Medical Imaging Biomarker Discovery and Integration Towards AI-Based Personalized Radiotherapy

Intensity-modulated radiation therapy (IMRT) has been used for high-accurate physical dose distribution sculpture and employed to modulate different dose levels into Gross Tumor Volume (GTV), Clinical Target Volume (CTV) and Planning Target Volume (PTV). GTV, CTV and PTV can be prescribed at different dose levels, however, there is an emphasis that their dose distributions need to be uniform, despite the fact that most types of tumour are heterogeneous. With traditional radiomics and artificial intelligence (AI) techniques, we can identify biological target volume from functional images against conventional GTV derived from anatomical imaging. Functional imaging, such as multi parameter MRI and PET can be used to implement dose painting, which allows us to achieve dose escalation by increasing doses in certain areas that are therapy-resistant in the GTV and reducing doses in less aggressive areas. In this review, we firstly discuss several quantitative functional imaging techniques including PET-CT and multi-parameter MRI. Furthermore, theoretical and experimental comparisons for dose painting by contours (DPBC) and dose painting by numbers (DPBN), along with outcome analysis after dose painting are provided. The state-of-the-art AI-based biomarker diagnosis techniques is reviewed. Finally, we conclude major challenges and future directions in AI-based biomarkers to improve cancer diagnosis and radiotherapy treatment.

In Real Life, Low-Level HER2 Expression May Be Associated With Better Outcome in HER2-Negative Breast Cancer: A Study of the National Cancer Center, China

BackgroundTo characterize the clinical and pathological features and survival of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer in China.MethodsThe China National Cancer Center database was used to identify 1,433 metastatic breast cancer patients with HER2-negative disease diagnosed between 2005 and 2015. Clinicopathological features, survival, and prognosis information were extracted. Overall survival (OS) was estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95% CI).ResultsThere were 618 (43.1%) and 815 (56.9%) HER2-low and HER2-zero tumors out of 1,433 tumors, respectively. The proportion of hormone receptor (HR)-positive tumors was significantly higher in HER2-low tumors than in those with HER2-zero tumors (77.8% vs. 69.2%, p < 0.001). Patients with HER2-low tumors survived significantly longer than those with HER2-zero tumors in the overall population (48.5 months vs. 43.0 months, p = 0.004) and HR-positive subgroup (54.9 months vs. 48.1 months, p = 0.011), but not in the HR-negative subgroup (29.5 months vs. 29.9 months, p = 0.718). Multivariate regression analysis revealed that HER2-low tumors were independently associated with increased OS in HER2-negative population (HR: 0.85, 95% CI: 0.73–0.98, p = 0.026).ConclusionOur findings demonstrate that HER2-low tumors could be identified as a more distinct clinical entity from HER2-zero tumors, especially for the HR-positive subgroup. A more complex molecular landscape of HER2-low breast cancer might exist, and more precise diagnostic algorithms for HER2 testing could be investigated, thus offering new therapeutic targets for breast cancer treatment.

LCN2 as a Potential Diagnostic Biomarker for Ulcerative Colitis-Associated Carcinogenesis Related to Disease Duration

BackgroundPatients with long-duration ulcerative colitis (UC) had a higher risk of developing ulcerative colitis-associated carcinogenesis (UCAC) when compared to those with short-duration UC. This study aimed to discover the biomarker for cancer surveillance related to disease duration.MethodsThe microarrays were divided into short-duration (<10 years) UC, long-duration (≥10 years) UC, UCAC, and normal groups in the Gene Expression Omnibus (GEO) datasets. Differentially expressed genes (DEGs) of GEO and the hub genes of the selected weighted gene co-expression network analysis (WGCNA) were intersected to obtain the overlapping genes. Among these genes, the key gene was identified by using the protein–protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the cytoHubba of Cytoscape, and the expression levels. Also, immunofluorescence of human colonic mucosa and animal experiment were used to validate the expression trend of the key gene in the progress of UC developing into UCAC.ResultsLipocalin-2 (LCN2) was more relevant with disease duration of UC and significantly negatively correlated with the risk of UCAC. The expression level of LCN2 in short-duration UC was higher than that of long-duration UC (P < 0.01), long-duration UC was higher than that of UCAC (P = 0.001), and UC and UCAC were all higher than that of the normal (P < 0.001). We then discovered that the expression trend of LCN2 in blood and stool samples was consistent with that in colorectal mucosa.ConclusionThe research indicates that LCN2 could be a novel biomarker to evaluate cancer surveillance related to disease duration of developing UC into UCAC. Compared with that of blood samples, stool detection of LCN2 may have more advantages for diagnosis value of early stage of UCAC as a complement to colonoscopy surveillance.

Impact of Anticipated Awake Surgery on Psychooncological Distress in Brain Tumor Patients

BackgroundBrain tumor patients present high rates of distress, anxiety, and depression, in particular perioperatively. For resection of eloquent located cerebral lesions, awake surgery is the gold standard surgical method for the preservation of speech and motor function, which might be accompanied by increased psychological distress. The aim of the present study was to analyze if patients who are undergoing awake craniotomy suffer from increased prevalence or higher scores in distress, anxiety, or depression.MethodsPatients, who were electively admitted for brain tumor surgery at our neurooncological department, were perioperatively screened regarding distress, anxiety, and quality of life using three established self-assessment instruments (Hospital Anxiety and Depression Scale, distress thermometer, and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30-BN20). Screening results were correlated regarding operation technique (awake vs. general anesthesia). Retrospective statistical analyses for nominal variables were conducted using chi-square test. Metric variables were analyzed using the Kruskal–Wallis test, the Mann–Whitney U-test, and independent-samples t-tests.ResultsData from 54 patients (26 male and 28 female) aged 29 to 82 years were available for statistical analyses. A total of 37 patients received primary resection and 17 recurrent tumor resection. Awake surgery was performed in 35 patients. There was no significant difference in awake versus non-awake surgery patients regarding prevalence (of distress (p = 0.465), anxiety (p = 0.223), or depression (p = 0.882). Furthermore, awake surgery had no significant influence on distress thermometer score (p = 0.668), anxiety score (p = 0.682), or depression score (p = 0.630) as well as future uncertainty (p = 0.436) or global health status (p = 0.943). Additionally, analyses revealed that primary or recurrent surgery also did not have any significant influence on the prevalence or scoring of the evaluated items.ConclusionAnalyses of our cohort’s data suggest that planned awake surgery might not have a negative impact on patients concerning the prevalence and severity of manifestation of distress, anxiety, or depression in psychooncological screening. Patients undergoing recurrent surgery tend to demonstrate increased distress, although results were not significant.

SPECT/CT-Guided Surgical Removal of a Positive External Iliac Sentinel Node in Primary Umbilical Melanoma: Report of a Case, and Up-to-Date Review of the Literature

Primary umbilical melanoma is rare tumor, representing about 5% of all umbilical malignancies.The lymphatic drainage from the tumor is challenging and can be to inguinal, axillary and retroperitoneal nodes. Dynamic and static lymphoscintigraphy with single-photon emission tomography/computed tomography (SPECT/CT) and sentinel lymph node biopsy (SLNB) is a widely validated technique in patients with clinically localized melanoma to search for and quantify nodal spread of cutaneous melanoma. Moreover, it offers the surgeon the preoperative information about the number and location of the sentinel lymph nodes (SLNs), which makes SLNB easier and quicker. This is the first report of an ulcerated thick melanoma of the umbilicus metastasizing only to an external iliac lymph-node without involvement of superficial inguinal SLNs. The preoperative high-resolution ultrasound (HR-US) examination of the regional lymph node field had been normal. This case-report shows how addition of SPECT/CT to planar imaging in a patient with clinically localized umbilical melanoma can help avoid incomplete SLNB when a deep SLN is not removed. A literature review of umbilical melanoma is also provided.

Prospects of Immunotherapy for Triple-Negative Breast Cancer

In the classification and typing of breast cancer, triple-negative breast cancer (TNBC) is one type of refractory breast cancer, while chemotherapy stays in the traditional treatment methods. However, the impact of chemotherapy is short-lived and may lead to recurrence due to incomplete killing of tumor cells. The occurrence, development, and relapse of breast cancer are relevant to T cell dysfunction, multiplied expression of related immune checkpoint molecules (ICIs) such as programmed death receptor 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) produce immunosuppressive effect. Immunotherapy (namely, immune checkpoint inhibitors, adoptive cellular immunotherapy, CAR-T immunotherapy and some potential treatments) provides new hope in TNBC. This review focuses on the new immune strategies of TNBC patients.

DNA Methylation-Driven Genes for Developing Survival Nomogram for Low-Grade Glioma

Low-grade gliomas (LGG) are heterogeneous, and the current predictive models for LGG are either unsatisfactory or not user-friendly. The objective of this study was to establish a nomogram based on methylation-driven genes, combined with clinicopathological parameters for predicting prognosis in LGG. Differential expression, methylation correlation, and survival analysis were performed in 516 LGG patients using RNA and methylation sequencing data, with accompanying clinicopathological parameters from The Cancer Genome Atlas. LASSO regression was further applied to select optimal prognosis-related genes. The final prognostic nomogram was implemented together with prognostic clinicopathological parameters. The predictive efficiency of the nomogram was internally validated in training and testing groups, and externally validated in the Chinese Glioma Genome Atlas database. Three DNA methylation-driven genes, ARL9, CMYA5, and STEAP3, were identified as independent prognostic factors. Together with IDH1 mutation status, age, and sex, the final prognostic nomogram achieved the highest AUC value of 0.930, and demonstrated stable consistency in both internal and external validations. The prognostic nomogram could predict personal survival probabilities for patients with LGG, and serve as a user-friendly tool for prognostic evaluation, optimizing therapeutic regimes, and managing LGG patients.

The Role of miR-4256/HOXC8 Signaling Axis in the Gastric Cancer Progression: Evidence From lncRNA-miRNA-mRNA Network Analysis

Gastric cancer is a deadly human malignancy and the molecular mechanisms underlying gastric cancer pathophysiology are very complicated. Thus, further investigations are warranted to decipher the underlying molecular mechanisms. With the development of high-throughput screening and bioinformatics, gene expression profiles with large scale have been performed in gastric cancer. In the present study, we mined The Cancer Genome Atlas (TCGA) database and analyzed the gene expression profiles between gastric cancer tissues and normal gastric tissues. A series of differentially expressed lncRNAs, miRNAs and mRNAs between gastric cancer tissues and normal gastric tissues were identified. Based on the differentially expressed genes, we constructed miRNA-mRNA network, lncRNA-mRNA network and transcriptional factors-mRNA-miRNA-lncRNA network. Furthermore, the Kaplan survival analysis showed that high expression levels of EVX1, GBX2, GCM1, HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13 were all significantly correlated with shorter overall survival of the patients with gastric cancer. On the other hand, low expression level of HOXA13 was associated with shorter overall survival of patients with gastric cancer. Among these hub genes, we performed the in vitro functional studies of HOXC8 in the gastric cancer cells. Knockdown of HOXC8 and overexpression of miR-4256 both significantly repressed the gastric cancer cell proliferation and migration, and miR-4256 repressed the expression of HOXC8 via targeting its 3’ untranslated region in gastric cancer cells. Collectively, our results revealed that a complex interaction networks of differentially expressed genes in gastric cancer, and further functional studies indicated that miR-4256/HOXC8 may be an important axis in regulating gastric cancer progression.

Peritumoral Enhancement for the Evaluation of Myometrial Invasion in Low-Risk Endometrial Carcinoma on Dynamic Contrast-Enhanced MRI

ObjectivesTo explore the clinical value of subendometrial enhancement (SEE), irregular thin-layered peritumoral early enhancement (ITLPE) and focal irregular peritumoral early enhancement (FIPE) on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for myometrial invasion in patients with low-risk endometrial carcinoma.MethodsSeventy-seven patients with low-risk endometrial carcinoma who preoperatively underwent DCE-MRI were included. Two radiologists independently evaluated and recorded the occurrences of SEE, ITLPE and FIPE on DCE-MRI in all patients. Interobserver agreement was calculated between the two radiologists, and the relationships between SEE, ITLPE, FIPE, and myometrial invasion were analyzed based on histologic findings. For statistically significant findings, the sensitivity and specificity were calculated, and the differences in myometrial invasion evaluations were analyzed. For those with no statistical significance, images were compared with the histopathologic sections.ResultsInter-observer agreement was good (k = 0.80; 95%CI, 0.577–0.955) for SEE, and very good (k = 0.88; 95%CI, 0.761–0.972) (k = 0.86; 95%CI, 0.739–0.973) for ITLPE and FIPE. After consensus, SEE was identified in 12/77 (15.6%) patients; ITLPE and FIPE were found in 53/77 (68.8%) and 30/77 (39.0%) patients, respectively. SEE and ITLPE were significantly correlated with myometrial infiltration (P = 0.000), but FIPE were not (P = 0.725).The sensitivity and specificity of SEE and ITLPE for myometrial invasion in patients with low-risk endometrial carcinoma were 95.0 and 52.9%, and 85.0 and 88.0%, respectively. The area under the curve (AUC) of SEE and ITLPE for myometrial invasion were 0.740 (95%CI, 0.584–0.896), and 0.866 (95%CI, 0.763–0.970), respectively. The sensitivity and specificity were statistically different between SEE and ITLPE for the detection of myometrial invasion (P = 0.031, 0.016). According to the comparison between FIPE and histopathologic findings, the irregular endomyometrial junction was found in 30/77 (38.9%) cases, 24/30 (80.0%) with myometrial infiltration and 6/30 (20.0%) cases without myometrial infiltration.ConclusionsFIPE was the irregular endomyometrial junction. It can be found in patients with or without myometrial infiltration and may lead to the overestimation of myometrial invasion by SEE on DCE-MRI. ITLPE presented high diagnostic performance and specificity for myometrial invasion in patients with low-risk endometrial carcinoma.

Multi-Omics Profiling Suggesting Intratumoral Mast Cells as Predictive Index of Breast Cancer Lung Metastasis

Breast cancer lung metastasis has a high mortality rate and lacks effective treatments, for the factors that determine breast cancer lung metastasis are not yet well understood. In this study, data from 1067 primary tumors in four public datasets revealed the distinct microenvironments and immune composition among patients with or without lung metastasis. We used multi-omics data of the TCGA cohort to emphasize the following characteristics that may lead to lung metastasis: more aggressive tumor malignant behaviors, severer genomic instability, higher immunogenicity but showed generalized inhibition of effector functions of immune cells. Furthermore, we found that mast cell fraction can be used as an index for individual lung metastasis status prediction and verified in the 20 human breast cancer samples. The lower mast cell infiltrations correlated with tumors that were more malignant and prone to have lung metastasis. This study is the first comprehensive analysis of the molecular and cellular characteristics and mutation profiles of breast cancer lung metastasis, which may be applicable for prognostic prediction and aid in choosing appropriate medical examinations and therapeutic regimens.