Change In Tumor Size Research Articles

Magnetic resonance imaging techniques for monitoring glioma response to chemoradiotherapy.

Treatment response assessment for gliomas currently uses changes in tumour size as measured with T1- and T2-weighted MRI. However, changes in tumour size may occur many weeks after therapy completion and are confounded by radiation treatment effects. Advanced MRI techniques sensitive to tumour physiology may provide complementary information to evaluate tumour response at early timepoints during therapy. The objective of this review is to provide a summary of the history and current knowledge regarding advanced MRI techniques for early treatment response evaluation in glioma. The literature survey included perfusion MRI, diffusion-weighted imaging, quantitative magnetization transfer imaging, and chemical exchange transfer MRI. Select articles spanning the history of each technique as applied to treatment response evaluation in glioma were chosen. This report is a narrative review, not formally systematic. Chemical exchange saturation transfer imaging potentially offers the earliest method to detect tumour response due to changes in metabolism. Diffusion-weighted imaging is sensitive to changes in tumour cellularity later during radiotherapy and is prognostic for progression-free and overall survival. Substantial evidence suggests that perfusion MRI can differentiate between tumour recurrence and treatment effect, but consensus regarding acquisition, processing, and interpretation is still lacking. Magnetization transfer imaging shows promise for detecting subtle white matter damage which could indicate tumour invasion, but more research in this area is needed. Advanced MRI techniques show potential for early treatment response assessment, but each technique alone lacks specificity. Multiparametric imaging may be necessary to aid biological interpretation and enable treatment guidance.

Understanding how CD19 expression levels impact the response to loncastuximab tesirine: a plain language summary.

In this article, we summarize results from a clinical study called LOTIS-2, in which researchers looked at patients with a type of blood cancer called diffuse large B-cell lymphoma, or DLBCL for short. Patients received the drug loncastuximab tesirine, or Lonca for short, which targets a marker on the surface of tumor cells called CD19.Patient information from the LOTIS-2 study, other studies of Lonca, and information from scientific publications was used to develop a quantitative systems pharmacology (QSP) model, which can predict how Lonca works in the body. The goal was to use the QSP model to see if CD19 levels can predict tumor size changes after Lonca treatment and if Lonca can still work to treat DLBCL when CD19 levels are very low. The prior LOTIS-1 and LOTIS-2 trials demonstrated an acceptable safety profile for Lonca, and therefore the current study did not evaluate safety data. Researchers used immunohistochemistry, a common technique to evaluate CD19 expression. They found that there was no association between patients who responded to Lonca treatment and levels of CD19 on their tumor cells. Some patients with low or even undetectable levels of CD19 on their tumor cells had observable decreases in tumor size after Lonca treatment. While Lonca uses the CD19 target to find and destroy cancer cells, Lonca does not require a large amount of CD19 to kill tumor cells. These results mean that Lonca may be an effective treatment for patients with DLBCL, even if CD19 expression in tumors is undetectable by immunohistochemistry.

Tissue and Imaging Biomarkers of Response to Neoadjuvant Nivolumab or Nivolumab plus Ipilimumab in Patients with Resectable Hepatocellular Carcinoma

Introduction: Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC. Methods: Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without were summarized using descriptive statistics and compared using the Wilcoxon rank-sum test. Results: Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size posttreatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a nonsignificant decrease in serum AFP (−24.20% vs. −14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs. −0.04%; p = 0.026), granzyme B (15.56% vs. −2.24%; p = 0.011), and PD-1 (20.17% vs. 0.40%; p = 0.048) but not PD-L1 (7.69% vs. 0.57%; p = 0.26). For imaging biomarkers, tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus nonresponders. Conclusion: Changes in tumor size, immune cell infiltration, and immune cell activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC.

Values of apparent diffusion coefficient in pancreatic cancer patients receiving neoadjuvant therapy

BackgroundTo investigate the values of apparent diffusion coefficient (ADC) for the treatment response evaluation in pancreatic cancer (PC) patients receiving neoadjuvant therapy (NAT).MethodsThis study included 103 NAT patients with histologically proven PC. ADC maps were generated using monoexponential diffusion-weighted imaging (b values: 50, 800 s/mm2). Tumors’ minimum, maximum, and mean ADCs were measured and compared pre- and post-NAT. Variations in ADC values measured between pre- and post-NAT completion for NAT methods (chemotherapy, chemoradiotherapy), tumor locations (head/neck, body/tail), tumor regression grade (TRG) levels (0–2, 3), N stages (N0, N1/N2) and tumor resection margin status (R0, R1), were further analyzed.ResultsThe minimum, maximum, and mean ADC values all increased dramatically after NAT, rising from 23.4 to 25.4% (all p < 0.001): mean (average: 1.626 × 10− 3 mm2/s vs. 1.315 × 10− 3 mm2/s), minimum (median: 1.274 × 10− 3 mm2/s vs. 1.034 × 10− 3 mm2/s), and maximum (average: 1.981 × 10− 3 mm2/s vs. 1.580 × 10− 3 mm2/s). The ADCs between the subgroups of all the criteria under investigation did not differ significantly for the minimum, maximum, or mean values pre- or post-NAT (P = 0.08 to 1.00). In the patients with borderline resectable PC (n = 47), the rate of tumor size changes after NAT was correlated with the pre-NAT mean ADC values (Spearman’s coefficient: 0.288, P = 0.049).ConclusionsThe ADC values of PC increased significantly following NAT; however, the percentage increases failed to provide any predictive value for the resection margin status or TRG levels.

An Unsupervised Approach for Treatment Effectiveness Monitoring Using Curvature Learning

Contrast-enhanced ultrasound could assess whether cancer chemotherapeutic agents work in days, rather than waiting 2–3 months, as is typical using the Response Evaluation Criteria in Solid Tumors (RECIST), therefore avoiding toxic side effects and expensive, ineffective therapy. A total of 40 mice were implanted with human colon cancer cells: treatment-sensitive mice in control (n = 10, receiving saline) and treated (n = 10, receiving bevacizumab) groups and treatment-resistant mice in control (n = 10) and treated (n = 10) groups. Each mouse was imaged using 3D dynamic contrast-enhanced ultrasound with Definity microbubbles. Curvature learning, an unsupervised learning approach, quantized pixels into three classes—blue, yellow, and red—representing normal, intermediate, and high cancer probability, both at baseline and after treatment. Next, a curvature learning score was calculated for each mouse using statistical measures representing variations in these three color classes across each frame from cine ultrasound images obtained during contrast administration on a given day (intra-day variability) and between pre- and post-treatment days (inter-day variability). A Wilcoxon rank-sum test compared score distributions between treated, treatment-sensitive mice and all others. There was a statistically significant difference in tumor score between the treated, treatment-sensitive group (n = 10) and all others (n = 30) (p = 0.0051). Curvature learning successfully identified treatment response, detecting changes in tumor perfusion before changes in tumor size. A similar technique could be developed for humans.

A theoretical study on evaluating brain tumor changes in tumor treating fields therapy by impedance detection.

TTFields is a novel FDA-approved technology utilized for treating glioblastoma multiforme (GBM) within the brain. Presently, the effectiveness of therapy is evaluated through MRI imaging at random two-month intervals. Electrical impedance is an important and effective parameter for reflecting changes in tissue properties. In TTFields treatment for brain tumors, electrodes attached to the scalp deliver electric field energy to the tumor region. We hypothesize that these electrodes can also serve as sensors to detect impedance changes caused by tumor alterations in real time, thus continuously assessing the effectiveness of the treatment. In this work, we propose and scrutinize this hypothesis by conducting an in silico study to confirm the potential feasibility of the proposed concept. Our results indicate that the impedance amplitude change measured between opposing TTFields electrode arrays utilizing voltage and frequency of 50 V and 200 kHz (typical TTFields treatment parameters), has enough resolution (> 1mm) and Signal-to-Noise Ratio (> 40 dB) to evaluate tumor size change in the head. The impedance detection technique may be a significant augmentation to TTFields cancer treatment, enabling the continuous evaluation of safety and efficacy throughout the procedure.

Efficacy and safety of laser ablation and microwave ablation to treat papillary thyroid microcarcinoma: A retrospective study

ObjectiveTo retrospectively analyze the efficacy and safety of laser ablation (LA) and microwave ablation (MWA) in the treatment of papillary thyroid microcarcinoma (PTMC). MethodsThis was a retrospective study of 103 patients (109 nodules) who underwent thermal ablation for PTMC between October 2019 and March 2023; 61 underwent LA and 48 underwent MWA. The mean patients' age was 43.50 ± 12.42 years. After ablation, changes in tumor size at different time points, local recurrence, new lesions, lymph node metastasis, and complications were evaluated and recorded. The feasibility, success rate, and safety of LA and MWA were analyzed. ResultsComplete absence of enhancement on contrast-enhanced ultrasonography was observed in all target tumors after ablation. At the last follow-up, the mean volume of the PTMC nodules decreased from 0.09 ± 0.09 to 0.03 ± 0.03 ml (LA group) and from 0.11 ± 0.10 to 0.06 ± 0.08 ml (MWA group) (both, P < 0.05). There was no significant difference in volume change between the groups (P (groups): 0.520; P (groups over time): 0.423), indicating similar efficacy between the groups. There was also no significant difference in the volume reduction rate between the groups during follow-up, except for at 3 months (P = 0.023). The complication rates did not differ between the LA group (8.2 %) and MWA group (6.3 %) (P > 0.05). ConclusionDuring the short-term follow-up, ultrasound-guided LA and MWA were effective and safe for PTMC, and there were no significant differences in treatment outcomes between the methods.

ESR Essentials: response assessment criteria in oncologic imaging-practice recommendations by the European Society of Oncologic Imaging.

Assessing the response to oncological treatments is paramount for determining the prognosis and defining the best treatment for each patient. Several biomarkers, including imaging, can be used, but standardization is fundamental for consistency and reliability. Tumor response evaluation criteria have been defined by international groups for application in pharmaceutical clinical trials evaluating new drugs or therapeutic strategies. RECIST 1.1 criteria are exclusively based on unidimensional lesion measurements; changes in tumor size are used as surrogate imaging biomarkers to correlate with patient outcomes. However, increased tumor size does not always reflect tumor progression. The introduction of immunotherapy has led to the development of new criteria (iRECIST, Level of Evidence (LoE) Ib) that consider the possibility that an increase in disease burden is secondary to the immune response instead of progression, with the new concept of Unconfirmed Progressive Disease (a first progression event which must be confirmed on follow-up). Specific criteria were devised for HCC (mRECIST, LoE IV), which measure only enhancing HCC portions to account for changes after local therapy. For GIST treated with imatinib, criteria were developed to account for the possible increase in size reflecting a response rather than a progression by assessing both tumor size and density on CT (Choi, LoE II). This article provides concise and relevant practice recommendations aimed at general radiologists to help choose and apply the most appropriate criteria for assessing response to treatment in different oncologic scenarios. Though these criteria were developed for clinical trials, they may be applied in clinical practice as a guide for day-to-day interpretation. KEY POINTS: Response evaluation criteria, designed for use in clinical trials, might serve as a surrogate biomarker for overall survival. RECIST 1.1 defines measurable and non-measurable disease among which target lesions and non-target lesions are selected at baseline as reference for follow-ups. Some therapies and/or cancers require the use of different criteria, such as iRECIST, mRECIST, and Choi criteria.

A novel Phase II single-arm hybrid design to minimize trial duration and enhance subsequent Phase III trial success rate

Many Phase III trials fail for lack of significant efficacy for the testing agents although their success has been demonstrated in preceding Phase II trials. One of the major reasons for this discordance is the use of different endpoints in Phase II and III trials, respectively. In oncology clinical trials, tumor response (surrogate endpoint) can be determined quickly whereas survival estimation (direct endpoint) requires a long period of follow-up. To better bridge the gap between two endpoints, we propose a novel two-stage single-arm hybrid design for Phase II trials whereby the percent of tumor size change is used as an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where survival is estimated to confirm the efficacy of agents. This design can improve trial efficiency and reduce cost by early stopping the evaluation of an ineffective agent based on the low percent of tumor size change. The second survival endpoint screening will substantially increase the success rate of the follow-up Phase III trial by using the same endpoint. Simulation studies demonstrated that our novel design has improved in terms of trial efficiency, trial length, and the success rate of following Phase III trials.

Evaluation of the Prognostic Role of D-dimer in Egyptian Hepatocellular Carcinoma Patients Undergoing Locoregional Treatment

Abstract Background The blood coagulation function is often abnormal in HCC patients due to hypercoagulatory state, hyperfibrinolytic state, and increased plasma D-dimer. HCC patients treated with locoregional treatment may show changes of D-dimer levels. Several studies explored the validity of D-dimer levels during locoregional treatment in HCC but definitive data are still lacking. Aim of the Work Determination of the efficacy of D-dimer profile as a prognostic marker regarding tumor features, and post interventional response in HCC subjects undergoing TACE or RFA. Patients and Methods The clinical data of 50HCC patients who underwent TACE or RFA in our hospital from October 2021 to June 2022 were collected, including the CBC, CRP Alfa-fetoproteins and plasma d-dimer level 1 week before TACE or RFA(D0), D-dimer level 1 month (D1) and 4 months(D2) after TACE or RFA. Contrast enhanced CT was performed within 1 week before locoregional treatment and was repeated 1month and 4 months after locoregional treatment to assess for treatment efficacy according to the mRECIST criteria based on change in tumor size as measured by CT scan. One month after TACE or RFA, these patients were divided into four groups according to the mRecist criteria: complete response, partial response, stationary disease and progressive disease. D0, D1 and D2 were compared between the 4 groups and the relation between D-dimer level and the efficacy of locoregional treatment was assessed. Results In patients with negative D-dimer before locoregional treatment (D0), there was no significant difference between D0 and D1 (P &amp;gt; 0.05), while patients with elevated pretreatment D-dimer levels (D0), D1 was significantly higher than D0 (P &amp;lt; 0.05) and the D1 is higher than that in patients with negative Do. Progressive rise of D-dimer levels 4months post locoregional treatment (D2) in HCC was associated with tumor progression suggesting aggressive tumor biology and poor outcome(P = 0.02). Conclusion The changes in plasma D-dimer level can be used as a potential prognostic biomarker in predicting the efficacy of locoregional treatment in HCC patients and thus, elevated D-dimer levels pre and post locoregional treatment may serve as predictors of adverse tumor profile and poor outcome.

125I seed implantation for lymph node metastasis from radioactive iodine-refractory differentiated thyroid carcinoma: a study on short-term efficacy and dosimetry.

To investigate the feasibility and evaluate the safety and effectiveness of Computed Tomography (CT) guided125I radioactive particle implantation for treating lymph node metastases in radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). To verify the accuracy of the computerized three-dimensional treatment planning system (TPS) in treating lymph node metastasis using125I particle implantation at the dosimetric level. A retrospective analysis was conducted on 42 patients with RAIR-DTC and lymph node metastases who were admitted to the General Hospital of the Northern Theater Command between December 2016 and January 2019. During this analysis, physicians utilized preoperative CT images to design an intraoperative plan using TPS. The dosimetric parameters of the postoperative plan were then compared to the preoperative plan. Additionally, this study examined the changes in tumor size and tumor-related marker Thyroglobulin (Tg) values in patients at 2, 6, and 12 months after the operation. The number of125I radioactive particles implanted in 42 patients was 226, with an average of 14.5 (range 2.0-30.0) particles implanted per lesion. The local remission rates were 97.62% (41/42), 88.10% (37/42), and 85.71% (36/42) at 2, 6, and 12 months postoperatively, respectively. The volume of the lesions was (4.44 ± 1.57) cm3, (4.20 ± 1.70) cm3, and (4.23 ± 1.77) cm3at 2, 6, and 12 months after treatment, respectively, which significantly decreased from the preoperative baseline level of (6.87 ± 1.67) cm3(t-values: 9.466, 9.923, 7.566, all P<0.05). The Tg levels were 15.95 (5.45, 73.93) μg/L, 8.90 (2.20, 39.21) μg/L, and 6.00 (1.93, 14.18) μg/L at 2, 6, and 12 months after treatment, respectively, which were significantly lower than the preoperative baseline levels of 53.50 (20.94, 222.92) μg/L (Z values: -5.258, -5.009, -4.987, all P < 0.001). Postoperatively, Delivered to 90% of the GTV(D90) was slightly lower than the prescribed dose in 95.23% (40/42) of patients, but the difference was not statistically significant [(12,378.8 ± 3,182.0), (12,497.8 ± 1,686.4) cGy; t=0.251, P>0.05], and postoperative dose parameters delivered to 100% of the gross tumor volume (GTV)(D100) (6,881.5 ± 1,381.8) cGy, the volume percentages of GTV receiving 150% of the prescribed dose(V150) (58.5 ± 18.40)%) were lower than the preoperative plan D100 (8,085.8 ± 2,330.0) cGy, V150 (66.5 ± 17.70)%; t-value=8.913 and 3.032, both P<0.05; the remaining indicators were not significantly different from the preoperative plan (the differences in the number of implanted particles, Planning Target Volume(PTV), the volume percentages of GTV receiving 100% of the prescribed dose(V100), Homogeneity Index(HI)were not statistically significant (t/Z = -0.593, -1.604, 1.493, -0.663, all P>0.05). Referring to the TPS preoperative plan, the125I particle implantation therapy for RAIR-DTC lymph node metastasis can achieve the expected dose distribution, ensuring precise short-term local tumor control efficacy.

IMG-12. CBTN BRAIN TUMOR SEGMENTATION INITIATIVE: UPDATES ON MODEL RELEASE, HGG SEGMENTATION, AND SURVIVAL ANALYSIS

Abstract BACKGROUND Assessment of treatment responses in pediatric brain tumors requires accurate tumor segmentation, particularly important for nonresectable tumors like diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPGs). Evaluating tumor progression in these tumors relies on monitoring tumor size changes in longitudinal MRI exams which is challenged by their infiltrative growth patterns. Our team developed a comprehensive multi-institutional, multi-histology autosegmentation deep learning (DL) model leveraging data from the Children’s Brain Tumor Network (CBTN), involving continuous enhancements and enriched by an expanding dataset including post-surgical/post-treatment studies. METHODS Recently, we trained and validated this DL model (publicly available) on a multi-institutional dataset of 644 PBTs, including 273 pediatric-type diffuse high-grade gliomas (HGGs, including DMG/DIPGs), using pre-operative and post-operative/post-treatment multiparametric MRI scans. We tested the model in 23 longitudinal MRI exams of 8 DMGs from the PNOC003 and PNOC007 clinical trials and applied Cox regression for predicting overall survival (OS) using tumor volume, computed with our autosegmentation model, as a time-varying variable in 18 patients. RESULTS For HGGs in treatment-naïve sessions, our model demonstrated strong performance with median Dice scores of 0.89 for whole tumor and tumor core (encompassing all regions, except for edema), and 0.73 for enhancing tumor segmentation. In longitudinal MRI exams of DMGs from the aforementioned clinical trials, the model achieved median Dice scores of 0.79 for whole tumor, and 0.78 for enhancing tumor and tumor core segmentation. Cox regression showed the significance of longitudinal volumetric measurements (p=0.08) for predicting OS in DMGs. CONCLUSIONS Our approach provides reliable tumor segmentation in HGGs across diverse datasets, crucial for treatment response assessment. Looking ahead, we plan to validate our model on a larger set of longitudinal exams and use volumetric measurements to predict tumor progression. This ongoing effort aims to improve model performance, extend its generalizability, and mitigate potential model decay.

On-treatment (tx) dynamic circulating tumor DNA changes (∆ctDNA) associated with progression-free survival (PFS) and overall survival (OS) of patients (pts) with HR+/HER2− advanced breast cancer (ABC) in MONALEESA-3 (ML-3).

1012 Background: In ML-3, ribociclib (RIB) demonstrated a significant PFS/OS benefit over placebo (PBO) in pts with HR+/HER2− ABC. We report associations of on-tx ∆ctDNA with OS/PFS and tumor size and of ctDNA detectability with radiological progression. Methods: Pts were randomized 2:1 to RIB or PBO + fulvestrant as 1st- or 2nd-line tx. ctDNA levels were measured by NGS at cycle 1 day 1 (C1D1), C4D1, C8D1, and every 8 cycles until end of tx. Analyses included: Wilcoxon rank sum text to compare ∆ctDNA from C1D1 to C4D1; Kaplan-Meier method to visualize relationship of ctDNA with PFS/OS; Cox proportional hazards model for associations of ctDNA and tumor metrics (objective response rate, best % change, % change at 1st tumor evaluation); Fisher’s exact test to compare ctDNA detectability between arms; and ∆ctDNA across time points to assess lead time between ctDNA level-based and radiological progression. Results: Overall, 534/726 (73.6%) pts had paired C1/C4 measurements. Rates of detectable (+) and undetectable (−) ctDNA at C1 and C4 were: C1+/C4+, 33.0%; C1+/C4−, 34.5%; C1−/C4−, 27.5%; and C1−/C4+, 5.1%. RIB vs PBO had a larger % decrease in ctDNA level from C1 to C4 (P=0.003). Pts with better best overall response also had larger ctDNA decreases from C1 to C4 (P&lt;0.0001). On-tx ∆ctDNA from C1 to C4 correlated with PFS/OS (P&lt;0.0001; Table). C1-/C4-, C1+/C4-, and C1+/C4+ strongly correlated with PFS within response categories (PR, SD, NCRNPD). C1-to-C4 % ∆ctDNA was only moderately correlated with tumor size change (best % change, r=0.41; change at 1st evaluation, r=0.32; both P&lt;0.001). Univariate/multivariate analyses showed significant correlations between ctDNA metrics (% change, detection pattern at C4D1) and PFS/OS. ctDNA detection and % change generally remained significantly associated with PFS/OS even after adjusting for change in tumor size. In a longitudinal analysis of pts who cleared ctDNA at C4D1 (C4–), the median lead time between ctDNA progression and radiological progression was 8.2 mo (IQR 4.5–15.6). Conclusions: On-tx ∆ctDNA from C1 to C4 was correlated with PFS/OS even after adjusting for tumor size changes, suggesting that ctDNA and tumor dynamics capture distinct aspects of tumor tx responses. Decreases in ctDNA were greater with RIB vs PBO, mirroring ML-3 efficacy readouts but at a much earlier timepoint. This longitudinal analysis of ctDNA in ML-3 suggests that detecting ∆ctDNA is a sensitive way to monitor progression and may be a potential surrogate for efficacy in HR+/HER2− ABC. Clinical trial information: NCT02422615 . [Table: see text]

Hearing preservation outcomes using direct cranial nerve eight and auditory brainstem response neuromonitoring in the resection of vestibular schwannomas.

Advancements in microsurgical technique and technology continue to improve outcomes in patients with skull base tumor. The primary cranial nerve eight monitoring systems used in hearing preservation surgery for vestibular schwannomas (VSs) are direct cranial nerve eight monitoring (DCNEM) and auditory brainstem response (ABR), although current guidelines are unable to definitively recommend one over the other due to limited literature on the topic. Thus, further research is needed to determine the utility of DCNEM and ABR. The authors performed a retrospective cohort study and created an interactive model that compares hearing preservation outcomes based on tumor size in patients receiving ABR+DCNEM and ABR-only monitoring. Twenty-eight patients received ABR+DCNEM and 72 patients received ABR-only monitoring during VS hearing preservation surgery at a single tertiary academic medical center between January 2008 and November 2022. Inclusion criteria consisted of adult patients with a preoperative American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) hearing classification of A or B. Tumor size was measured as the maximal medial to lateral length, including the internal auditory canal component. Overall hearing preservation (word recognition score [WRS] > 0%) was achieved in 31 patients with ABR-only monitoring (43.1%) and in 18 patients with ABR+DCNEM (64.3%). Serviceable hearing preservation (AAO-HNS class A or B) was attained in 19 patients with ABR-only monitoring (26.4%) and in 11 patients with ABR+DCNEM (39.3%). There was no difference in overall hearing preservation between the two groups (p = 0.13). Change in tumor size was not associated with the odds of serviceable hearing preservation for the ABR-only group (p = 0.89); however, for ABR+DCNEM, there was some indication of an interaction between tumor size and the association of ABR+DCNEM versus ABR-only monitoring, with the odds of serviceable hearing preservation at p = 0.089. Furthermore, with ABR+DCNEM, every 0.5-cm increase in tumor size was associated with a decreased odds of serviceable hearing preservation on multivariable analysis (p = 0.05). For both overall and serviceable hearing preservation, a worse preoperative AAO-HNS classification was associated with a decreased odds of preservation (OR 0.43, 95% CI 0.19-0.97, p = 0.042; OR 0.17, 95% CI 0.053-0.55, p = 0.0031, respectively). The result of this interactive model study proposes that there may be a higher chance of hearing preservation when using ABR+DCNEM rather than ABR alone for smaller tumors, with that relationship reversing as tumor size increases.

PRIMROSE: A modular phase 1/2a study of AZD3470, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP deficient advanced solid tumors.

TPS3179 Background: Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine substrates, regulating multiple cell processes. Deletion of the methylthioadenosine phosphorylase gene MTAP in tumor cells results in accumulation of the metabolite methylthioadenosine (MTA), a partial inhibitor of PRMT5, potentially rendering tumor cells susceptible to further PRMT5 targeting. Clinical activity of first-generation, non-selective PRMT5 inhibitors (PRMT5i) is limited by bone marrow toxicity due to lack of selectivity between normal cells and MTAP-deficient tumor cells. Second-generation PRMT5i, including AZD3470, should selectively target MTAP-deficient tumor cells whilst sparing normal cells. AZD3470 preferentially binds PRMT5 in the presence of MTA in MTAP-deficient tumor cells, inhibiting PRMT5 methylation activity, and is less effective in MTAP-proficient cells. PRIMROSE (NCT06130553) is a first-in-human, Phase 1/2a, open-label, multicenter study of AZD3470 as monotherapy and in combination with anti-cancer agents in patients with MTAP-deficient advanced / metastatic solid tumors. Methods: Eligible patients are aged ≥18 years with MTAP-deficient advanced or refractory solid tumors, ≥1 prior line of treatment in the recurrent / metastatic setting, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0/1, adequate organ and bone marrow function, and no prior treatment with PRMT5i. Module 1 will evaluate AZD3470 monotherapy. Part A (dose escalation) will enroll up to ~54 patients and follow a modified toxicity probability interval-2 (mTPI-2) design with once-daily dosing in 21-day cycles. Treatment will be given until progression or discontinuation criteria are met. Part B (dose optimization and expansion) will expand specific patient populations and / or tumor types, with up to ~30 patients per cohort; dosing will be based on safety and tolerability data from Part A. Further modules for combination treatments may be added based on emerging supportive data. The primary objectives are to assess safety and tolerability, including dose-limiting toxicities, and to determine the recommended phase 2 dose of AZD3470. The secondary objective is evaluation of efficacy, including objective response rate, duration of response, disease control rate, change in tumor size, progression-free survival, and overall survival. An additional secondary objective in Module 1 is to assess pharmacokinetics. The study is planned to take place in ~20 centers across eight countries. The study was opened to enrollment in December 2023. Clinical trial information: NCT06130553 .

Phase I clinical trial of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of advanced breast cancer.

1089 Background: In the treatment of breast cancer, the therapeutic efficacy of CAR-T cell therapy remains unsatisfactory. A possible approach to enhance the efficacy of CAR-T therapy is to combine CAR-T with PD-1 inhibition. This clinical trial was designed to assess the safety and tolerability of PD-1 knockout MUC1-targeted CAR-T cells in advanced breast cancer. Methods: Patients with advanced breast cancer were recruited according to the criteria in NCT05812326. PD-1 gene knockout (KO) MUC1-targeted CAR-T cells were prepared in 2 steps. MUC1-specific CARs were first constructed using 5E5 scFv in patient-derived T cells, and then PD-1 gene KO was achieved in these CAR positive T cells using the CRISPR-Cas9 system. Efficiency and validation were confirmed by sequencing and flow cytometry. MUC1-CAR+/PD-1-T cells were infused at a starting dose of 1-2x106 CAR+ cells/kg and then escalated to 0.9-1.8x107 CAR+ cells/kg. The safety and tolerability of therapeutic cells were evaluated using CTCAE v5.0. Patients’ general condition, levels of lymphocytes, and serum cytokines (IL-1β, IL-2R, IL-6, IL-8, TNF and IL-10) were monitored. Circulating CAR-T cells were checked regularly. Changes in tumor size were examined by MRI/CT scans. The primary endpoint was to assess the safety of this treatment. We also compared the responses in patients who received single and multiple cycles of infusion of therapeutic CAR-T cells. Results: A total of 12 patients (aged 34 to 61) diagnosed with recurrent/metastatic breast cancer were included in this study. All participants received at least 1 cycle of CAR-T cell treatment. Among the 12 patients, 8 received 1 cycle, 3 received 2 cycles, 1 received 3 cycles. Adverse events (AEs) included elevated AST level (7/12, 58.3%), acute fever (6/12), elevated ALT level (5/12), skin rash (5/12), chills (4/12), anemia (4/12), lymphopenia (4/12), diarrhea, vomiting and urinary tract infection (2/12). The most serious AE was lymphopenia (grade 4 lasting 1 day in 1 patient). No grade 3-5 CRS was observed. No patients experienced neurotoxicity. No predefined dose-limiting toxicities (DLT) or serious AEs were observed. Furthermore, there were no AEs resulting in discontinuation of treatment. Of the 12 patients evaluated, 5 had stable disease (SD), indicating that MUC1 CAR-T cell therapy can control the progression of some advanced breast cancers, despite the fact that the efficacy assessment is quite preliminary. The pharmacokinetic study indicated that improved clinical outcomes are associated with a high level of circulating CAR+ copy on day 7. Conclusions: Our data suggest that treatment of patients with advanced breast cancer with PD-1 disrupted MUC1-targeted CAR-T cells is safe and well-tolerated by all patients in this phase 1 clinical trial. No serious CRS or other EA was observed throughout the study. The efficacy of this unique combined therapy is currently being assessed. Clinical trial information: NCT05812326 .

Overexpression of Extracellular Superoxide Dismutase 3 Inhibits Cancer Cell Growth and Migration in Colorectal Cancer.

Incidence of colorectal cancer is rapidly increasing worldwide. Extracellular superoxide dismutase (EcSOD; SOD3) is an antioxidant enzyme. However, SOD3 roles in colorectal cancer progression remain uncertain. Superoxide dismutase 3 expression was evaluated, and we analyzed clinical relevance of SOD3 expression in colorectal cancer. Subsequently, SOD3 roles in colorectal cancer progression were detected by gain of function experiments. Changes in subcutaneous tumor and liver nodule size after SOD3 overexpression were examined in nude mice. The expression of proliferation marker Ki67 was assessed by immunohistochemical staining. Supperoxide dismutase 3 was downregulated in colorectal cancer (P <.01). Downregulation of SOD3 was correlated with unfavorable outcomes (P < .05). Superoxide dismutase 3 upregulation limited the proliferative (P <.05), migrative (P <.01) and invasive actions of colorectal cancer cells (P <.01) by suppressing epithelial-mesenchymal transition. Moreover, SOD3 overexpression reduced Ki67 expression (P <.01) and blocked tumor growth (P <01) and liver metastasis (P <.001) in mouse tumor model. Superoxide dismutase 3 upregulation attenuates tumor growth and liver metastasis in colorectal cancer, suggesting that SOD3 has potential diagnostic and prognostic values regarding colorectal cancer treatment.

Relationship between Tumor Infiltrating Lymphocytes and Neoadjuvant Chemoterapy Responsiveness: A Cross-Sectional Study on Breast Cancer Patients

Breast cancer is still a significant health problem in the world, with chemotherapy as an essential component in its management. Limited research on tumor- infiltrating lymphocytes (TIL) as a biomarker for the effectiveness of breast cancer treatment was conducted and is still contradictory. This study aims to investigate the relationship between TILs and the clinical response to neoadjuvant chemotherapy in breast cancer. The research used a cross-sectional study on eligible breast cancer patients in Wahidin Sudirohusodo Hospital in Makassar. TIL levels were grouped based on the histopathological examination results of breast tissue samples into three categories: low (0% to 10%), medium 15% to 50% and high (55% to 100%). Responsiveness was assessed based on changes in tumor size after neoadjuvant chemotherapy. The Chi-Square test is the primary analysis in this study. Results of 40 participants, the sample had a median age of 40 (27-73 years), mainly in the clinical stage III (40.0%), had moderate TIL concentration (47.5%), and was responsive to the neoadjuvant chemotherapy (87.5%). There was no significant association between TIL concentration and chemotherapy responsiveness (p &gt; 0.05). However, in post-chemotherapy conditions, the median value of tumor size in the group with the high TIL category was significantly lower than in the low and medium TIL groups (p=0.034). There was no association between TIL levels and the clinical response to neoadjuvant chemotherapy in breast cancer patients. Further research is needed to confirm these findings.

Deciphering Tumor Response: The Role of Fluoro-18-d-Glucose Uptake in Evaluating Targeted Therapies with Tyrosine Kinase Inhibitors.

Background/Objectives: The inhibitory effects of tyrosine kinase inhibitors (TKIs) on glucose uptake through their binding to human glucose transporter-1 (GLUT-1) have been well documented. Thus, our research aimed to explore the potential impact of various TKIs of GLUT-1 on the standard [18F]FDG-PET monitoring of tumor response in patients. Methods: To achieve this, we conducted an analysis on three patients who were undergoing treatment with different TKIs and harbored actionable alterations. Alongside the assessment of FDG data (including SUVmax, total lesion glycolysis (TLG), and metabolic tumor volume (MTV)), we also examined the changes in tumor sizes through follow-up [18F]FDG-PET/CT imaging. Notably, our patients harbored alterations in BRAFV600, RET, and c-KIT and exhibited positive responses to the targeted treatment. Results: Our analysis revealed that FDG data derived from SUVmax, TLG, and MTV offered quantifiable outcomes that were consistent with the measurements of tumor size. Conclusions: These findings lend support to the notion that the inhibition of GLUT-1, as a consequence of treatment efficacy, could be indirectly gauged through [18F] FDG-PET/CT imaging in cancer patients undergoing TKI therapy.

Digital "flipbooks" for enhanced visual assessment of simple and complex brain tumors.

Typical longitudinal radiographic assessment of brain tumors relies on side-by-side qualitative visualization of serial magnetic resonance images (MRIs) aided by quantitative measurements of tumor size. However, when assessing slowly growing tumors and/or complex tumors, side-by-side visualization and quantification may be difficult or unreliable. Whole-brain, patient-specific "digital flipbooks" of longitudinal scans are a potential method to augment radiographic side-by-side reads in clinical settings by enhancing the visual perception of changes in tumor size, mass effect, and infiltration across multiple slices over time. In this approach, co-registered, consecutive MRI scans are displayed in a slide deck, where one slide displays multiple brain slices of a single timepoint in an array (eg, 3 × 5 "mosaic" view of slices). The flipbooks are viewed similarly to an animated flipbook of cartoons/photos so that subtle radiographic changes are visualized via perceived motion when scrolling through the slides. Importantly, flipbooks can be created easily with free, open-source software. This article describes the step-by-step methodology for creating flipbooks and discusses clinical scenarios for which flipbooks are particularly useful. Example flipbooks are provided in Supplementary Material.