Heterogeneous Lesion Research Articles

Giant Parathyroid Adenoma: A case Report.

Giant parathyroid adenoma (GPA) is a large tumor weighing more than 3.5g but can weigh as much as 110g as compared to parathyroid adenomas which usually weigh in the vicinity of 1g and measure around 1-2cm. These mainly present with primary hyperparathyroidism. We describe an interesting case and clinical course of a young woman with giant parathyroid adenoma. A 30-year-old Indian female presented with acute pancreatitis and acute kidney injury and was found to have hypercalcemia and hyperparathyroidism on further evaluation. Her physical examination revealed firm, non-tender, and mobile swelling of size 5 × 2cm on the left side of her neck. USG neck showed a large heterogenous hypoechoic lesion in the left lower pole region of the left thyroid gland measuring 50 × 24 × 29mm with a volume of 18 ccs. A parathyroid scan was performed using 99Tc Sesta MIBI tracer which was suggestive of a large adenoma in relation to the left lobe of the thyroid gland. She underwent minimally invasive parathyroidectomy with excision of left parathyroid adenoma under general anesthesia. Intraoperative frozen section confirmed the specimen to be parathyroid tissue. Her parathyroid hormone (PTH) level decreased from 1900 pg/ml in the pre-operative level to 242 pg/ml in the immediate postoperative period.

Distinct subtypes of endometriosis identified based on stromal-immune microenvironment and gene expression: implications for hormone therapy.

Endometriosis (EMs) is a chronic inflammatory condition that is highly heterogeneous. Current clinical staging fails to accurately predict drug responses and prognosis. In this study, we aimed to reveal the heterogeneity of ectopic lesions and investigate the possible underlying mechanisms using transcriptomic data and clinical information. The EMs microarray dataset GSE141549 was obtained from the Gene Expression Omnibus database. Unsupervised hierarchical clustering was performed to identify EMs subtypes, which was followed by the functional enrichment analysis and estimation of immune infiltrates. Subtype-associated gene signatures were identified and further validated in other independent datasets, including GSE25628, E-MTAB-694, and GSE23339. Additionally, tissue microarrays (TMAs) were generated from premenopausal patients with EMs to investigate the potential clinical implications of the two identified subtypes. The unsupervised clustering analysis revealed that ectopic EMs lesions can be classified into two distinct subtypes: stroma-enriched (S1) and immune-enriched (S2). The functional analysis revealed that S1 correlated with fibroblast activation and extracellular matrix remodeling in the ectopic milieu, whereas S2 was characterized by the upregulation of immune pathways and a higher positive correlation with the immunotherapy response. Moreover, we identified a subtype signature composed of FHL1 and SORBS1, and constructed a subtype diagnostic model. Based on the cohort data from the TMAs, we found that S2 was strongly associated with the failure of/intolerance to hormone therapy. This study identified two distinct subtypes that are varyingly associated with hormone resistance, stroma-immunity, and molecular features, thereby highlighting the importance of this stromal-immune heterogeneity in identifying EMs subtypes and providing novel insights into future personalized hormone-free therapy in EMs.

Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma.

Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.

Treatment of Liver Metastases With Focused Ultrasound and Microbubbles in Patients With Colorectal Cancer Receiving Chemotherapy

Pre-clinical trials have obtained promising results that focused ultrasound (FUS) combined with microbubbles (MBs) increases tumor uptake and the therapeutic effect of drugs. The aims of the study described here were to investigate whether FUS and MBs could improve the effect of chemotherapy in patients with liver metastases from colorectal cancer and to investigate the safety and feasibility of using FUS+MBs. We included 17 patients with liver metastases from colorectal cancer, selected two lesions in each patient's liver and randomized the lesions for, respectively, treatment with FUS+MBs or control. After chemotherapy (FOLFIRI or FOLFOXIRI), the lesions were treated with FUS (frequency=1.67 MHz, mechanical index=0.5, pulse repetition frequency=0.33 Hz, 33 oscillations, duty cycle=0.2%-0.4% and MBs (SonoVue) for 35 min). Nine boluses of MBs were injected intravenously at 3.5 min intervals. Patients were scheduled for four cycles of treatment. Changes in the size of metastases were determined from computed tomography images. Treatment with FUS+MBs is safe at the settings used. There was considerable variation in treatment response between lesions and mixed response between lesions receiving only chemotherapy. There is a tendency toward larger-volume reduction in lesions treated with FUS+MBs compared with control lesions, but a mixed response to chemotherapy and lesion heterogeneity make it difficult to interpret the results. The combination of FUS and MBs is a safe, feasible and available strategy for improving the effect of chemotherapy in cancer patients. Therapeutic effect was not demonstrated in this trial. Multicenter trials with standardized protocols should be performed.

#5662 PRELIMINARY RESULTS FROM IBEAT ANCILLARY-STUDY: A NOVEL CLASSIFICATION OF RENAL DAMAGE IN DIABETES

Abstract Background and Aims Renal damage in diabetes can manifest as real diabetic glomerulosclerosis (DN) or non-diabetic renal disease (NDRD). DN and NDRD differ in terms of prognosis and treatment thus kidney biopsy remains the gold standard. The iBEAt study conducted within the frame of IMI project BEAt-DKD (https://www.beat-dkd.eu/; GA No 115974) aims to determine whether renal imaging biomarkers capture by magnetic resonance (MRI) and ultrasound (US) can dissect DKD heterogeneity. This ancillary sub-study in iBEAt aims to explore correlations between imaging biomarkers, clinical, molecular and renal histopathological data, in order to identify different DKD phenotypes. Method Up to January 2023 we enrolled 69 patients with: ages18-80; diagnosis of type 2 diabetes; eGFR > = 15 ml/min/1.73m2. Patients underwent kidney biopsy, US and MRI, along with biofluids and clinical data collection. For each patient, a total of three renal cores were collected, one was fixed in formalin, embedded in paraffin and used for routine diagnostics, the other was split and either included in OCT or used for electron microscopy, while the last was stored in RNA later for omics analysis. Results Among the 69 patients enrolled, 57 underwent kidney biopsy and US, with 47 also undergoing MRI. According to the KDIGO guidelines our cohort included: 12 A1 stage patients (1 G1, 1 G2, 2 G3a, 6 G3b, 2 G4); 27 in A2 stage (7 G1, 7 G2, 4 G3a, 7 G3b, 2 G4) and 21 in A3 (2 G1, 6 G3a, 6 G3b, 7 G4). According to the histological classification by Mazzucco et al (Am J Kidney Disease, 2002), 31% of DKD patients were categorized as Class 1 (diabetic glomerulosclerosis); 33% as Class 2 (vascular and ischemic glomerular changes); 4% as Class 3a (glomerular diseases superimposed on DN); 31% as Class 3b (other glomerulonephritis in the absence of DN). Pathologists assessment evidenced the presence of heterogeneous lesions among patients included within the same Mazzucco class. We thus proposed a novel classification of DKD, based both on renal pathology and according to the pathogenetic drivers. We identified 7 different histological classes of DKD: i) Class I: pure DN; ii) Class II: DN and nephroangiosclerosis; iii) Class III: DN and acute tubular necrosis; iv) Class IV: DN and Focal Segmental Glomerulosclerosis (FSGS); v) Class V: Nephroangiosclerosis; vi) Class VI: FSGS and other GN; vii) Class VII: FSGS and nephroangiosclerosis. According to the pathogenic drivers of DKD, we then grouped these classes in: pure metabolic damage (class I), metabolic damage and other drivers (including classes II, III, IV), pure vascular damage (class V) and immunological damage (classes VI, VII). Applying the newly proposed classification, we observed a significantly different distribution of key clinical parameters, uACR (p = 0.02), eGFR (p = 0.012), serum creatinine (p = 0.002) and proteinuria (p = 0.004). PAS glomerular staining positivity confirmed the more severe glomerular damage in the metabolic classes (p = 0.02); the wall-to-lumen ratio was able to significantly discriminate patients with vascular from those with immunological damage (p = 0.002). Finally, the renal resistive index measured through US significantly discriminated pure DN from mixed forms (p = 0.02) Conclusion The classification of renal damage in diabetes could represent a key strategy in the stratification of patients for precision medicine. The integration of renal pathology, US, ongoing MRI and omics data from the same patient has the potential to unlock new diagnostic tools and criteria to more accurately define the variety of renal phenotypes in diabetes.

MDB-43. GRADIENT ENTROPY-BASED RADIOMIC RISK-SCORE FROM T1-WEIGHTED PRE-TREATMENT MRI SCANS CAN PREDICT SURVIVAL IN PEDIATRIC MEDULLOBLASTOMA

Abstract BACKGROUND Medulloblastoma (MB) is the most frequent malignant brain tumor in children with an inadequate 5-year survival rate of 70-75%. A key determinate in MB treatment (consisting of radiation, chemotherapy) is the accurate risk-stratification of patients into low- and high-risk. The current stratification approaches (Chang’s classification, molecular categorization) are sub-optimal in predicting individual patient outcomes. Reliable risk-assessment approaches can significantly impact treatment management. Our group previously developed a new radiomics feature COLLAGE that measures the orientation of local intensity gradients as an estimate of lesion heterogeneity. We hypothesize that the disorder (i.e., heterogeneity) in orientation of local per-voxel intensity measured by COLLAGE, will tease-out differences in patients with low - versus high-risk MB tumors. METHODS T1-weighted MRI scans of 49 pediatric MB patients were retrospectively collected from Children’s Hospital Los Angeles and Cincinnati Children’s Hospital Medical Center. Registration of the scans was performed via age-specific pediatric atlases, followed by skull stripping and bias correction. Ground truth annotations for tumor sub-compartments; enhancing tumor, edema, and non-enhancing tumor, were generated by two experienced radiologists. Then, 52 Collage features were extracted from each of these sub-compartments, followed by conducting a Lasso model and a cox-proportional hazards model to identify the top features for risk-stratification. A continuous risk score was created for every patient and a risk threshold was obtained from the fitted cox model to stratify patients into low- and high-risk. RESULTS Our risk-score consisted of 13 top COLLAGE features from edema and 14 from non-enhancing tumor sub-compartments, respectively, and demonstrated significant differences between low- and high-risk patients (p = .017 for edema, p =0.0027 for non-enhancing tumor). CONCLUSION Our preliminary analysis suggests that gradient-entropy radiomic risk score maybe able to predict overall survival in pediatric MB tumors. In future, we plan to include additional patients to perform independent multi-site analysis.

Ewing’s Sarcoma of Rectum – A Rare Case Report

A 16-year-old male presented with constipation, acute retention of urine and abdominal swelling associated with pain. Per-rectal examination revealed painful growth in lateral and anterior wall of rectum 4cm from anal verge. X-ray erect abdomen was done which showed Indistinct bowel gas pattern suggestive of Intestinal obstruction. Diversion transverse colostomy was done in view of acute intestinal obstruction. Investigations revealed large well defined exophytic heterogenous lesion arising from lateral wall of rectum with normal CEA levels. Biopsy revealed small round blue cell tumour which was positive for Pan CK and CD99. He was planned for 6 cycles of Neoadjuvant chemotherapy (NACT) with VAC IE followed by reassessment for local therapy followed by adjuvant chemotherapy with 8 cycles of VAC IE. He received 6 cycles of VAC IE and Definitive radiation therapy 45Gy in 25 fractions by 3DCRT. After completion of radiation therapy, he received 8 more cycles of VAC IE in TATA memorial hospital. We present this case report, due to the rarity of Extraosseous Ewing’s sarcoma (EES)of the rectum.

Evaluation of the Blood-Brain Barrier, Demyelination, and Neurodegeneration in Paramagnetic Rim Lesions in Multiple Sclerosis on 7 Tesla MRI.

Paramagnetic rim lesions (PRLs) are associated with chronic inflammation in multiple sclerosis (MS). 7-Tesla (7T) magnetic resonance imaging (MRI) can evaluate the integrity of the blood-brain barrier (BBB) in addition to the tissue myelination status and cell loss. To use MRI metrics to investigate underlying physiology and clinical importance of PRLs. Prospective. Thirty-six participants (mean-age 47, 23 females, 13 males) of mixed MS subtypes. 7T, MP2RAGE, MULTI-ECHO 3D-GRE, FLAIR. Lesion heterogeneity; longitudinal changes in lesion counts; comparison of T1, R2*, and χ; association between baseline lesion types and disease progression (2-3 annual MRI visits with additional years of annual clinical follow-up). Two-sample t-test, Wilcoxon Rank-Sum test, Pearson's chi-square test, two-group comparison with linear-mixed-effect model, mixed-effect ANOVA, logistic regression. P-values <0.05 were considered significant. A total of 58.3% of participants had at least one PRL at baseline. Higher male proportion in PRL+ group was found. Average change in PRL count was 0.20 (SD = 2.82) for PRLs and 0.00 (SD = 0.82) for mottled lesions. Mean and median pre-/post-contrast T1 were longer in PRL+ than in PRL-. No differences in mean χ were seen for lesions grouped by PRL (P = 0.310, pre-contrast; 0.086, post-contrast) or PRL/M presence (P = 0.234, pre-contrast; 0.163, post-contrast). Median χ were less negative in PRL+ and PRL/M+ than in PRL- and PRL/M-. Mean and median pre-/post-contrast R2* were slower in PRL+ compared to PRL-. Mean and median pre-/post-contrast R2* were slower in PRL/M+ than in PRL/M-. PRL presence at baseline was associated with confirmed EDSS Plus progression (OR 3.75 [1.22-7.59]) and PRL/M+ at baseline with confirmed EDSS Plus progression (OR 3.63 [1.14-7.43]). Evidence of BBB breakdown in PRLs was not seen. Quantitative metrics confirmed prior results suggesting greater demyelination, cell loss, and possibly disruption of tissue anisotropy in PRLs. 2 TECHNICAL EFFICACY: Stage 2.

Abstract A043: Identifying tumor heterogeneity and drug sensitivity in primary prostate cancer towards personalized medicine

Abstract Introduction: Prostate cancer (PCa) is a highly heterogeneous disease with multiple and distinct cancer foci within the same prostate gland. We hypothesize that heterogeneous lesions, may be linked to different functional properties e.g. differential drug response sensitivity. Here we investigate which histopathological and molecular properties are associated with ability to maintain PCa cells as ex vivo organoid cultures and possibly specific drug responses. Methods: To simultaneously assess the histopathology, genetic profile and organoid drug sensitivity, we employed mirror biopsies for FFPE and cell preparations. Four cores of prostate tissue from radical prostatectomies (N=13) were used for generating patient-derived organoids (PDOs). Targeted genomic sequencing was performed on PDOs and their parental FFPE tissues. Drug response was evaluated by ATP-based viability assay after treatment with standard-of-care (AR inhibitors), and approved compounds for other malignancies (DNA synthesis, receptor tyrosine kinase (RTK) and mTOR inhibitors). RNA sequencing was performed on the parental cores. Associations among mutations, transcriptomic profile and PDO responses were being further explored using machine learning (ML) algorithms towards drug response prediction. Results: Histologically heterogeneous cores with different Gleason Score (GS range 6 to 9) per prostate were found in 76% of cases (N=10/13). A fraction of 78% of tumor-containing cores (N=22/28) and 66% of benign cores (N=16/24) gave rise to PDOs, showing a high formation efficiency. PCa somatic mutations were found in 19/32 cores, 11 cores of which shared mutations with their matching PDOs. The transcriptomic profile of each case was overall preserved among different cores. Drug responses in PDOs revealed not only inter- but also intra-patient heterogeneity with only 2 patient cases (N=2/13) having positive correlation within the different cores of the same case (Pearson’s R =0.58, 0.72 based on z-score viability). Instead, RTK inhibitors, Crizotinib and Ponatinib, showed high efficacy in the majority of cases (p&amp;lt;0.01 over vehicle, N=29/32 and N=30/32, respectively). Statistically significant correlations were found among 8 genomic mutations (mainly FGFR1, JAK2 and cell cycle members) and sensitivity to 5 drug compounds. Different features were tested for ML model, with RNA-seq outperforming the rest features; on average 260-1800 genes per drugs were selected for the drug prediction. ML linear regression models showed high Pearson’s correlation (R&amp;gt;0.8) between predicted and observed drug response values in 13/13 patients and 10/11 compounds tested. Conclusions: The majority of primary PCa cases showed genetic and histopathological multifocality, representing a highly heterogeneous cohort. PDOs recapitulated the genetic signature of the parental tissues. Drug responses of PDOs did not follow patient-specific patterns but rather revealed high inter- and intra-patient heterogeneity. Therapy response could be predicted based on transcriptomic profile for personalized treatment decision. Citation Format: Juening Kang, Sofia Karkampouna, Katja Ovchinnikova, Panagiotis Chouvardas, George Thalmann, Marianna Kruithof-de Julio. Identifying tumor heterogeneity and drug sensitivity in primary prostate cancer towards personalized medicine [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A043.

Abstract IA014: Drug sensitivity of multifocal primary prostate cancer

Abstract Prostate cancer (PCa) is a highly heterogeneous disease with multiple and distinct cancer foci within the same prostate gland. We hypothesize that heterogeneous lesions, in terms of genomic aberrations and tumour staging, may be linked to different functional properties e.g. differential drug response sensitivity. We investigate which histopathological and molecular properties are associated with ability to maintain PCa cells as ex vivo organoid cultures and possibly specific drug responses. Interestingly, the majority of primary PCa cases showed genetic and histopathological multifocality, representing a highly heterogeneous cohort. PDOs recapitulated the genetic signature of the parental tissues. Drug responses of PDOs did not follow patient-specific patterns but rather revealed high inter- and intra-patient heterogeneity. Therapy response could be predicted based on transcriptomic profile for personalized treatment decision. The transcriptomic profile of each case was overall preserved among different cores. Drug responses in PDOs revealed not only inter- but also intra-patient heterogeneity with only 2 patient cases having positive correlation within the different cores of the same case. Statistically significant correlations were found among 8 genomic mutations and sensitivity to 5 drug compounds. Different features were tested for ML model, with RNA-seq outperforming the rest features; on average 260-1800 genes per drugs were selected for the drug prediction. ML linear regression models showed high Pearson’s correlation between predicted and observed drug response values. Citation Format: Marianna Kruithof-de Julio, Juening Kang, Sofia Karkampouna, Katja Ovchinnikova, Panagiotis Chouvardas, George N Thalmann. Drug sensitivity of multifocal primary prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA014.

Size-related heterogeneity of colorectal liver metastases (CRLM) in patients with advanced RAS wild-type metastatic colorectal cancer (mCRC) treated in the PanaMa trial: Implication for treatment decisions.

3553 Background: In patients with mCRC, the liver represents the primary site of metastasis. In patients with primarily unresectable metastatic disease, primary tumor location and molecular subtypes mainly determine the therapeutic approach. In addition, image-based characterization of hepatic metastatic pattern may provide additional information concerning prognosis and treatment efficacy. Therefore, CRLM were characterized according to size-based heterogeneity in the PanaMa trial (maintenance therapy with 5-fluoruracil/leucovorin (FU/FA) plus panitumumab (Pmab) vs. FU/FA alone following induction therapy with six cycles of FU/FA, oxaliplatin and Pmab). Methods: Assessments were performed in patients with at least two lesions, considering target and non-target lesions, within a central radiological review of the trial. Variance in size expressed as ratio between the smallest and largest lesion measured (≤/ &gt; threefold difference in size) was evaluated for its prognostic and predictive impact on progression-free (PFS) and overall (OS) survival of maintenance therapy. Time-to-event endpoints were expressed by Kaplan-Meier method and compared by log-rank tests. Cox regressions were used to indicate Hazard ratios (HR) with 95% CIs. Results: Imaging data of 211/248 (85.1%) patients receiving maintenance therapy were evaluable for central radiological review (FU/FA+ Pmab, n = 106; FU/FA, n = 105). Of those, 165/211 patients (78.2%) had at least two CRLM. Size of CRLM ranged between 5–180mm, with the smallest metastasis in the individual assessments measuring a median of 12mm and the largest a median of 53mm. Large heterogeneity with more than a threefold difference in size between the smallest and largest CRLM was observed in 49.7% of patients, particularly pronounced in patients with polymetastatic disease ( &gt; 5 lesions). Homogeneous metastasis in terms of lesion size (≤ threefold difference) was associated with favorable OS (HR 0.63; 95% CI, 0.42–0.95; P = 0.027) - irrespective of study arm- compared to heterogeneous lesion disease. Maintenance therapy with FU/FA+ Pmab compared with FU/FA alone seemed favourably active in both patients with heterogeneous metastases (HR 0.53; 95% CI; 0.34–0.85; P = 0.008) as well as to a numerically lesser extent in patients with homogeneous metastases (HR 0.68; 95% CI, 0.43–1.10; P= 0.116). Conclusions: Imaging-based characterization of CRLM focusing on size-related heterogeneity was associated with favorable prognosis potentially indicating more aggressive underlying tumor dynamics in case of heterogeneous lesion size. In addition, the efficacy of Pmab during maintenance was evident in both patient groups (homogeneous and heterogeneous disease lesions) with a numerically greater effect in patients with heterogeneous lesions. Clinical trial information: NCT01991873 .

Sonographic Features of Primary Breast Lymphoma: An Analysis of 10 Cases.

Primary breast lymphoma (PBL) is a rare malignant breast tumor. The literature concerning PBL ultrasound is based primarily on case reports, with only a few cases reported to date. This study aimed to elucidate the sonographic characteristics of PBL and explore the value of ultrasonography in the preoperative diagnosis of PBL using the Breast Imaging Reporting and Data System (BI-RADS). A retrospective review of files involving a diagnosis of PBL (2013-2020) was conducted in the Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, and the First Affiliated Hospital of Wenzhou Medical University, Wenzhou. The clinical characteristics and sonographic features of 12 lesions in 10 patients were analyzed and discussed in light of the literature. All patients, aged 50.40 ± 14.31 years (range 30-66 years), had clinically palpable lumps. Most cases were on the right breast and were unilateral. Only one patient had mucosa-associated lymphoma. The histological type of the other patients was diffuse large B-cell lymphoma (DLBCL). Ultrasonography revealed nodular and diffuse PBL lesions without internal calcification. The nodular PBL was hypoechoic or mixed hypo- to hyperechoic, with a differential lobulated shape and horizontal growth. Although color Doppler flow imaging (CDFI) showed no significant features, the ultrasound findings were categorized as BI-RADS 4 in 10 of the 12 lesions and BI-RADS 5 in two lesions. All patients were suspected of having malignancies (BI-RADS 4 or 5). PBL was mostly found in middle-aged and elderly women, and the right breast was more prone to the development of malignancies. PBL lesions were classified as either nodular or diffuse based on the boundaries of the tumors in the ultrasound images. Typical PBL was characterized by hypoechoic or heterogeneous lesions with circumscribed or microlobulated margins and horizontal growth. The sonographic features of the PBL lesions and the BI-RADS categorizations of the lesions analyzed suggested malignancy.

Immunohistochemical expression of BCL-2 in hydatidiform moles: a tissue microarray study.

Hydatidiform moles (HM) are members of gestational trophoblastic diseases (GTD) and, in some cases, might progress to gestational trophoblastic neoplasia (GTN). HMs are either partial (PHM) or complete (CHM). Some HMs are challenging in arriving at a precise histopathological diagnosis. This study aims to investigate the expression of BCL-2 by immunohistochemistry (IHC) in HMs as well as in normal trophoblastic tissues "products of conception (POC) and placentas" using Tissue MicroArray (TMA) technique. TMAs were constructed using the archival material of 237 HMs (95 PHM and 142 CHM) and 202 control normal trophoblastic tissues; POC and unremarkable placentas. Sections were immunohistochemically stained using antibodies against BCL-2. The staining was assessed semi-quantatively (intensity and percentage of the positive cells) in different cellular components (trophoblasts and stromal cells). BCL-2 showed cytoplasmic expression in more than 95% of trophoblasts of PHM, CHM and controls. The staining showed a significant reduction of the intensity from controls (73.7%), PHMs (76.3%) to CHM (26.9%). There was a statistically significant difference between PHM and CHM in the intensity (p-value 0.0005) and the overall scores (p-value 0.0005), but not the percentage score (p-value > 0.05). No significant difference was observed in the positivity of the villous stromal cells between the different groups. All cellular components were visible using the TMA model of two spots/case (3 mm diameter, each) in more than 90% of cases. Decreased BCL-2 expression in CHM compared to PHM and normal trophoblasts indicates increased apoptosis and uncontrolled trophoblastic proliferation. Construction of TMA in duplicates using cores of 3 mm diameter can overcome tissue heterogeneity of complex lesions.

Tumor heterogeneity and treatment response assessment using next generation imaging and liquid biopsy in patients with metastatic castration resistant prostate cancer receiving abiraterone (ANGELA): A single-center prospective observational trial.

5057 Background: Metastatic castration resistant prostate cancer (mCRPC) is a disease of intra-patient tumor heterogeneity which poses obstacles in treatment and response evaluation. With the development of next generation imaging (NGI) and liquid biopsy, precise assessment of heterogeneity has entered a new era. In this study, we used longitudinal NGI (68Ga-PSMA and 18F-FDG PET/CT) and circulating tumor DNA (ctDNA) testing to assess tumor heterogeneity and treatment response in mCRPC patients receiving abiraterone. Methods: ANGELA is a single-center prospective observational trial (NCT05188911). We recruited mCRPC patients who received abiraterone as initial hormonal treatment. Eligible patients should have a life expectancy &gt;12 months. CtDNA testing and NGI were performed at baseline and after 12 weeks of abiraterone (Week 13). Conventional imaging and PSA testing were performed at Week 1 and every 12 weeks. Primary end-point of this study is intra-patient lesion heterogeneity evaluated by 3 dimensions: (1) Imaging heterogeneity: defined as at least 1 lesion with FDG+/PSMA- phenotype at baseline and/or Week 13; (2) Genomic heterogeneity: quantified by ctDNA fraction increase and mutational changes per gene between baseline and Week 13; (3) Response heterogeneity: defined as at least 1 new tumoral lesion with either PSMA or FDG abnormal uptake at Week 13. Secondary end-points are correlations of heterogeneity with conventional-evaluated progression-free survival (PFS) and 2-year overall survival (OS). Results: Between May 20, 2020 and Feb 02, 2021, we included 33 eligible patients in our study. FDG+/PSMA- tumoral lesion was observed in 7/33 (21.2%) and 8/33 (24.2%) of patients at baseline and Week 13, respectively. Notably, 5 of 8 patients with imaging heterogeneity at Week 13 had no FDG+/PSMA- lesion at baseline. For genomic heterogeneity, we detected ctDNA fraction increase in 4/33 patients (12.1%). In addition, we found new gene mutations detected in Week 13 ctDNA testing in 5/33 patients (15.2%), 2 of 5 had ctDNA fraction increase. For response heterogeneity, we observed 15/33 patients (45.5%) patients developed at least 1 new tumoral lesion (FDG+ or PSMA+) at Week 13. We correlated heterogeneity factors with prognosis, and found that detection of new mutated genes (P=0.005 and P&lt;0.001), new PSMA+ lesion (P&lt;0.001 and P&lt;0.001), and new FDG+ lesion (P=0.008 and P&lt;0.0001) at Week 13 were significant predictors of shorter PFS and decreased 2-year OS. Detailed biomarker study for response analysis is still in process. Conclusions: Intra-patient tumor heterogeneity was common among mCRPC patients receiving abiraterone. Combining liquid biopsy with NGI can monitor changes in tumor heterogeneity and indicate early combination therapy. Clinical trial information: NCT05188911 .

Comparing the predictive value of quantitative magnetic resonance imaging parametric response mapping and conventional perfusion magnetic resonance imaging for clinical outcomes in patients with chronic ischemic stroke.

Predicting clinical outcomes after stroke, using magnetic resonance imaging (MRI) measures, remains a challenge. The purpose of this study was to investigate the prediction of long-term clinical outcomes after ischemic stroke using parametric response mapping (PRM) based on perfusion MRI data. Multiparametric perfusion MRI datasets from 30 patients with chronic ischemic stroke were acquired at four-time points ranging from V2 (6 weeks) to V5 (7 months) after stroke onset. All perfusion MR parameters were analyzed using the classic whole-lesion approach and voxel-based PRM at each time point. The imaging biomarkers from each acquired MRI metric that was predictive of both neurological and functional outcomes were prospectively investigated. For predicting clinical outcomes at V5, it was identified that PRMTmax-, PRMrCBV-, and PRMrCBV+ at V3 were superior to the mean values of the corresponding maps at V3. We identified correlations between the clinical prognosis after stroke and MRI parameters, emphasizing the superiority of the PRM over the whole-lesion approach for predicting long-term clinical outcomes. This indicates that complementary information for the predictive assessment of clinical outcomes can be obtained using PRM analysis. Moreover, new insights into the heterogeneity of stroke lesions revealed by PRM can help optimize the accurate stratification of patients with stroke and guide rehabilitation.

Clinical and radiographic features of adult calcified thoracic disc herniation: a retrospective analysis of 31 cases.

To analyze the clinical and radiographic characteristics of calcified thoracic disc herniation (CTDH) and explore the possible pathogeneses. This is a retrospective clinical review of prospectively collected imaging data based at a single institute from 2004 to 2021. Clinical and radiographic parameters of CTDH patients were retrospectively collected and analyzed. All 31 patients included presented thoracic myelopathy with a 17.05-month preoperative disease duration. Three (9.7%) patients had a history of trauma, and the rest had insidious onset. The average spinal canal ventral-occupying ratio was 74.90 ± 15.16%. The most prominent radiographic feature was the calcification of the nucleus pulposus in the intervertebral disc and the calcified lesion contiguous with the disc space protruding into the spinal canal. Three main imaging forms of CTDH were found: calcium-ringed lesion (5), heterogeneous calcification lesion (19), and homogeneous calcification lesion (7). The radiographic manifestations, intraoperative findings, and postoperative pathologies of the three subtypes were different. The calcium-ringed lesion type was younger and had a shorter preoperative duration and significantly lower mJOA score. A special case was observed conservatively for five years, which suggested that a heterogeneous lesion could progress to a homogeneous lesion. Adult CTDH is a special thoracic disc disease with insidious onset, a long course, and a high spinal canal-occupying ratio. Calcium deposits in the spinal canal originate from the nucleus pulposus. The intraoperative findings and postoperative pathology of subtypes are different, which might indicate different pathological mechanisms.

Imaging Features of Intraosseous Schwannoma: A Case Series and Review of the Literature.

To characterize the imaging features of patients with pathologically confirmed intraosseous schwannoma (IOS), institutional pathology and imaging databases were searched for IOS cases over a period of 17 years. A musculoskeletal radiologist evaluated all imaging studies. Additionally, a literature search was performed to identify IOS cases that had imaging findings of at least two modalities. Six patients (one female, five males, mean age of 50 ± 14 years) with IOS were identified, with all lesions localized to the lumbosacral region. Radiographic imaging was available in four patients, while all patients underwent CT and MR imaging. Radiographs depicted lytic lesions, and CT depicted heterogeneous expansile lesions with centrally hypodense areas and peripheral sclerosis. All cases involved extra-osseous extension, producing a mass effect on adjacent soft tissues and nerve roots. On MRI, the neoplasms displayed iso- to- slightly- low signal intensity on T1-weighted images and hyperintense signal intensity on T2-weighted images with heterogeneous enhancement. The literature review resulted in 102 IOS cases, which to the best of our knowledge, is the largest review on IOS, and the imaging findings of the previously published cases were the same as our cases. IOSs are rare benign neoplasms that should be considered in the differential diagnosis of well-defined expansile lytic lesions with sclerotic borders. This is particularly important in middle-aged adults with mandibular, sacral, or vertebral body mass.

PO-04-001 COMPARISONS OF ABLATION LESION FEATURES ALONG PULMONARY VEIN ISOLATION LINES USING RADIOFREQUENCY ABLATION CATHETER AND CRYOBALLOON ABLATION CATHETER

Direct cell injury and intense inflammatory response occur in radiofrequency ablation (RFA), therefore, heterogeneous ablation lesions were created. Conversely, in cryoballoon ablation (CBA), ablation lesion is created without injury of endocardial tissue architecture and catheter position is stable by adhesion of the catheter to tissues, hence homogeneous ablation lesions were created. However, few studies have investigated the homogeneity of border zone between the left atrium and pulmonary vein isolation (PVI) lines among energy sources. We hypothesized that heterogeneous lesion along PVI lines are more frequently found in patients undergoing RFA than those undergoing CBA. The purpose of this study was to investigate the association between homogeneity of ablation lesions along PVI lines and energy source of catheter ablation. In total, 79 consecutive patients who underwent second AF ablation with RhythmiaTM mapping system (age, 70 ± 9 years; female, 26 [33%]) were retrospectively enrolled. As an indicator of heterogeneous lesion, gaps and fractionated signals along previous PVI lines was assessed during pacing from the right atrium. Fractionated signal was defined as electrograms with at least 7 deflections highlighted by LUMIPOINTTM complex activation tool. The proportion of line length with fractionated signals to anatomical line length was compared between patients undergoing RFA and patients undergoing CBA. CBA were performed for 31 (39%) patients in initial AF ablation. There were more PV gaps in CBA group than in RFA group (1 [1-2] versus 0 [0-1], p < 0.001). Anatomical line length of left pulmonary vein and right pulmonary vein were similar in CBA group and RFA group (left pulmonary vein, 121 [109-136] mm versus 118 [107-133] mm, p = 0.78; right pulmonary vein, 126 [116-139] mm versus 121 [108-131] mm, p = 0.08). The proportion of line length with fractionated signals to anatomical line length of left pulmonary vein and right pulmonary vein was significantly higher in RFA group than in CBA group (Figure). In regions other than left posterior region, left bottom region and right bottom region, the proportion of line length with fractionated signals to anatomical line length was also significantly higher in RFA group than in CBA group (Figure). PVI lines created by RFA demonstrated serrated bordering zones, whereas PVI using CBA created sharply delineated lesions.

Abstract IA11: Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions

Abstract Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS, but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia. Citation Format: Laura D. Wood. Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA11.

Pseudoangiomatous stromal hyperplasia of the breast

Pseudoangiomatous stromal hyperplasia of the breast is a rare benign mesenchymal lesion of the breast. We present a case of a 49-year-old female patient who consulted for having a rapidly and progressively growing tumor in her left breast. Breast ultrasound showed a heterogeneous and hypoechoic lesion with several nodules. Mammography showed an oval tumor with diffuse margins without microcalcifications. Ultrasound-guided core needle biopsy revealed cellular findings compatible with breast fibroma. The anatomopathological diagnosis was pseudoangiomatous stromal hyperplasia of the breast. This is a rare benign mesenchymal tumor secondary to exacerbated proliferation of mature fibroblasts and myofibroblasts, whose triggering factor is still unknown. Most present as diffuse lesions, and the diagnosis is often incidental or in the context of other breast pathologies.