Senthil N. Jayarajan

Prognostic Significance of Signet Ring Gastric Cancer

PURPOSE Studies in Asia have questioned the dictum that signet ring cell carcinoma (SRC) has a worse prognosis than other forms of gastric cancer. Our study determined differences in presentation and outcomes between SRC and gastric adenocarcinoma (AC) in the United States. PATIENTS AND METHODS The National Cancer Institute Surveillance, Epidemiology, and End Results database was reviewed for SRC and AC from 2004 to 2007. RESULTS We reviewed 10,246 cases of patients with gastric cancer, including 2,666 of SRC and 7,580 of AC. SRC presented in younger patients (61.9 v 68.7 years; P < .001) and less often in men (52.7% v 68.7%; P < .001). SRC patients were more frequently black (11.3% v 10.9%), Asian (16.4% v 13.2%), American Indian/Alaska Native (0.9% v 0.8%), or Hispanic (23.3% v 14.0%; P < .001). SRC was more likely to be stage T3-4 (45.8% v 33.3%), have lymph node spread (59.7% v 51.8%), and distant metastases (40.2% v 37.6%; P < .001). SRC was more likely to be found in the lower (30.7% v 24.2%) and middle stomach (30.6% v 20.7%; P < .001). Median survival was not different between the two (AC, 14.0 months v SRC, 13.0 months; P = .073). Multivariable analyses demonstrated SRC was not associated with mortality (hazard ratio [HR], 1.05; 95% CI, 0.96 to 1.11; P = .150). Mortality was associated with age (HR, 1.01; 95% CI, 1.01 to 1.02; P < .001), black race (HR, 1.10; 95% CI, 1.01 to 1.20; P = .026), and tumor grade. Variables associated with lower mortality risk included Asian race (HR, 0.83; 95% CI, 0.77 to 0.91; P < .001) and surgery (HR, 0.37; 95% CI, 0.34 to 0.39; P < .001). CONCLUSION In the United States, SRC significantly differs from AC in extent of disease at presentation. However, when adjusted for stage, SRC does not portend a worse prognosis.

Mitral valve repair at the time of continuous-flow left ventricular assist device implantation confers meaningful decrement in pulmonary vascular resistance

We hypothesized that the addition of mitral valve replacement or repair (MVR) to implantation of continuous-flow left ventricular assist device (cf-LVAD) may further decrease pulmonary vascular resistance (PVR) over Heartmate II (HMII) implantation alone. Patients undergoing MVR with concomitant HMII implantation were compared with those undergoing HMII implantation alone. Of the 57 patients undergoing cf-LVAD implantation, 21 (36.8%) underwent concomitant MVR and 36 (63.2%) underwent cf-LVAD implantation alone. Patients receiving MVR had greater decrement in PVR (59.4% vs. 35.2%, p = 0.01). Decrease in end-diastolic diameter was greater for patients receiving MVR but did not reach statistical significance (18.2 vs. 13.5 mm, p = 0.33). Duration of mechanical ventilation (121.6 vs. 181.4 hours, p = 0.45) and inotropic support (162.4 vs. 153.2 hours, p = 0.86), change in creatinine (0.19 vs. −0.26 mg/dl, p = 0.34), increase in bilirubin (2.54 vs. 1.55 mg/dl, p = 0.63), intensive care unit stay (168.0 vs. 231.5 hours, p = 0.38), and overall length of stay (32.0 vs. 42.5 days, p = 0.75) were similar. There was no difference in survival at 3 months (89.7% vs. 83.3%) and 1 year (83.7 vs. 67.3%, p = 0.34). Addition of MVR may result in greater decrement of PVR than HMII implantation alone. This may permit certain patients thought to be ineligible for transplantation to become candidates.

Insulin Regulates the Unfolded Protein Response in Human Adipose Tissue

Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼35 to ∼1,450 pmol/L). The insulin-induced UPR was not due to increased glucose uptake/metabolism and oxidative stress. It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and with multiple posttranslational protein modifications (acetylations, methylations, nitrosylations, succinylation, and ubiquitinations), some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative mechanism for the development of ER stress in obesity. They may also have clinical and therapeutic implications, e.g., in diabetic patients treated with high doses of insulin.

Examining rectal carcinoids in the era of screening colonoscopy: a surveillance, epidemiology, and end results analysis.

BACKGROUND: Little is known about the epidemiology of rectal carcinoids in the United States since the implementation of screening colonoscopy. OBJECTIVE: The goal of this study was to identify epidemiological differences between rectal and small intestinal carcinoids. DESIGN: This study was retrospective in design. SETTING: Surveillance, Epidemiology and End Results registry data from 1992 to 2008 were examined. PATIENTS: Patients with rectal carcinoids included those with carcinoid tumors of the rectum. Patients with small intestinal carcinoids included those with carcinoids in the duodenum, jejunum, or ileum. MAIN OUTCOME MEASURE: Epidemiological characteristics of rectal carcinoids were identified and compared with small intestinal carcinoids using multiple variable logistic regression. RESULTS: Patients with rectal carcinoids were more likely to be women (OR, 1.196 (95% CI, 1.090–1.311); p < 0.001). Rectal carcinoids were more common among all minorities, including Asians (OR, 10.063 (95% CI, 8.330–12.157); p < 0.001), blacks (OR, 1.994 (95% CI, 1.770–2.246); p < 0.001), and Hispanics (OR, 2.682 (95% CI, 2.291–3.141), p < 0.001). Patients in the 50- to 59-year age group (OR, 0.752 (95% CI, 0.599–0.944); p = 0.014) were more likely to be diagnosed with rectal carcinoids than those in the 60- to 69-year (OR, 0.481 (95% CI, 0.383–0.605); p < 0.001) and ≥70-year age groups (OR, 0.220 (95% CI, 0.175–0.277); p < 0.001). Rectal carcinoids were more likely to be diagnosed in the screening colonoscopy era among the 50- to 59-year age group (OR, 1.432 (95% CI, 1.082–1.895); p = 0.012). Since the implementation of screening colonoscopy in 2000, the proportion of patients diagnosed with rectal carcinoids has been greater than the proportion diagnosed with small intestinal carcinoids in every year except 2001, and the proportion of patients diagnosed with rectal carcinoids after 2000 has been greater than the proportion diagnosed with small intestinal carcinoids in 12 of 13 Surveillance, Epidemiology, and End Results registry reporting agencies. CONCLUSIONS: Rectal carcinoids and small intestinal carcinoids are epidemiologically distinct tumors with unique presentations. In the era of screening colonoscopy, rectal carcinoids are the more common tumor.

Double-Lung Transplantation Can Be Safely Performed Using Donors With Heavy Smoking History

BACKGROUND Lung transplantation using grafts from donors with a history of heavy smoking (>20 pack-years) is thought to confer worse prognosis. We attempt to determine if adult, double-lung transplantation can be safely performed with lungs from heavy-smoking donors (HSD). METHODS The United Network for Organ Sharing (UNOS) database was examined for adult, double-lung transplants from 2005 to 2011. RESULTS Of 5,900 double-lung transplants, 766 (13.0%) were from HSDs. The two groups were similar in recipient age (49.8 vs 50.5 years, p = 0.15), male sex (56.9% vs 56.5%, p = 0.87), and lung allocation score (45.8 vs 44.9, p = 0.18). Recipients of lungs from HSDs had lower forced expiratory volume in 1 second (FEV1; 34.3 vs 36.1% predicted, p = 0.04), longer ischemic time (5.75 vs 5.58 hours, p = 0.01), less human leukocyte antigen mismatch (4.51 vs 4.62, p = 0.01), and lower class I plasma reactive antigens (2.64 vs 3.69%, p = 0.001). HSDs were older (40.9 vs 32.6 years, p < 0.001) and less likely male (51.7 vs 59.7%, p < 0.001). Recipients of lungs from HSDs had longer median length of stay (18.0 vs 17.0 days, p < 0.001). Freedom from bronchiolitis obliterans syndrome (p = 0.09), decrement in FEV1 (p = 0.12), peak FEV1 (79.8% vs 79.0%, p = 0.51), and median survival (2,043 vs 1,928 days, p = 0.69) were not different. On multivariate analysis, HSD lungs were not associated with death (hazard ratio, 1.003; 95% confidence interval, 0.867 to 1.161, p = 0.96). Death was associated with donor age, ischemic time, race mismatch, mechanical ventilation, and extracorporeal membranous oxygenation before transplantation. CONCLUSIONS Double-lung transplantation can be safely performed with lungs from donors with a heavy smoking history.

Comparison of In Vivo Effects of Insulin on SREBP-1c Activation and INSIG-1/2 in Rat Liver and Human and Rat Adipose Tissue

The stimulatory effects of insulin on de novo lipogenesis (DNL) in the liver, where it is an important contributor to non‐alcoholic fatty liver disease (NAFLD), hepatic and systemic insulin resistance, is strong and well established. In contrast, insulin plays only a minor role in DNL in adipose tissue. The reason why insulin stimulates DNL more in liver than in fat is not known but may be due to differential regulation of the transcription and post‐translational activation of sterol regulatory element binding proteins (SREBPs). To test this hypothesis, we have examined effects of insulin on activation of SREBP‐1c in liver of rats and in adipose tissue of rats and human subjects.

The Relationships of Nutrients, Routes of Delivery, and Immunocompetence

Malnutrition has marked consequences on surgical outcomes. Adequate nutrition is important for the proper functioning of all organ systems, particularly the immune system. Determination of the type and amount of nutrient supplementation and the appropriate route of nutrient delivery is essential to bolster the immune system and enhance the hosts response to stress. Correct administration of immunonutrients could lead to reductions in patient morbidity following major surgery, trauma, and critical illness.

Continuous flow left ventricular assist device technology has influenced wait times and affected donor allocation in cardiac transplantation

OBJECTIVE Bridge to transplantation patients with continuous flow left ventricular assist devices (cfLVADs) are assigned United Network for Organ Sharing status 1A or 1B priority while awaiting orthotopic heart transplantation. We investigated the influence of cfLVAD on the waitlist times and organ allocation. METHODS The United Network for Organ Sharing database was examined from 2005 to 2012 for patients with cfLVAD and pulsatile flow LVAD (pLVAD). These 2 cohorts were compared with patients who did not receive LVAD. RESULTS Of 16,476 total orthotopic heart transplantations, 3270 (19.8%) were performed on patients with an LVAD as a bridge to transplantation. The cfLVAD group had the longest total waitlist time (259.6 days) compared with the pLVAD (134.6 days) and non-LVAD (121.7 days) groups (P < .001). The cfLVAD group spent more time in status 1A (44.7 days) than did the pLVAD (32.1 days) and non-LVAD (16.4 days) cohorts (P < .001). The median waitlist survival was better for the cfLVAD group (1234.0 days) than in the pLVAD (441.0 days) and non-LVAD (471.0 days) groups (P < .001). The cfLVAD recipients were older, had a greater body mass index, and more often had diabetes than did pLVAD and non-LVAD patients. The cfLVAD cohort received hearts from older, more often male donors, with a greater body mass index. Post-transplant survival was not significantly different among the 3 groups on Kaplan-Meier analysis (P = .12). CONCLUSIONS Despite being older, less favorable recipients, the cfLVAD patients spent more time in status 1A and had greater waitlist survival. This might allow cfLVAD patients to receive preferred donor hearts, which might allow for better post-transplant survival.

Impact of extracorporeal membrane oxygenation or mechanical ventilation as bridge to combined heart-lung transplantation on short-term and long-term survival.

Background Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation (MV) can be used as a bridge to heart-lung transplantation (HLT). The goal of this study was to determine if pretransplantation ECMO or MV affects survival in HLT. Methods The United Network for Organ Sharing database was reviewed for all adult patients receiving HLT from 1995 to 2011. The primary outcome measured was risk-adjusted all cause mortality. Results There were 542 adult patients received HLT during the study period. Of these, 15 (2.8%) required ECMO and 22 (4.1%) required MV as a bridge to transplantation. The groups were evenly matched with regards to recipient age, recipient gender, ischemic time, donor age, and donor gender. The ECMO cohort had worse survival than the control group at 30 days (20.0% vs. 83.5%) and 5 years (20.0% vs. 47.4%; P<0.001). When compared with control, patients requiring MV had worse survival at 1 month (77.3% vs. 83.5%) and 5 years (26.5% vs. 47.4%; P<0.001). The use of ECMO (hazard ratio [HR]=3.820, 95% confidence interval [CI]=1.600–9.116; P=0.003) or MV (HR=2.011, 95% CI=1.069–3.784; P=0.030) as a bridge to transplantation was independently associated with mortality on multivariate analysis. Recipient female gender was associated with survival (HR=0.754, 95% CI=0.570–0.998; P=0.048). Conclusions HLT recipients bridged by MV or ECMO have increased short-term and long-term mortality. Further studies are needed to optimize survival in these high-risk patients.

Cardiac transplantation can be safely performed using selected diabetic donors

OBJECTIVE Cardiac transplantation (OHT) using diabetic donors (DDs) is thought to adversely influence survival. We attempt to determine if adult OHT can be safely performed using selected DDs. METHODS The United Network for Organ Sharing (UNOS) database was examined for adult OHT from 2000 to 2010. RESULTS Of the 20,348 patients undergoing OHT, 496 (2.4%) were with DDs. DDs were older (39.6 vs 31.3 years; P < .001), more likely female (41.5% vs 28.3%; P < .001), and had a higher body mass index (BMI) (29.9 vs 26.4; P < .001). Recipients of DD hearts were older (53.4 vs 51.8; P = .004) and more likely to have diabetes (18.9% vs 14.9%; P = .024). The 2 groups were evenly matched with regard to recipient male gender (78.0% vs 76.1%; P = .312), ischemic time (3.3 vs 3.2 hours; P = .191), human leukocyte antigen mismatches (4.7 vs 4.6; P = .483), and requirement of extracorporeal membrane oxygenation (ECMO) as a bridge to transplant (0.8% vs 0.5%; P = .382). Median survival was similar (3799 vs 3798 days; P = .172). On multivariate analysis, DD was not associated with mortality (hazard ratio [HR], 1.155; 95% confidence interval [CI], 0.943-1.415; P = .164). As previously demonstrated, donor age, decreasing donor BMI, ischemic time, recipient creatinine, recipient black race, recipient diabetes, race mismatch, and mechanical ventilation or ECMO as a bridge to transplant were associated with mortality. On multivariate analysis of subgroups, neither insulin-dependent diabetes (1.173; 95% CI, 0.884-1.444; P = .268) nor duration of diabetes for more than 5 years (HR, 1.239; 95% CI, 0.914-1.016; P = .167) was associated with mortality. CONCLUSIONS OHT can be safely performed using selected DDs. Consensus criteria for acceptable cardiac donors can likely be revised to include selected DDs.