Positron emission tomography/computed tomography for optimized colon cancer staging and follow up.

OBJECTIVES: Optimal management of colon cancer (CC) requires detailed assessment of extent of disease. This study prospectively investigates the diagnostic accuracy of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) for staging and detection of recurrence in primary CC. MATERIAL AND METHODS: PET/CT for preoperative staging was performed in 66 prospectively included patients with primary CC. Diagnostic accuracy for PET/CT and CT was analyzed. In addition to routine follow up, 42 stages I-III CC patients had postoperative PET/CT examinations every 6 months for 2 years. Serological levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), carcinoembryonic antigen, and liberated domain I of urokinase plasminogen activator receptor were analyzed. RESULTS: Accuracy for tumor, nodal, and metastases staging by PET/CT were 82% (95% confidence interval [CI]: 70; 91), 66% (CI: 51; 78), and 89% (CI: 79; 96); for CT the accuracy was 77% (CI: 64; 87), 60% (CI: 46; 73), and 69% (CI: 57; 80). Cumulative relapse incidences for stages I-III CC at 6, 12, 18, and 24 months were 7.1% (CI: 0; 15); 14.3% (CI: 4; 25); 19% (CI: 7; 31), and 21.4% (CI: 9; 34). PET/CT diagnosed all relapses detected during the first 2 years. High preoperative TIMP-1 levels were associated with significant hazards toward risk of recurrence and shorter overall survival. CONCLUSIONS: This study indicates PET/CT as a valuable tool for staging and follow up in CC. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow up.

Regulation of APC and AXIN2 expression by intestinal tumor suppressor CDX2 in colon cancer cells.

Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3ß in migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions from APC, AXIN2 and GSK3ß were analyzed for gene regulatory activity and the expression pattern of APC and GSK3ß at the invasive front was evaluated by immunohistochemical procedures. Transfection of intestinal and non-intestinal cell lines demonstrated that CDX2 activated APC and AXIN2 promoter activities via intestinal cell-specific enhancer elements. Suppressed CDX2 expression was associated with endogenous downregulation of APC and AXIN2 expression in Caco-2 cells but did not affect GSK3ß expression. Furthermore, elevated levels of nuclear ß-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results suggest that a low CDX2 level has influence on the Wnt signaling in invasive colon cancer cells possibly promoting cellular migration.

Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor.

Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that (177)Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy.

Qualities of sessile serrated adenoma/polyp/lesion and its borderline variant in the context of synchronous colorectal carcinoma.

AIMS: Although much data have accumulated on sessile serrated adenoma/polyp/lesion (SSA/P/L) in general, its characteristics in specified contexts are less well elucidated. This lack of knowledge is even more conspicuous concerning its borderline counterpart, referred to as BSSA/P/L. The previous histological observations of the authors on SSA/P/L and BSSA/P/L in general are here extended to encompass attributes of these polyps in the context of synchronous colorectal carcinoma (SCRC), with a focus on the place of BSSA/P/L in the spectrum of non-dysplastic serrated polyps. METHODS: 219 SSA/P/Ls, 206 BSSA/P/Ls and 170 hyperplastic polyps (HPs) were examined for SCRC. Demographics, polyp details (size, site, BRAF((V600E))) and advanced synchronous conventional adenomas were recorded. RESULTS: SCRC was present in 12.3% of SSA/P/Ls, 7.1% of HPs (p=0.09) and 8.3% of BSSA/P/Ls. Patients' ages were comparable. Gender distribution of SSA/P/L and BSSA/P/L was equal, which differed, albeit insignificantly, from a male predominance of HPs. More SSA/P/Ls and BSSA/P/Ls than HPs exceeded 4 mm (p≤0.0001). A proximal site characterised SSA/P/L compared with BBSA/P/L and HP (p<0.0001). BRAF mutation was more prevalent in SSA/P/Ls and BSSA/P/Ls, which further coexisted with advanced synchronous conventional adenomas less commonly than HPs. CONCLUSIONS: BSSA/P/L was like SSA/P/L in most respects. The lower SCRC prevalence of BSSA/P/L could fit the idea of BSSA/P/L as a precursor to SSA/P/L, a notion that deserves attention when formulating guidelines for CRC screening.

The JAK2V617F allele burden and STAT3- and STAT5 phosphorylation in myeloproliferative neoplasms: early prefibrotic myelofibrosis compared with essential thrombocythemia, polycythemia vera and myelofibrosis.

Early prefibrotic myelofibrosis (early PMF) is a diagnosis that clinically and histologically mimic essential thrombocythemia (ET), but is important to distinguish from ET, polycythemia vera (PV) and primary myelofibrosis (PMF) due to its different prognosis and clinical evolution. In this study, we assessed the allele burden of JAK2V617F in bone marrow biopsies from patients with these chronic myeloproliferative neoplasms. We correlated our findings with the amount of phosphorylated STAT3 (P-STAT3) and STAT5 (P-STAT5) in megakaryocyte nuclei in the bone marrow. The JAK2V617F allele burden was significantly higher in patients with PV (median: 50.99, range: 23.08-97.29, p < 0.01 and p < 0.01) and PMF (median: 44.13, range: 33.61-92.17, p < 0.05 and p < 0.01) compared with a low allele burden in ET (median: 23.465, range: 8.67-47.92) and early PMF (median: 25.68, range: 0.61-49.13) respectively. In addition, we found a significantly higher phosphorylation of STAT5 and STAT3 in the JAK2V617F positive group than in the negative group. There was no positive correlation between increasing JAK2V617F allele burden and the amount of P-STAT3 and P-STAT5. However, we found low values of P-STAT5 in bone marrow biopsies from patients with ETJAK2V617F+ as compared with patients with early PMFJAK2V617F+. Although this difference was statistically significant, larger studies are needed to firmly support this conclusion.