Activated hedgehog gene pattern correlates with dismal clinical outcome and tumor microenvironment heterogeneity in hepatocellular carcinoma.

Background: Activation of the Hedgehog signaling pathway is linked to the initiation and development of human hepatocellular carcinoma (HCC). However, its impact on clinical outcomes and the HCC microenvironment remains unclear. Methods: We performed comprehensive analyses of Hedgehog pathway genes in a large cohort of HCC patients. Specifically, we utilized univariate Cox regression analysis to identify Hedgehog genes linked to overall survival, and the LASSO algorithm was used to construct a Hedgehog-related gene pattern. We subsequently examined the correlation between the Hedgehog pattern and the HCC microenvironment employing the CIBERSORT and ssGSEA algorithms. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the anti-PD-L1 treatment dataset (IMvigor210) are used to evaluate the clinical response of the Hedgehog pattern in predicting immune checkpoint inhibitors. Results: We found that the Hedgehog activation score (HHAS), a prognostic score based on 11 Hedgehog genes, was significantly associated with HCC patient survival. Patients exhibiting high HHAS experienced markedly reduced survival rates compared to those with low HHAS, and HHAS emerged as an independent prognostic factor for HCC. Functional enrichment analysis unveiled the association of the HHAS phenotype with functions related to the immune system, and further investigation demonstrated that HCC patients exhibiting low HHAS displayed elevated levels of anti-tumor immune activation in CD8+ T cells, while high HHAS were linked to immune escape phenotypes and increased infiltration of immune suppressive cells. In addition, in the Immune Checkpoint Inhibitor (ICI) cohort of IMvigor210, patients with higher HHAS had worse ICI treatment outcomes and shortened survival time, indicating that the HHAS is a useful indicator for predicting patient response to immunotherapy. Conclusions: In summary, our study offers valuable insights for advancing research on Hedgehog and its impact on tumor immunity, which provides an opportunity to optimize prognosis and immune therapy for HCC.

A multicenter study of cervical cancer using quantitative diffusion-weighted imaging.

BACKGROUND: Parameters from diffusion-weighted imaging (DWI) have been increasingly used as imaging biomarkers for the diagnosis and monitoring of treatment responses in cancer. The consistency of DWI measurements across different centers remains uncertain, which limits the widespread use of quantitative DWI in clinical settings. PURPOSE: To investigate the consistency of quantitative metrics derived from DWI between different scanners in a multicenter clinical setting. MATERIAL AND METHODS: A total of 193 patients with cervical cancer from four scanners (MRI1, MRI2, MRI3, and MRI4) at three centers were included in this retrospective study. DWI data were processed using the mono-exponential and intravoxel incoherent motion (IVIM) model, yielding the following parameters: apparent diffusion coefficient (ADC); true diffusion coefficient (D); pseudo-diffusion coefficient (D*); perfusion fraction (f); and the product of f and D* (fD*). Various parameters of cervical cancer obtained from different scanners were compared. RESULTS: The parameters D and ADC derived from MRI1 and MRI2 were significantly different from those derived from MRI3 or MRI4 (P <0.01 for all comparisons). However, there was no significant difference in cervical cancer perfusion parameters (D* and fD*) between the different scanners (P >0.05). The P values of comparisons of all DWI parameters (D, D*, fD*, and ADC) between MRI3 and MRI4 (same vendor in different centers) for cervical cancer were all >0.05, except for f (P = 0.05). CONCLUSION: Scanners of the same model by the same vendor can yield close measurements of the ADC and IVIM parameters. The perfusion parameters showed higher consistency among the different scanners.

Three-dimensional ultrashort echo time magnetic resonance imaging in pediatric patients with pneumonia: a comparative study.

BACKGROUND: UTE has been used to depict lung parenchyma. However, the insufficient discussion of its performance in pediatric pneumonia compared with conventional sequences is a gap in the existing literature. The objective of this study was to compare the diagnostic value of 3D-UTE with that of 3D T1-GRE and T2-FSE sequences in young children diagnosed with pneumonia. METHODS: Seventy-seven eligible pediatric patients diagnosed with pneumonia at our hospital, ranging in age from one day to thirty-five months, were enrolled in this study from March 2021 to August 2021. All patients underwent imaging using a 3 T pediatric MR scanner, which included three sequences: 3D-UTE, 3D-T1 GRE, and T2-FSE. Subjective analyses were performed by two experienced pediatric radiologists based on a 5-point scale according to six pathological findings (patchy shadows/ground-glass opacity (GGO), consolidation, nodule, bulla/cyst, linear opacity, and pleural effusion/thickening). Additionally, they assessed image quality, including the presence of artifacts, and evaluated the lung parenchyma. Interrater agreement was assessed using intraclass correlation coefficients (ICCs). Differences among the three sequences were evaluated using the Wilcoxon signed-rank test. RESULTS: The visualization of pathologies in most parameters (patchy shadows/GGO, consolidation, nodule, and bulla/cyst) was superior with UTE compared to T2-FSE and T1 GRE. The visualization scores for linear opacity were similar between UTE and T2-FSE, and both were better than T1-GRE. In the case of pleural effusion/thickening, T2-FSE outperformed the other sequences. However, statistically significant differences between UTE and other sequences were only observed for patchy shadows/GGO and consolidation. The overall image quality was superior or at least comparable with UTE compared to T2-FSE and T1-GRE. Interobserver agreements for all visual assessments were significant and rated "substantial" or "excellent." CONCLUSIONS: In conclusion, UTE MRI is a useful and promising method for evaluating pediatric pneumonia, as it provided better or similar visualization of most imaging findings compared with T2-FSE and T1-GRE. We suggest that the UTE MRI is well-suited for pediatric population, especially in younger children with pneumonia who require longitudinal and repeated imaging for clinical care or research and are susceptible to ionizing radiation.

Engineering siRNA-loaded and RGDfC-targeted selenium nanoparticles for highly efficient silencing of DCBLD2 gene for colorectal cancer treatment.

Effective and safe delivery of small interfering RNA (siRNA) by nanomaterials to cancer cells is one of the main challenges in cancer treatment. In this study, we constructed the selenium nanoparticles conjugated with RGDfC (one tumor-targeted polypeptide) to prepare a biocompatible gene vector (RGDfC-SeNPs) and then loaded with siDCBLD2 to synthesize the RGDfC-Se@siDCBLD2 for colorectal cancer (CRC) therapy. As expected, RGDfC-SeNPs could enhance the cellular uptake of siDCBLD2 in human HCT-116 colon cancer cells by targeting polypeptide RGDfC on the surface of colon cancer cells. RGDfC-Se@siDCBLD2 could be effectively internalized by HCT-116 cells mainly through a clathrin-related endocytosis pathway. In addition, RGDfC-Se@siDCBLD2 exhibited high siRNA release efficiency in an acidic tumor environment. Moreover, RGDfC-Se@siDCBLD2 could inhibit the proliferation and induce apoptosis in HCT-116 cells by special silencing gene DCBLD2 expression. RGDfC-Se@siDCBLD2 could be specifically accumulated to the tumor sites and exhibited significantly anti-CRC efficacy on HCT-116 tumor-bearing mice without obvious side effects. Taken together, these results suggest that selenium nanoparticles can be used as an effective gene vector with good biocompatibility, and RGDfC-Se@siDCBLD2 provides a promising strategy for combining tumor-target and siRNA delivery in treating CRC.

Clinical significance of enlarged cardiophrenic lymph nodes by CT in advanced ovarian cancer.

Aim: This study aims to assess the clinical influence of enlarged cardiophrenic lymph nodes (CPLN) on staging computed tomography (CT) among patients with advanced ovarian cancer. Methods: This retrospective cohort study included 320 patients with advanced epithelial ovarian cancer who underwent staging CT from May 2008 to January 2019. The CPLN diameter was the average of two radiologists' measurements. Enlarged CPLN was defined as a short-axis diameter of ≥5 mm. Clinical and imaging findings, management decisions, and progression-free survival(PFS) were compared between patients with and without enlarged CPLN. Results: Enlarged CPLN was found in 129 (40.3%) patients, which was significantly associated with more pelvic peritoneal carcinomatosis (odds ratio [OR]: 6.61 with 95% confidence interval [CI]: 1.51-28.99), and involved the greater omentum (OR: 6.41, 95% CI: 3.05-13.46), spleen capsule nodules (OR: 2.83, 95% CI: 1.58-5.06), and liver capsule nodules (OR: 2.55, 95% CI: 1.57-4.17). The optimal cytoreduction rates did not differ between patients with and without enlarged CPLN (p = 0.656). The presence of enlarged CPLN had a significant negative influence on PFS (median PFS, 23.5 vs. 80.6 months, respectively, CPLN ≥5 mm versus <5 mm; p = 0.023) in patients with no RD after primary debulking surgery, but no adverse effect on PFS among patients with RD (median PFS, 28.0 vs. 24.4 months, respectively, CPLN ≥5 mm versus <5 mm; p = 0.359). However, enlarged CPLN on staging CT did not affect PFS in patients treated with neoadjuvant chemotherapy, with (median PFS, 22.4 vs. 23.6 months, respectively, CPLN ≥5 mm versus <5 mm; p = 0.360) or without RD (median PFS, 17.7 vs. 23.3 months, respectively, CPLN ≥5 mm versus <5 mm; p = 0.400). The enlarged CPLN showed a decreased trend in 81.6% (n = 80) of the patients with enlarged CPLN. No significant difference was found in PFS (p = 0.562) between patients with decreased and increased in the size of CPLN. Conclusions: Enlarged CPLN on staging CT is associated with more abdominal disease but is not reliable in predicting complete resection. Enlarged CPLN awareness is necessary for patients with a primary chance of complete resection of abdominal disease.

PHANTOM AND CLINICAL STUDIES ON LOW-DOSE CT PROTOCOL FOR APPLICATOR RECONSTRUCTION IN THREE-DIMENSIONAL BRACHYTHERAPY USING SIZE-SPECIFIC DOSE ESTIMATES BASED ON WATER EQUIVALENT DIAMETER.

To verify the feasibility of low-dose computed tomography (CT) protocol for applicator reconstruction in three-dimensional brachytherapy among patients of different sizes, using size-specific dose estimate based on water equivalent diameter (SSDEdw) in phantom and clinical studies. Pre-scans of a female pelvic phantom were followed by reconstruction of each image set with iDose4 levels 3-5. Imaging data from 64 cervical cancer patients were divided into low, standard and high weight groups. Among two to five CT scans required for applicator reconstruction, the first scan was adopted by routine-dose CT protocol (tube voltage = 120 kV, tube current-exposure time product = 320 mA.s) and the remaining by low-dose CT protocol (tube voltage = 120 kV, tube current-exposure time product = 80 mA.s). The SSDEdw and image quality parameters were compared among the groups, and correlations between SSDEdw and body mass index, area of reference plane (AreaROI3) and mean CT value of reference plane (CTROI3) were analyzed. According to the phantom test results, we determined tube voltage to 120 kV and tube current-exposure time product to 80 mA.s as the low-dose protocol. Clinical study revealed no statistically significant differences in signal-to-noise ratio (SNR) and contrast-noise-ratio (CNR) between low-dose and routine-dose CT in Groups A and B; in Group C, these were significantly lower in the former. The SSDEdw was significantly lower under low-dose than routine-dose protocol in all groups, with strong negative correlation with BMI and AreaROI3 in Groups A and B and moderate-to-strong negative correlation in Group C. Because of the characteristics of three-dimensional brachytherapy, in patients with BMI < 24.0 kg per m2, low-dose CT protocol can minimize radiation exposure and achieve precise, individualized treatment.

Contrast computed tomography-based radiomics is correlation with COG risk stratification of neuroblastoma.

PURPOSE: Although a risk stratification strategy for neuroblastoma (NB) has been proposed, precise and convenient clinical risk estimation remains challenging. This study aimed to investigate the correlation of contrast computed tomography (CT)-based radiomics with NB risk stratification. METHODS: Patients with NB (n = 289) from two centers (244 and 45 patients in the training/testing and external validation cohorts, respectively) were divided into nonhigh- and high-risk groups. A total of 1648 radiomics features were extracted from the arterial phase, and the radiomics signature was constructed using rad scores, whereas the clinical model was established based on clinical factors. Further, a combined nomogram was developed based on the clinical factors and radiomics signatures. Finally, receiver operating characteristic curve and decision curve analyses (DCA) were used to assess the performance of the established models. RESULTS: Seventeen radiomics features were used to construct the radiomics signature. A significant difference was observed in the rad score between the two groups in the training (0.540 vs. 0.704, P < 0.001) and testing (0.563 vs. 0.969, P < 0.001) cohorts. The nomogram showed a higher area under the curve (AUC) in the training (AUC = 0.87), testing (AUC = 0.83), and external validation (AUC = 0.84) cohorts than other models. The Hosmer-Lemeshow test and calibration curves indicated that the nomogram fit perfectly. DCA demonstrated that the clinical-radiomics nomogram was more beneficial. CONCLUSIONS: Contrast CT-based radiomics shows correlation with COG risk stratification of NB. Radiomics features combined with clinical factors showed the best performance, which may improve the management of patients with NB.

Pneumocystis jirovecii diagnosed by next-generation sequencing of bronchoscopic alveolar lavage fluid: A case report and review of literature.

BACKGROUND: The advent of molecular targeted agents and immune checkpoint inhibitors has greatly improved the treatment of advanced renal cell carcinoma (RCC), thus significantly improving patient survival. The incidence of rare drug-related adverse events has gained increased attention. CASE SUMMARY: We report a patient with advanced RCC treated with multiple lines of molecular targeted agents and immune checkpoint inhibitors, who developed a pulmonary infection after treatment with everolimus in combination with lenvatinib. Determining the pathogenic organism was difficult, but it was eventually identified as Pneumocystis jirovecii by next-generation sequencing (NGS) of bronchoscopic alveolar lavage fluid (BALF) and successfully treated with trimethoprim-sulfamethoxazole. CONCLUSION: Rare pulmonary infections caused by molecular targeted agents are not uncommon in clinical practice, but their diagnosis is difficult. Evaluating BALF with NGS is a good method for rapid diagnosis of such infections.

Evaluation of tracer kinetic parameters in cervical cancer using dynamic contrast-enhanced MRI as biomarkers in terms of biological relevance, diagnostic performance and inter-center variability.

Objectives: This study assessed the clinical value of parameters derived from dynamic contrast-enhanced (DCE) MRI with respect to correlation with angiogenesis and proliferation of cervical cancer, performance of diagnosis and reproducibility of DCE-MRI parameters across MRI scanners. Materials and Methods: A total of 113 patients with cervical carcinoma from two centers were included in this retrospective study. The DCE data were centralized and processed using five tracer kinetic models (TKMs) (Tofts, Ex-Tofts, ATH, SC, and DP), yielding the following parameters: volume transfer constant (Ktrans), extravascular extracellular volume (Ve), fractional volume of vascular space (Vp), blood flow (Fp), and permeability surface area product (PS). CD34 counts and Ki-67 PI (proliferation index) of cervical cancer and normal cervix tissue were obtained using immunohistochemical staining in Center 1. Results: CD34 count and Ki-67 PI in cervical cancer were significantly higher than in normal cervix tissue (p<0.05). Parameter Ve from each TKM was significantly smaller in cervical cancer tissue than in normal cervix tissue (p<0.05), indicating the higher proliferation of cervical cancer cells. Ve of each TKM attained the largest AUC to diagnose cervical cancer. The distributions of DCE parameters for both cervical cancer and normal cervix tissue were not significantly different between two centers (P>0.05). Conclusion: Parameter Ve was similar to the expression of Ki-67 in revealing the proliferation of tissue cells, attained good performance in diagnosis of cervical cancer, and demonstrated consistent findings on measured values across centers.

Vulvovaginal myeloid sarcoma with massive pelvic floor infiltration: A case report and review of literature.

BACKGROUND: Myeloid sarcoma (MS), including isolated and leukaemic MS, is an extramedullary myeloid tumour. MS can involve any anatomical site, but MS of the female genital tract is rare, with the ovaries and uterine body and cervix being the most commonly seen sites. Involvement of the vagina and vulva is extremely rare. CASE SUMMARY: We report a rare case of MS with involvement of the vulva and vagina and massive infiltration of the pelvic floor. A 26-year-old woman presented with a vulvar mass, irregular vaginal bleeding and night sweats. Magnetic resonance imaging demonstrated an ill-defined, irregular vulvovaginal mass with massive involvement of the paravaginal tissue, urethra, posterior wall of the bladder, and pelvic floor. The signal and enhancement of the huge mass was homogeneous without haemorrhage or necrosis. Positron emission tomography/computed tomography showed high fluorodeoxyglucose uptake by the mass. Peripheral blood count detected blast cells. Vulvovaginal mass and bone marrow biopsies were performed, and immunohistochemistry confirmed the diagnosis of acute myeloid leukaemia (M-2 type, FAB classification) and vulvovaginal MS. The patient was treated with induction chemotherapy followed by allogeneic haematopoietic stem cell transplantation, and achieved complete remission. A systemic review of the literature on vulvovaginal MS was conducted to explore this rare entity's clinical and radiological features. CONCLUSION: Vulvovaginal MS is extremely rare. Diagnosis of vulvovaginal MS can only be confirmed histopathologically. Even though its clinical and imaging presentations are nonspecific, MS should be considered in the differential diagnosis of a newly developed T2-hyperintense, homogeneously enhanced vulvovaginal mass, especially in a patient with suspected haematological malignancy.

Case Report: ALK-Positive Histiocytosis With KIF5B-ALK Fusion in Cerebrum-Disseminated Lesions in a Child.

Background: Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare type of histiocytosis that could affect multiple systems in children and adults. 10 cases of ALK-positive histiocytosis invading the central nervous system (CNS) have been reported. Herein, we report a case of ALK-positive histiocytosis invading the central nervous system and lungs and the details of follow-up of tumor dynamic changes during treatment. Case Presentation: An 18-month-old boy was underweight and had slow growth of almost 3 months duration. The child could not stand and walk independently, and his language and intelligence development occurred later than those of his peers. Cranial magnetic resonance imaging revealed a giant suprasellar lesion with isosignal, measuring approximately 5.1× 3.6× 4.0 cm on T1-weighted imaging, with an obvious mass effect. Nodular, slightly low-signal shadows were also observed in the left temporal pole and left hippocampus, measuring approximately 1.0 cm × 0.7 cm× 0.5 cm and 0.9 cm× 0.8 cm × 0.5 cm on T1-weighted, respectively. The child underwent partial resection of the suprasellar lesion, and a diagnosis of ALK-positive histiocytosis was made histologically. Subsequently, the patient received chemotherapy (CHOP regimen) and anti-ALK therapy (crizotinib). The lesions were gradually shrinking without dissemination and the changes of intracranial and lung lesions were monitored with imaging during therapy. Unfortunately, the child died 8 months after the first surgery because of worsening intracranial infection. Conclusion: ALK-positive histiocytosis may involve the central nervous system and disseminate intracranially. ALK-positive histiocytosis should be considered for the differential diagnosis of suprasellar lesions.

Endometrial carcinoma: use of tracer kinetic modeling of dynamic contrast-enhanced MRI for preoperative risk assessment.

BACKGROUND: To compare two tracer kinetic models in predicting of preoperative risk types in endometrial carcinoma (EC) using DCE-MRI. METHODS: A prospective study of patients with EC was conducted with institutional ethics approval and written informed consent. DCE-MRI data was analyzed using the extended Tofts (ET) and the distributed parameter (DP) models. DCE parameters blood flow (F), mean transit time, blood volume (Vp), extravascular extracellular volume (Ve), permeability surface area product (PS), extraction fraction, transfer constant (Ktrans), and efflux rate (Kep) between high- and low-risk EC were compared using the Mann-Whitney test. Bland-Altman analysis was utilized to compare parameter consistency and Spearman test to assess parameter correlation. Diagnostic performance of DCE parameters was analyzed by receiver-operating characteristic curve and compared with traditional MRI assessment. RESULTS: Fifty-one patients comprised the study group. Patients with high-risk EC exhibited significantly lower Ktrans, Kep, F, Vp and PS (P < 0.001). ET-derived Ktrans and DP-derived F attained AUC of 0.92 and 0.91, respectively. Bland-Altman analysis showed that the consistency of Ve or Vp between the two models was low (P < 0.001) while Spearman test showed a strong correlation (r = 0.719, 0.871). Both Ktrans and F showed higher accuracy in predicting EC risk types than traditional MRI assessment. CONCLUSIONS: Kinetic parameters derived from DCE-MRI revealed a more hypovascular microenvironment for high risk EC than to low- risk ones, providing potential imaging biomarkers in preoperative risk assessment that might improve individualized surgical planning and management of EC.

MRI characteristics of the fetal tethered spinal cord: a comparative study.

Purpose: To compare fetuses and children with confirmed tethered cord syndrome to age-matched controls to provide a reference for prenatally identifying tethered spinal cord and to identify salient points on MRI for diagnosis.Materials and Methods: This retrospective study enrolled 13 fetuses and 20 children with tethered cord syndrome, and age-matched counterparts were included as controls. The MRI features including concomitant malformations, position of the conus medullaris, and thickened filum terminale of the two patient groups were evaluated and compared. Levels of the conus medullaris were discriminated between patients and an equivalent number of controls.Results: Various concomitant malformations manifested on the MRI of all patients, and there were differences between the two patient groups. Significant differences of the level of the conus medullaris were found between the fetal and child patients (U, 26.50; Z, -3.87; p < 0.001) and between the normal fetus and child controls (U, 23.50; Z, -4.13; p < 0.001). The position of the conus medullaris was visibly lower in the patient groups than in the control groups. No significant difference in the diameters of the filum terminale was found between the fetal and child patients (p = 0.67).Conclusions: The current study's results indicate that tethered spinal cord syndrome can be diagnosed in utero with MRI combined with several characteristics, particularly the position of the conus medullaris. Special attention should be paid to the gestational age of the fetus because normal changes in spinal cord position occur with gestational development.

CpG Island Methylator Phenotype Modulates the Immune Response of the Tumor Microenvironment and Influences the Prognosis of Pancreatic Cancer Patients.

BACKGROUND: CpG island methylator phenotype (CIMP), featured with concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have investigated the role of CIMP in pancreatic cancer (PC). The aim of this study was to explore the CIMP in PC patients and its impact on the immune response of the tumor microenvironment and prognosis. METHODS: DNA methylation, somatic mutation, mRNA, and corresponding clinical data of PC patients were downloaded from TCGA (184 patients) and the ICGC (264 patients). Univariate and multivariate regression analyses were used to identify prognosis-related CpGs. Consensus clustering analysis was used for identification of the CIMP in PC patients. ESTIMATE and CIBORORT were used for estimation of the tumor microenvironment (TME) in PC patients. RESULTS: In the TCGA PC cohort, 22,450 differential CpGs, including 12,937 hypermethylated CpGs and 9,513 hypomethylated CpGs, were identified between 184 PC patients and 10 normal controls. Univariate and multivariate Cox analysis further screened out 72 OS-related CpGs, and three distinct CIMP groups with distinctly different prognosis and molecular features, including the CIMP-L subgroup, CIMP-M subgroup, and CIMP-H subgroup, were identified based on unsupervised consensus clustering analysis of these CpGs. Patients of the CIMP-H subgroup had poorer OS and RFS, while patients of the CIMP-L subgroup had better OS and RFS. The CIMP status was also an independent prognostic factor for OS and PFS. In molecular features, significantly higher somatic mutation burden and tumor mutational burden were found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. Besides, lower stromal score, immune score, and higher cancer stemness indices and tumor purity were also found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. Correspondingly, significant total T cells, total B cells, CD8 T cells, memory CD4 T cells, and higher regulatory T cells were found in patients of the CIMP-H subgroup. Moreover, significantly lower expression of immune checkpoint genes, such as PD-1, CTLA4, CD86, VTCN1, and LAG-3, was also found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. In the end, we validated the CIMP status in PC patients of the ICGC dataset. CONCLUSION: The CIMP may modulate the immune response of the tumor microenvironment and influence the prognosis of pancreatic cancer patients, which may help to make an assertion to provide specific and efficient treatment options for patients of different subtypes.

A CT-based radiomics nomogram for predicting early recurrence in patients with high-grade serous ovarian cancer.

PURPOSE: To develop and validate a radiomics nomogram for predicting early recurrence in high-grade serous ovarian cancer (HGSOC) patients. MATERIALS AND METHODS: From May 2008 to December 2019, 256 eligible HGSOC patients were enrolled and divided into training (n = 179) and test cohorts (n = 77) in a 7:3 ratio. A radiomics signature (Radscore) was selected by using recursive feature elimination based on a support vector machine (SVM-RFE) and building a radiomics model for recurrence prediction. Independent clinical risk factors were generated by univariable and multivariable Cox regression analyses. A combined model was developed based on the Radscore and independent clinical risk factors and presented as a radiomics nomogram. Its performance was assessed by AUC, Kaplan-Meier survival analysis and decision curve analysis. RESULTS: Seven radiomics features were selected. The radiomics model yielded AUCs of 0.715 (95% CI: 0.640, 0.790) and 0.717 (95% CI: 0.600, 0.834) in the training and test cohorts, respectively. The clinical model (FIGO stage and residual disease) yielded AUCs of 0.632 and 0.691 in the training and test cohorts, respectively. The combined model demonstrated AUCs of 0.749 (95% CI: 0.678, 0.821) and 0.769 (95% CI: 0.662, 0.877) in the training and test cohorts, respectively. In the combined model, PFS was significantly shorter in the high-risk group than in the low-risk group (P < 0.0001). CONCLUSIONS: The radiomics nomogram performed well for early individualized recurrence prediction in patients with HGSOC and can also be used to differentiate high-risk patients from low-risk patients.

The Development and Validation of a CT-Based Radiomics Nomogram to Preoperatively Predict Lymph Node Metastasis in High-Grade Serous Ovarian Cancer.

PURPOSE: To develop and validate a radiomics model for predicting preoperative lymph node (LN) metastasis in high-grade serous ovarian cancer (HGSOC). MATERIALS AND METHODS: From May 2008 to January 2018, a total of 256 eligible HGSOC patients who underwent tumor resection and LN dissection were divided into a training cohort (n=179) and a test cohort (n=77) in a 7:3 ratio. A Radiomics Model was developed based on a training cohort of 179 patients. A radiomics signature (defined as the Radscore) was selected by using the random forest method. Logistics regression was used as the classifier for modeling. An Integrated Model that incorporated the Radscore and CT_reported LN status (CT_LN_report) was developed and presented as a radiomics nomogram. Its performance was determined by the area under the curve (AUC), calibration, and decision curve. The radiomics nomogram was internally tested in an independent test cohort (n=77) and a CT-LN-report negative subgroup (n=179) using the formula derived from the training cohort. RESULTS: The AUC value of the CT_LN_report was 0.688 (95% CI: 0.626, 0.759) in the training cohort and 0.717 (95% CI: 0.630, 0.804) in the test cohort. The Radiomics Model yielded an AUC of 0.767 (95% CI: 0.696, 0.837) in the training cohort and 0.753 (95% CI: 0.640, 0.866) in the test. The radiomics nomogram demonstrated favorable calibration and discrimination in the training cohort (AUC=0.821), test cohort (AUC=0.843), and CT-LN-report negative subgroup (AUC=0.82), outperforming the Radiomics Model and CT_LN_report alone. CONCLUSIONS: The radiomics nomogram derived from portal phase CT images performed well in predicting LN metastasis in HGSOC and could be recommended as a new, convenient, and non-invasive method to aid in clinical decision-making.

Identification of New Biomarker for Prediction of Hepatocellular Carcinoma Development in Early-Stage Cirrhosis Patients.

BACKGROUND: Liver cirrhosis is one of the major drivers of hepatocellular carcinoma (HCC). In the present study, we aimed to identify and validate new biomarker for early prediction of HCC development in early-stage cirrhosis patients. METHODS: mRNA expression and clinical parameters of GSE63898, GSE89377, GSE15654, GSE14520, and TCGA-HCC cohort and ICGC-HCC cohort were downloaded for analysis. Wilcoxon test was performed to identify DEGs. Univariate and multivariate Cox regression analysis were used to develop the risk signature, and ROC analysis was performed to analyze the predictive accuracy and sensitivity of the risk signature. RESULTS: There were 42 DEGs (including 28 upregulated genes and 14 downregulated genes) found in early-stage liver cirrhosis patients before developing HCC from GSE1565442. Then, a risk signature consisting of 8 DEGs could effectively classify early-stage cirrhosis patients into high-risk group with shorter HCC development time and low-risk group with longer HCC development time from GSE15654. Multivariate Cox analysis indicated that the risk signature was an independent prognostic factor for the prediction of HCC development and ROC analysis showed that the signature exhibited good predictive efficiency in predicting 2-, 5-, and 10-year HCC development. Mechanistically, significantly higher proportions of CD8 T cells were found to be enriched in cirrhosis patients with low risk score, and higher CD8 T cells were associated with longer HCC development time. Besides, the signature was an independent prognostic factor for poorer prognosis of early-stage liver cirrhosis patients of GSE15654. Moreover, the signature could also separate HCC patients from healthy controls and was also associated with the poorer prognosis of HCC patients from three HCC cohorts. Finally, we also identified HDAC inhibitors, such as trichostatin A, to be a potential chemopreventive treatment for the prevention of HCC development by targeting risk signature based on CMap analysis. CONCLUSION: A risk signature was developed and validated for early prediction of HCC development, which may be a useful tool to set up individualized follow-up interval schedules.

A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13-23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied. METHODS: We employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes. RESULTS: We found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib. CONCLUSIONS: Our study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.

Identification of an m6A-Related Signature as Biomarker for Hepatocellular Carcinoma Prognosis and Correlates with Sorafenib and Anti-PD-1 Immunotherapy Treatment Response.

BACKGROUND: N6-methyladenosine (m6A) modification plays an essential role in diverse key biological processes and may take part in the development and progression of hepatocellular carcinoma (HCC). Here, we systematically analyzed the expression profiles and prognostic values of 13 widely reported m6A modification-related genes in HCC. METHODS: The mRNA expression of 13 m6A modification-related genes and clinical parameters of HCC patients were downloaded from TCGA, ICGC, GSE109211, and GSE78220. Univariate and LASSO analyses were used to develop risk signature. Time-dependent ROC was performed to assess the predictive accuracy and sensitivity of risk signature. RESULTS: FTO, YTHDC1, YTHDC2, ALKBH5, KIAA1429, HNRNPC, METTL3, RBM15, YTHDF2, YTHDF1, and WTAP were significantly overexpressed in HCC patients. YTHDF1, HNRNPC, RBM15, METTL3, and YTHDF2 were independent prognostic factors for OS and DFS in HCC patients. Next, a risk signature was also developed and validated with five m6A modification-related genes in TCGA and ICGC HCC cohort. It could effectively stratify HCC patients into high-risk patients with shorter OS and DFS and low-risk patients with longer OS and DFS and showed good predictive efficiency in predicting OS and DFS. Moreover, significantly higher proportions of macrophages M0 cells, neutrophils, and Tregs were found to be enriched in HCC patients with high risk scores, while significantly higher proportions of memory CD4 T cells, gamma delta T cells, and naive B cells were found to be enriched in HCC patients with low scores. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in nonresponders, and anti-PD-1 immunotherapy-treated patients with lower risk scores had better OS than patients with higher risk scores. CONCLUSION: A risk signature developed with the expression of 5 m6A-related genes could improve the prediction of prognosis of HCC and correlated with sorafenib treatment and anti-PD-1 immunotherapy response.