Pancreatectomy in Stage I pancreas cancer: national underutilization of surgery persists.

BACKGROUND: Pancreatectomy in early pancreas adenocarcinoma has been historically underutilized. This retrospective study examines recent trends in the use of pancreatectomy in clinical Stage I (T1-2N0M0) pancreas cancer. METHODS: Using the 2004-2014 National Cancer Database, patients with clinical Stage I pancreas cancer were identified. Patients who underwent surgery or failed to undergo surgery with no identifiable reason were included in analysis. Chi-square, binary logistic regression, and Kaplan Meier estimate were used to identify risk factors for failure to undergo surgery. RESULTS: 23,365 patients were identified. Pancreatectomy increased from 38.4% in 2004 to 52.3% in 2014 (p < 0.001). 50% (n = 11,922) of patients underwent surgery and 48.0% (n = 11,433) did not, of whom 6.8% had a prohibitive co-morbidity, and 36.1% (n = 8594) had no identifiable reason for the lack of operation. Failure to operate was associated with older age, African American race, residence in lower income and less educated areas, lack of insurance, and treatment at community hospitals (all p < 0.001). 5-year survival was maximized in patients who underwent surgery and chemotherapy at 28.1%. CONCLUSION: While utilization of surgery increased overtime, 36% of patients fail to undergo surgery without an identifiable reason. Future investigation is warranted to explain continuing underuse of surgery in early pancreas cancer.

Prognostic Utility of Immunoprofiling in Colon Cancer: Results from a Prospective, Multicenter Nodal Ultrastaging Trial.

BACKGROUND: Retrospective data indicate that immunoprofiling of T cell markers can be prognostic in colon cancer. Prospective T cell immunoprofiling of colon cancer has not been well defined for patients whose lymph nodes are ultrastaged. STUDY DESIGN: A prospective cohort was selected from patients enrolled in an ongoing phase II multicenter trial of nodal ultrastaging for colon cancer. Primary tumor specimens from 89 patients were analyzed by immunohistochemistry for the T cells CD3(+), CD4(+), CD8(+), and FOXP3(+). Lymphocyte populations were quantified with digital image analysis. Results were examined for their association with 5-year disease-free survival along with TNM stage and clinicopathologic variables. RESULTS: Longer disease-free survival was associated with higher CD3(+) counts at the invasive margin (IM) (p = 0.005), higher CD8(+) counts at the tumor center (TC) and IM (p = 0.002), a lower CD4(+)/CD8(+) ratio at the TC+IM (p = 0.027), and a higher CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.020). After multivariable analysis, CD8(+) at the TC+IM (p = 0.002), the CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.004), and the number of tumor-positive lymph nodes (p = 0.003) remained significant. CONCLUSIONS: This is the first prospective demonstration of the prognostic utility of immunoprofiling in colon cancer after nodal ultrastaging. Staging based on tumor immunoprofile can augment TNM staging and provide targets for specific immunotherapies.

Immunoprofiling for prognostic assessment of colon cancer: a novel complement to ultrastaging.

BACKGROUND: Although AJCC/TNM staging remains the gold standard for prognostic assessment of colon cancer, stage-specific outcomes vary. We therefore prospectively evaluated the prognostic role of immunoprofiling. METHODS: Our cohort included 35 patients from an ongoing prospective trial of ultrastaging for colon cancer. Specimens were analyzed for T cell markers (CD3, CD4, CD8, and FoxP3). The number of tumor-infiltrating lymphocytes was analyzed at the tumor's margin and center and correlated with AJCC/TNM stage, clinicopathologic variables, and disease-free survival. RESULTS: There was a significant inverse association between number of CD3(+) cells in the tumor center and tumor stage (P = 0.05). The tumor center/margin ratio of CD3(+) cells also showed an inverse but non-significant relationship with nodal involvement (P = 0.07). Body mass index was inversely associated with numbers of CD3(+)(P = 0.04) and CD8(+)(P = 0.02) cells. Longer disease-free survival was correlated with higher CD8+ counts (P = 0.07), lower CD4(+)/CD8(+) ratios (P = 0.008), and higher CD8(+)/FoxP3(+) ratios (P = 0.02). CONCLUSIONS: This is the first prospective validation of immunoprofiling in patients whose colon cancer is staged with strict surgical and pathology quality measures. The apparent correlation between immunophenotypic response and clinical outcome warrants evaluation in a larger prospective trial.

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.

Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.

The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts.

Metastasis is a multistep process that requires acquisition of malignant cell phenotypes which allow tumor cells to escape from the primary tumor site. Each of the steps during metastatic progression involves co-evolution of the tumor and its microenvironment. Although tumor cells are the driving force of metastasis, new findings suggest that the host cells within the tumor microenvironment play a key role in influencing metastatic behavior. Many of these contributing cells are derived from the bone marrow; in particular, recruited bone marrow progenitor cells generate the "pre-metastatic niche" to which the tumor cells metastasize. Analysis of the molecular mechanisms involved in pre-metastatic niche formation has revealed that secreted soluble factors are key players in bone marrow cell mobilization during metastasis. In addition, membrane vesicles derived from both tumor and host cells have recently been recognized as new candidates with important roles in the promotion of tumor growth and metastasis. This review describes old ideas and presents new insights into the role of tumor and bone marrow-derived microvesicles and exosomes in pre-metastatic niche formation and metastasis.

When should we order a CT scan and when should we rely on the results to diagnose an acute appendicitis?

OBJECTIVE: The objective of this study was to retrospectively analyze the last 100 consecutive emergency appendectomies performed in the authors' institution, which is a community-based teaching hospital, and look at the accuracy of the CT scan in the diagnosis of acute appendicitis. DESIGN: Retrospective clinical study. SETTING: A 600-bed community-based teaching hospital. METHODS: The last 100 consecutive emergency appendectomies, which were performed at New York Methodist Hospital in 2004, were retrospectively analyzed. The collected data included the demographics of the patients, relevant history, physical examination, laboratory and radiological tests, and pathology results. The statistical analyses were performed using the JMP version 3.2 software (SAS Institute Inc., Cary, North Carolina). An alpha value of 0.05 was used in all statistical analyses, and p values were considered as being statistically significant at or below the alpha value of 0.05. RESULTS: There was no statistically significant correlation between the acute appendicitis and some of the typical presenting symptoms and signs of acute appendicitis (rebound tenderness, low-grade fever, elevated white blood cell count, and anorexia). The sensitivity, specificity, positive predictive value, and negative predictive value of the CT scan in this retrospective analysis were 96%, 75%, 98.5%, and 50%, respectively, with an overall efficiency of 95%. However, the sensitivity, specificity, positive predictive value, and negative predictive value of the CT scan increased after reevaluation of the false-positive, false-negative, and inconclusive CT results by an experienced radiologist in a blind fashion (97%, 100%, 100%, and 71%, respectively). The correlation between the CT scan and the pathology result was statistically significant when the CT result was positive or negative (p = 0.0001). CONCLUSION: The CT scan is indicated when the clinical presentation is equivocal, and it will be helpful if the result is positive or interpreted as negative only by an experienced radiology attending.