Citations

4022 Background: While the overall incidence of gastric cancer has declined in the United States, the incidence of proximal gastric cancers has increased. Understanding the differences between proximal and distal gastric cancer, may enable us to identify important risk factors and treatment patterns. Methods: Data on 6099 patients diagnosed with gastric adenocarcinoma were collected as a Patient Care Evaluation under the auspices of the American College of Surgeons Commission on Cancer. Clearly defined proximal and distal cancers were compared using the Pearson chi-square test and logistic regression. Results: The proximal cancer group included 1924 patients (87% cardia; 13% fundus) and the distal cancer group included 1312 patients (85% antrum; 15% pylorus). Proximal gastric cancers occurred more often in men (p<0.0001), whites (compared to Black, Hispanic, Native American and Asian races) (p<0.0001), and at younger age (p<0.0001) compared to distal cancers. Risk factors for proximal presentation included tobacco use (Hazard ratio (HR) 1.9, p= 0.002) alchohol use (HR 1.5, p= 0.038) and Barretts (HR 2.7, p<0.0001). Risk factors for distal presentation included H. Pylori (HR 2.3, p= 0.001). Despite increased use of multi-modality therapy, fewer proximal gastric cancers underwent resection compared to distal cancers (p<0.0001). Conclusions: Different risk factors can be identified for proximal and distal gastric cancers, which can impact on risk reduction, screening efforts and help define the pathogenesis of gastric cancer. While proximal cancer patients receive more aggressive multimodality treatments, including adjuvant and neoadjuvant therapy, fewer undergo surgical resection. Long term survival based upon proximal and distal tumor differences will be explored when follow-up data become available.Key Words: gastric adenocarcinoma, proximal gastric cancer, distal gastric cancer, risk factors, treatment. [Table: see text] No significant financial relationships to disclose.

3525 Background: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival rates. Oxaliplatin (OXAL) combined with capecitabine (CAPE) has demonstrated activity in advanced CRC. We report early results of an analysis of SYS OXAL plus CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS). Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. HAI + SYS therapy was initiated following metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1–14 weeks 1 & 2. SYS therapy included 130 mg/m2 OXAL d1, with CAPE at 1000 mg/m2 p.o. BID, d1–14, weeks 4 & 5. Two additional 3-wk courses of SYS therapy were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity (GI Cancer Symposium 2004). Patient Characteristics: 54 of 70 patients were able to initiate HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. Results: Patients completed median of 6 cycles (range 1 - 6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). No post-operative or treatment related deaths were reported. 69% (31/45) of evaluable patients are alive with a minimum 18 mos of follow-up. 6 deaths occurred in less than 2 yrs. 44% (20/45) have recurred, with 40% (8/20) having liver involvement. Median time-to-progression is 32 mos with an estimated 2YS rate of 86% (95% CI 76–97%). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. Updated follow-up is necessary to solidify the primary endpoint of 2YS. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc. Maximum Severity, Grade 3+ (N=54) [Table: see text] [Table: see text]

4057 Background: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival. Dual therapy OXAL+CAPE has demonstrated activity in advanced CRC. We report final results of an analysis of SYS OXAL+CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS), with 36 of 45 patients surviving 2 yrs as evidence of promising efficacy. Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. Prior adjuvant chemotherapy for completely resected primary was allowed. HAI+SYS therapy was initiated 21–56 days post-metastasectomy. Four alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1–14 wks 1&2. SYS included 130 mg/m2 OXAL d1, with CAPE at 1,000 mg/m2 po BID, d1–14, wks 4&5. Two additional 3-wk courses of SYS were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity. Results: 54 of 73 eligible patients initiated HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. Patients completed median of 6 cycles (range 1–6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). No HAI+SYS related deaths occurred. Median follow-up on the 42 survivors is 28 months (range 7–51). 6 deaths occurred within 2 yrs. 48% (26/54) have recurred; 42% (11/26) with liver involvement. Median time-to-progression is 30 months. The estimated 2YS rate is 88% (95% CI 80–98%) and median overall survival is 46 months (95% CI 41.3-NA). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. A 2YS of 88% exceeds our preplanned level of success, supporting the use of this combination in the ongoing NSABP trial C-09. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc. No significant financial relationships to disclose.

Replication of negative-strand RNA viruses relies on two components: a helical ribonucleocapsid and an RNA-dependent RNA polymerase composed of a catalytic subunit, the L protein, and a cofactor, the P protein. We show that the measles virus (MeV) C protein is an additional component of the replication complex. We provide evidence that the C protein is recruited to the ribonucleocapsid by the P protein and map the interacting segments of both C and P proteins. We conclude that the primary function of MeV C is to improve polymerase processivity and accuracy, rather than uniquely to antagonize the type I interferon response. Since most viruses of the Paramyxoviridae family express C proteins, their primary function may be conserved.

Abstract Abstract 2692 Background: Massive splenomegaly is occasionally encountered in patients with Non-Hodgkin's Lymphoma (NHL) and can be associated with abdominal symptoms, anemia and thrombocytopenia. The spleen may also be a primary focus of the disease itself. Splenectomy offers the benefit of localized treatment of the disease as well as relief of symptoms from splenomegaly and associated cytopenias. The safety and long term clinical outcomes of splenectomy for massive splenomegaly (>1500 gm) in patients with various histologies of NHL was analyzed. Methods: Data was obtained from clinical records of 90 patients with a diagnosis of NHL who underwent a splenectomy at Mayo Clinic Rochester from January 1998 to December 2007. Demographics, previous treatments, histology, post- surgical complications were collected and analyzed for the entire cohort. Additionally, median overall survival, improvement in symptoms, anemia and thrombocytopenia were analyzed by NHL type. Results: Median age at splenectomy was 67 years (range 42–84 yrs.) and 56 (62%) of patients were male. Average time from diagnosis to splenectomy was 3 months (range 0–217 months). Splenectomy was the first treatment in 56 (62%) patients; the other 34 patients were treated with chemotherapy with an average of two previous regimens. Most patients had involvement outside of the spleen, 65 (72%) with concurrent bone marrow involvement and 35 (50%) with lymph node involvement. Various different NHL histologies were represented: marginal zone (MZ) (34%), mantle cell (MC) (26%), diffuse large B-cell lymphoma (DLBCL) (10%), follicular (FL) (11%), lymphoplasmacytic (LP) (6%) and T cell NOS (4%). With a median follow-up time of 25 months, the median overall survival differed by histology type of NHL (Table 1). Indolent lymphomas such as FL, LP and MZ had more favorable survival compared with more aggressive lymphomas such as DLBCL and T cell NOS. Splenectomy was safe and well tolerated with only one treatment related death. There were no reported post-splenectomy septic events. Two patients did develop a portal vein thrombosis. 95% of patients had relief in pressure and abdominal symptoms post-splenectomy. With the exception of patients with DLBCL and T-cell NHL, a majority of patients had improvement in anemia and thrombocytopenia related to splenomegaly (Table 2). Conclusions: This represents the largest reported series of patients with lymphoma treated with splenectomy. Our results indicate that median overall survival after splenectomy is determined by the underlying type of NHL. Patients with LP, FL, MZ and MCL have a favorable outcomes following splenectomy. Splenectomy remains a safe and effective treatment option for massive splenomegaly in selected patients during the course of their disease management. Disclosures: No relevant conflicts of interest to declare.

ABSTRACT Here, we show that cells expressing the adherens junction protein nectin-1 capture nectin-4-containing membranes from the surface of adjacent cells in a trans-endocytosis process. We find that internalized nectin-1–nectin-4 complexes follow the endocytic pathway. The nectin-1 cytoplasmic tail controls transfer: its deletion prevents trans-endocytosis, while its exchange with the nectin-4 tail reverses transfer direction. Nectin-1-expressing cells acquire dye-labeled cytoplasmic proteins synchronously with nectin-4, a process most active during cell adhesion. Some cytoplasmic cargo remains functional after transfer, as demonstrated with encapsidated genomes of measles virus (MeV). This virus uses nectin-4, but not nectin-1, as a receptor. Epithelial cells expressing nectin-4, but not those expressing another MeV receptor in its place, can transfer infection to nectin-1-expressing primary neurons. Thus, this newly discovered process can move cytoplasmic cargo, including infectious material, from epithelial cells to neurons. We name the process nectin-elicited cytoplasm transfer (NECT). NECT-related trans-endocytosis processes may be exploited by pathogens to extend tropism. This article has an associated First Person interview with the first author of the paper.

Abstract Higher trait optimism and/or lower cynical hostility are associated with healthier behaviors and lower risk of morbidity and mortality, yet their association with health care utilization has been understudied. Whether these psychological attitudes are associated with breast cancer screening behavior is unknown. To assess the association of optimism and cynical hostility with screening mammography in older women and whether sociodemographic factors acted as mediators of these relationships, we used Women's Health Initiative (WHI) observational cohort survey data linked to Medicare claims. The sample includes WHI participants without history of breast cancer who were enrolled in Medicare Parts A and B for ≥2 years from 2005–2010, and who completed WHI baseline attitudinal questionnaires (n = 48,291). We used survival modeling to examine whether screening frequency varied by psychological attitudes (measured at study baseline) after adjusting for sociodemographic characteristics, health conditions, and healthcare-related variables. Psychological attitudes included trait optimism (Life Orientation Test-Revised) and cynical hostility (Cook Medley subscale), which were self-reported at study baseline. Sociodemographic, health conditions, and healthcare variables were self-reported at baseline and updated through 2005 as available. Contrary to our hypotheses, repeated events survival models showed that women with the lowest optimism scores (i.e., more pessimistic tendencies) received 5% more frequent screenings after complete covariate adjustment (p < .01) compared to the most optimistic group, and showed no association between cynical hostility and frequency of screening mammograms. Sociodemographic factors did not appear to mediate the relationship between optimism and screenings. However, higher levels of education and higher levels of income were associated with more frequent screenings (both p < .01). We also found that results for optimism were primarily driven by women who were aged 75 or older after January 2009, when changes to clinical guidelines lead to uncertainty about risks and benefits of screening in this age group. The study demonstrated that lower optimism, higher education, and higher income were all associated with more frequent screening mammograms in this sample after repeated events survival modeling and covariate adjustment.

We are investigating the changes in hepatic lipid catabolism that contribute to alcohol-induced fatty liver. Following chronic ethanol (EtOH) exposure, abstinence from alcohol resolves steatosis. Here, we investigated the hepatocellular events that lead to this resolution by quantifying specific catabolic parameters that returned to control levels after EtOH was withdrawn. We hypothesized that, after its chronic consumption, EtOH withdrawal reactivates lipid catabolic processes that restore lipostasis. Male Wistar rats were fed control and EtOH liquid diets for 6 wk. Randomly chosen EtOH-fed rats were then fed control diet for 7 days. Liver triglycerides (TG), lipid peroxides, key markers of fatty acid (FA) metabolism, lipophagy, and autophagy were quantified. Compared with controls, EtOH-fed rats had higher hepatic triglycerides, lipid peroxides, and serum free fatty acids (FFA). The latter findings were associated with higher levels of FA transporters (FATP 2, 4, and 5) but lower quantities of peroxisome proliferator-activated receptor-α (PPAR-α), which governs FA oxidation. EtOH-fed animals also had lower nuclear levels of the autophagy-regulating transcription factor EB (TFEB), associated with lower hepatic lipophagy and autophagy. After EtOH-fed rats were refed control diet for 7 days, their serum FFA levels and those of FATPs fell to control (normal) levels, whereas PPAR-α levels rose to normal. Hepatic TG and malondialdehyde levels in EtOH-withdrawn rats declined to near control levels. EtOH withdrawal restored nuclear TFEB content, hepatic lipophagy, and autophagy activity to control levels. EtOH withdrawal reversed aberrant FA metabolism and restored lysosomal function to promote resolution of alcohol-induced fatty liver.NEW & NOTEWORTHY Here, using an animal model, we show mechanisms of reversal of fatty liver and injury following EtOH withdrawal. Our data indicate that reactivation of autophagy and lysosome function through the restoration of transcription factor EB contribute to reversal of fatty liver and injury following EtOH withdrawal.

AbstractAlzheimer's disease (AD) is the most common type of dementia in the elderly with no effective treatment currently. Recent studies of noninvasive neuroimaging, resting‐state functional magnetic resonance imaging (rs‐fMRI) with graph theoretical analysis have shown that patients with AD and mild cognitive impairment (MCI) exhibit disrupted topological organization in large‐scale brain networks. In previous work, it is a common practice to threshold such networks. However, it is not only difficult to make a principled choice of threshold values, but also worse is the discard of potential important information. To address this issue, we propose a threshold‐free feature by integrating a prior persistent homology‐based topological feature (the zeroth Betti number) and a newly defined connected component aggregation cost feature to model brain networks over all possible scales. We show that the induced topological feature (Integrated Persistent Feature) follows a monotonically decreasing convergence function and further propose to use its slope as a concise and persistent brain network topological measure. We apply this measure to study rs‐fMRI data from the Alzheimer's Disease Neuroimaging Initiative and compare our approach with five other widely used graph measures across five parcellation schemes ranging from 90 to 1,024 region‐of‐interests. The experimental results demonstrate that the proposed network measure shows more statistical power and stronger robustness in group difference studies in that the absolute values of the proposed measure of AD are lower than MCI and much lower than normal controls, providing empirical evidence for decreased functional integration in AD dementia and MCI.