Robert A. Meguid

Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice.

Pancreatic ductal adenocarcinoma (PDAC) is believed to arise through a multistep model comprised of putative precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). Recent genetically engineered mouse models of PDAC demonstrate a comparable morphologic spectrum of murine PanIN (mPanIN) lesions. The histogenesis of PanIN and PDAC in both mice and men remains controversial. The most faithful genetic models activate an oncogenic KrasG12D knockin allele within the pdx1- or ptf1a/p48-expression domain of the entire pancreatic anlage during development, thus obscuring the putative cell(s)-of-origin from which subsequent mPanIN lesions arise. In our study, activation of this knockin KrasG12D allele in the Elastase- and Mist1-expressing mature acinar compartment of adult mice resulted in the spontaneous induction of mPanIN lesions of all histological grades, although invasive carcinomas per se were not seen. We observed no requirement for concomitant chronic exocrine injury in the induction of mPanIN lesions from the mature acinar cell compartment. The acinar cell derivation of the mPanINs was established through lineage tracing in reporter mice, and by microdissection of lesional tissue demonstrating Cre-mediated recombination events. In contrast to the uniformly penetrant mPanIN phenotype observed following developmental activation of KrasG12D in the Pdx1-expressing progenitor cells, the Pdx1-expressing population in the mature pancreas (predominantly islet β cells) appears to be relatively resistant to the effects of oncogenic Kras. We conclude that in the appropriate genetic context, the differentiated acinar cell compartment in adult mice retains its susceptibility for spontaneous transformation into mPanIN lesions, a finding with potential relevance vis-à-vis the origins of PDAC.

Association between Intraoperative Hypotension and Hypertension and 30-day Postoperative Mortality in Noncardiac Surgery.

Background:Although deviations in intraoperative blood pressure are assumed to be associated with postoperative mortality, critical blood pressure thresholds remain undefined. Therefore, the authors estimated the intraoperative thresholds of systolic blood pressure (SBP), mean blood pressure (MAP), and diastolic blood pressure (DBP) associated with increased risk-adjusted 30-day mortality. Methods:This retrospective cohort study combined intraoperative blood pressure data from six Veterans Affairs medical centers with 30-day outcomes to determine the risk-adjusted associations between intraoperative blood pressure and 30-day mortality. Deviations in blood pressure were assessed using three methods: (1) population thresholds (individual patient sum of area under threshold [AUT] or area over threshold 2 SDs from the mean of the population intraoperative blood pressure values), (2). absolute thresholds, and (3) percent change from baseline blood pressure. Results:Thirty-day mortality was associated with (1) population threshold: systolic AUT (odds ratio, 3.3; 95% CI, 2.2 to 4.8), mean AUT (2.8; 1.9 to 4.3), and diastolic AUT (2.4; 1.6 to 3.8). Approximate conversions of AUT into its separate components of pressure and time were SBP < 67 mmHg for more than 8.2 min, MAP < 49 mmHg for more than 3.9 min, DBP < 33 mmHg for more than 4.4 min. (2) Absolute threshold: SBP < 70 mmHg for more than or equal to 5 min (odds ratio, 2.9; 95% CI, 1.7 to 4.9), MAP < 49 mmHg for more than or equal to 5 min (2.4; 1.3 to 4.6), and DBP < 30 mmHg for more than or equal to 5 min (3.2; 1.8 to 5.5). (3) Percent change: MAP decreases to more than 50% from baseline for more than or equal to 5 min (2.7; 1.5 to 5.0). Intraoperative hypertension was not associated with 30-day mortality with any of these techniques. Conclusion:Intraoperative hypotension, but not hypertension, is associated with increased 30-day operative mortality.

Recurrence after neoadjuvant chemoradiation and surgery for esophageal cancer: Does the pattern of recurrence differ for patients with complete response and those with partial or no response?

OBJECTIVE We hypothesized that most relapses in patients with esophageal cancer having neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields. METHODS Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who had esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years. RESULTS Of 267 patients, 82 (30.7%) showed complete response to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) showing partial response or no response, respectively. Recurrence developed in 84 patients (patients with complete response 18/82, 21.4%; patients with partial response 39/108, 36.1%; patients with no response 27/77, 35.1%; P = .055, respectively). Most patients had recurrences at distant sites (65/84;77.4%) regardless of pathologic response, and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for patients with partial response or no response, but was longer for patients with complete response with distant recurrence, whose median disease-free survival was 27.3 months (P = .008). By multivariate analysis, no other factor except for pathologic response to neoadjuvant therapy was associated with disease recurrence or death. Patients with partial response or no response were 1.97 and 2.23 times more likely to have recurrence than patients with complete response (P = .024 and P = .012, respectively). CONCLUSIONS Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathologic response. Fewer patients achieving complete response had recurrences, and distant recurrences in these patients manifest later than in patients showing partial response and those showing no response. Only pathologic response is significantly associated with disease recurrence, suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.

The impact of center volume on survival in lung transplantation: an analysis of more than 10,000 cases.

BACKGROUND Whether center volume influences outcomes in lung transplantation is unknown. We reviewed United Network for Organ Sharing data to examine the effect of center volume on short-term mortality. METHODS We reviewed United Network for Organ Sharing data (1998 through 2007) to identify 10,496 first-time adult lung transplantation recipients at 79 centers. Centers were stratified by quartiles of mean annual volume. Risk of 30-day mortality and 1- and 5-year mortality (censored for 30-day death) were assessed by multivariable Cox proportional hazards regression. RESULTS Mean center volume ranged from less than 1 to 58.2 (median, 9.4 cases/year; volume quartiles: 0 to 2.1, 2.2 to 9.4, 9.5 to 19.9, and 20 to 58.2 cases). Each 1 case/year decrease led to a 2% increase in 30-day mortality (hazard ratio, 1.02; 95% confidence interval, 1.01 to 1.02; p < 0.001). Centers of lowest quartile (performing <or=2.1 lung transplantations/year) had a 30-day cumulative mortality of 9.6% or 89% increase in the risk of death (hazard ratio, 1.89; 95% confidence interval, 1.01 to 3.44; p = 0.05) compared with the highest quartile centers despite fewer idiopathic pulmonary fibrosis patients (15.6% versus 25.8%; p < 0.001) and younger age (40.9 versus 51.5 years; p < 0.001). Low-volume centers had double the risk of 30-day censored 1-year mortality (hazard ratio, 1.95; 95% confidence interval, 1.30 to 2.92; p = 0.001). High-volume centers (>or=20 lung transplantations/year) had the lowest 30-day mortality (4.1%). CONCLUSIONS We provide an initial examination of the relationship of volume and lung allocation score to outcomes for lung transplantation. Low center volume is associated with increased short-term and cumulative mortality despite fewer idiopathic pulmonary fibrosis patients and younger patients.

Increased Mortality at Low-Volume Orthotopic Heart Transplantation Centers: Should Current Standards Change?

BACKGROUND The Centers for Medicare and Medicaid Services (CMS) mandate that orthotopic heart transplantation (OHT) centers perform 10 transplants per year to qualify for funding. We sought to determine whether this cutoff is meaningful and establish recommendations for optimal center volume using the United Network for Organ Sharing (UNOS) registry. METHODS We reviewed UNOS data (years 1999 to 2006) identifying 14,401 first-time adult OHTs conducted at 143 centers. Stratification was by mean annual institution volume. Primary outcomes of 30-day and 1-year mortality were assessed by multivariable logistic regression (adjusted for comorbidities and risk factors for death). Sequential volume cutoffs were examined to determine if current CMS standards are optimal. Pseudo R2 and area under the receiver operating curve assessed goodness of fit. RESULTS Mean annual volume ranged from 1 to 90. One-year mortality was 12.6% (n = 1,800). Increased center volume was associated with decreased 30-day mortality (p < 0.001). Decreased center volume was associated with increases in 30-day (odds ratio [OR] 1.03, 95% confidence interval [CI]: 1.02 to 1.03, p < 0.001) and 1-year mortality (OR 1.01, 95% CI: 1.01 to 1.02, p = 0.03--censored for 30-day death). The greatest mortality risk occurred at very low volume centers (<or= 2 cases = 2.15 times increase in death, p = 0.03). Annual institutional volume of fewer than 10 cases per year increased 30-day mortality by more than 100% (OR 2.02, 95%CI: 1.46 to 2.80, p < 0.001) and each decrease in mean center volume by one case per year increased the odds of 30-day mortality by 2% (OR 1.02, 95% CI: 1.01 to 1.03, p < 0.001]. Additionally, centers performing fewer than 10 OHTs per year had increased cumulative mortality by Cox proportional hazards regression (hazard ratio 1.35, 95% CI: 1.14 to 1.60, p < 0.001). Sequential multivariable analyses suggested that current CMS standards may not be optimal, as all centers performing more than 40 transplants per year demonstrated less than 5% 30-day mortality. CONCLUSIONS Annual center volume is an independent predictor of short-term mortality in OHT. These data support reevaluation of the current CMS volume cutoff for OHT, as high-volume centers achieve lower mortality.

Long-term Survival Outcomes by Smoking Status in Surgical and Nonsurgical Patients With Non-small Cell Lung Cancer: Comparing Never Smokers and Current Smokers

BACKGROUND Survival outcomes of never smokers with non-small cell lung cancer (NSCLC) who undergo surgery are poorly characterized. This investigation compared surgical outcomes of never and current smokers with NSCLC. METHODS This investigation was a single-institution retrospective study of never and current smokers with NSCLC from 1975 to 2004. From an analytic cohort of 4,546 patients with NSCLC, we identified 724 never smokers and 3,822 current smokers. Overall, 1,142 patients underwent surgery with curative intent. For survival analysis by smoking status, hazard ratios (HRs) were estimated using Cox proportional hazard modeling and then further adjusted by other covariates. RESULTS Never smokers were significantly more likely than current smokers to be women (P < .01), older (P < .01), and to have adenocarcinoma (P < .01) and bronchioloalveolar carcinoma (P < .01). No statistically significant differences existed in stage distribution at presentation for the analytic cohort (P = .35) or for the subgroup undergoing surgery (P = .24). The strongest risk factors of mortality among patients with NSCLC who underwent surgery were advanced stage (adjusted hazard ratio, 3.43; 95% CI, 2.32-5.07; P < .01) and elevated American Society of Anesthesiologists classification (adjusted hazard ratio, 2.18; 95% CI, 1.40-3.40; P < .01). The minor trend toward an elevated risk of death on univariate analysis for current vs never smokers in the surgically treated group (hazard ratio, 1.20; 95% CI, 0.98-1.46; P = .07) was completely eliminated when the model was adjusted for covariates (P = .97). CONCLUSIONS Our findings suggest that smoking status at time of lung cancer diagnosis has little impact on the long-term survival of patients with NSCLC, especially after curative surgery. Despite different etiologies between lung cancer in never and current smokers the prognosis is equally dismal.

Impact of hospital teaching status on survival from ruptured abdominal aortic aneurysm repair

OBJECTIVES Controversy exists over the optimal hospital type to which high-risk surgical patients should be referred for operative management. While high volume centers have been traditionally advocated, recent evidence suggests teaching hospitals may have better outcomes for high-risk patients. We investigated whether mortality outcomes of patients undergoing surgery for ruptured abdominal aortic aneurysm (rAAA) were different between teaching hospitals and non-teaching hospitals, independent of hospital operative volume. METHODS A retrospective review of the Nationwide Inpatient Sample dataset (1998-2004) was performed to identify open and endovascular (EVAR) repair for rAAA. Hospitals were stratified by teaching status, including teaching hospitals (TH) with any type of residency training program, those with general surgery training programs (GSTH) and those with vascular surgery training programs (VSTH). The association of hospital teaching status with in-hospital mortality for open AAA repair and EVAR was assessed via multi-level multivariable logistic regression, controlling for patient demographics, comorbidities, and hospital operative volume. RESULTS Of 6636 open AAA repairs for rAAA, the overall perioperative mortality was 42%. Mortality was significantly lower at TH than non-TH (39.3% vs 44.5%; P < .05). Mortality was also lower at GSTH (38.7%) and VSTH (34.3%). After adjusting for hospital operative volume, patient demographics, and comorbidities, we found a 25% decrease in likelihood of in-hospital death at VSTH vs non-VSTH (odds ratio 0.75; 95% confidence interval 0.60-0.94; P < .05). CONCLUSION In-hospital mortality is significantly reduced for patients undergoing open AAA repair for rAAA at teaching hospitals and hospitals with vascular surgery training programs, independent of volume. These results suggest that in addition to factors associated with teaching hospitals in general, the type of specialty training within teaching institutions is a critical factor which may influence outcomes, specifically for patients with rAAA.

Surgical Risk Preoperative Assessment System (SURPAS): I. Parsimonious, Clinically Meaningful Groups of Postoperative Complications by Factor Analysis.

Objective:To use factor analysis to cluster the 18 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) perioperative complications into a reproducible, smaller number of clinically meaningful groups of postoperative complications, facilitating and streamlining future study and application in live clinical settings. Background:The ACS NSQIP collects and reports on eighteen 30-day postoperative complications (excluding mortality), which are variably grouped in published analyses using ACS NSQIP data. This hinders comparison between studies of this widely used quality improvement dataset. Methods:Factor analysis was used to develop a series of complication clusters, which were then analyzed to identify a parsimonious, clinically meaningful grouping, using 2,275,240 surgical cases in the ACS NSQIP Participant Use File (PUF), 2005 to 2012. The main outcome measures are reproducible, data-driven, clinically meaningful clusters of complications derived from factor solutions. Results:Factor analysis solutions for 5 to 9 latent factors were examined for their percent of total variance, parsimony, and clinical interpretability. Applying the first 2 of these criteria, we identified the 7-factor solution, which included clusters of pulmonary, infectious, wound disruption, cardiac/transfusion, venous thromboembolic, renal, and neurological complications, as the best solution for parsimony and clinical meaningfulness. Applying the last (clinical interpretability), we combined the wound disruption with the infectious clusters resulting in 6 clusters for future clinical applications. Conclusions:Factor analysis of ACS NSQIP postoperative complication data provides 6 clinically meaningful complication clusters in lieu of 18 postoperative morbidities, which will facilitate comparisons and clinical implementation of studies of postoperative morbidities.

Human immunodeficiency virus infection as a prognostic factor in surgical patients with non-small cell lung cancer

BACKGROUND The purpose of this study was to assess the effect of human immunodeficiency virus (HIV) infection on postoperative survival among non-small cell lung cancer (NSCLC) patients. METHODS A retrospective cohort study compared 22 HIV-infected lung cancer patients to 2,430 lung cancer patients with HIV-unspecified status who underwent resection at Johns Hopkins Hospital from 1985 to 2009. Subcohort comparative analyses were performed using individual matching methods. RESULTS Thirty-day mortality rates did not differ between HIV-infected and HIV-unspecified patients. Survival rates for HIV-infected lung cancer patients were significantly shorter than for HIV-unspecified patients (median, 26 versus 48 months; p=0.001). After adjustment, the relative hazard of mortality among HIV-infected NSCLC patients was more than threefold that of HIV-unspecified patients (adjusted hazard ratio, 3.08; 95% confidence interval: 1.85 to 5.13). When additional surgical characteristics were modeled in a matched subcohort, the association remained statistically significant (adjusted hazard ratio, 2.31; 95% confidence interval: 1.11 to 4.81). Moreover, HIV-infected lung cancer patients with CD4 counts less than 200 cells/mm3 had shortened median survival compared with patients whose CD4 counts were 200 cells/mm3 or greater (8 versus 40 months; p=0.031). Postoperative pulmonary and infectious complications were also elevated in the HIV-infected group (p=0.001 and p<0.001, respectively). After surgery, median time to cancer progression was shorter among HIV-infected patients (20.4 months) versus HIV-unspecified patients (p=0.061). CONCLUSIONS The HIV-infected NSCLC patients have more postoperative complications, rapid progression to disease recurrence, and poorer postoperative survival. Optimizing immune status before surgery and careful patient selection based on diffusion capacity of lung for carbon monoxide may improve patient outcomes.

Surgical Risk Preoperative Assessment System (SURPAS): II. Parsimonious Risk Models for Postoperative Adverse Outcomes Addressing Need for Laboratory Variables and Surgeon Specialty-specific Models.

Objective: To develop parsimonious prediction models for postoperative mortality, overall morbidity, and 6 complication clusters applicable to a broad range of surgical operations in adult patients. Summary Background Data: Quantitative risk assessment tools are not routinely used for preoperative patient assessment, shared decision making, informed consent, and preoperative patient optimization, likely due in part to the burden of data collection and the complexity of incorporation into routine surgical practice. Methods: Multivariable forward selection stepwise logistic regression analyses were used to develop predictive models for 30-day mortality, overall morbidity, and 6 postoperative complication clusters, using 40 preoperative variables from 2,275,240 surgical cases in the American College of Surgeons National Surgical Quality Improvement Program data set, 2005 to 2012. For the mortality and overall morbidity outcomes, prediction models were compared with and without preoperative laboratory variables, and generic models (based on all of the data from 9 surgical specialties) were compared with specialty-specific models. In each model, the cumulative c-index was used to examine the contribution of each added predictor variable. C-indexes, Hosmer-Lemeshow analyses, and Brier scores were used to compare discrimination and calibration between models. Results: For the mortality and overall morbidity outcomes, the prediction models without the preoperative laboratory variables performed as well as the models with the laboratory variables, and the generic models performed as well as the specialty-specific models. The c-indexes were 0.938 for mortality, 0.810 for overall morbidity, and for the 6 complication clusters ranged from 0.757 for infectious to 0.897 for pulmonary complications. Across the 8 prediction models, the first 7 to 11 variables entered accounted for at least 99% of the c-index of the full model (using up to 28 nonlaboratory predictor variables). Conclusions: Our results suggest that it will be possible to develop parsimonious models to predict 8 important postoperative outcomes for a broad surgical population, without the need for surgeon specialty-specific models or inclusion of laboratory variables.