MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

Prevalence and Associations of Beta2-Microglobulin Mutations in MSI-H/dMMR Cancers.

Microsatellite instability (MSI) has emerged as an important predictor of sensitivity for immunotherapy-based strategies. ß-2-Microglobulin (B2M) contains microsatellites within the coding regions and is prone to somatic changes in MSI/mismatch repair deficiency (MSI/dMMR) tumors. To delineate prevalence and associations of B2M mutations in MSI-H/dMMR cancers, we investigated the mutational profile of B2M and clinical and pathological features in gastric cancer (GC), colorectal cancer (CRC), and endometrial cancer (EC) with a high incidence of microsatellite instability-high (MSI-H)/dMMR. Formalin-fixed paraffin-embedded (FFPE) tumor tissues along with matched normal tissues were collected from 108 MSI/dMMR patients with GC, CRC, and EC. Genomic profiling of tissue and blood samples were assessed next-generation sequencing (NGS). Immunohistochemistry (IHC) was used to examine the presence or absence of B2M protein. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. NGS assay revealed that genes involved in chromatin regulation, the PI3K pathway, the WNT pathway, and mismatch repair were extensively altered in the MSI-H cohort. Signature 6 and 26, 2 of 4 mutational signatures associated with defective DNA mismatch repair, featured with high numbers of small insertion/deletions (INDEL) dominated in all 3 types of cancer. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. Tumor mutational burden (TMB) was significantly higher in the patients carrying MSI-H/dMMR tumors with B2M mutation than that in patients with wild-type B2M (P = .026).The frame shift alteration occurring at the exonic microsatellite sties caused loss of function of B2M gene. In addition, a case with CRC carrying indels in B2M gene resisted the ICI treatment was reported. In conclusion, patients carrying MSI-H/dMMR tumors with B2M mutation showed significantly higher TMB. Prescription of ICIs should be thoroughly evaluated for these patients.

KIT A502_Y503 duplication mutation serves as a potential and universal target for neoantigen peptide in Chinese GIST patients.

BACKGROUND AND AIM: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor with high prevalence of KIT and PDGFRA mutations. Few effective treatments can be exploited in imatinib or sunitinib resistant cases. While in immunotherapy, application of the highly individualized cancer neoantigen vaccines is hampered due to high economic and time cost. In this study we identified the most frequent mutation in Chinese GIST patients and predicted candidate neopeptide by next generation sequencing (NGS). METHODS: Tumor tissues and matched blood samples of 116 Chinese GIST patients were collected. Genomic profile was detected through NGS, and 450 cancer genes were deeply sequenced. KIT mutations were identified, and long peptides containing the mutation were queried in NetMHCpan 4.0 tools to predict MHC class I binding of mutant peptides. RESULTS: The most frequent mutated genes in detected GIST patients were KIT (81.9%, 95/116), CDKN2A (18.97%, 22/116), and CDKN2B (15.52%, 18/116) in this cohort. The most common mutation of KIT was A502_Y503 duplication (15.93%, 18/113) in exon 9. Among the 116 cases, 103 were HLA I genotyped, and 101 were HLA II genotyped. In total, 16 samples with the mutation of KIT p.A502_Y503dup were identified to produce neoantigens with qualified HLA affinity. CONCLUSIONS: KIT hotspot mutation (p.A502_Y503dup) has the highest incidence, which may further eliminate the need for whole genome sequencing and patient-specific neoantigen prediction and synthesis. Therefore, for those carrying such mutation, accounting for around 16% of Chinese GIST patients and are usually less sensitive to imatinib, effective immunotherapies are in prospect.

The efficacy of additional surgical resection after endoscopic resection in pT1b esophageal squamous cell carcinoma: A multi-institutional retrospective study in China.

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.

Combined assessment of tumour cell nest size and desmoplastic reaction as an excellent prognostic predictor in oesophageal squamous cell carcinoma.

AIMS: Tumour budding (TB) activity, cell nest size (CNS), and desmoplastic reaction (DR) have been confirmed to be significantly correlated with prognosis in oesophageal squamous cell cancer (ESCC) recently. However, there are limited data on the prognostic significance of combined assessment of cellular dissociation and tumour stroma in ESCC. METHODS: In all, 265 cases with resected ESCCs diagnosed between January 2018 and August 2019 were retrospectively reviewed. All slides were reviewed for assessing TB, CNS, and DR. The Cellular Dissociation Grading and our Combined CNS and DR (CNS/DR) Grading systems were adopted to re-grade ESCCs. RESULTS: High TB activity, small CNS, and immature DR had a strong association with shorter overall survival (OS) and progression-free survival (PFS) (P < 0.001, respectively) in ESCC. Combined assessment of CNS and DR in a 4-tiered grading system displayed a prognostic excellence for survival (P < 0.001), and outperformed the Cellular Dissociation Grading for both OS (area under the curve [AUC], 0.728 versus 0.644, P = 0.043) and PFS (AUC, 0.763 versus 0.667, P = 0.018) by receiver operator characteristic curves. Also, Combined CNS/DR Grading showed superiority in recognizing a G4 subgroup with the worst outcome in our cohort, to whom the most urgent attention needs to be called. CONCLUSIONS: This is the first study to propose a novel Combined Grading system based on CNS and DR in ESCC, which has been demonstrated to be relatively superior to Cellular Dissociation Grading in predicting prognosis. The findings shed new light on the histopathological grading of ESCC and facilitates identifying biologically aggressive ESCCs.

Vimentin loss promotes cancer proliferation through up-regulating Rictor/AKT/ß-catenin signaling pathway.

Vimentin protein is one of the main cytoskeleton and plays an important role in cell motility and metastasis. Nowadays, vimentin is widely studied as an epithelial-mesenchymal transition (EMT) marker of cancer cells while its involvement in cancer proliferation is poorly understood. In this study, we investigated the participation of vimentin in regulating cancer proliferation by silencing VIM gene in four cancer cell lines. Our results demonstrated that vimentin loss significantly induced cancer cell proliferation both in vitro and in vivo, which has not been reported so far. Mechanistically, knockdown of vimentin expression activated AKT phosphorylation and its downstream ß-catenin signaling. Nuclear translocation and transcriptional activity of ß-catenin was enhanced after silencing vimentin expression. Furthermore, vimentin loss could prevent Rictor from autophagy-dependent degradation via reducing AMPK-mediated autophagy signaling. AICAR, an AMPK activator, down-regulated Rictor and p-AKT levels while vimentin knockdown could rescue the effects. In vivo, it was also found that Ki67 expression and p-AKT/ß-catenin signaling pathway were obviously up-regulated in the tumor tissues in which vimentin was silenced compared to control groups. Taken together, these data showed the novel function of vimentin in regulating cancer proliferation via Rictor/AKT/ß-catenin signaling pathway, which suggested that it need more careful consideration before inhibiting metastatic cancers through targeting vimentin.

Clinical outcomes of early gastric cardiac cancer treated with endoscopic submucosal dissection in patients with different indications.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been accepted as a standard treatment for early gastric cardiac cancer (EGCC). Here, we investigate the clinical outcomes of the EGCC patients who underwent ESD in different indications. METHODS: From January 2011 to October 2019, we enrolled 502 EGCC lesions from 495 patients which were resected by ESD at our center. We retrospectively analyzed the short-term and long-term clinical outcomes among different indication groups. RESULTS: The number of the patients in the absolute indication (AI), expanded indication (EI) and beyond the expanded indication (BEI) groups was 265, 137 and 93, respectively. The en bloc resection rate was 100%, 100% and 98.9% (P = 0.185). The complete resection rate was 99.3%, 98.5% and 74.5%, respectively (P < 0.001). During a median follow-up of 48.1 months, the lymph node metastasis rate was 0%, 0% and 2.3% (P < 0.001). The distant metastasis rate was 0.4%, 0% and 2.3% (P = 0.150). The five-year disease-specific survival rate in the BEI group was 96.6% (P = 0.016), compared to 99.6% in the AI group and 100% in the EI group. CONCLUSION: The efficacy for ESD patients in EI group was almost equal to the AI group. Patients in the BEI group showed generally favorable clinical outcomes and needed to be carefully checked after ESD. ESD may be an optional treatment for patients unsuitable for gastrectomy.

Lipocalin-2 Exacerbates Lupus Nephritis by Promoting Th1 Cell Differentiation.

BACKGROUND: Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. METHODS: The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/lpr mice and analyzing pristane-treated LCN2-/- mice. RESULTS: LCN2 is highly expressed in CD4+ T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN-γ overexpression in CD4+ T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/lpr mice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. CONCLUSIONS: LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN.

An assessment of chromosomal alterations detected by fluorescence in situ hybridisation in pancreatobiliary tract malignancy.

BACKGROUND: Using fluorescence in situ hybridisation (FISH) to detect any gain of chromosomes 3, 7, or 17 and loss of the 9p21 locus has been proven to be sensitive in the diagnosis of pancreatobiliary tumors. However, both genetic and environmental factors contribute to the pathogenesis of pancreatobiliary tumors. Therefore, it is unknown whether this method is suitable for Chinese patients with pancreatobiliary tumors. This study aims to compare the sensitivity, specificity, predictive values and accuracy of cytology, ERCP/MRCP and FISH based on Chinese patients with pancreatobiliary tumors,and to analyze differences between brushing-based and formalin-fixed paraffin-embedded (FFPE)-based FISH. METHODS: A total of 66 brush cytology specimens obtained during ERCP were detected by FISH and cytology test respectively to compare the sensitivity, specificity, predictive values and accuracy. Besides, FFPE-based FISH was performed on 46 corresponding paraffin sections of pancreatobiliary tumors obtained by surgical resection. RESULTS: Our findings demonstrate that FISH greatly improves diagnostic sensitivity and negative predictive value compared to ERCP/MRCP and cytology without much reduction in specificity and positive predictive value. However, our results also indicate that FFPE-based FISH could not effectively identify the false-negative of brushing-based FISH. CONCLUSIONS: We believe that FISH can effectively distinguish true positive and false positive results of cytological or radiological suspicions of malignancy. However, FFPE-based FISH still does not precisely recognize the false-negative of brushing-based FISH. Both cytology-based and PPFE-based FISH had limitation in some specimens.

Functional genetic variants in centrosome-related genes CEP72 and YWHAG confer susceptibility to gastric cancer.

Structural and numeric centrosome aberrations can induce chromosome segregation errors and promote tumor development and progression. We systematically evaluated associations of 19,603 single nucleotide polymorphisms (SNPs) across 136 centrosome-related genes with gastric cancer (GC) risk using four GWAS datasets with a total of 3771 cases and 5426 controls. We identified two loci at 15p13.3 and 7q11.23 significantly associated with GC risk, whose risk alleles were correlated with increased mRNA expression of CEP72 (P = 7.30 × 10-4) and YWHAG (P = 1.60 × 10-3), respectively. Dual-luciferase reporter assays confirmed that the risk T allele of rs924607 at 15p13.3 significantly increased a promoter activity of the reporter gene, leading to a higher CEP72 expression level. At 7q11.23, the risk haplotype of rs2961037 [G]-rs2961038 [G] significantly elevated an enhancer activity and the expression of YWHAG. Both the mRNA and protein levels of CEP72 and YWHAG were overexpressed in GC tumor tissues compared with peritumor tissues and overexpression of either gene showed an unfavorable prognosis of GC patients. Moreover, knockdown of either CEP72 or YWHAG inhibited GC cell proliferation, migration and invasion and promoted GC cell apoptosis. The genes coexpressed with CEP72 or YWHAG in GC tumor tissues were enriched in the Ras signaling pathway, which was confirmed that knockdown of either one decreased the expression of cyclin D1 but increased the expression of p21 and p27. In conclusion, genetic variants at 15p13.3 and 7q11.23 may confer GC risk via modulating the biological functions of CEP72 and YWHAG, respectively, suggesting the importance of centrosome-regulated genes in GC development.

Submucosal gland neoplasms of the esophagus: an update and review.

Submucosal glands (SMGs) present throughout human esophagus with clusters at either the upper third or lower third of the organ. SMGs tend to atrophy with age, and neoplasms arising in these glands are rare. In order to bring convenience to diagnosis, we summarize the histopathologic characteristics of all esophageal submucosal gland tumors (SGTs). Due to the morphological similarity, the nomenclature of salivary tumors is adopted for SGTs. However, there is great confusion about the definition and histogenesis of these tumors, especially the malignant subtypes. In the literature, esophageal mucoepidermoid carcinoma and adenoid cystic carcinoma usually adjoin the surface squamous epithelium and coexist with intraepithelial neoplasia or invasive squamous cell carcinoma (SCC). In addition, the typical gene alterations of salivary tumors have not been reported in these SGTs. Therefore, we propose to apply stringent diagnostic criteria to esophageal SGTs so as to exclude mimickers that are SCCs with various degree of SMG differentiation.

Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis.

OBJECTIVE: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. DESIGN: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. RESULTS: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. CONCLUSIONS: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

Low risk of lymph node metastasis in 495 early gastric cardiac carcinomas: a multicenter clinicopathologic study of 2101 radical gastrectomies for early gastric carcinoma.

Clinical decision-making on endoscopic vs. surgical resection of early gastric cardiac carcinoma remains challenging because of uncertainty on risk of lymph node metastasis. The aim of this multicenter study was to investigate risk factors of lymph node metastasis in early gastric cardiac carcinoma. Guided with the World Health Organization diagnostic criteria, we studied 2101 radical resections of early gastric carcinoma for risk factors associated with lymph node metastasis, including tumor location, gross pattern, size, histology type, differentiation, invasion depth, lymphovascular, and perineural invasion. We found that the risk of lymph node metastasis was significantly lower in early gastric cardiac carcinomas (6.7%, 33/495), compared with early gastric non-cardiac carcinomas (17.1%, 275/1606) (p < 0.0001). In early gastric cardiac carcinoma, no lymph node metastasis was identified in intramucosal carcinoma (0/193) and uncommon types of carcinomas (0/24), irrespective of the gross pattern, size, histologic type, differentiation, and invasion depth. Ulceration, size > 3 cm, and submucosal invasion were not significant independent risk factors for lymph node metastasis. In 33 early gastric cardiac carcinomas with lymph node metastasis, either lymphovascular invasion or poor differentiation was present in 16 (48.5%) cases and together in six cases. By multivariate analysis, independent risk factors of lymph node metastasis in early gastric cardiac carcinoma included lymphovascular invasion (Odds Ratio (OR): 7.6, 95% Confidence Interval (CI): 2.8-20.2) (p < 0.0001) and poor differentiation (OR: 6.0, 95% CI: 1.4-25.9) (p < 0.05). In conclusion, lymph node metastasis was not identified in early gastric cardiac intramucosal carcinoma and uncommon types of carcinoma. The risk of lymph node metastasis was also significantly lower in tumors with submucosal invasion, especially for cases without lymphovascular invasion or poor differentiation. These results lend support to the role of endoscopic therapy in the treatment of patients with early gastric cardiac carcinoma.

BRM/SMARCA2-negative clear cell renal cell carcinoma is associated with a high percentage of BRM somatic mutations, deletions and promoter methylation.

AIMS: The aim of this study was to investigate potential molecular mechanisms associated with loss of BRM expression in poorly differentiated clear cell renal cell carcinoma (ccRCC). METHODS AND RESULTS: Nineteen previously selected BRM-negative RCC tissues were examined by DNA sequencing, fluorescence in-situ hybridization (FISH) and methylation-specific polymerase chain reaction (PCR) of the BRM gene. BRM mutation was identified in 78.9% (15 of 19) cases, chromosome 9 monosomy or BRM deletion in 43.8% (seven of 16) and BRM promoter region cytosine-phosphate-guanine (CpG) methylation in 42.8% (six of 14). These results indicated that 89.5% (17 of 19) of the cases harboured at least one type of BRM genetic alteration, with two or more types of alteration in 47.4% (nine of 19). Such alterations were found rarely in adjacent non-neoplastic tissues and low-grade areas of composite tumours. CONCLUSIONS: BRM gene mutation, chromosome 9 monosomy or BRM deletion and CpG methylation contribute collectively to the loss of BRM expression in ccRCC. This work focusing on composite tumours indicated that BRM abnormality occurred during tumour progression.

Gastric mixed adenoneuroendocrine carcinoma: correlation of histologic characteristics with prognosis.

Gastric mixed adenoneuroendocrine carcinomas (MANECs) are rare, with both the exocrine and neuroendocrine components exceeding 30% volume. Several classifications for MANECs have been proposed, yet they have not been clinically evaluated. The aim of this study was to evaluate the correlation between tumor grade, histologic characteristics, and prognosis of gastric MANECs. We collected eligible 14 cases in our series and 31 cases in the literature and compared the prognostic difference among gastric MANECs with different histologic characteristics. Gastric MANECs could be divided into subgroups according to tumor grade of the neuroendocrine component and adenocarcinoma types. The high grade and large proportion of neuroendocrine component correlated with aggressive behavior and a tendency of poor clinical outcome. Gastric MANECs with a poorly differentiated adenocarcinoma showed a significant lower survival rate than did MANECs with a differentiated adenocarcinoma or mucin-producing carcinoma (P = .0008). Gastric MANECs were a heterogeneous group with different tumor grades, histologic subtypes, combination patterns, and patient outcomes. Previous classifications were evaluated. This study proves that histologic characteristics correlate with clinical outcomes. Our findings are complements to the latest prognostic classification.

Renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions: clinical experience and literature review.

AIM: To analyze the clinicopathological features of renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 RCC) in our institution. MATERIALS & METHODS: We screened 983 RCC specimens. TFE3 immunohistochemical staining and FISH assay confirmed 22 Xp11.2 RCCs out of 65 suspicious cases. Clinicopathological and treatment outcomes of 22 patients were retrospectively analyzed. RESULTS: In total, 22 patients included 13 females and nine males with a mean age of 27 years. Ten patients showed gross hematuria. Treatments included surgeries, immunotherapy and molecular-targeted therapy. Seven cases were at stage III/IV and four cases had tumor thrombosis or distant metastasis. During a median follow-up of 34 months, 19 patients were alive while three died of distant metastasis. CONCLUSION: Xp11.2 RCC is rare and FISH proved a useful diagnostic tool. Surgical resection achieved favorable outcome for early disease. Adult patients at advanced stage had poorer outcomes even with postoperative adjuvant therapy.

MYC protein expression is associated with poor prognosis in diffuse large B cell lymphoma patients treated with RCHOP chemotherapy.

This study aims to investigate the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma (DLBCL) patients treated with RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). A total of 60 patients with DLBCL from 2008 to 2013 were included. Formalin-fixed, paraffin-embedded DLBCL samples were analyzed for MYC protein expression and divided into high or low MYC group. The MYC protein expression and the international prognostic variables were evaluated. The high MYC protein expression predicted a shorter 3-year estimated overall survival (OS) and progression-free survival (PFS) versus the low MYC protein expression (57 % vs. 96 %, P < 0.001 and 50 % vs. 96 %, P = 0.001, respectively). Multivariate analysis confirmed the prognostic significance of the MYC protein expression for both OS (HR, 11.862; 95 % CI, 1.462-96.218; P = 0.021) and PFS (HR, 6.073; 95 % CI, 1.082-34.085; P = 0.040). MYC protein expression with International Prognostic Index (IPI) score distinguished patients into three risk groups with different 3-year OS rates (χ (2) 23.079; P < 0.001) and distinct 3-year PFS rates (χ (2) 15.862; P < 0.001). This study suggests that the MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL treated with RCHOP. The combinative model with IPI score and MYC protein expression could stratify DLBCL patients into prognostically relevant subgroups more effectively than either the IPI or the MYC alone.

[HER2 protein testing in gastric cancer: a retrospective analysis of 1 471 cases during two different periods in a single medical center].

OBJECTIVE: To study the potential factors in influencing the performance of immunohistochemical testing for HER2 protein in gastric cancers. METHODS: The HER2 protein expression status of 1 471 surgically resected archival gastric cancer cases in Drum Tower Hospital collected during two different periods was retrospectively analyzed. The materials included 957 cases tested during the period from 2007 to 2009 (group 1) and 514 cases from 2012 to 2013 (group 2). The test procedures and results observed during these two periods were compared. RESULTS: The percentages of score 3 HER2 protein expression (14.4%, 74/514 versus 9.5%, 91/957) and score 2 or score 3 HER2 protein expression (27.2%, 140/514 versus 21.7%, 208/957) were both higher in group 2 than in group 1 (P < 0.05). In group 1, the cancer tissue was fixed in 10% formalin, stained manually with HER2 antibody A0485 (Dako) and assessed by different pathologists.In group 2, the tissue was fixed in 10% neutral buffered formalin (pH 7.2), stained using automated immunostaining system (Roche Benchmark XT) with HER2 antibody 4B5 (Ventana) and assessed by a specialized team of pathologists. CONCLUSION: The results of HER2 immunostaining in gastric cancer are influenced by a number of factors including type of fixative, clone number of primary antibody, staining methods and experience of pathologists.

Submucosal gland differentiation and implications in esophageal basaloid squamous cell carcinomas.

Esophageal basaloid squamous cell carcinoma (BSCC) is a heterogenous entity with multilineage differentiation. It lacks systematical analysis on submucosal gland differentiation (SGD) due to the histological diversity and low incidence of esophageal BSCC. This study aims to find the correlation of SGD and clinicopathological features. A total of 152 esophageal BSCCs were separated into three histological groups: pure, mixed, and borderline group. The clinicopathological features were compared between different groups. The prevalence of SGD was also compared between cases of different groups. A panel of antibodies were used to identify SGD. The pure group differed from the mixed and borderline groups in many aspects, lymph node metastasis (LNM), cancer embolus, perineural invasion, and advanced stage occurred less frequently in the pure group (P<0.01). The pure group had a better but statistically insignificant overall survival (P=0.097). The squamous cell carcinoma (SCC) component or focal squamous differentiation was present in metastatic lymph nodes in almost all mixed BSCCs (95.7%, 22/23) with LNM. The LNM rate of superficial (T1b) BSCCs (17.6%, 6/34) was comparable to that of superficial (T1b) SCCs (18.5%, 57/308). However, LNM exclusively occurred in superficial mixed (3/5) and borderline (3/10) BSCCs. The IHC results demonstrated a prevalence of SGD in pure group (77%, 43/56). SGD is considered to be a favorable factor, while the squamous differentiation or invasive SCC component is an adverse factor in esophageal BSCCs. Refinement of classification is a promising way to improve patient management.