Ultrasound-Based Deep Learning Radiomics Nomogram for the Assessment of Lymphovascular Invasion in Invasive Breast Cancer: A Multicenter Study.

RATIONALE AND OBJECTIVES: The aim of this study was to develop a deep learning radiomics nomogram (DLRN) based on B-mode ultrasound (BMUS) and color doppler flow imaging (CDFI) images for preoperative assessment of lymphovascular invasion (LVI) status in invasive breast cancer (IBC). MATERIALS AND METHODS: In this multicenter, retrospective study, 832 pathologically confirmed IBC patients were recruited from eight hospitals. The samples were divided into training, internal test, and external test sets. Deep learning and handcrafted radiomics features reflecting tumor phenotypes on BMUS and CDFI images were extracted. The BMUS score and CDFI score were calculated after radiomics feature selection. Subsequently, a DLRN was developed based on the scores and independent clinic-ultrasonic risk variables. The performance of the DLRN was evaluated for calibration, discrimination, and clinical usefulness. RESULTS: The DLRN predicted the LVI with accuracy, achieving an area under the receiver operating characteristic curve of 0.93 (95% CI 0.90-0.95), 0.91 (95% CI 0.87-0.95), and 0.91 (95% CI 0.86-0.94) in the training, internal test, and external test sets, respectively, with good calibration. The DLRN demonstrated superior performance compared to the clinical model and single scores across all three sets (p < 0.05). Decision curve analysis and clinical impact curve confirmed the clinical utility of the model. Furthermore, significant enhancements in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indicated that the two scores could serve as highly valuable biomarkers for assessing LVI. CONCLUSION: The DLRN exhibited strong predictive value for LVI in IBC, providing valuable information for individualized treatment decisions.

Diagnostic utility and sensitivities of matrix Gla protein (MGP), TRPS1 and GATA3 in breast cancer: focusing on metastatic breast cancer, invasive breast carcinoma with special features, and salivary gland-type tumours.

Matrix Gla protein (MGP) and trichorhinophalangeal syndrome type 1 (TRPS1) have recently emerged as novel breast-specific immunohistochemical (IHC) markers, particularly for triple-negative breast cancer (TNBC) and metaplastic carcinoma. The present study aimed to validate and compare the expression of MGP, TRPS1 and GATA binding protein 3 (GATA3) in metastatic breast carcinoma (MBC), invasive breast carcinoma (IBC) with special features, including special types of invasive breast carcinoma (IBC-STs) and invasive breast carcinoma of no special type with unique features, and mammary and non-mammary salivary gland-type tumours (SGTs). Among all enrolled cases, MGP, TRPS1 and GATA3 had comparable high positivity for ER/PR-positive (p=0.148) and HER2-positive (p=0.310) breast carcinoma (BC), while GATA3 positivity was significantly lower in TNBC (p<0.001). Similarly, the positive rates of MGP and TRPS1 in MBCs (99.4%), were higher than in GATA3 (90.9%, p<0.001). Among the IBC-STs, 98.4% of invasive lobular carcinomas (ILCs) were positive for all three markers. Among neuroendocrine tumours (NTs), all cases were positive for TRPS1 and GATA3, while MGP positivity was relatively low (81.8%, p=0.313). In the neuroendocrine carcinoma (NC) subgroup, all cases were positive for GATA3 and MGP, while one case was negative for TRPS1. All carcinomas with apocrine differentiation (APOs) were positive for GATA3 and MGP, while only 60% of the cases demonstrated moderate staining for TRPS1. Among mammary SGTs, MGP demonstrated the highest positivity (100%), followed by TRPS1 (96.0%) and GATA3 (72.0%). Positive staining for these markers was also frequently observed in non-mammary SGTs. Our findings further validate the high sensitivity of MGP and TRPS1 in MBCs, IBC-STs, and breast SGTs. However, none of these markers are capable of distinguishing between mammary and non-mammary SGTs.

Predicting Ki-67 expression in hepatocellular carcinoma: nomogram based on clinical factors and contrast-enhanced ultrasound radiomics signatures.

PURPOSE: To develop a contrast-enhanced ultrasound (CEUS) clinic-radiomics nomogram for individualized assessment of Ki-67 expression in hepatocellular carcinoma (HCC). METHODS: A retrospective cohort comprising 310 HCC individuals who underwent preoperative CEUS (using SonoVue) at three different centers was partitioned into a training set, a validation set, and an external test set. Radiomics signatures indicating the phenotypes of the Ki-67 were extracted from multiphase CEUS images. The radiomics score (Rad-score) was calculated accordingly after feature selection and the radiomics model was constructed. A clinic-radiomics nomogram was established utilizing multiphase CEUS Rad-score and clinical risk factors. A clinical model only incorporated clinical factors was also developed for comparison. Regarding clinical utility, calibration, and discrimination, the predictive efficiency of the clinic-radiomics nomogram was evaluated. RESULTS: Seven radiomics signatures from multiphase CEUS images were selected to calculate the Rad-score. The clinic-radiomics nomogram, comprising the Rad-score and clinical risk factors, indicated a good calibration and demonstrated a better discriminatory capacity compared to the clinical model (AUCs: 0.870 vs 0.797, 0.872 vs 0.755, 0.856 vs 0.749 in the training, validation, and external test set, respectively) and the radiomics model (AUCs: 0.870 vs 0.752, 0.872 vs 0.733, 0.856 vs 0.729 in the training, validation, and external test set, respectively). Furthermore, both the clinical impact curve and the decision curve analysis displayed good clinical application of the nomogram. CONCLUSION: The clinic-radiomics nomogram constructed from multiphase CEUS images and clinical risk parameters can distinguish Ki-67 expression in HCC patients and offer useful insights to guide subsequent personalized treatment.

An overview of ultrasound-derived radiomics and deep learning in liver.

Over the past few years, developments in artificial intelligence (AI), especially in radiomics and deep learning, have enabled the extraction of pathophysiology-related information from varied medical imaging and are progressively transforming medical practice. AI applications are extending into domains previously thought to be accessible only to human experts. Recent research has demonstrated that ultrasound-derived radiomics and deep learning represent an enticing opportunity to benefit preoperative evaluation and prognostic monitoring of diffuse and focal liver disease. This review summarizes the application of radiomics and deep learning in ultrasound liver imaging, including identifying focal liver lesions and staging of liver fibrosis, as well as the evaluation of pathobiological properties of malignant tumors and the assessment of recurrence and prognosis. Besides, we identify important hurdles that must be overcome while also discussing the challenges and opportunities of radiomics and deep learning in clinical applications.

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer.

Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.

Comparison of microwave alone and combined with ethanol ablation for different types of benign mixed thyroid nodules.

OBJECTIVE: To evaluate the efficacy and safety of microwave ablation (MWA) plus ethanol ablation (EA) for different types of benign mixed thyroid nodules. METHODS: A total of 81 patients with 81 benign mixed thyroid nodules were enrolled into the study; 39 were divided to the MWA group and 42 to the combined group (MWA combined with EA). Nodule ablation rate, volume reduction rate (VRR) and surgical complications of all patients were analyzed before and after treatment. RESULTS: The mean ablation rate were 86.49 ± 6.68% and 90.09 ± 5.79% in the microwave and combined groups respectively, and the ablation rate of nodule decreased as the nodule volume increased. For nodules ≥15 ml in volume, the mean ablation rate of the combined group was higher than that of the microwave group (all P < 0.05). The mean VRR at 12 months postoperatively was 89.58 ± 4.32% in the microwave group and 92.92 ± 3.49% in the combined group, showing statistical significantly different between both arms (P = 0.001). The combined group decreased in volume more significantly than the microwave group for nodules with 20-50% or 50-80% cystic proportions or >15 ml in volume (all P < 0.05). The complication rate was 23.08% and 2.38% respectively. CONCLUSION: MWA combined with EA is more effective than MWA for treating mixed thyroid nodules. MWA combined with EA may be the first approach for nodules with >20% cystic proportions or volume >15 ml.

A living biobank of patient-derived ductal carcinoma in situ mouse-intraductal xenografts identifies risk factors for invasive progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer (IBC). Due to a lack of biomarkers able to distinguish high- from low-risk cases, DCIS is treated similar to early IBC even though the minority of untreated cases eventually become invasive. Here, we characterized 115 patient-derived mouse-intraductal (MIND) DCIS models reflecting the full spectrum of DCIS observed in patients. Utilizing the possibility to follow the natural progression of DCIS combined with omics and imaging data, we reveal multiple prognostic factors for high-risk DCIS including high grade, HER2 amplification, expansive 3D growth, and high burden of copy number aberrations. In addition, sequential transplantation of xenografts showed minimal phenotypic and genotypic changes over time, indicating that invasive behavior is an intrinsic phenotype of DCIS and supporting a multiclonal evolution model. Moreover, this study provides a collection of 19 distributable DCIS-MIND models spanning all molecular subtypes.

Metastasis of breast cancer to bones alters the tumor immune microenvironment.

BACKGROUND: Bone is one of the most frequent sites for breast cancer metastasis. Breast cancer bone metastasis (BCBM) leads to skeletal morbidities including pain, fractures, and spinal compression, all of which severely impact quality of life. Immunotherapy is a promising therapy for patients with advanced cancer, but whether it may provide benefit to metastatic bone cancer is currently unknown. Thus, a better understanding of the immune landscape of bone-disseminated breast cancers may reveal new therapeutic strategies. In this study, we use histopathological analysis to investigate changes within the immune microenvironment of primary breast cancer and paired BCBM. METHODS: Sixty-three patients with BCBM, including 31 with paired primary and bone metastatic lesions, were included in our study. The percentage of stroma and stromal tumor-infiltrating lymphocytes (TILs) was evaluated by histopathological analysis. The quantification of stromal TILs (CD4 + and CD8 +), macrophages (CD68 + and HLA-DR +), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1) was evaluated through immunohistochemical (IHC) staining. Statistical analysis was performed with paired t test, Wilcoxon test, spearman correlation test, and univariate and multivariate cox regression. RESULTS: Median survival after BCBM pathological diagnosis was 20.5 months (range: 3-95 months). Of the immune parameters measured, none correlated with survival after bone metastasis was diagnosed. Compared to the primary site, bone metastases exhibited more tumor stroma (mean: 58.5% vs 28.87%, p < 0.001) and less TILs (mean: 8.45% vs 14.03%, p = 0.042), as determined by H&E analysis. The quantification of primary vs metastatic tissue area with CD4 + (23.95/mm2 vs 51.69/mm2, p = 0.027 and with CD8 + (18.15/mm2 vs 58.95/mm2, p = 0.004) TILs similarly followed this trend and was reduced in number for bone metastases. The number of CD68 + and HLA-DR + macrophages showed no significant difference between primary sites and bone metastases. PD-1 expression was present in 68.25% of the bone metastasis, while PD-L1 expression was only present in 7.94% of the bone metastasis. CONCLUSIONS: Our findings suggest that compared to the primary breast cancer site, bone metastases harbor a less active immune microenvironment. Despite this relatively dampened immune landscape, expression of PD-1 and PD-L1 in the bone metastasis indicates a potential benefit from immune checkpoint inhibitors for some BCBM cases.

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin.

BACKGROUND: Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC). MATERIALS AND METHODS: Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs. RESULTS: MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p < 0.001) or TRPS1 (p < 0.001), especially in HER2-positive (77.0%, p < 0.001) and TNBC (43.3%, p < 0.001) subtypes. TRPS1 had the highest positivity rate (97.9%) in metaplastic TNBCs, followed by MGP (88.6%), while only 47.1% of metaplastic TNBCs were positive for GATA3. When using MGP, GATA3, and TRPS1 as a novel IHC panel, 93.0% of breast carcinomas were positive for at least two markers, and only 9 cases were negative for all three markers. MGP was detected in 36 cases (3.0%) that were negative for both GATA3 and TRPS1. MGP showed mild-to-moderate positive expression in normal hepatocytes, renal tubules, as well as 31.1% (99/318) of hepatocellular carcinomas. Rare cases (0.6-5%) had focal MGP expression in renal, ovarian, lung, urothelial, and cholangiocarcinomas. CONCLUSIONS: Our findings suggest that MGP is a newly identified sensitive IHC marker to support breast origin. MGP, TRPS1, and GATA3 could be applied as a reliable diagnostic panel to determine breast origin in clinical practice.

Evaluation of Tissue Stiffness Around Lesions by Sound Touch Shear Wave Elastography in Breast Malignancy Diagnosis.

The aim of the study described here was to assess the evaluation of tissue stiffness around lesions by sound touch shear wave elastography (STE) in breast malignancy diagnosis. This was an institutional ethics committee-approved, single-center study. A total of 90 women with breast masses examined with conventional ultrasound and STE were eligible for enrollment from December 2020 to July 2021. The maximum and mean elastic values of masses, Emax and Emean, were determined. Shell function was used to measure the maximum and mean elastic values of tissues around masses in annular shells 0.5, 1.0, 1.5 and 2.0 mm wide, recorded as corresponding Emax-shell and Emean-shell. All parameters were analyzed and compared with histopathologic results. Receiver operating characteristic curves were constructed to assess diagnostic performance. Logistic regression analysis was conducted to determine the best diagnostic model. Collagen fiber content of tissues around breast lesions was evaluated using Masson staining and ImageJ software. Ninety women with breast masses were included in this study; 50 had benign (mean diameter 15.84 ± 4.39 mm) and 40 had malignant (mean diameter 17.40 ± 5.42 mm) masses. The diagnostic value of Emax-shell-2.0 was the highest (area under the curve = 0.930) with a sensitivity of 87.5% and specificity of 88%. According to stepwise logistic regression analysis, Emax-shell-2.0 and age were independent predictors of malignancy. Emax-shell-2.0 was also found to be highly correlated with the collagen fiber content of tissue in the malignant group (r = 0.877). Tissue stiffness around lesions measured by STE is a useful metric in identifying malignant breast masses by reflecting collagen fiber content, and Emax-shell-2.0 performs best.

C-Reactive Protein Levels Predict Responses to PD-1 Inhibitors in Hepatocellular Carcinoma Patients.

Background: Serum C-reactive protein (CRP) is a biomarker of an acute inflammatory response and has been successfully used as a prognostic predictor for several malignancies. However, the clinicopathological significance of CRP levels in hepatocellular carcinoma (HCC) patients being treated with PD-1 inhibitors remains unclear. Methods: Serum CRP levels were measured for a total of 101 HCC patients that had been treated with PD-1 inhibitors from July 2018 to November 2019. The clinicopathological data was retrospectively analyzed to identify any clinical implications between CRP levels and responses to PD-1 inhibitors and patients' progression-free survival (PFS). Results: The median PFS was 8.87 months in the CRP-low subgroup and 3.67 months in the CRP-high subgroup (P = 0.009). Univariate and multivariate Cox regression analysis demonstrated that both serum CRP and AFP levels were independent risk factors for the PFS of HCC patients treated with PD-1 inhibitors (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. A prognostic model combining CRP and AFP levels could significantly stratify HCC patients receiving PD-1 inhibitors into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar overall response rates (P = 0.625) and significantly different disease control rates (low- vs. intermediate- vs. high-risk groups: 81.6% vs. 65.1% vs. 35%, respectively, P = 0.002). Conclusions: The results of this study support the association between high serum CRP levels with the response and PFS for HCC patients receiving PD-1 inhibitors. Furthermore, the levels of both CRP and AFP in an HCC patient before treatment initiation show great potential for determining the efficacy of PD-1 inhibitors.

A Computational Tumor-Infiltrating Lymphocyte Assessment Method Comparable with Visual Reporting Guidelines for Triple-Negative Breast Cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are clinically significant in triple-negative breast cancer (TNBC). Although a standardized methodology for visual TILs assessment (VTA) exists, it has several inherent limitations. We established a deep learning-based computational TIL assessment (CTA) method broadly following VTA guideline and compared it with VTA for TNBC to determine the prognostic value of the CTA and a reasonable CTA workflow for clinical practice. METHODS: We trained three deep neural networks for nuclei segmentation, nuclei classification and necrosis classification to establish a CTA workflow. The automatic TIL (aTIL) score generated was compared with manual TIL (mTIL) scores provided by three pathologists in an Asian (n = 184) and a Caucasian (n = 117) TNBC cohort to evaluate scoring concordance and prognostic value. FINDINGS: The intraclass correlations (ICCs) between aTILs and mTILs varied from 0.40 to 0.70 in two cohorts. Multivariate Cox proportional hazards analysis revealed that the aTIL score was associated with disease free survival (DFS) in both cohorts, as either a continuous [hazard ratio (HR)=0.96, 95% CI 0.94-0.99] or dichotomous variable (HR=0.29, 95% CI 0.12-0.72). A higher C-index was observed in a composite mTIL/aTIL three-tier stratification model than in the dichotomous model, using either mTILs or aTILs alone. INTERPRETATION: The current study provides a useful tool for stromal TIL assessment and prognosis evaluation for patients with TNBC. A workflow integrating both VTA and CTA may aid pathologists in performing risk management and decision-making tasks. FUNDING: National Natural Science Foundation of China, Guangdong Medical Research Foundation, Guangdong Natural Science Foundation.

Preoperative prediction of axillary lymph node metastasis in patients with breast cancer based on radiomics of gray-scale ultrasonography.

BACKGROUND: To investigate the performance of a radiomics model based on gray-scale ultrasonography (US) for the preoperative non-invasive prediction of ipsilateral axillary lymph node (ALN) metastasis in patients with breast cancer (BC). METHODS: A total of 192 pathologically confirmed BC patients were included in this study. The training set was comprised of 132 patients from hospital 1 and the test set was comprised of 60 patients from hospital 2. All patients underwent US before percutaneous core biopsy and the results of ALN status reported by a radiologist with 12 years of experience were recorded. Radiomic features were extracted from the gray-scale US images. Max-relevance and min-redundancy (MRMR) and least absolute shrinkage and selection operator (LASSO) were used for data dimension reduction and feature selection. A radiomics model was constructed using LASSO and was validated using the leave group out cross-validation (LGOCV) method. The performance of the model was validated with receiver operating characteristic (ROC), calibration curve, and decision curve analysis. RESULTS: A total of 860 features were extracted from the gray-scale US images of each breast lesion, and 9 radiomic features were selected for model construction. The area under the curve (AUC), sensitivity, and specificity of the model for predicting ALN metastasis were 0.85, 78.9%, and 77.3% in the training set and 0.65, 68.0%, and 79.4% in the test set, respectively. The prediction performance of the model was significantly higher than that of the radiologist (AUC: 0.85 vs. 0.59, P<0.01) in the training set and was slightly higher than that of the radiologist (AUC: 0.65 vs. 0.63, P>0.05) in the test set. CONCLUSIONS: The non-invasive radiomics model has the ability to predict ALN metastasis for patients with breast cancer and may outperform US-reported ALN status performed by the radiologist.

Clinicopathologic and genetic features of metaplastic breast cancer with osseous differentiation: a series of 6 cases.

AIMS: Metaplastic breast cancer (MBC) comprises a heterogeneous group of tumors, of which MBC with osseous differentiation (MBC-OD) is extremely rare that only few cases have been reported. This study aimed to present the clinicopathologic and molecular features of MBC-OD. METHODS: We collected 6 cases of MBC-OD from five different centers and described its clinicopathologic and molecular characteristics based on the next-generation sequencing. Another 11 cases from the literature were also reviewed to better characterize the tumor. RESULTS: The tumor primarily showed an osteosarcoma-like appearance, which composed of high cellularity with spindle cells and osteoblast-like cells producing coarse lace-like neoplastic bone (4/6) or osteoid matrix (6/6). 55 somatic mutations including 39 missenses (70.9%), 9 frameshifts (16.4%), 3 splice sites (5.5%), 3 in-frame InDels (5.5%) and 1 nonsense (1.8%) were identified. TP53 was the most frequently mutated genes (5/6, 83.3%), followed by RB1 (3/6, 50.0%), BCOR (2/6, 33.3%), MED12 (2/6, 33.3%), PIK3CA (2/6, 33.3%), and TET2 (2/6, 33.3%). Genetic alterations suggesting therapies with clinical benefit, including mTOR inhibitors, tyrosine kinase inhibitors (TKI), and poly-ADP ribose polymerase inhibitor (PARPi), were observed in five cases. The median follow-up was 21 months (range, 3-80 months). Local recurrence was observed in two cases and three patients displayed distant metastasis. Two patients died of the disease at 3 months and 7 months, respectively. CONCLUSIONS: Based on this series, MBC-OD is a highly aggressive breast tumor with osteosarcoma-like morphology and a high incidence of recurrent disease showing specific genetic profiles.

Ultrastructure of antennal sensilla of Copidosomopsis nacoleiae (Eady) (Hymenoptera: Chalcidoidea: Encyrtidae), a parasitoid of Diaphania angustalis (Snellen) (Lepidoptera: Crambidae).

The antennal sensilla of Copidosomopsis nacoleiae (Eady) (Hymenoptera: Chalcidoidea: Encyrtidae) were observed under scanning and transmission electron microscopy in this study. The antennae of C. nacoleiae are geniculate, and the flagellum is composed of five subsegments in males and six in females. Six types of sensilla were observed, including sensilla trichodea, sensilla chaetica, sensilla basiconic capitate pegs, sensilla placodea, sensilla basiconica, and Böhm's bristles. Sensilla trichodea were evenly distributed throughout the antennae. Sensilla chaetica, sensilla basiconic capitate pegs and sensilla placodea were found on the flagellomeres. Sensilla basiconica were only found on the club, and Böhm's bristles were found on the radicle and the pedicel. Sensilla trichodea, sensilla placodea, sensilla chaetica, and sensilla basiconic capitate pegs were found to be the most common sensilla of the parasitoids in the superfamily Chalcidoidea. The external and internal characteristics, types, number, distribution, and dimensions of these sensilla are described, and their possible functions are discussed in accordance with host-detection behavior. Future studies on the host location mechanisms of C. nacoleiae will be based upon these observations.

Coexpression of CMTM6 and PD-L1 as a predictor of poor prognosis in macrotrabecular-massive hepatocellular carcinoma.

The "macrotrabecular-massive" (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients.

Clinical characteristics and prognostic implications of BRCA-associated tumors in males: a pan-tumor survey.

BACKGROUND: The BRCA mutation (BRCAm) in males has been reported to confer a higher risk for the development of various tumors. However, little is known about its clinicopathologic features and prognostic implications. DESIGN: We conducted a retrospective pan-tumor survey on 346 cases of BRCA-associated tumors in males. Comparative analyses were conducted among male and female patients with BRCAm (n = 349), as well as in male patients without BRCAm (n = 4577). RESULTS: Similar incidences of BRCAm (6.0 vs. 6.6%) and age at diagnosis of tumor (median, 65 vs. 60 years) were observed in male and female patients. Carcinomas of the lung, bladder, stomach, and cutaneous melanoma were the frequent tumors demonstrating BRCAm in males, of which the majority were stage II or III diseases with a higher frequency of BRCA2 mutations. Compared to that in the non-BRCAm group, cutaneous melanoma (16.3 vs. 5.0%), lung cancer (19.4 vs. 11.8%), bladder cancer (15.6 vs. 5.6%), and stomach cancer (11.9 vs. 5.5%) accounted for a higher proportion in the BRCAm group. Advanced disease and more mutation counts (median, 322 vs. 63 mutations) were also found in the BRCAm group. A total of 127 BRCA1 and 311 BRCA2 mutations were identified, of which 21.8 and 28.6% were deleterious, respectively. Frequent deleterious variants were identified in carcinomas of the breast (100.0%), colorectum (62.2%), prostate (43.3%), and stomach (42.9%). BRCA1 fusions with NF1, FAM134C, BECN1, or LSM12 and recurrent BRCA2 mutations at P606L/S, E832K/G, and T3033Lfs*29 were detected. Frameshift mutations in BRCA2 at N1784 (N1784Kfs*3, N1784Tfs*3) were frequently observed in both male and female patients. Compared with those in females, BRCA mutations in males were associated with decreased overall survival (OS) and progression-free survival (PFS). Male patients with deleterious BRCAm displayed increased OS compared with non-BRCAm carriers. The subgroup analysis demonstrated that BRCAm was associated with increased OS in gastric and bladder cancers, decreased PFS in prostate, esophageal, and head and neck cancers, and decreased OS in glioma/glioblastoma in males. CONCLUSION: These findings provide an overview of the distinct characteristics and clinical outcomes of male patients with BRCA-associated tumors, suggesting the importance of further genetic BRCA testing in males.

Erratum to: Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics.

The article "Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics", written by Xue-lin CHAO, Shu-zhen JIANG, Jian-wen XIONG, Jin-qiong ZHAN, Bo WEI, Chun-nuan CHEN, Yuan-jian YANG was originally published electronically on the publisher's internet portal on June 2020 without open access. With the author(s)' decision to opt for Open Choice, the copyright of the article is changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Immune parameters associated with survival in metaplastic breast cancer.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare histological type of breast cancer, which commonly shows resistance to standard therapies and is associated with poor prognosis. The immune microenvironment in MBC and its significance has not been well established due to its low incurrence rate and complex components. We aimed to investigate the diversity of immune parameters including subsets of TILs and PDL1/PD1 expression in MBC, as well as its correlation with prognosis. METHODS: A total of 60 patients diagnosed with MBC from January 2006 to December 2017 were included in our study. The percentage (%) and quantification (per mm2) of TILs and presence of tertiary lymphoid structures (TLS) were evaluated by hematoxylin and eosin staining (HE). The quantification of CD4+, CD8+ TILs (per mm2), and PD-1/PDL1 expression were evaluated through immunohistochemistry and analyzed in relation to clinicopathological characteristics. A ≥ 1% membranous or cytoplasmatic expression of PD1 and PDL1 was considered a positive expression. RESULTS: We found squamous cell carcinoma MBC (33/60, 55%) exhibiting most TILs of all the MBC subtypes (p = 0.043). Thirty-three of 60 (50%) of the patients had coexisting invasive ductal carcinoma of no special type (IDC-NST), and the average percentage of TILs in MBC components was lower compared with NST components (p < 0.001). Thirty (50%) patients exhibited positive (≥ 1%) PDL1 expression in their tumor cells, while 36 (60%) had positive (≥ 1%) PDL1 expression in their TILs. Twenty-seven (45%) of all the patients had positive (≥ 1%) PD1 expression in their tumor cells and 33 (55%) had PD1-positive (≥ 1%) stromal TILs. More CD8+ TILs were associated with positive PDL1 expression of tumor cells as well as positive PD1 expression in stromal cells. Greater number of stromal TILS (> 300/mm2, 20%), CD4+ TILs (> 250/mm2), and CD8+ TILs (> 70/mm2) in MBC were found associated with longer disease-free survival. Positive expression of PDL1 in tumor cells (≥ 1%) and PD1 in stromal cells (≥ 1%) were also associated with longer survival. CONCLUSIONS: The immune characteristics differ in various subtypes as well as components of MBC. Immune parameters are key predictive factors of MBC and provide the clinical significance of applying immune checkpoint therapies in patients with MBC.

Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics.

Accumulating evidence suggests that a disruption of early brain development, in which insulin-like growth factor-2 (IGF-2) has a crucial role, may underlie the pathophysiology of schizophrenia. Our previous study has shown that decreased serum IGF-2 was correlated with the severity of psychopathology in patients with schizophrenia. Here we conducted a prospective observation trial to investigate the effects of atypical antipsychotics on serum IGF-2 level and its relationship with clinical improvements in schizophrenia patients. Thirty-one schizophrenia patients with acute exacerbation and 30 healthy individuals were recruited in this study. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and serum IGF-2 levels were determined using ELISA. We found that schizophrenia patients with acute exacerbation had lower serum IGF-2 levels than control individuals at baseline (P<0.05). After 2 months of atypical antipsychotic treatment, a significant improvement in each PANSS subscore and total score was observed in patients (all P<0.01), and the serum IGF-2 levels of patients were significantly increased compared with those at baseline (203.13±64.62 vs. 426.99±124.26 ng/mL; t =-5.044, P<0.001). Correlation analysis revealed that the changes of serum IGF-2 levels in patients were significantly correlated with the improvements of negative symptoms (r=-0.522, P=0.006). Collectively, our findings demonstrated changes of serum IGF-2 response to improvements of negative symptoms in schizophrenia patients treated with atypical antipsychotics, suggesting that serum IGF-2 might be a treatment biomarker for schizophrenia.