Hari Nathan

Intrahepatic Cholangiocarcinoma: An International Multi-Institutional Analysis of Prognostic Factors and Lymph Node Assessment

PURPOSE To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. PATIENTS AND METHODS From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. RESULTS Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). CONCLUSION Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.

Predictors of survival after resection of early hepatocellular carcinoma

Objective:To identify clinicopathologic factors that predict survival following hepatectomy in patients with early hepatocellular carcinoma (HCC). Summary Background Data:Although surgical resection of early HCC is thought to be associated with a good outcome, factors predictive of prognosis following resection of these tumors remain ill-defined. Methods:The Surveillance, Epidemiology, and End Results database was used to identify patients with histologically confirmed early HCC (≤5 cm and no nodal involvement, metastases, or major vascular invasion) who underwent surgical resection (not ablation or transplantation) between 1988 and 2005. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazards models. Results:The study included 788 patients. Median tumor size was 3.2 cm, and 20% of patients had tumors ≤2 cm. Most HCC lesions were solitary (74%) and had no evidence of vascular invasion (82%). Following surgery, overall median and 5-year survival were 45 months and 39%, respectively. After adjusting for demographic factors and histological grade, tumor size >2 cm (hazard ratio [HR]: 1.51), multifocal tumors (HR: 1.51), and vascular invasion (HR: 1.44) remained independent predictors of poor survival (all P < 0.05). Based on these findings, a prognostic scoring system was developed that allotted 1 point each for these factors. Patients with early HCC could be stratified into 3 distinct prognostic groups (median and 5-year survival, respectively): 0 points (70 months, 55%), 1 point (52 months, 42%), and ≥2 points (24 months, 29%) (P < 0.001). Conclusions:Although early HCC is generally associated with a good prognosis, pathologic factors can still be used to stratify patients with respect to survival after resection. These data emphasize the importance of pathologic staging even in small HCC.

Trends in Survival after Surgery for Cholangiocarcinoma: A 30-Year Population-Based SEER Database Analysis

The prognosis of patients with cholangiocarcinoma historically has been poor, even after surgical resection. Although data from some single-institution series indicate improvement over historical results, survival after surgical therapy for cholangiocarcinoma has not been investigated in a population-based study. We used the Surveillance, Epidemiology, and End Results database to identify patients who underwent surgery for cholangiocarcinoma from 1973 through 2002. Multivariate modeling of survival after surgery for intrahepatic cholangiocarcinoma showed an improvement in survival only within the last decade studied, resulting in a cumulative 34.4% improvement in survival from 1992 through 2002. In contrast, multivariate modeling of survival after surgery for extrahepatic cholangiocarcinoma revealed a 23.3% increase in adjusted survival per each decade studied, resulting in a cumulative 53.7% improvement from 1973 through 2002. We conclude that survival after surgery for extrahepatic cholangiocarcinoma has dramatically improved since 1973. Patients with intrahepatic cholangiocarcinoma, however, have achieved an improvement in survival largely confined to more recent years. We suggest that these trends are largely caused by developments in imaging technology, improvements in patient selection, and advances in surgical techniques.

Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials.

Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta‐analysis and meta‐regression of 30 publications representing 19 randomized trials that compared steroid‐free with steroid‐based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid‐free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P = 0.08], and statistically significant decreases in cholesterol (standard mean difference −0.41, P < 0.001) and cytomegalovirus (RR 0.52, P = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P < 0.001), rejection (RR 0.68, P = 0.03), and severe rejection (RR 0.37, P = 0.001) were markedly lower in steroid‐free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid‐free arms (RR 1.31, P = 0.02) and reduction of diabetes was attenuated (RR 0.74, P = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta‐analysis demonstrated this important effect (RR 0.90, P = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid‐free regimens in LT. Liver Transpl 14:512–525, 2008.

Colorectal Liver Metastases Recurrence and Survival Following Hepatic Resection, Radiofrequency Ablation, and Combined Resection-Radiofrequency Ablation

HYPOTHESIS Although radiofrequency ablation (RFA) is increasingly an accepted option for patients with colorectal liver metastases, patients treated with resection vs RFA may have different tumor biology profiles, which might confound the relationship between choice of liver-directed therapy and outcome. DESIGN Retrospective review of a prospectively collected database. SETTING Major hepatobiliary center. PATIENTS Between January 1, 1999, and August 30, 2006, 258 patients with colorectal liver metastases underwent hepatic resection with or without RFA. MAIN OUTCOME MEASURES Evaluation of outcome following resection alone, combined resection-RFA, and RFA alone using 3 statistical methods (paired-match control, Cox proportional hazards multivariate model, and propensity index) to identify and adjust for potential confounding variables. RESULTS The median number of hepatic lesions was 2, and the median size of the largest lesion was 3.0 cm. One hundred ninety-two patients (74.4%) underwent resection alone, 55 patients (21.3%) underwent resection-RFA, and 11 patients (4.3%) underwent RFA alone. Patients who underwent resection-RFA had significantly increased risk of extrahepatic failure at 1 year vs patients who underwent resection alone or RFA alone (P < .05). On matched control and multivariate analyses, patients who underwent RFA with or without resection had significantly worse disease-free and overall survival than patients who underwent resection alone. Propensity score methods revealed that the aggregate distribution of clinical risk factors for resection-RFA was markedly different from that for resection alone. This suggested a lack of comparability to allow for statistical comparisons in the assessment of causal inferences regarding the efficacy of RFA therapy. CONCLUSION Although results of matched control and multivariate analyses suggested that RFA with or without resection was associated with worse outcome, propensity score methods revealed that the resection-RFA and resection-alone groups were different with regard to baseline tumor and treatment-related factors, making causal inferences about the efficacy of RFA unreliable.

The Volume-Outcomes Effect in Hepato-Pancreato-Biliary Surgery: Hospital Versus Surgeon Contributions and Specificity of the Relationship

BACKGROUND Although the relationship between hepato-pancreato-biliary (HPB) procedure volume and outcomes is established, the relative importance of hospital and surgeon effects and the specificity of the volume-outcomes effect remain ill-defined. We sought to comprehensively characterize the hospital and surgeon volume-outcomes relationships in high-risk HPB surgery. STUDY DESIGN The 1998 to 2005 State Inpatient Databases for Florida, Maryland, and New York were used to identify patients undergoing complex HPB surgery and to quantify hospital and surgeon procedure volumes. The effects of hospital and surgeon procedure volumes on casemix-adjusted inpatient mortality were analyzed using multilevel logistic regression models. RESULTS For hepatic resection, hospital procedure volume predicted mortality (high versus low volume, odds ratio [OR] 0.48, p=0.04), but surgeon volume did not (p=0.42). For pancreatic resection, in contrast, both hospital (OR 0.32, p < 0.001) and surgeon (OR 0.30, p < 0.001) procedure volume predicted mortality. The hospital volume effect for pancreatic resection was largely explained by surgeon volume. In both procedure groups, volume-outcomes effects were very specific. Only volumes of the primary procedure were predictive of mortality; volumes of related HPB procedures and overall HPB volume demonstrated no independent effect on mortality. CONCLUSIONS In HPB surgery, the relative contributions of hospital versus surgeon volume vary according to the specific procedure in question. In addition, the association between hospital or surgeon volume and in-hospital mortality is very specific to the procedure in question. High-volume expertise in one area of HPB surgery does not translate into improved outcomes for related procedures. These data may have implications for quality assessment and improvement, patient referral, and HPB surgical training.

Risk factors for pancreatic leak after distal pancreatectomy

Introduction:Pancreatic leak (PL) remains a major cause of postoperative morbidity in patients undergoing pancreatic resection. We sought to evaluate the incidence of and identify risk factors for the development of PL in patients undergoing distal pancreatectomy (DP) at a single high-volume institution. Methods:All patients who underwent primary open DP (excluding completion pancreatectomy and debridement) between January 1, 1984 and July 1, 2006 were identified, and their medical records were reviewed. χ2 and multivariable logistic regression analyses were performed to identify risk factors for PL. Results:In a cohort of 704 patients undergoing primary DP, the indications for DP were benign pancreatic neoplasm (34%), malignant pancreatic neoplasm (31%), other neoplasm (15%), chronic pancreatitis (14%), pseudocyst (3%), and trauma (3%). The pancreatic remnant was sutured alone in 83%, stapled alone in 5%, and both stapled and sutured in 9% of cases. Ligation of the pancreatic duct was performed in 22% of cases. Perioperative mortality was <1%, but overall morbidity was 33%, most commonly PL (12% clinically significant, 21% biochemical). Multivariable logistic regression analysis revealed that neither the method of closure of the pancreatic remnant (P = 0.41) nor ligation of the pancreatic duct (P > 0.05) affected the risk of clinically significant PL. Conclusions:This largest reported series of DP demonstrates that this procedure can be performed with low mortality but still carries a substantial risk of morbidity, particularly PL. In contrast to some previous studies, this analysis found that surgical management of the pancreatic remnant has no effect on the incidence of clinically significant PL.

Predictors of survival after resection of retroperitoneal sarcoma: A population-based analysis and critical appraisal of the AJCC Staging system

Objective:To identify predictors of survival after resection of retroperitoneal sarcoma (RPS) and to evaluate the performance of the American Joint Committee on Cancer (AJCC) staging system for RPS. Summary Background Data:Previous studies of survival after RPS resection are restricted to at most several institutions, yet the current AJCC staging system for RPS is based entirely on these relatively small studies. Methods:Patients undergoing resection of primary RPS from 1988 to 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models were used to analyze survival and evaluate AJCC staging. Results:In 1365 patient undergoing resection of primary RPS, the most prevalent histologies were liposarcoma (50%), leiomyosarcoma (26%), and malignant fibrous histiocytoma (11%). Median, 5-year, and 10-year survival after resection were 55 months, 47%, and 27%. Histological subtype (P < 0.001), histological grade (grade 3–4 vs. grade 1; HR, 2.42; P < 0.001), and tumor invasion of adjacent structures (HR, 1.37; P < 0.001) were associated with survival on multivariable analysis. However, tumor size had no prognostic value. Consequently, the AJCC T classification system demonstrated poor discriminatory ability (c = 0.50). The AJCC stage grouping system demonstrated moderate discriminatory ability (c = 0.66) but performed no better than a much simpler system that omits information on tumor size and lymph node metastasis (c = 0.67). Conclusions:Indicators of tumor aggressiveness (histological grade and invasion of adjacent structures) as well as histological subtype predict survival after RPS resection. Tumor size, however, does not impact survival. The AJCC staging system for RPS is in need of revision.

Influence of patient, physician, and hospital factors on 30-day readmission following pancreatoduodenectomy in the United States

UNLABELLED IMPORTANCE It is not known whether hospital and surgeon volumes have an association with readmission among patients undergoing pancreatoduodenectomy. OBJECTIVE To evaluate patient-, surgeon-, and hospital-level factors associated with readmission. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data with cases diagnosed from January 1, 1998, to December 31, 2005, and followed up until December 2007. Population-based cancer registry data were linked to Medicare data for the corresponding patients. A total of 1488 unique individuals who underwent a pancreatoduodenectomy were identified. INTERVENTIONS Undergoing pancreatoduodenectomy at hospitals classified by volume of pancreatoduodenectomy procedures performed at the facility were either very-low, low, medium, or high volume. Undergoing pancreatoduodenectomy by surgeons classified by volume of pancreatoduodenectomy procedures performed by the surgeon were either very-low, low, medium, or high volume. MAIN OUTCOMES AND MEASURES In-hospital morbidity, mortality, and 30-day readmission were examined. RESULTS The median age was 74 years, and 1436 patients (96.5%) had a least 1 medical comorbidity. Patients were treated by 575 distinct surgeons at 298 distinct hospitals. Length of stay was longest (median, 17 days) and 90-day mortality highest (17.2%) at very-low-volume hospitals (P < .001). Among all pancreatoduodenectomy patients, 292 (21.3%) were readmitted within 30 days of discharge. There was no effect of surgeon volume and a modest effect of hospital volume (odds ratio for highest- vs lowest-volume quartiles, 1.85; 95% CI, 1.22-2.80; P = .02). The presence of significant preoperative medical comorbidities was associated with an increased risk for hospital readmission after pancreatoduodenectomy. A comorbidity score greater than 13 had a pronounced effect on the chance of readmission following pancreatoduodenectomy (odds ratio, 2.06; 95% CI, 1.56-2.71; P < .001). The source of variation in readmission was primarily attributable to patient-related factors (95.4%), while hospital factors accounted for 4.3% of the variability and physician factors for only 0.3%. CONCLUSIONS AND RELEVANCE Nearly 1 in 5 patients are readmitted following pancreatoduodenectomy. While variation in readmission is, in part, attributable to differences among hospitals, the largest share of variation was found at the patient level.

Conditional Survival after Surgical Resection of Colorectal Liver Metastasis: An International Multi-Institutional Analysis of 949 Patients

BACKGROUND Traditionally, survival estimates have been reported solely as survival from the time of surgery, but future survival probability likely changes based on the survival time already accumulated after therapy-otherwise known as conditional survival (CS). We sought to assess the comparative performance of various colorectal liver metastasis prognostic scoring systems, as well as to investigate the CS of patients who underwent resection of colorectal liver metastasis. STUDY DESIGN Between 1982 and 2008, 949 patients who underwent colorectal liver metastasis resection were identified from an international multi-institutional database. Various prognostic scoring systems were evaluated using Cox proportional hazards models and calculated concordance index (c). CS estimates were calculated as CS = S((x+5))/S((x)). RESULTS Overall survival after liver resection was 65% at 3 years and 45% at 5 years, with a median survival of 52 months. All of the prognostic scoring systems had poor-to-moderate prognostic discriminatory ability (Fong c = 0.57, Nordlinger c = 0.56, Memorial Sloan-Kettering Cancer Center nomogram c = 0.58). Using CS, the probability of surviving an additional 5 years, given that the patient had already survived 1, 3, or 5 years, was 41%, 40%, or 50%, respectively. The inadequate performance of the prognostic scoring systems was explained by the fact that as survival from liver resection increased from 0 to 5 years, the 5-year observed CS improved substantially for patients who were initially predicted to have poor survival at the time of surgery. CONCLUSIONS Colorectal liver metastasis prognostic scoring systems have fair-to-moderate performance. CS can provide more accurate prognostic information for patients and physicians after colorectal liver metastasis resection and should be incorporated into the quantification of survival.