Steven H. Itzkowitz

A randomized controlled trial using patient navigation to increase colonoscopy screening among low-income minorities.

Organizational barriers play a key role in colorectal cancer (CRC) screening disparities in low-income minorities. This is a prospective, randomized trial to determine whether a patient navigator (PN) can help overcome the organizational barriers low-income minorities face in trying to obtain screening colonoscopy. Patients of average risk for CRC were referred by their primary care physician for screening colonoscopy. After the PN received the referral, patients were randomly assigned to either receive navigation (PN+) to screening colonoscopy or not receive navigation (PN-). We hypothesized that a PN would increase patient compliance with screening colonoscopy. A total of 21 patients were enrolled in the pilot study (PN+ = 13, PN- = 8); 54% of navigated patients completed screening colonoscopy versus 13% of nonnavigated patients (p = 0.058). Eighty-six percent of navigated patients had an excellent or very good colon prep; however, there was no difference in prep quality between groups ( p = 0.10). One-hundred percent of navigated patients were very satisfied with navigation services. A PN improves compliance with screening colonoscopy in low-income minorities. Larger studies are needed to evaluate what features of navigation are most effective in facilitating completion of screening colonoscopy.

Immunogenicity of synthetic TF-KLH (keyhole limpet hemocyanin) and sTn-KLH conjugates in colorectal carcinoma patients

Mucins of colorectal carcinomas overexpress the cancer-associated disaccharides Thomsen-Friedenreich antigen (TF) and sialyl-Tn antigen (sTn), making these antigens suitable for active specific immunotherapy. Patients at high risk for recurrent colon cancer, but free from disease after surgical resection, were immunized with synthetic TF and sTn covalently attached by a two-carbon crotyl linker to keyhole limpet hemocyanin (KLH). Four groups of patients were treated with TF-KLH without adjuvant, TF-KLH plus the immunological adjuvant Detox, sTn-KLH plus Detox, or sTn-KLH plus the immunological adjuvant QS-21, and the serological response was monitored. Enzyme-linked immunosorbent assay (ELISA), do-blot immunostains, and inhibition assays were used to identify antibody responses against synthetic TF and sTn epitopes and against natural antigens, including asialoglycophorin expressing TF antigen, and ovine submaxillary mucin and the human colon cancer line LS-C expressing sTn antigen. Our results demonstrate that vaccines containing TF or sTn-KLH conjugates plus immunological adjuvants Detox and especially QS-21 induced high IgM and IgG antibody titers against the respective synthetic disaccharide epitopes. However, when tested against natural antigens expressing these disaccharide epitopes, IgM antibodies showed weak to moderate reactivity, while IgG antibodies were almost totally unreactive. On the basis of these results we are continuing to test modifications of synthetic TF and sTn epitopes to identify those that induce IgM and IgG antibodies that are more reactive with these antigens as they are expressed on tumor mucins.

Clinical and Prognostic Features of Rectal Neuroendocrine Tumors

Background: Rectal neuroendocrine tumors (NETs) are among the most common NETs. The aim was to validate European Neuroendocrine Tumor Society (ENETS)/North American Neuroendocrine Tumor Society (NANETS) staging and grading systems with regard to clinical outcomes. Methods: A comprehensive database was constructed from existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation. Analysis was performed on 141 patients identified with rectal NETs seen at Mount Sinai Hospital between 1972 and 2011. Results: The median age was 52.7 years; 43% were males. Average tumor size was 0.88 cm. NETs <1 cm accounted for 75.6% of the tumors. Stage I, II, III and IV accounted for 79.4, 2.8, 5.0 and 12.8% of the tumors, respectively. G1 tumors accounted for 88.1%, G2 8.3% and G3 3.6%. Of G1 tumors, 94.6% were stage I and 5.4% were stage IV. The median survival time for all 141 patients was 6.8 years (range, 0.8-34.7 years). The overall 5-year survival rate was 84.4%. The 5-year survival rates for patients in stages I-IV were 92.7, 75.0, 42.9 and 33.2%, respectively. The 5-year survival rates for patients with G1-G3 tumors were 87.7, 47.6 and 33.3%, respectively. Univariate analysis of increased survival showed significance for lower stage, lower grade, smaller size, absence of symptoms and endoscopically treated tumors. Multivariate analysis showed that stage alone was statistically significant as the strongest predictor of survival. Conclusion: The results of our study validated ENETS/NANETS guidelines for staging and grading of rectal NETs in the US setting of a tertiary referral center. Staging according to ENETS/NANETS guidelines should be used in the treatment algorithm rather than size alone.

Clinicopathologic correlations of ABO and rhesus blood type in colorectal cancer

There is no specific association established between colorectal cancer and blood group type. In this study, the distribution of ABO and Rh blood groups was studied in 838 patients with colorectal cancer. There was no difference in distribution of ABO blood groups between patients who were Rh+ and Rh-. There was no difference in ABO blood group or Rh factor and tumor location. The highest A/O ratio was found in rectal cancer. Although there was no difference in stage distribution for each ABO blood group, there was a significant difference between the Rh+ and Rh-groups (P<0.037).It is not clear, however, whether the prognosis is different between the two groups since there were more early tumors as well as incurable tumors in the Rh-group. All patients with synchronous cancer were Rh+. Further studies on blood group antigens are needed to elucidate the relationship between these antigens and colorectal cancer.

Blood group antigen synthesis and degradation in normal and cancerous colonic tissues

ABH antigens are expressed by colonic epithelial cells throughout the colon during fetal life but only in proximal segments during adulthood. Malignant and premalignant colonic tumors frequently exhibit ABH reappearance (distal lesions) or ABH deletion (proximal lesions) and occasionally express incompatible A or B substances. Mechanisms governing these developmental and cancer-associated alterations are unknown. Therefore, experiments were performed to assess the activities of biosynthetic (glycosyltransferase) and degradative (glycosidase) enzymes in normal and cancerous tissues of the proximal and distal colon. In normal colonic mucosa, A, B, and H transferase activities were similar in proximal and distal segments. Analysis of enzyme substrate affinities and product characterization confirmed that the ABH transferases in colonic tissues were similar to the gene-specified transferases in human serum. Glycosidase enzyme activities were also comparable in proximal and distal normal colon. Cancers had lower A and B transferase but similar H transferase activities compared with paired normal mucosa. Thus, the absence of ABH antigen expression in normal distal colon is not caused by insufficient glycosyltransferase activity or excessive glycosidase activity.

Short-chain fatty acid induces intestinal mucosal injury in newborn rats and down-regulates intestinal trefoil factor gene expression in vivo and in vitro

Background: Luminal administration of short-chain fatty acids (SCFAs) induces dose-dependent intestinal mucosal injury in newborn rats. However, the mechanism underlying the injurious effects of SCFAs on intestinal mucosa in neonates is unclear. Intestinal trefoil factor (ITF) is a factor important for the maintenance and repair of the intestinal mucosal barrier. Regulation of ITF gene expression by SCFAs may be involved as one of the mechanisms. Objectives: To examine the effect of butyrate-induced colonic injury on ITF gene expression in vivo and to determine the molecular mechanisms underlying the butyrate regulation of ITF gene expression in vitro. Methods: Whole-section colonic tissues from 9- to 10-day-old Sprague-Dawley rats that have received butyric acid at two different concentrations (150 mmol/L and 300 mmol/L) and for different time periods were processed for total RNA extraction and Northern blot analysis. Littermates that received normal saline or lactic acid at 300 mmol/L served as controls. The effect of butyrate on ITF gene expression was also examined in vitro with human colonic epithelial LS 174T cells. To further define ITF gene regulation by butyrate, transient transfection assays were performed on a 930 bp human ITF promoter-luciferase reporter gene plasmid in LS174T cells with or without the presence of butyrate. Results: Concurrent with mucosal injury, butyric acid inhibited ITF gene expression in colonic tissues of newborn rats as well as in intestinal epithelial cells in a dose- and time-dependent manner. Furthermore, butyrate reduced ITF promoter report gene activity in transfected LS174T cell, suggesting that butyric acid regulation of ITF gene is by way of a specific ITF promoter. Conclusions: Butyric acid induced-intestinal mucosal injury in newborn rats is associated with down-regulation of ITF gene expression. The changes in ITF gene expression in vivo may play a role in the pathogenesis of SCFA-induced intestinal mucosal injury.

A novel human macrophage-derived intestinal mucin secretagogue: Implications for the pathogenesis of inflammatory bowel disease

BACKGROUND A novel 68-kilodalton macrophage-derived protein (MMS-68) stimulating mucin release from respiratory epithelial cells has previously been described. In this study, the effect of MMS-68 on mucin release from intestinal epithelial cells was determined. METHODS Colonic epithelial cells isolated from normal colon, ulcerative colitis, Crohns colitis, and cells from three colon cancer cell lines were labeled with [3H]-glucosamine and stimulated with MMS-68. High molecular weight glycoproteins were precipitated and counted. RESULTS In all of the cells tested, MMS-68 enhanced mucin secretion by 1.46-2.0-fold above control values, comparable to the level achieved with carbachol (10(-5) mol/L). Coincubation with anti-MMS-68 monoclonal antibody 1D-10 blocked this bioactivity. Freshly isolated intestinal macrophages reacted with monoclonal antibody 1D-10. Immunofluorescent staining of frozen sections revealed the presence of MMS-68-producing cells (macrophages) in the lamina propria of normal colon and Crohns colitis, with weaker expression in ulcerative colitis mucosa. CONCLUSIONS Intestinal macrophages produce a novel mucin secretagogue, which is as potent as carbachol for stimulating mucin secretion from colonic epithelial cells. This factor may explain, in part, the alterations in mucin secretion often seen in inflammatory bowel disease.

Prognostic significance of lymph node metastases in small intestinal neuroendocrine tumors.

Background/Aims: Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR): ≤0.2, >0.2-0.5, and >0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. Results: We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p < 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the ≤0.2, >0.2-0.5, and >0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p < 0.0001). Conclusions: The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy.

The risk of metachronous cancers in patients with small-intestinal carcinoid tumors: a US population-based study

Small-intestinal carcinoids (SIC) are the most common small-bowel malignancies. We sought to determine the risk of developing SIC before and after other primary malignancies (PM) and the prognosis of patients with SIC, with and without another PM. We used the Surveillance, Epidemiology, and End Results database to identify patients diagnosed with SICs between 1973 and 2007. Multiple primary-standardized incidence ratios were calculated as an approximation of relative risk (RR) to explore the association of SICs with metachronous malignancies. Survival analysis was performed using Kaplan-Meier methods and Cox proportional-hazard models. Among 8331 patients with SICs, 2424 (29%) had another PM at some time. The most common sites were prostate (26.2%), breast (14.3%), colon (9.1%), lung/bronchus (6.3%), and bladder (5.3%). Overall, 67% of patients had a PM diagnosed before SIC (pre-SIC), 33% after SIC (post-SIC), and 8% had a PM both before and after SIC. Among the pre-SIC group, the risk of future SIC was increased after cancers of the small bowel (RR 11.86 (95% CI: 6.13-20.72)), esophagus (4.05 (1.10-10.36)), colon (1.39 (1.05-1.81)), kidney (1.93 (1.12-3.09)), prostate (1.38 (1.17-1.62)), and leukemia (2.15 (1.18-3.61)). Among the post-SIC group, there was an increased risk of future PM of the small bowel (8.78 (4.54-15.34)), liver (2.49 (1.08-4.91)), prostate (1.25 (1.0-1.53)), and thyroid (2.73 (1.10-5.62)). Compared to patients with only SIC, those with a PM pre-SIC had worse mean survival (57.9 vs 40.9 months, HR 1.55 (1.42-1.69), P<0.001). In conclusion, almost one-third of patients with SICs have an associated metachronous primary tumor. When these primaries occur prior to (but not after) the SIC diagnosis, the prognosis is worse than with an initial SIC. The type of malignancies associated with SICs may guide future screening efforts.

Prognostic clinicopathologic factors in longitudinally followed patients with metastatic small bowel carcinoid tumors.

Objectives: Neuroendocrine tumors demonstrate heterogeneous behavior based on the site of origin and histology. This study aimed to delineate prognostic clinicopathologic features in patients with metastatic midgut carcinoid. Methods: All patients underwent resection of the primary tumor in the setting of metastatic disease. Survival was measured from the date of primary tumor resection and calculated by Kaplan-Meier estimation. Clinical data include age, sex, serum biomarkers, primary tumor size, Ki-67 index, and the performance of hepatic cytoreductive procedure. Serially collected serum biomarkers were considered as mean values within periods relative to primary resection: preoperative, 0 to 1 year postoperative, and years 1 to 5 postoperative. Log-rank comparisons were used to assess the prognostic value of the aforementioned features. Results: Forty-nine patients (21 men) with metastatic midgut carcinoid who underwent primary tumor resection were identified. Median survival was 121 months. The overall 5-year survival rate was 83%. Age higher than 65 years (P = 0.01) and late postoperative chromogranin A (CgA; P = 0.02) were associated with decreased survival. Conclusions: This study highlights the favorable prognosis of patients with metastatic small bowel carcinoid in a multidisciplinary treatment program. Among other factors, elevated postoperative CgA is associated with decreased survival. The significance of increased CgA over time underlies the importance of longitudinal follow-up for these patients.