Despite the loss of Adenomatous Polyposis Coli (APC) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear β-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear β-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear β-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl's mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear β-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear β-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated β-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.

The proto-oncogene β-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear β-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target β-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear β-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear β-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/β-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/β-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

Background While racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood. Methods We examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record and the survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated. Results Black patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.7, CI 1.01-2.9, p = 0.0467) for death. Though the response to therapy emerged as a strong predictor of survival (HR = 0.4, CI = 0.2-0.7, p = 0.0021), it was comparable between Blacks and Whites. Conclusions Despite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce the findings from previous studies regarding lower colorectal cancer survival in Black patients, and point to the importance of investigating other risk factors including genetic and pathogenic differences.

The 2008 recommendation appeared to reduce PSA screening rates in older men in 2009 and 2010; there was a substantial reduction in men aged 75 and older and a more modest reduction in men aged 65 to 74.

Pancreatic cancer is more common in older adults, who are underrepresented in clinical trials and frequently under treated. Chronological age alone should not deter clinicians from offering treatment to geriatric patients, as they are a heterogeneous population. Geriatric assessment, frailty assessment tools, and toxicity risk scores help clinicians select appropriate patients for therapy. For resectable disease, surgery can be safe but should be done at a high-volume center. Adjuvant therapy is important; though there remains controversy on the role of radiation, chemotherapy is well studied and efficacious. In locally advanced unresectable disease, chemoradiation or chemotherapy alone is an option. Neoadjuvant therapy improves the chances of resectability in borderline resectable disease. Chemotherapy extends survival in metastatic disease, but treatment goals and risk-benefit ratios have to be clarified. Adequate symptom management and supportive care are important. There are now many new treatment strategies and novel therapies for this disease.

e19069 Background: The prognostic factors influencing survival and optimal management of primary pulmonary lymphomas (PPLs) have not been clearly defined due to rarity of the disease. This study sought to characterize the significant prognostic factors of PPL and develop a prognostic nomogram for individualized prediction of survival outcomes in patients with PPL. Methods: Patients diagnosed with PPL between 1983 and 2010 were identified using the Surveillance, Epidemiology, and End Results (SEER) Program database. Kaplan-Meier survival analysis and Cox proportional hazards regression model were performed to identify significant independent prognostic factors for overall survival (OS) in patients with PPL. A nomogram was constructed for the prediction of 5-year OS probability based on these variables. Results: The study cohort of 2325 PPL patients has a 5-year OS rate of 52% and a median OS of 67 months. Older age at diagnosis (HR 1.031; 95% CI, 1.026-1.036; p<0.001], males (HR 1.434; 95% CI, 1.267-1.622; p<0.001), Hispanic race (HR 1.370; 95% CI, 1.113-1.687; p=0.003), non-marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT) histology (p<0.001), primary site at main bronchus (HR 1.326; 95% CI, 1.014-1.735; p=0.039), Ann Arbor stage IV (HR 1.542; 95% CI, 1.324-1.795; p<0.001) were significantly associated with worse OS. All treatment modalities, including chemotherapy (HR 0.615; 95% CI, 0.536-0.706; p<0.001), surgery (HR 0.666;95% CI, 0.577-0.769; p<0.001) and radiotherapy (HR 0.829; 95% CI, 0.693-0.992; p=0.041) were independent predictors of survival. The nomogram constructed using these variables has a higher concordance index of 0.716 (95% CI, 0.699-0.734) compared to that of Ann Arbor staging system [0.571 (95% CI,0.552-0.591); p<0.001]. Conclusions: Older age, male sex, Hispanic race, non-MALT histology, primary site at main bronchus, advanced Ann Arbor stage, not receiving treatment were independent prognostic factors that are associated with worse OS in patients with PPL. The nomogram demonstrated good agreement between the predicted probabilities and actual observations on calibration plots.

e16133 Background: Primary gallbladder carcinoma (GBC) is the most common biliary tract cancer with poor survival despite aggressive treatment. The purpose of our study was to investigate the trends of GBC incidence and incidence-based mortality (IBM), as well as to identify the factors responsible for any observed changes. Methods: GBC cases diagnosed between 1973 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database (SEER) database. Incidence and IBM rates age-adjusted to the 2000 US standard population were calculated and were stratified according to population and tumor-associated characteristics. Joinpoint Regression Analysis program was used to calculate the annual percent changes (APCs) for trend analysis. Results: Among the 10,792 patients with GBC, there was a predominance of white (81%) and female (71%) patients. The overall incidence rate was 1.086 (95% CI: 1.065 to 1.106) and the overall IBM rate was 0.995 (95% CI: 0.976 to 1.015). GBC incidence decreased by 1.645% (95% CI: 1.448 to 1.842, p < 0.001) per year, but the decreasing trend was only statistically significant from 1973 to 2002, after which the incidence rates stabilized. Conversely, IBM decreased by 1.689% (95% CI: 1.217 to 2.159, p < 0.001) per year from 1980 to 2015; the degree of decline in IBM rates during 1997-2015 (-1.194, 95% CI: -1.680 to -0.705, p < 0.001) was lower compared to that during 1980-1997 (-3.132, 95% CI: -3.682 to -2.578, p < 0.001). Mortality rates of GBC decreased in all age groups and in all races except for African American. There was a significant decrease in IBM in all SEER stages of GBC, except for distant stage GBC. Conclusions: GBC incidence and IBM rates have been decreasing over the last 40 years. However, the decrease in incidence and IBM appeared to have plateaued in the last two decades. The roles of increasing widespread use of laparoscopic cholecystectomy and use of newer treatment modalities, such as adjuvant chemotherapy and radiation, need to be investigated further.[Table: see text]

Background: High-dose melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT) has been shown to extend survival as well as to induce hematologic and clinical responses in selected patients with light chain (AL) amyloidosis. The most frequent toxicities of HDM are profound myelosuppression and gastrointestinal (GI) side effects. Studies have shown that 80% of melphalan is bound to plasma proteins (60% albumin bound) with ~20% free. We hypothesized that AL amyloidosis patients with severe nephrotic syndrome and profound hypoalbuminemia might have greater free melphalan fraction and more treatment-related toxicity. Methods: Patients with AL amyloidosis treated with HDM/SCT between 2011 and 2014 with severe hypoalbuminemia (SH), defined as a pre-transplant serum albumin of ≤2g/dL, were studied retrospectively. The stem cell transplant database was queried for patient demographic information, pre-transplant albumin level, HDM dose, renal function, pre-transplant 24-hour urine protein level, time to neutrophil and platelet engraftment, and treatment-related complications. Patients with AL amyloidosis treated between 2011 and 2012 without severe hypoalbuminemia, defined as serum albumin level of > 2g/dL (WSH), served as a control group. Results: Of the 84 patients with AL amyloidosis treated with HDM/SCT in this 4 year period, 16 (19%) with SH were identified. 41 patients were identified in the control group (WSH). There was no difference in the proportion of patients with all non-hematologic grade 3 or 4 adverse events between the groups. All patients suffered from expected grade 4 myelosuppression. The only statistically different non-hematologic grade 4 toxicity in SH was acute renal failure requiring temporary hemodialysis (n=4/16, 25% SH vs n=2/41, 5% WSH; p=0.05), with 1 subject eventually needing long term dialysis. There were no grade 4 mucositis or GI toxicities in either groups. The only statistically different grade 3 non-hematologic toxicity was lightheadedness (n=3/16, 19% SH vs n=0/41, 0% WSH; p=0.02). Conclusion: These data suggest that patients with severe hypoalbuminemia do not have more prolonged myelosuppression or GI toxicities when treated with HDM/SCT compared to those with higher serum albumin levels in AL amyloidosis. Grade 4 renal toxicity with acute renal failure requiring temporary hemodialysis (p=0.05) and grade 3 lightheadedness (p=0.02) occurred more commonly in SH than WSH group. In this retrospective study, we did not measure free melphalan concentrations in the blood. However, these data suggest that patients with severe hypoalbuminemia do not require adjustment of melphalan dosing. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.