Changes In Tumor Volume Research Articles

Locally advanced thymoma; does neoadjuvant chemotherapy make a difference?

BackgroundRegardless of its rare occurrence, Thymoma remains the most frequently encountered primary tumor of the anterior mediastinum comprising about 50% of all masses in the region. Surgical resection, via thymectomy, remains the mainstay treatment modality. In locally advanced and borderline resectable tumors, neoadjuvant chemotherapy (NACT) may be utilized to increase the chance of R0 resection, raising the question of its efficacy and safety.MethodsDemographic and clinical data from patients who presented to a tertiary cancer center between January 2015–October 2021 with a diagnosis of thymoma and underwent curative surgical resection was collected. Computed tomography scan was used to delineate clinical staging, tumor size and to detect post-therapeutic variations in tumor burden. The response evaluation criteria in solid tumors (RECIST) was used to classify the effect of NACT on tumor burden. The pathological response was determined by measuring the percentage of necrotic tissue.ResultsA total of 23 patients were diagnosed with thymoma. Most patients were male with a mean age 46 (± 15) years at diagnosis. The most common clinical stage was stage II with 5 patients (22%). A total of 12 patients had NACT as compared to 11 patients who had upfront surgery. The mean change in tumor volume was 165 cm3 (p = 0.079) and the change in and maximum diameter was 1.53 ± 1.49 cm (p < 0.01). The effect of NACT on tumor burden based on RECIST criteria was minimal as 8 patients had stable disease. Based on pathological findings, the average necrotic portion of the tumor was 39.5% (p = 0.152). The overall survival rate is 95.65%, mean survival was 115 months (4–125). Recurrence occurred in 5 patients. The NACT group had a higher risk for recurrence (4; 33.3%) with a mean survival of 43.8 months compared to 59.6 months in those who did not receive induction therapy.ConclusionsThe exact role of induction chemotherapy in locally advanced thymoma patients remains controversial. NACT effect after utilizing radiological and pathological assessment tools was not found to significantly improve oncological outcomes compared to upfront surgery in locally advanced disease, with minimal radiologic and pathologic effect. To further demonstrate the impact of induction chemotherapy, we recommend multicentric collaborative studies.

Automated Brain Tumor Detection and Segmentation for Treatment Response Assessment Using Amino Acid PET.

Evaluation of metabolic tumor volume (MTV) changes using amino acid PET has become an important tool for response assessment in brain tumor patients. MTV is usually determined by manual or semiautomatic delineation, which is laborious and may be prone to intra- and interobserver variability. The goal of our study was to develop a method for automated MTV segmentation and to evaluate its performance for response assessment in patients with gliomas. Methods: In total, 699 amino acid PET scans using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) from 555 brain tumor patients at initial diagnosis or during follow-up were retrospectively evaluated (mainly glioma patients, 76%). 18F-FET PET MTVs were segmented semiautomatically by experienced readers. An artificial neural network (no new U-Net) was configured on 476 scans from 399 patients, and the network performance was evaluated on a test dataset including 223 scans from 156 patients. Surface and volumetric Dice similarity coefficients (DSCs) were used to evaluate segmentation quality. Finally, the network was applied to a recently published 18F-FET PET study on response assessment in glioblastoma patients treated with adjuvant temozolomide chemotherapy for a fully automated response assessment in comparison to an experienced physician. Results: In the test dataset, 92% of lesions with increased uptake (n = 189) and 85% of lesions with iso- or hypometabolic uptake (n = 33) were correctly identified (F1 score, 92%). Single lesions with a contiguous uptake had the highest DSC, followed by lesions with heterogeneous, noncontiguous uptake and multifocal lesions (surface DSC: 0.96, 0.93, and 0.81 respectively; volume DSC: 0.83, 0.77, and 0.67, respectively). Change in MTV, as detected by the automated segmentation, was a significant determinant of disease-free and overall survival, in agreement with the physician's assessment. Conclusion: Our deep learning-based 18F-FET PET segmentation allows reliable, robust, and fully automated evaluation of MTV in brain tumor patients and demonstrates clinical value for automated response assessment.

Assessment of Changes in Tumor Volume Following Chemotherapy For Nodular Sclerosıng Hodgkin Lymphoma (NSHL)

Objective: Hodgkin lymphoma is a critical malignancy which may be seen during childhood and adolescence. Since it may be observed in younger patients, treatment strategies should be considered thoroughly to achieve optimal results in terms of local control and treatment related adverse effects. Systemic therapy plays a critical role in treatment of Hodgkin lymphoma. In this study, we evaluated changes in tumor volume following chemotherapy for nodular sclerosing Hodgkin lymphoma (NSHL).

Growth potential of small residual tumors after vestibular schwannoma surgery: comparison between remnants and the natural history of small tumors.

Due to the heterogeneous definitions of tumor regrowth and various tumor volume distributions, the nature of small remnants after vestibular schwannoma (VS) surgery and the appropriate timing of adjuvant stereotactic radiosurgery for these remnants remain unclear. In this study, the growth potential of small remnants (< 1 cm3) after VS surgery was compared with that of treatment-naïve (TN) small VSs. This retrospective single-center study included 44 patients with VS remnants following subtotal resection (STR) of a large VS (remnant group) and 75 patients with TN VS (< 1 cm3; TN group). A 20% change in tumor volume over the imaging interval indicated radiographic progression or regression. Tumor progression-free survival (TPFS) rates were estimated using the Kaplan-Meier method. In the remnant group, the mean preoperative tumor volume was 13.8 ± 9.0 cm3 and the mean tumor resection rate was 95% ± 5%. The mean tumor volume at the start of the observation period did not differ significantly between the two groups (remnant vs TN: 0.41 ± 0.29 vs 0.34 ± 0.28 cm3, p = 0.171). The median periods until tumor progression was detected were 15.1 (range 4.9-76.2) months and 44.7 (range 12.6-93.2) months in the TN and remnant groups, respectively. In the remnant group, the TPFS rates were 74% and 70% at 3 and 5 years after the surgery, respectively, compared with 59% and 47% in the TN group. The log-rank test demonstrated a significant difference (p = 0.008) in the TPFS rates between the two groups. Furthermore, 42 patients each from the remnant and TN groups were matched based on tumor volume. TPFS was significantly longer in the remnant group than in the TN group (3-year rates, 77% vs 62%; 5-year rates, 73% vs 51%; p = 0.02). In the remnant group, 18% of the tumor remnants demonstrated regression during follow-up, compared with 9% in the TN group, but this intergroup difference was not significant (p = 0.25). This study demonstrated that the growth potential of small VS remnants was lower than that of TN tumors. Observing for small remnants may be appropriate after STR of a large VS. Given the risk of tumor regrowth, careful observation using MRI should be mandatory during follow-up.

Association between immunohistochemical markers and tumor progression following resection of spinal chordomas: a multicenter study.

Chordomas are slow-growing tumors derived from notochord remnants. Despite margin-negative excision and postoperative radiation therapy, spinal chordomas (SCs) often progress. The potential of immunohistochemical (IHC) markers, such as epithelial membrane antigen (EMA), combined with machine learning algorithms to predict long-term (≥ 12 months) postoperative tumor progression, has been understudied. The authors aimed to identify IHC markers using trained tree-based algorithms to predict long-term (≥ 12 months) postoperative tumor progression. The authors reviewed the records of patients who underwent resection of SCs between January 2017 and June 2021 across the Mayo Clinic enterprise. Demographics, type of treatment, histopathology, and other relevant clinical factors were abstracted from each patient's record. Low tumor progression was defined as more than a 94.3-mm3 decrease in the tumor size at the latest radiographic follow-up. Decision trees and random forest classifiers were trained and tested to predict the long-term volumetric progression after an 80/20 data split. Sixty-two patients diagnosed with and surgically treated for SC were identified, of whom 31 were found to have a more advanced tumor progression based on the tumor volume change cutoff of 94.3 mm3. The mean age was 54.3 ± 13.8 years, and most patients were male (62.9%) and White (98.4%). The most common treatment modality was subtotal resection with radiation therapy (35.5%), with proton beam therapy being the most common (71%). Most SCs were sacrococcygeal (41.9%), followed by cervical (32.3%). EMA-positive SCs had a postoperative progression risk of 67%. Pancytokeratin-positive SCs had a progression rate of 67%; however, patients with S100 protein-positive SCs had a 54% risk of progression. The accuracy of this model in predicting the progression of unseen test data was 66%. Pancytokeratin (mean minimal depth = 1.57), EMA (mean minimal depth = 1.58), cytokeratin A1/A3 (mean minimal depth = 1.59), and S100 protein (mean minimal depth = 1.6) predicted the long-term volumetric progression. Multiway variable importance plots show the relative importance of the top 10 variables based on three measures of varying significance and their predictive role. These IHC variables with tree-based machine learning tools successfully demonstrate a high capacity to identify a patient's tumor progression pattern with an accuracy of 66%. Pancytokeratin, EMA, cytokeratin A1/A3, and S100 protein were the IHC drivers of a low tumor progression. This shows the power of machine learning algorithms in analyzing and predicting outcomes of rare conditions in a small sample size.

Early MRI Predictors of Relapse in Primary Central Nervous System Lymphoma Treated with MATRix Immunochemotherapy.

Primary Central Nervous System Lymphoma (PCNSL) is a highly malignant brain tumour. We investigated dynamic changes in tumour volume and apparent diffusion coefficient (ADC) measurements for predicting outcome following treatment with MATRix chemotherapy in PCNSL. Patients treated with MATRix (n = 38) underwent T1 contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) before treatment, after two cycles and after four cycles of chemotherapy. Response was assessed using the International PCNSL Collaborative Group (IPCG) imaging criteria. ADC histogram parameters and T1CE tumour volumes were compared among response groups, using one-way ANOVA testing. Logistic regression was performed to examine those imaging parameters predictive of response. Response after two cycles of chemotherapy differed from response after four cycles; of the six patients with progressive disease (PD) after four cycles of treatment, two (33%) had demonstrated a partial response (PR) or complete response (CR) after two cycles. ADCmean at baseline, T1CE at baseline and T1CE percentage volume change differed between response groups (0.005 < p < 0.038) and were predictive of MATRix treatment response (area under the curve: 0.672-0.854). Baseline ADC and T1CE metrics are potential biomarkers for risk stratification of PCNSL patients early during remission induction therapy with MATRix. Standard interim response assessment (after two cycles) according to IPCG imaging criteria does not reliably predict early disease progression in the context of a conventional treatment approach.

'Sandwich treatment' for posterior fossa brain metastases with volume larger than 4cm3: a multicentric retrospective study.

Single stereotactic radiosurgery (SRS) for posterior fossa brain metastases (BM) larger than 4cm3 is dangerous. 'Sandwich treatment' strategy was developed for these BMs. The strategy was one week treatment course which includes 2-stage SRS and using Bevacizumab once during SRS gap. Patients from four gamma knife center were retrospectively analyzed. The changes of tumor and peri-tumor edema volume were studied. The Dizziness Handicap Inventory (DHI) Vomiting Score (VS) and Glasgow Coma Scale (GCS) were used to evaluate patients' clinical symptom changes. Karnofsky performance scale (KPS) and Barthel Index (BI) were used to evaluate patients' overall fitness status and physical activity rehabilitation. Tumor local control (TLC) and patients' overall survival (OS) rate were also calculated. Forty patients with 45 LBMs received 'Sandwich treatment'. The mean edema volume reduced remarkably at the course of therapy and 3 months later (P < 0.01). The mean tumor volume greatly decreased 3 months later (P < 0.01). Patients' clinical symptoms that reflected by median score of DHI, VS, GCS were improved dramatically at the course of therapy and 3 months later (P < 0.01). Similar changes happened in median score of KPS and BI that reflected patients' overall fitness status and physical activity rehabilitation (P < 0.01). Patients' median OS was 14.3 months, with 95.4%, 76.2%, and 26.3% survival rate at 6, 12, 24 months. The TLC rate at 6, 12, 24 months was 97.5%, 86.0% and 62.2%.The 'Sandwich treatment' is safe and effective for patients with LBM over 4cm3 in the posterior fossa. The strategy could quickly improve patients' symptoms, well control tumor growth, prolong patient's OS, and has controllable side effects.

PREDICTORS OF TUMOR DYNAMICS DURING A COURSE OF 30-FRACTION RADIOTHERAPY FOR GLIOBLASTOMA

Abstract We aim to identify predictors of tumor dynamics during radiotherapy for glioblastoma. METHODS: This is a prospective serial MRI study in patients with glioblastoma. MRIs were obtained at radiotherapy planning (F0), fraction-10 (F10), and fraction-20 (F20). The tumor dynamics metrics (relative to F0) assessed included: relative gross tumor volume (GTV) changes (Vrel) and migration distance (dM). RESULTS: 129 patients were included in this study. Median GTV was 20.9cc at F0, 17.6cc at F10 (Vrel 0.85), and 16.1cc at F20 (Vrel 0.78). Patients with no corpus-callosum involvement (CCI) (vs with CCI) had more marked GTV volume reduction: Vrel 0.82 vs 1.02 at F10 (P=0.05), and Vrel 0.77 vs 0.88 at F20 (P=0.03). Patients with gross total resection (GTR) had more marked GTV volume reduction (vs subtotal resection (STR) vs biopsy (Bx)): Vrel 0.78, 0.85 and 1.07 at F10 (P=0.001), and Vrel 0.69, 0.80, 1.04 at F20 (P=0.001). The median dM were 4.7mm at both F10 and F20. Patients with CCI had larger dM (vs no CCI): 41% vs 12% had dM&amp;gt;10mm at F10 (P=0.01), and 45% vs 9% had dM&amp;gt;10mm at F20 (P&amp;lt;0.001). At F20, 0%, 25% and 19% of patients with GTR, STR and Bx had dM&amp;gt;10mm (P=0.002). Age, sex, MGMT methylation and IDH-mutation status were not associated with tumor dynamics during treatment. CONCLUSION: CCI and extent of surgery predict for tumor dynamics, which may allow us to better select patients who benefit the most from re-planning/ treatment adaptation during radiotherapy.

HOX Antisense Intergenic RNA Inhibitor Loaded on Magnetic Nanoparticles Inhibits Gastric Cancer Progression Through miR-20a-5p

Magnetic nanoparticles are easy to operate and highly efficient and acts as ideal molecular carriers. At the same time, research has found that inhibiting Homeotic Complex Gene transcript antisense RNA (HOTAIR) can inhibit tumor development. Therefore, this study intends to use magnetic nanoparticles to carry HOTAIR inhibitors to explore its role in gastric cancer progression. Magnetic nanoparticles loaded with HOTAIR inhibitor and mouse model of gastric cancer were constructed. Serum HOTAIR level was detected by ELISA, tumor volume and mass changes in mice were observed, and histopathology was assessed by HE staining. The effect of HOTAIR inhibitor loaded magnetic nanoparticles on miR-20a-5p expression and downstream apoptosis genes/proteins was also evaluated. (1) si-HOTAIR is the silent gene of HOTAIR. The obtained si-HOTAIR magnetic nanoparticles were used in various research groups. It was found that HOTAIR was highly expressed in gastric cancer mice. (2) HOTAIR inhibitor intervention reduced tumor mass and volume, and changed gastric histopathological conditions. (3) HOTAIR inhibitors inhibited the activities of gastric cancer MFC cells, promoted apoptosis, and downregulated miR-20a-5p. (4) Compared with other groups, miR-20a-5p in the cells of si-HOTAIR-loaded magnetic nanoparticles group was reduced and cancer progression was significantly inhibited. Magnetic nanoparticles loaded with HOTAIR inhibitors have a strong anti-tumor effect and this effect is achieved by inhibiting miR-20a-5p. At the same time, this process is related to Bcl-2.

Mechanism of polyethylene glycol and polyethylenimine combined with superparamagnetic nanoparticles in treating the brain glioma

This study assessed the mechanism of polyethylene glycol (PEG) and polyethylenimine (PEI) combined with superparamagnetic nanoparticles in treating brain glioma. Forty-eight male Stromal Derived Factor (SDF) grade Sprague Dawley (SD) rats were divided into control set, doxorubicin (DOX) set, set of DOX and Spions Medicine (SPIONs) and set of DOX, SPIONs and magnet followed by analysis of change of tumor volume, MRI imaging, HE staining, trypan-blue staining, and TUNEL staining. The dispersion of DOX-SPIONs nanoparticles was uniform. The form was circular. The average diameter was 15.4 nm. The saturation magnetization value of SPIONs and DOX-SPIONs were 45.8 emu · g and 23.6 emu · g. There was a good superparamagnetism in prepared magnetic nanoparticles. The tumor volume in set of DOX, SPIONs and magnet was the smallest. It was smaller in set of DOX and SPIONs than in DOX set and control set. There were excessive cells in tumor tissue in control set, DOX set and set of DOX and SPIONs. There were notable multifarious nucleuses. The quantity of tumor cells in set of DOX, SPIONs and magnet could be reduced. There were notable apoptosis and necrosis. The growth of brain glioma could be restrained by PEG and PEI combined with superparamagnetic nanoparticles through targeting DOX. The apoptosis could be prompted. The superparamagnetic nanoparticles could be prompted to be gathered in tumor site. The therapeutic effect of DOX could be improved through DOX carried with PEG and PEI combined with superparamagnetic nanoparticles. There are promising therapeutic values in the treatment with superparamagnetic nanoparticles through targeting DOX on brain glioma.

Tumor volume changes during stereotactic ablative radiotherapy for adrenal gland metastases under MRI guidance

PurposeGross tumor volume (GTV) changes during stereotactic ablative radiotherapy (SABR) for adrenal tumors are not well characterized. We studied treatment-induced GTV changes during, and after, 5-fraction MR-guided SABR on a 0.35 T unit. Methods and MaterialsDetails of patients treated for adrenal metastases using 5-fraction adaptive MR-SABR were accessed. GTV changes between simulation and first fraction (ΔSF1) and all fractions were recorded. Wilcoxon paired tests were used for intrapatient comparisons. Logistic and linear regression models were used for features associated with dichotomous and continuous variables, respectively. ResultsOnce-daily fractions of 8 Gy or 10 Gy were delivered to 70 adrenal metastases. Median simulation-F1 interval was 13 days; F1-F5 interval was 13 days. Median baseline GTVs at simulation and F1 were 26.6 and 27.2 cc, respectively (p < 0.001). Mean ΔSF1 was + 9.1% (2.9 cc) relative to simulation; 47% of GTVs decreased in volume at F5 versus F1. GTV variations of ≥ 20% occurred in 59% treatments at some point between simulation to end SABR, and these did not correlate with baseline tumor characteristics. At a median follow-up of 20.3 months, a radiological complete response (CR) was seen in 23% of 64 evaluable patients. CR was associated with baseline GTV (p = 0.03) and ΔF1F5 (p = 0.03). Local relapses were seen in 6%. ConclusionFrequent changes in adrenal GTVs during 5-fraction SABR delivery support the use of on-couch adaptive replanning. The likelihood of a radiological CR correlates with the baseline GTV and intra-treatment GTV decline.

Ultrasound stiffness and perfusion markers correlate with tumor volume responses to immunotherapy

Immunotherapy has revolutionized the treatment of dozens of cancers and became a standard of care for some tumor types. However, the majority of patients do not benefit from current immunotherapeutics and many develop severe toxicities. Therefore, the identification of biomarkers to classify patients as likely responders or non-responders to immunotherapy is a timely task. Here, we test ultrasound imaging markers of tumor stiffness and perfusion. Ultrasound imaging is non-invasive and clinically available and can be used both for stiffness and perfusion evaluation. In this study, we employed syngeneic orthotopic models of two breast cancers, a fibrosarcoma and a melanoma, to demonstrate that ultrasound-derived measures of tumor stiffness and perfusion (i.e., blood volume) correlate with the efficacy of immune checkpoint inhibition (ICI) in terms of changes in primary tumor volume. To modulate tumor stiffness and perfusion and thus, get a range of therapeutic outcomes, we employed the mechanotherapeutic tranilast. Mechanotherapeutics combined with ICI are advancing through clinical trials, but biomarkers of response have not been tested until now. We found the existence of linear correlations between tumor stiffness and perfusion imaging biomarkers as well as strong linear correlations between the stiffness and perfusion markers with ICI efficacy on primary tumor growth rates. Our findings set the basis for ultrasound biomarkers predictive of ICI therapy in combination with mechanotherapeutics. Statement of significanceHypothesis: Monitoring Tumor Microenvironment (TME) mechanical abnormalities can predict the efficacy of immune checkpoint inhibition and provide biomarkers predictive of response. Tumor stiffening and solid stress elevation are hallmarks of tumor patho-physiology in desmoplastic tumors. They induce hypo-perfusion and hypoxia by compressing tumor vessels, posing major barriers to immunotherapy. Mechanotherapeutics is a new class of drugs that target the TME to reduce stiffness and improve perfusion and oxygenation. In this study, we show that measures of stiffness and perfusion derived from ultrasound shear wave elastography and contrast enhanced ultrasound can provide biomarkers of tumor response.

Prediction of pathological response grading for esophageal squamous carcinoma after neoadjuvant chemoradiotherapy based on MRI imaging using PDX.

To confirm the efficacy of magnetic resonance-diffusion weighted imaging (MR-DWI) in esophageal squamous cell carcinoma (ESCC) early pathological response prediction and assessment to neoadjuvant chemoradiotherapy (nCRT) using patient-derived xenografts (PDXs). PDX-bearing mice were randomly divided into two groups: the experimental group receiving cisplatin combined with radiotherapy, whereas the control group receiving normal saline. MRI scans were performed in treatment groups in the before, middle, and end of treatment. The correlations between tumor volumes, ADC values and tumor pathological response at different time nodes were explored. Then, expression of proliferation marker and apoptotic marker were detected using immunohistochemistry, and apoptosis rate was detected by TUNEL assay to further verify the results observed in the PDX models. The ADC values of the experimental group were significantly higher than the control group in the both middle and end stage of treatment (all P< 0.001), however, significant difference was only observed in tumor volume at the end stage of treatment (P< 0.001). Furthermore, the △ADCmid-pre in our study may able to identify tumors with or without pCR to nCRT at an early stage, due to these changes were prior to the changes of tumor volume after treatment. Finally, TUNEL results also showed that the apoptosis rate of the experiment groups increased the most in the middle stage of treatment, especially the groups with pCR, but the highest apoptosis rate occurred in the end of the treatment. Further, the two PDX models with pCR exhibited the highest levels of apoptotic marker (Bax), and lowest levels of proliferation marker (PCNA and Ki-67) in the both middle and end stage of the treatment. ADC values could be used to determine the tumor's response to nCRT, especially in the middle stages of treatment and before the tumor tissue morphology changes, and further, the ADC values were consistent with the potential biomarkers reflecting histopathological changes. Therefore, we suggest that radiation oncologists could refer to the ADC values in the middle stages of treatment when predicting the tumor histopathological response to n CRT in patients with ESCC.

TRLS-03. IBRUTINIB DISRUPTS BLOOD-TUMOR BARRIER INTEGRITY TO ENHANCE CNS DRUG DELIVERY AND RODENT GLIOMA MODEL SURVIVAL

Abstract BACKGROUND In the setting of malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-brain-barrier (BBB). Identifying agents that transiently increase BBB permeability would advance glioma treatment. Ibrutinib, an FDA approved lymphoma treatment, has previously impaired aortic endothelial adhesion and in combination with cytotoxic therapy, increased rodent glioma model survival. In this study, we propose ibrutinib inhibits brain endothelial cell junctional expression to disrupt BBB integrity and increase chemotherapy delivery to malignant glioma cells. METHODS Using rat glioma cells, S635, we evaluated treatment effects with doxil (3mg/kg), ibrutinib (25mg/kg) and combination therapy. We measured effects with serial brain MRIs, doxil plasma and brain regional concentrations, along with 3kD dextran permeability. To evaluate the effects of ibrutinib on in vitro brain endothelial cells, we measured changes in cell-cell electrical impedance and rhodamine efflux, as a surrogate of Abcb1 transporter function, over time (0 to 8h) and at varied drug concentrations (1, 5, and 10µM ibrutinib). RESULTS Ibrutinib in combination with doxil, prolonged median survival in rodent glioma models (18 vs. 24days, p&amp;lt;0.05). MRI findings demonstrated a -14 or -53% vs -75% tumor volume change with doxil or ibrutinib alone vs. combination therapy, respectively (p&amp;lt;0.05). Comparing combination therapy vs. doxil alone, ibrutinib increased CNS concentrations of doxil in the tumor injected brain regions with statistical significance (56ng/mL vs. 74.6ng/mL, p&amp;lt;0.05). In in vitro studies, ibrutinib decreased brain endothelial cell-cell impedance maximally at 2 hours, in a dose dependently without affecting cell viability. Additionally, we observed ibrutinib dose dependently inhibit Abcb1 activity in both endothelial and glioma cells. CONCLUSION Our results suggest ibrutinib increases brain endothelial permeability by causing junctional disruption and inhibition of Abcb1, resulting in increased CNS drug entry and prolonged survival in glioma rat models.

XRT-03. EFFICACY OF RE-IRRADIATION FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS

Abstract OBJECTIVE To analyze the efficacy and prognosticators of pediatric diffuse intrinsic pontine glioma (DPC) treated with re-irradiation. METHODS The clinical data and prognostic information of DIPG children younger than 18 years old who received re-irradiation in the Department of Oncology of Guangdong Sanjiu Brain Hospital from May 1, 2021, to November 1, 2022, were collected. The overall survival (OS) was calculated, and univariate analysis was performed to analyze the effect of tumor volume change and rate of change on survival. RESULTS Fifteen patients met the inclusion criteria. The median interval between the first and second radiotherapy was 8.8 months. The median survival after re-irradiation was 3.9 months, and the median overall survival was 16.9 months. Severe complications such as fatal radiation brain necrosis was observed after re-irradiation. CONCLUSIONS Re-irradiation is still the primary treatment for pediatric diffuse intrinsic pontine glioma, prolonging their survival.

Registration-based biomarkers for neoadjuvant treatment response of pancreatic cancer via longitudinal image registration.

Pancreatic ductal adenocarcinoma (PDAC) frequently presents as hypo- or iso-dense masses with poor contrast delineation from surrounding parenchyma, which decreases reproducibility of manual dimensional measurements obtained during conventional radiographic assessment of treatment response. Longitudinal registration between pre- and post-treatment images may produce imaging biomarkers that more reliably quantify treatment response across serial imaging. Thirty patients who prospectively underwent a neoadjuvant chemotherapy regimen as part of a clinical trial were retrospectively analyzed in this study. Two image registration methods were applied to quantitatively assess longitudinal changes in tumor volume and tumor burden across the neoadjuvant treatment interval. Longitudinal registration errors of the pancreas were characterized, and registration-based treatment response measures were correlated to overall survival (OS) and recurrence-free survival (RFS) outcomes over 5-year follow-up. Corresponding biomarker assessments via manual tumor segmentation, the standardized response evaluation criteria in solid tumors (RECIST), and pathological examination of post-resection tissue samples were analyzed as clinical comparators. Average target registration errors were for a biomechanical image registration algorithm and for a diffeomorphic intensity-based algorithm, corresponding to 1-2 times voxel resolution. Cox proportional hazards analysis showed that registration-derived changes in tumor burden were significant predictors of OS and RFS, while none of the alternative comparators, including manual tumor segmentation, RECIST, or pathological variables were associated with consequential hazard ratios. Additional ROC analysis at 1-, 2-, 3-, and 5-year follow-up revealed that registration-derived changes in tumor burden between pre- and post-treatment imaging were better long-term predictors for OS and RFS than the clinical comparators. Volumetric changes measured by longitudinal deformable image registration may yield imaging biomarkers to discriminate neoadjuvant treatment response in ill-defined tumors characteristic of PDAC. Registration-based biomarkers may help to overcome visual limits of radiographic evaluation to improve clinical outcome prediction and inform treatment selection.

Tumor volume and T2 hyperintensity changes from DeFi: A phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors.

11514 Background: MRI tumor volume or T2 signal intensity changes may represent novel imaging techniques that could have a prognostic or predictive value for assessing response in desmoid tumors (DT). For example, hyperintense areas on T2-weighted images have been associated with active fibroblastic proliferation and ≥90% hyperintensity is associated with DT disease progression, whereas iso- or hypo-intense areas are associated with inactive sites of disease. In DeFi (NCT03785964), the novel gamma secretase inhibitor nirogacestat (n=70 patients) significantly improved the primary endpoint of PFS compared with placebo (n=72 patients; hazard ratio, 0.29 [95% CI, 0.15, 0.55; P&lt;0.001]) and significantly improved the secondary endpoint of ORR per blinded, independent central review (41% vs 8%; P&lt;0.001). Complete responses were achieved in 7% with nirogacestat and 0% with placebo. Here, we present an exploratory analysis of MRI tumor volume and T2 signal intensity changes in DeFi. Methods: Eligible adults had histologically confirmed DT that had progressed ≥20% per RECIST v1.1 within 12 months of screening. Patients were randomized 1:1 to receive nirogacestat 150 mg or placebo twice daily taken continuously in 28-day cycles. Volumetric MRI and T2 hyperintensity of the largest target tumor were evaluated at screening and every 6 cycles during the double-blind phase. MRI T2 signal intensity is represented as the ratio of hyperintensity in total tumor volume to muscle background. A blinded, independent, central radiologist reviewed all MRI scans. Results: Nirogacestat treatment led to more substantial reductions versus placebo in tumor volume and T2 hyperintensity ratio (Table). At baseline, similar proportions of patients in each arm had a T2 hyperintensity ratio ≥90% (95% vs 97%). This ratio changed from ≥90% at baseline to &lt;90% at any time after baseline in 34% of patients in the nirogacestat arm and 15% of those on placebo. Conclusions: In DeFi, nirogacestat demonstrated substantial reduction of tumor volume and T2 hyperintensity of the largest target tumors by MRI compared with placebo in adults with DT. These results are consistent with the significant improvement in ORR achieved with nirogacestat. These data suggest that volumetric MRI and T2 hyperintensity might provide additional information in the evaluation of treatment response in DT. The prognostic or predictive value of these imaging techniques in DT should be further studied. Clinical trial information: NCT03785964 . [Table: see text]

Anti-tumor Efficacy and Safety of the BAG3/HSP70 Inhibitor YM-1 ina Triple Negative Breast Cancer Model

Patients who treat with TNBC are usually with intense chemotherapy. Recently, BAG3 has been suggested as apotential therapeutic target for cancer. However, inhibiting BAG3 for therapy may result in unintended damage tocardiomyocytes. Thus, this research proposal will test whether or not the inhibition of BAG3 will significantly affectthe heart while still having potent anti-tumor efficacy. Human TNBC cell line BT-549 cells will be inoculated into CB17/SCID mice. When the tumor grows to 100 mm3, mice will be intraperitoneally injected with different doses of YM1, an inhibitor of BAG3/HSP70. The clinically used TNBC chemotherapy drug doxorubicin will be used as the positivecontrol. The tumor growth, expressed as the change in tumor volume and tumor growth inhibition percentage (TGI),will be measured. Troponin I level in the serum, ECG measurement, and Hematoxylin and Eosin staining will be used toassess heart damage. The results of our study will indicate whether the animals will tolerate the BAG3 inhibitor, YM-1,at its effective doses and whether inhibition of BAG3 may be a better option, particularly regarding unwanted effects oncardiomyopathy, compared to standard of care in TNBC. Future investigations are warranted.

Comment on "Surgical Outcomes in Patients With Low-Risk Papillary Thyroid Microcarcinoma from MAeSTro Study: Immediate Operation Versus Delayed Operation Following Active Surveillance A Multicenter Prospective Cohort Study".

The overdiagnosis and overtreatment of patients with low-risk papillary thyroid microcarcinoma (PTMC) led to the initiation of active surveillance studies in many institutions. We read the recent study by Hwang et al1 in which the authors conducted a multicenter prospective cohort study and evaluated the results of surgical and clinical outcomes in patients with low-risk PTMC who chose delayed operation following active surveillance. This study is clinically relevant and novel, and we would like to raise several concerns. Although the authors demonstrated that the extent of thyroidectomy and postoperative complications did not differ between delayed operation (DOP) and immediate operation (IOP), we would like to clarify that surgical decision-making for low-risk PTMC is a complex process that must consider multiple aspects.2 In this multicenter cohort study, multi-surgeon chose the surgical extent according to their experience, skill level, own and patient preference. In this context, there is a direct relationship between surgeon experience and postoperative complications. The postoperative complication rates are low in experienced hands. This study did not standardize this factor. Therefore, the relationship between unfavorable events and patients who underwent DOP was not causal but just an association affected by confounders. Another area of considerable variation surrounds patients’ preferences. Decision-making presenting the hemithyroidectomy or total thyroidectomy (TT) should inform the patient of their downstream risk, as it could significantly impact choices. Socioeconomic differences in medical centers worldwide can also significantly affect the surgical extent between different countries, as demonstrated in Japan where hemithyroidectomy was adopted as the standard therapy over TT earlier than in other countries.3 In addition, there was a significant difference in the proportion of multifocality between patients who underwent DOP and patients who underwent IOP. Multifocality as an indicator of tumor aggressiveness manifests a higher propensity of lymphatic invasion.4 Since multifocal tumors comprised 40.9% of cases in the DOP group, will such a high proportion affect the unfavorable pathological features? Additionally, the results indicated that 109 patients were known to be multifocal papillary thyroid cancer and 109 patients underwent TT in the IOP group. There was no detailed information on how many multifocal papillary thyroid cancer patients have been identified before the operation. Multifocality is an important factor for surgeons to consider the surgical extent,5 which can further affect the incidence of postoperative complications. We believe the results should be interpreted cautiously. Last but not least, disease progression was initially defined in this study to include a size increase of ≥3 mm in at least 1 dimension, or ≥2 mm in at least 2 dimensions. But with recent advances, the researchers also found significant differences in the rate of the extent of thyroidectomy when tumor volume changes were taken into account. We want to see the data of this part of patients and the difference with the IOP group and wonder if the research team would adjust the timing of surgery for those patients in the DOP group. Therefore, we have several questions that we would appreciate having answered.

Evaluation of efficacy of tumor-specific nanoliposomal radiosensitizer in radiotherapy

Radiotherapy is one of the cancer treatment options in which ionizing radiation is used. While the ionizing radiation used here damages the tumor cells, it also damages the surrounding healthy cells and tissues. One of the approaches used to reduce the undesirable side effects and increase the therapeutic efficacy of radiotherapy is the use of radiosensitizers. Up to now, different radiosensitizers have been investigated for this purpose and recently, nanotechnology-based radiosensitizer research has attracted much attention. In this study, the therapeutic efficacy of tumor-targeted, nano-sized liposomal radiosensitizers containing quantum dots-photosensitizer conjugate was evaluated in vivo. It was aimed to destroy more tumor cells by using same the radiation doses routinely used in cancer treatment in radiation oncology clinics or to destroy about the same amount of tumor cells by using lower radiation doses than the routinely used clinical dose. For this purpose, nano-sized, PEG-coated, and folic acid-modified tumor-specific liposomes loaded with quantum dots (QD = CdSe/ZnS) - photosensitizer (Ce6 = Clorine-e6) conjugate was prepared and their therapeutic efficacy was evaluated in 4T1 murine breast cancer cell tumor-bearing mice. Following the single dose of 10Gy 6 MV X-ray irradiation after administration of liposomal radiosensitizer, changes in animals' weights and tumor volumes were measured and animal survival was monitored to evaluate the efficacy of the treatment. Histopathological studies were also performed to examine possible damage to the tumor and normal tissues. In control groups, only X-ray irradiation was applied or no treatment was applied to mice. The results showed that the liposomal radiosensitizer plus radiotherapy killed more cancer cells than radiotherapy alone. While tumor volumes increased in the control group, approximately a 39% reduction in tumor volumes was observed in mice treated with x-ray irradiation following administration of the liposomal radiosensitizer. The obtained results showed that nano-sized liposomal radiosensitizers could be a promising radiosensitizer to achieve better treatment efficacy in radiotherapy by applying fewer radiation doses compared to clinically used radiation doses.