Search

The treatment strategies for T1 oesophageal squamous cell carcinoma (ESCC) patients with or without lymph node metastasis (LNM) are different. Given the advantages of the minimally invasive, sensitive and real-time detection, liquid biopsy has become an important cancer diagnostic and prognostic tool.MiRNA array and small-RNA sequencing were performed. Then, 222 formalin-fixed and paraffin-embedded tumour samples and 229 pretreatment serum samples from T1 ESCC patients were used to verify and evaluate the results.We demonstrated that serum miR-20b-5p could predict LNM in T1 ESCC patients. The AUC for serum miR-20b-5p was higher (0.827) than those for lymphovascular invasion (LVI) (0.751, P = 0.2128), invasion depth (0.662, P = 0.0027) and tumour differentiation grade (0.634, P = 0.0019). A nomogram for predicting LNM with three independent significant predictors (miR-20b-5p, LVI and invasion depth) was constructed with a concordance index of 0.931. Serum miR-20b-5p was also significantly correlated with disease-free survival (P 0.001). An algorithm of improved T1 ESCC treatment strategy after biopsy and/or after endoscopic resection based on serum miR-20b-5p level was constructed.This study suggests that serum miR-20b-5p is a potential biomarker for predicting LNM and can be helpful for precise clinical decision-making strategies and improve treatment outcomes for T1 ESCC patients.

Background pT1b esophageal squamous cell carcinoma (ESCC) patients treated by endoscopic resection (ER) required additional treatment with surgical resection (SR) or chemoradiotherapy (CRT) according to 2020 Japan Gastroenterological Endoscopy Society (JGES) guideline. Given the evidences for this recommendation were largely based on small-size studies, our study collected 166 cases of ER-treated pT1b patients in order to investigate the efficacy of additional SR as compared to ER-alone treatment. Methods A multi-institutional retrospective study in China was conducted. The pT1b ESCC treated by ER + SR (n = 42) and ER-alone (n = 124) from 2007 to 2018 were recruited. Meanwhile, patients with positive lymphovascular invasion (LVI(+)) and/or with positive vertical margin (VM(+)) were put into high-risk group, and those with both VM(−) and LVI(−) were selected into low-risk group. The clinicopathological parameters, lymph node metastasis (LNM), and survival between ER + SR and ER-alone groups were analyzed. Results In high-risk group, concurrent LNM revealed in surgically resected specimens accounted for 52.6% cases in ER + SR group. After surgical removal, the incidence of post-resection LNM dropped down to 5.6%. However, in low-risk group, patients with ER + SR treatment did not exhibit any concurrent LNM in surgically resected specimens, and the incidence of their overall LNM was similar to that in ER-alone group (0% vs. 2.8%, p = 1.000). More importantly, these cases demonstrated significantly shorter overall survival (OS) than that in ER-alone group (81.8% and 100.0%, respectively, at 3 years; log-Rank: P = 0.010). Conclusions For ER-treated pT1b patients in high-risk group, additional SR is strongly recommended. However, for those in low-risk group, additional SR does not generate much benefit for clearance of LNM, but brings harm to shorten their OS. Therefore, additional SR is not recommended for ER-treated pT1b patient in low-risk group.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is a type of low-grade malignant B-cell lymphoma. The aim of this study was to investigate the clinicopathological characteristics of thymic MALT lymphoma. We analyzed the clinical, morphological, immunophenotypical, cytogenetic, and molecular characteristics of 11 cases of thymic MALT lymphoma. The relevant literature was also reviewed. The median age of the 11 patients was 50 (range: 33-60). There was a female predominance with a female-to-male ratio of 10:1. Three patients presented with Sjögren syndrome, autoimmune thrombocytopenia purpura, and type B1 thymoma, respectively. Microscopically, thymic MALT lymphoma was characterized by epithelium-lined cysts that were surrounded by small lymphocytes, centrocyte-like cells, and monocytoid B-cells. Plasmacytic differentiation was observed in two cases. The tumor cells expressed CD20, CD79α, and BCL2. Clonal immunoglobulin genes were detected in all 8 examined cases. Fluorescence in situ hybridization (FISH) for 18q21 was performed in 7 cases, and no translocations involving 18q21 were found. Targeted gene sequencing was performed in five cases with available DNA samples, and TNFAIP3, CARD11, IGLL5, and CCND3 mutations were identified. Thymic MALT lymphoma is a rare type of B cell malignancy with a female predominance and excellent clinical outcomes. Molecular aberrations involving the NF-κB pathway are frequent in thymic MALT lymphoma, suggesting that dysregulation of the NF-κB pathway is an important mechanism underlying the pathogenesis of thymic MALT lymphoma.

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using Whole Exome Sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and on late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and TMB was lower in bSCC. bSCC with RNA expression pattern resembling cSCC had better survival than other bSCC. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and of CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had worse pathological response than neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. With outcome analysis for 6 bSCCs with neoadjuvant immunotherapy treatment and 4 late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCC. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explained the conflicting results of bSCC outcomes in existing studies. This article is protected by copyright. All rights reserved.

In this study, we reported a seldom case of pediatric high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS) with loss of B-cell markers (CD19, CD20, CD22, CD79a, CD38, Pax5, OCT2, and BOB1) and CD45, which bring great challenges to exclude a non-lymphomatous neoplasm. However, no evidence was found to support the diagnosis of sarcoma and carcinoma. Thus, due to the patient's prior history of Burkitt's lymphoma treated by rituximab-containing therapies, we carefully searched for any indication of B-cell differentiation. Eventually, NGS results revealed the monoclonal rearrangement of IGH (IGHD2-8-IGHJ6 and IGHV4-30-2-IGHJ4) in both pre-treatment and present tumors, confirming the same B-cell lineage. Moreover, both tumors exhibited the same IGHA1-MYC translocation and somatic mutations of c-MYC, TP53, ID3, and CCND3. Therefore, in addition to strong expression of BCL2 in the present tumor, we finally arrived at a diagnosis of pediatric HGBL, NOS with loss of B-cell lineage markers and CD45.

The progression of multiple primary lung cancer (MPLC) involves complex changes in cell composition and metabolic function. Here, we performed scRNA sequencing of 167,397 cells from six patients with MPLC, combined with bulk whole-exome sequencing. We revealed that both naïve and memory T cells participate in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells are exhausted T cells, which respond to stimuli and positively regulate cell death, and cytotoxic T cells, which are mainly implicated in the regulation of cytokine production. Multiple functional Tregs and naïve T cells contribute to the origin of CD4+ T cells. B cells, with two main functions, also play important roles in the immune response. We also uncovered the cellular metabolic activities that occur during tumor invasion. Positive regulation of blood vessel diameter has been observed in endothelial cells, while angiogenesis has not been found in early glandular neoplasia of the lung. The development of epithelial cells involves two functional states. In one state, cells respond to stress from the immune system, and in the other, some will undergo programmed cell death or enter the cell cycle due to the selective pressure that arises over the course of tumor development in synchronous MPLC. Our study showed the complete landscape of different dynamic cellular changes, which might reveal the key cellular mechanisms of MPLC and therefore provide new clues for the pathogenesis of tumors.

The time conformable heat equation is a generalization of classical heat equation involved local and limit-based derivative, which is called conformable fractional derivative. In this paper, we stu...

Esophageal squamous cell carcinoma (ESCC) patients with a synchronous or metachronous lung tumor can be diagnosed with lung metastasis (LM) or a second primary tumor (SPT), but the accurate discrimination between LM and SPT remains a clinical dilemma. This study aimed to investigate the feasibility of using the whole-exome sequencing (WES) technique to distinguish SPT from LM. Methods: We performed WES on 40 tumors from 14 patients, including 12 patients with double squamous cell carcinomas (SCCs) of the esophagus and lung (lymph node metastases were sequenced as internal controls) diagnosed as LM according to pathological information and 2 patients with paired primary ESCC and non-lung metastases examined as external controls. Results: Shared genomic profiles between esophageal (T) and lung (D) tumors were observed in 7 patients, suggesting their clonal relatedness, thus indicating that the lung tumors of these patients should be LM. However, distinct genomic profiles between T and D tumors were observed in the other 5 patients, suggesting the possibility of SPTs that were likely formed through independent multifocal oncogenesis. Conclusions: Our data demonstrate the limitations and insufficiency of clinicopathological criteria and that WES could be useful in understanding the clonal relationships of multiple SCCs.

Background The tumour microenvironment (TME) serves as an important factor in tumorigenesis and metastasis. Although distinct cell subsets can be identified via single-cell RNA sequencing (scRNA-seq), the spatial composition of cells within the TME is difficult to characterise. Methods Tissue samples were collected from three patients with oesophageal squamous cell carcinoma (ESCC), and scRNA-seq was performed to identify distinct cell subsets. In addition, a microarray-based spatial transcriptomic (ST) method was used to characterise the spatial landscape of expression data via an array of spots. Using multimodal intersection analysis (MIA) to integrate scRNA-seq and ST, the exact cellular components of the tumour and stromal regions were annotated. Results The subpopulations of seven stromal cells were identified within the TME of ESCC, and the architecture of scRNA-seq-determined subsets was mapped in cancer and stromal regions. The distribution of various stromal cells and their subpopulations was heterogeneous. Compared with immune cells, non-immune stromal cells were significantly enriched in the TME. Most subsets of epithelial cells were enriched in the cancer regions, whereas inflammatory cancer-associated fibroblasts were correlated with the stromal regions. Furthermore, TME features were different between metastatic and non-metastatic samples and between the primary and metastatic sites of the metastatic sample. Conclusions This study revealed the spatial landscape of various cell subsets within the TME and the potential cross-talk among diverse cells, which provides novel insights into cancer intervention.

CXCR4 (C-X-C chemokine receptor type 4) is the most commonly expressed of all chemokine receptors in malignant tumors. However, studies on CXCR4 in non-small cell lung cancer (NSCLC) tumor immune microenvironment, including those determining its immune efficacy and prognostic potential, are still scarce. Therefore, in this study, we determined the ability of CXCR4 to predict immunotherapy response and prognosis in NSCLC using immunohistochemical staining and RT-PCR, respectively, in two independent cohorts from the National Cancer Center of China. We analyzed transcriptome sequencing data and clinical information from multiple public databases to assess immune cell infiltration in NSCLC and constructed immune risk prognostic signatures based on CXCR4-related immunomodulators. We found that immune cell infiltration is significant differences in NSCLC tissues and is moderately correlated with CXCR4 expression. High CXCR4 expression was significantly associated with poor prognosis in NSCLC patients and a higher response rate to immunotherapy. The ROC curve showed that CXCR4 expression exhibited excellent performance in predicting the efficacy of immunotherapy in NSCLC. We identified 30 CXCR4-related immunomodulators in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and constructed immune prognostic signatures based on CXCR4-related immunomodulators and CXCR4-related mutant genes. The signature-based prognostic risk score showed good performance in predicting patient prognosis in both LUAD and LUSC; high risk scores were significantly associated with poor prognosis (P

P53 suppresses tumorigenesis through multiple cellular functions/mechanisms, including genomic stability surveillance. Recently, it has also be reported for its role in cancer immune response modulation. Deficiency in DNA repair pathways lead to the accumulation of genomic alterations and tumor mutation burden and in consequence resulting in the activation of immune response. We investigated the interaction of p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies by mining cBioPortal data of a range of human cancers. We found that in the majority of human cancers, p53 mutations are equally distributed between DNA repair gene mutation positive and negative cases and in a number of human cancers, p53 and DNA repair gene mutations have a tendency of co-occurrence. Only in colorectal cancer, there is a tendency of ‘mutual exclusivity’ of mutations in p53 and DNA repair genes. In most tumors, p53 and DNA repair gene mutations have synergistic/additive effect in increasing tumor mutation burden, but not in colorectal cancer where they are mutually exclusive. The impact of p53 and DNA repair gene mutations and their interaction on tumor microenvironment immune cells are complex and tumor type specific and not always correlated with tumor mutation burden. In colorectal cancers, these two types of mutations resulted in similar immune cell subpopulation changes and in tumors where the mutations have a tendency of co-occurrence, p53 showed dominant roles on immune response, although they can also counter-act each other for their effect on certain immune cell subtypes.

Lung cancer has the highest morbidity and mortality among all cancer types. Reliable prognostic biomarkers are needed to identify high-risk patients apart from TNM system for precision medicine. The present study is designed to identify robust prognostic biomarkers in lung adenocarcinoma (LUAD) based on integration of multiple GEO datasets, The Cancer Genome Atlas (TCGA) database and Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Four LUAD GEO datasets (GSE10072, GSE2514, GSE43458, and GSE32863) and TCGA database were implemented to analyze the differently expressed genes (DEGs). Gene ontology, KEGG pathway, and protein–protein interaction network (PPI) were conducted based on the above DEGs. Hub genes were selected based on connectivity degree in the PPI network. Expression analysis and Kaplan–Meier survival analysis were conducted in CPTAC lung adenocarcinomas cohort. Kaplan–Meier survival analysis and Cox proportional hazards regression were performed on these hub genes using TCGA and our own cohort. A total of 430 shared genes in all five datasets were identified as DEGs. Based on their PPI network, nine hub genes were selected and all of them were significantly associated with overall survival using GEPIA analysis. Two hub genes, TOP2A and UBE2C, were further combined and showed poorer prognosis in both TCGA dataset and our validated cohort. Analysis in CPTAC revealed that TOP2A and UBE2C were significantly highly expressed in tumor sample. Multivariable analysis suggested TOP2A and UBE2C as independent prognostic factors in LUAD. Using data mining approach, we identified TOP2A and UBE2C as two robust prognostic factors in LUAD. We also demonstrated the TOP2A/UBE2C co-expression status in LUAD, and TOP2A/UBE2C co-expression correlated with poorer prognosis. More in-depth research is needed for transforming this result into clinical setting.

There is limited evidence regarding the relationship between the expression of Sushi Domain Containing 2 (SUSD2) and prognosis of patients with surgically resected lung adenocarcinoma (LUAD). This retrospective study aimed to investigate the clinical significance of SUSD2 expression in LUAD. To assess SUSD2 expression in LUAD, we conducted both integrated bioinformatic analysis based on the TCGA database and also immunohistochemistry study using a tissue microarray encompassing 578 LUAD cases from our hospital. Reduced SUSD2 expression was associated with gender, smoking history, higher pathological grade, lymph node metastasis, larger tumor length, advanced TNM stage. LUAD patients with SUSD2-positive tumors showed significantly better overall survival (OS) than those with SUSD2-negative tumors (P = 0.000). When patients were stratified into those with stage I (218, 37.7%), II (152, 26.3%) and III (208, 36.0%) disease, and those without (254, 43.9%) and with (324, 56.1%) lymph node metastasis, the prognostic effect was almost consistent. The OS of patients with positive SUSD2 expression was significantly better in patients with stage I (P = 0.000), III (P = 0.000), without (P = 0.000) and with (P = 0.001) lymph node metastasis. Multivariate analysis showed that loss of SUSD2 predicted a shorter survival time and was an independent prognostic factor for LUAD patients. Our study indicated that SUSD2 may serve as a new prognostic and potential therapeutic target in LUAD.

The effect of chemotherapy on programmed cell death-ligand 1 (PD-L1) expression has been previously studied in lung cancer, while the results remain controversial. The aim of this study was to investigate the variation of PD-L1 expression after neoadjuvant chemotherapy and explore the association between chemotherapy response, prognosis and the variation of PD-L1 expression in lung cancer patients. A total of 63 lung cancer patients who received platinum-based neoadjuvant chemotherapy and subsequently underwent surgical resection were selected. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was assessed by immunohistochemistry using 22C3 monoclonal antibody in these 63 matched lung cancer specimens before and after neoadjuvant chemotherapy. The positivity of PD-L1 on TC changed from 17.5% to 39.7% after neoadjuvant chemotherapy and the positivity of PD-L1 on IC changed from 19.0% to 71.4% after neoadjuvant chemotherapy. The elevation of PD-L1 expression on TC after neoadjuvant chemotherapy was more frequently observed in patients achieving stable disease or progressive disease than in patients achieving partial response (P=0.026). Patients with elevated PD-L1 expression on TC after neoadjuvant chemotherapy showed a trend to have a shorter progression-free survival than patients without elevated PD-L1 expression on TC, although the difference was not statistically significant in multivariate analysis (hazard ratio=2.38, 95% confidence interval=0.99-5.73, P=0.053). PD-L1 expression can be elevated by chemotherapy in lung cancer. Furthermore, elevation of PD-L1 expression on TC after neoadjuvant chemotherapy was associated with reduced chemotherapy response and inferior progression-free survival in patients with lung cancer.

e16062 Background: Esophageal squamous cell carcinoma (SCC) is one of the most common cancers and the leading cause of cancer-related death in China, and esophageal basaloid squamous cell carcinoma (BSC) is a rare variant (2.2%-11.3%) of SCC with highly aggressive behavior due to its propensity for vessel invasion and distant metastasis. Most reports stated that BSCs had poorer prognosis than conventional esophageal SCC. However, because of the histological morphologic similarity and lacking of diagnostic approaches, esophageal BSC can easily result in misdiagnosis as SCC. Methods: To deepen our understanding of esophageal BSC and seek for diagnostic biomarkers, we analyze the difference of mRNA expression between esophageal BSC and conventional SCC. Nanostring nCounter PanCancer Progression gene expression panel was used on different tumor components from 36 patients diagnosed with esophageal BSC component (Ba) coexisting with conventional SCC component (Co), who underwent esophagectomy at our Hospital (Cancer Hospital, Chinese Academy of Medical Sciences, China). Immunohistochemistry (IHC) was used for verification of candidate biomarkers sFRP1 concluded from mRNA expression analysis. The expression of sFRP1 was evaluated by H-score = % cells staining (0-100%) * intensity (1 to 3). Results: Among 770 RNAs analyzed in the study, 22.9% (176/770) showed downregulation (FDR-adjusted p < 0.05) in Ba than Co, while 5.3% (41/770) showed upregulation. A set of significantly upregulated RNAs (FDR-adjusted p < 0.01, log2(fold change) > 2) were observed in Ba, including sFRP1, FGFR1, ITGA9, VIT, VWA2 and PROM1, which were associated with angiogenesis response, basement membrane, and epithelial-mesenchymal transition (EMT). Besides, significant downregulation (FDR-adjusted p < 0.01, log2(fold change) < -2) of KRT14 was observed in Ba, which was well known as a biomarker for squamous differentiation. Clustering analysis with different pathway scores according to mRNA expression results of Ba yielded two major clusters: Cluster1 with higher pathway scores with resembled to Co, and Cluster2 with lower pathway scores. Survival analysis revealed that patients in Cluster1 seemed to have a longer RFS and a longer OS than those in Cluster2 (Figure 4C&D), although with no statistically significance (RFS: p = 0.322, median RFS = 23.7 vs 10.8 months; OS: p = 0.217, median OS = 51.6 vs 26.5 months), which was probably due to the limited number of patients evolved (10 patients in Cluster1 and 26 in Cluster2). The most upregulated mRNA, sFRP1, was validated by IHC. Receiver operating characteristic (ROC) curve revealed that sFRP1 IHC could be a remarkable diagnosis biomarker to distinguish BSC from conventional SCC (area under ROC = 0.935, p < 0.001 95%CI = 0.871-1.000). Conclusions: Our results revealed BSC as a subtype with distinct RNA expression pattern compared with conventional SCC, and provided a remarkable biomarker, sFRP1, for diagnosis.

Purpose ER-treated patients with pT1b ESCC were strongly recommended to receive additional treatments, mainly radical surgical resection (SR). In view of high morbidity and mortality of additional SR treatment, this recommendation remained open to debate. Herein, our research aimed to access the efficacy of current risk predictors for metastasis based on the histological findings in ER specimens, and the effectiveness of additional SR. Methods We conducted a retrospective study of ER-treated pT1b ESCC patients with (n = 42) and without (n = 124) additional SR from 2007 to 2018 in China. Lymph node metastasis & distant organ metastasis (LNM&DOM) reflecting the overall metastasis risk of ESCC after ER treatment were used. The relationships between clinicopathological parameters and metastasis were assessed. And Overall survival(OS) and progression-free survival (PFS) were also analyzed. Results Patients with submucosal invasion depth (SMI) ≥ 200µm didn't demonstrate significant difference in LNM&DOM and survival, as compared with those with SMI

BackgroundLung adenocarcinoma (LUAD), as the most common histological subtype of lung cancer, is a high-grade malignancy and a leading cause of cancer-related death globally. Identification of biomarkers with prognostic value is of great significance for the diagnosis and treatment of LUAD. Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an RNA-binding protein “reader” of N6-methyladenosine (m6A) methylation, and is related to the progression of various cancers; however, its role in LUAD is unclear. The aims of this study aims were to study the expression and prognostic value of HNRNPC in LUAD.MethodsThe Oncomine database and gene expression profiling interactive analysis (GEPIA) were used for preliminary exploration of HNRNPC expression and prognostic value in LUAD. LUAD cases from The Cancer Genome Atlas (TCGA) (n = 416) and the Kaplan-Meier plotter database (n = 720) were extracted to study the differential expression and prognostic value of HNRNPC. HNRNPC expression in the National Cancer Center of China (NCC) cohort was analyzed by immunohistochemical staining, and the relationship between HNRNPC expression and survival rate evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. Several pathways that were significantly enriched in the HNRNPC high expression group were identified by Gene Set Enrichment Analysis (GSEA).ResultsFive data sets from the Oncomine and GEPIA databases all supported that HNRNPC expression is significantly higher in LUAD than in normal lung tissue. In TCGA cohort, HNRNPC was highly expressed in LUAD tissues and significantly related to age, sex, smoking history, ethnicity, lymph node metastasis, and TNM staging (P < 0.001). High HNRNPC expression was significantly correlated with poor prognosis in the three cohorts (NCC, TCGA, and K-M plotter) (P < 0.05). Multivariate Cox regression analysis showed that HNRNPC expression was an independent prognostic factor in both TCGA and NCC cohorts (P < 0.05). Further, 10 significantly enriched pathways were identified from TCGA data and 118 lung cancer cell lines in CCLE, respectively.ConclusionsHigh HNRNPC expression is significantly related to poor overall survival in patients with LUAD, suggesting that HNRNPC may be a cancer-promoting factor and a potential prognostic biomarker in LUAD.

BackgroundDespite Adenoid cystic carcinoma (ACC) with cribriform or tubular components being recognized as a potentially indolent malignancy, ACC displaying solid or, more rarely, high-grade transformation (HGT) components is considered a more aggressive variant of the disease. As it is difficult to measure the proportion of the solid component objectively, and the role of HGT in the current grading system remains unclear, the prognostic influence of tumor grading remains controversial. In addition, postoperative radiotherapy (PORT) has been proven to be effective in local control of ACC of the head and neck (ACCHN) with a high rate of nerve invasion and close surgical margin. However it remains to be explored that whether PORT could improve the survival of patients with ACC, particularly those with HGT.MethodsA series of 73 surgically treated primary ACCHN cases were retrospectively accessed. Immunohistochemical staining was performed to observe the biphasic ductal-myoepithelial differentiation and to identify the HGT components of ACC for tumor grading. The correlation between tumor grading and clinicopathological characteristics was analyzed. Univariate and multivariate prognostic analysis were performed for progression-free survival (PFS) and overall survival (OS).ResultsOf the 73 included cases, 47 were grade I-II ACC and 26 were grade III ACC. Among the grade III cases, 14 with loss of biphasic ductal-myoepithelial differentiation identified by immunostaining were classified as HGT, and could be distinguished from conventional grade III cases. These HGT cases were correlated with a high propensity of lymph node metastases and more advanced stage. Univariate analysis demonstrated that tumor grading, perineural invasion, T stage, stage groups, and PORT were predictors for PFS, whereas tumor grading, margin status, and PORT were predictors for OS. However, only tumor grading and PORT were independent predictors for PFS and OS. The patients with HGT had significantly worse prognosis than those with conventional ACC. Moreover, disease progression tended to occur more frequently in younger patients. Among the patients with HGT, those who received PORT had a longer median survival time than those who did not.ConclusionHGT ACC identified by loss of biphasic differentiation should be considered in tumor grading. Tumor grading and PORT were independent predictors for disease progression and OS in surgically treated ACCHN patients.

Background: Several studies have assessed the comparability of various immunohistochemical assays for programmed cell death 1 ligand 1 (PD-L1) expression in different kinds of tumours. However, there is a lack of relevant research on the detection efficacy of different PD-L1 clones in esophageal squamous cell carcinoma (ESCC). This study was performed to compare the PD-L1 expression results of three PD-L1 antibodies to assess their effectiveness.Methods: Three hundred and twenty-four cases of ESCC tissues in our medical institution were used to prepare tissue microarrays (TMAs). TMAs were stained with three validated assays (Ventana’s SP263 and Dako’s 28-8 and 22C3). Then, pathologists scored each tissue according to PD-L1 staining.Results: We found very high concordance when comparing 28-8 with SP263 at both the 1% (95.7%) and 50% (99.1%) cutoffs. Low overall concordance was found between 28-8 and 22C3 at the 1% cutoff (85.5%). Moreover, sensitivities of 91.2% and 87.5% were found for 28-8 compared with SP263 at the 1% and 50% cutoffs, respectively. Sensitivities of only 75.6% and 50% were found for 28-8 compared with 22C3 at the 1% and 50% cutoffs, respectively, which may result in more false negatives.Conclusions: We demonstrate that the PD-L1 SP263 shows high levels of overall agreement with 28-8 and relatively high sensitivity, with a low false negative rate. Thus, SP263 seems to be a reliable assay for PD-L1 testing in ESCC when considering pembrolizumab as immunotherapy.

Background Recently, copy number alteration (CNA) of 9p24.1 were demonstrated in 10% of diffuse large b-cell lymphoma (DLBCL), with gene expression and mutation profiles that were similar to those of primary mediastinal large B-cell lymphoma (PMBCL). However, their CNA-based profile and clinical impact still remain unclear. Methods Multiplex ligation-dependent probe amplification were employed to investigate the prevalence of JAK2/PD-L2 amplification in DLBCL and their CNA-based pattern of driver genes. The clinical outcome and characteristics were also analyzed. Results Using unsupervised hierarchical clustering, a small group of DLBCL (10.5%, 8/76) was clustered together with PMBCL as Cluster_2, demonstrating amplification of JAK2 (100%,8/8) and PD-L2 (75.0%,6/8). This subgroups of DLBCL demonstrated significant higher expression of PD-L1 than those with MYD88 L265P mutation(p = 0.024). And they exhibited dismal OS and PFS as compared with DLBCL_others(p = 0.003 and 0.001, respectively), which is similar to DLBCL with MYD88 L265P mutation. Conclusions DLBCL with amplification of JAK2/PD-L2 exhibits CNA pattern that is similar to PMBCL, and demonstrates unfavorable clinical outcome that resembles those with MYD88 L265P mutation. It is essential to identify this subgroup of DLBCL who may acquire more benefits from the JAK2 and PD-L1 signaling inhibition.

In this paper, we present a new fractional Tikhonov regularization method for solving an inverse problem for a time-fractional diffusion equation which is highly ill-posed in the two-dimensional setting. Fractional Tikhonov regularization method not only retains the advantage of classical Tikhonov method, but also overcomes the effect of over-smoothing of classical Tikhonov method. We give the selection of regularization parameters of the new method and the corresponding error estimation. Furthermore, numerical results show that the fractional Tikhonov method outperforms the classical one.

In this paper, we study a modified Landweber iteration method via a gradient flow equation induced by a weighted least squares functional. We investigate the proposed scheme for solving ill-posed problems under the setting of compact operator and pseudo-differential operator. The a-priori and the a-posteriori choice rules for regularization parameters are given and both rules yield the order optimal error estimates. Relative to the classical Landweber method, the new method significantly reduces the number of iterations needed to match an appropriate stopping criterion. As applications, we focus on some important ill-posed problems arising from mathematical physics. Numerical experiments are conducted for showing the validity of the scheme. We give a new modified Landweber method via gradient flow method, which is different from the other modified Landweber methods.We make a systematic study on the modified Landweber iteration method including the stationary and nonstationary schemes, the a-priori and a-posteriori parameter choices.The modified method has the advantage that it requires a fewer number of iterations to achieve the same accuracy.

Both antigenic drive and genetic change play a critical role in the development of MALT lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and IGHV usage in 179 MALT lymphomas from various sites. We showed that: 1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 (encoding a global negative regulator of the canonical NF-B pathway) in ocular adnexal MALT lymphoma; 2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of salivary gland, but not associated with mutation in any of the 17 genes investigated; and 3) MALT lymphoma lacked mutations frequently seen in other B-cell lymphomas characterised by constitutive NF-B activities, including CD79B, CARD11, MYD88, TNFRSF11A and TRAF3. Our findings show for the first time a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-B regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic BCR signalling and driving oncogenesis in lymphoma development.

Lung adenocarcinoma (LUAD) accounts for an increasing proportion of non-small-cell lung cancer and an increasing number of cancer-related deaths worldwide. However, few biomarkers are available for prognosis and patient stratification. In all eight datasets from the Oncomine and The Cancer Genome Atlas (TCGA) LUAD cohorts, solute carrier family 2 member 1 (SLC2A1) was significantly more highly expressed in LUAD tissue than in normal lung tissue. High SLC2A1 expression was also significantly (

Additional file 7: Figure S4. The frequencies of JAK2 gain and amplification, and their survival analysis. a. The frequencies of JAK2 gain and amplification in DLBCL_JAK2/PD-L2_amp and PMBCL. b. the OS and PFS of DLBCL with JAK2 gain or with JAK2 amplification.

Additional file 3: Table S1. The details of MLPA probes of genes in DLBCL. The locations and lengths of MLPA probes of genes are showed in this table.

Additional file 2: Figure S1. Representative results of MLPA. Representative results of MLPA are showed in this figure.

AIM To identify the clinicopathological characteristics of pT1N0 esophageal squamous cell carcinoma (ESCC) that are associated with tumor recurrence. METHODS We reviewed 216 pT1N0 thoracic ESCC cases who underwent esophagectomy and thoracoabdominal two-field lymphadenectomy without preoperative chemoradiotherapy. After excluding those cases with clinical follow-up recorded fewer than 3 mo and those who died within 3 mo of surgery, we included 199 cases in the current analysis. Overall survival and recurrence-free survival were assessed by the Kaplan-Meier method, and clinicopathological characteristics associated with any recurrence or distant recurrence were evaluated using univariate and multivariate Cox proportional hazards models. Early recurrence (≤ 24 mo) and correlated parameters were assessed using univariate and multivariate logistic regression models. RESULTS Forty-seven (24%) patients had a recurrence at 3 to 178 (median, 33) mo. The 5-year recurrence-free survival rate was 80.7%. None of 13 asymptomatic cases had a recurrence. Preoperative clinical symptoms, upper thoracic location, ulcerative or intraluminal mass macroscopic tumor type, tumor invasion depth level, basaloid histology, angiolymphatic invasion, tumor thickness, submucosal invasion thickness, diameter of the largest single tongue of invasion, and complete negative aberrant p53 expression were significantly related to tumor recurrence and/or recurrence-free survival. Upper thoracic tumor location, angiolymphatic invasion, and submucosal invasion thickness were independent predictors of tumor recurrence (Hazard ratios = 3.26, 3.42, and 2.06, P < 0.001, P < 0.001, and P = 0.002, respectively), and a nomogram for predicting recurrence-free survival with these three predictors was constructed. Upper thoracic tumor location and angiolymphatic invasion were independent predictors of distant recurrence. Upper thoracic tumor location, angiolymphatic invasion, submucosal invasion thickness, and diameter of the largest single tongue of invasion were independent predictors of early recurrence. CONCLUSION These results should be useful for designing optimal individual follow-up and therapy for patients with T1N0 ESCC.

Objective The novel fully automated immunohistochemistry (IHC) assay-Ventana anaplastic lymphoma kinase (ALK)-D5F3 for screening ALK rearrangements has been approved by China’s Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK (+) and ALK (-) lung adenocarcinoma. Methods A total of 1,504 consecutive surgical lung adenocarcinoma cases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma. Fully automated Ventana ALK-D5F3 IHC staining with a binary scoring was adopted to evaluate staining and correlated with clinicopathological characters, including age, sex, differentiation degree, histological subtype, lymph node metastasis, and clinical staging. ALK (+) patients were followed-up, and targeted therapy of ALK-inhibitors was adopted and observed in patients with stage IV according to the NCCN guideline. Results ALK positive adenocarcinomas were identified in 6.6% of the surgically resected 1,504 NSCLCs, and significantly younger than the negative group (P

Both antigenic drive and genetic change play critical roles in the development of mucosa-associated lymphoid tissue (MALT) lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and immunoglobulin heavy chain variable region (IGHV) usage in 179 MALT lymphomas from various sites. We showed that: (1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 [encoding a global negative regulator of the canonical nuclear factor-κB (NF-κB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of the salivary gland, but was not associated with mutation in any of the 17 genes investigated; and (3) MALT lymphoma lacked mutations that are frequently seen in other B-cell lymphomas characterized by constitutive NF-κB activities, including mutations in CD79B, CARD11, MYD88, TNFRSF11A, and TRAF3. Our findings show, for the first time, a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-κB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B-cell receptor signalling and driving oncogenesis in lymphoma development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.