Americans in 2022 with more than 11,000 dying as a result. The treatment of HNC often involves aggressive multimodal therapy including surgery, radiotherapy, and systemic therapy. HNC and its treatments are associated with multiple painful and function-limiting neuromusculoskeletal and visceral long-term and late effects. Among these is head and neck lymphedema (HNL), the abnormal accumulation of protein rich fluid, in as many as 90% of survivors. Though HNL is common and potentially contributory to other function-limiting issues in this population, it is notoriously understudied, underrecognized, underdiagnosed, and undertreated. This study seeks to determine the incidence of HNC-related lymphedema diagnosis and treatment in a large US healthcare claims repository database.MethodsA retrospective observational cohort design and data from an integrated US healthcare claims repository—the IBM MarketScan Commercial Claims and Encounters (CCAE) and Medicare Supplemental and Coordination of Benefits (MDCR) Databases spanning the period April 1, 2012 through March 31, 2020.ResultsOf the 16,654 HNC patients eligible for evaluation, 1,082 (6.5%) with a diagnosis of lymphedema were identified based on eligibility criteria. Of the 521 HNC patients evaluated for lymphedema treatment, 417 (80.0%) patients received 1.5 courses of MLD, 71 (13.6%) patients were prescribed compression garments, and 45 (8.6%) patients received an advanced pneumatic compression device.ConclusionHNL in this population of HNC survivors was underdiagnosed and treated compared with contemporary assessments HNL incidence.

Clinicopathologic features, treatment, and prognosis of pregnancy-associated breast cancer.

To identify the clinicopathological features, treatment, and prognosis of patients with breast cancer, who were diagnosed during and after pregnancy. We searched for patients with pregnancy-associated breast cancer (PABC) using the big data query and analysis system of Peking Union Medical College Hospital from between January 1, 2013, and December 31, 2021, and matched each patient with two non-PABC patients by age at diagnosis, year at diagnosis, and tumor stage. The clinicopathologic features, treatment, and outcomes of breast cancer during pregnancy (BC-P) and breast cancer during the first-year post-partum (BC-PP) were examined retrospectively in two case-control studies. Eighteen BC-P cases, 36 controls for BC-P cases, 62 BC-PP cases, and 124 controls for BC-PP cases were enrolled in our study. The expression of HER-2 and Ki-67 was higher in BC-PP cases than in its controls (P=0.01, 0.018, respectively). Patients with BC-PP were more likely to choose mastectomy than breast-conserving surgery (P=0.001). There were no significant differences in event-free survival (EFS) between patients with BC-P and BC-PP and their controls. BC-P and BC-PP patients displayed adverse clinicopathological features in our population. However, when matched by age at diagnosis, year of diagnosis, and tumor stage, BC-P and BC-PP patients did not show inferior outcomes to controls, probably due to aggressive multimodality therapy.

Impact of CD4 T cells on intratumoral CD8 T-cell exhaustion and responsiveness to PD-1 blockade therapy in mouse brain tumors

BackgroundGlioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (Tex) in many malignancies, has not shown efficacy in glioblastoma....

NIMG-67. MULTI-PARAMETRIC MRI-BASED MACHINE LEARNING ANALYSIS FOR PREDICTION OF NEOPLASTIC INFILTRATION AND RECURRENCE IN PATIENTS WITH GLIOBLASTOMA: UPDATES FROM THE MULTI-INSTITUTIONAL RESPOND CONSORTIUM

Abstract PURPOSE Glioblastoma is extremely infiltrative with malignant cells extending beyond the enhancing rim where recurrence inevitably occurs, despite aggressive multimodal therapy. We hypothesize that important characteristics of peritumoral tissue heterogeneity captured and analyzed by multi-parametric MRI and artificial intelligence (AI) methods are generalizable in the updated multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium and predictive of neoplastic infiltration and future recurrence. METHODS We used the most recent update of the ReSPOND consortium to evaluate and further refine generalizability of our methods with different scanners and acquisition settings. 179 de novo glioblastoma patients with available T1, T1Gd, T2, T2-FLAIR, and ADC sequences at pre-resection baseline and after complete resection with subsequent pathology-confirmed recurrence were included. To establish generalizability of the predictive models, training and testing of the refined AI model was performed through Leave-One-Institution-Out-Cross-Validation schema. The multi-institutional cohort consisted of the Hospital of the University of Pennsylvania (UPenn, 124), Case Western Reserve University/University Hospitals (CWRU/UH, 27), New York University (NYU, 13), Ohio State University (OSU, 13), and University Hospital Río Hortega (RH, 2). Features extracted from pre-resection MRI were used to build the model predicting the spatial pattern of subsequent tumor recurrence. These predictions were evaluated against regions of pathology-confirmed post-resection recurrence. RESULTS Our model predicted the locations that later harbored tumor recurrence with overall odds ratio (99% CI)/AUC (99% CI), 12.0(11.8-12.2)/0.80(0.76-0.85), and per institute, CWRU/UH, 11.0(10.7-11.3)/0.80 (0.64-0.97); NYU, 7.0(6.7-7.3)/0.78(0.56-1.00); OSU, 18.3(17.5-19.1)/0.83(0.54-1.00); RH, 40.0(35.3-45.5)/0.93(0.00-1.00); UPenn, 8.00(7.7-8.3)/0.80(0.75-0.84). CONCLUSION This study provides extensive multi-institutional validated evidence that machine learning tools can identify peritumoral neoplastic infiltration and predict location of future recurrence, by decrypting the MRI signal heterogeneity in peritumoral tissue. Our analyses leveraged the unique dataset of the ReSPOND consortium, which aims to develop and validate AI-based biomarkers for individualized prediction and prognostication and establish generalizability in a multi-institutional setting.

Outcome of Patients with Central Nervous System Multiple Myeloma (CNS-MM) Treated with CNS-Directed Radiation Therapy

<h3>Purpose/Objective(s)</h3> Extramedullary spread of multiple myeloma into the central nervous system (CNS-MM) is rare and confers a poor prognosis, with reported overall survival (OS) of 2-7 months. Outside of case reports, there is an undefined role of CNS-directed radiation therapy (RT) in managing CNS-MM. Here, we report our institutional outcomes in a cohort of patients with CNS-MM treated with CNS-directed RT. <h3>Materials/Methods</h3> We retrospectively identified patients with CNS-MM (established by CSF cytology, flow cytometry, or MRI brain/spine), treated with CNS-directed RT from 2015-2020. CNS-MM was defined as having leptomeningeal disease (LMD), parenchymal disease, or CSF involvement. Complete response (CR) was defined as having no cells in CSF or resolution of radiographic disease on MRI. Otherwise, patients were recorded as having partial response (PR) or stable disease (SD). The Kaplan-Meier method was used to estimate OS. <h3>Results</h3> Sixteen patients met inclusion criteria. CNS-MM was confirmed in 11 patients (69%) by CSF and MRI, 3 patients (19%) by CSF alone, and 2 patients (12%) by MRI alone. At CNS-MM diagnosis, 7 patients (43.8%) had received ≥3 prior lines of therapy, 7 (43.8%) were in 1^st/2^nd relapse, and 2 were newly diagnosed. The median time to CNS-MM from initial MM diagnosis was 40.3 mos (range: 0-105). Nine patients (56.3%) had high-risk disease as defined by plasmablastic morphology, cytogenetic features, or LDH elevation. Time to RT from CNS-MM diagnosis was 27 days (range: 9-264). Ten patients (62.5%) underwent craniospinal irradiation (CSI), four (25%) received brain RT (3 focal, 1 whole brain), and 2 (12.5%) received spine RT. The median dose was 23.4 Gy (3.6-30 Gy) in 12 fractions (2-15). Eight patients (50%) also received intrathecal therapy with cytarabine following CNS-MM diagnosis. Two patients (12.5%) underwent SCT post-RT. For the entire cohort (n=16), median OS was 46.6 mos (range: 11-125) from MM diagnosis, 4.2 mos (0.7-60.6) post-diagnosis of CNS-MM, and 3.9 mos (0.43-52) from start of RT. Fifteen patients completed the intended RT and 9 patients (60%) were evaluable post-RT with adequate follow-up consisting of CSF analysis and/or MRI imaging. For the 9 evaluable patients, the median OS from the start of RT was 7.23 mos (range: 3.1-52.1), with CR following RT in 6 patients (66.7%), PR in 2 patients (22.2%) by imaging, and SD in 1 patient (11.1%) by imaging and CSF cytology. Among the 6 patients that completely responded to RT, local relapse occurred in 2 patients at 3 mos and 1 patient at 24 mos post-RT. For the 6 patients with CR after RT, the median OS was 7.27 mos (3.2-52.1) from the start of RT, and 9.2 mos (3.8-60.6) from CNS-MM diagnosis. <h3>Conclusion</h3> Multiple myeloma patients with CNS involvement represent a high-risk patient population. Aggressive multimodality therapy may induce durable CNS control in a small subset of patients. CNS-directed RT may be an effective treatment strategy in selected patients and may increasingly be important to consider in the era of CAR T-cell therapy.

Pre-Radiation CT-Based Radiomic Features Predict Locoregional and Distant Failure in Locally Advanced Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Locally advanced head and neck cancer treatment often involves aggressive multimodal therapy. While outcomes have improved in certain groups (HPV-positive disease), locoregional (LRF) and distant failure (DF) remain persistent problems. Accurate prediction of these risks would provide vital clinical insight; for instance, a patient with low LRF risk could be de-escalated, while a patient at high-risk for DF could be offered systemic options in lieu of aggressive local therapy. In this study we explore the use of CT-based radiomic features (quantitative sub-visual cues) for this purpose. <h3>Materials/Methods</h3> We identified patients with primary or recurrent locally advanced head/neck cancer treated between 2014-2020 who received a definitive or adjuvant RT course (naïve to RT prior). Histologies included squamous cell carcinoma (SCC), poorly differentiated carcinoma (nasopharyngeal or salivary origin), high-risk parotid malignancies, and skin SCC metastatic to the parotid/neck. Patients had at least 12 months of follow-up and charts were assessed for LRF and DF. CT simulation images were extracted from our treatment planning system, and specific contoured regions of interest (ROIs) were selected including the peritumoral region or post-surgical tumor bed (high-risk clinical tumor volume, CTV HR) and involved/elective neck levels (CTV Necks). CT scans were resampled to be isotropic and 3D radiomic features (Gabor wavelet, Hara lick, and CoLlAGe) were extracted from within CTV HR and CTV Necks ROIs. Using a Wilcoxon rank sum test, differential expression for each feature was calculated between patients experiencing treatment failure (LRF and DF) and those with no evidence of disease progression. A similar process was done with baseline clinical features including performance status, tumor stage, age, p16 status and smoking history. Where required, a chi-squared test was used for categorical clinical variables. <h3>Results</h3> 95 patients were analyzed (45 definitive, 50 adjuvant). There were 17 LRF (17.9%) and 16 DF (16.8%) events. 304 radiomic features were extracted from CTV HR and CTV Necks (the latter was only performed for patients with bilateral neck contours). 2 features extracted from CTV HR ROIs were significantly associated with LRF and 29 features with DF (p < 0.05). 30 features extracted from CTV Necks ROIs were significantly associated with LRF and 0 features with DF (p < 0.05). There were no statistically significant clinical features associated with LRF or DF. <h3>Conclusion</h3> CT-based radiomic features derived from specific ROIs in simulation images were associated with both LRF and DF events, which was not the case for canonical clinical features. Interestingly, the CTV HR was more prominently associated with DF, whereas the CTV Necks was associated with LRF. Further studies with larger, more diverse datasets are needed to refine this model and provide a path for clinical validation.