Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab.

BACKGROUND: The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity represents HER2 heterogeneity, we aimed to investigate this in a larger cohort with longer follow-up duration. METHODS: Data of 153 HER2-positive advanced GC patients who received first-line trastuzumab-based chemotherapy were analyzed. Repeat endoscopic biopsy was performed in patients with initially HER2-negative GC. Survival outcomes were analyzed according to the immunohistochemistry (IHC) score (IHC 2+ /in situ hybridization [ISH] + vs IHC 3+), HER2 status (initially vs rescued HER2 positive), and H-score. RESULTS: IHC 2+ /ISH + patients showed worse progression-free survival (PFS) and overall survival (OS) than those with IHC 3+ (p < 0.05). Rescued HER2-positive patients showed worse PFS and OS than initially HER2-positive patients (p < 0.05). Although survival outcomes were comparable according to HER2 status in IHC 2+ /ISH + patients, initially HER2-positive patients showed more favorable PFS and OS than rescued HER2-positive patients (p < 0.05) among those with IHC 3+ . Among the subgroups determined by HER2 status and IHC score, the initially IHC 3+ subgroup had the highest H-score. The low H-score group (H-score ≤ 210) had significantly worse survival outcomes than the high H-score group (H-score > 210) (p < 0.05). An H-score of ≤ 210 was independently associated with shorter OS (HR = 1.54, 95% CI 1.02-2.31, p = 0.04). CONCLUSIONS: Rescued HER2-positive patients showed worse clinical outcomes than initially HER2-positive patients, especially those with IHC 3+ . This finding highlights the impact of HER2 heterogeneity, which can be quantified indirectly as an H-score.

Radio-pathologic correlation of biphenotypic primary liver cancer (combined hepatocellular cholangiocarcinoma): changes in the 2019 WHO classification and impact on LI-RADS classification at liver MRI.

OBJECTIVES: To explain the new changes in pathologic diagnoses of biphenotypic primary liver cancer (PLC) according to the updated 2019 World Health Organization (WHO) classification and how it impacts Liver Imaging Reporting and Data System (LI-RADS) classification using gadoxetic acid-enhanced MRI (Gd-EOB-MRI). METHODS: We retrospectively included 209 patients with pathologically proven biphenotypic PLCs according to the 2010 WHO classification who had undergone preoperative Gd-EOB-MRI between January 2009 and December 2018. Imaging analysis including LI-RADS classification and pathologic review including the proportion of tumor components were performed. Frequencies of each diagnosis and subtype according to the 2010 and 2019 WHO classifications were compared, and changes in LI-RADS classification were evaluated. Univariable and multivariable analysis were performed to determine significant tumor component for LI-RADS classification. RESULTS: Of the 209 biphenotypic PLCs of the 2010 WHO classification, 177 (84.7%) were diagnosed as bipheonotypic PLCs, 25 (12.0%) as hepatocellular carcinomas (HCCs), and 7 (3.3%) as cholangiocarcinomas (CCAs) using the 2019 WHO classification. Of the 177 biphenotypic PLCs, LR-M, LR-4, and LR-5 were assigned in 77 (43.5%), 21 (11.9%), and 63 (35.5%), respectively. There were no significant differences in the proportion of LR-5 and LR-M categories between the WHO 2010 and 2019 classifications (p = 0.941). Proportion of HCC component was the only independent factor for LI-RADS classification (adjusted odds ratio, 1.02; p < 0.001). CONCLUSION: According to the 2019 WHO classification, 15% of biphenotypic PLCs from the 2010 WHO classification were re-diagnosed as HCCs or CCAs, and a substantial proportion of biphenotypic PLCs of the 2019 WHO classification could be categorized as LR-4 or LR-5 on Gd-EOB-MRI. KEY POINTS: • Among 209 diagnosed biphenotypic PLCs according to the 2010 WHO classification, 177 (84.7%) lesions were reclassified as bipheonotypic PLCs, 25 (12.0%) as HCCs, and 7 (3.3%) as CCAs using the 2019 WHO classification. • Of the 177 biphenotypic PLCs at the 2019 WHO classification, LR-M, LR-4, and LR-5 were assigned in 77 (43.5%), 21 (11.9%), and 63 (35.5%), respectively. • LI-RADS classification relied on the proportion of HCC component (adjusted odds ratio,1.02; p < 0.001).

Effects of Proton Pump Inhibitor on the Distribution of Helicobacter pylori and Associated Gastritis in Patients with Gastric Atrophy.

BACKGROUND/AIMS: Acid suppression therapy is thought to be associated with the topography of Helicobacter pylori and associated gastritis, leading to corpus-predominant gastritis. This study was aimed to investigate the influence of proton pump inhibitor (PPI) treatment on the distribution of H. pylori and associated gastritis in patients with atrophic change. METHODS: Patients who underwent endoscopic resection for gastric neoplasms and received PPI for 2 months were prospectively analyzed. Biopsy specimens were obtained from 5 areas in the stomach before, during, and after the treatment with PPI. Histological examination was -performed using the updated Sydney system, and -bacterial density of H. pylori was further graded by immunohistochemistry (ClinicalTrials.gov registration number NCT02449941). RESULTS: A total of 15 patients were analyzed, of whom 7 had H. pylori infection. The degree of activity and inflammation were greater in patients with H. pylori infection than in those without H. pylori infection. During the PPI treatment, the density of H. pylori decreased not only in the antrum but also in the corpus. The degree of activity and inflammation improved significantly in the antrum, particularly in the presence of H. pylori infection, while the corpus gastritis was not affected by PPI use. Atrophy and intestinal metaplasia remained unchanged in both regions of the stomach. The observed changes reverted following the discontinuation of PPI treatment. CONCLUSION: PPI treatment decreased H. pylori both in the antrum and the corpus in patients with atrophic gastritis. Antral gastritis improved during PPI treatment, whereas no changes were found in the corpus.

Role of Resection Following Focal Progression with Standard Doses of Imatinib in Patients with Advanced Gastrointestinal Stromal Tumors: Results of Propensity Score Analyses.

BACKGROUND: There are limited data on the clinical benefits of adding surgical resection in patients with focally progressive gastrointestinal stromal tumor (GIST). This study aims to compare the clinical outcomes of resection plus imatinib dose escalation or maintenance (S group) with imatinib dose escalation alone (NS group) in patients with advanced GIST following focal progression (FP) with standard doses of imatinib. MATERIALS AND METHODS: A total of 90 patients with advanced GISTs who experienced FP with standard doses of imatinib were included in this retrospective analysis. The primary endpoints were time to imatinib treatment failure (TTF) and overall survival (OS). RESULTS: Compared with the NS group (n = 52), patients in the S group (n = 38) had a higher proportion of primary tumor site involvement and lower tumor burden at FP. With a median follow-up duration of 31.0 months, patients in the S group had significantly better TTF and OS than patients in the NS group (median TTF: 24.2 vs. 6.5 months, p < .01; median OS: 53.2 vs. 35.1 months, p = .009). Multivariate analysis showed that S group independently demonstrated better TTF (hazard ratio [HR], 0.29; p < .01) and OS (HR, 0.47; p = .01). Even after applying inverse probability of treatment-weighting adjustments, S group demonstrated significantly better TTF (HR, 0.36; p < .01) and OS (HR, 0.58; p = .049). CONCLUSION: Our results suggested that resection following FP with standard doses of imatinib in patients with advanced GIST provides additional benefits over imatinib dose escalation alone. IMPLICATIONS FOR PRACTICE: This is the first study to compare the clinical outcomes of resection plus imatinib dose escalation or maintenance (S group) with imatinib dose escalation alone (NS group) in patients with advanced gastrointestinal stromal tumor (GIST) following focal progression (FP) with standard doses of imatinib. These findings suggest that resection can be safely performed following FP, and the addition of surgical resection provides further clinical benefit over imatinib dose escalation alone. Based on these results, the authors recommend resection following FP in patients with advanced GIST provided that an experienced multidisciplinary team is involved in the patient's treatment.

LI-RADS Classification and Prognosis of Primary Liver Cancers at Gadoxetic Acid-enhanced MRI.

Purpose To (a) evaluate the postsurgical prognostic implication of the Liver Imaging Reporting and Data System (LI-RADS) categories of primary liver cancers and (b) determine the performance of LI-RADS version 2017 in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (IHCC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC) at gadoxetic acid-enhanced MRI. Materials and Methods In this retrospective study, 194 patients with cirrhosis and surgically proven single primary liver cancer (53 with cHCC-CC, 44 with IHCC, and 97 with HCC) were evaluated with gadoxetic acid-enhanced MRI between 2009 and 2014. The mean patient age was 57 years (age range, 30-83 years). There were 155 men with a mean age of 56 years (range, 30-81 years) and 39 women with a mean age of 58 years (range, 38-83 years). Two independent readers assigned an LI-RADS category for each nodule. Overall survival (OS), recurrence-free survival (RFS), and their associated factors were evaluated by using the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Results In the multivariable analysis, the LI-RADS category was an independent factor for OS (hazard ratio, 4.2; P < .001) and RFS (hazard ratio, 2.6; P = .01). The LR-M category showed more correlation with poorer OS and RFS than did the LR-4 or LR-5 category for all primary liver cancers (P < .001 for both), HCCs (P = .01 and P < .001, respectively), and cHCC-CCs (P = .01 and P = .03, respectively). The LR-5 category had a sensitivity of 69% (67 of 97) and a specificity of 87% (84 of 97) in the diagnosis of HCC; most false-positive diagnoses (85%, 11 of 13) were the result of misclassification of cHCC-CCs. Conclusion The Liver Imaging Reporting and Data System (LI-RADS) category was associated with postsurgical prognosis of primary liver cancers, independent of pathologic diagnosis. The LI-RADS enabled the correct classification of most hepatocellular carcinomas (HCCs) and intrahepatic cholangiocarcinomas, whereas differentiation of combined hepatocellular-cholangiocarcinoma from HCC was unreliable. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Bashir and Chernyak in this issue.

Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3).

BACKGROUND: Although discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy. METHODS: We enrolled 48 HER2-positive advanced gastric cancer patients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression. RESULTS: At baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH-. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4-36.8) months. CONCLUSION: A substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.

The combination of histone deacetylase and p53 expressions and histological subtype has prognostic implication in uterine leiomyosarcoma.

OBJECTIVE: To investigate the expression of different histone deacetylases and their association with disease characteristics and survival outcomes in uterine leiomyosarcoma patients. METHODS: The immunohistochemical expression of different histone deacetylases and p53 by tissue microarray and histological subtypes were assessed in tumor tissue samples of 42 eligible patients. RESULTS: Histone deacetylases 1-4, 6 and 8 showed prevalent and strong (3+) expression (88.1, 90.5, 95.2, 92.9, 83.3 and 100%, respectively). Histone deacetylases 5, 7 and 9 showed infrequent strong expression (33.3, 50 and 38.1%, respectively). There were trends of higher disease-free survival rates according to the combination of weaker expression of histone deacetylase 5, 7 or 9 with positive p53 expression or with non-epithelial subtype. The patients with triple-positive favorable prognostic factors (any of weaker histone deacetylase 5, 7 and 9 expression, p53 positive, and non-epithelioid subtype) had the better survival outcomes while the patients with other combinations had the worse survival outcomes. In multivariate analysis, histone deacetylase 5 in combination with epithelioid subtype was an independent predictor for disease-free survival. CONCLUSIONS: Expression of histone deacetylase 5, 7 and 9 is a potential prognostic marker in uterine leiomyosarcoma when combined with pathologically relevant prognostic factors (p53 and histological subtype). This prevalent and strong histone deacetylase expression warrants further study in well-designed investigations of histone deacetylases as therapeutic targets in uterine leiomyosarcoma.

Clinical significance of MET gene amplification in metastatic or locally advanced gastric cancer treated with first-line fluoropyrimidine and platinum combination chemotherapy.

OBJECTIVE: To investigate the clinical significance of MET gene amplification in patients with gastric cancer in the palliative setting. METHODS: MET amplification was assessed using fluorescence in situ hybridization (FISH) in 50 patients and quantitative polymerase chain reaction (qPCR) in 326 patients; 259 patients treated with first-line fluoropyrimidine and platinum were included for survival analysis. RESULTS: The results of FISH and qPCR indicated that the c-MET/CEP7 ratio was correlated with gene copy number. The optimal cutoff value for the copy number using qPCR to detect MET gene amplification with FISH was 5 (κ=0.778, P<0.001). Twenty-one out of 326 patients (6.4%) were identified asMET amplification with a copy number of >5 detected by qPCR. MET-amplified gastric cancer was associated with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≥2 (33.3% vs. 10.5% P=0.007), peritoneal metastasis (76.2% vs. 46.2%, P=0.008), and elevated bilirubin levels (28.6% vs. 7.3%, P=0.006). The median overall survival (OS) and progression-free survival (PFS) were 11.9 and 5.6 months, respectively. MET-amplified gastric cancer was not associated with survival outcomes [hazard ratio (HR)=0.68, 95% confidence interval (95% CI): 0.35-1.32, P=0.254 for PFS; HR=0.68, 95% CI: 0.35-1.32, P=0.251 for OS]. CONCLUSIONS: qPCR can be used to detect MET gene amplification. MET amplification was not a predictor of poor prognosis in patients with metastatic or unresectable gastric cancer.

Combinatory RNA-Sequencing Analyses Reveal a Dual Mode of Gene Regulation by ADAR1 in Gastric Cancer.

BACKGROUND: Adenosine deaminase acting on RNA 1 (ADAR1) is known to mediate deamination of adenosine-to-inosine through binding to double-stranded RNA, the phenomenon known as RNA editing. Currently, the function of ADAR1 in gastric cancer is unclear. AIMS: This study was aimed at investigating RNA editing-dependent and editing-independent functions of ADAR1 in gastric cancer, especially focusing on its influence on editing of 3' untranslated regions (UTRs) and subsequent changes in expression of messenger RNAs (mRNAs) as well as microRNAs (miRNAs). METHODS: RNA-sequencing and small RNA-sequencing were performed on AGS and MKN-45 cells with a stable ADAR1 knockdown. Changed frequencies of editing and mRNA and miRNA expression were then identified by bioinformatic analyses. Targets of RNA editing were further validated in patients' samples. RESULTS: In the Alu region of both gastric cell lines, editing was most commonly of the A-to-I type in 3'-UTR or intron. mRNA and protein levels of PHACTR4 increased in ADAR1 knockdown cells, because of the loss of seed sequences in 3'-UTR of PHACTR4 mRNA that are required for miRNA-196a-3p binding. Immunohistochemical analyses of tumor and paired normal samples from 16 gastric cancer patients showed that ADAR1 expression was higher in tumors than in normal tissues and inversely correlated with PHACTR4 staining. On the other hand, decreased miRNA-148a-3p expression in ADAR1 knockdown cells led to increased mRNA and protein expression of NFYA, demonstrating ADAR1's editing-independent function. CONCLUSIONS: ADAR1 regulates post-transcriptional gene expression in gastric cancer through both RNA editing-dependent and editing-independent mechanisms.

Combined hepatocellular-cholangiocarcinoma: Gadoxetic acid-enhanced MRI findings correlated with pathologic features and prognosis.

PURPOSE: To evaluate gadoxetic acid-enhanced magnetic resonance imaging (MRI) findings of combined hepatocellular cholangiocarcinoma (cHCC-CC) with special emphasis on correlation of MRI findings with histopathologic tumor characteristics and survival outcomes after curative surgery. MATERIALS AND METHODS: Our Institutional Review Board approved this study, with a waiver of informed consent. For 82 patients (64 men, 18 women; mean age, 54.0 years; age range, 30-81) with surgically confirmed cHCC-CCs, we evaluated clinical features, histologic findings, and tumor morphologic and enhancement features on gadoxetic acid-enhanced liver MRI at 1.5T (n = 67) or 3.0T (n = 15). Imaging features of cHCC-CCs were correlated with pathologic findings according to the 2010 World Health Organization classification system. Tumors were categorized as hypervascular or nonhypervascular based on arterial phase enhancement and were compared with respect to overall and recurrence-free survival after curative-intent surgery. RESULTS: Of the 82 lesions, 48 showing global arterial phase enhancement were categorized as the hypervascular group, while 34 lesions demonstrating rim, peripheral, or isoenhancement were categorized as the nonhypervascular group. There was no significant difference in MRI findings between pathologic tumor types (classical type versus stem cell feature type, P = 0.324-1.0). Compared with the nonhypervascular group, the hypervascular group had a larger HCC component (P = 0.014), smaller CC component (P = 0.001), and lesser amount of fibrotic stroma (P = 0.006) on pathologic analysis and was an independent factor associated with better overall survival after surgical resection (P = 0.033). CONCLUSION: Gadoxetic acid-enhanced MRI findings of cHCC-CCs were diverse, reflecting heterogeneous histologic features. The hypervascular group on MRI is associated with a larger HCC component, smaller CC component, less fibrotic stroma, and better overall survival after curative surgery than the nonhypervascular group. LEVEL OF EVIDENCE: 4 J. MAGN. RESON. IMAGING 2017;46:267-280.

Liver Stiffness Measured by Shear-wave Elastography for Evaluating Intrahepatic Portal Hypertension in Children.

OBJECTIVES: The aim of the study was to correlate liver stiffness (LS) and hepatic venous-pressure gradient (HVPG) and to evaluate the diagnostic performance of shear-wave elastography (SWE) for predicting clinically significant portal hypertension in children with suspected liver diseases, in consideration of the reliability criteria. METHODS: We identified 33 SWEs from 32 children who underwent HVPG measurement within 2 weeks between June 2012 and October 2015. The correlation between LS and HVPG was assessed. The diagnostic performance for predicting clinically significant portal hypertension (HVPG ≥ 10 mmHg) was assessed using the receiver-operating characteristic curve. Reliable measurement was evaluated based on the coefficient of variation (CV). RESULTS: LS was significantly correlated with HVPG (r = 0.742, P < 0.001). The area under the receiver-operating characteristic curve for predicting clinically significant portal hypertension was 0.914, and the best cutoff value of 18.4 kPa showed sensitivity of 87.5% and specificity of 84.0%. LS measurements having CV ≤ 0.2 were significantly correlated with HVPG (r = 0.774, P < .001), whereas those having CV > 0.2 did not show a significant correlation with HVPG (r = 0.598, P = 0.089). CONCLUSIONS: SWE had excellent diagnostic performance for predicting clinically significant portal hypertension in children with suspected liver diseases. LS measurements having CV ≤ 0.2 may possibly be used as a reliability criterion in SWE measurement.

Investigation of New Therapeutic Targets in Undifferentiated Endometrial Sarcoma.

BACKGROUND: Undifferentiated endometrial sarcoma (UES) is a very rare subtype of uterine sarcoma, which has no consensus on the treatment. We investigated the expression of potential new therapeutic targets in UES to improve its aggressive clinical course and poor survival outcome. METHODS: The immunohistochemical expressions of vascular endothelial growth factor (VEGF), c-KIT, c-ABL, platelet derived growth factor receptor (PDGFR), protein kinase B (AKT1), mammalian target of rapamycin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER2), Wilms tumor (WT1), aromatase inhibitor (CYP19A1), and histone deacetylase (HDAC) series in 10 UES patients were assessed using tissue microarrays. RESULTS: Strongly positive immunoreactivities were observed for VEGF, AKT1, and HDAC2/7 in 8 (80.0%) tumors; for CYP19A1 and HDAC6 in 9 (90%) tumors; and for HDAC1/4/8 in 10 (100%) tumors. Strong expression of CYP19A1 and HDAC6 was associated with distant recurrence (p = 0.030, both), and expression of WT1 indicated a more advanced stage (p = 0.033). UES treated with adjuvant therapy showed better disease-free and overall survivals (both 0 vs. 33.3%, p = 0.003). CONCLUSION: VEGF, AKT1, CYP19A1, and the HDAC1/2/4/6/7/8 series show an especially high frequency of strong immunoreactivity in UES and can be considered potential therapeutic targets.

Cap-assisted EMR for rectal neuroendocrine tumors: comparisons with conventional EMR and endoscopic submucosal dissection (with videos).

BACKGROUND AND AIMS: The incidence of rectal neuroendocrine tumors (NETs) is increasing, and most small rectal NETs can be treated endoscopically. Cap-assisted EMR (EMR-C) was suggested as an effective treatment for rectal NETs in a few studies. We aimed to compare the outcomes of conventional EMR, EMR-C, and endoscopic submucosal dissection (ESD) for the treatment of rectal NETs. METHODS: A total of 138 rectal NETs were treated endoscopically by a single endoscopist at Asan Medical Center. We analyzed 122 rectal NETs that had been removed by using EMR (n = 56), EMR-C (n = 34), or ESD (n = 32). RESULTS: The histologic complete resection rate was higher in the EMR-C group than in the EMR group (94.1% vs 76.8%, P = .032). Intraprocedural bleeding tended to be more frequent in the EMR-C group than in the EMR group (8.8% vs 0%, P = .051). No differences in the rates of adverse events or histologic complete resections were observed between the EMR-C group and the ESD group for 6-mm to 8-mm NETs; however, the procedure time was significantly shorter in the EMR-C group (3.9 ± 1.1 minutes) than in the ESD group (19.0 ± 12.1 minutes) (P < .001). There was no recurrence in any of the 3 groups. CONCLUSIONS: EMR-C is the preferable technique for endoscopic resection of small rectal NETs.

Associations between the neuron-specific glucocorticoid receptor (NR3C1) Bcl-1 polymorphisms and suicide in cancer patients within the first year of diagnosis.

BACKGROUND: Cancer diagnosis is associated with an increased suicide risk, particularly within the first 1 year after diagnosis of cancer. Abnormal function of the hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depression and suicide. We examined genetic associations of the functional Bcl-1 polymorphism of (rs41423247) neuron-specific glucocorticoid receptor (NR3C1) gene, with death by suicide in cancer patients. Suicides occurring within a year of cancer diagnosis ('early suicide') were considered separately from those suicides during the second or subsequent year ('late suicide') after cancer diagnosis. METHODS: The subjects consisted of 343 cancer patients admitted to a general hospital in Seoul, South Korea from 1996 to 2009, of which 182 had died by suicide and 161 were alive on December 31, 2009. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue sample of patients with cancer. We conducted a case-control association analysis of Bcl-1 polymorphism of NR3C1 gene. RESULTS: Subjects carrying the GG genotype of Bcl-1 polymorphism were at increased risk of early suicide when compared to those carrying the CC genotype (OR 3.80, 95 % CI 1.02-14.16, p = .047). Similarly, those individuals carrying the GG genotype (recessive mode) had an increased risk of early suicide relative to the CC or CG genotype (OR 3.71, 95 % CI 1.03-13.43, p = .045). However, there were no differences in the genotype distributions of the NR3C1 Bcl-1 polymorphism between late suicide cases and controls. CONCLUSIONS: Our findings suggest that the NR3C1 Bcl-1 polymorphisms may be involved in the susceptibility to suicide within the first year after cancer diagnosis among cancer patients in Korean population.

Prognostic value of glucosylceramide synthase and P-glycoprotein expression in oral cavity cancer.

BACKGROUND: Glucosylceramide synthase (GCS) and P-glycoprotein (P-gp) overexpression are associated with multidrug resistance in several human cancers. This study investigated the prognostic value of GCS and P-gp in oral cavity squamous cell carcinoma (OSCC). METHODS: The association between GCS and P-gp overexpression and clinical outcomes was assessed in 186 human clinical specimens of primary tumors obtained from curative surgery. Immunohistochemistry staining results were scored as high or low for GCS, and positive or negative for P-gp. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to assess the significance of differences in recurrence or survival outcomes between variables. RESULTS: GCS overexpression was observed in 128 (68.8 %) patients and P-gp overexpression in 43 (23.1 %) patients. High GCS expression was significantly correlated with P-gp immunopositivity (P = 0.005). GCS and P-gp overexpression was significantly correlated with cervical nodal metastasis (P < 0.05). Univariate analyses showed that tumor lymphovascular invasion, positive neck lymph nodes, advanced overall TNM stage, high GCS expression, and P-gp immunopositivity were associated with poor locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) (P < 0.05). Multivariate analyses showed that lymphovascular invasion, nodal positivity, and P-gp overexpression remained independent prognostic variables for LRC, DFS, and OS, and that GCS expression was an independent predictor of LRC and DFS (P < 0.05). CONCLUSION: GCS and P-gp expression is associated with poor prognosis, suggesting suitability as novel biomarkers in OSCC.

Clinical Outcomes of Cryopreserved Arterial Allograft Used as a Vascular Conduit for Hemodialysis.

This single center cohort study aimed to test the hypothesis that use of a cryopreserved arterial allograft could avoid the maturation or healing process of a new vascular access and to evaluate the patency of this technique compared with that of vascular access using a prosthetic graft. Between April 2012 and March 2013, 20 patients underwent an upper arm vascular access using a cryopreserved arterial allograft for failed or failing vascular accesses and 53 using a prosthetic graft were included in this study. The mean duration of catheter dependence, calculated as the time interval from upper arm access placement to removal of the tunneled central catheter after successful cannulation of the access, was significantly longer for accesses using a prosthetic graft than a cryopreserved arterial allograft (34.4 ± 11.39 days vs. 4.9 ± 8.5 days, P < 0.001). In the allograft group, use of vascular access started within 7 days in 16 patients (80%), as soon as from the day of surgery in 10 patients. Primary (unassisted; P = 0.314) and cumulative (assisted; P = 0.673) access survivals were similar in the two groups. There were no postoperative complications related to the use of a cryopreserved iliac arterial allograft except for one patient who experienced wound hematoma. In conclusion, upper arm vascular access using a cryopreserved arterial allograft may permit immediate hemodialysis without the maturation or healing process, resulting in access survival comparable to that of an access using a prosthetic graft.

Cytoplasmic iASPP expression as a novel prognostic indicator in oral cavity squamous cell carcinoma.

BACKGROUND: Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is a key inhibitor of tumor suppressor p53 that is overexpressed in several human cancers; however, its role in oral cavity squamous cell carcinomas (OSCC) remains unknown. The present study investigated the prognostic role of iASPP in patients with OSCC. METHODS: This study included 186 OSCC patients who underwent curative surgery at our institution between 2000 and 2011. Cytoplasmic and nuclear iASPP expression were examined separately by immunohistochemistry, and dichotomized to low and high. Clinicopathological variables associated with locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were identified by univariate and multivariate analyses. RESULTS: Patients were followed-up for a median period of 74 months (range 16-166 months), and 5-year LRC, DFS, and OS was 73.6, 70.2, and 75.3 %, respectively. High iASPP immunostaining reactivity was detected in the cytoplasm and nucleus in 132 (71.0 %) and 93 (50.0 %) patients, respectively. In univariate analysis, pathologic nodal metastasis, advanced overall stage III-IV, lymphovascular invasion, and cytoplasmic iASPP were significantly associated with poor LRC, DFS, and OS (p < 0.05). High-grade and positive resection margins were significant factors associated with poor DFS and OS (p < 0.02). In multivariate analysis, N classification, lymphovascular invasion, and cytoplasmic iASPP expression remained independent variables for LRC, DFS, and OS (p < 0.05). CONCLUSION: High iASPP expression in the tumor cell cytoplasm is associated with poor outcomes of OSCC patients in terms of recurrence and survival, suggesting a role for iASPP as a novel biomarker and therapeutic target for OSCC.

MET is a predictive factor for late recurrence but not for overall survival of early stage hepatocellular carcinoma.

The MET and RON receptors are tyrosine kinases that form a non-covalent complex on the cell surface that functions in several steps of tumor progression. The purpose of this study was to determine the clinical significance of MET and RON expression on long-term survival and recurrence after curative resection in a large cohort of hepatocellular carcinoma (HCC) patients. We performed immunohistochemical analyses on microarrays of the tumors using antibodies against MET and RON. We evaluated the prognostic value of biomarker expression using Cox regression and the Kaplan-Meier method in 490 HCC patients. MET-positive patients had higher overall recurrence rates than MET-negative patients (P = 0.041); however, MET positivity was not associated with overall survival (OS) (P = .249). RON was not associated with overall recurrence rates and OS. MET was independently associated with late but not early phase recurrence. Particularly, the prognostic significance of MET is limited in early stage disease. MET+/RON+ patients had higher overall recurrence rates than those with the other expression patterns (P = 0.071), although the result did not reach statistical significance. Immunohistological activation of MET expression has no prognostic significance for OS in patients with HCC. However, MET positivity was correlated with late recurrence after HCC resection in early stage disease.

Interpreting CD56+ and CD163+ infiltrates in early versus late renal transplant biopsies.

BACKGROUND: CD56+ and CD163+ cell infiltration in human kidney transplant biopsies have not been fully evaluated. METHODS: We investigated the association of CD56+ and CD163+ cell infiltration with human kidney transplant biopsies with antibody- or T-cell-mediated rejection (TCMR) and other histologic lesions. One hundred and seventy four clinically indicated transplant biopsies were included in this analysis. Immunohistochemical staining for C4d, CD56 and CD163 was performed. RESULTS: One hundred and seventy four indication biopsies were divided into early (≤1 year posttransplant; n = 49) and late (>1 year posttransplant; n = 125) biopsies. High numbers of CD56+ cells were uncommon in early biopsies except for those with antibody-mediated rejection (AMR) only. On the other hand, high numbers of CD56+ cells were observed in late biopsies diagnosed as TCMR only, AMR only, and TCMR combined with AMR. In early biopsies, both CD56+ and CD163+ infiltrates correlated strongly with interstitial inflammation, tubulitis, and peritubular capillaritis (ptc) scores. The ci and ct scores, however, were correlated only with the number of CD56+ cells. In late biopsies, on the other hand, the number of CD56+ infiltrates was correlated only with ptc, while the number of CD163+ infiltrates was weakly correlated with any histologic lesion. Multivariable analyses showed that chronic active AMR and the number of CD56+ cells/10 HPF were independently associated with death-censored graft failure post-biopsy. The number of CD163+ cells was not correlated with any pathologic lesion and post-biopsy graft failure. CD56+ infiltrates were also associated with interstitial fibrosis and tubular atrophy. CONCLUSIONS: Intragraft CD56+ cell infiltrates were significantly associated with AMR and subsequent poor clinical outcomes.

Prospective evaluation of new 22 gauge endoscopic ultrasound core needle using capillary sampling with stylet slow-pull technique for intra-abdominal solid masses.

GOALS: The aim of this study was to evaluate the adequacy and diagnostic yield of the histologic core obtained with a 22 G endoscopic ultrasound histology needle using capillary sampling with stylet slow-pull technique without on-site cytopathologist. BACKGROUND: No standard technique for new EUS histology needle has been established. STUDY: A total of 125 consecutive patients with intra-abdominal solid masses were enrolled prospectively between October 2011 and March 2013. EUS-guided fine needle biopsy (EUS-FNB) with a 22 G histology needle using capillary sampling with stylet slow-pull technique was performed. RESULTS: A total of 133 EUS-FNB procedures targeting the pancreas, lymph node, retroperitoneal mass, ampulla of Vater, gallbladder, common bile duct, duodenum, and liver were performed in 125 patients. EUS-FNB was technically feasible in all cases, and a visible core was obtained in 128 cases (96%). Histologic core specimens suitable for pathologic assessment were reported in 111 cases (83%). There were no procedure-related adverse events. According to the determinants of malignancy with EUS-FNB, the sensitivity, specificity, positive and negative predictive values, and accuracy were 85%, 98%, 99%, 77%, and 89%, respectively. In addition, histologic architecture with or without immunohistochemical staining of the core biopsy specimens was useful for pathologic confirmation in 101 cases (76%). CONCLUSIONS: A 22 G EUS-FNB using capillary sampling with stylet slow-pull technique showed a high diagnostic yield and histologic core acquisition for the histologic diagnosis of various intra-abdominal masses without an on-site cytopathologist. Furthermore, a histologic core with or without immunohistochemical staining was helpful for clinical decision making in 76% of the intra-abdominal solid masses.