Thomas A. Aloia

Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in the NSQIP database

BACKGROUND For the past two decades multiple series have documented that liver resection has become safer. The purpose of this study was to determine the current status of hepatic resection in the USA by analysing the multi-institutional experience within the National Surgical Quality Improvement Program (NSQIP) dataset. METHODS Of the 363,897 cases in the 2005-2007 NSQIP Participant Use File, 2313 elective open hepatectomy cases were identified (1344 partial, 230 left, 510 right and 229 extended hepatectomies). A total of 57 perioperative risk factors and 28 postoperative complications were compared. To determine the applicability of NSQIP general risk models to hepatic surgery, the prognostic value of standard multivariate analysis was compared with the NSQIP general surgery aggregate risk indices (expected probability of morbidity [morbprob], expected probability of mortality [mortprob]). RESULTS The median age of patients listed in the database was 60 years; sex distributions were equivalent; 78% were White; 65% of patients had an ASA score of 3 or 4, and the most prevalent co-morbidity was hypertension (46%). A total of 41% of patients had disseminated cancer, 19% of whom had received chemotherapy within 30 days of surgery. The overall 30-day mortality rate was 2.5% (57/2313) and the 30-day major morbidity rate was 19.6% (453/2313). Multivariate analysis identified nine risk factors associated with major morbidity and two risk factors associated with mortality. In contrast, the morbprob and mortprob statistics did not predict outcomes accurately. For those patients who developed major morbidity, the median length of stay was longer (10 vs. 6 days; P = 0.001) and the mortality rate was higher (11.3% vs. 0.3%; P = 0.001). CONCLUSIONS Analysis of the NSQIP experience with hepatectomy indicates that the current mortality and major morbidity rate benchmarks are 2.5% and 19.6%, respectively. Poor outcomes were associated with nutritional status, liver function and the extent of hepatectomy. The NSQIP general surgery morbprob and mortprob values were relatively poor predictors of post-hepatectomy observed morbidity, indicating the need for specialty-specific NSQIP modelling.

Molecular biologic substaging of stage I lung cancer according to gender and histology

BACKGROUND This study is designed to assess molecular biologic substaging according to gender and histology in patients with stage I non-small cell lung cancer (NSCLC). METHODS Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I NSCLC, with follow-up of at least 5 years. A panel of nine molecular markers was chosen for immunohistochemical analysis of the tumor: recessive oncogenes p53 and bcl-2, the protooncogene erbB-2, KI-67 proliferation index, retinoblastoma oncogene (Rb), epidermal growth factor receptor (EGFr), angiogenesis factor viii, sialyl-Tn antigen (STN), and CD-44. Cox proportional hazards regression analysis was used to construct a risk model for cancer-specific survival according to marker status, gender, and histologic subtype. RESULTS Among men, the only molecular marker associated with decreased cancer-specific survival is erbB-2; among women, there are four markers: p53, Rb, CD-44, and factor viii. Among patients with squamous cell carcinoma, the only molecular marker associated with decreased cancer-specific survival is erbB-2; among patients with adenocarcinoma (AC), there are three markers: p53, CD-44, and factor viii. Multivariable analysis of interactions among molecular markers, gender, and histology demonstrates two important relationships (hazard ratio): p53+/women (2.269) and CD-44+/AC (2.266). CONCLUSIONS Molecular biologic substaging of patients with stage I NSCLC demonstrates differential cancer-specific survival according to marker expression, gender, and histologic subtype.

Predicting the Sites of Metastases From Lung Cancer Using Molecular Biologic Markers

BACKGROUND The use of molecular markers in staging non-small cell lung cancer (NSCLC) has been supported in retrospective prognostic models but has not been evaluated in predicting sites of metastases. METHODS Pathologic specimens were collected from 202 patients after complete resection for stage I NSCLC, who were subsequently found to have no metastases at 5 years (n = 108), isolated brain metastases (n = 25), or other distant metastases (n = 69). A panel of eight molecular markers of metastatic potential was chosen for immunohistochemical analysis of the tumor: p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin, urokinase plasminogen activator (UPA), UPA receptor, and plasminogen activator inhibitor. RESULTS Patients with isolated brain relapse had significantly higher expression of p53 (p = 0.02) and UPA (p = 0.002). The quantitative expression of E-cadherin was used to predict the site of metastases using recursive partitioning: 0 of 92 patients with E-cadherin expression of 0, 1, or 2 developed isolated cerebral metastases; 0 of 33 patients with E-cadherin expression of 3 with UPA of 1 or 2 and ErbB2 of 0 developed brain metastases. Of the remaining patients at risk (UPA = 3), the risk of isolated cerebral metastases was 21 of 57 patients (37%). CONCLUSIONS This study demonstrates that molecular markers may predict the site of relapse in early stage NSCLC. If validated in an ongoing prospective study, these results could be used to select patients with isolated brain metastases for adjuvant therapy, such as prophylactic cranial irradiation.

Tumor marker expression is predictive of survival in patients with esophageal cancer

BACKGROUND This study was designed to determine the prognostic value of immunohistochemical tumor marker expression in a population of patients with node-negative esophageal cancer treated with complete resection alone. METHODS Resection specimens were collected from 61 patients with node-negative T1 (n = 31), T2 (n = 14), and T3 (n = 16) esophageal cancer. A panel of 10 tumor markers was chosen for immunohistochemical analysis, based on associations with differing oncologic mechanisms: apoptosis (p53), growth regulation (transforming growth factor-alpha, epidermal growth factor receptor, and Her2-neu), angiogenesis (factor VIII), metastatic potential (CD44), platinum resistance (p-glycoprotein and metallothionein), 5-fluorouracil resistance (thymidylate synthetase), and carcinogenic detoxification (glutathione S-transferase-pi). RESULTS Complete resection was performed in all patients (44 adenocarcinoma, 17 squamous cell carcinoma), with no operative deaths. Multivariable analysis demonstrated a significant relationship between cancer-specific death and the following variables: low-level P-gp expression (p = 0.004), high-level expression of p53 (p = 0.04), and low-level expression of transforming growth factor-alpha (p = 0.03). In addition, the number of involved tumor markers present was strongly predictive of negative outcome (p = 0.0001). CONCLUSIONS This study supports the prognostic value of immunohistochemical tumor markers, specifically the expression pattern of P-gp, p53, and transforming growth factor-alpha, in patients with esophageal carcinoma treated with complete resection alone.

Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer.

PURPOSE To correlate FDG activity on PET with the expression of glucose transporter proteins Glut-1 and Glut-3 in patients with early stage non-small cell lung cancer (NSCLC). METHODS Over a 5 year period, all patients with a PET scan and clinical stage I NSCLC underwent an immunohistochemical analysis of their tumor for Glut-1 and Glut-3 expression. The amount of FDG uptake in the primary lesion was measured by a standardized uptake ratio (SUR) and correlated with immunohistochemical results. RESULTS Seventy-three patients with a mean age of 66 years had clinical stage I disease. The final pathologic stage showed 64 patients with stage IA/B disease, eight with stage IIA disease, and one patient with pathologic stage IIIA (T1N2) disease. Glut-1 transporter expression was significantly higher than Glut-3 (P<0.0001), and although there was some association between the SUR and Glut-1 (P=0.085) and SUR and Glut-3 (P=0.074) expression, this did not reach statistical significance. CONCLUSIONS Glut-1 and Glut-3 transporter expression did not demonstrate a statistically significant correlation with FDG uptake in potentially resectable lung cancer. It appears that these transporters alone do not affect the variation in FDG activity in early stage NSCLC.

Analysis of Liver Transplant Outcomes for United Network for Organ Sharing Recipients 60 Years Old or Older Identifies Multiple Model for End-Stage Liver Disease-Independent Prognostic Factors

Older recipient age is associated with worse posttransplant survival. Although the median age of liver disease patients undergoing orthotopic liver transplantation (OLT) continues to rise, prognostic factors for posttransplant survival specific to older patients have not been defined. To address this issue, the United Network for Organ Sharing/Organ Procurement and Transplantation Network outcome database was searched to identify prognostic factors for the 8070 liver recipients 60 years old or older who underwent transplantation from 1994 to 2005. Prognostic factors were assessed with univariate analysis and multivariate modeling. The 5 strongest prognostic variables (ventilator status, diabetes mellitus, hepatitis C virus, creatinine levels ≥1.6 mg/dL, and recipient and donor age ≥120 years) were aggregated to define a novel older recipient prognostic score (ORPS). The overall 1‐ and 5‐year posttransplant survival rates were 83% and 67%, respectively. The risk model, created by the assignment of 1 point to each ORPS factor, stratified patient outcomes into distinct prognostic groups at the 1‐, 3‐, and 5‐year posttransplant time points (P < 0.001). The 5‐year survival rates for patients with ORPS values of 0, 1, and 2 points were 75%, 69%, and 58%, respectively. Patients who underwent transplantation with an ORPS > 2 points consistently experienced 5‐year survival rates of less than 50%. In conclusion, in liver transplant recipients 60 years old or older, the ORPS was able to predict significant and clinically relevant differences in posttransplant survival. By optimization of donor selection for recipients over the age of 60 years, clinical utilization of the ORPS model may enhance organ utilization for all patients awaiting OLT. Liver Transpl, 2010.

Analysis of recent pediatric orthotopic liver transplantation outcomes indicates that allograft type is no longer a predictor of survivals.

Two strategies to increase the donor allograft pool for pediatric orthotopic liver transplantation (OLT) are deceased donor segmental liver transplantation (DDSLT) and living donor liver transplantation (LDLT). The purpose of this study is to evaluate outcomes after use of these alternative allograft types. Data on all OLT recipients between February 2002 and December 2004 less than 12 years of age were obtained from the United Network for Organ Sharing database. The impact of allograft type on posttransplant survivals was assessed. The number of recipients was 1260. Of these, 52% underwent whole liver transplantation (WLT), 33% underwent DDSLT, and 15% underwent LDLT. There was no difference in retransplantation rates. Immediate posttransplant survivals differed, with WLT patients having improved 30‐day patient survivals compared to DDSLT and LDLT patients (P = 0.004). Although unadjusted 1‐year patient survivals were better for WLT versus DDSLT (P = 0.01), after risk adjustment, 1‐year patient survivals for WLT (94%), DDSLT (91%), and LDLT (93%) were similar (P values > 0.05). Unadjusted allograft survivals were better for WLT and LDLT in comparison with DDSLT (P = 0.009 and 0.018, respectively); however, after adjustment, these differences became nonsignificant (all P values > 0.05). For patients ≤ 2 years of age (n = 833), the adjusted 1‐year patient and allograft survivals were also similar (all P values > 0.05). In conclusion, in the current era of pediatric liver transplantation, WLT recipients have better immediate postoperative survivals. By 1 year, adjusted patient and allograft survivals are similar, regardless of the allograft type. Liver Transpl 14:1125–1132, 2008.

Liver Transplant for Hepatocellular Carcinoma

Currently, liver transplantation stands as the best treatment modality for early-stage hepatocellular carcinoma in patients with decompensated cirrhosis, giving patients the opportunity to be free from the potentially lethal complications from both cancer and their advanced underlying liver disease. Following a historical period characterized by high hepatocellular carcinoma recurrence rates following transplantation of patients with advanced stage disease, introduction of the “Milan criteria” encouraged a focus on early stage hepatocellular carcinoma and improved patient and oncologic outcomes were achieved. Data are emerging that patients with tumor size and tumor number slightly in excess of those proposed in the Conventional Milan Criteria share equivalent survivals with traditional early stage patients and should also be considered for liver transplantation. In settings where the number of patients with hepatocellular carcinoma and indications for transplant exceed the number of cadaveric liver allografts, alternative strategies are requisite. These include more liberal use of liver resection, interventional and systemic treatments, and living-related liver transplantation. The field has seen tremendous development and is now under considerable pressure due to epidemic rates of hepatocellular carcinoma in both hepatitis and fatty liver disease-induced cirrhotics. In this setting, multiple controversies in the field require resolution by clinical trial and/or consensus.