201 Early Referral for 24-Hour Esophageal pH Monitoring Is More Cost-Effective Than Prolonged Use of...
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199 Clinical Significance of Serum Col6a3 Isoforms in Pancreatic Ductal Adenocarcinoma Christopher Y. Kang, Dierdre Axell-House, Pranay Soni, Galina Chipitsyna, Konrad Sarosiek, Mazhar Al-Zoubi, Hwyda A. Arafat, Charles J. Yeo Introduction: Type VI collagen (COL6) forms a microfibrillar network associated with type I collagen fibrils and constitutes a major component of the prominent desmoplastic reaction in pancreatic ductal adenocarcinoma (PDA). We have demonstrated recently that a subunit of COL6, COL6A3, is expressed in high levels in PDA tissue. We also showed that COL6A3 gene undergoes tumor-specific alternative splicing to produce 3 isoforms E3, E4 and E6 that are tumor tissue-specific. The aim of this study is to investigate the diagnostic value and clinical significance of circulating COL6A3 isoforms mRNA in PDA. Methods: Serum samples were obtained from patients that underwent pancreatic resection at a single institution between 2006 and 2009. COL6A3 levels in the sera from patients with pathologically confirmed PDA (n=40), intraductal papillary mucinous neoplasms (IPMN) (n=20), and chronic pancreatitis (n=10) were analyzed by real time PCR using isoform-specific primers for E3, E4 and E6 . In addition, sera from age-matched healthy volunteers were analyzed (n=30). The prediction levels for malignancy were determined by the area under the receiver operating characteristic curve (AUC). In vitro, wound healing, cell proliferation and soft- agar colony formation assays evaluated the functional impact of each isoform in PDA cells (MIAPACA-2 and ASP-C-1) transfected with isoform-specific siRNA. A panel of inflammation- and invasion/angiogenesis-related genes was also evaluated. Results: Circulating E6 mRNA levels were significantly (p=0.006) elevated in PDA patients when compared to all benign lesions. E3 and E4 were expressed at extremely low levels in all patients. Compared to IPMN alone, E6 levels were significantly higher in PDA (p=0.0036). There were no significant differences between E6 levels in IPMN and Normal sera (p= 0.59). Using a logistic regression model, we found that for each increasing unit of log E6 COL6A3, patients are 9.5 times more likely to harbor a cancer rather than a benign lesion, 95% CI (2.4, 38.1), p=0.002. The area under the ROC curve, AUC, was 0.72. Knocking down E3 or E4 or E6 with isoform-specific siRNA resulted in reduced PDA cell migration and invasion and concomitant reduction of the expression of several inflammation and angiogenesis-related genes, such as MMP-9, OPN, MCP-1 and VEGF. Interestingly, knocking down any of the 3 isoforms resulted in increased expression of TNF-alpha. Conclusions: Our data show for the first time the potential clinical significance of circulating E6 COL6A3 levels in the diagnosis of pancreatic malignancy. Our in vitro data suggests a role for COL6A3 isoforms in PDA progression and metastatic potential. 200 Treatment Sequencing for Resectable Pancreatic Cancer: Influence of Early Metastases and Surgical Complications on Multimodality Therapy Completion Rates and Survival Ching-Wei D. Tzeng, Daniel E. Abbott, Jeffrey E. Lee, Peter W. Pisters, Jason B. Fleming, Jean-Nicolas Vauthey, Matthew Katz Introduction: Multimodality therapy (MMT) is important to the long-term survival of patients with resectable pancreatic adenocarcinoma (PDAC), but its completion can be hindered by early cancer progression or by treatment complications. We sought to compare the influence of each of these factors on the MMT completion rates of operable patients with resectable PDAC treated with either a neoadjuvant (NT) or surgery-first (SF) sequencing strategy. Methods: We retrospectively evaluated all patients with PDAC at our institution from 2002- 2007, who had 1) a radiographically resectable pancreatic head tumor, 2) a performance status (PS) and comorbidities suitable for immediate surgery, and 3) a carbohydrate antigen (CA) 19-9 ,1000 U/ml. MMT was defined as resection before or after completion of planned pre- or post-operative therapy. Postoperative major complications (PMC) were defined as Clavien Grade ≥3. Disease progression was considered early when it developed within 3 months in SF patients or prior to planned resection in NT patients. Reasons for and rates of failure to complete MMT, 90-day PMC, and overall survival (OS) were compared between the two cohorts. Results: 112 NT and 58 SF patients met inclusion criteria. 92/112 (82%) NT and 33/56 (59%) SF patients with complete follow-up completed MMT (p ,0.001). NT patients did not complete MMT due to early progression (n=13, including 8 nontherapeutic laparotomies) and PS (n=7). SF patients did not complete MMT due to early progression (n=10), PMC (n=6), and PS (n= 3); 4 SF patients also underwent nontherapeutic laparotomy due to metastases. Among all patients, those who completed MMT lived longer than those who did not (36 vs. 11 mo, p ,0.001). The median OS durations of all NT and SF patients (NT 28 vs. SF 21 mo, p=0.082), the subset in each cohort who completed MMT (NT 36 vs. SF 36 mo, p=0.565), and the subset in each cohort who did not complete MMT (NT 11 vs SF 13 mo, p=0.325) were not statistically different. The rate of PMC did not differ between NT and SF groups (19% vs. 17%, p=0.782). SF patients with no PMC had a 71% (31/44) MMT completion rate vs. 25% (2/8) after PMC (p=0.014). When resected NT patients suffered PMC, there was no significant decrease in OS (36 vs. 30 mo, p=0.934), in contrast to the negative effect of PMC in SF patients (26 vs. 10 mo, p ,0.001). Conclusions: Completion of multimodality therapy is strongly associated with improved survival of opera- ble patients with resectable PDAC. Even in the highly selected cohort evaluated in this study, early cancer progression and PMC negatively impacted MMT completion rates and OS, particularly among SF patients. Thus, NT sequencing remains a valuable alternative to SF sequencing for tumor biology evaluation and patient selection. S-1045 SSAT Abstracts 201 Early Referral for 24-Hour Esophageal pH Monitoring Is More Cost-Effective Than Prolonged Use of Proton Pump Inhibitors in Patients With Suspected Gastroesophageal Reflux Disease David Kleiman, Toni Beninato, Brian P. Bosworth, Laurent Brunaud, Thomas Ciecierega, Carl V. Crawford, Brian G. Turner, Thomas J. Fahey, Rasa Zarnegar BACKGROUND: Gastroesophageal reflux disease (GERD) affects nearly 25% of adults, but the diagnostic algorithm remains controversial. Most guidelines recommend an empiric 8- week trial of proton-pump inhibitors (PPIs), but many patients remain on PPIs for much longer periods. Twenty-four hour esophageal pH monitoring can help rule out GERD and avoid the unnecessary cost and risks of prolonged PPI use. We hypothesized that performing pH monitoring promptly after an 8-week PPI trial would be a more cost-effective strategy than prolonged courses of PPIs. METHODS: A cost model was created from a third-party payer perspective over a 10-year period. Average wholesale unit prices of generic and name- brand PPIs were obtained from the 2012 Micromedex Redbook®. Low-dose (20 mg daily) generic PPI and high-dose (40 mg twice daily) name-brand PPI costs were used as the low- end and high-end PPI costs, respectively. The cost of 24-hour pH monitoring and manometry was obtained from 2012 Medicare fees. Manometry was necessary to determine esophageal function and for appropriate positioning of the pH probe. A cohort of 100 patients who underwent pH monitoring at an academic institution was retrospectively reviewed for type of GERD symptoms and duration of PPI use prior to pH monitoring. The sensitivity of 24- hour pH monitoring by literature review ranged from 30% to 96%. The cost of unnecessary PPIs was subtracted from the cost of pH monitoring for all patients to evaluate the cost- effectiveness. RESULTS: The weekly cost of PPIs ranged from $29.06 to $107.70, and the cost of 24-hour pH monitoring was $690. The cost of PPI therapy reaches equivalence with pH monitoring after 6.4 to 23.7 weeks, depending on the PPI regimen. Patients who experienced esophageal and extra-esophageal GERD symptoms reported a median of 208 and 52 weeks of PPI use, respectively, prior to referral. The cohort was prescribed a total of 21,411 weeks of PPIs beyond the initial 8-week trial, 32% of which were for patients who had a negative 24-hour pH monitoring study and were therefore unnecessary. If the sensitivity of pH monitoring was 100%, performing pH monitoring on all patients after an 8-week PPI trial would have saved between $1,966 and $7,285 per patient over 10 years. This strategy remains cost-effective as long as the sensitivity of pH monitoring is above 35% (Figure 1). In this model, since patients with extra-esophageal GERD symptoms were referred a median of 156 weeks sooner than patients with esophageal symptoms, the cost savings were less (Table 1). CONCLUSIONS: Most patients are maintained on PPIs for periods greatly surpassing the cost-equivalence point with 24-hour esophageal pH monitoring. Early referral for pH monitoring after a brief empiric PPI trial may result in substantial cost savings for patients with both esophageal and extra-esophageal GERD symptoms. Table 1. Estimated range of cost savings over 10-yearts (per patient) of performing early 24-hour pH monitoring across the range of reported sensitivity for diagnosing GERD. (1) Range of savings from low-dose generic PPI to high-dose name-brand PPI, (2) Negative values reflect additional cost over 10-years. SSAT Abstracts
Transcript of 201 Early Referral for 24-Hour Esophageal pH Monitoring Is More Cost-Effective Than Prolonged Use of...
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Clinical Significance of Serum Col6a3 Isoforms in Pancreatic DuctalAdenocarcinomaChristopher Y. Kang, Dierdre Axell-House, Pranay Soni, Galina Chipitsyna, KonradSarosiek, Mazhar Al-Zoubi, Hwyda A. Arafat, Charles J. Yeo
Introduction: Type VI collagen (COL6) forms a microfibrillar network associated with typeI collagen fibrils and constitutes a major component of the prominent desmoplastic reactionin pancreatic ductal adenocarcinoma (PDA). We have demonstrated recently that a subunitof COL6, COL6A3, is expressed in high levels in PDA tissue. We also showed that COL6A3gene undergoes tumor-specific alternative splicing to produce 3 isoforms E3, E4 and E6that are tumor tissue-specific. The aim of this study is to investigate the diagnostic valueand clinical significance of circulating COL6A3 isoforms mRNA in PDA. Methods: Serumsamples were obtained frompatients that underwent pancreatic resection at a single institutionbetween 2006 and 2009. COL6A3 levels in the sera from patients with pathologicallyconfirmed PDA (n=40), intraductal papillary mucinous neoplasms (IPMN) (n=20), andchronic pancreatitis (n=10) were analyzed by real time PCR using isoform-specific primersfor E3, E4 and E6 . In addition, sera from age-matched healthy volunteers were analyzed(n=30). The prediction levels for malignancy were determined by the area under the receiveroperating characteristic curve (AUC). In vitro, wound healing, cell proliferation and soft-agar colony formation assays evaluated the functional impact of each isoform in PDA cells(MIAPACA-2 and ASP-C-1) transfectedwith isoform-specific siRNA. A panel of inflammation-and invasion/angiogenesis-related genes was also evaluated. Results: Circulating E6 mRNAlevels were significantly (p=0.006) elevated in PDA patients when compared to all benignlesions. E3 and E4 were expressed at extremely low levels in all patients. Compared toIPMN alone, E6 levels were significantly higher in PDA (p=0.0036). There were no significantdifferences between E6 levels in IPMN and Normal sera (p= 0.59). Using a logistic regressionmodel, we found that for each increasing unit of log E6 COL6A3, patients are 9.5 timesmore likely to harbor a cancer rather than a benign lesion, 95% CI (2.4, 38.1), p=0.002.The area under the ROC curve, AUC, was 0.72. Knocking down E3 or E4 or E6 withisoform-specific siRNA resulted in reduced PDA cell migration and invasion and concomitantreduction of the expression of several inflammation and angiogenesis-related genes, such asMMP-9, OPN, MCP-1 and VEGF. Interestingly, knocking down any of the 3 isoformsresulted in increased expression of TNF-alpha. Conclusions: Our data show for the firsttime the potential clinical significance of circulating E6 COL6A3 levels in the diagnosis ofpancreatic malignancy. Our in vitro data suggests a role for COL6A3 isoforms in PDAprogression and metastatic potential.
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Treatment Sequencing for Resectable Pancreatic Cancer: Influence of EarlyMetastases and Surgical Complications on Multimodality Therapy CompletionRates and SurvivalChing-Wei D. Tzeng, Daniel E. Abbott, Jeffrey E. Lee, Peter W. Pisters, Jason B. Fleming,Jean-Nicolas Vauthey, Matthew Katz
Introduction: Multimodality therapy (MMT) is important to the long-term survival of patientswith resectable pancreatic adenocarcinoma (PDAC), but its completion can be hindered byearly cancer progression or by treatment complications. We sought to compare the influenceof each of these factors on the MMT completion rates of operable patients with resectablePDAC treated with either a neoadjuvant (NT) or surgery-first (SF) sequencing strategy.Methods: We retrospectively evaluated all patients with PDAC at our institution from 2002-2007, who had 1) a radiographically resectable pancreatic head tumor, 2) a performancestatus (PS) and comorbidities suitable for immediate surgery, and 3) a carbohydrate antigen(CA) 19-9,1000 U/ml. MMT was defined as resection before or after completion of plannedpre- or post-operative therapy. Postoperative major complications (PMC) were defined asClavien Grade ≥3. Disease progression was considered early when it developed within 3months in SF patients or prior to planned resection in NT patients. Reasons for and ratesof failure to complete MMT, 90-day PMC, and overall survival (OS) were compared betweenthe two cohorts. Results: 112 NT and 58 SF patients met inclusion criteria. 92/112 (82%)NT and 33/56 (59%) SF patients with complete follow-up completed MMT (p,0.001). NTpatients did not complete MMT due to early progression (n=13, including 8 nontherapeuticlaparotomies) and PS (n=7). SF patients did not complete MMT due to early progression(n=10), PMC (n=6), and PS (n= 3); 4 SF patients also underwent nontherapeutic laparotomydue to metastases. Among all patients, those who completed MMT lived longer than thosewho did not (36 vs. 11 mo, p,0.001). The median OS durations of all NT and SF patients(NT 28 vs. SF 21 mo, p=0.082), the subset in each cohort who completed MMT (NT 36vs. SF 36 mo, p=0.565), and the subset in each cohort who did not complete MMT (NT11 vs SF 13 mo, p=0.325) were not statistically different. The rate of PMC did not differbetween NT and SF groups (19% vs. 17%, p=0.782). SF patients with no PMC had a 71%(31/44) MMT completion rate vs. 25% (2/8) after PMC (p=0.014). When resected NTpatients suffered PMC, there was no significant decrease in OS (36 vs. 30 mo, p=0.934),in contrast to the negative effect of PMC in SF patients (26 vs. 10 mo, p,0.001). Conclusions:Completion of multimodality therapy is strongly associated with improved survival of opera-ble patients with resectable PDAC. Even in the highly selected cohort evaluated in this study,early cancer progression and PMC negatively impacted MMT completion rates and OS,particularly among SF patients. Thus, NT sequencing remains a valuable alternative to SFsequencing for tumor biology evaluation and patient selection.
S-1045 SSAT Abstracts
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Early Referral for 24-Hour Esophageal pH Monitoring Is More Cost-EffectiveThan Prolonged Use of Proton Pump Inhibitors in Patients With SuspectedGastroesophageal Reflux DiseaseDavid Kleiman, Toni Beninato, Brian P. Bosworth, Laurent Brunaud, Thomas Ciecierega,Carl V. Crawford, Brian G. Turner, Thomas J. Fahey, Rasa Zarnegar
BACKGROUND: Gastroesophageal reflux disease (GERD) affects nearly 25% of adults, butthe diagnostic algorithm remains controversial. Most guidelines recommend an empiric 8-week trial of proton-pump inhibitors (PPIs), but many patients remain on PPIs for muchlonger periods. Twenty-four hour esophageal pH monitoring can help rule out GERD andavoid the unnecessary cost and risks of prolonged PPI use. We hypothesized that performingpH monitoring promptly after an 8-week PPI trial would be a more cost-effective strategythan prolonged courses of PPIs. METHODS: A cost model was created from a third-partypayer perspective over a 10-year period. Average wholesale unit prices of generic and name-brand PPIs were obtained from the 2012 Micromedex Redbook®. Low-dose (20 mg daily)generic PPI and high-dose (40 mg twice daily) name-brand PPI costs were used as the low-end and high-end PPI costs, respectively. The cost of 24-hour pH monitoring and manometrywas obtained from 2012 Medicare fees. Manometry was necessary to determine esophagealfunction and for appropriate positioning of the pH probe. A cohort of 100 patients whounderwent pH monitoring at an academic institution was retrospectively reviewed for typeof GERD symptoms and duration of PPI use prior to pH monitoring. The sensitivity of 24-hour pH monitoring by literature review ranged from 30% to 96%. The cost of unnecessaryPPIs was subtracted from the cost of pH monitoring for all patients to evaluate the cost-effectiveness. RESULTS: The weekly cost of PPIs ranged from $29.06 to $107.70, and thecost of 24-hour pH monitoring was $690. The cost of PPI therapy reaches equivalence withpH monitoring after 6.4 to 23.7 weeks, depending on the PPI regimen. Patients whoexperienced esophageal and extra-esophageal GERD symptoms reported a median of 208and 52 weeks of PPI use, respectively, prior to referral. The cohort was prescribed a totalof 21,411 weeks of PPIs beyond the initial 8-week trial, 32% of which were for patientswho had a negative 24-hour pH monitoring study and were therefore unnecessary. If thesensitivity of pH monitoring was 100%, performing pH monitoring on all patients after an8-week PPI trial would have saved between $1,966 and $7,285 per patient over 10 years.This strategy remains cost-effective as long as the sensitivity of pH monitoring is above 35%(Figure 1). In this model, since patients with extra-esophageal GERD symptoms were referreda median of 156 weeks sooner than patients with esophageal symptoms, the cost savingswere less (Table 1). CONCLUSIONS: Most patients are maintained on PPIs for periodsgreatly surpassing the cost-equivalence point with 24-hour esophageal pH monitoring. Earlyreferral for pH monitoring after a brief empiric PPI trial may result in substantial cost savingsfor patients with both esophageal and extra-esophageal GERD symptoms.Table 1. Estimated range of cost savings over 10-yearts (per patient) of performing early24-hour pH monitoring across the range of reported sensitivity for diagnosing GERD.
(1) Range of savings from low-dose generic PPI to high-dose name-brand PPI, (2) Negativevalues reflect additional cost over 10-years.
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Risk Factors Associated With 30-Day Readmissions in Major GastrointestinalResectionsKristin N. Kelly, James C. Iannuzzi, Aaron S. Rickles, Veerabhadram Garimella, John R.Monson, Fergal Fleming
PURPOSE: Preventable readmissions represent a major burden on the health care systemand by risk stratifying patients resources can be directed to prevent these costly complications.This study examines patient characteristics, surgical factors, and postoperative complicationsassociated with 30-day readmissions in gastrointestinal (GI) resections. METHODS: Inpa-tients undergoing major GI surgery were selected from the 2011 ACS National SurgicalQuality Improvement Program prospectively collected database. Procedures were classifiedinto esophageal, gastric, small bowel, large bowel, liver, and pancreatic resections usingCommon Procedural Terminology codes. Postoperative complications were divided into pre-and post-discharge groups by comparing time to complication and discharge. Operativetimes were grouped by 75th percentile(./=4 hours). Univariate analysis using Chi-square,Mann Whitney-U, and Student's T-test were used to compare patient comorbidities, surgicalcharacteristics, and postoperative complications with 30-day unplanned readmission rates.Factors with a p,0.1 were included in multivariate logistic regression. Odds ratios(OR) and95% confidence intervals(CI) are reported and p-value ,0.05 was considered statisticallysignificant. RESULTS: For 43,894 patients undergoing GI resection, the overall 30-dayunplanned readmission rate was 12.0% ranging from 11.4% for colorectal resections to15.7% for pancreatic resections. Median postoperative length of stay was longer in thereadmission group (7 vs. 6 days p,0.0001). Major predictors of 30-day readmissionsincluded pre-discharge major complications (OR=1.28; CI: 1.14,1.44, p,0.0001), preopera-tive steroid use (OR=1.62; CI: 1.39,1.89, p,0.0001), operative time ./=4 hours (OR=1.61; CI: 1.45,1.78, p,0.0001) and discharge to a facility other than home (OR=1.48;CI: 1.28,1.70, p,0.0001). Other factors associated with increased readmission includeddependent functional status, open surgery, pulmonary comorbidity, neurologic comorbidity,higher ASA score, diabetes, and preoperative anemia(table 1). Post-discharge major andminor complications were highly correlated with 30-day readmission rates (OR=59.3; CI:52.2,67.3, p,0.0001 and OR=6.3; 95%CI: 5.8,6.9, p,0.0001) and not included in thefinal model. CONCLUSIONS: Unplanned 30-day readmissions represent a major medicaland financial concern, but some may be foreseeable and thus preventable. Although previousstudies have identified major complications as a strong risk factor for readmissions, thismight represent an overestimate of the risk due to confounding by including post-dischargecomplications that may in fact cause, not predict, readmissions. This model provides insightinto factors that could inform resource utilization and post-operative care to help preventreadmissions in select high-risk GI surgical patients.Table 1: Factors associated with unplanned 30-day readmissions following GI resection.
Logistic regression model also controlled for age, hepatic insufficiency, cardiac comorbidity,renal insufficiency, wound class, smoking, bleeding disorder, chemotherapy/radiation, weightloss, preoperative sepsis, and LOS.
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Link Between VEGF Expression, Angiogenesis and Inflammation in PediatricCrohn's DiseaseJennifer L. Knod, Kelly M. Crawford, Mary R. Dusing, Artur Chernoguz, Margaret H.Collins, Jason Frischer
Purpose: Early-onset Crohn's disease (CD) accounts for 25% of cases but is distinct fromadult-onset CD by a more severe disease activity index, increased immunosuppressantrequirement, andmore extensive intestinal involvement. The pathogenic link between chronicinflammatory diseases and angiogenesis prompted investigations into its role in inflammatorybowel disease. We hypothesize that VEGF driven angiogenesis plays a significant role inCrohn's disease inflammation. Methods: Pediatric patients (n=13), ages 12 to 16, at ourinstitution having undergone resection involving the terminal ileum for CD were comparedto controls (n=5) with non-inflammatory indications for resection. Additionally, from eachCrohn's pathology specimen, inflamed and non-inflamed ileum were obtained for compari-son. Samples were evaluated for inflammation using the Crohn's Histology Index of Severity(range 0-13) and for microvessel density by quantitative endothelial cell immunohistochemis-try using CD31. Corresponding tissues were assessed for VEGF-A mRNA and protein expres-sion by RT-PCR andWestern blot respectively. Results expressed as mean±SEMwere analyzedfor significance (P≤0.05) by ANOVA and Student's t-test. Results: Inflammation scores weresignificantly increased (Fig 1) between inflamed CD and controls (5.8±0.7 vs 0.62±0.38,P,0.001), and between paired inflamed and non-inflamed ileum (5.8±0.7 vs 1.2±0.6, P ,0.001). Increased microvessel density was observed in both inflamed and non-inflamed CDgroups compared to controls (inflamed 24,955±3,202μm2, non-inflamed 18,719±2,050μm2,control 9,032±1,474μm2), with statistical significance (P=0.008) only present betweeninflamed CD and control subjects (Fig 2). Expression of tissue VEGF-A mRNA was upregu-lated in CD (CD 8.5±2.51 vs control 2.32±0.58, P=0.034), and was associated with anincreased trend in VEGF-A protein levels (VEGF/GAPDH, CD 3.96 vs control 2.20, P=0.53). Conclusion: Angiogenesis is associated with pediatric Crohn's disease as observed byincreased microvessel density that correlates with greater inflammation in resected ilealspecimens. At the molecular level, we demonstrate elevated VEGF transcription and proteinlevels, which implicates a VEGF pathway for angiogenesis associated inflammation in early-onset Crohn's disease. Further investigations regarding mechanism of angiogenesis, its rela-tionship to inflammation, and effectiveness of anti-angiogenic therapies are warranted.
Fig 1 Inflammation score (range 0-13) of inflamed pediatric Crohn's disease ileum increasedcompared to both non-inflammed Crohn's diseae and control. Results expressed as mean± SEM (*P ,0.001).
