- Email: [email protected]
Intestinal Alkaline Phosphatase Functions as a Longevity Factor
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
Additionally, laparoscopic (lap) and open techniques were compared. Primary outcome was 30-day mortality. Secondary outcomes included overall and serious morbidity, as well as prolonged length of stay (LOS). Multivariable logistic regressions were constructed with clinically and statistically relevant covariates, which were used to predict the impact of age and surgical approach on the studied outcomes. Results: Of 19,505 patients, 91.38% underwent FP or PEH repair, and 8.62% underwent HM. The elderly represented 32.36% of the studied population. Lap repair was performed in 84.26% of patients, while the remaining 15.74% underwent repair via open abdominal or thoracic approach. Stratification by age groups showed that the elderly experienced significantly higher 30-day mortality compared to the younger group. As expected, older patients experienced higher mortality after open surgery compared to lap surgery, while in the young group there was no difference in mortality, regardless the approach. However, when stratified by surgical technique, the older group had significantly higher mortality and overall morbidity compared to the younger patients after both lap and open repair (Table 1). Multivariate analysis showed that advanced age among lap patients was associated with higher odds of mortality (OR, 3.60; 95% CI, 1.89-6.86; p<0.001) and overall morbidity (OR, 1.87; 95% CI, 1.61-2.19; p<0.001). Moreover, patients 65 years in the lap group were nearly twice more likely to experience prolonged LOS (OR, 1.88; 95% CI, 1.74-2.03; p<0.001). Conclusions: Surgery for benign foregut disease in the elderly carries a burden of mortality and morbidity that should not be neglected, even when a lap approach is used. The benefit of surgery should be weighed against the potential risks, notwithstanding the demonstrably improved outcomes afforded by minimally invasive techniques. If surgery is necessary, our analysis shows that laparoscopy may be the safer option in elderly patients. 42.8. Intestinal Alkaline Phosphatase Functions as a Longevity Factor. S. R. Hamarneh,1,2 J. E. Irazoqui,2 R. A. Hodin1; 1 Massachusetts General Hospital - Department Of Surgery, Harvard Medical School, Boston, MA, USA; 2Massachusetts
629
General Hospital - Department Of Pediatrics, Harvard Medical School, Boston, MA, USA Introduction: A hallmark of aging is the deterioration of cellular functions, including the immune and inflammatory responses. ‘Inflammaging’ is a chronic low-grade inflammatory state that increases with age and thus is a companion manifestation of aging. It is thought that body fat accretion, increased intestinal permeability, persistent endotoxemia, cellular immunity decay, and ectopic activation of oxidative stress are responsible for inflammaging. The brush border enzyme Intestinal alkaline phosphatase (IAP) detoxifies many bacterial inflammatory factors, including lipopolysaccharides (LPS), reduces gut permeability to endotoxins, and prevents systemic inflammation. Recent studies show that IAP activity declines with age in animals. We therefore hypothesized that IAP plays a major role in inflammaging and lifespan determination. Methods: As a first step in elucidating the cellular pathways targeted by exogenous IAP, we developed a C.elegans model to examine the effect of IAP supplementation on total lifespan. 35 wild type C.elegans were incubated on 5 cm nematode growth medium (NGM) plates containing heatkilled OP50 bacteria and supplemented with 200 U IAP in triplicate. Survival was scored daily. To focus on a known longevity pathway, we performed experiments as described above using daf-16 mutant nematodes, in which transcription downstream of insulin signaling is disrupted. In mice, C57BL/6 IAP-KO (Akp3-/-) and wild type littermates were used to compare the effect of the absence of IAP on lifespan. They were observed for 18 months. In a second set of experiments, 12 month old KO and WT littermates (n¼5) were sacrificed and investigated for hematological and inflammatory changes. Results: In nematodes, we found that IAP supplementation caused major lifespan extension in wild type animals (Day 15 survival %, IAP vs.Vehicle,85% vs.45%, p<0.001), suggesting that IAP delayed aging, detoxified damaging factors (including limiting the host inflammatory response), or both. Loss of daf-16 strongly suppressed the lifespan-extending effect
630
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
of IAP (Day 13 survival %, IAP vs. Veh, 45% vs. 40% p¼0.96), indicating that IAP exerts its anti-aging affects through DAF-16. We found that IAP-KO mice show decreased lifespan compared withwild type littermates (16 mo. Survival %, IAP-KO vs. WT, 40% vs.100%, p<0.001). As an additional measure of aging, we measured expression of SIRT1, an anti-aging protein. Using liver homogenate, we found that 12 mo old IAP KO mice had less SIRT1 protein than WT mice, suggesting that endogenous IAP determines the levels of expression of SIRT1 and may thus impact aging through the SIRT1 pathway. Conclusions: IAP is important for lifespan determination in mammals, possibly through control of SIRT1 expression. Furthermore, exogenous supplementation of IAP is sufficient for lifespan extension in an established model for aging. Oral IAP supplementation could represent a novel therapy to prevent early senescence and aging associated diseases in humans.
ated with PM (z¼3.69, OR¼1.11), but lower preoperative hematocrit (Hct) was more strongly predictive (z¼4.4, OR¼1.13). Other factors significantly associated with PM were: elevated white blood count (z¼3.09, OR¼1.14), overweight body mass index (z¼-2.6, OR¼0.41), dependent functional status (z¼2.3, OR¼2.34), emergent surgery (z¼2.3, OR¼1.97), and ventral hernia repair (z¼2.19, OR¼2.52). In patients with a preoperative Hct30% the PM rate was 37% compared to 15% with Hct>30% (p<0.0001). For patients with a MELD<10 the PM rate was 15%; for MELD 10-19 PM was 20%; for MELD 20-29 PM was 42%; and for MELD30 PM was 100% (p<0.0001). Conclusions: Prior to hernia repair, the MELD score can be used to risk stratify cirrhotic patients not only for mortality but also PM. Hernia repair in patients with MELD>20 should be considered with great caution, and other factors such as preoperative Hct should be accounted for when counseling patients on their perioperative risk.
42.9. Hernia Repair in the Cirrhotic Patient: An Analysis of the ACS NSQIP Database. E. K. Bartlett,2 R. Hoffman,2 G. C. Karakousis,2 R. E. Roses,2 D. L. Fraker,2 J. B. Morris,2 R. R. Kelz2; 2Hospital Of The University Of Pennsylvania Department Of Surgery, Philadelphia, PA, USA
42.10. Surgical Research Society of Australasia Young Investigators Award
Introduction: Approximately 10% of patients with liver disease undergo surgery in the final two years of life. Surgical intervention in these patients carries a substantial risk. The model for end-stage liver disease (MELD) has been validated as a prediction tool for postoperative mortality, but its role in predicting postoperative morbidity (PM) has not been well studied. We sought to determine the role of MELD, among other factors, in predicting PM in cirrhotic patients undergoing hernia repair. Methods: Using the ACS NSQIP database (FY 2008-2011) we selected all hernia repair patients >18 years of age. Decompensated cirrhosis was defined as the presence of ascites in the absence of disseminated cancer. The primary outcome variable of interest was 30-day PM. Patient factors associated with PM were determined using a Chi-square or Fisher’s exact test, as appropriate. A MELD score was calculated for each patient with complete data, and subset analysis was performed on these patients. Multivariate logistic regression was used to evaluate the association between MELD score and PM with adjustment for potential confounders. The association of significant factors with the rate of PM was displayed using a best-fit linear regression. Results: Of 138,366 hernia repairs, 778 (0.56%) were performed on patients with decompensated cirrhosis. 30-day PM (4% vs. 19%) and mortality (0.2 vs. 5.3%) were significantly more frequent in patients with cirrhosis (p<0.0001). Among cirrhotics, a MELD score could be calculated in 636 patients. The MELD score was <10 in 143 patients (22%), 10-19 in 424 (67%), 2029 in 67 (11%), and 30+ in 2 patients (<1%). In univariate analysis, MELD was associated with both PM and mortality (p<0.0001 for each). In multivariate analysis, MELD remained significantly associ-
ONCOLOGY 4: LIVER/COLORECTAL
TITLE TBD
43.1. Management of Synchronous Colorectal Cancer Liver Metastases in Older Patients. G. M. Vargas,1 A. D. Parmar,1,2 K. M. Sheffield,1 N. P. Tamirisa,1,2 K. M. Brown,1 T. S. Riall1; 1University Of Texas Medical Branch - General Surgery, Galveston, TX, USA; 2University Of California, San Francisco-East Bay - General Surgery, Oakland, CA, USA Introduction: Liver-directed therapy in stage IV colon cancer is reserved for highly selected patients with low disease burden and/or good response to chemotherapy. Our goal was to evaluate population-based treatment patterns and outcomes in use of liver directed therapy in older patients presenting with stage IV colorectal cancer concurrent with the introduction of more effective chemotherapeutic agents. Methods: We used Texas Cancer Registry and SEER-Medicare linked data to identify patients aged 66 years and older presenting with stage IV colorectal cancer (2001-2007). Analysis was limited to patients undergoing both surgical resection of the primary tumor and chemotherapy. Liver directed therapy was defined as liver resection or ablative procedures (ablation or chemoembolization). Results: We identified 5,500 patients with a mean age of 74.3 +/- 5.7 years. 50.2% were female. 82.4% of tumors were colonic and 17.6% were rectal primaries. 1,918 patients (34.9%) underwent liver directed therapy; resection was performed in 30.7% and ablative procedures in 10.1% of patients. 322 patients underwent both resection and an ablative procedure. Liver directed therapy was performed concurrently with resection of the primary tumor in 74.4%, after in 21.2%, and before in 4.5% of patients. In a multivariable model controlling for comorbidity and economic status, there was a negative association between liver directed therapy and each increasing year (OR¼0.96, 95% CI 0.93-0.99), age >85 (OR¼0.61, 95% CI 0.45-0.82), and poor tumor differentiation (OR¼0.73, 95% CI 0.64-0.83). Patients treated with oxaliplatin or irinotecan containing chemotherapy compared to standard chemotherapy were more likely to receive liver directed therapy (OR¼1.44, 95% CI 1.25-1.66). The median survival was 28.4 months for patients undergoing liver-directed therapy compared to 21.1 months in patients who did not (P<0.0001). Kaplan Meier analysis (see Figure) and a Cox proportional hazards model demonstrated improved survival in patients diagnosed in the later time period compared to those diagnosed in the early time period, regardless of use of liver directed therapy. Conclusions: Our data demonstrate that aggressive treatment of hepatic metastases in combination with systemic therapy and surgical resection of the primary tumor is associated with improved survival in highly selected older patients.
Additionally, laparoscopic (lap) and open techniques were compared. Primary outcome was 30-day mortality. Secondary outcomes included overall and serious morbidity, as well as prolonged length of stay (LOS). Multivariable logistic regressions were constructed with clinically and statistically relevant covariates, which were used to predict the impact of age and surgical approach on the studied outcomes. Results: Of 19,505 patients, 91.38% underwent FP or PEH repair, and 8.62% underwent HM. The elderly represented 32.36% of the studied population. Lap repair was performed in 84.26% of patients, while the remaining 15.74% underwent repair via open abdominal or thoracic approach. Stratification by age groups showed that the elderly experienced significantly higher 30-day mortality compared to the younger group. As expected, older patients experienced higher mortality after open surgery compared to lap surgery, while in the young group there was no difference in mortality, regardless the approach. However, when stratified by surgical technique, the older group had significantly higher mortality and overall morbidity compared to the younger patients after both lap and open repair (Table 1). Multivariate analysis showed that advanced age among lap patients was associated with higher odds of mortality (OR, 3.60; 95% CI, 1.89-6.86; p<0.001) and overall morbidity (OR, 1.87; 95% CI, 1.61-2.19; p<0.001). Moreover, patients 65 years in the lap group were nearly twice more likely to experience prolonged LOS (OR, 1.88; 95% CI, 1.74-2.03; p<0.001). Conclusions: Surgery for benign foregut disease in the elderly carries a burden of mortality and morbidity that should not be neglected, even when a lap approach is used. The benefit of surgery should be weighed against the potential risks, notwithstanding the demonstrably improved outcomes afforded by minimally invasive techniques. If surgery is necessary, our analysis shows that laparoscopy may be the safer option in elderly patients. 42.8. Intestinal Alkaline Phosphatase Functions as a Longevity Factor. S. R. Hamarneh,1,2 J. E. Irazoqui,2 R. A. Hodin1; 1 Massachusetts General Hospital - Department Of Surgery, Harvard Medical School, Boston, MA, USA; 2Massachusetts
629
General Hospital - Department Of Pediatrics, Harvard Medical School, Boston, MA, USA Introduction: A hallmark of aging is the deterioration of cellular functions, including the immune and inflammatory responses. ‘Inflammaging’ is a chronic low-grade inflammatory state that increases with age and thus is a companion manifestation of aging. It is thought that body fat accretion, increased intestinal permeability, persistent endotoxemia, cellular immunity decay, and ectopic activation of oxidative stress are responsible for inflammaging. The brush border enzyme Intestinal alkaline phosphatase (IAP) detoxifies many bacterial inflammatory factors, including lipopolysaccharides (LPS), reduces gut permeability to endotoxins, and prevents systemic inflammation. Recent studies show that IAP activity declines with age in animals. We therefore hypothesized that IAP plays a major role in inflammaging and lifespan determination. Methods: As a first step in elucidating the cellular pathways targeted by exogenous IAP, we developed a C.elegans model to examine the effect of IAP supplementation on total lifespan. 35 wild type C.elegans were incubated on 5 cm nematode growth medium (NGM) plates containing heatkilled OP50 bacteria and supplemented with 200 U IAP in triplicate. Survival was scored daily. To focus on a known longevity pathway, we performed experiments as described above using daf-16 mutant nematodes, in which transcription downstream of insulin signaling is disrupted. In mice, C57BL/6 IAP-KO (Akp3-/-) and wild type littermates were used to compare the effect of the absence of IAP on lifespan. They were observed for 18 months. In a second set of experiments, 12 month old KO and WT littermates (n¼5) were sacrificed and investigated for hematological and inflammatory changes. Results: In nematodes, we found that IAP supplementation caused major lifespan extension in wild type animals (Day 15 survival %, IAP vs.Vehicle,85% vs.45%, p<0.001), suggesting that IAP delayed aging, detoxified damaging factors (including limiting the host inflammatory response), or both. Loss of daf-16 strongly suppressed the lifespan-extending effect
630
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS
of IAP (Day 13 survival %, IAP vs. Veh, 45% vs. 40% p¼0.96), indicating that IAP exerts its anti-aging affects through DAF-16. We found that IAP-KO mice show decreased lifespan compared withwild type littermates (16 mo. Survival %, IAP-KO vs. WT, 40% vs.100%, p<0.001). As an additional measure of aging, we measured expression of SIRT1, an anti-aging protein. Using liver homogenate, we found that 12 mo old IAP KO mice had less SIRT1 protein than WT mice, suggesting that endogenous IAP determines the levels of expression of SIRT1 and may thus impact aging through the SIRT1 pathway. Conclusions: IAP is important for lifespan determination in mammals, possibly through control of SIRT1 expression. Furthermore, exogenous supplementation of IAP is sufficient for lifespan extension in an established model for aging. Oral IAP supplementation could represent a novel therapy to prevent early senescence and aging associated diseases in humans.
ated with PM (z¼3.69, OR¼1.11), but lower preoperative hematocrit (Hct) was more strongly predictive (z¼4.4, OR¼1.13). Other factors significantly associated with PM were: elevated white blood count (z¼3.09, OR¼1.14), overweight body mass index (z¼-2.6, OR¼0.41), dependent functional status (z¼2.3, OR¼2.34), emergent surgery (z¼2.3, OR¼1.97), and ventral hernia repair (z¼2.19, OR¼2.52). In patients with a preoperative Hct30% the PM rate was 37% compared to 15% with Hct>30% (p<0.0001). For patients with a MELD<10 the PM rate was 15%; for MELD 10-19 PM was 20%; for MELD 20-29 PM was 42%; and for MELD30 PM was 100% (p<0.0001). Conclusions: Prior to hernia repair, the MELD score can be used to risk stratify cirrhotic patients not only for mortality but also PM. Hernia repair in patients with MELD>20 should be considered with great caution, and other factors such as preoperative Hct should be accounted for when counseling patients on their perioperative risk.
42.9. Hernia Repair in the Cirrhotic Patient: An Analysis of the ACS NSQIP Database. E. K. Bartlett,2 R. Hoffman,2 G. C. Karakousis,2 R. E. Roses,2 D. L. Fraker,2 J. B. Morris,2 R. R. Kelz2; 2Hospital Of The University Of Pennsylvania Department Of Surgery, Philadelphia, PA, USA
42.10. Surgical Research Society of Australasia Young Investigators Award
Introduction: Approximately 10% of patients with liver disease undergo surgery in the final two years of life. Surgical intervention in these patients carries a substantial risk. The model for end-stage liver disease (MELD) has been validated as a prediction tool for postoperative mortality, but its role in predicting postoperative morbidity (PM) has not been well studied. We sought to determine the role of MELD, among other factors, in predicting PM in cirrhotic patients undergoing hernia repair. Methods: Using the ACS NSQIP database (FY 2008-2011) we selected all hernia repair patients >18 years of age. Decompensated cirrhosis was defined as the presence of ascites in the absence of disseminated cancer. The primary outcome variable of interest was 30-day PM. Patient factors associated with PM were determined using a Chi-square or Fisher’s exact test, as appropriate. A MELD score was calculated for each patient with complete data, and subset analysis was performed on these patients. Multivariate logistic regression was used to evaluate the association between MELD score and PM with adjustment for potential confounders. The association of significant factors with the rate of PM was displayed using a best-fit linear regression. Results: Of 138,366 hernia repairs, 778 (0.56%) were performed on patients with decompensated cirrhosis. 30-day PM (4% vs. 19%) and mortality (0.2 vs. 5.3%) were significantly more frequent in patients with cirrhosis (p<0.0001). Among cirrhotics, a MELD score could be calculated in 636 patients. The MELD score was <10 in 143 patients (22%), 10-19 in 424 (67%), 2029 in 67 (11%), and 30+ in 2 patients (<1%). In univariate analysis, MELD was associated with both PM and mortality (p<0.0001 for each). In multivariate analysis, MELD remained significantly associ-
ONCOLOGY 4: LIVER/COLORECTAL
TITLE TBD
43.1. Management of Synchronous Colorectal Cancer Liver Metastases in Older Patients. G. M. Vargas,1 A. D. Parmar,1,2 K. M. Sheffield,1 N. P. Tamirisa,1,2 K. M. Brown,1 T. S. Riall1; 1University Of Texas Medical Branch - General Surgery, Galveston, TX, USA; 2University Of California, San Francisco-East Bay - General Surgery, Oakland, CA, USA Introduction: Liver-directed therapy in stage IV colon cancer is reserved for highly selected patients with low disease burden and/or good response to chemotherapy. Our goal was to evaluate population-based treatment patterns and outcomes in use of liver directed therapy in older patients presenting with stage IV colorectal cancer concurrent with the introduction of more effective chemotherapeutic agents. Methods: We used Texas Cancer Registry and SEER-Medicare linked data to identify patients aged 66 years and older presenting with stage IV colorectal cancer (2001-2007). Analysis was limited to patients undergoing both surgical resection of the primary tumor and chemotherapy. Liver directed therapy was defined as liver resection or ablative procedures (ablation or chemoembolization). Results: We identified 5,500 patients with a mean age of 74.3 +/- 5.7 years. 50.2% were female. 82.4% of tumors were colonic and 17.6% were rectal primaries. 1,918 patients (34.9%) underwent liver directed therapy; resection was performed in 30.7% and ablative procedures in 10.1% of patients. 322 patients underwent both resection and an ablative procedure. Liver directed therapy was performed concurrently with resection of the primary tumor in 74.4%, after in 21.2%, and before in 4.5% of patients. In a multivariable model controlling for comorbidity and economic status, there was a negative association between liver directed therapy and each increasing year (OR¼0.96, 95% CI 0.93-0.99), age >85 (OR¼0.61, 95% CI 0.45-0.82), and poor tumor differentiation (OR¼0.73, 95% CI 0.64-0.83). Patients treated with oxaliplatin or irinotecan containing chemotherapy compared to standard chemotherapy were more likely to receive liver directed therapy (OR¼1.44, 95% CI 1.25-1.66). The median survival was 28.4 months for patients undergoing liver-directed therapy compared to 21.1 months in patients who did not (P<0.0001). Kaplan Meier analysis (see Figure) and a Cox proportional hazards model demonstrated improved survival in patients diagnosed in the later time period compared to those diagnosed in the early time period, regardless of use of liver directed therapy. Conclusions: Our data demonstrate that aggressive treatment of hepatic metastases in combination with systemic therapy and surgical resection of the primary tumor is associated with improved survival in highly selected older patients.