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The diagnosis of type 2 autoimmune pancreatitis (AIP) is dependent on typical radiologic imaging and the presence of the granulocytic epithelial lesion (GEL), which is characterized by ductal neutrophilic infiltration with or without neutrophilic acinar infiltration.We evaluated GEL and related clinicopathologic factors in 165 resected heterotopic pancreata (HPs) [57 gastric (35%), 56 duodenal (34%), 30 omental (18%), and 22 jejunal (13%)] and 29 matched orthotopic pancreata routinely examined during surgery.GEL was noted in 8% (13/165) of HPs, including ductal epithelial (6/13, 46%) and intraluminal (8/13, 62%) neutrophilic infiltrations. However, there was no GEL in orthotopic pancreata. Abdominal pain was observed in 6 (46%) patients with GEL-positive HPs. GEL was more commonly observed in HPs having symptoms (p = 0.029), a larger size (p = 0.028), and an infiltrative growth pattern (p = 0.006). In addition, periductal lymphoplasmacytic infiltration and fibrosis (both p 0.001), interstitial fibrosis (p = 0.017), acinar neutrophilic infiltration (p = 0.032), venulitis (p = 0.050), acinar ductal metaplasia (ADM; p = 0.040), and pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasms (PanIN/IPMN; p 0.001) were more commonly seen in HPs with GEL than in those without GEL. Inflammatory bowel disease was present only in one patient with GEL-negative HP.GELs are detected in a subset of HPs without clinical evidence of AIP. Therefore, for the diagnosis of AIP, GEL should be carefully interpreted with the context of other histologic, clinical, and radiologic findings.

The T category of distal extrahepatic bile duct carcinoma (DBDC) is based on invasion depth from the basal lamina to the deepest infiltrating tumor cells. Recently, invasive tumor thickness (ITT) was proposed, defined as maximal vertical distance of invasive tumor components regardless of the basal lamina. We compared the predictive value of T category, and ITT grading in 424 surgically resected DBDCs. DBDCs were categorized as 6 Tis (1.4%), 134 T1 (5 mm; 31.6%), 204 T2 (5 to 12 mm; 48.1%), and 80 T3 (12 mm; 18.9%). With ITT, there were 6 G0 (no invasion; 1.4%), 3 G1 (1 mm; 0.7%), 90 G2 (≥1 and5 mm; 21.2%), 188 G3 (≥5 and10 mm; 44.4%), and 137 G4 (≥10 mm; 32.3%). The 5-year survival rates of T1, T2, and T3 were 58.9%, 44.2%, and 18.2%, and those of ITT G1, G2, G3, and G4 were 33.3%, 54.1%, 51.6%, and 26.7%, respectively. The T category discriminated patient survival by overall (P0.001) and pairwise (T1 vs. T2, P=0.007; T2 vs. T3, P0.001) comparisons. ITT grading distinguished survival by overall and between G3-G4 (both P0.001), with no survival differences observed between G1-G2 and G2-G3 comparisons. The T category more accurately discriminated patient survival than ITT grading. To determine the T category for DBDCs, (1) longitudinal sectioning on gross examination, especially for DBDCs with large papillary or nodular growth patterns; (2) evaluation of serial sections or alternative hematoxylin and eosin slides; (3) use of a straight or curved baseline depending on the shape of the peritumoral normal bile duct wall and/or the basal lamina of the peritumoral normal biliary epithelia/biliary intraepithelial neoplasias are recommended.

Background: Invasive breast carcinoma with a choriocarcinomatous pattern (IBC-CP) is extremely rare, and its molecular basis is yet unclear. The choriocarcinomatous pattern is characterized by the biphasic arrangement of multinucleated syncytiotrophoblast-like cells around clusters of monotypic tumor cells in a hemorrhagic background, along with β-human chorionic gonadotropin (β-hCG) expression. The differentiation of IBC-CP from metastatic choriocarcinoma of the breast (MC-B) is difficult due to the histologic similarity. Methods: Based on a literature review and our own case, the clinicopathologic differences between IBC-CP patients (n = 17) and MC-B patients (n = 8) were analyzed. Moreover, in our case of IBC-CP, next-generation sequencing (NGS) comparative analysis was conducted for both choriocarcinomatous and invasive breast carcinoma (IBC) components. Results: Compared to the MC-B patients, the IBC-CP patients were older (p < 0.001) and less frequently had past histories of gestational trophoblastic disease/pregnancy/abortion (p = 0.001) and distant metastases (p = 0.005). Our case, a 49-year-old female patient, presented with masses in the right breast and axilla. Following neoadjuvant chemotherapy, a radical mastectomy found an 8.5-cm-sized tumor. Microscopically, multinucleated syncytiotrophoblast-like cells were observed around mononuclear tumor cells with hemorrhage and necrosis. Some tumor cells showed β-hCG immunopositivity, which was compatible with IBC-CP. NGS results showed a missense mutation in exon 5 of the TP53 gene in both the choriocarcinomatous and IBC components. Meanwhile, copy number loss in the PTEN gene was only identified in the choriocarcinomatous components. Conclusion: The present IBC-CP case is triple-negative breast cancer with TP53 mutation. The PTEN gene may be associated with choriocarcinomatous differentiation. Obtaining a medical history is mandatory to exclude metastatic lesions.

Cyclin D1 is mainly known as an oncogenic driver in cancers, and the dysregulated cyclin D1/cyclin-dependent kinase (CDK) 4/6 axis is considered an attractive target for cancer therapy. Recent studies have reported that tumors respond to therapeutic interventions targeting altered cyclin D1 expression via application of the CDK4/6 inhibitor. However, the prognostic and therapeutic contributions of cyclin D1 to colorectal cancer (CRC) remain controversial. Herein, we assessed the associations between cyclin D1 expression and clinicopathological factors, including patients’ overall survival (OS) and recurrence-free survival (RFS), in 495 surgically resected primary CRCs. We also examined previous studies for cyclin D1 in CRCs. High expressions of cyclin D1 (cyclin D1High) was observed in 389 CRC cases (78.6%). Cyclin D1High consistently predicted better patient OS and RFS in CRCs. Based on multivariate analysis, cyclin D1High and young age of patients remained as independent prognosticators of higher OS rate, whereas cyclin D1High, females, chemotherapy, absence of nodal metastasis, and lower T-category remained as independent prognosticators of better RFS. Cyclin D1 is commonly overexpressed in CRCs, and its expression can be used as a favorable prognostic indicator in patients with CRCs; this may be important for predicting responses to subsequent CDK4/6 inhibitors.

Context.— The tumor-host interaction in the tumor microenvironment (TME) affects the prognosis of patients with malignant tumors. TME assessed via tumor budding (BD) and tumor-infiltrating lymphocyte (TIL) had a prognostic impact in patients with nonampullary small intestinal and colorectal carcinomas. In ampullary carcinoma (AC), MUC5AC was recently revealed as a significant prognosticator, but studies about the TME have not been conducted. Objective.— To assess TME-based prognostic risk in AC. Design.— We generated a collective TME risk index based on high-grade BD at the invasive front (BD3) and high density of stromal-TIL (>5%) in 64 surgically resected ACs. We evaluated its predictive values for overall survival (OS) and recurrence-free survival (RFS). We also investigated the relationship of TME to MUC5AC expression. Results.— TME prognostic risk index was classified into low-risk (BDLow/TILHigh; 26 of 64; 41%), intermediate-risk (BDLow/TILLow or BDHigh/TILHigh; 23; 36%), and high-risk (BDHigh/TILLow; 15; 23%) groups. Higher TME prognostic risk was associated with higher tumor grade (P = .03), lymphovascular invasion (P = .05), and MUC5AC immunopositivity (P = .02). TME prognostic risk index displayed better predictive ability for both OS (53.9 versus 46.1 versus 42.2) and RFS (24.8 versus 16.9 versus 15.3) than BD or TIL alone. In multivariate analysis, TME prognostic risk index was an independent prognosticator for OS (P = .003) and RFS (P = .03). Conclusions.— TME risk index in combination with BD and TIL was a stronger predictor of prognostic risk stratification than either BD or TIL alone for both OS and RFS in patients with AC. MUC5AC may modulate the interaction between tumor cells and immunity toward enhancing invasiveness in TME.

This study was performed to compare endoscopic mucosal resection (EMR) with hot snare polypectomy (HSP) in terms of the complete resection rate and the incidence of adverse events for resecting small (5–10 mm) colorectal polyps. Small colorectal polyps (5–10 mm) with neoplastic features were randomly allocated to either the HSP or EMR group. A submucosal injection was performed prior to hot snaring in the EMR group only. Complete resection was defined as the absence of neoplastic tissue from two additional biopsies of the polypectomy site. R0 resection was defined as the absence of neoplastic tissue at the margin of the resected specimen. A total of 362 colon polyps from 272 patients were included, and 167 polyps in the HSP group and 155 polyps in the EMR group were analyzed. Between the polypectomy techniques, there was no significant difference in the complete resection rates, which were 96.4% (161/167) in the HSP group and 95.5% (148/155) in the EMR group (P = 0.67). The R0 resection rate in the HSP and EMR groups was significantly different, with 49.7% (83/167) and 74.8% (116/155), respectively (P

The diagnosis of small intestinal adenocarcinoma (SIAC) is usually determined at an advanced stage due to non-specific symptoms and the difficulty of exploring the small intestine. Therefore, the majority of SIAC patients have limited chemotherapeutic options. Until recently, the development of novel and effective therapies for SIAC have been limited owing to the low number of samples that have been collected and the low incidence of SIAC. Immunotherapies are becoming a focus. However, in SIAC, only a few studies to identify immunotherapy-responsive subgroups and their prognostic indicators have been reported. In the present study, we categorise primary SIAC into four types of tumour immune microenvironments and propose a strategy for identifying patient subgroups that are most likely to be immunotherapy-responsive. Formalin-fixed, paraffin-embedded tissue samples of a multicentre cohort of patients with SIAC (n=195) were collected using tissue microarrays. Immunohistochemical (IHC) stains for PD-L1, PD-1, and CD8 were performed, and microsatellite instability was evaluated using an IHC stain. Tumour microenvironment immune type (TMIT) I [PD-L1-positive tumour cells and CD8-high tumour-infiltrating lymphocytes (TILs)] and TMIT III (PD-L1-positive tumour cells and CD8-low TILs) show the best and worse prognoses, respectively. PD-L1 expression was significantly associated with high microsatellite instability (MSI) status. CD8-high TILs were positively correlated with PD-1-high TILs and high MSI. The TMIT I subgroup demonstrated a more patent CD8/PD-L1/PD-1 signalling pathway compared to other TMITs. Therefore, the TMIT I subgroup can be expected to have an effective response to immune checkpoint inhibitor therapies in SIAC. Such classification of SIACs into four immune types can be useful in predicting the prognosis of patients and the identification of immunotherapy-responsive subgroups.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p &lt, 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p &lt, 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

Context.— The roles of the gallbladder and cystic duct (CD) invasions in distal bile duct carcinoma (DBDC) have not been well elucidated. Objective.— To define the characteristics and prognostic significance of gallbladder or CD invasions in patients with DBDC. Design.— Organ invasion patterns with clinicopathologic features were assessed in 258 resected DBDCs. Results.— CD invasions (N = 31) were associated with frequent concomitant pancreatic and/or duodenal invasions (23 of 31, 74%) and showed stromal infiltration (16 of 31, 52%) and intraductal cancerization (15 of 31, 48%) patterns. In only 2 cases, invasions with intraductal cancerization were observed in the gallbladder neck. Conversely, all pancreatic (N = 175) and duodenal (83) invasions developed through stromal infiltration. CD invasions were associated with larger tumor size (P = .001), bile duct margin positivity (P = .001), perineural invasions (P = .04), and higher N categories (P = .007). Patients with pancreatic or duodenal invasions had significantly lower survival rates than those without pancreatic (median, 31.0 versus 93.9 months) or duodenal (27.5 versus 56.8 months, P < .001, both) invasions. However, those with gallbladder or CD invasions did not have different survival times (P = .13). Patients with concomitant gallbladder/CD and pancreatic/duodenal invasions demonstrated significantly lower survival rates than those without organ invasions (P < .001). Conclusions.— Gallbladder invasions were rare in DBDCs as neck invasions with intraductal cancerization. CD invasions occurred by stromal infiltrations and intraductal cancerization, whereas all pancreatic and duodenal invasions had stromal infiltration patterns. Gallbladder and/or CD invasions did not affect survival rates of patients with DBDC, while pancreatic and duodenal invasions affected survival rates. Therefore, these differences in survival rates may originate from the different invasive patterns of DBDCs.

Purpose To investigate the correlation of the strain elasticity of breast cancer with histologic features, immunohistochemical markers and molecular subtypes that are known to be factors related to prognosis. Materials and Methods B-mode ultrasound and strain elastography were performed in 123 patients (mean age, 53.4; range, 28–82) with invasive ductal carcinoma (IDC) (mean size, 1.54 cm; range, 0.4–7.0 cm). Histologic grade, lymph node (LN) status, lymphovascular invasion, immunohistochemical biomarkers [estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), CK5/6, epidermal growth factor receptor, and Ki-67] and molecular subtypes were determined from surgical pathology reports. The relationships between these factors and elasticity scores were evaluated. Results LN involvement was associated with a higher elasticity score which was statistically significant (p = 0.042). The tumor size, lymphovascular invasion, histologic grades, immunohistochemical markers and molecular subtypes had no significant correlation with the elasticity score (p > 0.05 for all). However, the IDCs with larger size and a positive lymphovascular invasion tended to have higher elasticity scores. Furthermore, higher histologic grade cancers and the HER2 overexpression-type tended to have lower elasticity scores. Conclusion The elasticity score of IDC had a significant correlation with LN involvement but no statistically significant correlation with the histologic features, immunohistochemical markers or molecular subtypes.

Background and Aims Cold snare polypectomy (CSP) and jumbo forceps polypectomy (JFP) have been shown to be effective for removing diminutive colorectal polyps (DCPs) (≤5 mm). However, no study has compared complete resection rates between CSP and JFP for DCPs. The aim of this study was to compare the efficacy and safety of JFP with CSP for the removal of DCPs. Methods This was a prospective randomized controlled trial from 2 tertiary-care referral centers. A total of 1003 patients were screened, and 169 patients with 196 DCPs were enrolled. The main outcome was complete polyp resection rate. Results Of 196 diminutive polyps, 177 (90.3%) were adenomatous polyps. The overall complete resection rate was 92.1% (163/177). The complete resection rate was not significantly different between JFP and CSP groups (92.0% vs 92.2%; P = .947). JFP achieved complete resection rates comparable with CSP for polyps >3 mm (90.3% vs 89.8%; P = .928). Polypectomy procedure time, tissue retrieval rate, and rate of postpolypectomy adverse events were not significantly different between the 2 groups. Conclusions Both JFP and CSP achieved complete resection rates of >90% for DCPs. Thus, JFP may be considered for polypectomy of DCPs. (International clinical trial registry number: KCT0002805.)

BackgroundGallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs.Materials and MethodsTo determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively.ResultsThree of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status.ConclusionMMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

Background: Endoscopic ultrasound-guided ablation (EUS-A) therapy is a minimally invasive procedure for pancreatic-cystic tumors in patients with preoperative comorbidities or in patients who are not indicated for surgical resection. However, histopathologic characteristics of pancreatic cysts after ablation have not been well-elucidated. Methods: Here, we analyzed pathological findings of 12 surgically resected pancreatic cysts after EUS-A with ethanol and/or paclitaxel injection. Results: Mean patient age was 49.8 ± 13.6 years with a 0.3 male/female ratio. Clinical impression before EUS-A was predominantly mucinous cystic neoplasms. Mean cyst size before and after ablation therapy was similar (3.7 ± 1.0 cm vs. 3.4 ± 1.6 cm; p = 0.139). Median duration from EUS-A to surgical resection was 18 (range, 1–59) months. Mean percentage of the residual neoplastic lining epithelial cells were 23.1 ± 37.0%. Of the resected cysts, 8 cases (67%) showed no/minimal (Conclusion: Above all, diffuse egg shell-like calcification along the pancreatic cystic walls with residual lining epithelia and/or ovarian-type stroma were characteristics of pancreatic cysts after EUS-A. Therefore, understanding these histologic features will be helpful for precise pathological diagnosis of pancreatic cystic tumor after EUS-A, even without knowing the patient’s history of EUS-A.

The tumor microenvironment (TME) has become an important area of investigation with respect to improving prognosis in malignancies. Here we evaluated TME prognostic risk in small intestinal adenocarcinomas based on histologic assessment of tumor budding at the peritumoral-invasive front (pTB) and stromal tumor-infiltrating lymphocytes (sTILs). pTB and sTILs were analyzed in 230 surgically resected small intestinal adenocarcinomas, as recommended by the International Tumor Budding Consensus Conference (ITBCC) and the International TILs Working Group (ITWG). On the basis of high levels of pTB count (≥10) and sTIL density (≥20%), we combined pTB and sTIL to produce a collective TME-based prognostic risk index: low-risk (pTBLow/sTILHigh; n=39, 17.0%), intermediate-risk (pTBLow/sTILLow or pTBHigh/sTILHigh; n=99, 43.0%), and high-risk groups (pTBHigh/sTILLow; n=92, 40.0%). TME risk index provided better prognostic stratification than the individual pTB and sTIL (14.9 vs. 6.7 vs. 10.3). Tumors with higher TME prognostic risk were associated with an infiltrative growth pattern and nonintestinal immunophenotype (both P=0.001), pancreatic invasion (P=0.010), lymphovascular (P

We thank Giuffrida et al [...]

Objective: Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to KRAS mutations. HES-1 has been proposed as harboring oncogenic activity in colorectal cancer but has not been investigated in adenocarcinoma of the small intestine, where the drivers of oncogenesis are not as well understood. Materials and Methods: To investigate the clinicopathologic and prognostic implications of HES-1, HES-1 immunohistochemical expression was analyzed in digital images along with clinicopathological variables, including survival and KRAS genotype, in 185 small intestinal adenocarcinomas. Results: The loss of HES-1 expression (HES-1Loss) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category (P = 0.018), pancreatic invasion (P = 0.005), high grade (P =0.043), and non-tubular histology (P = 0.004). Specifically, in tumors with mutant KRAS (KRASMT), HES-1Loss was related to proximal location (P = 0.024), high T and N categories (P = 0.005 and P = 0.047, respectively), and pancreatic invasion (P = 0.004). Patients with HES-1Loss showed worse overall survival compared to those with intact HES-1 (HES-1Intact) (P = 0.013). Patients with HES-1Loss/KRASMT (median, 17.3 months) had significantly worse outcomes than those with HES-1Intact/KRASWT (39.9 months), HES-1Intact/KRASMT (47.6 month), and HES-1Loss/KRASWT (36.2 months) (P = 0.010). By multivariate analysis, HES-1Loss (hazard ratio = 1.55, 95% confidence interval (CI), 1.07 – 2.26; P = 0.022) remained an independent prognostic factor. Conclusion: HES-1 expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters &le, 4 tumor cells) and PDC (clusters &ge, 5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (&le, 4), grade-2 (5&ndash, 9), or grade-3 (&ge, 10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months, p = 0.007) in the lower stage (stages I&ndash, II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.

Purpose T category of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for distal bile duct carcinoma (DBDC) was changed to include tumor invasion depth measurement, while the N category adopted a 3-tier classification system based on the number of metastatic nodes. Materials and Methods To validate cancer staging, a total of 200 surgically resected DBDCs were staged and compared according to the seventh and eighth editions. Results T categories included T1 (n=37, 18.5%), T2 (n=114, 57.0%), and T3 (n=49, 24.5%). N categories included N0 (n=133, 66.5%), N1 (n=50, 25.0%), and N2 (n=17, 8.5%). Stage groupings included I (n=33, 16.5%), II (n=150, 75.0%), and III (n=17, 8.5%). The overall 5-year survival rates (5-YSRs) of T1, T2, and T3 were 59.3%, 42.4%, and 12.2%, respectively. T category could discriminate patient survival by both pairwise (T1 and T2, p=0.011; T2 and T3, p < 0.001) and overall (p < 0.001) comparisons. The overall 5-YSRs of N0, N1, and N2 were 47.3%, 17.0%, and 14.7%, respectively. N category could partly discriminate patient survival by both pairwise (N0 and N1, p < 0.001; N1 and N2, p=0.579) and overall (p < 0.001) comparisons. The overall 5-YSRs of stages I, II, and III were 59.0%, 35.4%, and 14.7%, respectively. Stages could distinguish patient survival by both pairwise (I and II, p=0.002; II and III, p=0.015) and overall (p < 0.001) comparisons. On multivariate analyses, T and N categories (p=0.014 and p=0.029) and pancreatic invasion (p=0.006) remained significant prognostic factors. Conclusion The T andNcategories of the eighth edition AJCC staging system for DBDC accurately predict patient prognosis.

The presence of KRAS mutation enhances the stem cell features of colorectal carcinoma cells containing mutant adenomatous polyposis coli (APC). However, their potential role in small intestinal adenocarcinoma remains elusive. Here, we aimed to investigate the clinical significance of cancer stem cell markers expression in the context of small intestinal adenocarcinoma with the KRAS genotype. SOX2, NANOG, and OCT4 expression were assessed by immunohistochemistry and digital image analysis, and their potential association with KRAS was further examined in 185 Korean patients with small intestinal adenocarcinomas, which were collected from 22 institutions in South Korea. Positive expression of SOX2, NANOG, and OCT4 was detected in 65 (35.1%), 94 (50.8%), and 82 (44.3%) of patients, respectively. Patients with high SOX2 (SOX2+) expression displayed worse overall survival compared to those with low SOX2 (SOX2−) expression (P < 0.001). Patients with SOX2+/mutant KRAS (KRAS(MT)) (11.1 months) had significantly shorter overall survival than those with SOX2−/KRAS(WT) (53.6 months) (P < 0.001). In multivariate analysis, SOX2+, distal location, high pT and pN categories, microsatellite stable, and absence of predisposing diseases were independent prognostic factors for worse overall survival. These results suggest that SOX2 expression has the potential to predict clinical outcomes in patients with small intestinal adenocarcinomas.

Heme oxygenase-1 (HO-1), a stress-response protein, is highly induced in various carcinomas. It is implicated in carcinogenesis and tumor progression. High HO-1 expression is associated with better prognosis of patients with colorectal and gastric cancers. Induction or inhibition of HO-1 can mediate chemo-sensitivity, therefore it might be a therapeutic target to develop anticancer agents. To define the clinicopathological and prognostic significance of HO-1 expression in small-intestinal adenocarcinomas (SIACs), immunohistochemical microarray analysis of HO-1 expression was performed for 191 surgically resected SIAC cases and results were compared with various clinicopathologic variables, including survival. HO-1 was highly expressed in 127 (66.5%) cases. Patients with high HO-1 expression were associated with younger age (P = 0.048), lower pT category (P = 0.017), and less pancreatic invasion (P = 0.047). Patients with high HO-1 expression tended to have longer overall survival (median, 38.5 months) than those with low HO-1 expression (24.5 months), although the difference in overall survival was not statistically significant (P = 0.677). In summary, high HO-1 expression is frequently observed in SIACs. It is related to favorable clinicopathologic parameters, including younger age, lower T category, and less pancreatic invasion. Therefore, HO-1 may serve as a prognostic marker and a new target to modulate chemotherapeutic effects in patients with SIACs.

This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2′3′-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC). Among the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. Meanwhile, CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. During the median follow-up duration of 39 months, 14 (15.7%) patients experienced disease recurrence. Among the five immune checkpoint proteins, CD274, LAG3, and IDO1 expressions in TIICs were significantly associated with a better disease-free survival (DFS) in a univariate analysis (P = 0.028, 0.037, and 0.030 respectively). Moreover, co-expression of CD274, LAG3, and IDO1 in TIICs showed an even better survival for DFS (P = 0.010). In a multivariate survival analysis, CD274, LAG3, and IDO1 expressions in TIICs remained as independent prognostic factors for a better DFS. CD274, LAG3, and IDO1 expressions in TIICs showed a better prognosis for patients with MSI-H colon cancer. Thus, the potential therapeutic implications of these immune checkpoint molecules should be further investigated.

Background Histologic grade is the most important predictor of the clinical outcome of non-muscle invasive (Ta, T1) papillary urothelial carcinoma (NMIPUCa), but its ambiguous criteria diminish its power to predict recurrence/progression for individual patients. We attempted to find an objective and reproducible histologic predictor of NMIPUCa that correlates well with the clinical outcome. Methods A total of 296 PUCas were collected from the Departments of Surgical Pathology of 11 institutions in South Korea. The clinical outcome was grouped into no event (NE), recurrence (R), and progression (P) categories. All 25 histological parameters were numerically redefined. The clinical pathology of each case was reviewed individually by 11 pathologists from 11 institutions based on the 2004 WHO criteria and afterwards blindly evaluated by two participants, based on our proposed parameters. Univariate and multivariate logistic regression analyses were performed using the R software package. Results The level of mitoses was the most reliable parameter for predicting the clinical outcome. We propose a four-tiered grading system based on mitotic count (> 10/10 high-power fields), nuclear pleomorphism (smallest-to-largest ratio of tumor nuclei >20), presence of divergent histology, and capillary proliferation (> 20 capillary lumina per papillary core). Conclusions The level of mitoses at the initial bladder biopsy and transurethral resection (TUR) specimen appeared to be an independent predictor of the Ta PUCa outcome. Other parameters include the number of mitoses, nuclear pleomorphism, divergent histology, and capillary proliferation within the fibrovascular core. These findings may improve selection of patients for a therapeutic strategy as compared to previous grading systems. Electronic supplementary material The online version of this article (doi:10.1186/s13000-017-0639-y) contains supplementary material, which is available to authorized users.

// Sun-Young Jun 1 , Eui-Jin Lee 2 , Mi-Ju Kim 3 , Sung Min Chun 4 , Young Kyung Bae 5 , Soon Uk Hong 6 , Jene Choi 4 , Joon Mee Kim 7 , Kee-Taek Jang 8 , Jung Yeon Kim 9 , Gwang Il Kim 10 , Soo Jin Jung 11 , Ghilsuk Yoon 12 , Seung-Mo Hong 4 1 Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea 2 Institute of Catholic Integrative Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea 3 Asan Institute for Life Science, Asan Medical Center, Seoul, Korea 4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 5 Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea 6 Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea 7 Department of Pathology, Inha University College of Medicine, Incheon, Korea 8 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9 Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea 10 Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, Korea 11 Department of Pathology, Inje University College of Medicine, Busan, Korea 12 Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea Correspondence to: Seung-Mo Hong, email: smhong28@gmail.com Ghilsuk Yoon, email: gsyoon@knu.ac.kr Keywords: small intestinal adenocarcinoma, Lynch syndrome, hereditary nonpolyposis colorectal cancer syndrome, microsatellite instability, DNA mismatch repair Received: September 09, 2016 Accepted: January 24, 2017 Published: February 11, 2017 ABSTRACT Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P =0.04) and more likely to have mucinous adenocarcinomas ( P= 0.003), and tended to survive longer ( P =0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.

The clinicopathological and prognostic significance of olfactomedin-4 (OLFM4) expression has not yet been elucidated in extrahepatic bile duct carcinomas (EBDCs). Immunohistochemical analysis of OLFM4 expression in 31 normal biliary epithelia, 33 biliary intraepithelial neoplasias (BilINs), and 180 surgically resected EBDCs (54 perihilar and 126 distal) was performed and was used to analyze clinicopathological variables including patient survival. The expression of OLFM4 showed a progressive increase from normal biliary epithelia (0.2 ± 0.4) to BilINs (2.8 ± 3.2) to EBDCs (4.6 ± 4.2; P0.001). OLFM4 was highly expressed in 26.1% (47/180) of the EBDC cases, and high OLFM4 levels were more frequently observed in tumors with nodular growth (P = 0.029), well differentiation (P = 0.011), and lower T-category (P = 0.025) and stage grouping (P = 0.013). Patients with EBDC having high expression of OLFM4 had better survival than those with low expression of OLFM4 (median, 43.3 vs. 29.2 months; P = 0.037). OLFM4 might play an important role in carcinogenesis and in the progression from BilINs to EBDCs. High OLFM4 expression predicted less aggressive clinical behavior in patients with EBDC.

International audience; The popular superalloy Alloy 625 was produced by Selective Laser Melting (SLM) and post-processing heat treatments were designed to optimize the inhomogeneous and constrained as-built microstructure (AB) for high temperature structural applications. A single-step solution heat treatment (RX) was designed to promote full recrystallization and approach the conventional wrought microstructure. To enhance high temperature properties, a grain boundary serration heat treatment (GBS) was successfully designed involving higher solution temperature and time to promote recrystallization and homogeneity, and a direct slow cooling step followed by a short aging to assist solute diffusion and grain boundary motion. The resulting microstructures were characterized by fully recrystallized fine equiaxed grains and fine intra and intergranular NbC precipitates. The GBS alloy also exhibited as much as 80% of serrated grain boundaries with enhanced resistance to cracking at high temperatures. Tensile properties of all three materials were evaluated at room temperature, 500 °C, 600 °C and 700 °C and compared with their conventional solutionized wrought Alloy 625 counterpart (Wrought). While the AB material exhibited high strength and low ductility, due for the most part to the high density of tangled dislocations resulting from SLM, both RX and GBS alloys showed tensile properties comparable to the conventional wrought material, higher strength in particular. At all temperatures, all four alloys exhibited yield strength values well over 200 MPa. Due to significantly different microstructures, deformation and fracture behaviors were different. While Wrought clearly presented irregular plastic flow at elevated temperatures typically attributed to dynamic strain aging (DSA), the materials produced by SLM and moreover those subjected to post-processing heat treatments exhibited more stable plastic deformation. The results and characterization reported in the present article highlight the predominant role of microstructure and outstanding potential of SLMed Alloy 625.

Objectives Assessment of tumor-infiltrating lymphocytes (TILs) may predict the prognosis and therapeutic benefit of immunotherapy in small intestinal adenocarcinoma (SIAC) patients. Methods TILs were evaluated in 231 surgically resected SIACs and compared with microsatellite instability (MSI) and clinicopathologic variables. The average number of intraepithelial TILs (iTILs) and the average density of stromal TILs (sTILs) were calculated separately. Results High iTIL count (≥2 per high-power field) was associated with MSI-high, whereas high sTIL density (≥20% on ×200 magnification) was not. High iTIL count and high sTIL density were related to distal tumor location, medullary carcinoma, high Crohn-like lymphoid reaction counts, and fewer pancreatic invasions. SIAC patients with high iTIL count or high sTIL density had better survival than those with low values. On multivariate analysis, MSI, high sTIL density, proximal locations, lower N category, and absence of lymphovascular invasions and retroperitoneal seeding were the best independent prognostic predictors. Conclusions High sTIL density can be used as a prognostic indicator and high iTIL count may provide a basis for the clinical use of targeted immunotherapy in SIAC patients.

The detection of high-risk human papillomavirus (HR-HPV) is important for early diagnosis of precancerous cervical lesion. The distribution of HR-HPV genotypes in East Asia is different from that in Western countries. HR-HPVs non-16/18 including HPV-58 are highly prevalent in East Asia. Thus, a variety of HPV tests that could identify individual genotypes have been widely used. HPV 9G DNA is a deoxyribonucleic acid-based chip test, while PANArray HPV chip is a peptide nucleic acid-based array. We compared the analytic performance of these two chips for detecting and genotyping HR-HPV using 356 liquid-based cytology specimens and evaluated their diagnostic accuracies based on direct sequencing. For identifying HR-HPV, PANArray HPV and HPV 9G DNA chips agreed with each other for 85.1% of samples. Overall strength of agreement between the two tests was substantial (k = 0.68). Specifically, these two tests almost perfectly agreed for detecting several types of HR-HPV, including HPV-16, -18, -35, -52, -58, and -59 (k>0.81 for all). According to direct sequencing, PANArray HPV produced consistently higher sensitivities for detecting HR-HPV than HPV 9G DNA for either overall or individual genotypes of HR-HPV. Sensitivities and specificities for detecting HPV-58 were perfect (100%) with PANArray HPV. In conclusion, PANArray HPV is more effective than HPV 9G DNA in detecting HR-HPV. It is more useful for regions with high prevalent HPV-58 infection.

Nonductal pancreatic neoplasms, including solid pseudopapillary neoplasms, acinar cell carcinomas, and pancreatoblastomas, are uncommon. These entities share overlapping gross, microscopic, and immunohistochemical features, such as well-demarcated solid neoplasms, monotonous cellular tumor cells with little intervening stroma, and abnormal beta-catenin expression. Each tumor also has unique clinicopathologic characteristics with diverse clinical behavior. To differentiate nonductal pancreatic neoplasms, identification of histologic findings, such as pseudopapillae, acinar cell features, and squamoid corpuscles, is important. Immunostainings for acinar cell or neuroendocrine markers are helpful for differential diagnosis. This article describes the clinicopathologic and immunohistochemical features of nonductal pancreatic cancers.

Several techniques are recommended for the histologic diagnosis of gastric subepithelial tumors (SETs). The purpose of our study was to evaluate the diagnostic yield and safety of endoscopic ultrasonography-guided single-incision needle knife (SINK) biopsy for the diagnosis of gastric SETs. A retrospective review of patients who received biopsy for gastric SETs from August 2012 to May 2015 was conducted. Patients who received endoscopic ultrasonography and were found to have a SET originating from the muscularis propria of the stomach were included in the study. The aim of our study was to investigate the safety and diagnostic yield of SINK biopsy for gastric SETs. A total of 31 patients received SINK biopsy for SETs. The diagnostic yield of SINK biopsy was 87 % (95 % CI 75–100 %), and the diagnostic accuracy was 89 % (95 % CI 74–105 %). The sensitivity of SINK biopsy to identify gastrointestinal stromal tumors was 83 % (95 % CI 52–98 %); the specificity was 100 % (95 % CI 59–100 %); the positive predictive value was 100 % (95 % CI 69–100 %); and the negative predictive value was 78 % (95 % CI 40–97 %). There were no procedure-related adverse events during and after procedure. The use of SINK biopsy technique in patients with SETs is a good diagnostic tool with high diagnostic yield and accuracy. The method is simple, safe, and associated with few complications.

The influence of 0.015 wt% Ti addition on the formation of MX precipitates and the creep resistances of a reduced activation ferritic/martensitic (RAFM) steel has been studied. 0.1 wt% Ta was also added as same as conventional RAFM steels. Transmission electron micrographs taken from extraction replicas indicated that the area fraction of MX particles in Ta/Ti-added RAFM steel was 2.3 times higher than that in the reference steel. Atom probe tomography was employed to identify the types of MX precipitates and their interactive distribution. By using isoconcentration surfaces with different elemental concentration values, it was newly found that there are three types of MX precipitates, i.e. (Ta,V)-rich MX, Ti-rich MX and W-rich MX in the Ta/Ti-added RAFM steel. They appeared to be distributed independently in the matrix. However, in some cases, smaller sized (Ti or W)-rich MX particles were in contact with large (Ta,V)-rich MX particle. The creep rupture life of the Ta/Ti-added RAFM steel was significantly improved, as compared with the reference steel. The enhanced creep resistance can be rationalized in terms of a high density of dislocations, which were produced by a strong interaction with a higher fraction of the nano-sized MX particles within laths.

Recently, a high-risk human papillomavirus (HR-HPV) detecting assay alone could be used as a first-line screening tool for cervical cancer, although the test system has been limited to the Cobas 4800 HPV test. However, the screening efficiency of the HPV chip, which is widely used in Eastern Asia because of the high prevalence of non16/18 HR-HPV genotypes, has not been well elucidated. After selecting 300 women who were co-tested using the PANArray HPV chip and the ThinPrep assay and had confirmed histological diagnoses, we evaluated the diagnostic accuracy of the PANArray HPV test based on direct sequencing and clinical performance compared to the ThinPrep alone and co-testing. HR-HPVs were identified in 212 (70.7 %) patients by the PANArray HPV test. The results of the PANArray HPV test and direct sequencing for detecting HR-HPVs were in almost perfect agreement, consistent in 95.3 % of the cases (k = 0.89). HR-HPVs were more commonly detected by the PANArray HPV assay in patients with high-grade squamous intraepithelial lesions (HSILs) or worse (p < 0.001, both) by cytological and histological examinations. The PANArray HPV test had higher sensitivity (91.7 %) than the ThinPrep (52.6 %) but co-testing increased the sensitivity for predicting HSIL or worse cervical lesions to 99.2 %. In conclusion, the PANArray HPV test accurately detected HR-HPVs determined by cytological and histological examinations to be HSIL or worse cervical lesions. The PANArray HPV assay alone was more sensitive than the ThinPrep alone for detecting HSIL or worse cervical lesions, however, co-testing enhanced the sensitivity. Co-testing is more useful for screening HSIL or worse lesions than use of either the ThinPrep or PANArray HPV genotyping alone.

In this study, the selective electron beam melting (SEBM) process was used to fabricate Inconel 718 superalloy, and their microstructures and creep resistances were investigated. The proper SEBM condition ensuring a relative density higher than 99.9% was found in electron beam current range of 24–30 mA at a scanning speed of 4500 mm/s and a preheat temperature of 1025 °C, from which the SEBMed Inconel 718 exhibited an unidirectional columnar grain microstructure with a strong texture along building direction. It was suggested that the local thermal condition during solidification after SEBM facilitates a continuation of epitaxial growth of crystals on layer beneath. The γ″ precipitates formed in the as-built condition regardless of focus offset, and their size increased with increasing focus offset from 1 to 12 mA. The creep rupture life of the as-built sample fabricated with focus offset of 12 mA showed 2 times longer than that of conventional forged Inconel 718 subjected to full heat treatment under creep condition of 650 °C/700 MPa. EBSD analysis on the crept samples indicated that strain accumulation was significant at the porosities and the high-angle grain boundaries. Additionally, the grain boundaries inclined to loading axis were more damaged during creep. The γ″ particles were occasionally sheared by matrix dislocations with Burger vector of a/2 , without leaving stacking faults behind. The enhanced creep resistance of SEBMed Inconel 718 superalloy can be attributed to the columnar microstructure with a strong texture and the high density of dislocations resulted from strong interaction with the γ″ particles.

Background The optimal technique for removal of diminutive or small colorectal polyps is debatable. Objective To compare the complete resection rates of cold snare polypectomy (CSP) and cold forceps polypectomy (CFP) for the removal of adenomatous polyps ≤7 mm. Design Prospective randomized controlled study. Setting A university hospital. Patients A total of 139 patients who were found to have ≥1 colorectal adenomatous polyps ≤7 mm. Interventions Polyps were randomized to be treated with either CSP or CFP. After the initial polypectomy, additional EMR was performed at the polypectomy site to assess the presence of residual polyp tissue. Main Outcome Measurements Absence of residual polyp tissue in the EMR specimen of the polypectomy site was defined as complete resection. Results Among a total of 145 polyps, 128 (88.3%) were adenomatous polyps. The overall complete resection rate for adenomatous polyps was significantly higher in the CSP group compared with the CFP group (57/59, 96.6% vs 57/69, 82.6%; P = .011). Although the complete resection rates for adenomatous polyps ≤4 mm were not different (27/27, 100% vs 31/32, 96.9%; P = 1.000), the complete resection rates for adenomatous polyps sized 5 to 7 mm was significantly higher in the CSP group compared with the CFP group (30/32, 93.8% vs 26/37, 70.3%; P = .013). Limitations Single-center study. Conclusion CSP is recommended for the complete resection of colorectal adenomatous polyps ≤7 mm. (Clinical trial registration number: NCT01665898.)

Background: This study investigated survival differences following intra-operative frozen-section examination of bile duct resection margins and final longitudinal margin status (LMS) in distal bile duct cancer confined to the intra-pancreatic portion. No studies have examined the relationship between LMS and survival for distal bile duct cancer. Methods: Overall, 193 patients underwent Whipple's operation for curative resection of distal bile duct cancer from 2008 to 2016 at the Asan Medical Center, Seoul, Republic of Korea. Patients were sorted into 2 and 3 groups according to LMS of frozen-sections and LMS of the final pathological specimen results: R0 on first bile duct resection (Primary R0), R0 after additional resection (Secondary R0), and no evidence of residual carcinoma (FR0), carcinoma in situ or high-grade dysplasia (FR1-CIS/HGD), or invasive carcinoma (FR1-INV). Survival and prognostic factors according to LMS were analyzed. Findings: There were no differences between primary R0 and secondary R0 in 5-year overall survival (OS) (60.8% vs. 46.1%, P = 0.969) or diseasefree survival (DFS) (54·6% vs. 54·9%, P = 0·903). The 5-year OS after FR0, FR1-CIS/HGD, FR1-INV were 59·3%, 59·5%, 14·3%, respectively. There was no difference between FR0 and FR1-CIS/HGD (P = 0·842). Final margin status of the bile duct was an independent prognostic factor by multivariable analyses. Interpretation: If R0 of final longitudinal margin status was achieved, it would help to improve survival regardless of R0 through additional resection. And, it should be avoided remaining invasive cancer at the longitudinal margin whenever possible. Funding Statement: This study was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (grant number: HI14C2640). Declaration of Interests: The authors declare no competing interests in relation to this study. Ethics Approval Statement: Data collection and analysis were performed according to the institutional guidelines, which conformed to the ethical standards of the Declaration of Helsinki. Institutional Review Board approval was obtained on December 22, 2017 (No. 2017-1407).

Heme oxygenase-1 (HO-1), a stress-response protein, is highly induced in various carcinomas. It is implicated in carcinogenesis and tumor progression. High HO-1 expression is associated with better prognosis of patients with colorectal and gastric cancers. Induction or inhibition of HO-1 can mediate chemo-sensitivity, therefore it might be a therapeutic target to develop anticancer agents. To define the clinicopathological and prognostic significance of HO-1 expression in small-intestinal adenocarcinomas (SIACs), immunohistochemical microarray analysis of HO-1 expression was performed for 191 surgically resected SIAC cases and results were compared with various clinicopathologic variables, including survival. HO-1 was highly expressed in 127 (66.5%) cases. Patients with high HO-1 expression were associated with younger age (P = 0.048), lower pT category (P = 0.017), and less pancreatic invasion (P = 0.047). Patients with high HO-1 expression tended to have longer overall survival (median, 38.5 months) than those with low HO-1 expression (24.5 months), although the difference in overall survival was not statistically significant (P = 0.677). In summary, high HO-1 expression is frequently observed in SIACs. It is related to favorable clinicopathologic parameters, including younger age, lower T category, and less pancreatic invasion. Therefore, HO-1 may serve as a prognostic marker and a new target to modulate chemotherapeutic effects in patients with SIACs.

Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs (57 gastric [35%], 56 duodenal [34%], 30 omental [18%], and 22 jejunal [13%]). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P

The clinicopathological and prognostic significance of CDX2 and mucin expression have not been comprehensively evaluated in small intestinal adenocarcinoma. Immunohistochemical microarray analyses of CDX2, MUC1, MUC5AC, and MUC6 protein expressions in 189 surgically resected small intestinal adenocarcinoma cases were examined and compared with various clinicopathologic variables, including survival. CDX2, MUC1, MUC5AC, and MUC6 expressions were observed in 43.4% (82 patients), 37.6% (71), 31.7% (60), and 21.7% (41) of patients, respectively. Whereas CDX2 expression was found to be associated with low-grade tumors (P=0.034), fewer nodal metastases (P=0.019), and less perineural invasion (P=0.049) in small intestinal adenocarcinoma patients, patients expressing MUC1 tended to demonstrate high-grade (P=0.021) and nodular or infiltrative (P=0.020) tumors. On the basis of the combined CDX2, MUC1, MUC5AC, and MUC6 expression patterns, small intestinal adenocarcinoma patients were further classified as intestinal (CDX2+/MUC1-; 29.6%), pancreatobiliary (CDX2-/MUC1+; 23.8%), mixed (CDX2+/MUC1+; 13.8%), gastric (CDX2-/MUC1-/MUC5AC+ or MUC6+; 13.8%), or null (CDX2-/MUC1-/MUC5AC-/MUC6-; 19.0%). Among these immunophenotypes, intestinal-type patients demonstrated more frequent distal (jejunal or ileal; P=0.033), tubular (P=0.039), and low-grade tumors (P=0.004) and significantly better survival according to univariate (P

Pseudomyxoma peritonei (PMP) cases can be classified into the prognosis-related subtypes of disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). To investigate the mechanisms of mucinous invasion and the differing prognoses of these two subtypes, we examined the expression levels of proteins involved in cellular adhesion and invasion, including E-cadherin, vimentin, β-catenin, and S100A4, in single isolated tumor cells (SICs) and cohesive cellular strips within mucin pools isolated from DPAM (n = 31) and PMCA (n = 21) patients. In both PMCA and DPAM cases, SICs showed a complete loss of E-cadherin expression, whereas cells in cohesive cellular clusters retained E-cadherin expression. The frequency of high numbers of SICs (>8) in PMCA cases was significantly greater than that in DPAM cases (86% and 26%, respectively) and was correlated with poor progression-free survival (P = 0.019) in a univariate analysis. In both PMP subtypes, strong vimentin expression was identified in most of the SICs but not the cohesive cellular strips. The relatively slow progression of DPAM may be attributable to the smaller number of SICs that lack E-cadherin expression and have increased vimentin expression, whereas the rapid progression of PMCA may be due to larger numbers of these SICs.