Tumor Growth Pattern Research Articles

Prognostic MRI features to predict postresection survivals for very early to intermediate stage hepatocellular carcinoma

ObjectivesContrast-enhanced MRI can provide individualized prognostic information for hepatocellular carcinoma (HCC). We aimed to investigate the value of MRI features to predict early (≤ 2 years)/late (> 2 years) recurrence-free survival (E-RFS and L-RFS, respectively) and overall survival (OS).Materials and methodsConsecutive adult patients at a tertiary academic center who received curative-intent liver resection for very early to intermediate stage HCC and underwent preoperative contrast-enhanced MRI were retrospectively enrolled from March 2011 to April 2021. Three masked radiologists independently assessed 54 MRI features. Uni- and multivariable Cox regression analyses were conducted to investigate the associations of imaging features with E-RFS, L-RFS, and OS.ResultsThis study included 600 patients (median age, 53 years; 526 men). During a median follow-up of 55.3 months, 51% of patients experienced recurrence (early recurrence: 66%; late recurrence: 34%), and 17% died. Tumor size, multiple tumors, rim arterial phase hyperenhancement, iron sparing in solid mass, tumor growth pattern, and gastroesophageal varices were associated with E-RFS and OS (largest p = .02). Nonperipheral washout (p = .006), markedly low apparent diffusion coefficient value (p = .02), intratumoral arteries (p = .01), and width of the main portal vein (p = .03) were associated with E-RFS but not with L-RFS or OS, while the VICT2 trait was specifically associated with OS (p = .02). Multiple tumors (p = .048) and radiologically-evident cirrhosis (p < .001) were the only predictors for L-RFS.ConclusionTwelve visually-assessed MRI features predicted postoperative E-RFS (≤ 2 years), L-RFS (> 2 years), and OS for very early to intermediate-stage HCCs.Clinical relevance statementThe prognostic MRI features may help inform personalized surgical planning, neoadjuvant/adjuvant therapies, and postoperative surveillance, thus may be included in future prognostic models.Key Points• Tumor size, multiple tumors, rim arterial phase hyperenhancement, iron sparing, tumor growth pattern, and gastroesophageal varices predicted both recurrence-free survival within 2 years and overall survival.• Nonperipheral washout, markedly low apparent diffusion coefficient value, intratumoral arteries, and width of the main portal vein specifically predicted recurrence-free survival within 2 years, while the VICT2 trait specifically predicted overall survival.• Multiple tumors and radiologically-evident cirrhosis were the only predictors for recurrence-free survival beyond 2 years.Graphical

Posterior fossa hemangioblastoma in children: literature review

Introduction: Posterior fossa hemangioblastomas (HBs) are uncommon benign neoplasms, comprising 1.5-2.5% of intracranial tumors and 7-8% of posterior cranial fossa tumors. They predominantly impact the central nervous system, often localizing within the cerebellar hemispheres of individuals aged 50-60 years, with higher prevalence among adults and limited occurrence in the pediatric population. This review sheds light on the distinctive clinical characteristics of pediatric HBs Methods: Employing the PRISMA guidelines, databases like SciELO, Lilacs, and PubMed were meticulously searched, deploying keywords "hemangioblastoma" and "posterior fossa." Inclusion criteria spanned articles published from 2003-2023 in English or Portuguese, focusing on pediatric cases. Results: The search yielded 16 relevant articles from PubMed and 72 from Lilacs, with SciELO yielding no relevant results. Rigorous assessment against the predetermined criteria identified 10 pertinent articles from Lilacs discussing pediatric posterior fossa HBs, encompassing topics like imaging, pathophysiology, immunohistochemistry, and therapeutic modalities. Diverse themes were explored, including pregnancy-related manifestations, tumor growth patterns, and treatment approaches such as surgical resection, radiotherapy, neuronavigation, and presurgical embolization. Advanced imaging techniques, like high-resolution 3D multifusion medical imaging, were also explored. Conclusion: Early diagnosis and a comprehensive multidisciplinary strategy are essential in managing pediatric posterior fossa HBs. Genetic insights and advanced imaging techniques, coupled with precise surgical interventions, play a pivotal role in improving prognosis and elevating the quality of life for patients. The genetic context of VHL mutations, the centrality of MRI in early detection, and the prominence of complete surgical resection underscore the multifaceted comprehension indispensable for effective management.

Computed tomographic imaging features to differentiate gastric schwannomas from gastrointestinal stromal tumours: a matched case–control study

To investigate clinical data and computed tomographic (CT) imaging features in differentiating gastric schwannomas (GSs) from gastric stromal tumours (GISTs) in matched patients, 31 patients with GSs were matched with 62 patients with GISTs (1:2) in sex, age, and tumour site. The clinical and imaging data were analysed. A significant (P < 0.05) difference was found in the tumour margin, enhancement pattern, growth pattern, and LD values between the 31 patients with GSs and 62 matched patients with GISTs. The GS lesions were mostly (93.5%) well defined while only 61.3% GIST lesions were well defined.The GS lesions were significantly (P = 0.036) smaller than the GIST lesions, with the LD ranging 1.5–7.4 (mean 3.67 cm) cm for the GSs and 1.0–15.30 (mean 5.09) cm for GIST lesions. The GS lesions were more significantly (P = 0.001) homogeneously enhanced (83.9% vs. 41.9%) than the GIST lesions. The GS lesions were mainly of the mixed growth pattern both within and outside the gastric wall (74.2% vs. 22.6%, P < 0.05) compared with that of GISTs. No metastasis or invasion of adjacent organs was present in any of the GS lesions, however, 1.6% of GISTs experienced metastasis and 3.2% of GISTs presented with invasion of adjacent organs. Heterogeneous enhancement and mixed growth pattern were two significant (P < 0.05) independent factors for distinguishing GS from GIST lesions. In conclusion: GS and GIST lesions may have significantly different features for differentiation in lesion margin, heterogeneous enhancement, mixed growth pattern, and longest lesion diameter, especially heterogeneous enhancement and mixed growth pattern.

Predictive value of infiltrating tumor border configuration of rectal cancer on MRI

BackgroundInfiltrating tumor border configuration (iTBC) is assessed by postoperative pathological examination, thus, is not helpful for preoperative treatment strategies. The study aimed to detect iTBC by magnetic resonance imaging (MRI) and evaluate its predictive value.Materials and methodsA total of 153 patients with rectal cancer were retrospectively analyzed. Clinicopathological and MRI data mainly including tumor border configuration (TBC) on MRI, MRI-detected extramural vascular invasion (MEMVI), tumor length, tumor growth pattern, maximal extramural depth, pathology-proven lymph node metastasis (PLN) and pathology-proven extramural vascular invasion (PEMVI) were analyzed. The correlation of MRI factors with PEMVI and PLN was analyzed by univariate and multivariate logistic regression analyses. The nomograms were established based on multivariate logistic regression analysis and were confirmed by Bootstrap self-sampling. The receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to evaluate the diagnostic efficiency.ResultsFifty cases of PEMVI and 48 cases of PLN were found. Forty cases of PEMVI and 34 cases of PLN in 62 cases of iTBC were also found. iTBC, MEMVI and maximal extramural depth were significantly associated with PEMVI and PLN (P < 0.05). iTBC (odds ratio = 3.84 and 3.02) and MEMVI (odds ratio = 7.27 and 3.22) were independent risk factors for PEMVI and PLN. The C-indices of the two nomograms for predicting PEMVI and PLN were 0.863 and 0.752, respectively. The calibration curves and ROC curves of the two nomograms showed that the correlation between the predicted and the actual incidence of PEMVI and PLN was good. The AUCs of iTBC for predicting PEMVI and PLN were 0.793 (95% CI: 0.714–0.872) and 0.721 (95% CI: 0.632–0.810), respectively. The DeLong test showed that the predictive efficiency of the nomogram in predicting PEMVI was better than that of iTBC (P = 0.0009) and MEMVI (P = 0.0095).ConclusioniTBC and MEMVI are risk factors for PEMVI and pelvic lymph node metastasis. The nomograms based on iTBC show a good performance in predicting PEMVI and pelvic lymph node metastasis, possessing a certain clinical reference value.Trial registrationThis study was approved by the Ethics Committee of Beijing Friendship Hospital, and individual consent was waived for this retrospective analysis.

Effects of imipramine on cancer patients over-expressing Fascin1; description of the HITCLIF clinical trial.

Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression. The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration). Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and anti-metastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front. https:///www.clinicaltrialsregister.eu/ctr-search/trial/2021-001328-17/ES, identifier 2021-001328-17.

B-359 Bap1 Overexpression Enhances Epithelial-mesenchymal Transition in Cholangiocarcinoma

Abstract Background BRCA1-associated protein 1 (BAP1) is a nuclear protein that considered as a tumor suppressor by its involvement in DNA double-strand-break repair. However, BAP1 overexpression was observed in many kinds of cancer, such as intrahepatic cholangiocarcinoma (iCCA). Methods and Results Formalin-fixed paraffin-embedded cancer tissues were acquired from the archive of the Department of Pathology, Chang Gung Memorial Hospital at Kaohsiung, Taiwan. In this study, we identified 23.8% cytoplasmic BAP1 overexpression and 20.8% nuclear BAP1 overexpression cases in 101 iCCA patients. There were significant correlations between cytoplasmic expression of BAP1 with tumor growth pattern (P = 0.005), T classification (P = 0.006), and clinical AJCC seventh staging (P &amp;lt; 0.001). In cell models (iCCA cell line RBE), overexpressed BAP1 were accumulated in cytoplasm. The translatome profile suggested that BAP1 overexpression may promote the migratory and invasive capacities of iCCA cells. In-vitro assays validated that BAP1 overexpression enhanced cell migration and invasion. Furthermore, we found that BAP1 overexpression induced epithelial-mesenchymal transition (EMT) in iCCA cells, showing E-cadherin and fibronection down-regulation and vimentin up-regulation. Conclusion These findings indicated that cytoplasmic BAP1 overexpression increased migratory and invasive capacities in iCCA cells, at least in part, via enhanced EMT regulations. Based on these findings, cytoplasmic BAP1 expression could be a candidate predictor for metastasis of iCCA.

Impact of three surgical approaches on the therapeutic efficacy of intraventricular craniopharyngiomas: a single-center retrospective analysis.

This study aimed to investigate the therapeutic efficacy of three different surgical approaches for the treatment of intraventricular craniopharyngiomas (IVCs). The three surgical approaches investigated in this study were the endoscopic endonasal approach (EEA), pterional trans-lamina terminalis approach (PTA), and interhemispheric trans-lamina terminalis approach (ITA). Patient demographics, preoperative symptoms, endocrine and hypothalamic status, tumor characteristics, and surgical outcomes were analyzed and compared among the different surgical groups. A total of 31 patients with IVCs were included in the analysis, with 12 patients in the EEA group, 8 patients in the ITA group, and 11 patients in the PTA group. The mean follow-up time was 39 ± 23months. Statistical analysis of the data revealed significant differences in the gross total resection (GTR) rate among the three surgical groups (P = 0.033). The GTR rate for the EEA group was 100%, that for the ITA group was 88%, and that for the PTA group was 64%, which was the lowest rate observed. After surgery, only 8.3% of the patients in the EEA group did not experience new postoperative hypopituitarism, while the percentages in the ITA and PTA groups were 75% and 73%, respectively (P = 0.012). Finally, we found that postoperative hypopituitarism may be related to the transection of the pituitary stalk during the operation (P = 0.020). Based on the results of this study, we recommend using the EEA and the ITA instead of the PTA for the surgical resection of IVCs. Furthermore, the appropriate surgical approach should be selected based on the tumor's growth pattern.

T1a Renal Cell Carcinoma With Metastasis: Japanese Society of Renal Cancer Retrospective Multi-institute Results.

Small renal cell carcinomas (sRCC) have drastically increased in recent years. Considering that sRCC have heterogeneous biology, it would be clinically relevant if specific clinical or pathological parameters could predict sRCC metastasis. In the present study, we aimed to assess the clinicopathological factors of pathologic T1a RCC (pT1a RCC) with or without metastasis to explore factors predicting metastasis. The present study included 198 patients with pT1a RCC who underwent radical or partial nephrectomy at fifteen institutions belonging to the Japanese Society of Renal Cancer, between1985 and 2017. Clinicopathological parameters, including age, sex, tumour size, tumour side, histological subtype, histological nuclear grade, lymphovascular invasion, and histological growth patterns, were analysed. Fuhrman grade 3 or 4 tumours and infiltrative tumour growth patterns were significantly higher in patients with metastasis than in those without. The most common site of synchronous metastasis was the bone in patients with pT1a RCC (65.4%), whereas for patients with post-surgery metachronous metastasis (46.2%), it was the lungs. Histological growth pattern and nuclear grade are vital for predicting metastasis in pT1a RCC, suggesting careful long-term follow-up for such patients.

Evaluation of the clinical behavior of unclassified renal cell carcinoma and its imaging findings on computed tomography and magnetic resonance imaging based on World Health Organization (WHO) 2022

ObjectivesTo ascertain the clinical behaviors of unclassified renal cell carcinoma (RCC) and its characteristic imaging findings on CT and MRI.MethodsSubjects in this retrospective study were 10 patients who had received a histological diagnosis of unclassified RCC based on World Health Organization (WHO) 2022 and who had undergone CT and/or MRI prior to surgery. In terms of clinical behaviors, TNM classification, stage, postoperative recurrence, time to recurrence, and postoperative survival were evaluated. In terms of imaging findings, tumor size, growth pattern, CT density, dynamic contrast-enhancement (DCE) pattern, internal appearance, presence of a pseudocapsule, and signal intensity on MRI were evaluated. We compared clinical behaviors and imaging findings, and investigated associations between them.ResultsOne patient could not be followed-up due to death from other causes. Postoperative recurrence was observed in 4 patients, all of whom had Stage 3 RCC. In the remaining 5 patients without recurrence, all 5 patients showed Stage 2 or below. On imaging, unclassified RCC tended to be large (58.7 mm) and solid (100%), and heterogeneous interiors (80%), cystic degeneration (80%) and high intensity on diffusion-weighted imaging (DWI) (71.4%) were common. Comparing patients with and without recurrence, the following findings tended to differ between recurrence and recurrence-free groups: tumor size (73.4 ± 33.9 mm vs. 50.2 ± 33.9 mm, P = 0.286), growth pattern (invasive: 100% vs. 0%, expansive: 0% vs. 100%, P = 0.008 each), DCE pattern (progressive enhancement pattern, 66.7% vs. 0%, washout pattern, 0% vs. 66.7%, P = 0.135 each) and presence of a pseudocapsule (25% vs. 80%, P = 0.167).ConclusionThe clinical behavior of unclassified RCC varies widely. Although imaging findings are also variable, findings of large, heterogeneous tumors with cystic degeneration and high intensity on DWI were common. Several imaging findings such as large size, invasive growth, progressive enhancement pattern and no pseudocapsule may enable prediction of prognosis in unclassified RCC.

Machine learning for classification of cutaneous sebaceous neoplasms: implementing decision tree model using cytological and architectural features

BackgroundThis observational study aims to describe and compare histopathological, architectural, and nuclear characteristics of sebaceous lesions and utilized these characteristics to develop a predictive classification approach using machine learning algorithms.MethodsThis cross-sectional study was conducted on Iranian patients with sebaceous tumors from two hospitals between March 2015 and March 2019. Pathology slides were reviewed by two pathologists and the architectural and cytological attributes were recorded. Multiple decision tree models were trained using 5-fold cross validation to determine the most important predictor variables and to develop a simple prediction model.ResultsThis study assessed the characteristics of 123 sebaceous tumors. Histopathological findings, including pagetoid appearance, neurovascular invasion, atypical mitosis, extensive necrotic area, poor cell differentiation, and non-lobular tumor growth pattern, as well as nuclear features, including highly irregular nuclear contour, and large nuclear size were exclusively observed in carcinomatous tumors. Among non-carcinomatous lesions, some sebaceoma and sebaceous adenoma cases had features like high mitotic activity, which can be misleading and complicate diagnosis. Based on multiple decision tree models, the five most critical variables for lesion categorization were identified as: basaloid cell count, peripheral basaloid cell layers, tumor margin, nuclear size, and chromatin.ConclusionsThis study implemented a machine learning modeling approach to help optimally categorize sebaceous lesions based on architectural and nuclear features. However, studies of larger sample sizes are needed to ensure the accuracy of our suggested predictive model.

ConvLSTM coordinated longitudinal transformer under spatio-temporal features for tumor growth prediction

Accurate quantification of tumor growth patterns can indicate the development process of the disease. According to the important features of tumor growth rate and expansion, physicians can intervene and diagnose patients more efficiently to improve the cure rate. However, the existing longitudinal growth model can not well analyze the dependence between tumor growth pixels in the long space-time, and fail to effectively fit the nonlinear growth law of tumors. So, we propose the ConvLSTM coordinated longitudinal Transformer (LCTformer) under spatiotemporal features for tumor growth prediction. We design the Adaptive Edge Enhancement Module (AEEM) to learn static spatial features of different size tumors under time series and make the depth model more focused on tumor edge regions. In addition, we propose the Growth Prediction Module (GPM) to characterize the future growth trend of tumors. It consists of a Longitudinal Transformer and ConvLSTM. Based on the adaptive abstract features of current tumors, Longitudinal Transformer explores the dynamic growth patterns between spatiotemporal CT sequences and learns the future morphological features of tumors under the dual views of residual information and sequence motion relationship in parallel. ConvLSTM can better learn the location information of target tumors, and it complements Longitudinal Transformer to jointly predict future imaging of tumors to reduce the loss of growth information. Finally, Channel Enhancement Fusion Module (CEFM) performs the dense fusion of the generated tumor feature images in the channel and spatial dimensions and realizes accurate quantification of the whole tumor growth process. Our model has been strictly trained and tested on the NLST dataset. The average prediction accuracy can reach 88.52% (Dice score), 89.64% (Recall), and 11.06 (RMSE), which can improve the work efficiency of doctors.

Type B2 vessels and infiltrative growth patterns b and c are associated with lymphatic invasion in pT1a-lamina propria mucosa esophageal squamous cell carcinoma.

Tumor growth pattern correlates with outcomes in patients with esophageal squamous cell carcinoma (ESCC), however, the clinical significance of the tumor growth pattern in pT1a-lamina propria mucosa (LPM) type of ESCC was unclear. This study was conducted to clarify clinicopathological features of tumor growth patterns in pT1a-LPM type ESCC and the relationship between tumor growth patterns and magnifying endoscopic findings. Eighty-seven lesions diagnosed as pT1a-LPM ESCC were included. Clinicopathological findings including tumor growth pattern and narrow band imaging with magnifying endoscopy (NBI-ME) in the LPM area were investigated. Eighty-seven lesions were classified as infiltrative growth pattern-a (INF-a): expansive growth (n = 81), INF-b: intermediate growth (n = 4) and INF-c: infiltrative growth pattern (n = 2). Lymphatic invasion was shown in one INF-b and one INF-c lesion. NBI-ME and histopathological images were matched for 30 lesions. The microvascular pattern was classified into types B1 (n = 23) and B2 (n = 7) using the JES classification. All 23 type B1 lesions were classified as INF-a without lymphatic invasion. Type B2 lesions were classified as INF-a (n = 2), INF-b (n = 4) and INF-c (n = 1), and lymphatic invasion was present in two lesions (INF-b and INF-c). The rate of lymphatic invasion was significantly higher in type B2 than type B1 (p = 0.048). The tumor growth pattern of pT1a-LPM ESCC was mostly INF-a in type B1 patterns. Type B2 patterns are rarely present in pT1a-LPM ESCC, however lymphatic invasion with INF-b or INF-c was frequently observed. Careful observation before endoscopic resection with NBI-ME is important to identify B2 patterns to predict histopathology.

MRI Semiotics Features and Difficulties of Differential Diagnosis of Hepatic Metastases from Neuroendocrine Tumours

Relevance: Isolated bilobar multifocal hepatic lesion is consider to be the most common metastatic neuroendocrine tumor(NET) growth pattern. Underestimation of the metastatic burden in the NET patients at the initial diagnosis frequently occurs, thus leading to a high postoperative recurrence rate (more than 60 % of cases within 5 years).Purpose: To identify the MRI-hallmarks of liver metastatic NETs and to present the most difficult diagnostic cases.Material and methods: 103 patients with histology confirmed liver metastatic NET were enrolled in the study. All patients underwent abdominal contrast-enhanced (CE) MRI. A total of 241 lesions were assessed. Quantitative indicators of signal intensity (SI) on native and post-contrast T1-weighted images (WI) were measured in metastases. Additionally, the shape, contours, surface of metastases, SI on native images, characteristics of CE, the presence of hemoglobin degradation products and the boundary levels in the structure of metastases were qualitatively assessed.Results: Metastatic liver disease in NET is mostly multifocal: 78 (75.7 %) patients had 5 or more lesions. Metastases were round in 53.5 % of cases, oval in 17.5 % of cases, irregular in 29 % of cases. In 61 % of cases, the contours of the lesions were clear, in 39 % — indistinct. Smooth and bumpy surface of metastases was determined in 31.5 % and 68.5 % of cases, respectively. The presence of hemoglobin degradation products in the structure of metastases was determined in 26.2 % of patients, the formation of the boundary levels — in 8.1 % of patients. Most of the lesions had a hyperintense signal on T2-WI with and without FS and a hypointense signal on native T1-WI. The proportions of actively, moderately and poorly MR contrast agent (MRCA) enhanced lesions were 30.8, 32.6 and 36.6 %, in the arterial phase and 16.3, 55.4 and 28.3 % in the venous phase, respectively. The apparent diffusion coefficient (ADC) values varied significantly. In some cases, small metastatic NET were visualized only in the arterial phase of CE and were not detected on other MRI sequences, thus requiring differentiation from other hepatic hypervascular lesions.Conclusion. The MRI semiotics features of hepatic metastases from NETs is described. Small flesions of active accumulation of MRCA in the arterial phase in the presence of primary NET must be differentiated from metastatic lesions.

Correlation of Programmed Death-Ligand 1 Expression With Lung Adenocarcinoma Histologic and Molecular Subgroups in Primary and Metastatic Sites

Programmed death-ligand 1 (PD-L1) expression in terms of the tumor proportion score (TPS) is the main predictive biomarker approved for immunotherapy against lung nonsmall cell carcinoma. Although some studies have explored the associations between histology and PD-L1 expression in pulmonary adenocarcinoma, they have been limited in sample size and/or extent of examined histologic variables, which may have resulted in conflicting information. In this observational retrospective study, we identified primary and metastatic lung adenocarcinoma cases in the span of 5 years and tabulated the detailed histopathologic features, including pathological stage, tumor growth pattern, tumor grade, lymphovascular and pleural invasion, molecular alterations, and the associated PD-L1 expression for each case. Statistical analyses were performed to detect associations between PD-L1 and these features. Among 1658 cases, 643 were primary tumor resections, 751 were primary tumor biopsies, and 264 were metastatic site biopsies or resections. Higher TPS significantly correlated with high-grade growth patterns, grade 3 tumors, higher T and N stage, presence of lymphovascular invasion, and presence of MET and TP53 alterations, whereas lower TPS correlated with lower-grade tumors and presence of EGFR alterations. There was no difference in PD-L1 expression in matched primary and metastases, although higher TPS was observed in metastatic tumors due to the presence of high-grade patterns in these specimens. TPS showed a strong association with a histologic pattern. Higher-grade tumors had higher TPS, which is also associated with more aggressive histologic features. Tumor grade should be kept in mind when selecting cases and blocks for PD-L1 testing.

Fibulin-2 Facilitates Malignant Progression of Hepatocellular Carcinoma.

Identification of biomarkers to assist in the clinical management of hepatocellular carcinoma represents an urgent requirement. Fibulin-2 is known to contribute to the development and progression of various cancer types. This research investigated the role of fibulin-2 in hepatocellular carcinoma and explored the possible mechanisms. The expression of fibulin-2 in hepatocellular carcinoma was measured by bioinformatic analysis and confirmed by western blot and immunohistochemical staining in cell lines or patients' samples. The clinicopathologic features of hepatocellular carcinoma patients was analyzed. Cell viability assays were used to explore the role of fibulin-2 on proliferation in hepatocellular carcinoma. Western blot was conducted to uncover changes of protein expression of Ras-MEK-ERK1/2 pathway when Fibulin-2 was overexpressed or silenced. Flow cytometry analyses were used to determine the roles of fibulin-2 in the function of apoptosis and cell cycle. Subcutaneous xenograft mouse models showed the tumor growth pattern after fibulin-2 silence in vivo. We reported the upregulation of fibulin-2 in most hepatocellular carcinoma tissues and cells lines. Fibulin-2 promoted the proliferation of hepatocellular carcinoma cells in vitro by regulating Ras-MEK-ERK1/2 signaling pathway, whereas knockdown of fibulin-2 incurred the opposite effect on proliferation. Consistently, knockdown of fibulin-2 resulted in increased apoptosis and induced growth arrest during the G0/G1 phase transition. In vivo xenograft assessment confirmed that knockdown of fibulin-2 inhibited hepatocellular carcinoma tumor growth. Fibulin-2 exhibited tumor promotor activities in malignant progression of hepatocellular carcinoma. The results of the study highlighted the potential of fibulin-2 to be utilized as a promising biomarker and therapeutic target for hepatocellular carcinoma.

Sialic acid metabolism orchestrates transcellular connectivity and signaling in glioblastoma.

In glioblastoma (GBM), the effects of altered glycocalyx are largely unexplored. The terminal moiety of cell coating glycans, sialic acid, is of paramount importance for cell-cell contacts. However, sialic acid turnover in gliomas and its impact on tumor networks remain unknown. We streamlined an experimental setup using organotypic human brain slice cultures as a framework for exploring brain glycobiology, including metabolic labeling of sialic acid moieties and quantification of glycocalyx changes. By live, 2-photon and high-resolution microscopy we have examined morphological and functional effects of altered sialic acid metabolism in GBM. By calcium imaging we investigated the effects of the altered glycocalyx on a functional level of GBM networks. The visualization and quantitative analysis of newly synthesized sialic acids revealed a high rate of de novo sialylation in GBM cells. Sialyltrasferases and sialidases were highly expressed in GBM, indicating that significant turnover of sialic acids is involved in GBM pathology. Inhibition of either sialic acid biosynthesis or desialylation affected the pattern of tumor growth and lead to the alterations in the connectivity of glioblastoma cells network. Our results indicate that sialic acid is essential for the establishment of GBM tumor and its cellular network. They highlight the importance of sialic acid for glioblastoma pathology and suggest that dynamics of sialylation have the potential to be targeted therapeutically.

Biopsies of Caudal Brainstem Tumors in Pediatric Patients—A Single-Center Retrospective Case Series

The indication for performing biopsies in patients with diffuse lesions in the brain stem is controversial. Possible risks associated with the technical challenging interventions need to be balanced against clarifying the diagnosis and possible therapeutic options. We reviewed the feasibility, risk profile and diagnostic yield of different biopsy techniques in a pediatric cohort. We retrospectively included all patients under 18 years of age that received a biopsy of the caudal brainstem region (pons, medulla oblongata) at our pediatric neurosurgical center from 2009-2022. We identified 27 children. Biopsies were performed using frameless stereotactic (Varioguide) (n=12), robotic assisted (Autoguide) (n=4), endoscopic (n=3) and open biopsy (n=8) technique. Intervention related mortality was not observed. Three patients experienced transient post-surgical neurological deficit. No patient showed intervention related permanent morbidity. Biopsy yielded histopathological diagnosis in all cases. Molecular analysis was feasible in 97% of cases. Most common diagnosis was H3K27M mutated diffuse midline glioma (60%). Low-grade gliomas were identified in 14%. Overall survival was 62.5% after 24 months of follow up. Biopsies of the caudal brainstem in children were feasible and safe in the presented setup. The amount of acquired tumor material allowing integrated diagnosis and was obtained at reasonable risk. The selection of the surgical technique depends on tumor location and growth pattern. We recommend brainstem tumor biopsies in children being performed at specialized centers to better understand the biology and enable possible novel therapeutic options.

A deep learning model for the prediction of microsatellite instability and pathogenic POLE mutations in colorectal cancer using histopathologic images.

3543 Background: Immunotherapy has brought about a landmark change in anti-tumor treatment in the past years. High microsatellite instability (MSI-H) is now the only clinically approved biomarker predicting response to immunotherapy in CRC. Increasing evidence suggests that POLE mutations in the exonuclease domain could drive an ultra-mutational phenotype and improve the treatment outcomes of ICI in solid tumors. In this study, we set out to apply a deep learning model using H&amp;E-stained, formalin-fixed, paraffin-embedded (FFPE) whole slide images (WSIs) of CRC primary tumors. Methods: The deep learning model is developed and validated through five-fold cross-validation using WSI of primary tumors from 506 CRC patients and externally validated using 52 WSIs from a prospective cohort. The microsatellite status, tumor mutation burden (TMB) and POLE genotype were determined by next-generation sequencing (NGS). Patients with MSS status and a low TMB (＜20Mutations/Mb) were admitted to the MSS group, and CRCs with a POLE mutation which was defined as an oncogenic mutation referring to the POLE functional mutation list at OncoKB( POLE (oncokb.org) were admitted to the POLE mutant group. Clustering-constrained-attention multiple-instance learning (CLAM) model is employed as the base model, and we conduct the model ensemble by performing a large-scale hyper-parameter search, selecting five models with the highest value in one of the performance metrics, including the AURoC, accuracy, precision, recall, and f1 score, and finally averaging the predictions of the five models. Results: The internal dataset included 237 MSS, 142 MSI-H, and 127 POLE mutant CRC. The three groups had significant differences in primary location (p ＜ 0.0001), histology (p ＜ 0.0001), tumor differentiation (p = 0.002), tumor stage (p ＜ 0.0001), Crohn's-like reaction (p ＜ 0.0001) and tumor growth pattern (p = 0.001). The cross-validation performance of the ensemble model (M E) in the internal dataset achieves an AURoC of 0.944 for three-way classification task (POLE vs. MSI-H vs. MSS) and 0.940 for two-way classification task (POLE &amp; MSI-H vs. MSS) which were superior to the performance of each single CLAM model. To demonstrate the generalizability of the deep learning model, a domestic perspective cohort consisting of 20 MSS, 17 MSI-H, and 15 POLE mutant CRC H&amp;E images were used to validate the external performance. And the M E retained robust performance on the external dataset, with an AURoC of 0.904 for three-way classification task and 0.836 for two-way classification task. Conclusions: A CLAM-based deep learning model could directly predict the MSI-H and POLE mutation from histological images that could be used to stratify CRC patients for immunotherapy with faster turnaround time and lower costs compared with traditional sequencing methods.

Effectiveness of HCC surveillance programs using multitarget blood test: A modeling study.

The effectiveness of ultrasound-based surveillance for HCC in patients with cirrhosis is limited by suboptimal sensitivity for early tumor detection and poor adherence. Emerging blood-based biomarkers have been proposed as an alternative surveillance strategy. We aimed to evaluate the comparative effectiveness of a multitarget HCC blood test (mt-HBT)-with and without improved adherence-against ultrasound-based HCC surveillance. We developed a Markov-based mathematical model that simulated a virtual trial in patients with compensated cirrhosis comparing potential surveillance strategies: biannual surveillance using ultrasound, ultrasound plus AFP, and mt-HBT with or without improved adherence (+10% increase). We used published data to inform underlying liver disease progression rates, HCC tumor growth patterns, performance characteristics of surveillance modalities, and efficacy of treatments. Primary outcomes of interest were the number of early-stage HCCs detected and life years gained. Per 100,000 patients with cirrhosis, mt-HBT detected 1680 more early-stage HCCs than ultrasound alone and 350 more early-stage HCCs than ultrasound + AFP, yielding an additional 5720 and 1000 life years, respectively. mt-HBT with improved adherence detected 2200 more early-stage HCCs than ultrasound and 880 more early-stage HCCs than ultrasound + AFP, yielding an additional 8140 and 3420 life years, respectively. The number of screening tests needed to detect one HCC case was 139 with ultrasound, 122 with ultrasound + AFP, 119 with mt-HBT, and 124 with mt-HBT with improved adherence. mt-HBT is a promising alternative to ultrasound-based HCC surveillance, particularly given anticipated improved adherence with blood-based biomarkers could increase HCC surveillance effectiveness.

안장가로막에 대한 종양의 기원과 개구부 상태에 따른 두개인두종의 성장양상

Background: Advances in the endoscopic endonasal approach (EEA) have increased the under-standing of craniopharyngioma anatomy. We have previously proposed a relationship among cranio-pharyngioma growth pattern, their origin relative to the diaphragm sellae, and their aperture compe-tency. To reappraise that relationship, we retrospectively reviewed the diaphragm sellae anatomy of patients who underwent EEA for craniopharyngioma. Materials and Methods: From May 2010 to January 2013, thirty five patients underwent EEA procedures for craniopharyngiomas. Twenty patients without a surgical history were included in the study, and medical records describing the spatial relations between the tumors and the diaphragma sellae were reviewed and correlated with the tumor growth patterns on preoperative images. Results: All of the tumors were completely removed. Three prechiasmatic tumors were located un-der intact diaphragma sellae. Six retrochiasmatic tumors were composed of supra- and subdiaphrag-matic components that were continuous through an incomplete aperture of the diaphragm. Eleven retrochiasmatic tumors were located above intact diaphragms. Visual symptoms were normalized or improved in twelve of the sixteen patients with preoperative visual deficits. Preoperative hypotha-lamic dysfunction was recovered in ten of twelve patients. Conclusions: The EEA revealed the detailed tumor anatomy and confirmed our previous hypoth-esis that craniopharyngioma growth patterns are principally determined by the origin of the tumor relative to the diaphragma sellae and by the aperture competency. The EEA is indicated for removing both prechiasmatic and retrochiasmatic craniopharyngiomas.