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Rearrangements involving the neurotrophic-tropomyosin receptor kinase (NTRK) gene family (NTRK1, NTRK2, and NTRK3) have been identified as drivers in a wide variety of human cancers. However, the association between NTRK rearranged thyroid carcinoma and clinicopathological characteristics has not yet been established. In our study, we retrospectively reviewed medical records of thyroid cancer patients and identified 2 cases with NTRK rearrangement, no additional molecular alterations were observed in either of these cases. The fusion of the rearrangement in both cases was ETV6(E4)::NTRK3(E14). By analyzing the clinicopathological features of these two cases, we found that both were characterized by multiple tumor nodules, invasive growth, and central lymph node metastases, indicating the follicular subtype of papillary thyroid carcinoma. Immunohistochemical staining profiles showed CD56-, CK19+, Galectin-3+, HBME1+. These clinicopathological features suggest the possibility of ETV6-NTRK3 rearranged thyroid carcinoma and highlight the importance of performing gene fusion testing by FISH or NGS for these patients.

PurposeBulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART.Methods and materialsWe defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV’s border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents.Results21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14–85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009).ConclusionSCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials.

BackgroundGastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, with the potential to metastasize. Metastases to bone and soft tissue are more frequent in advanced cases, where targeted therapy is the standard treatment. However, around 10–15% of patients develop disease progression despite treatment. Studies have shown the efficacy of ablation in managing bone and soft tissue metastases (1, 2), but there are no reports of ablation for treating GIST bone or soft tissue metastases.Case presentationIn 2022, a 58-year-old man complaining of left back pain was admitted to Sichuan Cancer Hospital. He had undergone radical resection of the primary gastric GIST and vertebral metastases in 2014 and 2018, respectively. In 2019, rib metastases still occurred despite the use of targeted therapy. During the course of radiotherapy, targeted therapy, and immunotherapy, he experienced persistent chest wall pain. In addition, new lesions occurred in the lungs and chest wall in 2022. After a thorough assessment, microwave ablation (MWA) was recommended in response to his demand for immediate pain relief. The large rib metastasis constricted the spleen, so we completed the ablation in two sessions to reduce the risk of complications. He had 17 months of follow-up until September 2023, during which time his discomfort was considerably reduced.ConclusionFor GIST patients with soft tissue and bone metastases, MWA may offer substantial immediate pain alleviation. When other treatment procedures fail to achieve adequate efficacy, it provides an option.

ObjectiveTo analyze the clinical and ultrasonic characteristics of breast sclerosing adenosis (SA) and invasive ductal carcinoma (IDC), and construct a predictive nomogram for SA.Materials and methodsA total of 865 patients were recruited at the Second Hospital of Shandong University from January 2016 to November 2022. All patients underwent routine breast ultrasound examinations before surgery, and the diagnosis was confirmed by histopathological examination following the operation. Ultrasonic features were recorded using the Breast Imaging Data and Reporting System (BI-RADS). Of the 865 patients, 203 (252 nodules) were diagnosed as SA and 662 (731 nodules) as IDC. They were randomly divided into a training set and a validation set at a ratio of 6:4. Lastly, the difference in clinical characteristics and ultrasonic features were comparatively analyzed.ResultThere was a statistically significant difference in multiple clinical and ultrasonic features between SA and IDC (P

IntroductionIn early-stage epithelial ovarian cancer (EOC), how to perform lymphadenectomy to avoid stage migration and achieve reliable targeted excision has not been explored in depth. This study comprehensively considered the stage migration and survival to determine appropriate numbers of examined lymph node (ELN) for early-stage EOC and high-grade serous ovarian cancer (HGSOC).MethodsFrom the Surveillance, Epidemiology, and End Results database, we obtained 10372 EOC cases with stage T1M0 and ELN ≥ 2, including 2849 HGSOC cases. Generalized linear models with multivariable adjustment were used to analyze associations between ELN numbers and lymph node stage migration, survival and positive lymph node (PLN). LOESS regression characterized dynamic trends of above associations followed by Chow test to determine structural breakpoints of ELN numbers. Survival curves were plotted using Kaplan-Meier method.ResultsMore ELNs were associated with more node-positive diseases, more PLNs and better prognosis. ELN structural breakpoints were different in subgroups of early-stage EOC, which for node stage migration or PLN were more than those for improving outcomes. The meaning of ELN structural breakpoint varied with its location and the morphology of LOESS curve. To avoid stage migration, the optimal ELN for early-stage EOC was 29 and the minimal ELN for HGSOC was 24. For better survival, appropriate ELN number were 13 and 8 respectively. More ELNs explained better prognosis only at a certain range.DiscussionNeither too many nor too few numbers of ELN were ideal for early-stage EOC and HGSOC. Excision with appropriate numbers of lymph node draining the affected ovary may be more reasonable than traditional sentinel lymph node resection and systematic lymphadenectomy.

Paratesticular liposarcoma (PLS) causes scrotal mass changes, rarely in the urinary system. Before surgery, PLS causes scrotal mass changes that are difficult to distinguish from other causes. There has been a report of a giant paratestis liposarcoma resection and refusal to undergo orchiectomy. A 65-year-old man presented with finding the left scrotal mass after 2 years. Physical examination showed that the left scrotal mass was obviously difficult to retract. Pelvic CT showed that the left scrotal mass and flaky fat density shadow accompanied with left inguinal hernia. During surgery, laparoscopic exploration was performed to rule out inguinal hernia, and a scrotal exploration was also performed concurrently. The intraoperative frozen pathology considered lipogenic tumor, and the patient’s wife refused to undergo simultaneous left radical orchiectomy. Later the mass was completely removed, and postoperative pathology confirmed paratestis liposarcoma. During a 15-month routine follow-up, the tumor did not recur locally or metastasize distantly. PLS should be focused on early diagnosis and treatment, preoperative examinations and postoperative pathology should be combined, and highly personalized treatment will be implemented.

AGR2 is a secreted protein widely existing in breast. In precancerous lesions, primary tumors and metastatic tumors, the expression of AGR2 is increased, which has aroused our interest. This review introduces the gene and protein structure of AGR2. Its endoplasmic reticulum retention sequence, protein disulfide isomerase active site and multiple protein binding sequences endow AGR2 with diverse functions inside and outside breast cancer cells. This review also enumerates the role of AGR2 in the progress and prognosis of breast cancer, and emphasizes that AGR2 can be a promising biomarker and a target for immunotherapy of breast cancer, providing new ideas for early diagnosis and treatment of breast cancer.

PurposeTo evaluate the relationship between novel serum lipid index and chemoresistance as well as prognosis of epithelial ovarian cancer (EOC).Patients and methodsPatients’ serum lipid profiles of 249 cases diagnosed with epithelial ovarian cancer, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) as well as their ratios, the novel indicators HDL-C/TC and HDL-C/LDL-C, and clinicopathologic characteristics were retrospectively collected and calculated from January 2016 to January 2020 and correlation between serum lipid index and clinicopathological features such as chemoresistance as well as prognosis were evaluated.Results249 patients pathologically diagnosed EOC who underwent cytoreductive surgery were included in our cohort. The mean age of these patients was 55.20 ± 11.07 years. Binary logistic regression analyses indicated Federation International of Gynecology and Obstetrics (FIGO(stage and HDL-C/TC ratio had significant association with chemoresistance. Univariate analyses demonstrated pathological type, chemoresistance, FIGO stage, neoadjuvant chemotherapy, maintenance treatment, HDL-C/LDL-C ratio, HDL-C/TC ratio were related to Progression-Free Survival (PFS) and Overall Survival (OS) (P

BackgroundUterine corpus endometrial carcinoma (UCEC) is the third most common gynecologic malignancy. Fatty acid metabolism (FAM) is an essential metabolic process in the immune microenvironment that occurs reprogramming in the presence of tumor signaling and nutrient competition. This study aimed to identify the fatty acid metabolism-related genes (FAMGs) to develop a risk signature for predicting UCEC.MethodsThe differentially expressed FAMGs between UCEC samples and controls from TCGA database were discovered. A prognostic signature was then constructed by univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses. Based on the median risk score, UCEC samples were categorized into high- and low-FAMGs groups. Kaplan-Meier (K-M) curve was applied to determine patients’ overall survival (OS). The independent prognostic value was assessed by uni- and multivariate analyses. The associations between the risk score and immune status, immune score, and drug resistance were evaluated. Quantitative Real-time PCR (qRT-PCR) was utilized to confirm FAMGs expression levels in UCEC cells.ResultsWe built a 10-FAMGs prognostic signature and examined the gene mutation and copy number variations (CNV). Patients with a high-FAMGs had a worse prognosis compared to low-FAMGs patients in TCGA train and test sets. We demonstrated that FAMGs-based risk signature was a significant independent prognostic predictor of UCEC. A nomogram was also created incorporating this risk model and clinicopathological features, with high prognostic performance for UCEC. The immune status of each group was varied, and immune score was higher in a low-FAMGs group. HLA-related genes such as DRB1, DMA, DMB, and DQB2 had higher expression levels in the low-FAMGs group. Meanwhile, high-FAMGs patients were likely to response more strongly to the targeted drugs Bortezomib, Foretinib and Gefitinib. The qRT-PCR evidence further verified the significant expression of FAMGs in this signature.ConclusionsA FAMGs-based risk signature might be considered as an independent prognostic indicator to predict UCEC prognosis, evaluate immune status and provide a new direction for therapeutic strategies.

ObjectivesTo propose a deep learning-based classification framework, which can carry out patient-level benign and malignant tumors classification according to the patient’s multi-plane images and clinical information.MethodsA total of 430 cases of spinal tumor, including axial and sagittal plane images by MRI, of which 297 cases for training (14072 images), and 133 cases for testing (6161 images) were included. Based on the bipartite graph and attention learning, this study proposed a multi-plane attention learning framework, BgNet, for benign and malignant tumor diagnosis. In a bipartite graph structure, the tumor area in each plane is used as the vertex of the graph, and the matching between different planes is used as the edge of the graph. The tumor areas from different plane images are spliced at the input layer. And based on the convolutional neural network ResNet and visual attention learning model Swin-Transformer, this study proposed a feature fusion model named ResNetST for combining both global and local information to extract the correlation features of multiple planes. The proposed BgNet consists of five modules including a multi-plane fusion module based on the bipartite graph, input layer fusion module, feature layer fusion module, decision layer fusion module, and output module. These modules are respectively used for multi-level fusion of patient multi-plane image data to realize the comprehensive diagnosis of benign and malignant tumors at the patient level.ResultsThe accuracy (ACC: 79.7%) of the proposed BgNet with multi-plane was higher than that with a single plane, and higher than or equal to the four doctors’ ACC (D1: 70.7%, p=0.219; D2: 54.1%, p

BackgroundMany breast cancer survivors face long-term postoperative challenges as a result of developing lymphedema symptoms and chronic lymphedema. The-Optimal-Lymph-Flow (TOLF) program is an intervention based on physiological-cognitive-behavioral principles that teaches patients self-management strategies to activate lymphatic system and promote lymph flow to decrease lymphatic pain, reduce the risk and severity of lymphedema.ObjectiveThe purpose of this pilot clinical trial was to evaluate the use of TOLF program as an early intervention on improving lymphedema symptom experience (i.e., symptom number, symptom severity, symptom distress, and the impact of symptoms on patients’ activities of daily living) and optimizing lymph fluid levels (measured by the arm volume differences) among breast cancer survivors.MethodsThis study is a parallel, randomized clinical trial. A total of 92 breast cancer patients were randomly assigned to either the TOLF intervention group or the control group focusing on promoting arm mobility. Data were collected at baseline and end of the trial at the 3-month post intervention. The Breast Cancer and Lymphedema Symptom Experience Index was used to measure lymphedema symptom experience. Anthropometric measurements were used for circumferential arm measurements. Generalized linear mixed-effects models were used to evaluate the trial outcomes.ResultsSignificant improvements of lymphedema symptom experience were found in patients in the TOLF intervention group in comparison with patients in control group: the number of lymphedema symptoms (P

BackgroundTo investigate the value of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) to discriminate spinal metastasis from tuberculous spondylitis.MethodsThis study included 50 patients with spinal metastasis (32 lung cancer, 7 breast cancer, 11 renal cancer), and 20 with tuberculous spondylitis. The IVIM parameters, including the single-index model (apparent diffusion coefficient (ADC)-stand), double exponential model (ADCslow, ADCfast, and f), and the stretched-exponential model parameters (distributed diffusion coefficient (DDC) and α), were acquired. Receiver operating characteristic (ROC) and the area under the ROC curve (AUC) analysis was used to evaluate the diagnostic performance. Each parameter was substituted into a logistic regression model to determine the meaningful parameters, and the combined diagnostic performance was evaluated.ResultsThe ADCfast and f showed significant differences between spinal metastasis and tuberculous spondylitis (all p < 0.05). The logistic regression model results showed that ADCfast and f were independent factors affecting the outcome (P < 0.05). The AUC values of ADCfast and f were 0.823 (95% confidence interval (CI): 0.719 to 0.927) and 0.876 (95%CI: 0.782 to 0.969), respectively. ADCfast combined with f showed the highest AUC value of 0.925 (95% CI: 0.858 to 0.992).ConclusionsIVIM MR imaging might be helpful to differentiate spinal metastasis from tuberculous spondylitis, and provide guidance for clinical treatment.

This is a prospective, single center study aimed to evaluate the predictive power of peritumor and intratumor radiomics features assessed using T2 weight image (T2WI) of baseline magnetic resonance imaging (MRI) in evaluating pathological good response to NAC in patients with LARC (including Tany N+ or T3/4a Nany but not T4b). In total, 137 patients with LARC received NAC between April 2014 and August 2020. All patients were undergoing contrast-enhanced MRI and 129 patients contained small field of view (sFOV) sequence which were performed prior to treatment. The tumor regression grade standard was based on pathological response. The training and validation sets (n=91 vs. n=46) were established by random allocation of the patients. Receiver operating characteristic curve (ROC) analysis was applied to estimate the performance of different models based on clinical characteristics and radiomics features obtained from MRI, including peritumor and intratumor features, in predicting treatment response; these effects were calculated using the area under the curve (AUC). The performance and agreement of the nomogram were estimated using calibration plots. In total, 24 patients (17.52%) achieved a complete or near-complete response. For the individual radiomics model in the validation set, the performance of peritumor radiomics model in predicting treatment response yield an AUC of 0.838, while that of intratumor radiomics model is 0.805, which show no statically significant difference between then(P>0.05). The traditional and selective clinical features model shows a poor predictive ability in treatment response (AUC=0.596 and 0.521) in validation set. The AUC of combined radiomics model was improved compared to that of the individual radiomics models in the validation sets (AUC=0.844). The combined clinic-radiomics model yield the highest AUC (0.871) in the validation set, although it did not improve the performance of the radiomics model for predicting treatment response statically (P>0.05). Good agreement and discrimination were observed in the nomogram predictions. Both peritumor and intratumor radiomics features performed similarly in predicting a good response to NAC in patients with LARC. The clinic-radiomics model showed the best performance in predicting treatment response.

Background and ObjectivesAfter diagnosing a primary bone tumor involving the forearm, various excision strategies and reconstruction methods must be considered. This study explored the oncological and functional outcomes of limb salvage surgery for primary malignant bone tumors in the forearm.MethodsPatients with primary forearm bone tumors (n = 369) were retrospectively analyzed between 2000 and 2017. There were 266 patients with radial tumors, and 46 (17.3%) were malignant, whereas 103 patients had ulnar lesions and 22 (21.4%) were malignant tumors. The oncological results, prognostic factors, and functional results after limb salvage surgery of forearm malignancies were analyzed.ResultsThe follow-up averaged 72.1 (7–192, median 62.5) months. Fifty-six patients who received limb salvage surgery were included in the final evaluation. Radius resection was performed in 38 patients, and distal radius (25 patients) was most frequent. Ulnar resection was performed in 18 patients, and the proximal ulna (13 patients) was most frequent. The surgical margins obtained were intralesional in 3 patients, marginal in 8 patients and wide in 45 patients. Local recurrence occurred in 11 patients (19.6%), and distant metastasis occurred in 14 patients (25%). The 5-year recurrence-free survival rate was 79.8%. Unplanned excision, ulnar involvement, proximal forearm location and inadequate surgical margins were associated with recurrence. The overall 5-year and 10-year survival rates were 83.5 and 71.7%, respectively. Distant metastasis was a poor prognostic factor for the survival rate. Forty-two patients were evaluated by MSTS score with an average of 27.9 ± 1.5.ConclusionsThe incidence of radial malignant tumors is higher than that of ulnar lesions. The distal radius and the proximal ulna are the most frequently involved sites. Unplanned excisions, ulnar tumors, proximal forearm tumors, and inadequate surgical margin are the risk factors for local recurrence. Distant metastasis is an independent poor prognostic factor of death. The oncology control and functional results of limb salvage surgery were satisfactory.

BackgroundRecently, the Turing test has been used to investigate whether machines have intelligence similar to humans. Our study aimed to assess the ability of an artificial intelligence (AI) system for spine tumor detection using the Turing test.MethodsOur retrospective study data included 12179 images from 321 patients for developing AI detection systems and 6635 images from 187 patients for the Turing test. We utilized a deep learning-based tumor detection system with Faster R-CNN architecture, which generates region proposals by Region Proposal Network in the first stage and corrects the position and the size of the bounding box of the lesion area in the second stage. Each choice question featured four bounding boxes enclosing an identical tumor. Three were detected by the proposed deep learning model, whereas the other was annotated by a doctor; the results were shown to six doctors as respondents. If the respondent did not correctly identify the image annotated by a human, his answer was considered a misclassification. If all misclassification rates were >30%, the respondents were considered unable to distinguish the AI-detected tumor from the human-annotated one, which indicated that the AI system passed the Turing test.ResultsThe average misclassification rates in the Turing test were 51.2% (95% CI: 45.7%–57.5%) in the axial view (maximum of 62%, minimum of 44%) and 44.5% (95% CI: 38.2%–51.8%) in the sagittal view (maximum of 59%, minimum of 36%). The misclassification rates of all six respondents were >30%; therefore, our AI system passed the Turing test.ConclusionOur proposed intelligent spine tumor detection system has a similar detection ability to annotation doctors and may be an efficient tool to assist radiologists or orthopedists in primary spine tumor detection.

BackgroundsOvarian cancer (OC) is still the leading aggressive and lethal disease of gynecological cancers, and platinum-based regimes are the standard treatments. However, nearly 20%–30% of patients with OC are initial platinum resistant (IPR), and there is a lack of valid tools to predict whether they will be primary platinum resistant or not prior to chemotherapy.MethodsTranscriptome data from The Cancer Genome Atlas (TCGA) was downloaded as the training data, and transcriptome data of GSE15622, GSE102073, GSE19829, and GSE26712 were retrieved from Gene Expression Omnibus (GEO) as the validation cohorts. Differentially expressed genes (DEGs) were selected between platinum-sensitive and platinum-resistant patients from the training cohort, and multiple machine-learning algorithms [including random forest, XGboost, and least absolute shrinkage and selection operator (LASSO) regression] were utilized to determine the candidate genes from DEGs. Then, we applied logistic regression to establish the IPR signature based on the expression. Finally, comprehensive clinical, genomic, and survival feature were analyzed to understand the application value of the established IPR signature.ResultsA total of 532 DEGs were identified between platinum-resistant and platinum-sensitive samples, and 11 of them were shared by these three-machine learning algorithms and utilized to construct an IPR prediction signature. The area under receiver operating characteristic curve (AUC) was 0.841 and 0.796 in the training and validation cohorts, respectively. Notably, the prediction capacity of this signature was stable and robust regardless of the patients’ homologous recombination deficiency (HRD) and mutation burden status. Meanwhile, the genomic feature was concordant between samples with high- or low-IPR signature, except a significantly higher prevalence of gain at Chr19q.12 (regions including CCNE1) in the high-IPR signature samples. The efficacy of prediction of platinum resistance of IPR signature successfully transferred to the precise survival prediction, with the AUC of 0.71, 0.72, and 0.66 to predict 1-, 3-, and 5-year survival, respectively. At last, we found a significantly different tumor-infiltrated lymphocytes feature, including lower abundance of CD4+ naive T cells in the samples with high-IPR signature. A relatively lower tumor immune dysfunction and exclusion (TIDE) value and more sensitivity to multiple therapies including Gefitinib may suggest the potency to transfer from platinum-based therapy to immunotherapy or target therapies in patients with high-IPR signature.ConclusionOur study established an IPR signature based on the expression of 11 genes that could stably and robustly distinguish OC patients with IPR and/or poor outcomes, which may guide therapeutic regimes tailoring.

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.

Oral squamous cell carcinoma (OSCC) predominantly consists of squamous cells and is the tumor with the highest incidence of the head and neck. Carnosic acid (CA), a natural monomer drug obtained from rosemary and salvia, shows various pharmacological effects, including of tumor development. This study aimed to assess for an effect of CA on the development of OSCC and the underlying mechanisms. In CAL27 and SCC9 cells, CA inhibited cell proliferation and migration, increased intracellular levels of reactive oxygen species (ROS) and Ca2+, decreased the mitochondrial membrane potential (MMP), and promoted apoptosis. In CAL27- and SCC9-xenotransplanted BALB/c nude mice, CA inhibited the tumor growth without affecting the body weight and tissue morphology. CA upregulated Bax, Bad, cleaved Caspase-3 and -9 levels, and the cleaved PARP1/PARP1 ratio but downregulated Bcl-2 in CA-treated OSCC cells and OSCC cells-xenotransplanted BALB/c nude mice. These results indicate that CA suppresses OSCC at least via the mitochondrial apoptotic pathway and offers this natural compound as a potential therapeutic against OSCC.

Angiogenesis is an important mechanism underlying the development and metastasis of colorectal cancer (CRC) and has emerged as a therapeutic target for metastatic CRC (mCRC). Our recent studies found that Peroxisome proliferator-activated receptor β/δ/D (PPARδ) regulates vascular endothelial growth factor A(VEGFA) secretion and the sensitivity to bevacizumab in CRC. However, its exact effect and underlying mechanisms remain unidentified. In this study, we showed that PPARδ expression was inversely associated with the microvascular density in human CRC tissues. Knockdown of PPARδ enhanced VEGFA expression in HCT116 cells and HUVEC angiogenesis in vitro; these phenomena were replicated in the experimental in vivo studies. By tandem mass tag (TMT)-labeling proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) analyses, endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) was screened and predicted as a target gene of PPARδ. This was verified by exploring the effect of coregulation of PPARδ and ERO1A on the VEGFA expression in HCT116 cells. The results revealed that PPARδ induced VEGFA by interacting with ERO1A. In conclusion, our results suggest that knockdown of PPARδ can promote CRC angiogenesis by upregulating VEGFA through ERO1A. This pathway may be a potential target for mCRC treatment.

ObjectiveThe purpose of this study was to compare the clinicopathological characteristics of type 1 and type 2 papillary renal cell carcinoma (PRCC) and to explore the prognostic factors of PRCC in the Chinese population.MethodsA total of 242 patients with PRCC from five Chinese medical centers were retrospectively included. From them, 82 were type 1 PRCC and 160 were type 2 PRCC. Clinicopathological features and oncologic outcomes were reviewed. The Kaplan–Meier analysis and log-rank test were performed to describe the progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic factors of PRCC.ResultsOf the 242 patients, the average age at surgery was 55.3 ± 13.1 years. The mean tumor size was 5.1 ± 3.1 cm. Compared with type 1 PRCC patients, type 2 PRCC patients had a larger tumor size and were more likely to undergo radical nephrectomy. Besides, type 2 PRCC patients had higher tumor stage (p < 0.001) and WHO International Society of Urological Pathology (WHO/ISUP) grading (p < 0.001). Furthermore, tumor necrosis was more common in type 2 PRCC than type 1 PRCC (p = 0.030). The Kaplan–Meier survival analysis showed that the PFS and OS of type 1 PRCC patients were significantly better than those of type 2 PRCC patients (p = 0.0032 and p = 0.0385, respectively). Univariate analysis showed that tumor size, surgical procedures, pT stage, WHO/ISUP grading, and microvascular invasion were significant predictors of PFS and OS for type 2 PRCC patients. In the multivariate analysis, only pT stage (p = 0.004) and WHO/ISUP grading (p = 0.010) were the independent risk factors. Among type 2 PRCC patients with pT1 stage, no significant difference was found in PFS and OS between the partial nephrectomy and radical nephrectomy groups (p = 0.159 and p = 0.239, respectively).ConclusionThis multi-institutional study reveals the significant differences in clinicopathological variables and oncologic outcomes between type 1 and 2 PRCC. For type 2 PRCC in pT1 stage, the prognosis of partial nephrectomy is not inferior to that of radical nephrectomy, and nephron-sparing surgery can be considered.

BackgroundData on efficacy of adjuvant therapy for surgically resected small cell lung cancer are scant. This study was determined to reveal the survival benefits of different adjuvant treatment modalities for limited-stage small cell lung cancer patients following surgical resection.MethodsData of patients with histologically confirmed small cell lung cancer after surgical resection were collected from November 2006 to June 2019. Survival analyses were calculated by Kaplan–Meier method, with log-rank test to evaluate statistical significance. Prognostic factors were identified by multivariate analysis using cox proportional hazards model. Further survival analysis and cox regression analysis stratified by clinicopathologic features were conducted to evaluate the survival benefits of different adjuvant treatment modalities.ResultsIn total, 153 out of 157 patients were analyzed. Multivariate analysis showed male sex, lymph node metastasis, residual tumor, VPI and non-adjuvant therapy were independently associated with poor prognosis. Subgroup analyses revealed both adjuvant chemotherapy and adjuvant chemoradiotherapy were significantly associated with superior survival for stage pT2-4 (HR=0.176, 95%CI:0.053-0.578, p=0.004; and HR=0.115, 95%CI:0.033-0.405, p=0.001) and pure SCLC patients (HR=0.182, 95%CI:0.067-0.494, p=0.001; and HR=0.181, 95%CI:0.071-0.465, p

Background and PurposeAs a third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib is approved for treating advanced non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation after progression on first- or second-generation EGFR-TKIs such as gefitinib, erlotinib and afatinib. We aim at exploring the feasibility and effectiveness of using radiomic features from chest CT scan to predict the prognosis of metastatic non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation receiving second-line osimertinib therapy.MethodsContrast-enhanced and unenhanced chest CT images before osimertinib treatment were collected from 201 and 273 metastatic NSCLC patients with EGFR-T790M mutation, respectively. Radiomic features were extracted from the volume of interest. LASSO regression was used to preliminarily evaluate the prognostic values of different radiomic features. We then performed machine learning-based analyses including random forest (RF), support vector machine (SVM), stepwise regression (SR) and LASSO regression with 5-fold cross-validation (CV) to establish the optimal radiomic model for predicting the progression-free survival (PFS) of osimertinib treatment. Finally, a combined clinical-radiomic model was developed and validated using the concordance index (C-index), decision-curve analysis (DCA) and calibration curve analysis.ResultsDisease progression occurred in 174/273 (63.7%) cases. CT morphological features had no ability in predicting patients’ prognosis in osimertinib treatment. Univariate COX regression followed by LASSO regression analyses identified 23 and 6 radiomic features from the contrast-enhanced and unenhanced CT with prognostic value, respectively. The 23 contrast-enhanced radiomic features were further used to construct radiomic models using different machine learning strategies. Radiomic model built by SR exhibited superior predictive accuracy than RF, SVR or LASSO model (mean C-index of the 5-fold CV: 0.660 vs. 0.560 vs. 0.598 vs. 0.590). Adding the SR radiomic model to the clinical model could remarkably strengthen the C-index of the latter from 0.672 to 0.755. DCA and calibration curve analyses also demonstrated good performance of the combined clinical-radiomic model.ConclusionsRadiomic features extracted from the contrast-enhanced chest CT could be used to evaluate metastatic NSCLC patients’ prognosis in osimertinib treatment. Prognostic models combing both radiomic features and clinical factors had a great performance in predicting patients’ outcomes.

Long non-coding RNAs (lncRNAs) play important roles in various biological processes and human diseases, including cancer. In this study, we demonstrated a regulatory relationship between lncRNA GRIK1-AS1 and miR-375/IFIT2 axis in gastric cancer. Our results show a decreased expression of GRIK1-AS1 in gastric cancer tissues compared to adjacent normal gastric tissues. Gastric cell lines also have reduced levels of GRIK1-AS1 compared to gastric epithelial cell line GES-1. Ectopic expression of GRIK1-AS1 in gastric cancer cell lines significantly inhibits cellular viability, migration, and invasion. RNA-pull down and the luciferase activity assays show that GRIK1-AS1 mainly interacts specifically with miR-375. We further demonstrate a negatively regulatory relationship between lncRNA GRIK1-AS1 and miR-375. We discovered that IFIT2 was one of the direct key downstream target genes of miR-375, and established the important role of the GRIK1-AS1/miR-375/IFIT2 axis in the progression of gastric cancer. Taken together, our results revealed a novel mechanism of GRIK1-AS1 as a sponge to miR-375 that impacts gastric cancer progression via modulating target mRNA IFIT2 translation, and as a result, opens a new strategy to future GRIK1-AS1 based therapeutic development.

Simple SummaryGlioblastoma (GBM) is the most common and aggressive primary brain tumor. Diffusion kurtosis imaging (DKI) has characterized non-Gaussian diffusion behaviors in brain normal tissue and gliomas, but there are very limited efforts in investigating treatment responses of kurtosis in GBM. This study aimed to investigate whether any parameter derived from the DKI is a significant predictor of overall survival (OS). We found that the large mean, 80 and 90 percentile kurtosis values in the contrast enhanced gross tumor volume (Gd-GTV) on post-Gd T1-weighted images pre-RT were significantly associated with reduced OS. In the multivariate Cox model, the mean kurtosis Gd-GTV pre-RT after considering effects of age, extent of surgery, and methylation were significant predictors of OS. In addition, the 80 and 90 percentile kurtosis values in Gd-GTV post RT were significantly associated with progression free survival (PFS). The DKI model demonstrates the potential to predict outcomes in the patients with GBM.PurposeNon-Gaussian diffusion behaviors in gliomas have been characterized by diffusion kurtosis imaging (DKI). But there are very limited efforts in investigating the kurtosis in glioblastoma (GBM) and its prognostic and predictive values. This study aimed to investigate whether any of the diffusion kurtosis parameters derived from DKI is a significant predictor of overall survival.Methods and MaterialsThirty-three patients with GBM had pre-radiation therapy (RT) and mid-RT diffusion weighted (DW) images. Kurtosis and diffusion coefficient (DC) values in the contrast enhanced gross tumor volume (Gd-GTV) on post-Gd T1 weighted images pre-RT and mid-RT were calculated. Univariate and multivariate Cox models were used to evaluate the DKI parameters and clinical factors for prediction of OS and PFS.ResultsThe large mean kurtosis values in the Gd-GTV pre-RT were significantly associated with reduced OS (p = 0.02), but the values at mid-RT were not (p > 0.8). In the multivariate Cox model, the mean kurtosis in the Gd-GTV pre-RT (p = 0.009) was still a significant predictor of OS after adjusting effects of age, O6-Methylguanine-DNA Methyl transferase (MGMT) methylation and extent of resection. In Gd-GTV post-RT, 80 and 90 percentile kurtosis values were significant predictors (p ≤ 0.05) for progression free survival (PFS).ConclusionThe DKI model demonstrates the potential to predict OS and PFS in the patients with GBM. Further development and histopathological validation of the DKI model will warrant its role in clinical management of GBM.

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases globally. Despite continuous improvement of treatment methods, high postoperative recurrence rate remains an urgent problem. In order to determine the mechanism underlying recurrence of liver cancer and identify prognostic genes, data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were integrated and analyzed. Differentially expressed genes (DEGs) between HCC tissue and normal liver tissue were identified, and a protein–protein interaction network was constructed to find hub genes. Clinical correlation analysis and disease-free survival (DFS) analysis were performed using the R language and GEPIA to identify relapse-related genes. Correlation analysis was used to identify a potential regulatory axis. Dual-luciferase reporter gene assay was used to confirm the reliability of the long non-coding RNA (lncRNA)–microRNA (miRNA)–mRNA regulatory axis. Immune infiltration analysis was performed using the TIMER database. Correlations between immune gene markers and ASF1B were verified using quantitative real-time polymerase chain reaction (RT-qPCR). In this work, we found that nine lncRNAs and five mRNAs were significantly overexpressed in HCC tissues from patients with recurrence. SNHG3, LINC00205, ASF1B, AURKB, CCNB1, CDKN3, and DTL were also closely related to HCC grade and stage. Survival analysis showed that these seven DEGs were significantly correlated with poor DFS. Correlation analysis identified SNHG3–miR-214-3p–ASF1B as a potential regulatory axis. Dual-luciferase reporter gene assay showed that SNHG3 and ASF1B directly bound to miR-214-3p. ASF1B was negatively regulated by miRNA-214-3p, and overexpression of SNHG3 could inhibit the expression of miRNA-214-3p. In addition, ASF1B was positively correlated with immune infiltration. A reduction in ASF1B could markedly inhibit the expression of CD86, CD8, STAT1, STAT4, CD68, and PD1 in HCC cells. Flow cytometry showed that SNHG3 promoted the PD-1 expression by regulating ASF1B. Meanwhile, elevated ASF1B predicted poor prognosis of HCC patients in subgroups with decreased B cells, CD8+ T cells, or neutrophils, and those with enriched CD4+ T cells. In conclusion, we found that a novel lncRNA SNHG3/miR-214-3p/ASF1B axis could promote the recurrence of HCC by regulating immune infiltration.

The histological transformation from epidermal growth factor receptor (EGFR)-mutated adenocarcinoma (ADC) to squamous cell carcinoma (SCC) after tyrosine kinase inhibitor (TKI) treatment is rare. We present a case of a patient who transitioned from early-stage primary lung ADC with partial squamous differentiation, EGFR mutation and amplification, to adrenal gland metastasis as SCC with EGFR amplification disappearance 115-months after surgery, during which gefitinib and local radiotherapy were utilized for the metastasis in the right femoral head and mediastinal lymph nodes. This case might indicate a possible mechanism of EGFR inhibition resistance with SCC transition and EGFR amplification loss from the initially well-responding ADC, especially those with SCC or partial squamous differentiation. The optimal post-progression therapy for ADC-SCC patients is challenging and further studies are needed.

BackgroundThe role of primary tumor resection in occult M1a lung adenocarcinoma remains unclear, especially for patients receiving targeted therapy. The purpose of this study is to assess the effect of primary tumor resection on overall survival (OS) in lung adenocarcinoma patients with occult pleural disseminations receiving targeted therapy.MethodsLung adenocarcinoma patients with intraoperatively-confirmed occult pleural dissemination (M1a), who hospitalized in the Department of Thoracic Surgery in Fudan Shanghai Cancer Center from May 2008 to December 2017 and received EGFR-TKIs therapy, were enrolled. Log-rank tests were used to compare the survival differences between groups.Results34 patients receiving EGFR-TKIs were enrolled. The majority of them were never smokers (29/34, 85.3%). Among the enrolled patients, 20 (58.8%) patients underwent primary tumor resection, while 14 (41.2%) patients not. There was no distributional difference of baselines between patients undergoing and not undergoing primary tumor resection. Further analyses demonstrated that the patients undergoing primary tumor resection had a prolonged OS compared with those not (log-rank P= 0.042). The 2-year and 5-year OS for patients receiving primary tumor resection and EGFR-TKIs was 90.0% and 60.1%.ConclusionsPrimary tumor resection was associated with improved survival in patients with occult intraoperatively-confirmed M1a adenocarcinoma receiving EGFR-TKIs.

Objective: With the rapid development of cancer genomics and immunomics, some new treatments of small cell lung cancer (SCLC) are emerging. However, there are limitations to the clinical use of tumor tissue. Our study aimed to evaluate the potential use of bronchial washing fluid (BWF) in the liquid biopsy of SCLC.Methods: Twenty-one extensive SCLC (ES-SCLC) patients were enrolled in this study. For all patients, four sample types, BWF supernatant (BWFs), BWF precipitate (BWFp), plasma and tumor tissue, were collected before receiving chemotherapy, and one type, plasma, was collected after chemotherapy. All samples were conducted to NGS using the 1021-gene panel. The concordance rates of genomic profiling using NGS in the four types of samples were evaluated. Multiple clinical information was analyzed for correlation.Results: We successfully tested 20 BWFs samples, 21 BWFp samples, 21 tumor tissue samples, 20 pre-treatment plasma, and 13 post-treatment plasma of these 21 patients. The detectability of somatic mutations was 100% for BWFs, BWFp, tumor tissues, and post-treatment plasma, and only one pre-treatment plasma was absent with any mutation. Matched tumor tissue, BWFs, BWFp, and pre-treatment plasma samples were subsistent for 19 patients. For these patients, 204 genomic alterations were identified in tissue samples, while 189 (92.6%), 175 (85.5%), and 163 (79.9%) alterations were detected in the matched BWFs, BWFp, and pre-treatment plasma, respectively. Moreover, we found that the three tumor markers associated with SCLC have a lower sensitivity than genomic alterations. The endocrine resistance pathway was found enriched in hyponatremia patients which may be related to the hyponatremia. The TMBs of BWF, BWFp, and pre-treatment plasma samples all had a strong correlation with that of tissue samples. Both the VAF and the MVAF of mutations in post-treatment plasma were less than those in pre-treatment plasma, which was in accordance with the evaluation of curative effect.Conclusions: For ES-SCLC patients, the liquid biopsy of BWF showed a highly potential advantage to identify DNA alterations, which suggested that genomic analysis of BWF liquid biopsy may have clinical value as a supplement for tissue and blood detection. Through the restricted validation, it can be widely used in routine clinical practice.

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

BackgroundAccumulating evidences indicate significant alterations in the aerobic glycolysis in clear cell renal cell carcinoma (ccRCC). We aim to develop and validate a glycolysis-related genes signature for predicting the clinical outcomes of patients with ccRCC.MethodsmRNA expression profiling of ccRCC was obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and lasso Cox regression model were performed to identify and construct the prognostic gene signature. The protein expression levels of the core genes were obtained from the Human Protein Atlas database. We used four external independent data sets to verify the predictive power of the model for prognosis, tyrosine kinase inhibitor (TKI) therapy, and immunotherapy responses, respectively. Finally, we explored the potential mechanism of this signature through gene set enrichment analysis (GSEA).ResultsThrough the GSEA, glycolysis-related gene sets were significantly different between ccRCC tissues and normal tissues. Next, we identified and constructed a seven-mRNA signature (GALM, TGFA, RBCK1, CD44, HK3, KIF20A, and IDUA), which was significantly correlated with worse survival outcome and was an independent prognostic indicator for ccRCC patients. Furthermore, the expression levels of hub genes were validated based on the Human Protein Atlas databases. More importantly, the model can predict patients’ response to TKI therapy and immunotherapy. These findings were successfully validated in the external independent ccRCC cohorts. The mechanism exploration showed that the model may influence the prognosis by influencing tumor proliferation, base mismatch repair system and immune status of patients.ConclusionsOur study has built up a robust glycolysis-based molecular signature that predicts the prognosis and TKI therapy and immunotherapy responses of patients with ccRCC with high accuracy, which might provide important guidance for clinical assessment. Also, clinical investigations in large ccRCC cohorts are greatly needed to validate our findings.

Background: The clinical value and delineation of clinical target volume (CTV) of postoperative radiotherapy (PORT) in completely resected (y)pN2 non-small cell lung cancer (NSCLC) remain controversial. Investigations specifically focusing on the cumulative incidence and prognostic significance of initial disease recurrence at the supraclavicular region (SCR) in this disease population are seldom reported.Methods: Consecutive patients with curatively resected (y)pN2 NSCLC who received adjuvant chemotherapy from January 2013 to December 2018 at our cancer center were retrospectively examined. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was defined as loco-regional recurrence (LRR). Disease recurrence beyond LRR and SCR, was defined as distant metastasis (DM). Overall survival (OS1 and OS2) were calculated from surgery and disease recurrence to death of any cause, in the entire cohort and in patients with recurrent disease, respectively.Results: Among the 311 patients enrolled, PORT without elective supraclavicular nodal irradiation (ESRT) was performed in 94 patients and neoadjuvant chemotherapy was administered in 31 patients. With a median follow-up of 26 months, 203 patients developed recurrent disease, including 27 SCRs, among which 16 were without DM and 22 involved the ipsilateral supraclavicular region. The 1, 3, and 5-year cumulative incidence of SCR were 6.53, 13.0, and 24.7%, respectively. Chosen DM as a competing event, cN2, ypN2, not receiving lobectomy, and negative expression of CK7 were significantly associated with SCR using the univariate competing risk analysis, while ypN2 was identified as the only independent risk factor of SCR (p = 0.012). PORT significantly reduced LRR (p = 0.031) and prolonged OS1 (p = 0.018), but didn't impact SCR (p = 0.254). Pattern of failure analyses indicated that the majority of LRRs developed within the actuarial or virtual CTV of PORT, and 15 of the 22 ipsilateral SCRs could be covered by the virtual CTV of proposed ESRT. In terms of OS2, patients who developed SCR but without DM had intermediate prognosis, compared with those who had DM (p = 0.009) and those who had only LRR (p = 0.048).Conclusions: SCR is not uncommon and has important prognostic significance in completely resected (y)pN2 NSCLC. The clinical value of PORT and ESRT in such patients need to be further investigated.

Purpose: This study aimed to determine whether detecting elastic fibers in tumor stroma (EFTS) could be used as a new method for predicting the prognosis of gastric cancer (GC) patients.Materials and Methods: EFTS expression was determined by histochemistry in 160 GC patients who underwent gastrectomy. Based on the staining results, the patients were divided into three groups according to their EFTS expression level: low (n = 57), moderate (n = 50), and high (n = 53). The clinicopathological data and 6-year survival data were analyzed among different EFTS groups.Results: The expression of EFTS was closely related to lymphovascular invasion (P = 0.010), blood transfusion in operation (P < 0.001), recurrence rate (P < 0.001), and motility (P < 0.001). High expression of EFTS was also correlated with recurrence-free survival (RFS) and overall survival (OS) in GC patients by Kaplan–Meier curve (P < 0.001 for RFS and P < 0.001 for OS).Conclusions: Multivariate analysis showed that EFTS was an independent prognostic factor for RFS and OS. In conclusion, detecting EFTS to predict the prognosis of GC patients is effective and highly feasible.

Background: MRE11 plays an important role in DNA damage response for the maintenance of genome stability, and is becoming a prognostic marker for cancers, including colorectal cancer (CRC). However, the correlations of MRE11 to prognosis and tumor-infiltrating inflammatory cells (TIICs) in different locations of CRC remains unclear.Methods: Among Swedish and TCGA-COREAD patients, we investigated the association of MRE11 expression, tumor-infiltrating inflammatory cells (TIICs) and microsatellite status with survival in right-sided colon cancer (RSCC) and left-sided colon and rectal cancer (LSCRC). The signaling of MRE11-related was further analyzed using weighted gene co-expression network analysis and ClueGO.Results: High MRE11 expression alone or combination of high MRE11 expression with high TIICs was related to favorable prognosis in LSCRC. Moreover, high MRE11 expression was associated with favorable prognosis in LSCRC with microsatellite stability. The relationships above were adjusted for tumor stage, differentiation, and/or TIICs. However, no such evidence was observed in RSCC. Several signaling pathways involving MRE11 were found to be associated with cell cycle and DNA repair in RSCC and LSCRC, whereas, the activation of the immune response and necrotic cell death were specifically correlated with LSCRC.Conclusions: High MRE11 expression is an independent prognostic marker in LSCRC and enhanced prognostic potency of combining high MRE11 with high TIICs in LSCRC, mainly due to differential immune signaling activated by MRE11 in RSCC and LSCRC, respectively.

Purpose: To retrospectively identify the relationships between both CT morphological features and histogram parameters with pulmonary metastasis in patients with colorectal cancer (CRC) and compare the efficacy of single-slice and whole-lesion histogram analysis.Methods: Our study enrolled 196 CRC patients with pulmonary nodules (136 in the training dataset and 60 in the validation dataset). Twenty morphological features of contrast-enhanced chest CT were evaluated. The regions of interests were delineated in single-slice and whole-tumor lesions, and 22 histogram parameters were extracted. Stepwise logistic regression analyses were applied to choose the independent factors of lung metastasis in the morphological features model, the single-slice histogram model and whole-lesion histogram model. The areas under the curve (AUC) was applied to quantify the predictive accuracy of each model. Finally, we built a morphological-histogram nomogram for pulmonary metastasis prediction.Results: The whole-lesion histogram analysis (AUC of 0.888 and 0.865 in the training and validation datasets, respectively) outperformed the single-slice histogram analysis (AUC of 0.872 and 0.819 in the training and validation datasets, respectively) and the CT morphological features model (AUC of 0.869 and 0.845 in the training and validation datasets, respectively). The morphological-histogram model, developed with significant morphological features and whole-lesion histogram parameters, achieved favorable discrimination in both the training dataset (AUC = 0.919) and validation dataset (AUC = 0.895), and good calibration.Conclusions: CT morphological features in combination with whole-lesion histogram parameters can be used to prognosticate pulmonary metastasis for patients with colorectal cancer.

The gut microbiota, including pathogenic microorganisms and probiotics, has been involved in tumor initiation and progression by regulating the components of intestinal flora. Canmei formula (CMF), a traditional Chinese medicine, chronicled in the Chuang Yang Jing Yan Quan Shu, has been clinically used as an adjuvant therapy to treat patients with colorectal carcinoma (CRC) in China. In this study, we investigate the treatment effect of CMF in the azoxymethane (AOM) and dextran sodium sulfate (DSS) induced and high-fat diet augmented colitis-associated colorectal cancer in vivo, and explore its mechanism of action. We found that CMF treatment relieved the inflammation and alteration of the gut microbiota and significantly inhibited the development of intestinal adenoma. Linear discriminant analysis showed that the flora diversity in the normal mice, model mice and CMF treatment mice was different. At the family level, the relative abundance of Desulfovibrionaceae decreased in CMF groups. The relative abundance of Desulfovibrionaceae were lower in the CMF groups than in model group, whereas Rikenellaceae and Alistipes were increased. Altogether our results indicate that CMF treatment ameliorate colitis-associated colorectal carcinogenesis by modulating the composition of the gut microbiota in vivo.

Purpose: Our study aimed to provide data on effectiveness, safety of crizotinib treatment, brain metastases, progression patterns, and sequential therapy beyond crizotinib treatment in patients with advanced ALK-positive NSCLC in China.Methods: We reviewed the medical records of crizotinib-treated NSCLC patients with ALK-rearrangement between May 2014 and May 2018 at Fudan University Shanghai Cancer Center. All patients received crizotinib with 250 mg twice daily. Main outcome measures were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), the second PFS (PFS2), overall survival (OS), and adverse events.Results: One hundred and four patients with ALK-positive NSCLC were included in this retrospective study. ORR and DCR were 82.7 and 98.1%, respectively. The estimated PFS and OS were 13.0 months (95% CI 9.0–17.0 months) and 36.0 months (95% CI 31.0–41.0 months), respectively. Multivariable analysis showed that young age, presence of baseline adrenal gland metastases and non-adenocarcinoma were independent predictive factors for poorer PFS. Presence of baseline adrenal gland metastases, non-adenocarcinoma, intrathoracic progression and shorter crizotinib treatment time were associated with worse OS. Patients without baseline brain metastases (BBM) who were administered with crizotinib as first-line therapy can achieve a significantly longer PFS than those who received crizotinib as second or later line therapy (p = 0.006). For patients with BBM receiving sequential therapy beyond the first disease progression after crizotinib treatment (1st PD), crizotinib beyond progressive disease (CBPD) plus local therapy can lead to a significantly longer PFS2 (67.0 vs. 21.0 weeks; p = 0.046). Additionally, the OS was significantly longer in patients achieving 1st PD who received CBPD plus local therapy than those who did not receive CBPD or local therapy (35.0 vs. 24.0 months, p = 0.041). Presence of brain metastases at any time was in association with worse PFS. No unexpected adverse effects were reported.Conclusions: Crizotinib was effective and well tolerated in Chinese patients with ALK-positive, advanced NSCLC in real-world clinical practice. For patients without BBM, crizotinib as first-line therapy can lead to a longer PFS than second-or later line therapy. CBPD plus local therapy after 1st PD beyond crizotinib is feasible and effective in clinical routine practice.

Multiple myeloma (MM) drug resistance highlights a need for alternative therapeutic strategies. In this study, we show that CASIN, a selective inhibitor of cell division cycle 42 (Cdc42) GTPase, inhibited proliferation and survival of melphalan/bortezomib-resistant MM cells more profoundly than that of the sensitive cells. Furthermore, CASIN was more potent than melphalan/bortezomib in inhibiting melphalan/bortezomib-resistant cells. In addition, CASIN sensitized melphalan/bortezomib-resistant cells to this drug combination. Mechanistically, Cdc42 activity was higher in melphalan/bortezomib-resistant cells than that in the sensitive cells. CASIN inhibited mono-ubiquitination of Fanconi anemia (FA) complementation group D2 (FANCD2) of the FA DNA damage repair pathway in melphalan-resistant but not melphalan-sensitive cells, thereby sensitizing melphalan-resistant cells to DNA damage. CASIN suppressed epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and extracellular signal-regulated kinase (ERK) activities to a larger extent in bortezomib-resistant than in melphalan-sensitive cells. Reconstitution of ERK activity partially protected CASIN-treated bortezomib-resistant cells from death, suggesting that CASIN-induced killing is attributable to suppression of ERK. Importantly, CASIN extended the lifespan of mouse xenografts of bortezomib-resistant cells and caused apoptosis of myeloma cells from bortezomib-resistant MM patients. Finally, CASIN had negligible side effects on peripheral blood mononuclear cells (PBMC) from healthy human subjects and normal B cells. Our data provide a proof of concept demonstration that rational targeting of Cdc42 represents a promising approach to overcome MM drug resistance.

Background: Vascular adhesion protein-1 (VAP-1), a dual-function glycoprotein, has been reported to play a crucial role in inflammation and tumor progression. We conducted a community-based cohort study to investigate whether serum VAP-1 could be a potential biomarker for predicting incident cancers and mortality. Method: From 2006 to 2018, we enrolled 889 cancer-free subjects at baseline. Serum VAP-1 levels were measured using a time-resolved immunofluorometric assay. Cancer and vital status of the participants were obtained by linking records with the computerized cancer registry and death certificates in Taiwan. Results: During a median follow-up of 11.94 years, 69 subjects developed incident cancers and 66 subjects died, including 29 subjects who died from malignancy. Subjects in the highest tertile of serum VAP-1 had a significantly higher risk of cancer incidence (p=0.0006), cancer mortality (p=0.0001), and all- cause mortality (p=0.0002) than subjects in the other tertiles. The adjusted hazard ratios per one standard deviation increase in serumVAP-1 concentrations were 1.28 for cancer incidence (95% CI=1.01-1.62), 1.60 for cancer mortality (95% CI=1.14-2.23), and 1.38 for all-cause mortality (95% CI=1.09-1.75). The predictive performance of serum VAP-1 was better than that of gender, smoking, body mass index, hypertension, diabetes, and estimated glomerular filtration rate but lower than that of age for cancer incidence, cancer mortality, and all-cause mortality, as evidenced by higher increments in concordance statistics and area under the receiver operating characteristic curve. Conclusion: Serum VAP-1 levels are associated with a 12-year risk of incident cancer, cancer mortality, and all-cause mortality in a general population. [ABSTRACT FROM AUTHOR]

IntroductionThis paper was to assess the diagnostic performance and clinical value of three-dimensional ultrasonography (3DUS), three-dimensional ultrasonography power Doppler (3DPD), and 3DUS combined with 3DPD in ovarian cancer (OC).MethodsThe study was registered with PROSPERO (CRD 42023405765). PubMed and Web of Science were searched from inception to 25 January 2022, and reference lists of potentially eligible studies were also manually searched. Patient and study characteristics were extracted by two independent reviewers. Any discrepancies were addressed through discussion. The sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR, respectively), and the area under the receiver operating characteristic curve (AUC) were pooled separately.ResultsWe retrieved 2,566 studies, of which 18 were finally enrolled, with 2,548 cases. The pooled sensitivity, specificity, PLR, NLR, and AUC for 3DUS were 0.89 (95% CI: 0.85–0.93), 0.93 (95% CI: 0.88–0.96), 13.1 (95% CI: 7.3–23.4), 0.11 (95% CI: 0.08–0.16), and 0.90 (95% CI: 0.87–0.93), respectively. The pooled sensitivity, specificity, PLR, NLR, and AUC for 3DPD were 0.90 (95% CI: 0.80–0.95), 0.85 (95% CI: 0.71–0.92), 5.8 (95% CI: 3.0–11.2), 0.12 (95% CI: 0.06–0.24), and 0.94 (95% CI: 0.91–0.96), respectively. The pooled sensitivity, specificity, PLR, NLR, and AUC for 3DUS combined with 3DPD were 0.99 (95% CI: 0.73–1.00), 0.95 (95% CI: 0.85–0.99), 21.9 (95% CI: 6.1–78.9), 0.01 (95% CI: 0.00–0.37), and 0.99 (95% CI: 0.98–1.00), respectively.Conclusions3DUS, 3DPD, and 3DUS combined with 3DPD are promising diagnostic tools for OC, alongside elevated sensitivity and specificity. However, the combination of 3DUS and 3DPD techniques has higher diagnostic efficiency.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD 42023405765.