Changes In Tumor Volume Research Articles

1059: Predictive value of tumor volume change during chemoradiotherapy in non-small cell lung cancer

1059: Predictive value of tumor volume change during chemoradiotherapy in non-small cell lung cancer

Effects of bipolar irreversible electroporation with different pulse durations in a prostate cancer mouse model.

Irreversible electroporation (IRE) is a non-thermal ablation technique for local tumor treatment known to be influenced by pulse duration and voltage settings, affecting its efficacy. This study aims to investigate the effects of bipolar IRE with different pulse durations in a prostate cancer mouse model. The therapeutic effectiveness was assessed with in vitro cell experiments, in vivo tumor volume changes with magnetic resonance imaging, and gross and histological analysis in a mouse model. The tumor volume continuously decreased over time in all IRE-treated groups. The tumor volume changes, necroptosis (%), necrosis (%), the degree of TUNEL-positive cell expression, and ROS1-positive cell (%) in the long pulse duration-treated groups (300μs) were significantly increased compared to the short pulse duration-treated groups (100μs) (all p < 0.001). The bipolar IRE with a relatively long pulse duration at the same voltage significantly increased IRE-induced cell death in a prostate cancer mouse model.

Optimizing Treatment Quality in Head and Neck Cancer Therapy: Impact of Adaptive Intensity-Modulated Radiotherapy on Plan Quality and Tumor Volume Changes

Objective: This research analyses whether volumetric changes and PTV shifting affect adaptive intensity-modulated radiotherapy (IMRT) plan quality and head and neck cancer therapy. Methods: The research was carried out at the Sohag Cancer Centre in Egypt, including a sample of 36 individuals diagnosed with head and neck squamous cell carcinoma (HNSCC). Patients were chosen on the basis of the following criteria: locally progressed and node-positive malignancy, oropharyngeal cancer, oral cavity cancer, and unknown primary. The research used dynamic intensity-modulated radiation therapy (D-IMRT) to establish treatment plans and Siemens SOMATOM DEFINITION CT scanners to acquire 3D anatomical images. A range of 1.64 to 2.12 Gy was observed for the median dosage per fraction. Using the conformance index (CI) and the homogeneity index, the quality of the plan was assessed (HI). The threshold for statistical significance was set at 0.05. Results: The study analysed patients with unilateral and bilateral HNSCC tumors, with a majority having bilateral tumors. The findings demonstrated that the tumor PTV was significantly reduced as a consequence of the suggested adaptive radiation techniques. Both the homogeneity index and the conformity index were used to evaluate the plan's quality (HI). The maximal homogeneity index (HI) was reached after 7 and 14 fractions, respectively. The positive correlation between PTV reduction and CI after 7 fractions, while a negative correlation found after fractions 14 and 21. It was also shown that HI is positively correlated with PTV changes after 7 and 14. Conclusion: The use of adaptive radiotherapy in intensity-modulated radiation therapy (IMRT) treatment planning improves plan quality and decreases error rates due to tumor margin movement. Following radiation fractions, PTV shifting affects the homogeneity index (HI).

Abstract CT106: First-in-human phase 1 study of paclitaxel-eluting PTM-101 film in subjects with borderline resectable or locally advanced pancreatic cancers

Abstract Background Unlike many other types of cancer, improvements in the treatment of pancreatic cancer have been very limited, in part due to the inability to deliver chemotherapy to the tumor at efficacious concentrations for a prolonged time. PTM-101 is a novel biodegradable film containing paclitaxel and is designed to continuously release high concentrations of paclitaxel precisely to the site of a pancreatic tumor over one month. Methods This first in human study was conducted at one center in Australia to assess the safety, toxicity, and surgical feasibility of a single administration of PTM-101 containing 100 mg of paclitaxel. PTM-101 was sutured directly onto the pancreatic surface overlying the tumor by a surgical oncologist using standard laparoscopic equipment during a disease-staging assessment. Approximately 3 weeks after PTM-101 placement, all participants began standard of care therapy which included mFOLFIRINOX. This study enrolled 3 subjects that had treatment naïve, borderline resectable or locally advanced, pancreatic adenocarcinoma. Subjects were monitored closely for local and systemic toxicities, as well as for preliminary signals of efficacy. An independent central imaging lab reviewed CT scans to determine changes in tumor volume. Results PTM-101 was successfully implanted over the tumor site in all three subjects. In all cases, there were no adverse events reported during the procedure. Overall, PTM-101 was well tolerated with a total of five Grade 1 adverse events judged at least possibly related to the procedure or the mFOLFIRINOX. No serious adverse events (SAEs) or deaths occurred. Paclitaxel was undetectable in the circulation at all time points. Subjects were followed for 6 months. Best overall response rate according to RECIST was stable disease (2 subjects) and partial response (1 subject). An independent analysis showed that all tumors had a reduction in size in the anterior/posterior diameter, which was consistent with unidirectional paclitaxel release from PTM-101. Two of the 3 subjects had a &amp;gt;30% tumor volume reduction, importantly, with the initial decrease in tumor size detected prior to mFOLFIRINOX. Conclusion PTM-101 was readily implanted during diagnostic laparoscopy and was well tolerated with no SAEs or deaths reported during 6 months of follow up. This study demonstrated that a PTM-101 implant was surgically feasible, safe, resulted in no systemic paclitaxel exposure, and caused a tumor size reduction in all 3 subjects. Additional studies may demonstrate the potential for PTM-101 to be a first-line adjunct prior to neoadjuvant therapy in treatment naïve, borderline resectable or locally advanced, pancreatic cancer. Citation Format: Charles Pilgrim, Marty Smith, Ee-Jun Ban, Samantha Ellis, John Zalcberg, Benjamin Markman, Margaret Lashof-Sullivan, Laura Indolfi. First-in-human phase 1 study of paclitaxel-eluting PTM-101 film in subjects with borderline resectable or locally advanced pancreatic cancers [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 CT106.

Adapt-On-Demand: A Novel Strategy for Personalized Adaptive Radiation Therapy for Locally Advanced Lung Cancer

Real-time adaptation of thoracic radiation plans is compelling because offline adaptive experiences show that tumor volumes and lung anatomy can change during therapy. We present and analyze a novel adaptive-on-demand (AOD) workflow combining online adaptive radiation therapy (o-ART) on the ETHOS system with image guided radiation therapy delivery on a Halcyon unit for conventional fractionated radiation therapy of locally advanced lung cancer (LALC). We analyzed 26 patients with LALC treated with the AOD workflow, adapting weekly. We timed segments of the workflow to evaluate efficiency in a real-world clinic. Target coverage and organ at risk (OAR) doses were compared between adaptive plans (ADP) and nonadaptive scheduled plans (SCH). Planning robustness was evaluated by the frequency of preplanning goals achieved in ADP plans, stratified by tumor volume change. The AOD workflow was achievable within 30 minutes for most radiation fractions. Over the course of therapy, we observed an average 26.6% ± 23.3% reduction in internal target volume (ITV). Despite these changes, with o-ART, ITV and planning target volume (PTV) coverage (V100%) was 99.2% and 93.9% for all members of the cohort, respectively. This represented a 2.9% and 6.8% improvement over nonadaptive plans (P < .05), respectively. For tumors that grew >10%, V100% was 93.1% for o-ART and 76.4% for nonadaptive plans, representing a median 17.2% improvement in the PTV coverage (P < .05). In these plans, critical OAR constraints were met 94.1% of the time, whereas in nonadaptive plans, this figure was 81.9%. This represented reductions of 1.32 Gy, 1.34 Gy, or 1.75 Gy in the heart, esophagus, and lung, respectively. The effect was larger when tumors had shrunk more than 10%. Regardless of tumor volume alterations, the PTV/ITV coverage was achieved for all adaptive plans. Exceptional cases, where dose constraints were not met, were due to large initial tumor volumes or tumor growth. The AOD workflow is efficient and robust in responding to anatomic changes in LALC patients, providing dosimetric advantages over standard therapy. Weekly adaptation was adequate to keep pace with changes. This approach is a feasible alternative to conventional offline replanning workflows for managing anatomy changes in LALC radiation therapy.

Predicting survival of patients with advanced hepatocellular carcinoma receiving combination targeted immunotherapy: an evaluation of volumetric imaging parameters.

To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy. Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis. Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis. Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy.

Abstract 1120: CD8 ImmunoPET imaging identifies an immunogenically active tumor microenvironment following radiotherapy in primary TNBC

Abstract Background: Tumor immune composition has been shown to drive therapy response in triple negative breast cancer (TNBC). Radiation is a component of standard-of-care treatments for TNBC, however immune populations have not been studied in the context of radiation resistance in breast cancer. Positron emission tomography (PET) allows for quantifying molecular signatures of the tumor microenvironment, which can precede anatomical changes in tumor volume. Recently, development of immune-targeted imaging approaches has allowed for noninvasive quantification of immune cells, allowing for quantification and long-term therapy response. Preclinical studies have demonstrated that combining therapies, such as radiotherapy and immunotherapy, could be beneficial in treating cancer. The goal of this study is to quantify changes in immune infiltration with [89Zr]-CD8 ImmunoPET following radiation therapy to determine variations in immune activation that can affect therapeutic response in radiation sensitive or radiation resistant tumors. Methods: Syngeneic radiation sensitive 4T1 or a radiation-resistant 4T1 tumors were treated with fractionated radiation (2 Gy/day) from day 0-5, injected with [89Zr]-CD8 minibody on day 6, and imaged with [89Zr]-CD8 PET on day 7. Following imaging, tumors were excised for biological assays (N = 20) or monitored for longitudinal changes in tumor volume (N = 15). Biological assays included CD8 immunofluorescence or assessment of immune population differences with flow cytometry against T-cells (CD3, CD4, CD8, IFN-gamma), macrophages (CD45, F4/80, CD86 and CD206), and natural killer cells (CD56 and CD16). A non-parametric T-test was used to assess for statistical differences. Results: In radiation sensitive tumors, [89Zr]-CD8 PET indicated that radiation significantly increases CD8 immune infiltration (p = 0.02) compared to controls, which was correlated with immunofluorescence (p &amp;lt; 0.01). Immune infiltration was increased in radiation sensitive tumors when treated with radiation therapy (4.6-fold increase in CD86+ M1-like macrophages, 4.7-fold increase in CD206+ M2-like macrophages, 5.3-fold increase in CD8 T-cells and 4.3-fold increase in CD4 T-cells) compared to control tumors. Radiation was observed to increase cytotoxic CD8 immune infiltration in radiation sensitive tumors. In radiation resistant tumors, no significant difference was observed in either CD8 immune infiltration or tumor volume in treated tumors compared to controls (p = 0.63). Conclusions: [89Zr]-CD8 ImmunoPET reveals significant increases in CD8 immune infiltration in a radiation sensitive model of TNBC and identifies an immune altered tumor immune microenvironment. Fractionated radiotherapy was also observed to significantly increase the infiltration of innate and adaptive immune cells. Citation Format: Patrick N. Song, Shannon E. Lynch, Chloe T. DeMellier, Alessandro Mascioni, Jia Fang, Anna G. Sorace. CD8 ImmunoPET imaging identifies an immunogenically active tumor microenvironment following radiotherapy in primary TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1120.

Abstract 4216: Indication agnostic evaluation of CAR T cell function using patient-derived immunocompetent tumoroid modelling platform

Abstract Introduction: Engineered T cells redirected towards tumor-specific cytotoxicity is a promising immunotherapeutic modality that has been well characterized for efficacy against B cell malignancies and evaluated in multiple tumor types. However, the development and optimization of CAR T cell therapies requires a rigorous preclinical model for the evaluation of CAR T cell function, tumor killing, cytokine production, and memory responses. Experimental Procedure: We are evaluating our model platform Custom Organoid Modelling Platform for Accurate and Speedy SolutionS (COMPASS 2) as a comprehensive platform for testing developmental and functional stages of CAR T cells including activation, memory, and exhaustion. We are performing qualitative and quantitative analyses of surface markers to recapitulate the complexity of human cancer. Additionally, since CAR T cells mediate crosstalk with other immune components in the TME, we also evaluate and monitor the presence of B cells, NK cells, macrophages, and endogenous T cells. Triple Negative Breast Cancer (TNBC); Immunophenotyping (IP); Immunofluorescence (IF); Fluorescence Activated Cell Sorting (FACS); T regulatory (Treg). Summary of Results: Our evaluation of COMPASS 2 for functional testing of CAR T cells demonstrates the feasibility of the platform in preclinical CAR T cell evaluation. We showed T cell infiltration and analyzed cytokine production that may alter tumor cells and TME. Crosstalk with other immune cells will be evaluated. We are currently evaluating the tumor volume changes using an EGFRvIII-targeted CART cell therapy on TNBC model systems, followed by apoptosis and EGFR analysis using FACS. Conclusion: Our COMPASS 2 model platform enables studies that require recapitulating hurdles to CAR therapy, including antigen escape, T cell dysfunction and trafficking; to reveal an essential role of the endogenous immune response mediating the antitumor effect following CAR therapy. Citation Format: Damieanus O. Ochola, Huckie Dell Mundo, Preethi Samuel, Natalia Korkorina, Bhuvanesh Dave. Indication agnostic evaluation of CAR T cell function using patient-derived immunocompetent tumoroid modelling platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4216.

Abstract 4230: Patient-derived tumoroid platforms with progressing tumor microenvironment representability reveals efficacy and resistance patterns in pre-clinical HSP90i regimen testing for improved clinical insights

Abstract Introduction: Drug candidates advance to phase I clinical trial after rigorous optimization at preclinical stage and yet nine out of ten drug candidates fail during clinical trials and approval stage. Lack of clinical efficacy is a major contributor (~ 50%) towards this 90% of the failure at clinical trials. Tremendous efforts are being taken to demonstrate drug efficacy in preclinical studies by mitigating the biological discrepancy of molecular target between human disease and the model used for the validation. Herein this study, we aim to showcase therapeutic responses of heat-shock protein 90 (HSP90) inhibitor regimens (HSP90i only and HSP90i + Doxorubicin combination) against three-dimensional (3D), patient-derived tumoroid (PDT) model platforms with progressing tumor microenvironment (TME) representability by incorporating supplementary TME structure, immunity, and oxygenation. Revelations on efficacy and resistance patterns of such drug treatments on increasingly complex models is aimed at providing unique insights to tumor and drug-drug interplay. Methods: Human Uterine Adenosarcoma PDT models were prepared across three COMPASS (Custom Organoid Modeling Platform for Accurate SolutionS) platforms: 1) COMPASS 1a - Non-scaffold 2) COMPASS 3b - Scaffold + Immune cells and 3) COMPASS 3d - Scaffold + Immune cells + Oxygenation. The various platforms were tested against two regimens A) HSP90i only [50 nM and 100 nM] and B) HSP90i [50 nM and 100 nM] + Doxorubicin [50 nM]. Tumor size and volume assessment were carried out on Days 3 and 7 post-treatment -with statistical done via one-way ANOVA, followed by student’s t test for significance (p&amp;lt;0.05, n=3). Results: While a simpler platform COMPASS 1a showcased the therapeutic efficacy of monotherapeutic HSP90i [at 100 nM] (p&amp;lt;0.05), progressively complex models (COMPASS 3b and COMPASS 3d) have otherwise indicated the lack of significant tumor volume changes. On the other hand, current findings on combination therapies of HSP90i and Doxorubicin have revealed persistent therapeutic resistance (even suggestive of patterns of increasing tumor growth) on COMPASS 1a, necessitating further comparisons on the more complex models. Conclusion: Our results demonstrate the need to test drugs in context of TME and oxygenation to help stratify patients to develop better clinical trials based on patient tumor characteristics of vascularization and immunogenicity. We plan to test several different drug modalities and cancer types for these parameters to demonstrate the need and effectiveness of testing prior to taking the drugs to the clinic. Citation Format: Huckie Del Mundo, Damieanus O. Ochola, Bhuvanesh Dave, Preethi Samuel. Patient-derived tumoroid platforms with progressing tumor microenvironment representability reveals efficacy and resistance patterns in pre-clinical HSP90i regimen testing for improved clinical insights [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4230.

Abstract 6486: Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors

Abstract Background: KRAS mutations are found in a variety of tumor types, including non-small cell lung cancer (NSCLC), where KRAS G12C mutation is present in ~12% of NSCLC patients. KRAS G12C inhibitors (KRAS G12Cis), sotorasib and adagrasib, are approved for the treatment of KRAS G12C-mutated, locally advanced or metastatic NSCLC. The mTOR pathway is often activated in patients with KRAS mutations and may contribute to resistance to KRAS G12Cis. nab-Sirolimus is a nanoparticle albumin-bound intravenously (IV) administered form of the mTOR inhibitor (mTORi) sirolimus and is approved for the treatment of patients with advanced malignant perivascular epithelioid cell tumors. This study assessed tumor and blood drug level correlation with antitumor activity of nab-sirolimus or everolimus alone or in combination with KRAS G12Cis. Methods: Athymic mice bearing subcutaneous KRAS G12C- and STK11-mutated NSCLC xenografts (NCI-H2122) were treated with saline, mTORis nab-sirolimus (IV) or everolimus (oral) at clinically relevant and equal weekly dose of 15 mg/kg/wk, or KRAS G12Cis sotorasib (oral) or adagrasib (oral) at 30 mg/kg/day alone or in combination. Tumor volume changes from baseline were assessed; tumor and blood samples were harvested at the end of study (6 wks) for analysis of trough drug levels by LC-MS/MS, and tumor lysates were analyzed for downstream markers for mTOR inhibition by Western blot. Results: In nab-sirolimus plus KRAS G12Ci treated groups, significantly slower tumor growth was observed compared with single agent treated groups and everolimus plus KRAS G12Ci treated groups. Compared with single-agent nab-sirolimus (170.1 ng/g), treatment with nab-sirolimus plus sotorasib resulted in reduced tumor nab-sirolimus drug levels (73.6 ng/g, P=0.0040); while similar tumor nab-sirolimus drug levels were observed for nab-sirolimus plus adagrasib (121.6 ng/g, P=ns). Corresponding to greater antitumor activity, significantly greater tumor trough mTORi drug levels were observed in nab-sirolimus plus either sotorasib or adagrasib treated groups compared with similar everolimus combinations (85-fold, P&amp;lt;0.0001; and 91-fold, P=0.0050, respectively). Correspondingly, stronger mTOR downstream target inhibition of pS6 were observed for nab-sirolimus plus KRAS G12Ci treated groups compared with everolimus plus KRAS G12Ci treated groups. Conclusions: The addition of a KRAS G12Ci to nab-sirolimus significantly reduced tumor volume and increased tumor drug levels, suggesting enhanced tumor targeting compared with everolimus plus KRAS G12Cis and correlating to improved antitumor activity and mTOR target suppression. Clinical dose-finding studies are needed to determine potential drug-drug interactions between nab-sirolimus and KRASis. Citation Format: Shihe Hou, Jorge Nieva, Maria Zalath, Neil Desai. Correlation of nab-sirolimus tumor drug levels and improved tumor suppression in KRAS G12C non-small cell lung cancer xenografts treated with nab-sirolimus in combination with KRAS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6486.

Abstract 1934: The PLK1 inhibitor, onvansertib, is active as monotherapy and in combination with cetuximab in RAS wild-type colorectal cancer patient-derived xenografts

Abstract Background: Cetuximab and panitumumab are monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), that provide clinical benefit to metastatic colorectal cancer (mCRC) patients with RAS wild-type (RASWT) tumors. Unfortunately, intrinsic or acquired resistance to these therapies limits their clinical effectiveness, necessitating the development of more efficient therapeutic strategies. Onvansertib is an oral, small molecule, selective inhibitor of the PLK1 kinase, currently in clinical development for KRAS-mutant mCRC. The aim of this study was to assess the anti-tumor activity of onvansertib monotherapy and in combination with cetuximab in RASWT CRC patient-derived xenograft (PDX) models. Methods: Twenty RASWT CRC PDXs were selected and engrafted in nude mice. Once tumors reached 200-350-mm3, mice were treated with vehicle, onvansertib (60mg/kg, QD), cetuximab (20mg/kg, BIW) or the combination for 18 days. PDX models were chosen based on their sensitivity to cetuximab, resulting in a selection of 7 cetuximab-sensitive (CetuxS) and 13 cetuximab-resistant (CetuxR) PDXs, including 7 with intrinsic resistance and 6 with acquired-resistance. Tumor volume change from baseline (TVC) was calculated as 100%x(Vt-Vo)/Vo and tumor growth inhibition (TGI) as 100%x(TVCcontrol-TVCtreated)/TVCcontrol. Tumor regression was defined as TVCD18&amp;lt;0 and tumor stasis 0≤TVCD18&amp;lt;100. Results: Cetuximab sensitivity was confirmed in the selected models, cetuximab induced tumor regression in all the CetuxS PDXs, while no or limited activity was observed in the resistant models (median TGI=29%, IQR 16-61). Onvansertib exhibited potent anti-tumor activity in 17 (85%) PDXs, resulting in tumor regression (n=11) or tumor stasis (n=6). Onvansertib TGI at Day 18 was not significantly different in CetuxS PDXs (median TGI 102, IQR 76-103) compared to CetuxR PDXs (median TGI 108, IQR 74-124), supporting that onvansertib anti-tumor activity is independent of the sensitivity/resistance to cetuximab. The combination of onvansertib and cetuximab induced tumor regression in 18 (90%) PDXs. The combination showed significantly improved efficacy compared to individual therapies in some of the models. Conclusions: Onvansertib monotherapy displayed potent anti-tumor activity in RASWT CRC PDX models, independently of their sensitivity to cetuximab. Additionally, onvansertib combined with cetuximab exhibited either comparable or superior anti-tumor activity than the monotherapies. Collectively, this data supports the clinical development of the PLK1 inhibitor onvansertib for RASWT mCRC. Citation Format: Maya Ridinger, Preeti Kanikarla Marie, Fengqin Gao, Zhensheng Liu, Giulia Maddalena, David Menter, Alexey Sorokin, Tod Smeal, Scott Kopetz. The PLK1 inhibitor, onvansertib, is active as monotherapy and in combination with cetuximab in RAS wild-type colorectal cancer patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1934.

Appraisal of Changes in Tumor Volume After Neoadjuvant Systemic Therapy for Hepatocellular Carcinoma (HCC)

Appraisal of Changes in Tumor Volume After Neoadjuvant Systemic Therapy for Hepatocellular Carcinoma (HCC)

The Effect of Photodynamic Therapy Using 5-Aminolevulinic Acid in Bone and Soft Tissue Sarcoma Cells.

5-Aminolevulinic acid (5-ALA) is a natural amino acid and a precursor of protoporphyrin IX (PpIX). Following light irradiation, the PpIX generates reactive oxygen species (ROS) in the presence of oxygen. Increased ROS levels can cause apoptotic cell death and necrosis of targeted cancer cells. This study examined whether photodynamic therapy using 5ALA (5-ALA PDT) could be used as a potential adjuvant therapy for bone and soft tissue sarcomas. The human osteosarcoma (143B), mouse osteosarcoma (LM8), human fibrosarcoma cell (HT1080) cell lines were used. In vitro, cultured cells were exposed to 5-ALA at various concentrations followed by strobe scope light irradiation for 10 min as 5-ALA PDT. Cell viability was then measured. In vivo, each tumor cell line was inoculated subcutaneously into the backs of mice. In the 5-ALA PDT group, 5-ALA (250 mg/kg) was administered intraperitoneally followed by light irradiation. Change in tumor volume by 5-ALA PDT were primarily evaluated. In vitro, treatment of sarcoma cells with 100 and 200 μg/ml 5-ALA PDT significantly inhibited cell proliferation at 24 and 48 h compared with the group treated with 0 and 10 μg/ml 5-ALA PDT. In vivo, in all cell lines, a significant inhibition of the tumor volume was observed in the 5-ALA-PDT group as compared to that in control, strobe scope light, and 5-ALA groups. 5-ALA PDT effectively inhibited proliferation of bone and soft tissue sarcoma cell lines. Further in vivo research using other subtypes of bone and soft tissue sarcoma is warranted to confirm the applicability in the clinical setting.

Prostatic Artery Embolization in Patients with Advanced Prostate Cancer: A Prospective Single Center Pilot Study.

To assess efficacy and safety of prostatic artery embolization (PAE) in patients with advanced prostate cancer (PCa). In this prospective single-center, single-arm, pilot study, 9 men with advanced PCa underwent PAE. PAE was performed with the use of 250-400µm Embozene microspheres (Boston Scientific, Natick, Massachusetts, USA). International Prostate Symptoms Score (IPSS), urinary peak flow (Qmax) and post-void residual urine volume (PVR) was assessed at 12 weeks and up to 12 months. Changes in total prostate volume (TPV) and tumor responses by PSA, changes in tumor volume and evaluation of tumor regression by multiparametric magnetic resonance imaging were assessed at 12 weeks after PAE. IPSS reduction in median 6 points (0-19) and a significant decrease in PVR from median 70 (20-600)mL to 10 (0-280)mL could be achieved within 12 weeks after PAE. Median TPV and tumor volumes (TV) increased slightly from 19.7 (6.4-110.8)mL to 23.4 (2.4-66.3)mL and 6.4 (4.6-18.3)mL to 8.1 (2.4-25.6)mL at a median of 12 weeks after the procedure. Significant tumor necrosis (≥ 50%) was found in one patient. Eight patients showed > 50% of viable tumor on post-PAE MRI according to MRI. Only one Clavien-Dindo Grade 1 adverse event related to PAE occurred. PAE with the use of 250-400 µm microspheres is feasible, safe and effective in some patients with advanced PCa regarding functional outcomes. A cytoreductive effect might be achieved in individual patients but must be further assessed. NCT03457805.

Correlation of CT Scan Response to Necrosis and Volume Changes With Histopathology in Children With Wilms' Tumor

BackgroundWilms’ tumor is the most common renal tumor in children. ObjectiveTo correlate the percentage of necrosis and tumor volume change found in preoperative Contrast Enhance Computed Tomography (CECT) scan of the abdomen with post-operative histopathological findings of Wilms Tumor (WT). MethodsIn this prospective study from January 2020 to December 2022, out of 33 patients, 15 patients with unilateral localized WT (stage I, II, and III) treated according to SIOP UMBRELLA protocol 2016 were included. Bilateral, syndromic, and stage IV WT were excluded. The radiological response was measured in preoperative CECT by estimating the percentage of necrosis found in static images and compared with post-operative histopathological findings. Tumor volume changes were measured by comparing CECT at diagnosis and following chemotherapy. Tumor volume change was also compared with histology. ResultsThere was a significant positive correlation between radiological response to necrosis with histology as per Pearson correlation. Significant positive correlation also found between volume changes on pre and post chemotherapy CECT with histology as per Spearman correlation. ConclusionsThe changes in tumors during preoperative radiological evaluation and histologically confirmed necrosis are strongly related.

Anticancer Effects of BRD4 Inhibitor in Epithelial Ovarian Cancer.

Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry. BRD4 and c-Myc expression and apoptosis-related molecules were detected using RT-PCR and real-time PCR and Western blot. We confirmed the OPT-0139 effect and mechanism of action in epithelial ovarian cancer. OPT-0139 significantly reduced cell viability and proliferation and induced apoptosis and cell cycle arrest. In the mouse xenograft model, significant changes in tumor growth, volume, weight, and BRD4-related gene expression were observed, suggesting the antitumor effects of BRD4 inhibitors. Combination therapy with cisplatin promoted apoptosis and suppressed tumor growth in vitro and in vivo. Our results suggest OPT-0139, a BRD4 inhibitor, as a promising anticancer drug for the treatment of ovarian cancer by inhibiting cell proliferation, decreasing cell viability, arresting cell cycle, and inducing apoptosis.

Clinical Experience With an Offline Adaptive Radiation Therapy Head and Neck Program: Dosimetric Benefits and Opportunities for Patient Selection

PurposeTo develop a LINAC-based adaptive radiotherapy (ART) workflow for head and neck that is informed by automated image tracking to identify major anatomic changes warranting adaptation. In this study we report our initial clinical experience with the program and an investigation into potential trigger signals for ART. Methods and MaterialsOffline ART was systematically performed on patients receiving radiotherapy for head and neck cancer on C-arm LINACs. Adaptations were performed at a single timepoint during treatment with resimulation approximately 3 weeks into treatment. Throughout treatment, all patients were tracked using an automated image tracking system called the IN_HOUSE_SOFTWARE*. IN_HOUSE_SOFTWARE measures volumetric changes in gross tumor volumes (GTV) and selected normal tissues via cone-beam computed tomography (CBCT) scans and deformable registration. The benefit of ART was determined by comparing adaptive plan dosimetry and normal tissue complication probabilities (NTCP) against the initial plans recalculated on resimulation CT scans. Dosimetric differences were then correlated with IN_HOUSE_SOFTWARE-measured volume changes to identify patient-specific triggers for ART. Candidate trigger variables were evaluated using receiver operator characteristic (ROC) analysis. ResultsN=46 patients received ART in this study. Amongst these patients, we observed a significant decrease in dose to the submandibular glands (mean ± standard deviation: -219.2±291.2cGy, p-value<10−5), parotids (-68.2±197.7cGy, p-value=0.001) and oral cavity (-238.7±206.7cGy, p-value<10−5) with the adaptive plan. NTCPs for xerostomia computed from mean parotid doses also decreased significantly with the adaptive plans (p-value=0.008). We also observed systematic intra-treatment volume reductions (ΔV) for GTVs and normal tissues. Candidate triggers were identified which did predict significant improvement with ART including parotid ΔV=7%, neck ΔV=2%, and nodal GTV ΔV=29%. ConclusionsSystematic offline head and neck ART was successfully deployed on conventional LINACs and reduced doses to critical salivary structures and oral cavity. Automated CBCT tracking provided information regarding anatomic changes that may aid patient-specific triggering for ART. (*Anonymized for review)

Different tumor growth pattern of clinically nonfunctioning pituitary neuroendocrine tumor according to sex and age: a longitudinal study

PurposeAsymptomatic patients with clinically non-functional pituitary neuroendocrine tumors (CNF-PitNETs) are usually followed up. However, the natural course of CNF-PitNETs according to sex and age remains unclear. Therefore, this study assessed growth patterns of CNF-PitNETs according to sex and age.MethodsIn this longitudinal study, we enrolled 431 consecutive patients with CNF-PitNETs who were treated at Seoul National University Hospital from 1997 to 2021. The patients underwent hormone function testing and visual field testing, and were subsequently followed up with imaging over a median duration of 66 months.ResultsThe median age of the patients was 53.0 years, and 37.1% (n = 160) were men. Men were older and harbored more macroadenomas than women. The annual tumor volume change was higher in men than in women (0.21 vs. 0.04 cm3/year, P < 0.001). The estimated cutoff value of age for significant tumor growth was 51 years. In men, the annual tumor volume change was similar across all age groups. In women, those aged ≤ 50 years showed significantly lower annual tumor volume change than those aged > 50 years (0.01, 0.11, and 0.17 cm3/year, P = 0.001). When comparing sexes within the same age group, the annual tumor volume changes was significantly lower for women than for men, only in patients aged ≤ 50 years (0.01 vs. 0.15 cm3/year, P < 0.001).ConclusionsAmong patients with CNF-PitNET, tumor growth was slower in women aged ≤ 50 years than in men and women aged > 50. These findings may guide the customization of surveillance strategies for CNF-PitNETs according to sex and age.

Development of a multiparametric model for predicting the response to neoadjuvant chemotherapy in breast cancer.

Choosing the appropriate treatment early and predicting the efficacy of neoadjuvant chemotherapy (NAC) for locally advanced breast cancer patients are of particular importance for clinicians. Developing and validating a multiparametric model for predicting NAC would be very meaningful for clinical practice. This study included 91 patients with locally advanced breast cancer treated from 2016 to 2020. The correlation between multiparametric characteristics and the efficacy of NAC was examined. The data were randomly divided into training and validation sets. A least absolute shrinkage and selection operator (LASSO) regression analysis was used for the variable screening. A multivariable logistic regression analysis was used to construct the model. Calibration and decision curves were used to assess the performance of the established model. Lymph node metastasis, the first standard apparent diffusion coefficient (ADC) at the baseline, the change in the standard ADC at the first follow-up, the change in tumor volume at the first follow-up, and the clinical stage of the tumor at the baseline were selected for inclusion in the model. In the receiver operating characteristic (ROC) analysis, the areas under the curve (AUCs) were 0.984 [95% confidence interval (CI): 0.958-1] and 0.815 (95% CI: 0.509-1) for the primary and validation cohorts, respectively. The utility of the established model was confirmed by calibration and decision curves, and a nomogram was obtained. A multiparametric model based on clinical-pathological-magnetic resonance imaging (MRI) features was established to predict the effect of NAC in patients with locally advanced breast cancer.

An exploratory prospective phase II study of preoperative neoadjuvant bevacizumab and temozolomide for newly diagnosed glioblastoma

PurposeThis multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB).MethodsPatients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1–5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy.ResultsTumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively.ConclusionPreoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively.Trial Registration Number: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233. Registration Date: Jan. 16, 2017