Intratumoral Signal Research Articles

Assessment of magnetic resonance imaging findings in ovarian granulosa cell tumors along with clinical prognostic factors.

To determine the role of preoperative MRI in the diagnosis and treatment of patients with granulosa cell tumors (GCTs) of the ovary. Twenty-four patients who were operated on between 2018 and 2022 and who were pathologically diagnosed with GHT and met the inclusion criteria were retrospectively examined. The findings were compared with the patients' demographic data, symptoms, surgical findings (laterality, stage, lymph node involvement, endometrial pathology, tumor size), and CA-125 levels. The final cohort included 24 patients with a mean age of 54.71 ± 16.52. All the patients had the pathological diagnosis of adult type GCT. In the morphological evaluation, the most common finding was a solid-cystic mixed type (14 patients, 58.3%), while intratumoral hemorrhage signal was observed in 10 patients (41.7%). In the majority of cases (91.7%), the mass showed regular contours. The honeycomb/Swiss cheese sign was detected in 54.2% of the cases. When the T1 and T2 signal of the solid component of the mass were examined relative to the myometrium, the majority of GCTs appeared isointense on both sequences (83.3% and 62.5%, respectively). The mean ADC value of the solid component obtained from diffusion-weighted imaging was 0.78 ± 0.15 × 10-3. Pelvic fluid was observed in 41.7% of the cases. The average endometrial thickness was 9.74 ± 6.43 mm. Thickened endometrium more than 9 mm was observed in 9 out of the remaining 21 patients (42.9%). Understanding the key imaging features for GCTs plays an essential role in the diagnosis and guiding the treatment effectively.

Bienzyme-Locked Activatable Fluorescent Probes for Specific Imaging of Tumor-Associated Mast Cells.

Tumor-associated mast cells (TAMCs) have been recently revealed to play a multifaceted role in the tumor microenvironment. Noninvasive optical imaging of TAMCs is thus highly desired to gain insights into their functions in cancer immunotherapy. However, due to the lack of a single enzyme that is specific to mast cells, a common probe design approach based on single-enzyme activation is not applicable. Herein, we reported a bienzyme-locked molecular probe (THCMC) based on a photoinduced electron transfer-intramolecular charge-transfer hybrid strategy for in vivo imaging of TAMCs. The bienzyme-locked activation mechanism ensures that THCMC exclusively turns on near-infrared (NIR) fluorescence only in the presence of both tryptase and chymase specifically coexpressed by mast cells. Thus, THCMC effectively distinguishes mast cells from other leukocytes, including T cells, neutrophils, and macrophages, a capability lacking in single-locked probes. Such a high specificity of THCMC allows noninvasive tracking of the fluctuation of TAMCs in the tumor of living mice during cancer immunotherapy. The results reveal that the decreased intratumoral signal of THCMC after combination immunotherapy correlates well with the reduced population of TAMCs, accurately predicting the inhibition of tumor growth. Thus, this study not only presents the first NIR fluorescent probe specific for TAMCs but also proposes a generic bienzyme-locked probe design approach for in vivo cell imaging.

Misleading clinical and imaging features in atypical aggressive angiomyxoma of the female vulvovaginal or perianal region: report of three cases and review of the literature.

Aggressive (deep) angiomyxoma (AAM) is a rare mesenchymal tumor that typically originates from the vulvovaginal region, perineum, and pelvis in adult women. The objective of this case report and literature review is to comprehensively analyze the clinical, imaging, and pathological characteristics of atypical AAM in the female lower genital tract and pelvic floor in order to minimize preoperative misdiagnosis or missed diagnosis and ultimately optimize the clinical management strategy. The data of three cases with atypical AAM, which demonstrate similarities with other lesions observed in the female lower genital tract over the past 1.5 years, were retrospectively described. This description included clinical management, images and reports of ultrasonography (US) and magnetic resonance imaging (MRI), clinicopathological features, follow-up, and outcomes. In the Discussion section, a review of the literature on MEDLINE (PubMed) and Web of Science from the past 50 years was conducted. The three cases all underwent preoperative ultrasonography, and two of them also underwent preoperative MRI examination. Complete resection of the lesions was performed in all three cases, followed by postoperative pathological examination. The histopathology of these three cases revealed invasive angiomyxoma, as confirmed by immunohistochemical staining, which demonstrated positive expression of desmin, vimentin, estrogen, and progesterone receptors. The patients experienced a smooth postoperative recovery. Ultrasound had a diagnostic accuracy rate of 100% (3/3) for locating and determining the extent of the lesions; however, its specific diagnostic accuracy rate for identifying the pathological type was only 33% (1/3). In contrast, MRI had a diagnostic accuracy rate of 100% (2/2) for locating and determining the extent of lesions but did not show any specific diagnostic accuracy for identifying the pathological types. Our findings indicate that even if a vulvovaginal lesion presents with a superficial location, small size, limited scope, and regular shape, suspicion of atypical AAM should arise when palpation reveals toughness, tensility, and deformability under pressure. US reveals a well-defined hypoechoic to anechoic mass with uniformly distributed coarse dot echoes, with or without detectable intratumoral blood flow signal. MRI shows prolonged T1 and T2 signals with inhomogeneous enhancement and evident diffusion restriction on diffusion-weighted imaging (DWI).

High Peritumoral and Intratumoral T2 Signal Intensity in HER2-Positive Breast Cancers on Preneoadjuvant Breast MRI: Assessment of Associations With Histopathologic Characteristics.

BACKGROUND. Intratumoral necrosis and peritumoral edema are features of aggressive breast cancer that may present as high T2 signal intensity (T2 SI). Implications of high T2 SI in HER2-positive cancers are unclear. OBJECTIVE. The purpose of this study was to assess associations with histopathologic characteristics of high peritumoral T2 SI and intratumoral T2 SI of HER2-positive breast cancer on MRI performed before initiation of neoadjuvant therapy. METHODS. This retrospective study included 210 patients (age, 24-82 years) with 211 HER2 breast cancers who, from January 1, 2015, to July 30, 2022, underwent breast MRI before receiving neoadjuvant therapy. Two radiologists independently assessed cancers for high peritumoral T2 SI and high intratumoral T2 SI on fat-suppressed T2-weighted imaging and classified patterns of high peritumoral T2 SI (adjacent to tumor vs prepectoral extension). A third radiologist resolved discrepancies. Multivariable logistic regression analyses were performed to identify associations of high peritumoral and intratumoral T2 SI with histopathologic characteristics (associated ductal carcinoma in situ, hormone receptor status, histologic grade, lymphovascular invasion, and axillary lymph node metastasis). RESULTS. Of 211 HER2-positive cancers, 81 (38.4%) had high peritumoral T2 SI, and 95 (45.0%) had high intratumoral T2 SI. A histologic grade of 3 was independently associated with high peritumoral T2 SI (OR = 1.90; p = .04). Otherwise, none of the five assessed histopathologic characteristics were independently associated with high intratumoral T2 SI or high peritumoral T2 SI (p > .05). Cancers with high T2 SI adjacent to the tumor (n = 29) and cancers with high T2 SI with prepectoral extension (n = 52) showed no significant difference in frequency for any of the histopathologic characteristics (p > .05). Sensitivities and specificities for predicting the histopathologic characteristics ranged from 35.6% to 43.7% and from 59.7% to 70.7%, respectively, for high peritumoral T2 SI, and from 37.3% to 49.6% and from 49.3% to 62.7%, respectively, for high intratumoral T2 SI. Interreader agreement was almost perfect for high peritumoral T2 SI (Gwet agreement coefficient [AC] = 0.93), high intratumoral T2 SI (Gwet AC = 0.89), and a pattern of high peritumoral T2 SI (Gwet AC = 0.95). CONCLUSION. The only independent association between histopathologic characteristics and high T2 SI of HER2-positive breast cancer was observed between a histologic grade of 3 and high peritumoral T2 SI. CLINICAL IMPACT. In contrast with previously reported findings in broader breast cancer subtypes, peritumoral and intratumoral T2 SI had overall limited utility as prognostic markers of HER2-positive breast cancer.

Development of a novel prediction model for differential diagnosis between spinal myxopapillary ependymoma and schwannoma

Spinal myxopapillary ependymoma (MPE) and schwannoma represent clinically distinct intradural extramedullary tumors, albeit with shared and overlapping magnetic resonance imaging (MRI) characteristics. We aimed to identify significant MRI features that can differentiate between MPE and schwannoma and develop a novel prediction model using these features. In this study, 77 patients with MPE (n = 24) or schwannoma (n = 53) who underwent preoperative MRI and surgical removal between January 2012 and December 2022 were included. MRI features, including intratumoral T2 dark signals, subarachnoid hemorrhage (SAH), leptomeningeal seeding, and enhancement patterns, were analyzed. Logistic regression analysis was conducted to distinguish between MPE and schwannomas based on MRI parameters, and a prediction model was developed using significant MRI parameters. The model was validated internally using a stratified tenfold cross-validation. The area under the curve (AUC) was calculated based on the receiver operating characteristic curve analysis. MPEs had a significantly larger mean size (p = 0.0035), higher frequency of intratumoral T2 dark signals (p = 0.0021), associated SAH (p = 0.0377), and leptomeningeal seeding (p = 0.0377). Focal and diffuse heterogeneous enhancement patterns were significantly more common in MPEs (p = 0.0049 and 0.0038, respectively). Multivariable analyses showed that intratumoral T2 dark signal (p = 0.0439) and focal (p = 0.0029) and diffuse enhancement patterns (p = 0.0398) were independent factors. The prediction model showed an AUC of 0.9204 (95% CI 0.8532–0.9876) and the average AUC for internal validation was 0.9210 (95% CI 0.9160–0.9270). MRI provides useful data for differentiating spinal MPEs from schwannomas. The prediction model developed based on the MRI features demonstrated excellent discriminatory performance.

The Role of Pre-Operative MRI for Prediction of High-Grade Intracranial Meningioma: A Retrospective Study.

High histological grade (WHO grade 2 and 3) intracranial meningiomas have been linked to a greater risk for tumor recurrence and worse clinical outcomes compared to low-grade (WHO grade 1) tumors. Preoperative magnetic resonance imaging (MRI) plays a crucial role in tumor evaluation and allows a better understanding of tumor grading, which could potentially alter clinical outcomes. The present study sought to determine whether preoperative MRI features of intracranial meningiomas can serve as predictors of high-grade tumors. This retrospective study reviewed 327 consecutive confirmed cases of intracranial meningiomas, among whom 210 (64.2%) had available preoperative MRI studies. Thereafter, imaging features such as intratumoral signal heterogeneity, venous sinus invasion, necrosis or hemorrhage, mass effect, cystic component, bone invasion, hyperostosis, spiculation, heterogeneous tumor enhancement, capsular enhancement, restricted diffusion, brain edema, and unclear tumor-brain interface were obtained and data were analyzed using univariate and multivariate analyses. 249 (76.1%) patients had low-grade (grade I), and 78 (23.9%) had high-grade (grades 2 and 3) intracranial meningioma. The majority of cases were females (274 cases, 83.3%) and most patients were below 60 years of age (mean age, 52.50 ± 11.51 years). The multivariate analysis with Multiple Logistic regression analysis using factors determined to be significant during univariate analysis via a backward stepwise selection method with statistical significance set at 0.05 identified three MRI features including necrosis or hemorrhage (adjusted OR = 2.94, 95% CI: 1.15-7.48, p = 0.024), hyperostosis (adjusted OR = 0.31, 95% CI: 0.12-0.79, p = 0.014), and brain edema (adjusted OR = 2.33, 95% CI: 1.13-4.81, p = 0.022) as significant independent predictors of high-grade meningioma after adjusting for confounders. Our study suggested that certain preoperative MRI features of intracranial meningiomas including necrosis or hemorrhage and brain edema could potentially predict high-grade tumors while hyperostosis is a predictor for low-grade tumors.

Sudan Black B treatment for reducing autofluorescence in human glioma tissue and improving fluorescent signals of bacterial LPS staining.

The 3D visualization based on tissue clearing technology allows us to have a deeper understanding of the 3D spatial information of deep molecules in the tissue. Tissue clearing and bacterial labeling methods have been used for in situ 3D microbiota imaging, and we have developed a pipeline for 3D visualization of in situ microbiota in human gliomas. Anti-LPS antibodies are appropriate to label and characterize bacteria in situ within tumors. However, autofluorescence (AF) is common in biological tissues, especially in brain tissues filled with lipofuscin-like (LF) substances. This natural fluorescent signal is usually considered to be a problem because it affects the 3D visualization of fluorescent signals in bacterial LPS staining. Here, we used Sudan Black B (SBB) to mask the AF of human glioma tissue and explored in detail the optimal quencher concentration, which allows 3D visualization of intratumoral bacteria to reduce AF and maintain the intensity of intratumoral bacteria-specific LPS fluorescent signals.

Theranostic Cancer Treatment Using Lentinan-Coated Selenium Nanoparticles and Label-Free CEST MRI.

Selenium nanoparticle (SeNP)-based nanotherapeutics have become an emerging cancer therapy, while effective drug delivery remains a technical hurdle. A theranostic approach, through which imaging companions are integrated with SeNPs, will allow image-guided drug delivery and, therefore, is highly desirable. Traditional methods require the chemical conjugation of imaging agents to the surface of nanoparticles, which may impede the later clinical translation. In this study, we developed a label-free strategy in which lentinan-functionalized SeNPs (LNT-SeNPs) are detected using MRI by the hydroxyl protons carried on LNT molecules. The in vitro phantom study showed that LNT and LNT-SeNPs have a strong CEST signal at 1.0 ppm apart from the water resonance, suggesting an in vivo detectability in the µM concentration range. Demonstrated on CT26 colon tumor cells, LNT-SeNPs exert a strong anticancer effect (IC50 = 4.8 μM), prominently attributed to the ability to generate intracellular reactive oxygen species. However, when testing in a mouse model of CT26 tumors, administration of LNT-SeNPs alone was found unable to deliver sufficient drugs to the tumor, leading to poor treatment responses. To improve the drug delivery, we co-injected LNT-SeNPs and TNF-α, a previously reported drug that could effectively damage the endothelial cells in the tumor vasculature, thereby increasing drug delivery to the tumor. Our results revealed a 75% increase in the intratumoral CEST MRI signal, indicating a markedly increased delivery efficiency of LNT-SeNPs when combined with TNF-α. The combination therapy also resulted in a significantly enhanced treatment outcome, as revealed by the tumor growth study. Taken together, our study demonstrates the first label-free, SeNP-based theranostic system, in which LNT was used for both functional surface coating and CEST MRI signal generating. Such a theranostic LNT-SeNP system is advantageous because it requires chemical labeling and, therefore, has high biocompatibility and low translatable barriers.

Collagenase-Loaded H-TiO2 Nanoparticles Enhance Ultrasound Imaging-Guided Sonodynamic Therapy in a Pancreatic Carcinoma Xenograft Model via Digesting Stromal Barriers.

Sonodynamic therapy (SDT), a noninvasive therapy that relies on sonosensitizers and generates reactive oxygen species (ROS), has attracted considerable attention in the treatment of pancreatic cancer. However, being surrounded by dense stromal barriers, pancreatic cancer exhibits high interstitial fluid pressure (IFP) and hypoxia in the tumor microenvironment (TME), resulting in poor SDT efficacy. Collagenase-loaded hollow TiO2 (Col-H-TiO2) nanoparticles (NPs) capable of degrading stromal barriers and producing sufficient ROS production were synthesized in this study. After administration of NPs in the patient-derived xenograft (PDX) model, ultrasonic irradiation-released collagenase degraded tumor matrix fibers, decreased intratumoral IFP, and enhanced the penetration and retention of NPs within tumor tissues. Moreover, the NPs accumulated within the tumor not only generate abundant ROS under the influence of ultrasound irradiation but also improve intratumoral ultrasound signal, providing ultrasonic imaging-guided highly effective SDT for pancreatic cancer. In conclusion, this research improves the SDT technique and enhances the visualization of pancreatic cancer by remodeling the TME and is a promising strategy for further clinical applications.

Correlation of dynamic contrast-enhanced MRI and diffusion-weighted MR imaging with prognostic factors and subtypes of breast cancers.

ObjectiveTo determine the preoperative magnetic resonance imaging (MRI) findings of breast cancer on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted magnetic resonance imaging (DWI) in different molecular subtypes.Materials and methodsA retrospective study was conducted on 116 breast cancer subjects who underwent preoperative MRI and surgery or biopsy. Three radiologists retrospectively assessed the morphological and kinetic characteristics on DCE-MRI and tumor detectability on DWI, by using apparent diffusion coefficient (ADC) values of lesions. The clinicopathologic and MRI features of four subtypes were compared. The correlation between clinical and MRI findings with molecular subtypes was evaluated using the chi-square and ANOVA tests, while the Mann–Whitney test was used to analyze the relationship between ADC and prognostic factors.ResultsOne hundred and sixteen women diagnosed with breast cancer confirmed by surgery or biopsy had the following subtypes of breast cancer: luminal A (27, 23.3%), luminal B (56, 48.2%), HER2 positive (14, 12.1%), and triple-negative breast cancer (TNBC) (19, 16.4%), respectively. Among the subtypes, significant differences were found in axillary node metastasis, histological grade, tumor shape, rim enhancement, margin, lesion type, intratumoral T2 signal intensity, Ki-67 index, and paratumoral enhancement (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, and p = 0.02, respectively). On DWI, the mean ADC value of TNBC (0.910 × 10−3 mm2/s) was the lowest compared to luminal A (1.477×10−3 mm2/s), luminal B (0.955 × 10−3 mm2/s), and HER2 positive (0.996 × 10−3 mm2/s) (p < 0.001). Analysis of the correlation between different prognostic factors and ADC value showed that only axillary lymph node status and ADC value had a statistically significant difference (p = 0.009).ConclusionThe morphologic features of MRI can be used as imaging biomarkers to identify the molecular subtypes of breast cancer. In addition, quantitative assessments of ADC values on DWI may also provide biological clues about molecular subtypes.

Abstract 4157: Using a multivalent immunotherapy platform to extend intratumoral therapeutic durability

Abstract Purpose: There is a critical need in immunotherapy drug development to enable focused and sustained immune cell modulation within a tumor to induce and propagate a system-wide anti-tumor response. We have developed a novel immunotherapy platform that could be used to generate geographically focused cancer cell growth inhibition or immune cell activation, thereby stimulating an anti-tumor immune response against primary solid tumors that can also travel to secondary metastases. Methods: Using published methods, we synthesized multivalent protein (MVP) conjugates by conjugating multiple copies (i.e. valency) of immune stimulating proteins, checkpoint inhibitors or anti-tumor antibodies to soluble, long-chain biopolymers. We verified that we can reproducibly generate MVP valencies ranging from 20-120 protein copies (±10%) per polymer backbone. We determined the binding affinity of these MVPs to their respective targets using biolayer interferometry and cell bioassays, and we measured the hydrodynamic radius of these immunotherapies using dynamic light scattering. Then, we injected fluorescently modified MVPs or their unconjugated counterparts directly into a variety of solid tumor models in mice. By taking longitudinal in vivo fluorescence measurements of the intratumoral (IT) drug signal over multiple days, we measured the IT half-life of each treatment. Results: Based on binding affinity measurements, we found that MVP potency increased directly with protein valency, and at high valency, the potency of MVPs were substantially greater than the unconjugated protein controls. Multivalent conjugation also increased the hydrodynamic radius of the MVPs to at least ten times larger than the unconjugated therapeutics. This large size was sufficient to slow the diffusion of MVP immunotherapies through dense tissues, such as solid tumors, as demonstrated by our in vivo studies. MVPs exhibited a higher IT drug signal with a more durable gradient within the tumor compared to the unconjugated controls, resulting in an extension of their IT half-lives by &amp;gt;5X in mouse solid tumors. Conclusions: The MVP platform can be used to modulate the potency and therapeutic durability for a wide range of immunotherapy targets. Further, the MVPs stay focused within the tumor after IT injection where they could generate a sustained anti-tumor immune response with minimal systemic exposure. Therefore, we expect MVP immunotherapies to have a better safety profile than IT or systemic delivery of an unconjugated therapeutic. We will continue to develop our internal MVP pipeline to finalize a candidate for IND-enabling studies. We are also seeking collaborations for co-development of additional immunotherapies that could benefit from the extended IT exposure and potency modulation enabled by the MVP platform. Citation Format: Livia Brier, Amy A. Twite, Adam Barnebey, Mavish Mahomed, Wesley M. Jackson. Using a multivalent immunotherapy platform to extend intratumoral therapeutic durability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4157.

Resection of petroclival clear cell meningioma by the anterior transpetrosal approach: diagnosis of rare pathology and improvement of preoperative hearing disturbance.

Clear cell meningioma is a rare histological variant of meningioma, which often recurs aggressively. This video demonstrates a patient with a petroclival clear cell meningioma, which was resected completely through the anterior transpetrosal approach. The absence of intratumoral spotty signal voids on preoperative susceptibility-weighted imaging (SWI) suggested that the tumor was a meningioma rather than a schwannoma, although typical imaging features of meningioma were not observed. After surgery, the patient’s preoperative hearing disturbance improved from class D to class A, which the authors had sometimes experienced in cerebellopontine angle meningioma surgeries. Careful observation over a 2.5-year period revealed no tumor recurrence, without additional treatment.The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21219

Sodium MRI at 7T for Early Response Evaluation of Intracranial Tumors following Stereotactic Radiotherapy Using the CyberKnife.

Conventionally, early treatment response to stereotactic radiotherapy in intracranial tumors is often determined by structural MR imaging. Tissue sodium concentration is altered by cellular integrity and energy status in cells. In this study, we aimed to investigate the feasibility of sodium MR imaging at 7T for the preliminary evaluation of radiotherapeutic efficacy for intracranial tumors. Data were collected from 16 patients (12 men and 4 women, 24-75 years of age) with 22 intracranial tumors who were treated with stereotactic radiation therapy using CyberKnife at our institution between December 1, 2016, and August 15, 2019. Sodium MR imaging was performed at 7T before and 48 hours, 1 week, and 1 month after CyberKnife radiation therapy. Tissue sodium concentration (TSC) was calculated and analyzed based on manually labeled regions of tumors. Ultra-high-field sodium MR imaging clearly showed the intratumoral signal, which is significantly higher than that of normal tissue (t = 5.250, P <.001)., but the edema zone has some influence. The average TSC ratios of tumor to CSF in the 22 tumors, contralateral normal tissues, edema zones, frontal cortex, and frontal white matter were 0.66 (range, 0.23-1.5), 0.30 (range, 0.15-0.43), 0.58 (range, 0.25-1.21), 0.25 (range, 0.17-0.42), and 0.30 (range, 0.19-0.49), respectively. A total of 12 tumors in 8 patients were scanned at 48 hours, 1 week, and 1 month after treatment. The average TSC at 48 hours after treatment was 0.06 higher than that before treatment and began to decrease at 1 week. The TSC ratios of 10 continued to decline and 2 tumors increased at 1 month, respectively. Tumor volume decreased by 2.4%-99% after 3 months. Changes in the TSC can be quantified by sodium MR imaging at 7T and used to detect radiobiologic alterations in intracranial tumors at early time points after CyberKnife radiation therapy.

Abstract P027: Extending intratumoral therapeutic durability using a multivalent immunotherapy platform

Abstract Purpose: The risk of severe side effects has limited the development of immune cell activating immunotherapies. There is a critical need in immunotherapy drug development to enable focused and sustained immune cell activation within a tumor to induce a system-wide anti-tumor response. We have developed a novel immunotherapy platform that could be used to generate geographically focused cancer cell growth inhibition or immune cell activation, thereby stimulating an anti-tumor immune response against primary solid tumors that can also travel to secondary metastases. Methods: Using published methods, we synthesized multivalent protein (MVP) conjugates by conjugating multiple copies (i.e. valency) of immune stimulating proteins (e.g. Interleukin-15) or anti-tumor antibodies (e.g. anti-Epidermal Growth Factor Receptor) to soluble, long-chain biopolymers (e.g. carboxymethylcellulose or hyaluronic acid, ~700 kDa). We verified that we can reproducibly generate MVP valencies ranging from 20-120 protein copies (±10%) per polymer backbone. We determined the binding affinity of these MVPs to their respective targets using biolayer interferometry and cell bioassays, and we measured the hydrodynamic radius of these immunotherapies using dynamic light scattering. Then, we injected flurosecently modified MVPs or their unconjugated counterparts directly into a variety of solid tumor models in mice. By taking longitudinal in vivo fuorescence measurments of the intratumoral (IT) drug signal over multiple days, we measured the IT half-life of each treatment. Results: Based on binding affinity measurements, we found that MVP potency increased directly with their protein valency, and at high valency, the potency of MVPs were substantially greater than the unconjugated protein controls. Multivalent conjugation also increased the hydrodynamic radius of the MVPs to at least ten times larger than the unconjugated therapeutics. This large size was sufficient to slow the diffusion of MVP immunotherapies through dense tissues, such as solid tumors, as demonstrated by our in vivo studies. MVPs exhibited a higher IT drug signal with a more durable gradient within the tumor compared to the unconjugated controls, resulting in an extension of their IT half-lives by &amp;gt;5X in mouse solid tumors. Conclusions: The MVP platform can be used to modulate the potency and therapeutic durability for a wide range of immunotherapy targets. Further, the MVPs stay focused within the tumor after IT injection where they could generate a sustained anti-tumor immune response with minimal systemic exposure. Therefore, we expect MVP immunotherapies to have a better safety profile than IT or systemic delivery of an unconjugated therapeutic. We will continue to develop our internal MVP pipeline to finalize a candidate for IND-enabling studies. We are also seeking to collaborations for co-development of additional immunotherapies that could benefit from the extended IT exposure and potency modulation enabled by the MVP platform. Citation Format: Livia W. Brier, Mavish Mahomed, Amy A. Twite, Adam Barnebey, Wesley M. Jackson. Extending intratumoral therapeutic durability using a multivalent immunotherapy platform [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P027.

Utility of MRI in diagnosis of molecular subtypes of breast cancer

Background: Breast cancer is a collection of diseases defined by distinct pathological (e.g., ductal, lobular, mucinous) and molecular characteristics (e.g., ER and PR, HER2 amplification, and more recently transcriptome-based classifications such as luminal and basal cancers). Molecular subtyping is beneficial for the diagnosis and individualized treatment of breast cancer.MRI is a supplemental technique to mammography and ultrasonography for the evaluation of breast lesions and to predict molecular subtypes of breast cancer. Studies have highlighted the value of DCE-MRI in reflecting the anatomic and functional properties of tumors and facilitating treatment. Objectives: The aim of this work was to assess the utility of MRI as an accurate method for detection of molecular subtypes of breast cancer. Patients and Methods: a retrospective clinical study of 2-years enrollment duration. The study was conducted at Radiology Department, Assuit University Hospitals on 50 lesions, patient age ranging from 23 to 66 years old with mean age was (46.9 ± SD) years. MR imaging studies were performed using a 1.5 T Magnetom Vision scanner with dedicated bilateral phased-array breast coil (Siemens, Erlangen, Germany). MRI sequences were 1. Axial T1WI. 2. Axial T2WI. 3. Axial STIR. 4. Axial DWI and ADC. 5. DCE-MRI. Results: The study included 50 lesions; 21 lesions were Luminal A, 15 lesions were Luminal B, 10 lesions were HER2+, and 4 lesions were TN. Histopathology 39 lesions were IDC-NOS, 1 lesion was IDC (medullary type), 7 lesions were mixed pathology IDC + DCIS, and 3 lesions were ILC. As regard the correlation between the histopathological type and grade, both were specific in differentiation between the molecular subtypes. According to the MRI findings it was found that T2 Intratumoral signal intensity, STIR, and the margin of the lesion were highly specific in differentiation, both L.N status and number were found that they were highly specific in differentiation (p <0.001), while size of the lesion, T1WI signal, ADC values were found that they were non-specific in differentiation between the molecular subtypes of breast cancer. Conclusion: Breast MRI may help in assessing different molecular subtypes of breast cancer.

Machine learning with multiparametric breast MRI for prediction of Ki-67 and histologic grade in early-stage luminal breast cancer.

To investigate whether machine learning-based prediction models using 3-T multiparametric MRI (mpMRI) can predict Ki-67 and histologic grade in stage I-II luminal cancer. Between 2013 and 2019, consecutive women with luminal cancers who underwent preoperative MRI with diffusion-weighted imaging (DWI) and surgery were included. For prediction models, morphology, kinetic features using computer-aided diagnosis (CAD), and apparent diffusion coefficient (ADC) at DWI were evaluated by two radiologists. Logistic regression analysis was used to identify mpMRI features for predicting Ki-67 and grade. Diagnostic performance was assessed using eight machine learning algorithms incorporating mpMRI features and compared using the DeLong method. Of 300 women, 203 (67.7%) had low Ki-67 and 97 (32.3%) had high Ki-67; 242 (80.7%) had low grade and 58 (19.3%) had high grade. In multivariate analysis, independent predictors for higher Ki-67 were washout component > 13.5% (odds ratio [OR] = 4.16; p < 0.001) and intratumoral high SI on T2-weighted image (OR = 1.89; p = 0.022). Those for higher grade were washout component > 15.5% (OR = 7.22; p < 0.001), rim enhancement (OR = 2.59; p = 0.022), and ADC value < 0.945 × 10-3 mm2/s (OR = 2.47; p = 0.015). Among eight models using these predictors, six models showed the equivalent performance for Ki-67 (area under the receiver operating characteristic curve [AUC]: 0.70) and Naive Bayes classifier showed the highest performance for grade (AUC: 0.79). A prediction model incorporating mpMRI features shows good diagnostic performance for predicting Ki-67 and histologic grade in patients with luminal breast cancers. • Among multiparametric MRI features, kinetic feature of washout component >13.5% and intratumoral high signal intensity on T2-weighted image were associated with higher Ki-67. • Washout component >15.5%, rim enhancement, and mean apparent diffusion coefficient value < 0.945 × 10-3 mm2/s were associated with higher histologic grade. • Machine learning-based prediction models incorporating multiparametric MRI features showed good diagnostic performance for Ki-67 and histologic grade in luminal breast cancers.

Intratumoral Intensity in T2-weighted MRI and the Association With Histological and Molecular Prognostic Factors in Women With Invasive Breast Cancer.

To compare the intratumoral T2 signal intensity on MRI and histopathological and molecular expression of biomarkers of aggressiveness (histological grade, hormonal status, HER2, and Ki-67). This retrospective study included all women with invasive breast cancer undergoing MRI from January 2014 to October 2016. The intratumoral T2 signal as interpreted at consensus by two radiologists was compared to histopathological and molecular prognostic factors from the surgical specimen. Statistical analyses used Pearson χ 2 test with a confidence level of 95% (P ≤ 0.05). Fifty patients with 50 lesions met study criteria (mean age 65.8 ± 13.5 years). Mean lesion size was 28 mm ± 15.7 mm (range, 15 to 76 mm). Cancer types were invasive ductal (35/50, 70%), invasive lobular (10/50, 20%), and mixed (5/50, 10%). Most lesions were histological grade 1 or 2 (41/50, 82%) and luminal type (45/50, 90%). On T2 images, lesions were hypointense in 62% (31/50), isointense in 20% (10/50), and hyperintense in 18% (9/50) of cases. Among hypointense lesions, 94% (29/31) were low or intermediate grade tumors (P = 0.02), low HER2 overexpression (30/31, 97%) (P = 0.005), and high ER status (30/31, 97%) (P = 0.006), high PR (26/31, 84%) (P = 0.02), and low incidence of necrosis (2/31, 6%). The difference in Ki-67 tumoral expression between groups was not significant. Intratumoral T2 hypointensity in invasive breast cancer is associated with better prognostic tumors, such as histological low-grade high hormone receptor status.

Dynamic contrast enhanced-MRI and diffusion-weighted image as predictors of lymphovascular invasion in node-negative invasive breast cancer

BackgroundLymphovascular invasion (LVI) is an important risk factor for prognosis of breast cancer and an unfavorable prognostic factor in node-negative invasive breast cancer patients. The purpose of this study was to evaluate the association between LVI and pre-operative features of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) in node-negative invasive breast cancer.MethodsData were collected retrospectively from 132 cases who had undergone pre-operative MRI and had invasive breast carcinoma confirmed on the last surgical pathology report. MRI and DWI data were analyzed for the size of tumor, mass shape, margin, internal enhancement pattern, kinetic enhancement curve, high intratumoral T2-weighted signal intensity, peritumoral edema, DWI rim sign, and apparent diffusion coefficient (ADC) values. We calculated the relationship between presence of LVI and various prognostic factors and MRI features.ResultsPathologic tumor size, mass margin, internal enhancement pattern, kinetic enhancement curve, DWI rim sign, and the difference between maximum and minimum ADC were significantly correlated with LVI (p < 0.05).ConclusionsWe suggest that DCE-MRI with DWI would assist in predicting LVI status in node-negative invasive breast cancer patients.

Studying The Imaging Properties Of Liver Tumors On Magnetic Resonance Imaging With Primovist - A Hepatospecific Paramagnetic Gadolinium-Based Contrast Agent

The study was performed on 25 patients diagnosed with liver tumors, assigned magnetic resonance imaging (MRI) with Primovist - a hepatospecific paramagnetic gadolinium-based contrast agent at the International Medical Center of Hue Central Hospital. The result is as followed: 11 HCCs, 1 biliary tract malignant tumor, 1 hepatic adenoma, 6 metastates, 2 FNH, 1 hepatic AML, 3 hemangiomas. 47 lesions in total, including 9 lesions smaller than 1cm, 12 lesions 1-2 cm, 26 lesions larger than 2 cm. All 11 HCCs are hypointense on T1W, hyperintense on T2W, intratumoral high signal on DWI, 9 cases have typical enhancement pattern on Dynamic phase (arterial enhancement with washout assessed on the portal venous phase), 10 cases have no enhancement on Hepatocellular phase. Metastasis lesions have peripheral enhancement on both arterial and venous phases, no enhancement on delayed phase due to not having hepatic cells. The the biliary tract tumor is pathologically correct, with minor peripheral enhancement 30 seconds after injection, gradual centripetal enhancement after 60 and 90 seconds, no enhancement on delayed phase due to not having hepatic cells. 3 cases with hemangiomas are hyperintense on T2WI, similar to blood vessels, hypointense on T1WI, pheripherally enhanced 30 seconds after injection, fully centripetal fill-in after 90 seconds, non-enhanced on delayed phase (20 minutes) due to not having hepatic cells. 2 cases with FNH have iso- or mildly hyperintense on T1W, isointense on T2W and hypointense on DWI, isointense on hepatocellular phase due to the reservation of hepatic cells. Liver MRI with Primovist is specific for Hepatic cells, playing a critical role in detecting small lesions and differentiating benign and malignant lesions of the liver, especially those without typical enhancement pattern on Dynamic phase.

The role of MRI and clinicopathologic features in predicting the invasive component of biopsy-confirmed ductal carcinoma in situ

BackgroundThe upgrade rate of biopsy-confirmed ductal carcinoma in situ (DCIS) to invasive carcinoma is up to 50% on final pathology. We investigated MRI and clinicopathologic predictors of the invasive components of DCIS diagnosed by preoperative biopsy and then compared MRI features between patients with DCIS, microinvasive ductal carcinoma (mIDC), and invasive ductal carcinoma (IDC) diagnosed on final pathology.MethodsTwo hundred and one patients with 206 biopsy-confirmed DCIS lesions were enrolled. MRI and clinicopathologic features were used to predict either mIDC or IDC via a cumulative logistic regression analysis. For the lesions detected on MRI, morphologic and kinetic analyses were performed using the Chi-square, Fisher’s exact, and Kruskal-Wallis tests.ResultsOf all the lesions, 112 (54.4%) were diagnosed as DCIS, 50 (24.3%) were upgraded to mIDC, and 44 (21.4%) to IDC. The detection on MRI as mass (Odds ratio (OR) = 8.84, 95% confidence interval (CI) = 1.05–74.04, P = 0.045) or non-mass enhancement (NME; OR = 11.17, 95% CI = 1.35–92.36, P = 0.025), negative progesterone receptor (PR; OR = 2.40, 95% CI = 1.29–4.44, P = 0.006), and high Ki-67 level (OR = 2.42, 95% CI = 1.30–4.50, P = 0.005) were significant independent predictors of histologic upgrade. On MRI, 87 (42.2%) lesions appeared as mass and 107 (51.9%) as NME. Irregularly shaped, not-circumscribed, heterogeneous, or rim-enhancing masses with intratumoral high signal intensity or peritumoral edema, clumped or clustered ring-enhancing NMEs, and high peak enhancement were significantly associated with histologic upgrade (P < 0.001).ConclusionMRI detection, negative PR, and high Ki-67 levels are associated with a histologic upgrade in patients with biopsy-confirmed DCIS. Suspicious MRI features are more frequent in such patients.