Varying malignant potential of appendiceal neuroendocrine tumors: importance of histologic subtype.

BACKGROUND: Neuroendocrine tumors (NETs) of the appendix include malignant carcinoid tumor (MCT), goblet cell carcinoid (GCT), and composite goblet cell carcinoid-adenocarcinoma (CGCC-A). METHODS: We compared characteristics and outcomes of these histologic subtypes. Patients with appendiceal NETs were identified from the National Cancer Database (1998-2007). Descriptive statistics were used to compare cohorts and associations between clinicopathologic factors and overall survival (OS) were examined using Cox proportional hazards models. RESULTS: A total of 2,812 patients with appendiceal NETs were identified. The most common histologic subtype was GCT (59.6%), followed by MCT (32.1%), CGCC-A (6.9%), and others (1.4%). CGCC-A had a significantly higher incidence of lymph node metastases (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.1-4.8) and distant metastases (OR, 6.0; 95% CI = 3.8-9.3) than GCT. The 5-year OS was 86.3% (95% CI, 81.4-89.9) for MCT, 77.6% (95% CI, 74.0-80.8) for GCT, and 56.3% (95% CI, 42.1-68.4) for CGCC-A (P < 0.0001). CONCLUSION: Appendiceal NETs represent a spectrum of disease with varying malignant potential: MCT (low), GCT (intermediate), and CGCC-A (high). GCTs represent the most common subtype, whereas CGCC-As place the patient at highest risk for regional and distant metastases and have the worst prognosis.

Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is deregulated in many human diseases including cancer, diabetes, obesity, and autoimmunity. PI3K consists of a p110 catalytic protein and a p85alpha regulatory protein, required for the stabilization and localization of p110-PI3K activity. The p110-PI3K enzyme generates the key signaling lipid phosphatidylinositol 3,4,5-trisphosphate, which is dephosphorylated by the PI3-phosphatase PTEN. Here we show another function for the p85alpha regulatory protein: it binds directly to and enhances PTEN lipid phosphatase activity. We demonstrate that ectopically expressed FLAG-tagged p85 coimmunoprecipitates endogenous PTEN in an epidermal growth factor dependent manner. We also show epidermal growth factor dependent coimmunoprecipitation of endogenous p85 and PTEN proteins in HeLa cells. Thus p85 regulates both p110-PI3K and PTEN-phosphatase enzymes through direct interaction. This finding underscores the need for caution in analyzing PI3K activity because anti-p85 immunoprecipitations may contain both p85:p110-PI3K and p85:PTEN-phosphatase enzymes and thus measure net PI3K activity. We identify the N-terminal SH3-BH region of p85alpha, absent in the smaller p55alpha and p50alpha isoforms, as the region that mediates PTEN binding and regulation. Cellular expression of p85DeltaSH3-BH results in substantially increased magnitude and duration of pAkt levels in response to growth factor stimulation. The ability of p85 to bind and directly regulate both p110-PI3K and PTEN-PI3-phosphatase allows us to explain the paradoxical insulin signaling phenotypes observed in mice with reduced PI3K or PTEN proteins. This discovery will impact ongoing studies using therapeutics targeting the PI3K/PTEN/Akt pathway.

recurrence following hepatectomy for metastatic colorectal cancer: development of a model that predicts patterns of recurrence and survival.

BACKGROUND: While several prognostic models have been developed to predict survival of patients who undergo hepatectomy for metastatic colorectal cancer (mCRC), few data exist to predict survival after recurrence. We sought to develop a model that predicts survival for patients who have developed recurrence following hepatectomy for mCRC. METHODS: A retrospective analysis was performed on data from consecutive patients that underwent hepatectomy for mCRC. Clinicopathologic data, recurrence patterns, and outcomes were analyzed. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed. An integer-based model was created to predict the patterns of recurrence and survival after recurrence. RESULTS: This analysis included 280 patients with a median follow-up of 50.1 months. Of these, 53% underwent major hepatectomy and 87% had negative margins. Recurrent disease developed in 63% of patients. After hepatectomy, factors associated with short disease-free interval (DFI) and overall survival (OS) included CEA > 200 ng/ml (P < 0.0005), >1 metastasis (P < 0.0005), and a high Fong score (P < 0.0005). After recurrence, the pattern of recurrence was a strong predictor of OS (P < 0.0005). Independent predictors of the pattern of recurrence on multivariate analysis include CEA > 200 ng/ml, tumor size >5 cm, and >1 liver metastasis. A simple predictive scoring system was developed from the beta coefficients of this analysis that correlated with recurrence pattern (P < 0.0005). CONCLUSIONS: After hepatectomy, survival of patients with recurrent mCRC is strongly predicted by the patterns of recurrence, and the recurrence pattern can be predicted with a simple model. This can also be extended to create a scoring system that estimates expected survival.

Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection.

BACKGROUND: The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival. METHODS: A retrospective review from seven centres was performed. Metabolic factors, tumour characteristics and outcomes of patients undergoing resection for PDAC were collected. Univariate and multivariable analyses were performed to determine factors associated with disease-free (DFS) and overall survival (OS). RESULTS: Of the 509 patients in the present study, 31.2% had diabetes. Scoring systems were devised to predict OS and DFS based on a training set (n= 245) and were subsequently tested on an independent set (n= 264). Pre-operative diabetes (P < 0.001), tumour size >2 cm (P= 0.001), metastatic nodal ratio >0.1 (P < 0.001) and R1 margin (P < 0.001) all correlated with DFS and OS on univariate analysis. Scoring systems were devised based on multivariable analysis of the above factors. Diabetes and the metastatic nodal ratio were the most important factors in each system, earning two points for OS and four points for DFS. These scoring systems significantly correlated with both DFS (P < 0.001) and OS (P < 0.001). CONCLUSION: Pre-operative diabetes status provides useful information that can help to stratify patients in terms of predicted post-operative OS and DFS.

A-Raf associates with and regulates platelet-derived growth factor receptor signalling.

Raf kinases are important intermediates in epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) mediated activation of the mitogen-activated protein kinase (MAPK) pathway. In this report, we show that the A-Raf kinase is associated with activated EGF receptor complexes and with PDGF receptor (PDGFR) complexes independent of prior PDGF treatment. The ability of A-Raf to associate with receptor tyrosine kinases could provide a Ras-GTP-independent mechanism for the membrane localization of A-Raf. Expression of a partially activated A-Raf mutant resulted in decreased tyrosine phosphorylation of the PDGFR, specifically on Y857 (autophosphorylation site) and Y1021 (phospholipase Cgamma1 (PLCgamma1) binding site), but not the binding sites for other signalling proteins (Nck, phosphatidylinositol 3'-kinase (PI3K), RasGAP, Grb2, SHP). Activated A-Raf expression also altered the activation of PLCgamma1, and p85-associated PI3K. Thus, A-Raf can regulate PLCgamma1 signalling via a PDGFR-dependent mechanism and may also regulate PI3K signalling via a PDGFR-independent mechanism.

Medically managed hypercholesterolemia and insulin-dependent diabetes mellitus preoperatively predicts poor survival after surgery for pancreatic cancer.

INTRODUCTION: Although patients with pancreatic ductal adenocarcinoma (PDAC) frequently require medications to treat pre-existing conditions, the impact of these treatments on outcomes post-resection is unknown. The purpose of this study was to determine the impact of preoperative medications on overall survival after pancreatic resection. METHODS: Multi-institutional data on preoperative medications and outcomes in patients undergoing resection for PDAC were analyzed. Univariate and multivariate analyses were performed to determine which medications were predictive of early mortality. RESULTS: Of the 518 patients resected for PDAC, 13.3% were being treated preoperatively with insulin, 14.8% were on a statin, 1.7% were on steroids, and 7.6% were on thyroxin. On univariate analysis, patients taking preoperative insulin had a higher 90-day mortality rate relative to those not on insulin (13.0% vs. 4.8%, p = 0.024), and those on a statin had a higher 90-day mortality than those who were not (10.8% vs. 4.6%, p = 0.035). Preoperative steroids and thyroxin were not associated with 90-day mortality (p = 0.409 and p = 0.474, respectively). Insulin and statin use was a stronger predictor of 90-day mortality than history of diabetes (p = 0.101), BMI ≥ 30 (p = 0.166), cardiac disease (p = 0.168), pulmonary disease (p = 1.000), or renal dysfunction (p = 1.000). Older patients also had a higher risk of early postoperative death (p = 0.011). On multivariate analysis, only preoperative insulin usage and statin treatment independently predicted early mortality (odds ratio (OR) = 3.043; 95% confidence interval (CI), 1.256-7.372; p = 0.014, and OR = 2.529; 95% CI, 1.048-6.104; p = 0.039, respectively). Based on the beta coefficients, a simple scoring system was devised to predict survival after resection from preoperative medication use. Zero points were assigned to patients who were on neither insulin nor a statin, one point to those who were on one or the other, and two points to those who were on both insulin and a statin. The score correlated with early postoperative survival (90-day mortality rates of 3.4%, 11.5%, and 13.3% for 0, 1, and 2 points, respectively, p = 0.004). Increasing score was also associated with poorer long-term outcomes, with a median overall survival of 19.6, 15.6, and 11.2 months for 0, 1, and 2 points, respectively (p = 0.002, median follow-up 14.4 months). CONCLUSIONS: Patients with PDAC being treated for pre-existing diabetes or hypercholesterolemia with either insulin or statin-based therapy have an increased risk of early postoperative mortality. A simple scoring system based on preoperative medications can be used to predict early and overall survival following resection.

Early mortality following endovascular versus open repair of ruptured abdominal aortic aneurysms.

PURPOSE: To determine whether endovascular repair (EVAR) offers a survival advantage over open repair (OAR) with ruptured abdominal aortic aneurysms (RAAA). METHODS: Retrospective analysis of RAAA patients treated between 2003 and 2008. Univariate and multivariate analyses were performed. RESULTS: 167 patients presented with RAAA (OAR = 135, 80.8%, EVAR = 32, 19.2%). On univariate analysis, EVAR was associated with a decreased mortality relative to OAR, (15.6% vs 43.7%, P = .004). Patients who survived were younger (P < .0005), had a higher blood pressure (P < .0005), level of consciousness (P < .0005), and hemoglobin (P = .018), and a lower urea (P = .005) and international normalized ratio (INR; P = .001). On multivariate analysis, type of repair remained an independent predictor of 30-day mortality (OR: 0.121; 95% CI: 0.021-0.682, P = .017). CONCLUSION: Controlling for preoperative factors, EVAR is an independent predictor of lower 30 day mortality relative to open repair after RAAA. This supports the wider use of endovascular repair in all patients with RAAA.

Factors associated with improved survival among young adult melanoma patients despite a greater incidence of sentinel lymph node metastasis.

INTRODUCTION: We sought to evaluate the factors that affect sentinel lymph node (SLN) metastasis and survival among young melanoma patients (< or =30 y). METHODS: The Sunbelt Melanoma Trial is a multi-institutional prospective randomized trial of patients aged 18 to 70 y. Statistical analyses were performed to determine if patients < or =30 y of age had a significantly different outcome in terms of SLN metastasis, disease-free survival (DFS), and overall survival (OS) compared to older patients. RESULTS: The median age of the 3031 patients in this study was 50 y (range 18 to 77 y); the 315 patients (10.4%) < or =30 y old were compared with those >30 y old. Of the 1944 patients with follow-up, the median follow-up was 48 mo. On univariate analysis, younger patients were more often female (54.7% versus 40.9%, P < 0.0005), with tumors <4 mm thick (94.9% versus 89.4%, P = 0.001) without ulceration (80.3% versus 70.9%, P < 0.0005) or evidence of regression (93.8% versus 87.8%, P = 0.003), and were less likely to have lentigo maligna (0.0% versus 2.6%) or acral lentiginous (0.4% versus 3.1%, P < 0.0005) subtype. Patient age < or =30 was associated with SLN metastasis on univariate (24.6% versus 19.7%, P = 0.05) and multivariate (OR = 1.77, 95% CI = 1.26-2.49, P = 0.001) analyses. With a median follow-up of 48 mo, younger patients had a significantly improved 5-y DFS (86.2% versus 79.1%, P = 0.036) and OS (89.9% versus 80.1%, P = 0.010). On multivariable Cox regression analysis, however, age group was not a significant independent prognostic factor affecting DFS or OS. CONCLUSION: Despite a higher rate of SLN metastasis, patients < or =30 y old do not have a worse survival attributable to a more favorable clinicopathologic profile.