Optical genome mapping identifies clinically relevant genomic rearrangements in prostate cancer biopsy sample.

BACKGROUND: Prostate cancer (PCa) is characterized by complex genomic rearrangements such as the ETS oncogene family fusions, yet the clinical relevance is not well established. While paneled genetic tests of DNA repair genes are recommended in advanced PCa, conventional genomic or cytogenetic tools are not ideal for genome-wide screening of structural variations (SVs) such as balanced translocation due to cost and/or resolution issues. METHODS: In this study, we tested the feasibility of whole-genome optical genomic mapping (OGM), a newly developed platform for genome-wide SV analysis to detect complex genomic rearrangements in consecutive unselected PCa samples from MRI/US-fusion targeted biopsy. RESULTS: We tested ten samples, and nine (90%) passed quality check. Average mapping rate and coverage depth were 58.1 ± 23.7% and 157.3 ± 97.7×, respectively (mean ± SD). OGM detected copy number alterations such as chr6q13 loss and chr8q12-24 gain. Two adjacent tumor samples were distinguished by inter/intra-chromosomal translocations, revealing that they're from the same ancestor. Furthermore, OGM detected large deletion of chr13q13.1 accompanied by inter-chromosomal translocation t(13;20)(q13.1;p13) occurring within BRCA2 gene, suggesting complete loss of function. CONCLUSION: In conclusion, clinically relevant genomic SVs were successfully detected in PCa samples by OGM. We suggest that OGM can complement panel sequencing of DNA repair genes BRCA1/2 or ATM in high-risk PCa.

Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.

Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.

Imaging Features of Gadoxetic Acid-enhanced and Diffusion-weighted MR Imaging for Identifying Cytokeratin 19-positive Hepatocellular Carcinoma: A Retrospective Observational Study.

Purpose To determine the preoperative magnetic resonance (MR) imaging findings potentially most useful for predicting cytokeratin 19 (CK19)-positive hepatocellular carcinoma (HCC) and to evaluate the prognosis after curative resection in patients with a single HCC lesion positive for CK19 compared with patients with HCC who are negative for CK19. Materials and Methods The institutional review board approved this study and waived the requirement for informed consent. Two hundred four patients with CK19-negative HCC and 38 with CK19-positive HCC who underwent curative resection after gadoxetic acid-enhanced and diffusion-weighted MR imaging were retrospectively evaluated in a single institution. Two radiologists evaluated preoperative findings at MR imaging. Significant findings for differentiating the two groups were identified at univariate and multivariate analyses. By using receiver operating characteristic analysis, the optimal cut-off values for quantitative variables were determined. Recurrence-free survival rates after surgery were also compared between groups. Results At multivariate analysis, irregular tumor margin (P = .024), arterial rim enhancement (P < .001), lower tumor-to-liver signal intensity (SI) ratio on hepatobiliary phase (HBP) images (≤0.522; P = .01), and lower tumor-to-liver apparent diffusion coefficient (ADC) ratio (≤0.820; P < .001) were independent significant factors to predict CK19-positive HCC. When three of these four criteria were combined, 63.2% (24 of 38; 95% confidence interval: 46.0%, 78.2%) of CK19-positive HCCs were identified with a specificity of 90.7% (185 of 204; 95% confidence interval: 46.0%, 78.2%). When all four criteria were satisfied, specificity was 99.5% (203 of 204; 95% confidence interval: 97.3%, 100%). Recurrence-free survival rates were significantly lower in patients with CK19-positive HCCs compared with those with CK19-negative HCCs after curative resection (63.9% vs 90.0% at 1 year, 63.9% vs 79.9% at 2 years, and 54.8% vs 70.2% at 3 years, P = .001 by log-rank test). Conclusion At gadoxetic acid-enhanced and diffusion-weighted MR imaging, irregular margin, arterial phase rim enhancement, lower tumor-to-liver ADC ratio, and lower tumor-to-liver SI ratio at HBP imaging may be helpful to predict CK19-positive HCC with early recurrence (<2 years) after curative resection. © RSNA, 2017 Online supplemental material is available for this article.

Preoperative gadoxetic acid-enhanced MRI for predicting microvascular invasion in patients with single hepatocellular carcinoma.

BACKGROUND & AIMS: This study aimed to identify preoperative magnetic resonance (MR) imaging biomarkers for predicting microvascular invasion (MVI), to determine their diagnostic performance and to evaluate whether they are associated with early recurrence after surgery for single hepatocellular carcinoma (HCC). METHODS: The study included 197 patients with surgically resected HCC (≤5cm) who underwent preoperative gadoxetic acid-enhanced MR imaging. Significant MR imaging findings for predicting MVI were identified by univariate and multivariate analyses. Early recurrence rates (<2years) were analyzed with respect to significant imaging findings for predicting MVI. RESULTS: Three MR imaging features were independently associated with MVI: arterial peritumoral enhancement (odds ratio [OR]=5.184; 95% confidence interval [CI]: 2.228, 12.063; p<0.001), non-smooth tumor margin (OR=3.555; 95% CI: 1.627, 7.769; p=0.001), and peritumoral hypointensity on hepatobiliary phase (HBP) (OR=4.705; 95% CI: 1.671, 13.246; p=0.003). When two of three findings were combined, the specificity was 92.5% (124/134). When all three findings were satisfied, the specificity was 99.3% (133/134). Early recurrence rates were significantly higher in patients with single HCC, with two or three significant MR imaging findings, compared to those with none (27.9% vs. 12.6%, respectively, p=0.030). CONCLUSIONS: A combination of two or more of the following; arterial peritumoral enhancement, non-smooth tumor margin, and peritumoral hypointensity on HBP, can be used as a preoperative imaging biomarker for predicting MVI, with specificity >90%, and is associated with early recurrence after surgery of single HCC. Lay summary: A combination of two or more of the following; arterial peritumoral enhancement, non-smooth tumor margin, and peritumoral hypointensity on hepatobiliary phase, can be used as a preoperative imaging biomarker for predicting microvascular invasion, with specificity >90%, and is associated with early recurrence after curative resection of single HCC.

Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase.

UNLABELLED: Hepatocyte chromosome polyploidization is an important feature of liver development and seems to be required for response to liver stress and injury signals. However, the question of how polyploidization can be tightly regulated in liver growth remains to be answered. Using a conditional knockout mouse model, liver-specific depletion of Ssu72 protein phosphatase was found to result in impairment in regulation of polyploidization. Interestingly, the aberrant polyploidization in Ssu72-depleted mice was associated with impaired liver damage response and increased markers of liver injury and seemed to mimic the phenotypic features of liver diseases such as fibrosis, steatosis, and steatohepatitis. In addition, depletion of Ssu72 caused deregulation of cell cycle progression by overriding the restriction point of the cell cycle and aberrantly promoting DNA endoreplication through G2 /M arrest. CONCLUSION: Ssu72 plays a substantial role in the maintenance of hepatic chromosome homeostasis and would allow monitoring of liver function.

Clinicopathological characteristics of KIT and protein kinase C-δ expression in adenoid cystic carcinoma: comparison with chromophobe renal cell carcinoma and gastrointestinal stromal tumour.

AIMS: KIT overexpression is frequently observed in adenoid cystic carcinomas (AdCCs), chromophobe renal cell carcinomas (ChRCCs), and gastrointestinal stromal tumours (GISTs). Persistent KIT activation has been reported to be mediated by protein kinase C (PKC)-δ in a subset of colon cancers with wild-type KIT overexpression, and by PKC-θ in GISTs with mutant KIT overexpression. To elucidate the clinical implications of PKC-δ and PKC-θ expression in KIT-expressing tumours, we investigated the expression of KIT, PKC-δ and PKC-θ in AdCCs and ChRCCs in comparison with GISTs. METHODS AND RESULTS: KIT expression, PKC-δ expression and PKC-θ expression were analysed in whole sections from 41 AdCCs, 40 ChRCCs and 56 GISTs by immunohistochemistry. Membranous expression of KIT was found in 34 AdCCs and all ChRCCs, whereas cytoplasmic expression of KIT was found in 46 GISTs. In AdCCs, PKC-δ expression was associated with histological grade (P = 0.049), lymphovascular invasion (P = 0.004), perineural invasion (P = 0.002), and KIT positivity (P = 0.002). PKC-δ positivity was associated with shorter relapse-free survival (RFS) (P = 0.017) and a tendency for there to be shorter overall survival (OS) (P = 0.090) in patients with AdCCs. No clinicopathological associations were observed between PKC-δ and KIT expression in ChRCCs. In GISTs, PKC-θ expression was associated with higher mitotic count (P = 0.011) and high grade according to the modified National Institutes of Health criteria (P < 0.001). PKC-θ positivity was associated with shorter RFS (P = 0.016) and a tendency for there to be shorter OS (P = 0.051) in patients with GISTs. CONCLUSIONS: PKC-δ expression is associated with KIT expression and the prognosis of patients with AdCCs, suggesting that PKC-δ may be a potential therapeutic target for AdCCs.

Histologic purity of signet ring cell carcinoma is a favorable risk factor for lymph node metastasis in poorly cohesive, submucosa-invasive early gastric carcinoma.

BACKGROUND: The prediction of biologic behavior of poorly cohesive early gastric carcinoma (EGC) is an important issue in the selection of the treatment modality. To elucidate the risk factors for lymph node metastasis (LNM) of poorly cohesive EGC, we focused on the histologic purity of the poorly cohesive component and evaluated the impact of this factor on LNM. METHODS: We divided poorly cohesive EGC into (1) pure signet ring cell (SRC) carcinoma, which was defined as composed only of signet ring cells or poorly cohesive cells and (2) mixed SRC carcinoma, defined as poorly cohesive carcinoma with minor tubular components. We reviewed the clinicopathologic features, including age, sex, location, size, depth, lymphovascular invasion (LVI), LNM, ulceration, and intestinal metaplasia between the two groups in a large series of poorly cohesive, submucosa-invasive EGC (n = 317). RESULTS: LNM was found in 58 cases (18.3 %). Mixed SRC carcinoma histologic type (p < 0.001), larger tumor size (more than 2 cm) (p = 0.012), and the presence of LVI (p < 0.001) were associated with LNM. Pure SRC carcinomas accounted for 56.2 % (178/317) of the cases. Fourteen pure SRC carcinomas (7.8 %) showed LNM, whereas 44 mixed SRC carcinomas (31.9 %) exhibited LNM (p < 0.001). On multivariate logistic regression, the presence of LVI (odds ratio 6.737; 95 % confidence interval 2.714-16.720; p < 0.001) and mixed SRC carcinoma histologic type (odds ratio 4.674; 95 % confidence interval 2.370-9.216; p < 0.001) were independent predictors of LNM in poorly cohesive, submucosa-invasive EGC. CONCLUSIONS: The presence of a tubular component in SRC carcinoma was a risk factor for LNM in poorly cohesive, submucosa-invasive EGC. On the basis of this finding, we propose that the presence of a minor tubular component or the purity of the poorly cohesive/SRC carcinoma component should be reported in daily pathologic practice.

Expression of cancer-associated fibroblast-related proteins differs between invasive lobular carcinoma and invasive ductal carcinoma.

Cancer-associated fibroblasts (CAFs) are classified into various functional subtypes such as fibroblast activation protein-α (FAP-α), fibroblast specific protein-1 (FSP-1), platelet-derived growth factor receptor-α (PDGFR-α), and PDGFR-ß. In this study, we compared the expression of CAF-related proteins in invasive lobular carcinoma (ILC) with those in invasive carcinoma of no special type (NST) and assessed the implications of the differences observed. Using tissue microarrays of 104 ILC and 524 invasive carcinoma (NST) cases, immunohistochemistry for CAF-related proteins [podoplanin, prolyl 4-hydroxylase, FAP-α, FSP-1/S100A4, PDGFR-α, PDGFR-ß, and chondroitin sulfate proteoglycan (NG2)] was conducted. In invasive carcinoma (NST), tumor cells expressed a high level of PDGFR-α, whereas ILC tumor cells expressed high levels of podoplanin, prolyl 4-hydroxylase, FAP-α, and FSP-1/S100A4. In stromal cells of invasive carcinoma (NST), high expression levels of prolyl 4-hydroxylase, PDGFR-α, and NG2 were observed, whereas ILC stromal cells expressed high levels of FAP-α, FSP-1/S100A4, and PDGFR-ß. In ILC, tumoral FSP-1/S100A4 positivity was associated with higher Ki-67 labeling index (p = 0.010) and non-luminal A type cancer (p = 0.014). Stromal PDGFR-α positivity was associated with lymph node metastasis (p = 0.011). On survival analysis of entire cases, tumoral FSP-1/S100A4 positivity (p = 0.002), stromal podoplanin positivity (p = 0.041), and stromal FSP-1/S100A4 negativity (p = 0.041) were associated with shorter disease-free survival; only tumoral FSP-1/S100A4 positivity (p = 0.044) was associated with shorter overall survival. In ILC, the expression of FAP-α and FSP-1/S100A4 was higher in both tumor and stromal cells than that observed in invasive carcinoma (NST). These results indicate that CAFs are a potential target in ILC treatment.

Diagnostic group classifications of gastric neoplasms by endoscopic resection criteria before and after treatment: real-world experience.

BACKGROUND AND STUDY AIMS: There are often discrepancies between the pretreatment evaluation of gastric neoplasms by endoscopy with biopsy and the final diagnosis of resected specimen in terms of pathology and depth of invasion. We evaluated the spectrum of discrepancies between pretreatment and posttreatment diagnosis which may deliver significant differences on clinical practice. PATIENTS AND METHODS: A total of 2041 patients with gastric dysplasia or cancer who underwent curative endoscopic resections or surgeries in 2012 were enrolled. Patients were classified into five different diagnostic groups: low-grade dysplasia (LGD), high-grade dysplasia (HGD), absolute indication early gastric cancer (AI-EGC), beyond absolute indication early gastric cancer (BAI-EGC), and advanced gastric cancer (AGC). The choice of initial treatment and final pathologic diagnosis was analyzed. RESULTS: The study patients belonged to the following pretreatment diagnostic groups: LGDs in 162, HGDs in 164, AI-EGCs in 396, BAI-EGCs in 824, and AGCs in 495 cases. Posttreatment diagnostic groups were LGDs in 140, HGDs in 121, AI-EGCs in 322, BAI-EGCs in 947, AGCs in 505, and no residual tumor in 6 cases. In general, 6.9 % (141/2041) of cases were downgraded and 15.9 % (324/2041) were upgraded. Thirty-four percent of pretreatment HGDs (56/164) were changed to cancers after endoscopic resection. Thirty-three percent of pretreatment AI-EGCs (131/396) were regrouped as posttreatment BAI-EGCs. The additional surgery rate in each pretreatment group was 0.6 % in LGD, 4.3 % in HGD, 15.7 % in AI-EGC, 23.6 % in BAI-EGC among the patients with initial endoscopic resection (p < 0.01). CONCLUSIONS: Twenty-three percent of gastric neoplasms changed in their final diagnostic group after endoscopic resection or surgery. This discrepancy should be considered when the initial treatment strategy is being selected.

In-depth N-glycome profiling of paired colorectal cancer and non-tumorigenic tissues reveals cancer-, stage- and EGFR-specific protein N-glycosylation.

Glycomics may assist in uncovering the structure-function relationships of protein glycosylation and identify glycoprotein markers in colorectal cancer (CRC) research. Herein, we performed label-free quantitative glycomics on a carbon-liquid chromatography-tandem mass spectrometry-based analytical platform to accurately profile the N-glycosylation changes associated with CRC malignancy. N-Glycome profiling was performed on isolated membrane proteomes of paired tumorigenic and adjacent non-tumorigenic colon tissues from a cohort of five males (62.6 ± 13.1 y.o.) suffering from colorectal adenocarcinoma. The CRC tissues were typed according to their epidermal growth factor receptor (EGFR) status by western blotting and immunohistochemistry. Detailed N-glycan characterization and relative quantitation identified an extensive structural heterogeneity with a total of 91 N-glycans. CRC-specific N-glycosylation phenotypes were observed including an overrepresentation of high mannose, hybrid and paucimannosidic type N-glycans and an under-representation of complex N-glycans (P < 0.05). Sialylation, in particular α2,6-sialylation, was significantly higher in CRC tumors relative to non-tumorigenic tissues, whereas α2,3-sialylation was down-regulated (P < 0.05). CRC stage-specific N-glycosylation was detected by high α2,3-sialylation and low bisecting ß1,4-GlcNAcylation and Lewis-type fucosylation in mid-late relative to early stage CRC. Interestingly, a novel link between the EGFR status and the N-glycosylation was identified using hierarchical clustering of the N-glycome profiles. EGFR-specific N-glycan signatures included high bisecting ß1,4-GlcNAcylation and low α2,3-sialylation (both P < 0.05) relative to EGFR-negative CRC tissues. This is the first study to correlate CRC stage and EGFR status with specific N-glycan features, thus advancing our understanding of the mechanisms causing the biomolecular deregulation associated with CRC.

Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers.

Colorectal cancers (CRCs) with microsatellite instability-high (MSI+) but without detectable germline mutation or hypermethylation in DNA mismatch repair (MMR) genes can be classified as Lynch-like syndrome (LLS). The underlying mechanism and clinical significances of LLS are largely unknown. We measured MSI and MMR protein expression in 4,765 consecutive CRC cases. Among these, MSI+ cases were further classified based on clinical parameters, germline sequencing of MMR genes or polymerase ε (POLE) and δ (POLD1) and promoter methylation analysis of MLH1 and MSH2. We found that MSI+ and MMR protein-deficient CRCs comprised 6.3% (N = 302) of this cohort. On the basis of germline sequencing of 124 cases, we identified 54 LS with MMR germline mutation (LS-MMR), 15 LS with EPCAM deletions (LS-EPCAM) and 55 LLS patients. Of the 55 LLS patients, six (10.9%) had variants of unknown significance in the genes tested, and one patient had a novel somatic mutation (p.S459P) in POLE. In patients with biallelic deletions of EPCAM, all tumors and their matched normal mucosa showed promoter hypermethylation of MSH2. Finally, we found that patients with LLS and LS-EPCAM shared clinical features that differed from LS-MMR patients, including lower frequency of fulfillment of the revised Bethesda guidelines (83.6 and 86.7% vs. 98.1% for LS-MMR) and older mean age at CRC diagnosis (52.6 and 52.7 years vs. 43.9 years for LS-MMR). We identified somatic mutation in POLE as a rare underlying cause for MMR deficiency in LLS. The similarity between LLS and LS-EPCAM suggests LLS as a subset of familial MSI+ CRC.

HER2-positive gastric cancer with concomitant MET and/or EGFR overexpression: a distinct subset of patients for dual inhibition therapy.

Growth factor receptors, often carrying tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers. Coactivation of receptor tyrosine kinases (RTKs) plays a critical role in tumor response to targeted therapeutics. We examined concomitant overexpression of EGFR and MET in patients with HER2(+) and HER2(-) gastric cancers (GCs). Tissue microarray samples obtained from 1,589 GC patients who received R0 gastrectomy with extensive node dissection and adjuvant chemoradiationtherapy were analyzed by immunohistochemistry and fluorescence in situ hybridization. HER2(+) was observed in 169 patients (11%). Out of 169 HER2(+) patients, 15 (9%) were EGFR(+) and MET(+) , 29 (17%) were EGFR(+) , 37 (22%) were MET(+) and the remaining 88 patients (52%) were HER2(+) only, without concomitant EGFR or MET overexpression. Greater number of overexpressed RTKs correlated with younger age (p < 0.001), larger tumor size (p = 0.027), intestinal histology (p < 0.001) and shorter overall survival (p = 0.002). The mean overall survival was 113 months for HER2(-) /EGFR(-) /MET(-) and 63 months for HER2(+) /EGFR(+) /MET(+) subgroups. Patients with HER2(+) /EGFR(+) /MET(+) GCs had a substantial risk of death with a hazard ratio of 3.01 (95% CI: 1.54-5.90), compared with HER2(-) /EGFR(-) /MET(-) GC patients. Using patient-derived tumor cell models isolated from pericardial effusion of HER2(+) and MET(+) GC cases, we demonstrated that the combination of HER2-inhibitor (lapatinib) and MET-inhibitor offered a more profound inhibition in the ERK/AKT pathway and cell proliferation than lapatinib alone. Co-overexpression of RTKs was demonstrated in small subsets of GC associated with aggressive behavior and in these cases, combination therapy may be considered as potential treatment options.

Microsteatosis may not interact with macrosteatosis in living donor liver transplantation.

BACKGROUND & AIMS: The insignificance of pure microsteatosis (MiS) was reported in living donor liver transplantation (LDLT). However, since steatosis is mostly found in a mixed form of microsteatosis (MiS) and macrosteatosis (MaS), we aimed to determine the importance of MiS mixed with MaS in LDLT. METHODS: Donor matching and recipient matching were independently performed with unfixed matching ratios. In donor matching, 51 donors with high (⩾30%) MiS mixed with MaS (H-MiS) were matched with 160 donors with low (⩽10%) MiS mixed with MaS (L-MiS), based on MaS degree, remnant liver volume, and others. In recipient matching, 50 recipients who received H-MiS grafts were matched with 176 recipients who received L-MiS grafts, based on MaS degree, graft volume, MELD score, and others. RESULTS: The median MiS degree was 10% (range 0%-10%) vs. 35% (range 30%-80%) in L-MiS livers vs. H-MiS livers after both matching. L-MiS and H-MiS donors were not significantly different regarding postoperative biochemical liver function (e.g. peak AST 232 vs. 246 IU/L, p=0.931). L-MiS and H-MiS recipients were not significantly different regarding 2-week graft regeneration (51% for both) and 5-year survival (HR 0.87, 95% CI 0.43-1.76, p=0.699). Post-transplant donor/recipient complication rates were not significantly different, either. CONCLUSIONS: There were no evidences of a significant impact of MiS mixed with MaS on post-LDLT outcomes. The results suggest less importance of MiS, and further indicate that there is no interaction between MiS and MaS. Thus, the risk of steatosis may be determined by the relative composition of MiS and MaS, rather than the total quantitative degree.

SIRT1 regulates oncogenesis via a mutant p53-dependent pathway in hepatocellular carcinoma.

BACKGROUND & AIMS: SIRT1 is a class III histone deacetylase that plays diverse roles in various cancers. However, the clinical significance of SIRT1 in hepatocellular carcinoma (HCC) remains unknown. METHODS: We analysed p53 mutations and the activation of SIRT1 in 252 hepatitis B virus-positive HCC cases. None of the patients had been subjected to pre-operative treatment. RESULTS: We examined 57 p53 mutations from 248 HCC tissues. Activated SIRT1 (phosphorylated form of Ser47), in the context of mutant p53, predicted a longer relapse-free survival (RFS) but not a longer overall survival (OS) (RFS: p = 0.007, OS: p = 0.280) in HCC tissues harbouring mutant p53. In multivariate analysis, activated SIRT1 remained a significant predictor of longer RFS (OR = 0.307, CI: 0.143-0.660, p=0.002). Analysis of 248 paired specimens revealed a significant correlation between activated SIRT1 (Ser47) and activated AMPK (Thr172) in HCC tissues harbouring mutant p53 (p = 0.003, n = 57). The combination of these 2 parameters was a powerful predictor for a good prognosis in these patients. In vitro, SIRT1 inactivation stimulated the growth of HCC cells, bearing mutated p53, by suppressing AMPK activity and subsequently enhancing mammalian target of rapamycin (mTOR) activity, resulting in induction of p70S6K1 activation in HCC cells. Metformin, an AMPK activator, more strongly suppressed cell growth in p53-mutant cell lines with inactive SIRT1 than in p53-mutant cell lines with active SIRT1. CONCLUSIONS: SIRT1 exerted anti-carcinogenic effects via the AMPK-mTOR pathway in HCC in the context of mutant p53. Metformin could be a therapeutic drug for HCC in patients with mutated p53, inactivated SIRT1, and AMPK expression.

Surveillance strategy based on the incidence and patterns of recurrence after curative endoscopic submucosal dissection for early gastric cancer.

BACKGROUND AND STUDY AIMS: To suggest an appropriate surveillance strategy after curative endoscopic submucosal dissection (ESD) for early gastric cancers, based on incidence and patterns of local, metachronous, and extragastric recurrence. PATIENTS AND METHODS: Between 2003 and 2011, 1497 consecutive patients with 1539 differentiated-type early gastric cancers meeting absolute or expanded indication criteria underwent curative ESD. They were followed up with esophagogastroduodenoscopy (EGD) and abdominal computed tomography (CT) under a standardized surveillance protocol. Long-term outcomes were analyzed for 1306 patients with at least 1 year's follow-up. RESULTS: Incidences of residual and synchronous lesions detected within 1 year were 0.13 % and 0.87 %, respectively. During median 47 months of follow-up, there was 1 local recurrence (0.08 %; early gastric cancer) and 47 cases of metachronous recurrence (3.6 %; 44 early gastric cancers, 3 pT2 advanced gastric cancers); all were curatively treated. During a 5-year surveillance, the cumulative incidence curve of metachronous recurrence increased linearly. Median time from ESD to metachronous recurrence was 30 months. There were 2 extragastric recurrences (0.15 %) in lymph nodes, at 5 and 4 years, respectively, after curative ESD for absolute and expanded indications. The patient with the expanded indications underwent a palliative operation and died of gastric cancer progression. CONCLUSIONS: There was a constant incidence rate of metachronous recurrence during a 5-year surveillance period and there was extragastric recurrence at least 4 years after ESD of early gastric cancer even for absolute indications. Therefore, annual or biannual surveillance EGD and abdominal CT might be necessary for at least 5 years after curative ESD for early gastric cancers, with absolute as well as expanded indications.

Outcomes of endoscopic submucosal dissection for differentiated-type early gastric cancer with histological heterogeneity.

BACKGROUND: Long-term clinical outcomes after endoscopic submucosal dissection (ESD) is unclear for differentiated-type-predominant early gastric cancer (EGC) mixed with undifferentiated component (MUC-EGC). Therefore, the role and appropriate indication of ESD for MUC-EGC remain to be evaluated. METHODS: Between 2007 and 2011, 1,577 differentiated-type EGC lesions [1,408 pure differentiated-type (PuD)-EGCs and 169 MUC-EGCs] in 1,527 consecutive patients were treated by ESD. After ESD, MUC-EGC was managed in the same way as PuD-EGC. The clinicopathological features and long-term outcomes after ESD of MUC-EGC were compared with those of PuD-EGC. RESULTS: En bloc resection and en bloc with R0 resection rates in MUC-EGC cases were 94.1 % and 81.7 %, respectively. MUC-EGC was significantly associated with larger tumor size, more frequent submucosal invasion, and lymphovascular invasion compared to PuD-EGC. Despite these aggressive features of MUC-EGC, no lymph node metastasis or extragastric recurrence occurred during follow-up after ESD if MUC-EGC met the curative endoscopic resection (ER) criteria for tumors of absolute or expanded indications. Four MUC-EGC cases meeting the curative ER criteria underwent additional radical gastrectomy after ESD, and no case showed lymph node metastasis. During a median 48 months of follow-up, overall survival rates for MUC-EGC meeting the curative ER criteria for tumors of absolute or expanded indications (3-year survival rates, 100 % and 100 %) were comparable to those of PuD-EGC. CONCLUSIONS: Long-term outcomes after ESD were favorable for MUC-EGCs meeting the curative ER criteria for tumors of absolute or expanded indications. Therefore, ESD may be used as a promising treatment option for these cases.

Relationship Between the Size of Metastatic Lymph Nodes and Positron Emission Tomographic/Computer Tomographic Findings in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: We measured the sizes of metastatic lymph nodes and the relationships thereof by (18)F-fluorodeoxyglucose positron emission tomography/computer tomography (PET/CT). We identified risk factors for nodal upstaging in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Eighty-five patients with ESCC who underwent esophagectomy with extensive mediastinal lymphadenectomy were assessed. Two radiologists blinded to pathology data reviewed PET/CT scans, evaluating both primary tumors and lymph node involvement. A pathologist examined all metastatic lymph nodes in terms of maximal diameter (LNmax), the size of the metastatic focus (Fmax), and the metastasis occupation ratio (MOR = Fmax/LNmax). RESULTS: The maximal tumor length averaged 2.9 ± 0.2 cm and the mean SUVmax of the primary lesion 5.3 ± 0.5. On PET/CT scans, 26 (30.6 %) patients exhibited nodal metastasis and 59 (69.4 %) did not. Pathology grades of pN0, pN1, pN2, and pN3 were assigned to 45 (52.9 %), 24 (28.2 %), 13 (15.3 %), and 3 (3.5 %) patients, respectively. Nodal upstaging was evident in 29 (34.1 %) cases. In 123 metastatic nodes of 4212 nodes dissected, the LNmax was 6.60 ± 0.39 mm, the Fmax 4.47 ± 0.35 mm, and the MOR 0.68 ± 0.03. Of 123 nodes, 85 (69.1 %) were retrieved from PET-negative stations, and the LNmax and Fmax values of these nodes were 5.88 ± 0.42 and 3.75 ± 0.31 mm, respectively. Upon multivariate analysis, tumor length (OR 1.666, p = 0.019) and lymphovascular invasion (OR 41.038, p < 0.001) were risk factors for nodal upstaging. CONCLUSION: A significant proportion of nodal metastases were too small to detect via PET/CT imaging. Therefore, meticulous lymph node dissection might be helpful in ESCC patients.

Frequency, CT findings, and fate of multiple infarcted regenerative nodules in liver cirrhosis after variceal bleeding or septic shock.

PURPOSE: To evaluate the frequency, CT findings, and fate of multiple infarcted regenerative nodules in patients with liver cirrhosis after variceal bleeding or septic shock. METHODS: During a recent 3-year period, 492 patients with hematemesis or melena (n = 445) and septic shock (n = 47) in liver cirrhosis visited our hospital. After applying the exclusion criteria, 136 patients with active variceal bleeding and 29 patients with septic shock were finally included in the study. We diagnosed multiple infarcted regenerative nodules based on the findings of the first follow-up (within 30 days) CT after events. We evaluated the shape, number, size, margin, location, and distribution of the infarcted regenerative nodules. RESULTS: Thirty-four patients were diagnosed with multiple infarcted regenerative nodules (20.6% [34/165]): 29 among 136 patients with variceal bleeding (21.3% [29/136]) and 5 among 29 patients with septic shock (17.2% [5/29]). Most of the infarcted regenerative nodules were round in shape, more than ten in number (79.4%), measured 1 cm or less (76.3%), had well-defined margins (61.8%), were present in the periphery (67.6%), and had a clustered distribution (67.6%). Almost all of the infarcted regenerative nodules disappeared on the second follow-up CT (88.9% [16/18]). CONCLUSIONS: In cirrhotic patients, multiple infarcted regenerative nodules were not rare (they were found in about one-fifth of the patients) on the first follow-up CT after variceal bleeding or septic shock. Majority of the infarcted regenerative nodules were more than ten in number, measured 1 cm or less, were located in the periphery, and had a clustered distribution.

Intrahepatic metastasis is more risky than multiple occurrence in hepatocellular carcinoma patients after curative liver resection.

BACKGROUND/AIMS: The characteristics of multiple nudules in hepatocellular carcinomas (HCCs) after curative liver resection remain obscure. We compare the clinicopathologic characteristics and prognoses between patients with hepatic lesions with multicentric occurrence (MO) and intrahepatic metastasis (IM) at the time of surgical resection. METHODOLOGY: The histopathologic features of multiple tumors from 198 patients of HCC were analyzed and divided into MO group (n = 51, 25.8%) for multicentric HCCs and an IM group (n = 147, 74.2%) in cases with intrahepatic metastases. Overall survival rate, disease-free survival and clinicopathologic differences were compared between the two groups. RESULTS: Microvascular invasion and increased tumor size were the most important factors discriminating the IM group from the MO group (P < 0.001 and P = 0.027, respectively). Kaplan-Meier and log rank tests revealed that disease-free survival and overall survival rates in the MO group were significantly higher than those for the IM group (P < 0.001 and P < 0.001, respectively). A multivariate analysis of Cox's proportional hazards model showed that increased alpha-fetoprotein (AFP) and protein induced by vitamin K antagonist-II (PIVKA-II) levels, portal vein invasion and intrahepatic metastases were the most important prognostic factors. CONCLUSIONS: Among HCCs, the prognosis of patients with MO is significantly better than that of patients with IM.

Expression of prothymosin alpha predicts early recurrence and poor prognosis of hepatocellular carcinoma.

BACKGROUND: Prothymosin alpha (PTMA) is a nuclear oncoprotein-transcription factor essential for cell cycle progression and proliferation. PTMA was overexpressed in several human malignancies including hepatocellular carcinoma (HCC). However, the prognostic significance of PTMA protein expression in HCC remains unclear. In the present study, we evaluated PTMA protein expression by immunohistochemistry in order to elucidate the prognostic roles of PTMA in HCC patients. METHODS: By immunohistochemistry, we investigated the expression of PTMA protein in tumor tissue from 226 HCC patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 120 months. RESULTS: PTMA expression was observed in 162 (71.7%) of the 226 HCC patients and was significantly associated with higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T-stage, and lower albumin level. PTMA expression was an independent predictor of early recurrence (P=0.001). PTMA expression showed an unfavorable influence on recurrence-free survival (RFS) (P<0.001). Subgroup analysis showed that among patients with tumor size ≤5.0 cm (140 patients), patients at AJCC T-stage 1 (95 patients) and patients with alpha-fetoprotein ≤20 ng/mL (83 patients), the differences in RFS between PTMA-positive and PTMA-negative groups were also statistically significant (P=0.017, P=0.002 and P=0.002, respectively). In addition, PTMA expression was an independent predictor of shorter RFS (P=0.011). PTMA expression showed an unfavorable influence on overall survival (P=0.014), but was not an independent predictor of shorter overall survival (P=0.161). CONCLUSIONS: PTMA protein expression might be a novel predictor of early recurrence and RFS in HCC patients, even those at early stage or with alpha-fetoprotein-negative after curative hepatectomy. PTMA could be used as an immunohistochemical biomarker to detect patients with a high risk of recurrence.