Primary Tumors
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Nicolin Hainc ◽  
Noor Alsafwani ◽  
Andrew Gao ◽  
Philip J. O’Halloran ◽  
Paul Kongkham ◽  

Abstract Purpose Differentiation of radiation necrosis from tumor progression in brain metastases treated with stereotactic radiosurgery (SRS) is challenging. For this, we assessed the performance of the centrally restricted diffusion sign. Methods Patients with brain metastases treated with SRS who underwent a subsequent intervention (biopsy/resection) for a ring-enhancing lesion on preoperative MRI between 2000 and 2020 were included. Excluded were lesions containing increased susceptibility limiting assessment of DWI. Two neuroradiologists classified the location of the diffusion restriction with respect to the post-contrast T1 images as centrally within the ring-enhancement (the centrally restricted diffusion sign), peripherally correlating to the rim of contrast enhancement, both locations, or none. Measures of diagnostic accuracy and 95% CI were calculated for the centrally restricted diffusion sign. Cohen's kappa was calculated to identify the interobserver agreement. Results Fifty-nine patients (36 female; mean age 59, range 40 to 80) were included, 36 with tumor progression and 23 with radiation necrosis based on histopathology. Primary tumors included 34 lung, 12 breast, 5 melanoma, 3 colorectal, 2 esophagus, 1 head and neck, 1 endometrium, and 1 thyroid. The centrally restricted diffusion sign was seen in 19/23 radiation necrosis cases (sensitivity 83% (95% CI 63 to 93%), specificity 64% (95% CI 48 to 78%), PPV 59% (95% CI 42 to 74%), NPV 85% (95% CI 68 to 94%)) and 13/36 tumor progression cases (difference p < 0.001). Interobserver agreement was substantial, at 0.61 (95% CI 0.45 to 70.8). Conclusion We found a low probability of radiation necrosis in the absence of the centrally restricted diffusion sign.

2021 ◽  
Shabaz Sultan ◽  
Mark A. J. Gorris ◽  
Lieke L. van der Woude ◽  
Franka Buytenhuijs ◽  
Evgenia Martynova ◽  

Tissue specimens taken from primary tumors or metastases contain important information for diagnosis and treatment of cancer patients. Multispectral imaging allows in situ visualization of heterogeneous cell subsets, such as lymphocytes, in tissue samples. Many image processing pipelines first segment cell boundaries and then measure marker expression to assign cell phenotypes. In dense tissue environments such as solid tumors, segmentation-based phenotyping can be inaccurate due to segmentation errors or overlapping cell boundaries. Here we introduce a machine learning pipeline design called ImmuNet that directly identifies the positions and phenotypes of immune cells without determining their exact boundaries. ImmuNet is easy to train: human annotators only need to click on immune cells and rank their expression of each marker; full annotation of tissue regions is not necessary. We demonstrate that ImmuNet is a suitable approach for immune cell detection and phenotyping in multiplex immunohistochemistry: it compares favourably to segmentation-based methods, especially in dense tissues, and we externally validate ImmuNet results by comparing them to flow cytometric measurements from the same tissue. In summary, ImmuNet performs well on diverse tissue specimens, takes relatively little effort to train and implement, and is a simpler alternative to segmentation-based approaches when only cell positions and phenotypes, but not their shapes are required for downstream analyses. We hope that ImmuNet will help cancer researchers to analyze multichannel tissue images more easily and accurately.

2021 ◽  
Vol 11 (1) ◽  
Diem Vuong ◽  
Marta Bogowicz ◽  
Leonard Wee ◽  
Oliver Riesterer ◽  
Eugenia Vlaskou Badra ◽  

AbstractThe anatomical location and extent of primary lung tumors have shown prognostic value for overall survival (OS). However, its manual assessment is prone to interobserver variability. This study aims to use data driven identification of image characteristics for OS in locally advanced non-small cell lung cancer (NSCLC) patients. Five stage IIIA/IIIB NSCLC patient cohorts were retrospectively collected. Patients were treated either with radiochemotherapy (RCT): RCT1* (n = 107), RCT2 (n = 95), RCT3 (n = 37) or with surgery combined with radiotherapy or chemotherapy: S1* (n = 135), S2 (n = 55). Based on a deformable image registration (MIM Vista, 6.9.2.), an in-house developed software transferred each primary tumor to the CT scan of a reference patient while maintaining the original tumor shape. A frequency-weighted cumulative status map was created for both exploratory cohorts (indicated with an asterisk), where the spatial extent of the tumor was uni-labeled with 2 years OS. For the exploratory cohorts, a permutation test with random assignment of patient status was performed to identify regions with statistically significant worse OS, referred to as decreased survival areas (DSA). The minimal Euclidean distance between primary tumor to DSA was extracted from the independent cohorts (negative distance in case of overlap). To account for the tumor volume, the distance was scaled with the radius of the volume-equivalent sphere. For the S1 cohort, DSA were located at the right main bronchus whereas for the RCT1 cohort they further extended in cranio-caudal direction. In the independent cohorts, the model based on distance to DSA achieved performance: AUCRCT2 [95% CI] = 0.67 [0.55–0.78] and AUCRCT3 = 0.59 [0.39–0.79] for RCT patients, but showed bad performance for surgery cohort (AUCS2 = 0.52 [0.30–0.74]). Shorter distance to DSA was associated with worse outcome (p = 0.0074). In conclusion, this explanatory analysis quantifies the value of primary tumor location for OS prediction based on cumulative status maps. Shorter distance of primary tumor to a high-risk region was associated with worse prognosis in the RCT cohort.

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258802
Mohammad Alabduljabbar ◽  
Diego Strianese ◽  
Osama Al-Sheikh ◽  
Hind M. Alkatan ◽  
Hailah Al-Hussain ◽  

To evaluate and compare the clinical and histopathological profile of primary and recurrent orbital-periorbital plexiform neurofibromas (OPPN) in patients with neurofibromatosis type 1. We retrospectively evaluated 43 primary or recurrent neurofibroma (NF) specimens from 26 patients (2002 to 2018) at the King Khaled Eye Specialist Hospital, Saudi Arabia. Demographics, clinical presentation, and surgical intervention data were collected. Histopathological specimens were studied with hematoxylin-eosin, Alcian blue, and immunohistochemical markers; S-100, CD44, CD117, smooth muscle actin (SMA), neurofilament, and Ki-67. Of the 43 NFs specimens, 20 were primary and 23 recurrent tumors. For primary NF, the ratio of plexiform to the diffuse type was 13:7, however in recurrent tumors was 3:8 after the first recurrence, and 1:5 after multiple recurrences. Of the 17 patients with primary tumors that had paired recurrent tumors, 12/17 (70.6%) primary NFs were plexiform and 5/17 (29.4%) were diffuse. However, when tumors recurred, 13/17 tumors (76.5%) were diffuse and only 4/17 tumors (23.5%) had a plexiform pattern. The odds of a tumor having a diffuse pattern in recurrent NF was significantly higher than the plexiform pattern [OR = 7.8 (95% confidence interval 1.69:36.1) P = 0.008]. Primary plexiform NFs underwent an excision at a significantly younger age than the diffuse type. Recurrent NFs had significantly higher CD44, CD117, and neurofilament labeling (P = 0.02, P = 0.01 and P<0.001 respectively) but had significantly decreased Alcian blue, and S-100 labeling (P = 0.03, and P = 0.02 respectively) compared to primary tumors. SMA and Ki-67 proliferation index were not different between primary and recurrent NFs (P = 0.86, and P = 0.3 respectively). There appears to be a high risk for primary plexiform NFs to develop a diffuse histologic pattern when they recur. Immunohistochemical staining suggests a role of mast cells (CD117) and expression of infiltration makers (CD44) in the transformation of plexiform tumors to the diffuse phenotype.

2021 ◽  
Vol 12 ◽  
Mingjun Gao ◽  
Jin Yang ◽  
Hailong Gong ◽  
Yuancai Lin ◽  
Jing Liu

Gliomas are primary tumors originating from glial progenitor cells. Traditional treatments, including surgery, radiotherapy, and chemotherapy, have many limitations concerning the prognosis of patients with gliomas. Therefore, it is important to find novel drugs to effectively treat gliomas. Trametinib has been shown to inhibit the MAPK pathway and regulate its downstream extracellular-related kinases. It has widely been used in the treatment of BRAF V600E mutant metastatic melanomas. Previous studies found that trametinib can improve the prognosis of patients with melanoma brain metastases. In this study, we investigated the therapeutic effects of trametinib on gliomas in vivo and in vitro. We found that trametinib can inhibit proliferation, migration, and invasion of glioma cells, while inducing apoptosis of glioma cells. Specifically, trametinib can suppress both the expression of PKM2 in glioma cells and the transport of PKM2 into the cellular nucleus via suppression of ERK1/2 expression. However, inhibition of these cellular effects and intracellular glycolysis levels were reversed by overexpressing PKM2 in glioma cells. We also found inhibition of c-myc with trametinib treatment, but its expression could be increased by overexpressing PKM2. Interestingly, when PKM2 was overexpressed but c-myc silenced, we found that the initial inhibition of cellular effects and glycolysis levels by trametinib were once again restored. These inhibitory effects were also confirmed in vivo: trametinib inhibited the growth of the transplanted glioma cell tumor, whereas PKM2 overexpression and c-myc silencing restored the inhibition of trametinib on the growth of the transplanted tumor. In conclusion, these experimental results showed that trametinib may inhibit the growth and intracellular glycolysis of glioma cells by targeting the PKM2/c-myc pathway.

2021 ◽  
Vol 11 (11) ◽  
pp. 2109-2114
Hui Wan ◽  
Tingting Liu ◽  
Yuanxiang Lin

Glioma is the most common intracranial malignancy and has been recognized as one of the most invasive primary tumors. Although there have been many studies on its growth mechanism, the molecular mechanism for growth inhibition is still unclear. The aim of this study was to show that microRNA-362-3p inhibits glioma growth by targeting PAX3 and regulating Wnt/beta-catenin pathway. We collected platelets from 12 healthy controls and 8 patients with glioma from the GEO database for comparison. The ncRNA and transcription factors that regulate the module were predicted to reveal the mechanism of microRNA-362-3p through co-expression module analysis, enrichment analysis, and hypergeometric testing. Two functional modules were obtained by integrating potential pathogenic genes and co-expression analysis. GPATCH4 and MYOD1 genes were expressed differentially and had active regulatory roles in the dysfunction module; thus, they were identified as key genes for glioma growth. Next, we performed ncRNA pivot and transcription factors (TFs) especially about the pivot analysis. The results showed microRNA-362-3p gene interest that significantly regulated the dysfunction module. Therefore, we identified microRNA-362-3p as a dysfunctional molecule in the growth process of glioma. MicroRNA-362-3p could inhibit glioma growth by targeting PAX3 and regulating the Wnt/beta-catenin pathway. The inhibition of this pathway may be a new target for the treatment of glioma. This study improves our understanding of growth inhibition in glioma and provides reference values for the treatment of this disease.

2021 ◽  
Jie Wu ◽  
Haifeng Zhao ◽  
Ke Yan ◽  
Xiangtong Xie ◽  
Donghua Gu ◽  

Abstract Background: The links between brain metastases of lung cancer and human cytomegalovirus (HCMV) infection have been controversial for a long time. This study aims to explore the links between brain metastases of lung cancer and HCMV infection from the perspective of expression and detection of HCMV immediate early gene (IE), guanine nucleotide-binding protein 4 (GBP4), CXC chemokine receptor 4 (CXCR4), thyroid transcription factor 1 (TTF1) and epidermal growth factor receptor (EGFR) proteins. Methods: We collected brain metastases specimens and lung primary tumor specimens of a series of patients that have not undergone any treatment. Conventional hematoxylin and eosin staining and immunohistochemical staining of target molecules was performed. We used the ImageJ software to process the average optical density value of immune complexes and GraphPad Prism 8.0.1 to perform image analysis, and the SPSS 22.0 statistics package (t test) to analyze the expression differences of target molecules.Results: Based on five cases of brain metastases and two cases of lung primary tumors, a total of seven samples were investigated. Conventional pathology diagnosis reported four cases of brain metastases of lung adenocarcinoma and one case of brain metastases of mixed small cell lung cancer with adenocarcinoma. Among the 19 molecular immunopathological test samples, only GBP4, related to HCMV infection, and TTF1, related to metastases, were highly expressed in all seven samples. A comparison of the AOD values of the primary lung cancer to the AOD values of brain metastases, yielded statistically significant differences as follows: in Case No.1, GBP4 (p=0.016), EGRF (p<0.001); in Case No. 2, IE (p<0.001), CXCR4 (p=0.005), EGFR (p=0.023), TTF1 (p=0.004). Conclusions: Although TTF1 is known to be a kinesin for brain metastases of lung cancer cells and it is associated with poor survival prognosis, the role of GBP4, which is closely related to HCMV infection and a key protein of brain metastases of lung cancer, remains unknown. The findings provide new knowledge into the role of GBP4 and could provide clues for devising novel strategies for target molecular therapy research in brain metastases of lung cancer in the context of HCMV infection.

2021 ◽  
Vol 12 ◽  
Violaine Randrian ◽  
Amandine Desette ◽  
Sheik Emambux ◽  
Valentin Derangere ◽  
Pauline Roussille ◽  

Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their survival has improved. CD3 T-cells and, lately, DGMate (DiGital tuMor pArameTErs) score, have been identified as prognostic factors in locally advanced CRC. Until now, there is no data concerning the prognostic value of these markers in patients with CRC-derived brain metastases. All consecutive patients with CRC-derived brain metastases diagnosed between 2000 and 2017 were retrospectively included. Staining for CD3, CD8, PD-1, PD-L1 and DGMate analyses were performed using tissue micro-array from primary tumors and, if available, brain metastases. All in all, 83 patients were included with 80 primary tumor samples and 37 brain metastases samples available. CD3 and CD8 T-cell infiltration was higher in primary tumors compared to brain metastases. We observed a significant higher DGMate score in rectal tumors compared to colon tumors (p=0.03). We also noted a trend of higher CD3 T-cell infiltration in primary tumors when brain metastases were both supra and subtentorial compared to brain metastases that were only subtentorial or supratentorial (p=0.36 and p=0.03, respectively). No correlation was found between CD3 or CD8 infiltration or DGMate score in primary tumors or brain metastases and overall survival (OS) in the overall population. In patients with rectal tumors, a high DGMate score in brain metastases was associated with longer OS (13.4 ± 6.1 months versus 6.1 ± 1.4 months, p=0.02). High CD3 T-cell infiltration in brain metastases was associated with lower OS in patients with supratentorial brain metastases (9.8 ± 3.3 months versus 16.7 ± 5.9 months, p=0.03). PD-L1 overexpression was rare, both in primary tumors and brain metastases, but PD-L1 positive primary tumors were associated with worse OS (p=0.01). In contrast to breast and lung cancer derived brain metastases, CD3 and CD8 infiltration and DGMate score are not major prognostic factors in patients with CRC-derived brain metastases.

2021 ◽  
Mohamed A. Naser ◽  
Kareem A. Wahid ◽  
Lisanne V. van Dijk ◽  
Renjie He ◽  
Moamen Abobakr Abdelaal ◽  

Auto-segmentation of primary tumors in oropharyngeal cancer using PET/CT images is an unmet need that has the potential to improve radiation oncology workflows. In this study, we develop a series of deep learning models based on a 3D Residual Unet (ResUnet) architecture that can segment oropharyngeal tumors with high performance as demonstrated through internal and external validation of large-scale datasets (training size = 224 patients, testing size = 101 patients) as part of the 2021 HECKTOR Challenge. Specifically, we leverage ResUNet models with either 256 or 512 bottleneck layer channels that are able to demonstrate internal validation (10-fold cross-validation) mean Dice similarity coefficient (DSC) up to 0.771 and median 95% Hausdorff distance (95% HD) as low as 2.919 mm. We employ label fusion ensemble approaches, including Simultaneous Truth and Performance Level Estimation (STAPLE) and a voxel-level threshold approach based on majority voting (AVERAGE), to generate consensus segmentations on the test data by combining the segmentations produced through different trained cross-validation models. We demonstrate that our best performing ensembling approach (256 channels AVERAGE) achieves a mean DSC of 0.770 and median 95% HD of 3.143 mm through independent external validation on the test set. Concordance of internal and external validation results suggests our models are robust and can generalize well to unseen PET/CT data. We advocate that ResUNet models coupled to label fusion ensembling approaches are promising candidates for PET/CT oropharyngeal primary tumors auto-segmentation, with future investigations targeting the ideal combination of channel combinations and label fusion strategies to maximize seg-mentation performance.

2021 ◽  
Vol 22 (20) ◽  
pp. 11192
Giorgio Treglia ◽  
Barbara Muoio ◽  
Hessamoddin Roustaei ◽  
Zahra Kiamanesh ◽  
Kamran Aryana ◽  

Several recent studies comparing radiolabeled fibroblast activation protein inhibitors (FAPI) and fluorine-18 fluorodeoxyglucose ([18F]F-FDG) as positron emission tomography (PET) radiotracers in oncology have been published. The aim of this systematic review is to perform an updated evidence-based summary about the comparison of these PET radiotracers in oncology to better address further research in this setting. Studies or subsets of studies comparing radiolabeled FAPI and [18F]F-FDG as PET radiotracers in oncology were eligible for inclusion in this systematic review. A systematic literature search of PubMed/MEDLINE and Cochrane library databases was performed until August 2021. Literature data about the comparison of [18F]F-FDG and radiolabeled FAPI are rapidly increasing. Overall, taking into account radiotracer uptake and tumor-to-background uptake ratio, compared to [18F]F-FDG PET, an equal or higher detection of primary tumors and/or metastatic lesions was usually demonstrated by using radiolabeled FAPI PET. In particular, the cancer entities with better detection rate of tumor lesions by using radiolabeled FAPI PET, compared to [18F]F-FDG PET, were gastrointestinal tumors, liver tumors, breast cancer and nasopharyngeal carcinoma. Further comparison studies are needed to better evaluate the best field of application of radiolabeled FAPI PET.

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