Cdc7 kinase is required for postnatal brain development.

The evolutionally conserved Cdc7 kinase plays crucial roles in initiation of DNA replication as well as in other chromosomal events. To examine the roles of Cdc7 in brain development, we have generated mice carrying Cdc7 knockout in neural stem cells by using Nestin-Cre. The Cdc7Fl/Fl NestinCre mice were born, but exhibited severe growth retardation and impaired postnatal brain development. These mice exhibited motor dysfunction within 9 days after birth and did not survive for more than 19 days. The cerebral cortical layer formation was impaired, although the cortical cell numbers were not altered in the mutant. In the cerebellum undergoing hypoplasia, granule cells (CGC) decreased in number in Cdc7Fl/F l NestinCre mice compared to the control at E15-18, suggesting that Cdc7 is required for DNA replication and cell proliferation of CGC at mid embryonic stage (before embryonic day 15). On the other hand, the Purkinje cell numbers were not altered but its layer formation was impaired in the mutant. These results indicate differential roles of Cdc7 in DNA replication/cell proliferation in brain. Furthermore, the defects of layer formation suggest a possibility that Cdc7 may play an additional role in cell migration during neural development.

[A 30-Month Survival Case of Undifferentiated Carcinoma of the Duodenum Treated by Pancreaticoduodenectomy].

The patient was an elderly man in his early 80s who was admitted to our hospital due to anemia and tarry stools. An upper gastrointestinal endoscopy revealed a type 2 tumor in the second portion of the duodenum. An endoscopic biopsy revealed poorly differentiated adenocarcinoma. We performed a pancreaticoduodenectomy because neither lymphadenopathy nor distant metastases were found. Macroscopic findings revealed that the lesion was mainly in the second portion of the duodenum, and there was no evidence of invasion of the main pancreatic duct, the bile duct, or the ampulla of Vater. Histologically, the tumor was composed of atypical cells with polymorphic or spindle-shaped nuclei proliferating in a scattered fashion, and immunohistological examinations showed weakly positive results for cytokeratin(CK)AE1/AE3 and CK20 and positive results for vimentin but negative results for CK7. The tumor was diagnosed as undifferentiated carcinoma of the duodenum(pT4N0M0, pStage ⅡB). The patient recovered enough to be discharged and was followed up without postoperative adjuvant chemotherapy. He maintained recurrence-free survival for 27 months, after which lymph node and lung metastases reoccurred. This is a rare case of undifferentiated carcinoma of the duodenum treated by curative resection with a relatively favorable prognosis.

Phosphacan acts as a repulsive cue in murine and rat cerebellar granule cells in a TAG-1/GD3 rafts-dependent manner.

Phosphacan, a chondroitin sulfate proteoglycan, is a repulsive cue of cerebellar granule cells. This study aims to explore the molecular mechanism. The glycosylphosphatidylinositol-anchored neural adhesion molecule TAG-1 is a binding partner of phosphacan, suggesting that the repulsive effect of phosphacan is possibly because of its interaction with TAG-1. The repulsive effect was greatly reduced on primary cerebellar granule cells of TAG-1-deficient mice. Surface plasmon resonance analysis confirmed the direct interaction of TAG-1 with chondroitin sulfate C. On postnatal days 1, 4, 7, 11, 15, and 20 and in adulthood, phosphacan was present in the molecular layer and internal granular layer, but not in the external granular layer. In contrast, transient TAG-1 expression was observed exclusively within the premigratory zone of the external granular layer on postnatal days 1, 4, 7, and 11. Boyden chamber cell migration assay demonstrated that phosphacan exerted its repulsive effect on the spontaneous and brain-derived neurotrophic factor (BDNF)-induced migration of cerebellar granule cells. The BDNF-induced migration was inhibited by MK-2206, an Akt inhibitor. The pre-treatment with a raft-disrupting agent, methyl-ß-cyclodextrin, also inhibited the BDNF-induced migration, suggesting that lipid rafts are involved in the migration of cerebellar granule cells. In primary cerebellar granule cells obtained on postnatal day 7 and cultured for 7 days, the ganglioside GD3 and TAG-1 preferentially localized in the cell body, whereas the ganglioside GD1b and NB-3 localized in not only the cell body but also neurites. Pre-treatment with the anti-GD3 antibody R24, but not the anti-GD1b antibody GGR12, inhibited the spontaneous and BDNF-induced migration, and attenuated BDNF-induced Akt activation. These findings suggest that phosphacan is responsible for the repulsion of TAG-1-expressing cerebellar granule cells via GD3 rafts to attenuate BDNF-induced migration signaling.

Laparoscopic delayed and interval appendectomy in the workstyle reform era.

PURPOSE: Excessive working hours have been reported to contribute to burnout among surgeons. In Japan, work-style reform is a problem that needs immediate attention. Acute appendectomy, which often occurs at nighttime, is one of the most common emergency surgeries. The feasibility of delayed and interval appendectomy remains to be investigated. METHODS: Two hundred forty-five consecutive patients who underwent laparoscopic appendectomy in our hospital were enrolled. They were divided into three groups: emergency appendectomy (immediate surgery, soon after the diagnosis [EA group], n = 153), delayed appendectomy (surgery during daytime the following day [DA group], n = 38) and interval appendectomy (antibiotics treatment followed by selective surgery three to four months later [IA group], n = 54). The clinical background and surgical outcomes were compared. Next, the residents' excess working time per month was calculated. RESULTS: The surgical outcomes (operation time, blood loss, length of hospital stay, postoperative complications) were similar between the EA and DA groups. However, no DA was performed during nighttime hours whereas 15.7% of EA was performed during nighttime hours (p = 0.0007). The surgical outcomes of the IA group were also comparable. The residents' excess working time declined following the introduction of DA and workstyle reform. CONCLUSION: Delayed and interval laparoscopic appendectomy are feasible, and can be performed to promote workstyle reform without impairing patient safety.

Impact of a 7.5-Fr Pancreatic Stent for Preventing Pancreatic Fistula after Pancreaticoduodenectomy.

INTRODUCTION: Pancreatic duct stents are widely used to reduce the incidence of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD); however, small stents may cause adverse effects, such as occlusion. Recently, we have tried placing a 7.5-Fr pancreatic duct stent to achieve more effective exocrine output from the pancreas; however, the association between pancreatic duct stent size and POPF remains unknown. METHODS: Sixty-five patients with soft pancreatic texture who underwent PD were retrospectively analyzed. After dividing the pancreas, a pancreatic duct stent (stent size 4.0 in 29 patients, 5.0 in 18, and 7.5 Fr in 18) was placed in the main pancreatic duct. RESULTS: Twenty-five of 65 patients with soft pancreatic texture (38.5%) developed POPF. POPF became less frequent as the pancreatic duct stent size increased (p = 0.003). The factors associated with POPF development were a 7.5-Fr pancreatic duct stent (p = 0.005), 5.0-Fr pancreatic duct stent (p = 0.031), and male sex (p = 0.008). Pancreatic duct stent size and pancreatic duct diameter did not differ between the POPF and non-POPF groups. DISCUSSION/CONCLUSIONS: In patients with a soft pancreas, the placement of a 7.5-Fr pancreatic duct stent may reduce the incidence of POPF.

Efficacy of neoadjuvant chemotherapy in patients with high-risk resectable colorectal liver metastases.

BACKGROUND: The role of preoperative neoadjuvant chemotherapy (NAC) in patients with resectable colorectal liver metastases (CRLM) remains undetermined. This study aimed to assess the efficacy of NAC in patients with resectable CRLM, especially in high-risk subgroups for recurrence, with special reference to synchronicity and the CRLM grade in the Japanese classification system. METHODS: A retrospective analysis of a multi-institutional cohort who was diagnosed with resectable CRLM was performed. CRLM was classified into three grades (A, B, and C) according to the combination of H stage (H1: ≤ 4 lesions and ≤ 5 cm, H2: ≥ 5 lesions or > 5 cm, H3: ≥ 5 lesions and > 5 cm), nodal status of the primary tumor (pN0/1: ≤ 3 metastases, pN2: ≥ 4 metastases), and the presence of resectable extrahepatic metastases. RESULTS: Among 222 patients with resectable CRLM, 97 (43.7%) had synchronous CRLM. The surgical failure-free survival (SF-FS) of patients with synchronous CRLM (without NAC) was significantly worse than that of patients with metachronous CRLM (P = 0.0264). The SF-FS of patients with Grade B/C was also significantly worse than that of Grade A (P = 0.0058). Among the 53 patients with synchronous and Grade B/C CRLM, 31 were assigned to NAC, and all of them underwent liver surgery. In this high-risk subgroup, the SF-FS and OS in the NAC group were significantly better than those in the upfront surgery group (P < 0.0001 and P = 0.0004, respectively). CONCLUSIONS: Patients with synchronous and Grade B/C CRLM could be good candidates for indication of NAC.

Mitochondrial expression of the DNA repair enzyme OGG1 improves the prognosis of pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: 8-Hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and causes transversion mutations and carcinogenesis. 8-OHdG is excision repaired by 8-OHdG DNA glycosylase 1 (OGG1), which is classified as nuclear and mitochondrial subtypes. We aimed to clarify the role of OGG1 in pancreatic ductal adenocarcinoma (PDAC). METHODS: Ninety-two patients with PDAC who had undergone surgical resection at multiple institutions were immunohistochemically analyzed. The OGG1 and 8-OHdG expression levels were scored using the Germann Immunoreactive Score. The cutoff values of OGG1, as well as that of 8-OHdG, were determined. RESULTS: The low nuclear OGG1 expression group (n = 41) showed significantly higher carbohydrate antigen (CA)19-9 (p = 0.026), and higher s-pancreas antigen (SPAN)-1 (p = 0.017) than the high expression group (n = 51). Nuclear OGG1 expression has no effect on the prognosis. The low mitochondrial OGG1 expression group (n = 40) showed higher CA19-9 (p = 0.041), higher SPAN-1 (p = 0.032), and more histological perineural invasion (p = 0.037) than the high expression group (n = 52). The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox proportional hazards model revealed that low mitochondrial OGG1 expression is an independent risk factor of the PDAC prognosis. OGG1 expression was negatively correlated with 8-OHdG expression (p = 0.0004), and high 8-OHdG expression shortened the recurrence-free survival of patients with PDAC. CONCLUSIONS: Low mitochondrial OGG1 expression might aggravate the PDAC prognosis.

Correction: Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

[This corrects the article DOI: 10.1371/journal.pgen.1005778.].

Laparoscopic spleen-preserving distal pancreatectomy for a solid-cystic intraabdominal desmoid tumor at a gastro-pancreatic lesion: a case report.

BACKGROUND: We report a case of an intraabdominal desmoid tumor that occurred at a gastro-pancreatic lesion with spontaneous cystic features, and present the successful laparoscopic resection of the tumor. CASE PRESENTATION: A 20-mm retroperitoneal cystic mass with a solid component was found adjacent to the stomach and pancreatic body in a 52-year-old woman with no history of familial adenomatous polyposis. Laparoscopic spleen-preserving distal pancreatectomy with wedge resection of the stomach was performed, and complete resection was achieved without intraoperative and postoperative complications. Histopathological examination by immunohistochemistry enabled diagnosis of a desmoid tumor that had originated from the stomach and invaded the pancreatic parenchyma with a spontaneous cystic change. We herein report an extremely rare case of an intraabdominal desmoid tumor with a spontaneous cystic change. CONCLUSION: Regardless of its rarity, desmoid tumor should be included in the preoperative differential diagnosis of a cystic intraabdominal mass, and laparoscopic function-preserving surgery may be an optimal treatment option.

[Immune Response on Outcomes in Hepatocellular Carcinoma].

Recently, immune checkpoint inhibitors(ICI)has been developed considerably. ICI has already been approved for malignant melanoma, lung cancer and renal cancer. We expected ICI to be taken for many cancers in the future. Therefore, the development of biomarker for them are needed. The recent large phase Ⅲ study IMbrave 150 evaluated atezolizumab plus bevacizumab vs sorafenib as the first treatment for patients with unresectable hepatocellular carcinoma(HCC). IMbrave 150 demonstrated statistically significant and clinically meaningful improvements in both OS and RFS for atezolizumab plus bevacizumab compared with sorafenib in HCC patients. A paradigm shift in the treatment of unresectable HCC is about to occur. In this article, we discussed the significance and biomarkers of tumor immunity in HCC microenvironment.

Significance of bile culture surveillance for postoperative management of pancreatoduodenectomy.

BACKGROUND: The management of infectious complications is important in pancreatoduodenectomy (PD). We sought to determine the significance of preoperative surveillance bile culture in perioperative management of PD. METHODS: This study enrolled 69 patients who underwent PD for malignant tumors at a single institute between 2014 and 2017. Surveillance bile culture was performed before or during surgery. Correlations between the incidence of infectious postoperative complications and clinicopathological parameters, including bile cultures, were evaluated. RESULTS: Preoperative positive bile culture was confirmed in 28 of 51 patients (55%). Bile culture was positive in 27 of 30 cases (90%) with preoperative biliary drainage, and 1 of 21 cases (5%) without drainage (p < 0.01). Preoperative isolated microorganisms in bile were consistent with those detected in surgical sites in 11 of 27 cases (41%). Cases with positive multi-drug-resistant bacteria in preoperative bile culture showed significantly higher incisional SSI after PD (p = 0.01). The risk factors for the incidence of organ/space SSI were soft pancreatic texture (p = 0.01) and smoking history (p = 0.02) by multivariate analysis. Preoperative positive bile culture was neither associated with organ/space SSI nor overall postoperative complications. CONCLUSIONS: Preoperative surveillance bile culture is useful for the management of wound infection, prediction of causative pathogens for infectious complications, and the selection of perioperative antibiotic prophylaxis.

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

Serial mutational tracking in surgically resected locally advanced colorectal cancer with neoadjuvant chemotherapy.

BACKGROUND: We aim to investigate the utility of serial gene mutation tracking for locally advanced CRC in those who underwent curative resection following neoadjuvant chemotherapy. METHODS: We prospectively collected 10 locally advanced CRC cases for which curative resection was performed following preoperative neoadjuvant chemotherapy. Tissues from the primary tumour, distant metastatic tumours, and blood plasma were obtained during serial treatment. Comprehensive mutation analysis of 47 cancer-associated genes was performed using a pre-designed gene panel and next-generation sequencing. RESULTS: All cases showed a partial response to neoadjuvant chemotherapy, and pathological R0 resection was accomplished. In primary tumours, non-synonymous mutations were detected at between 1 and 14 sites before chemotherapy and at between 1 and 2 sites after. Founder mutations were precisely detected in blood plasma and metastatic tumours during longitudinal treatment. CONCLUSIONS: Serial mutational analysis indicated that subclonal selection occurs during chemotherapy and that plasma can substitute for tumourous tissue in mutational analysis for drug selection and treatment decisions.

A BTB-ZF protein, ZNF131, is required for early B cell development.

Members of the BTB-ZF transcription factor family play important roles in lymphocyte development. During T cell development, ZNF131, a BTB-ZF protein, is critical for the double-negative (DN) to double-positive (DP) transition and is also involved in cell proliferation. Here, we report that knockout of Znf131 at the pre-pro-B cell stage in mb1-Cre knock-in mouse resulted in defect of pro-B to pre-B cell transition. ZNF131 was shown to be required for efficient pro-B cell proliferation as well as for immunoglobulin heavy chain gene rearrangement that occurs in the proliferating pro-B cells. We speculate that inefficient gene rearrangement may be due to loss of cell proliferation, since cell cycle progression and immunoglobulin gene rearrangement, which would occur in a mutually exclusive manner, may be interconnected or coupled to avoid occurrence of genomic instability. ZNF131 suppresses expression of Cdk inhibitor, p21cip1, and that of pro-apoptotic factors, Bax and Puma, targets of p53, to facilitate cell cycle progression and suppress unnecessary apoptosis, respectively, of pro-B cells. There results demonstrate the essential roles of ZNF131 in coordinating the B cell differentiation and proliferation.

Identification of UHRF2 as a Negative Regulator of Epithelial-Mesenchymal Transition and Its Clinical Significance in Esophageal Squamous Cell Carcinoma.

OBJECTIVE: The involvement of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Here, we aimed to identify EMT-related genes associated with TGF-ß in ESCC and to clarify the role of these genes in the progression of ESCC. METHODS: EMT-related genes associated with TGF-ß expression were identified in patients with ESCC using microarray analysis and public datasets. The effects of ubiquitin-like with PHD and ring finger domains 2 (UHRF2) expression were analyzed in ESCC cell lines. Cell proliferation and invasion were measured using MTT and invasion assays, respectively. UHRF2 mRNA expression was also analyzed in 75 ESCC specimens to determine the clinical significance of UHRF2 in ESCC. RESULTS: Treatment of ESCC cell lines with TGF-ß increased UHRF2 expression. UHRF2 overexpression increased CDH1 (E-cadherin) expression and decreased invasive capacity. The 75 ESCC specimens were divided into the UHRF2 high-expression group (n = 61) and the UHRF2 low-expression group (n = 14). Low UHRF2 expression was significantly correlated with vascular invasion (p = 0.034) and was an independent prognostic factor for poor prognosis (p = 0.005). CONCLUSION: UHRF2 may be a negative regulator of EMT and a novel prognostic biomarker for ESCC.

Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC). METHODS: The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro. RESULTS: In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells. CONCLUSIONS: Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.

Altered Expression of Hippo Signaling Pathway Molecules in Intrahepatic Cholangiocarcinoma.

OBJECTIVE: MOB1, a core component of the Hippo signaling pathway, suppresses cell proliferation, and MOB1 liver conditional knockout mice develop intrahepatic cholangiocarcinoma (ICC). However, its clinical significance in human ICC has not been established. The aim of this study was to characterize protein levels and the role of Hippo and TGF pathways in ICCs. METHODS: The protein levels of yes-associated protein 1 (YAP1), MOB1, Smad2, and TGFß2 in 88 ICC cases were analyzed. Protein level was graded by a scoring system; then, the clinicopathological factors, including prognosis, were analyzed based on protein level. RESULTS: Nuclear overexpression of YAP1 was seen in 28 cases (31.8%), and it was significantly associated with a poor overall survival rate (p = 0.01). MOB1 expression decreased in 42 cases (47.7%) and was associated with a poor overall survival rate (p = 0.02). SMAD2 nuclear localization was significantly correlated with a high YAP1 level independent of TGFß2. Multivariate analysis revealed that a high YAP1 level, a low MOB1 level, and lymphatic permeation were independent risk factors for overall survival. CONCLUSIONS: These results showed that key components of the Hippo signaling pathway are aberrantly expressed and associated with the malignant potential of human ICC.

The Expression of CCAT2, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers.

Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC.

BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells.

Many members of the BTB-ZF family have been shown to play important roles in lymphocyte development and function. The role of zinc finger Znf131 (also known as Zbtb35) in T cell lineage was elucidated through the production of mice with floxed allele to disrupt at different stages of development. In this article, we present that Znf131 is critical for T cell development during double-negative to double-positive stage, with which significant cell expansion triggered by the pre-TCR signal is coupled. In mature T cells, Znf131 is required for the activation of effector genes, as well as robust proliferation induced upon TCR signal. One of the cyclin-dependent kinase inhibitors, p21(Cip1) encoded by cdkn1a gene, is one of the targets of Znf131. The regulation of T cell proliferation by Znf131 is in part attributed to its suppression on the expression of p21(Cip1).

Overexpression of CXCR7 Is a Novel Prognostic Indicator in Gastric Cancer.

BACKGROUND: Among several candidate genes that promote peritoneal dissemination extracted by comprehensive expression analysis of both in vivo selected metastatic cell lines and patients with gastric cancer, we focused on the chemokine (C-X-C motif) receptor (CXCR7) and explored its clinicopathological significance in gastric cancer. METHODS: CXCR7 expression was evaluated by microarray data in the Singapore cohort (n = 196) and by immunohistochemistry and reverse transcription quantitative real-time polymerase chain reaction in the Japanese cohort (n = 195). The biological function of CXCR7 in gastric cancer was explored using gene set enrichment analysis (GSEA). RESULTS: CXCR7 expression was upregulated in tumor tissues compared to normal tissues. High CXCR7 mRNA expression was associated with peritoneal dissemination and poor prognosis in the Singapore cohort. Consistent with this, the high CXCR7 mRNA expression group showed significantly poorer prognosis and a more aggressive disease course than the low expression group in the Japanese cohort. High CXCR7 mRNA expression and peritoneal dissemination were clinically relevant. GSEA revealed that CXCR7 was significantly enriched in gene expression signatures associated with tumor progression. CONCLUSIONS: CXCR7 may be a prognostic indicator and therapeutic target for gastric cancer with peritoneal dissemination.