Evolution of genome and immunogenome in esophageal squamous cell carcinomas driven by neoadjuvant chemoradiotherapy.

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. The clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than the clone-extinct ones. In contrast to the clone-extinct patients, the clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in the clone-extinct patients. The number of T cell receptor-neoantigen interactions was higher in the clone-extinct patients than in the clone-persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone-extinct patients. In conclusion, we identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT.

HMGB1-Mediated Neutrophil Extracellular Trap Formation Exacerbates Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury.

Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I-mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor-mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.

Detection of Human Papillomavirus DNA, E6/E7 Messenger RNA, and p16INK4a in Lung Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: The etiologic link between human papillomavirus (HPV) and lung cancer is still controversial. METHODS: PubMed and Cochrane databases were searched from inception to December 2020 to identify studies on the infection of HPV in lung cancer. We calculated the attributable proportion of HPV in lung cancer by pooling the infection of cases positive for both HPV DNA and biomarkers of carcinogenesis that may be induced by HPV (E6/E7 messenger RNA or p16INK4a). RESULTS: A total of 117 studies, comprising data of 12 616 lung cancer cases from 22 countries across 5 continents, were included. The overall HPV DNA positivity in primary lung cancer cases worldwide was 16.4% (95% confidence interval, 12.7%-20.5%). HPV DNA positivity of lung cancer varied significantly by pathological type and geographic region. Notably, the expression rate of p16INK4a is significantly higher than the positivity of HPV DNA and of HPV E6/E7 mRNA (P < .05). The estimate of HPV attributable proportion defined by expression of E6/E7 mRNA was 0 and of p16INK4a was 7.3%. CONCLUSIONS: The data in this systematic review is robust enough to contradict the possible participation of HPV in lung cancer carcinogenesis. Prophylactic vaccines targeting HPV cannot have the potential to prevent lung cancer.

Immune-related adverse events predict responses to PD-1 blockade immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune-related adverse events (irAEs). However, the association between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti-PD-1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs+ ), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs+ group showed a higher tumor response rate than those in the irAEs- group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression-free survival (PFS) times were 14.8 months in the irAEs+ group and 4.1 months in the irAEs- group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs+ /rash+ group was better than that of those in the irAEs+ /rash- or irAEs- group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio [HR]: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti-PD-1 antibodies.

Prognostic Value of a Four-miRNA Signature in Patients With Lymph Node Positive Locoregional Esophageal Squamous Cell Carcinoma Undergoing Complete Surgical Resection.

OBJECTIVE: This study was intended to identify prognostic biomarkers for lymph node (LN)-positive locoregional esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: Surgery is a major treatment for LN-positive locoregional ESCC patients in China. However, patient outcomes are poor and heterogeneous. METHODS: ESCC-associated miRNAs were identified by microarray and validated by quantitative real-time polymerase chain reaction analyses in ESCC and normal esophageal epithelial samples. A multi-miRNA based classifier was established using a least absolute shrinkage and selection operator model in a training set of 145 LN-positive locoregional ESCCs, and further assessed in internal testing and independent validation sets of 145 and 243 patients, respectively. RESULTS: Twenty ESCC-associated miRNAs were identified and validated. A 4-miRNA based classifier (miR-135b-5p, miR-139-5p, miR-29c-5p, and miR-338-3p) was generated to classify LN-positive locoregional ESCC patients into high and low-risk groups. Patients with high-risk scores in the training set had a lower 5-year overall survival rate [8.7%, 95% confidence interval (CI): 0-20.3] than those with low-risk scores (50.3%, 95% CI: 40.0-60.7; P < 0.0001). The prognostic accuracy of the classifier was validated in the internal testing (P < 0.0001) and independent validation sets (P = 0.00073). Multivariate survival analyses showed that the 4-miRNA based classifier was an independent prognostic factor, and the combination of the 4-miRNA based classifier and clinicopathological prognostic factors significantly improved the prognostic accuracy of clinicopathological prognostic factors alone. CONCLUSION: Our 4-miRNA based classifier is a reliable prognostic prediction tool for overall survival in LN-positive locoregional ESCC patients and might offer a novel probability of ESCC treatment individualization.

HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats.

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.

Genome-wide CRISPR-based gene knockout screens reveal cellular factors and pathways essential for nasopharyngeal carcinoma.

Early diagnosis of nasopharyngeal carcinoma (NPC) is difficult because of a lack of specific symptoms. Many patients have advanced disease at diagnosis, and these patients respond poorly to treatment. New treatments are therefore needed to improve the outcome of NPC. To better understand the molecular pathogenesis of NPC, here we used an NPC cell line in a genome-wide CRISPR-based knockout screen to identify the cellular factors and pathways essential for NPC (i.e. dependence factors). This screen identified the Moz, Ybf2/Sas3, Sas2, Tip60 histone acetyl transferase complex, NF-κB signaling, purine synthesis, and linear ubiquitination pathways; and MDM2 proto-oncogene as NPC dependence factors/pathways. Using gene knock out, complementary DNA rescue, and inhibitor assays, we found that perturbation of these pathways greatly reduces the growth of NPC cell lines but does not affect growth of SV40-immortalized normal nasopharyngeal epithelial cells. These results suggest that targeting these pathways/proteins may hold promise for achieving better treatment of patients with NPC.

Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial.

BACKGROUND: Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients. OBJECTIVE: This study aimed to investigate the efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI. METHODS: In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety. RESULTS: Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (n = 63) or FU group (n = 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (p = 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events. CONCLUSIONS: Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI. TRIAL REGISTRATION: Trial number: NCT03192618.

Tumor necrosis as a poor prognostic predictor on postoperative survival of patients with solitary small hepatocellular carcinoma.

BACKGROUND: Small hepatocellular carcinoma (sHCC) is a special subtype of HCC with the maximum tumor diameter ≤ 3 cm and excellent long-term outcomes. Surgical resection or radiofrequency ablation provides the greatest chance for cure; however, many patients still undergo tumor recurrence after primary treatment. To date, there is no clinical applicable method to assess biological aggressiveness in solitary sHCC. METHODS: In the current study, we retrospectively evaluated tumor necrosis of 335 patients with solitary sHCC treated with hepatectomy between December 1998 and 2010 from Sun Yat-sen University Cancer Center. RESULTS: The presence of tumor necrosis was observed in 157 of 335 (46.9%) sHCC patients. Further correlation analysis showed that tumor necrosis was significantly correlated with tumor size and vascular invasion (P = 0.026, 0.003, respectively). The presence of tumor necrosis was associated closely with poorer cancer-specific overall survival (OS) and recurrence-free survival (RFS) as evidenced by univariate (P <  0.001; hazard ratio, 2.821; 95% CI, 1.643-4.842) and multivariate analysis (P = 0.005; hazard ratio, 2.208; 95% CI, 1.272-3.833). Notably, the combined model by tumor necrosis, vascular invasion and tumor size can significantly stratify the risk for RFS and OS and improve the ability to discriminate sHCC patients' outcomes (P <  0.0001 for both). CONCLUSIONS: Our results provide evidence that tumor necrosis has the potential to be a parameter for cancer aggressiveness in solitary sHCC. The combined prognostic model may be a useful tool to identify solitary sHCC patients with worse outcomes.

Cancer cells invasion to the gastric bare area adipose tissue: a poor prognostic predictor for gastric cancer.

BACKGROUND: The relationship between gastric bare area adipose tissues invasion (GBAI) confirmed pathologically and the prognosis of gastric cancer (GC) patients is undefined. Till present, there has not been literature investigating this phenomenon. Here, we aimed at analyzing the implication of GBAI in GC. METHODS: The data of 1822 patients who underwent radical surgery between January 2000 and December 2013 at the Sun Yat-sen University Cancer Center were retrieved. Pathologically, tumor deposits (TDs) located > 5 mm from the leading edge of the primary tumor and the lymph nodes (LNs) station number 1, 2, 7, and 9 were considered GBAI. Kaplan-Meier method, log-rank test, and Cox's proportional hazards model were employed to analyze. RESULTS: Two hundred and five (11.3%) patients were pathologically diagnosed with GBAI, which was more commonly found in proximal or linitis lastica than distal GC (P < 0.001). There was significant difference in 5-year survival between patients with and without GBAI for stages IIB, IIIA, IIIB, and IIIC, respectively (P < 0.009 for IIB, IIIA, and IIIB; P = 0.021 for IIIC). Among the 205 GBAI patients, 61 had detailed radiological follow-up data in which 26 (34.7%) were found to have retroperitoneal infiltration, 27 (36.0%) had peritoneal metastasis, 10 (13.3%) had hematogenous metastasis, 16 (21.3%) had lymphatic metastasis, and 16 (21.3%) had others. CONCLUSIONS: GBAI was identified as a predictor of unfavorable prognosis for GC and was more commonly found in the proximal or linitis plastica of the stomach than in distal stomach. Retroperitoneal infiltration was one of the most commonly identified metastatic route for GC associated with GBAI after radical surgery.

Nasopharyngeal carcinoma super-enhancer-driven ETV6 correlates with prognosis.

Nasopharyngeal carcinoma (NPC) most frequently occurs in southern China and southeast Asia. Epidemiology studies link NPC to genetic predisposition, Epstein-Barr virus (EBV) infection, and environmental factors. Genetic studies indicate that mutations in chromatin-modifying enzymes are the most frequent genetic alterations in NPC. Here, we used H3K27ac chromatin immune precipitation followed by deep sequencing (ChIP-seq) to define the NPC epigenome in primary NPC biopsies, NPC xenografts, and an NPC cell line, and compared them to immortalized normal nasopharyngeal or oral epithelial cells. We identified NPC-specific enhancers and found these enhancers were enriched with nuclear factor κB (NF-κB), IFN-responsive factor 1 (IRF1) and IRF2, and ETS family members ETS1 motifs. Normal cell-specific enhancers were enriched with basic leucine zipper family members and TP53 motifs. NPC super-enhancers with extraordinarily broad and high H3K27ac signals were also identified, and they were linked to genes important for oncogenesis including ETV6. ETV6 was also highly expressed in NPC biopsies by immunohistochemistry. High ETV6 expression correlated with a poor prognosis. Furthermore, we defined the EBV episome epigenetic landscapes in primary NPC tissue.

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Targeting intestinal epithelial cell-programmed necrosis alleviates tissue injury after intestinal ischemia/reperfusion in rats.

BACKGROUND: Intestinal dysfunction, especially acute pathologies linked to intestinal ischemia/reperfusion (I/R) injury, is profoundly affected by inflammation and improper execution of cell death. Few studies have examined the efficacy of combined strategies in regulated intestinal epithelial necrosis after intestinal I/R. Here, we evaluated the functional interaction between poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1)-induced parthanatos and receptor-interacting protein 1/3 (RIP1/3) kinase-induced necroptosis in the pathophysiological course of acute ischemic intestinal injury. METHODS: Anesthetized adult male Sprague-Dawley rats were subjected to superior mesenteric artery occlusion consisting of 1.5 h of ischemia and 6 h of reperfusion. The PARP-1-specific inhibitor PJ34 (10 mg/kg) and the RIP1-specific inhibitor Necrostatin-1 (1 mg/kg) were intraperitoneally administered 30 min before the induction of ischemia. RESULTS: Intestinal I/R was found to result in PARP-1 activation and RIP1/3-mediated necrosome formation. PJ34 or Necrostatin-1 treatment significantly improved the mucosal injury, while the combined inhibition of PARP-1 and RIP1/3 conferred optimal protection of the intestine. Meanwhile, results from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay showed a decrease in intestinal epithelial cell death. Interestingly, we further showed that PARP-1 might act as a downstream signaling molecule of RIP1 in the process of I/R-induced intestinal injury and that the RIP1/PARP-1-dependent cell death signaling pathway functioned independently of caspase 3 inhibition. CONCLUSIONS: The results of our study provide a molecular basis for combination therapy that targets both pathways of regulated necrosis (parthanatos and necroptosis), to treat acute intestinal I/R-induced intestinal epithelial barrier disruption.

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury.

Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor-interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain-like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin-1. In addition, the combined treatment of necrostatin-1 and the pan-caspase inhibitor Z-VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin-1 pre-treatment reduced the necroptotic death of oxygen-glucose deprivation challenged intestinal epithelial cell-6 cells, which in turn dampened the production of pro-inflammatory cytokines (tumour necrosis factor-α and interleukin-1ß), and suppressed high-mobility group box-1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll-like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3-dependent necroptosis pathway in intestinal I/R-induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.

MIIP expression predicts outcomes of surgically resected esophageal squamous cell carcinomas.

The migration and invasion inhibitory protein (MIIP) was shown to function as a tumor suppressor gene in gliomas by inhibiting tumor cell growth, migration, and invasion. However, its role and clinical significance in esophageal squamous cell carcinoma (ESCC) have not been elucidated. We investigated the correlation of MIIP expression and clinical outcome in a group of surgically resected ESCCs. Tissue microarrays constructed of 253 surgically resected ESCC primary tumors and paired paracancerous normal esophageal epithelia were used for MIIP evaluation by immunohistochemistry. The clinical and prognostic significance of MIIP expression was analyzed statistically. The expression of MIIP expression in cancer tissues was increased significantly in comparison with the paired paracancerous normal epithelia (P < 0.001). And, MIIP expression was associated with ESCC cells' differentiation (P < 0.001). By Kaplan-Meier analysis, patients with low MIIP expression exhibited significantly improved overall survival (OS, P = 0.039) and a tendency of improved disease-free survival (DFS, P = 0.086) than those with high MIIP expression. In addition, MIIP expression could distinguish OS or DFS of patients with tumors in stage T3-4 (P = 0.020, 0.028), N0 (P = 0.008, 0.032), and stage II (P = 0.004, 0.019), as well as at lower thoracic esophagus (P = 0.024, 0.090). Multivariate analysis showed that MIIP expression was an independent prognostic factor in ESCC OS and DFS. In conclusion, MIIP expressed higher in ESCCs than in paracancerous normal esophageal epithelia and was a positive, independent prognostic factor in resected ESCCs.

Pseudoepitheliomatous hyperplasia mimicking invasive squamous cell carcinoma in extranodal natural killer/T-cell lymphoma: a report of 34 cases.

AIMS: Pseudoepitheliomatous hyperplasia (PEH) is defined as a pattern of epidermal reaction. However, it has not yet been extensively documented in extranodal natural killer/T-cell lymphoma (ENKTL). The aim of our study was to analyse a series of ENKTLs concomitant with PEH mimicking squamous cell carcinoma (SCC). METHODS AND RESULTS: We analysed 34 cases of ENKTL with PEH. In our study, the incidence of PEH was 3.8% in ENKTLs diagnosed over a 13-year period. All 34 cases presented with PEH, appearing as tongue-like projections of squamous epithelium into the underlying submucosa/dermis with variable depths and jagged borders. The keratinocytes sometimes showed a minor degree of cytological atypia, mostly in the stratum basale, and keratinocyte necrosis was absent. Atypical mitoses and a high nuclear/cytoplasmic ratio were absent. The submucosa and the squamous cell cords were also permeated by atypical lymphocytes. CONCLUSIONS: ENKTL can be associated with PEH, and the atypical lymphoid cell population can be highly subtle, and therefore may be easily mistaken for SCC, leading to inappropriate therapy. A correct diagnosis requires awareness and recognition of this pitfall by recognizing the associated conditions listed above, which distinguish PEH from SCC.

The prognostic significance of tyrosine-protein phosphatase nonreceptor type 12 expression in nasopharyngeal carcinoma.

Tyrosine-protein phosphatase nonreceptor type 12 (PTPN12) has been proposed to predict prognosis of various human cancers. However, the clinicopathologic and prognostic significance of PTPN12 expression in NPC has not yet been elucidated. The objective of this study was to investigate the clinicopathological and prognostic implication of PTPN12 in nasopharyngeal carcinoma (NPC) patients. Protein expression levels of PTPN12 were explored by semiquantitative immunohistochemical staining on archival formalin-fixed, paraffin-embedded pathological specimens consisting of 203 NPCs, and 40 normal nasopharyngeal mucosa tissues. Receiver operating characteristic (ROC) curve analysis was employed to determine the cutoff score of PTPN12 expression in NPCs. The PTPN12 immunohistochemical staining results were then correlated with various clinicopathological features and patients' prognosis using various statistical models. Our results showed that decreased expression of PTPN12 was more frequently observed in NPC tissues compared with the normal nasopharyngeal mucosa. Further correlation analyses indicated that the decreased expression of PTPN12 was significantly associated with tumor T classification, N classification, distant metastasis, and clinical stage in NPCs (P < 0.05). Univariate analysis showed a significant association between the decreased expression of PTPN12 and adverse overall survival and disease-free survival (P < 0.05). More importantly, multivariate analysis identified the PTPN12 expression in NPC as an independent prognostic factor. The decrease expression of PTPN12 might be important in conferring a more aggressive behavior in NPC. Thus, PTPN12 expression may be used as a novel independent prognostic biomarker for patients with NPC.

The prognostic significance of lymphovascular invasion in patients with resectable gastric cancer: a large retrospective study from Southern China.

BACKGROUND: The focus of this study was to assess the impact of lymphovascular invasion (LVI) on both the recurrence of cancer and the long-term survival of Chinese patients with resectable gastric cancer (GC). METHODS: A retrospective analysis of the clinicopathological data for 1148 GC patients who had undergone gastrectomy with regional lymphadenectomy was performed. The primary objective was to assess the correlation between LVI and post-surgery outcomes for each patient. This was done by routine H & E staining for LVI on patients' disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: LVI was detected in 404 (35.2%) of the 1148 GC patients. The presence of LVI was significantly correlated with the level of CA19-9, the tumor size, the Lauren classification, tumor differentiation, gastric wall invasive depth, lymph node involvement, distant metastasis and an advanced TNM stage. There was a lower DFS and DSS in the patients with LVI as compared to the patients without LVI. A multivariate analysis also identified LVI as an independent prognostic factor of both DSS and DFS. CONCLUSIONS: The presence of LVI is a risk factor for the recurrence of cancer and an independent indicator of a poor outcome in GC patients following surgery. The LVI status should be taken into consideration when determining the best approach for the treatment of the individual.

The prognostic effect of perineural invasion in esophageal squamous cell carcinoma.

BACKGROUND: Perineural invasion (PNI) is correlated with adverse survival in several malignancies, but its significance in esophageal squamous cell carcinoma (ESCC) remains to be clearly defined. The objective of this study was to determine the association between PNI status and clinical outcomes. METHODS: We retrospectively evaluated the PNI of 433 patients with ESCC treated with surgery between 2000 and 2007 at a single academic center. The resulting data were analyzed using Spearman's rank correlation, the Kaplan-Meier method, Cox proportional hazards regression modeling and Harrell's concordance index (C-index). RESULTS: PNI was identified in 209 of the 433 (47.7%) cases of ESCC. The correlation analysis demonstrated that PNI in ESCC was significantly correlated with tumor differentiation, infiltration depth, pN classification and stage (P < 0.05). The five-year overall survival rate was 0.570 for PNI-negative tumors versus 0.326 for PNI-positive tumors. Patients with PNI-negative tumors exhibited a 1.7-fold increase in five-year recurrence-free survival compared with patients with PNI-positive tumors (0.531 v 0.305, respectively; P < 0.0001). In the subset of patients with node-negative disease, PNI was evaluated as a prognostic predictor as well (P < 0.05). In the multivariate analysis, PNI was an independent prognostic factor for overall survival (P = 0.027). The C-index estimate for the combined model (PNI, gender and pN status) was a significant improvement on the C-index estimate of the clinicopathologic model alone (0.739 v 0.706, respectively). CONCLUSIONS: PNI can function as an independent prognostic factor of outcomes in ESCC patients, and the PNI status in primary ESCC specimens should be considered for therapy stratification.