The Number of Lymph Nodes Examined is Associated with Survival Outcomes of Neuroendocrine Tumors of the Jejunum and Ileum (siNET): Development and Validation of a Prognostic Model Based on SEER Database.

PURPOSE: The number of neuroendocrine tumors (NETs) is gradually increasing worldwide, and those located in the small intestine (siNETs) are the most common. As some biological and clinical characteristics of tumors of the jejunum and the ileum differ, there is a need to assess the prognosis of individuals with siNETs of the jejunum and ileum separately. We generated a predictive nomogram by assessing individuals with siNETs from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: We used univariate Cox regression analysis to determine both the overall survival (OS) and the cancer-specific survival (CSS) of 2501 patients with a pathological confirmation of siNETs of the jejunum and ileum. To predict 3-, 5-, and 10-year OS of siNETs, a nomogram was generated based on a training cohort and validated with an external cohort. Accuracy and clinical practicability were evaluated separately by Harrell's C-indices, calibration plots, and decision curves. The correlation was examined between dissected lymph nodes and positive lymph nodes. RESULTS: Dissection of 7 or more lymph nodes significantly improved patient OS and was found to be a protective factor for patients with siNETs. In Cox regression analyses, age, primary site, tumor size, N stage, M stage, and regional lymph node examination were significant predictors in the nomogram. A significant positive correlation was found between dissected lymph nodes and positive lymph nodes. CONCLUSIONS: Patients with 7 or more dissected lymph nodes showed an accurate tumor stage and a better prognosis. Our nomogram accurately predicted the OS of patients with siNETs.

Molecular profiling and identification of prognostic factors in Chinese patients with small bowel adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Despite prior studies, molecular characterization of this disease is not well defined, and little is known regarding Chinese SBA patients. In this study, we conducted multigene next-generation sequencing and 16S ribosomal RNA gene sequencing on samples from 76 Chinese patients with surgically resected primary SBA. Compared with colorectal cancer and Western SBA cohorts, a distinctive genomic profile was revealed in Chinese SBA cohorts. According to the levels of clinical actionability to targetable alterations stratified by OncoKB system, 75% of patients harbored targetable alterations, of which ERBB2, BRCA1/2, and C-KIT mutations were the most common targets of highest-level actionable alterations. In DNA mismatch repair-proficient (pMMR) patients, significant associations between high tumor mutational burden and specific genetic alterations were identified. Moreover, KRAS mutations/TP53 wild-type/nondisruptive mutations (KRASmut /TP53wt/non-dis ) were independently associated with an inferior recurrence-free survival (hazard ratio [HR] = 4.21, 95% confidence interval [CI] = 1.94-9.14, P < .001). The bacterial profile revealed Proteobacteia, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Cyanobacteria were the most common phyla in SBA. Furthermore, patients were clustered into three subgroups based on the relative abundance of bacterial phyla, and the distributions of the subgroups were significantly associated with the risk of recurrence stratified by TP53 and KRAS mutations. In conclusion, these findings provided a comprehensive molecular basis for understanding SBA, which will be of great significance in improving the treatment strategies and clinical management of this population.

Characteristics and prognosis of jejunoileal gastrointestinal stromal tumours (GISTs) in the era of imatinib: a comparative study with gastric GISTs

Backgroung Gastrointestinal stromal tumours (GISTs) located in the jejunum or ileum (JI-GIST) are considered worse prognosis compared to those of gastric (G-GIST) location. It has been suggested that this dogma should be revised. The aim of this study was to describe the characteristics of jejunoileal GISTs and its prognosis and to compare them with G-GISTs in the era of imatinib. Methods We retrospectively reviewed the clinical histories of all the patients diagnosed with GISTs between January 2000 and November 2016: Clinical and pathological data, as recurrence, metastatic state, disease-free survival (DFS) as well as overall survival (OS) rates of patients were reviewed. Results JI-GIST patients comprise 29 cases (37.7%). Compared to G-GIST, JI-GIST patients had undergone emergency surgery more frequently (37.9% vs. 10.4%, p = 0.007). According to the NIH-Fletcher classification, the low or very-low risk group represents 17.2% of JI-GISTs as opposed to 37.6% of G-GISTs (p < 0.005). When the AFIP-Miettinen system was used the low or very-low group represented 17.2% of JI-GISTs vs. 58.4% in the G-GISTs group (p < 0.001). Both local recurrence (24.1% vs. 12.5%, p < 0.05) and metastatic rate (34.5% vs. 22.9%, p < 0.05) were higher in the JI-GIST group than in G-GIST. 5- and 10-year DFS and 10-year OS rate were lower for JI-GIST (54.5% and 39.6% vs. 77.2% and 60.8%, and 57.9% vs. 65%, respectively, p < 0.05). Conclusions The observed differences between both groups in DFS and OS rates at long term could be attributed to the effect of imatinib (AU)

Clinical features, treatment, and prognosis of different histological types of primary small bowel adenocarcinoma: A propensity score matching analysis based on the SEER database.

PURPOSE: This aim of this study was to provide a comprehensive understanding of the clinical characteristics, treatment, and prognosis of patients with small bowel adenocarcinoma (SBA), mucinous small bowel adenocarcinoma (MSBA), and signet ring cell carcinoma of the small bowel (SRCSB). METHODS: Information on patients with SBA, MSBA, and SRCSB (2004-2015) was obtained from the Surveillance, Epidemiology and End Results (SEER) database. Cox proportional hazards models and Kaplan-Meier curves were used for the survival analyses. Propensity-score matching (PSM) was implemented to determine the differences among these tumors. RESULTS: In all, 3697 patients with SBA (n = 3196), MSBA (n = 325) and SRCSB (n = 176) were ultimately eligible for this study. Poor differentiation, local invasion, and lymph node metastasis were more likely to be observed in SRCSB than in SBA and MSBA. Surgery was the most common treatment modality in all groups. The prognosis of SBA was similar to that of MSBA, but better than that of SRCSB in both unmatched and matched cohorts. M stage, surgery, and chemotherapy were identified as independent predictors of survival in all patients. Surgery and chemotherapy could significantly improve outcomes in all groups before and after PSM. Radiotherapy was associated with a survival benefit in patients with SBA, but this trend was not maintained after PSM. Survival advantages of SBA and MSBA were remarkable in the stratified analysis of surgery after PSM. CONCLUSION: Patients with SRCSB had the worst prognosis among all histological types examined. However, surgery and chemotherapy could improve patients survival, regardless of histological type.

Preoperative serum chromogranin-a is predictive of survival in locoregional jejuno-ileal small bowel neuroendocrine tumors.

BACKGROUND: Small bowel neuroendocrine tumors (SB-NET) frequently metastasize to regional lymphatic or distant sites. Although most prognostication of SB-NET focuses on lymph node involvement, findings from studies of neuroendocrine tumors from other primary sites have suggested that preoperative serum chromogranin-A (CgA) levels may provide a more accurate metric. METHODS: Using the National Cancer Database (2004-2016), we analyzed patients with locoregional SB-NET who underwent curative resection including an adequate lymphadenectomy (n = 1,274). A statistically optimized cut-point was used to dichotomize CgA cohort based on preoperative serum CgA levels. RESULTS: We determined that a CgA ≥139 ng/mL identified patients with significantly shorter estimated mean overall survival (6.6 years vs 7.6 years, log-rank P = .00001). These patients were also older (63 vs 57 years, P < .001) and had higher rates of poorly differentiated tumors (2.1% vs 0.7%, P = .04) or primary tumors >1 cm (88.2% vs 79.2%, P = .001). Clinical features associated with shorter overall survival included preoperative CgA ≥139 ng/mL (HR = 2.19, 95% CI 1.22-3.92; P = .009), age at diagnosis (HR = 1.06, 95% CI 1.03-1.09; P < .001), Charlson-Deyo score ≥2 (HR = 3.93, 95% CI 1.71-9.01; P = .001), and poorly differentiated tumors (HR = 11.22, 95% CI 4.16-30.24; P < .001). Neither lymph node metastasis nor T-stage were independently associated with shorter overall survival in patients with locoregional SB-NET. CONCLUSION: Elevated preoperative serum CgA is an adverse prognostic marker associated with shorter overall survival in patients with locoregional SB-NET.

Tumor Microenvironmental Prognostic Risk in Primary Operable Small Intestinal Adenocarcinoma.

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<0.001) or perineural invasion (P=0.006), higher T-category (P<0.001), N-category (P=0.004), and stage grouping (P=0.002), and KRAS mutation (P=0.008). In multivariate analysis, higher TME prognostic risk index (P<0.001), distal tumor location and nonintestinal immunophenotype (both P=0.001), higher N-category (P<0.001), and microsatellite stable (P=0.015) were worse-independent prognosticators. TME prognostic risk index consistently stratified patient survival regardless of tumor location (P<0.001 in proximal; P=0.002 in distal), stages (P<0.001 in lower stages I to II; P=0.028 in stage III), and DNA mismatch repair gene status (P<0.001 in microsatellite stable; P=0.001 in microsatellite instability). TME risk index is a powerful prognostic predictor for risk stratification of patients with small intestinal adenocarcinoma.

Characteristics and prognosis of jejunoileal gastrointestinal stromal tumours (GISTs) in the era of imatinib: a comparative study with gastric GISTs.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) located in the jejunum or ileum (JI-GIST) are considered worse prognosis compared to those of gastric (G-GIST) location. It has been suggested that this dogma should be revised. The aim of this study was to describe the characteristics of jejunoileal GISTs and its prognosis and to compare them with G-GISTs in the era of imatinib. METHODS: We retrospectively reviewed the clinical histories of all the patients diagnosed with GISTs between January 2000 and November 2016: Clinical and pathological data, as recurrence, metastatic state, disease-free survival (DFS) as well as overall survival (OS) rates of patients were reviewed. RESULTS: JI-GIST patients comprise 29 cases (37.7%). Compared to G-GIST, JI-GIST patients had undergone emergency surgery more frequently (37.9% vs. 10.4%, p = 0.007). According to the NIH-Fletcher classification, the low or very-low risk group represents 17.2% of JI-GISTs as opposed to 37.6% of G-GISTs (p < 0.005). When the AFIP-Miettinen system was used the low or very-low group represented 17.2% of JI-GISTs vs. 58.4% in the G-GISTs group (p < 0.001). Both local recurrence (24.1% vs. 12.5%, p < 0.05) and metastatic rate (34.5% vs. 22.9%, p < 0.05) were higher in the JI-GIST group than in G-GIST. 5- and 10-year DFS and 10-year OS rate were lower for JI-GIST (54.5% and 39.6% vs. 77.2% and 60.8%, and 57.9% vs. 65%, respectively, p < 0.05). CONCLUSIONS: The observed differences between both groups in DFS and OS rates at long term could be attributed to the effect of imatinib.

Small Bowel Adenocarcinomas: Impact of Location on Survival.

BACKGROUND: Proximal (duodenal) small bowel adenocarcinomas have a worse prognosis than distal (jejuno-ileal) tumors, but differences in patient, tumor, and treatment factors between locations remain unclear. METHODS: Patients in the National Cancer Database with surgically resected pathologic stage I-IV small bowel adenocarcinomas between 2004 and 2015 were analyzed. Clinical stage IV patients were excluded. RESULTS: Proximal tumors (n = 3767) were more likely to be higher grade (OR 1.52, CI 1.22-1.85 for moderately; OR 1.83, CI 1.49-2.33 for poorly differentiated, P < 0.01 for both) and have positive lymph nodes (OR 2.04, CI 1.30-3.23, P < 0.01), while distal tumors (n = 3252) were likely to be larger (OR 1.31, CI 1.07-1.60 for size > 5 cm, P < 0.01). Proximal tumors were associated with worse overall survival (OS) and stage-specific survival compared with distal tumors (all P < 0.01). Cox regression analysis of the entire cohort showed worse survival with community versus academic cancer programs, higher comorbidity scores, pathologic stage IV, poorly differentiated histology, positive nodal or margin status, and proximal location, while female gender, larger tumor size, and chemotherapy predicted better survival. On separate Cox regression analyses of each location, neoadjuvant chemotherapy was associated with better OS in the proximal cohort (HR 0.70, CI 0.55-0.88, P < 0.01), while adjuvant chemotherapy was associated with better OS for both proximal (HR 0.49, CI 0.42-0.57, P < 0.01) and distal tumors (HR 0.68, CI 0.57-0.81, P < 0.01). CONCLUSIONS: Proximal small bowel adenocarcinomas are associated with worse overall and stage-specific survival. This may be due to tumor biologic differences as proximal tumors were more likely to have higher grade. Future studies should further investigate differences between proximal and distal tumors to guide targeted treatment algorithms.

Prognostic relevance of programmed death-ligand 1 expression and microsatellite status in small bowel adenocarcinoma.

Background: Small bowel adenocarcinoma (SBA) is a dreadful disease. Patient prognosis is limited due to late presentation and ineffective chemotherapy. PD-1/PD-L1 checkpoint immunotherapy is regarded as a promising approach in several cancer entities. The association of PD-1/PD-L1 expression and its impact on patient prognosis with SBA is unclear. Material and methods: Seventy-five consecutive patients who underwent surgery for SBA were retrospectively analyzed and stained for PD-L1 expression in the tumour or the stroma. Analysis of mismatch repair genes was performed to determine microsatellite status. Kaplan-Meier estimate was used to analyze patient survival. Univariate and multivariable Cox regression-analyses were used to assess the impact of PD-L1 expression and microsatellite status on patient survival.Results: PD-L1 was weakly upregulated within the tumour or the stroma and associated with prolonged survival (p = .0071 and p = .0472, respectively). Fifty-one tumours (68%) revealed microsatellite stability (MSS) and 24 tumours (32%) were microsatellite instable (MSI) without correlating with patient survival (p = .611). Neither PD-L1 expression in the tumour nor in the stroma was identified as an independent risk factor influencing survival (p = .572 and p = .3055).Conclusion: Although PD-L1 expression is associated with prolonged survival, it was not identified as an independent prognostic marker. Microsatellite status did not influence long-term survival.

An Examination of Lymph Node Sampling as a Predictor of Survival in Resected Node-Negative Small Bowel Adenocarcinoma: a SEER Database Analysis.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare disease. Current recommendations are largely extrapolated from the colorectal literature. For node-negative (N -ve) cases, optimally stratifying cases into high or low risk, may help define optimal management. The objective of this analysis was to determine the importance of lymph node sampling for prognostication and to define what number of lymph nodes sampled is adequate. METHODS: Cases of non-metastatic SBA with complete staging, pathologic, and demographic information were selected from the SEER database and SAS 9.4 software was used. Variables included age, gender, race, grade, TNM staging, and number of lymph nodes were examined. Comparisons were made between N -ve and N +ve cases. Survival analysis using N -ve cases was performed to characterize the impact of nodal sampling on survival and to determine which nodal cut-offs best predict survival. RESULTS: A total of 523 cases from 2004 to 2014 were included in this analysis. Statistically significant differences identified included the median number of nodes sampled between the N -ve and N +ve groups, and the distribution of T stage and grade. Survival analysis in the N -ve cases demonstrated that the strongest predictor of survival was sampling of 16 or more lymph nodes. CONCLUSION: In this analysis, lymph node sampling was shown to be the most important pathologic predictor of survival in cases of N -ve SBA. Replicating these findings in a secondary dataset and determining whether a clinical benefit of adjuvant chemotherapy exists for SBA patients with inadequate sampling are both important next steps.

Primary Pediatric Non-Hodgkin Lymphomas of the Gastrointestinal Tract: A Population-based Analysis.

BACKGROUND/AIM: The aim of this study was to present the clinical characteristics, natural history and survival outcomes of primary gastrointestinal non-Hodgkin lymphomas (PGINHL) in the pediatric population. PATIENTS AND METHODS: Surveillance, Epidemiology, and End Results (SEER) database was queried for patients aged 0 to 19 years with PGINHL between 1973 and 2014. RESULTS: A total of 452 cases were identified [mean age 11.0 (±5.1)] years, whites 84.1%, males (76.5%). The majority of tumors were noted in the small bowel (SB) (47.6%), followed by large bowel (LB) (28.5%) and the stomach (10.0%). Overall, the most common histological subtype was Burkitt lymphoma (51.8%), followed by diffuse large B-cell lymphoma (DLBCL) (26.1%). Mean overall survival (OS) of the entire cohort was 33,33 years with a 5-yr, 10-yr and 30-yr survival rate of 86%, 86% and 79%, respectively. Large bowel tumors had the best long-term survival rates whereas; gastric tumors had the worst with 30-yr survival rate 84% and 74%, respectively. Overall, 328 (72.6%) patients received surgery. No significant survival difference was noted between patients who underwent surgery and those who did not. CONCLUSION: This study presents the largest dataset of pediatric PGINHL and describes the clinical features and outcomes of these patients in addition to summarizing the literature.

Prognostic impact of a large mesenteric mass >2 cm in ileal neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Ileal neuroendocrine tumors (i-NETs) frequently metastasize to mesenteric lymph nodes and the liver. Regional lymphadenopathy is associated with desmoplasia of the mesentery forming a large mesenteric mass (LMM). Although the latest American Joint Committee on Cancer TNM staging (8th edition) defined LMM >2 cm as N2, the prognostic impact of LMM is ill-defined. We evaluated whether LMM is prognostic for patients with i-NETs. METHODS: This single-institution, retrospective cohort study included 106 patients who underwent resection of i-NETs between 2007 and 2018. Overall survival (OS) and liver progression-free survival (LPFS) were compared between patients with and without LMM. RESULTS: LMM was present in 66 patients (62%) and was not associated with the presence or absence of liver metastasis (P = .969) or the extent of liver involvement (P = .938). OS and LPFS differed significantly between patients with and without LMM (5-year OS rates of 64.8% and 92.9%, respectively, P = .011; 3-year LPFS rates of 45.3% and 67.5%, respectively, P = .025). In multivariate analysis, LMM was an independent prognostic factor for both OS (hazard ratio: 4.69, 95% confidence interval: 1.63-17.6) and LPFS (1.99, 1.08-3.88). CONCLUSION: LMM >2 cm is prognostic for OS and LPFS and represents aggressive tumor biology.

Clinical Outcomes of Small Bowel Adenocarcinoma.

BACKGROUND: Small bowel adenocarcinomas (SBAs) are rare tumors. Management of SBA is extrapolated from colorectal cancer treatments. Recent evidence suggests that the biology and molecular features of SBA differ from colorectal cancer. The aim of this study was to evaluate the management and outcome of SBA patients. PATIENTS AND METHODS: The National Cancer Data Base (NCDB) was queried for patients with SBA between 2004 and 2013 using ICD-O-3 histology code 8140/3 and topography codes C17.0, C17.1, C17.2, C17.8, and C17.9. Univariate and multivariate survival analyses were conducted to analyze the association between SBA location and overall survival (OS) stratified by stage. Treatment outcomes of surgery, radiation, and systemic therapy were compared. RESULTS: A total of 7954 SBA patients were identified; duodenum (D) 4607 (57.9%), jejunum (J) 1241 (15.6%), ileum (I) 857 (10.8%), and unspecified 1249 (15.7%). A total of 53.6% patients were male, and 76.6% white. Median age was 66 years. D mostly presented as stage IV disease (37.6%), J as stage II (34.5%) and IV disease (33.8%), and I as stage II (32.2%) and III (30.3%) disease (P < .001). Grade distribution was similar among D, J, and I; the majority were moderately differentiated (40.8%-55.0%), followed by poorly differentiated (30.9%-35.8%) and well differentiated (6.0%-12.4%) (P < .001). D underwent surgery (50.2%) less often than J (90.8%) and I (94.5%) (P < .001). Adjuvant radiation was provided in 8.5% of D, 2.6% of J, and 2.1% of I (P < .001). Adjuvant chemotherapy was provided in 21.9% of D, 50.2% of J, and 42.0% of I (P < .001). The rate of adjuvant chemotherapy was the highest in patients with stage III SBA, and was as follows: D (43.4%), J (65.4%), and I (63.6%) (P < .001). In univariate and multivariate analyses of all patients, adjuvant chemotherapy was associated with improved OS in stage II-III SBA patients. J had the best 5-year OS rate (42.0%; 95% confidence interval, 38.8-45.1, P < .001), and D had the worst (23.0%; 95% confidence interval, 21.6-24.2, P < .001). In multivariate analysis stratified by stage, chemotherapy was associated with improved OS in patients with stage II-IV SBA. CONCLUSION: Most SBA patients present with stage IV disease. D underwent surgery less often than J and I. Stage II and III D received adjuvant chemotherapy less often compared to stage II and III J and I. Adjuvant chemotherapy was associated with improved OS in patients with stage II-III disease. J had the best 5-year OS rate, and D had the worst.

Neuroendocrine Tumors in Meckel's Diverticulum: Recommendation for Lymphadenectomy Regardless of Tumor Size Based on the NCDB Experience.

BACKGROUND: Meckel's diverticulum (MD) is an anomaly of the small intestine from which malignancy may arise. Among MD neoplasms, neuroendocrine tumors (NETs) are considered the most common. However, their metastatic potential and optimal surgical therapy remain ill-defined. METHODS: In a retrospective analysis of the National Cancer Database (2004-2015), patients with a diagnosis of MD malignancy were identified. Clinicopathologic factors were extracted and tumors arising in MD were compared. In the subgroup of patients with NET, the association between tumor factors and node involvement was investigated. RESULTS: Three hundred twenty primary MD malignancies were captured in the National Cancer Database, consisting of 280 (87.5%) NET. The median age at diagnosis was 64 years. Patients were predominantly male (207, 73.9%) and white (269, 96.1%). Most tumors were well-differentiated (118, 42.1%) and sub-centimeter (median size, 0.7 cm). Distant metastasis was present in a minority (16, 5.7%), and the median overall survival was 114 months in the entire cohort. The regional lymph node status was known in 87 NET patients, out of which 39 (44.8%) harbored node metastasis. Although the risk of node involvement increased with larger tumor size, it remained significant even among sub-centimeter (9 out of 34, 26.5%) and well-differentiated (18 out of 44, 41%) tumors. Regional node involvement was associated with the presence of distant metastasis (p < 0.001). CONCLUSION: Lymph node involvement was common irrespective of the size and grade of NET arising from Meckel's diverticulum. Therefore, regional lymphadenectomy should be considered in the curative-intent surgical management of these neoplasms regardless of tumor size and grade.

The Influence of Tumor Stage on the Prognostic Value of Ki-67 Index and Mitotic Count in Small Intestinal Neuroendocrine Tumors.

Tumor cell proliferation rate determined by either Ki-67 index or mitotic count (MC) has shown to be a prognostic factor for gastrointestinal neuroendocrine tumors in general, and after its incorporation in the 2010 World Health Organization tumor grading system, it has become essentially mandatory in pathology reports for all gastrointestinal neuroendocrine tumors, regardless of tumor location. Nevertheless, clinical significance for the Ki-67 index or MC has not been well demonstrated in small intestinal neuroendocrine tumor (SINET), especially those without distant metastasis, the majority of which have very low proliferation rates. We assessed the clinical behavior of 130 SINETs in relation to stage, Ki-67 index, MC, and other pathologic features. Most SINETs (86%) were grade 1 and 14% were grade 2. There were no grade 3 tumors or poorly differentiated neuroendocrine carcinomas. On multivariate analysis, age, Ki-67 index >5%, MC >10/50 high-power field, stage IV, and liver metastases were associated with increased risk of death in all patients. When both stage and grade were considered, Ki-67 index >5% was associated with a nearly 4-fold increased risk of death in stage IV cases (n=60). In contrast, Ki-67 index did not show prognostic value for patients with stages I to III disease (n=70), although MC >1/50 high-power field was significantly associated with death on multivariable analysis. Our study confirms that liver metastasis and increased tumor cell proliferation rate are independent prognostic factors for SINETs, but shows that most SINETs have a very low proliferation rate, which limits its value for predicting tumor behavior. By combining staging and grading information, we demonstrate different roles and cutoff values of Ki-67 index and MC in SINET with different stages.

The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational study.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1-2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA. METHODS: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013. RESULTS: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3-4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months. CONCLUSIONS: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.

Loss of succinate dehydrogenase subunit B (SDHB) as a prognostic factor in advanced ileal well-differentiated neuroendocrine tumors.

PURPOSE: Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases. METHODS: We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n = 106) and metastases (n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens. RESULTS: SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p < 0.0001). SDH intensity was higher in primitive specimens (p < 0.0001). SDHB score was 9-12 in 96 specimens of the primitive group and 2 metastatic specimens (p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %. CONCLUSIONS: SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.

Gastrointestinal Bleeding Due to Gastrointestinal Tract Malignancy: Natural History, Management, and Outcomes.

BACKGROUND: Gastrointestinal (GI) tumor bleeding can vary from occult bleeding to massive hemorrhage and can be the presenting sign of malignancy. AIMS: Our primary aims were to: (1) characterize the natural history, treatment, and outcomes in patients with GI tumor bleeding and (2) compare and contrast bleeding in upper GI (UGI)/small bowel (SB) and lower GI malignancies. METHODS: Patients with endoscopically confirmed tumor bleeding were identified through search of consecutive electronic medical records: Bleeding was determined by the presence of melena, hematochezia, hematemesis, or fecal occult blood. Comprehensive clinical and management data were abstracted. RESULTS: A total of 354 patients with GI tumors were identified: 71 had tumor bleeding (42 UGI/SB and 29 colonic). GI bleeding was the initial presenting symptom of malignancy in 55/71 (77%) of patients; 26/71 patients had widely metastatic disease at presentation. Further, 15 of 26 patients with metastatic disease presented with GI bleeding. Visible bleeding was present in 14/42 (33%) and 4/29 (14%) of UGI/SB and colonic tumors, respectively. Endoscopic hemostasis was attempted in 10 patients, and although initial control was successful in all, bleeding recurred in all of these patients. The most common endoscopic lesion was clean-based tumor ulceration. Overall mortality at 1 year was 57% for esophageal/gastric, 14% for SB, and 33% for colonic tumors. CONCLUSIONS: When patients with GI malignancy present with GI bleeding, it is often the index symptom. Initial endoscopic hemostasis is often successful, but rebleeding is typical. Esophageal and gastric tumors carry the poorest prognosis, with a high 1-year mortality rate.

Ileal "carcinoid" tumors-small size belies deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size.

Neuroendocrine tumors (NETs) account for 2% of tumors of the gastrointestinal tract, most occurring in the small intestine. A size of 2 cm is generally regarded as a cut-off point for risk of lymph node metastasis in intestinal neuroendocrine tumors in the absence of other high-risk features; however, metastatic disease has been reported in 12% of tumors of the jejunum and ileum measuring 1 cm or less. Archives from 2 institutions were searched for ileal NETs measuring 1 cm or less, and selected data were recorded. Twenty-one ileal NETs were identified measuring ≤1 cm. Six (29%) were multifocal and 7 (33%) had distant metastasis at diagnosis. Regional lymph nodes were examined in 14 cases (67%), and 10 of these cases (71%) showed lymph node metastasis. Mean primary tumor size in cases with nodal metastasis was 7.3 mm. In this series of ileal NETs ≤1 cm in size, the rate of lymph node metastasis was 48% overall and 71% for cases with regional lymph node resections. In addition, 33% showed distant metastasis at the time of diagnosis. Tumors as small as 3 mm and those confined to the submucosa can give rise to nodal metastasis, emphasizing the need for consideration of local resection with regional lymphadenectomy, even for subcentimeter ileal NETs.

Treatment and Survival of Small-bowel Adenocarcinoma in the United States: A Comparison With Colon Cancer.

BACKGROUND: Small-bowel adenocarcinoma is rare and fatal. Because of data paucity, there is a tendency to extrapolate treatment from colon cancer, particularly in the adjuvant stetting. OBJECTIVE: The purpose of this study was to evaluate the current surgical and adjuvant treatments of small-bowel adenocarcinoma and compare with colon cancer. DESIGN: This was a retrospective cohort study. SETTINGS: The linked Surveillance, Epidemiology, and End Results and Medicare database was used at a tertiary referral hospital. PATIENTS: Patients with small-bowel adenocarcinoma and colon cancer identified from 1992 to 2010, using International Classification of Diseases for Oncology, 3 Revision, site, behavior, and histology codes were included. MAIN OUTCOME MEASURES: Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method and competing risk analysis. RESULTS: A total of 2123 patients with small-bowel adenocarcinoma and 248,862 patients with colon cancer were identified. Five-year overall survival rates for patients with small-bowel adenocarcinoma and colon cancer were 34.9% and 51.5% (p < 0.0001). A total of 1550 patients with small-bowel adenocarcinoma (73.0%) underwent surgery, compared with 177,017 patients with colon cancer (71.1%). The proportion of patients who received chemotherapy was similar, at 21.3% for small bowel and 20.0% for colon. In contrast to colon cancer, chemotherapy did not improve overall or cancer-specific survival for patients with small-bowel adenocarcinoma, regardless of stage. Predictors of poor survival for small-bowel adenocarcinoma on multivariate analysis included advanced age, black race, advanced stage, poor tumor differentiation, high comorbidity index, and distal location. Chemotherapy did not confer additional survival benefit compared with surgery alone (HR, 1.04 (95% CI, 0.90-1.22)). LIMITATIONS: This was a retrospective review. The reliance on Medicare data limited granularity and may have affected the generalizability of the results. CONCLUSIONS: The prognosis for small-bowel adenocarcinoma is worse than that for colon cancer, and only surgery improves survival. In contrast to colon cancer, a survival benefit from current chemotherapy regimens for small-bowel adenocarcinoma is not seen, suggesting that it may be overused and needs more rigorous study.