Combination of the Distance From Tumor Edge to Subventricular Zone and IDH Mutation Predicts Prognosis of Patients With Glioma

Both subventricular zone (SVZ) contact and isocitrate dehydrogenase 1 (IDH1) mutation have been reported to be related to the outcome of glioma, respectively. However, far too little attention has been paid to the role of tumor edge-SVZ distance in the outcome of glioma. We aim to assess the value of tumor-SVZ distance, as well as combined tumor-SVZ distance and IDH status, in predicting the outcome of gliomas (WHO grade II–IV). Here, the MR images and clinical data from 146 patients were included in the current study. The relationship between survival and the tumor-SVZ distance as well as survival and combination of tumor-SVZ distance and IDH status were determined via univariate and multivariate analyses. In univariate analysis of tumor-SVZ distance, the patients were divided into three types (SVZ involvement, tumor-SVZ distance from 0 to 10 mm, and tumor-SVZ distance >10 mm). The results showed that the OS (p = 0.02) and PFS (p = 0.002) for the patients had a positive correlation with the tumor-SVZ distance. In addition, simple linear correlation found a significant relationship between the two parameters (OS and PFS) and tumor-SVZ distance in patients with non-SVZ-contacting glioma. Combination analysis of the tumor-SVZ distance and IDH status showed that IDH1 mutation and SVZ non-involvement enable favorable outcomes, whereas IDH1 wild type with SVZ involvement indicates a significantly worse prognosis in all patients. Moreover, in patients with non-SVZ-contacting glioma, IDH1 mutation concurrent with tumor-SVZ distance >10 mm has better OS and PFS. IDH1 wild type and tumor-SVZ distance from 0 to 10 mm suggest poorer OS and PFS. Multivariate analysis showed WHO grade IV, SVZ involvement, tumor-SVZ distance from 0 to 10 mm, IDH1 mutation, gross total resection, and chemotherapy serve as independent predictors of OS. WHO grade IV, SVZ involvement, tumor-SVZ distance from 0 to 10 mm, IDH1 mutation, and chemotherapy serve as independent predictors of PFS of patients with glioma. In conclusion, tumor-SVZ distance and IDH1 mutation status are the determinants affecting patient outcome.

OTME-12. Role of the transsulfuration pathway in glioblastoma invasion

Glioblastoma (GBM) is a primary malignant brain tumor with a median survival under two years. The poor prognosis GBM caries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Numerous factors have been proposed as the primary driving forces behind GBM’s ability to invade adjacent tissues rapidly, including alterations in the tumor’s cellular metabolism. Though studies have investigated links between GBM’s metabolic profile and its invasive capability, these studies have had two notable limitations. First, while infiltrating GBM cells extending beyond the tumor edge utilize adaptive cellular machinery to overcome stressors in their microenvironment, these cells at the invasive front have not been the ones sampled in invasive studies, which have used cell lines or banked tumor tissue taken from the readily accessible tumor core. Second, studies of invasion have primarily used two-dimensional (2D) culture systems, which fail to capture the dimensionality, mechanics, and heterogeneity of GBM invasion. To address these limitations, our team has developed two parallel approaches: acquisition of site-directed biopsies from patient GBMs to define regional heterogeneity in invasiveness, and engineering of 3D platforms to study invasion in vitro. Through utilization of these platforms, and by taking advantage of the system-wide, unbiased screens of metabolite profile and gene expression available, our team looks to identify targetable metabolic factors which drive cellular invasion in GBM. Untargeted metabolomics revealed cystathionine to be selectively enriched in the invasive tumor front of both site directed biopsies (fold change 5.8), and 3D organoid models (fold change 14.2). RNA sequencing revealed 7/30(23%) metabolic genes upregulated in the invasive tumor front were involved in cysteine or glutathione metabolism. These results highlight a clear role of the transsulfuration pathway in GBM invasion that our team looks to investigate with further targeted assays.

Comparison of Diagnostic Performance of Spread Through Airspaces of Lung Adenocarcinoma Based on Morphological Analysis and Perinodular and Intranodular Radiomic Features on Chest CT Images

ObjectSTAS is associated with poor differentiation, KRAS mutation and poor recurrence-free survival. The aims of this study are to evaluate the ability of intra- and perinodular radiomic features to distinguish STAS at non-contrast CT.Patients and MethodsThis retrospective study included 216 patients with pathologically confirmed lung adenocarcinoma (STAS+, n = 56; STAS−, n = 160). Texture-based features were extracted from intra- and perinodular regions of 2, 4, 6, 8, 10, and 20 mm distances from the tumor edge using an erosion and expansion algorithm. Traditional radiologic features were also analyzed including size, consolidation tumor ratio (CTR), density, shape, vascular change, cystic airspaces, tumor–lung interface, lobulation, spiculation, and satellite sign. Nine radiomic models were established by using the eight separate models and a total of the eight VOIs (eight-VOI model). Then the prediction efficiencies of the nine radiomic models were compared to predict STAS of lung adenocarcinomas.ResultsAmong the traditional radiologic features, CTR, unclear tumor–lung interface, and satellite sign were found to be associated with STAS significantly, and the AUCs were 0.796, 0.677, and 0.606, respectively. Radiomic model of combined tumor bodies and all the distances of perinodular areas (eight-VOI model) had better predictive efficiency for predicting STAS+ lung adenocarcinoma. The AUCs of the eight-VOI model in the training and verification sets were 0.907 (95%CI, 0.862–0.947) in the training set, and 0.897 (95%CI, 0.784–0.985) in the testing set, and 0.909 (95%CI, 0.863–0.949) in the external validation set, and the diagnostic accuracy in the external validation set was 0.849.ConclusionRadiomic features from intra- and perinodular regions of nodules can best distinguish STAS of lung adenocarcinoma.

Development of a semi-automated method for tumor budding assessment in colorectal cancer and comparison with manual methods

Tumor budding is an established prognostic feature in multiple cancers but routine assessment has not yet been incorporated into clinical pathology practice. Recent efforts to standardize and automate assessment have shifted away from haematoxylin and eosin (H&E)-stained images towards cytokeratin (CK) immunohistochemistry. In this study, we compare established manual H&E and cytokeratin budding assessment methods with a new, semi-automated approach built within the QuPath open-source software. We applied our method to tissue cores from the advancing tumor edge in a cohort of stage II/III colon cancers (n=186). The total number of buds detected by each method, over the 186 TMA cores, were as follows; manual H&E (n=503), manual CK (n=2290) and semi-automated (n=5138). More than four times the number of buds were detected using CK compared to H&E. A total of 1734 individual buds were identified both using manual assessment and semi-automated detection on CK images, representing 75.7% of the total buds identified manually (n=2290) and 33.7% of the total buds detected using our proposed semi-automated method (n=5138). Higher bud scores by the semi-automated method were due to any discrete area of CK immunopositivity within an accepted area range being identified as a bud, regardless of shape or crispness of definition, and to inclusion of tumor cell clusters within glandular lumina ('luminal pseudobuds'). Although absolute numbers differed, semi-automated and manual bud counts were strongly correlated across cores (ρ=0.81, p<0.0001). Despite the random, rather than 'hotspot', nature of tumor core sampling, all methods of budding assessment demonstrated poorer survival associated with higher budding scores. In conclusion, we present a new QuPath-based approach to tumor budding assessment, which compares favorably to current established methods and offers a freely-available, rapid and transparent tool that is also applicable to whole slide images.

Nanomedicine is offering promising strategies for tumor blockade treatment

Nanomedicine-designed tumor blockade treatment (TVBT) approaches include angiogenesis suppression, vascular disruption, and infarction. VEGF, VEGFR, mTOR, EGFR, bFGF, ROS and other components have become promising candidates for angiogenesis reduction. The system of nanomedicine successfully reduced tumor neovascularization employing silencing, chemotherapy, phototherapy, and other treatments. Nanomaterial-led VDAs were bonded with bonding sites of CA4, COL, PTX, and other microtubular medications to promote rapid disintegration of tumor vascular wall cells. Multiple therapies combined substantially boosted tumor therapeutic outcome. For example, loss of tumor blood arteries caused by nanoparticle-mediated physical methods coupled with chemotherapy was successful in a large-volume tumor model. Several carriers, including nanoparticles, DNA nanorobot, platelet membrane, and so on, are used to carry thrombin, tTF, and other drugs for local thrombosis and safe and efficient tumor treatment.Nanomedicine-involved TVBT still has significant drawbacks. First, basic TVBT has tumor edge residual tumor cells (Tozer, Kanthou, &amp; Baguley, 2005). While customized nanoparticles significantly increase anti-tumor medication efficacy while avoiding resistance and severe side effects, combination treatment is an appropriate treatment strategy. Multiple treatment methods should be extensively examined when establishing a combination therapy approach. For example, nanomedicine chemotherapy has a high tumor peripheral lethality, but the permeability is limited, resulting in insufficient tumor core efficacy. Researchers may build nanoscale drug-loading devices targeting tumor peripheral and tumor blood arteries to deliver multiple medications to different places for more complete tumor treatment. Second, the worry about pharmaceutical safety can not be overlooked, since free agents exhibited detrimental effects in earlier clinical trials. Although delivery of nanoparticles has proven remarkable safety in animal models, complete examination of side effects is still needed, which will need rigorous preclinical and clinical investigations. Furthermore, the toxicity of nanomaterials or leftover compounds from the preparation process should be fully investigated. Third, although VDAs and thrombosis can rapidly eliminate large-scale tumor cells, necrotic cells' released toxic components are a serious potential problem. Using customized nanoparticles to eliminate harmful components and maintain neighboring tissues is therefore crucial. Fourth, certain nanomaterials are complex and difficult to mass-produce. Additionally, raw materials are expensive and well-accessible. In response to these difficulties, structures of nanoparticles must be logically constructed and simple, efficient nanoplatforms built. More shortcomings should be identified and rectified in future investigations.

Multi-Omics Analysis of Fibroblasts from the Invasive Tumor Edge Reveals that Tumor-Stroma Crosstalk Induces O-glycosylation of the CDK4-pRB Axis

The invasive leading edge represents a potential gateway for tumor invasion. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in the activation of key biological pathways depending on their location in the tumor (edge vs core). Here, we highlight phenotypic differences between Tumor-Adjacent-Fibroblasts (TAFs) from the invasive edge and Cancer-Associated Fibroblasts (CAFs) from the tumor core, established from human lung adenocarcinomas. We use an innovative multi-omics approach that includes genomics, proteomics and, O-glycoproteomics to characterize crosstalk between TAFs and cancer cells. Our analysis shows that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the CDK4-pRB axis in the stroma, and indirectly modulates pro-invasive features of cancer cells. In summary, aside from improving the efficacy of CDK4 inhibitors anti-cancer agents, the O-glycoproteome poses a new consideration for important biological processes involved in tumor-stroma crosstalk.

Optimal margins for early stage peripheral lung adenocarcinoma resection

Background A pathologically confirmed negative margin is required when performing sublobar resection in patients with early stage peripheral lung adenocarcinoma. However, the optimal margin distance to ensure complete tumor resection while preserving healthy lung tissue remains unknown. We aimed to establish a reliable distance range for negative margins. Methods A total of 52 intraoperative para-cancer tissue specimens from patients with peripheral lung adenocarcinoma with pathological tumors ≤2 cm in size were examined. Depending on the distance from the tumor edge (D), the para-cancer tissues were divided into the following five groups: D < 0.5 cm (group I); 0.5 cm ≤ D < 1.0 cm (group II); 1.0 cm ≤ D < 1.5 cm (group III); 1.5 cm ≤ D < 2.0 cm (group IV); and D ≥ 2.0 cm (group V). During pathological examination of the specimens under a microscope, the presence of atypical adenomatous hyperplasia or more severe lesions was considered unsafe, whereas the presence of normal lung tissue or benign hyperplasia was considered safe. Results Group V, in which the margin was the farthest from the tumor edge, was the safest. There were significant safety differences in between groups I and V (χ2 = 26.217, P < 0.001). Significant safety differences also existed between groups II and V (χ2 = 9.420, P < 0.005). There were no significant safety differences between group III or IV and group V (P = 0.207; P = 0.610). Conclusions We suggest that when performing sublobar resection in patients with early stage peripheral lung adenocarcinoma with pathological tumor sizes ≤2 cm, the resection margin distance should be ≥1 cm to ensure a negative margin.

Locoregional recurrence via mucus-mediated extension following lung resection for mucinous tumors

Background Clinically, locoregional recurrences following mucinous tumor resection are often experienced. However, it remains unclear whether mucinous tumors directly affect local recurrence or not, and if so, the mechanism is not known. Therefore, we investigated whether mucinous tumors are associated with locoregional recurrence after pulmonary resection and whether mucus extension is a risk factor for locoregional recurrence. Methods The data of 152 patients who underwent pulmonary resection for metastases were reviewed. When mucus was partially or wholly present in the tumor based on macro- or microscopic identification, we assigned the tumor as mucinous. In mucinous tumors, when mucus was identified within the air spaces in the normal lung parenchyma, beyond the edge of the tumor, we assigned the tumor as positive for “mucus extension.” Results The 5-year cumulative incidence of locoregional recurrence in patients with mucinous tumors was 48.1%, which was significantly higher than that observed in those with non-mucinous tumors (14.9%). Within the mucinous tumor, the presence of mucus extension beyond the tumor edge was an independent risk factor for locoregional recurrence after pulmonary resection (hazard ratio, 5.52; P = 0.019). Conclusions During the resection of mucinous cancer, surgeons should maintain sufficient distance from the tumor edge to prevent locoregional recurrences.

Locoregional Recurrence via Mucus-Mediated Extension Following Lung Resection for Mucinous Tumors

Background Clinically, locoregional recurrences following mucinous tumor resection are often experienced. However, it is unclear whether mucinous tumors directly affect local recurrence or not, and if so, what the mechanism is. Therefore, we investigated whether mucinous tumors are associated with locoregional recurrence after pulmonary resection and whether mucus extension is a risk factor for locoregional recurrence. Methods The data of 90 patients who underwent pulmonary resection for metastases were reviewed. If mucus was partially or wholly present in the tumor based on macro- or microscopic identification, we assigned the tumor as mucinous. In mucinous tumors, if mucus was identified within the air spaces in the normal lung parenchyma, beyond the edge of the tumor, we assigned the tumor as positive for “mucus extension.” Results The 5-year cumulative incidence of locoregional recurrence in patients with mucinous tumors was 80.3%, which was significantly higher than the 15.5% observed in patients with non-mucinous tumors. Within the mucinous tumor, presence of mucus extension beyond the tumor edge was an independent risk factor for locoregional recurrence after pulmonary resection (hazard ratio, 8.08; P = 0.049). Conclusion During the resection of mucinous cancer, surgeons should maintain sufficient distance from the tumor edge to prevent locoregional recurrences.