Ryan S. Turley

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.

The Type III Transforming Growth Factor-β Receptor as a Novel Tumor Suppressor Gene in Prostate Cancer

The transforming growth factor-beta (TGF-beta) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-beta. Although the loss of expression of either the type I (TbetaRI) or type II (TbetaRII) TGF-beta receptor has been documented in approximately 30% of prostate cancers, most prostate cancers become TGF-beta resistant without mutation or deletion of TbetaRI, TbetaRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-beta receptor (TbetaRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TbetaRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TbetaRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TbetaRIII promoter. Functionally, restoring TbetaRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TbetaRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity.

Recurrence after operative management of intrahepatic cholangiocarcinoma

INTRODUCTION Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. METHODS We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. RESULTS During the median follow up duration of 31 months (range 1-208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34-3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01-2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10-2.25; P = .04), and tumor size ≥ 5 cm (HR, 1.84; 95% CI, 1.28-2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. CONCLUSION Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence.

TβRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity

The transforming growth factor-beta (TGF-beta) superfamily has essential roles in lung development, regulating cell proliferation, branching morphogenesis, differentiation and apoptosis. Although most lung cancers become resistant to the tumor suppressor effects of TGF-beta, and loss or mutation of one of the components of the TGF-beta signaling pathway, including TbetaRII, Smad2 and Smad4 have been reported, mutations are not common in non-small cell lung cancer (NSCLC). Here we demonstrate that the TGF-beta superfamily co-receptor, the type III TGF-beta receptor (TbetaRIII or betaglycan) is lost in the majority of NSCLC specimens at the mRNA and protein levels, with loss correlating with increased tumor grade and disease progression. Loss of heterozygosity at the TGFBR3 genomic locus occurs in 38.5% of NSCLC specimens and correlates with decreased TbetaRIII expression, suggesting loss of heterozygosity as one mechanism for TbetaRIII loss. In the H460 cell model of NSCLC, restoring TbetaRIII expression decreased colony formation in soft agar. In the A549 cell model of NSCLC, restoring TbetaRIII expression significantly decreased cellular migration and invasion through Matrigel, in the presence and absence of TGF-beta1, and decreased tumorigenicity in vivo. In a reciprocal manner, shRNA-mediated silencing of endogenous TbetaRIII expression enhanced invasion through Matrigel. Mechanistically, TbetaRIII functions, at least in part, through undergoing ectodomain shedding, generating soluble TbetaRIII, which is able to inhibit cellular invasiveness. Taken together, these results support TbetaRIII as a novel tumor suppressor gene that is commonly lost in NSCLC resulting in a functional increase in cellular migration, invasion and anchorage-independent growth of lung cancer cells.

Current Trends in Regional Therapy for Melanoma: Lessons Learned from 225 Regional Chemotherapy Treatments between 1995 and 2010 at a Single Institution

BACKGROUND Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are used to manage advanced extremity melanoma, but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment. STUDY DESIGN Using a prospectively maintained database, we reviewed our experience with melphalan-based HILP (which included 62 first-time and 10 second-time) and ILI (which included 126 first-time and 18 second-time) procedures performed in 188 patients. PET/CT was obtained 3 months postregional treatment for 1 year and then every 6 months thereafter. RESULTS Overall response rate (complete response [CR] + partial response) of HILP was 81% (80% CI, 73-87%), and overall response rate from ILI was 43% (80% CI, 37-49%) for first-time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, and ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR after repeat HILP (50%, n = 10) compared with repeat ILI (28%, n = 18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2 of 62) than ILI (0 of 122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25 of 49; 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%. CONCLUSIONS In the largest single-institution regional therapy series reported to date, we found that although ILI is effective and well-tolerated, HILP is a more definitive way to control advanced disease.

Major Liver Resection in Elderly Patients: A Multi-Institutional Analysis

BACKGROUND Because of the aging United States population, increase in overall life expectancy, and rising incidence of hepatobiliary tumors, more elderly patients are considered for hepatic resection. The objective of this study was to assess the influence of age on postoperative outcomes after major hepatectomy among a contemporary cohort from 2 high volume centers. STUDY DESIGN Demographics, diagnoses, surgical treatments, and postoperative outcomes of patients who underwent major hepatic resection were reviewed. RESULTS There were 856 patients who underwent major hepatectomy (resection of 3 or more segments) from 2002 to 2009. Postoperative mortality and morbidity occurred in 53 (6.2%) and 403 (47.1%) patients, respectively. Increasing age was independently associated with postoperative mortality (p = 0.0345). Each 1-year and 10-year increase in age resulted in an odds ratio of mortality after major hepatic resection of 1.036 (95% CI [1.003-1.071]) and 1.426 (95% CI [1.026-1.982]), respectively. This relationship was independent of American Society of Anesthesiology (ASA) score. Increasing age was associated with postoperative sepsis (p = 0.0224, odds ratio for each year 1.025 [range 1.003 to 1.048]) after major hepatic resection, but not overall postoperative morbidity. CONCLUSIONS In the contemporary era, increasing age is independently associated with postoperative mortality after major hepatic resection at high volume academic centers.

Examining Reoperation and Readmission after Hepatic Surgery

BACKGROUND Although the perioperative mortality from hepatic resection has improved considerably, this procedure is still associated with substantial morbidity and resource use. The goal of this investigation was to characterize the incidence, patterns, and risk factors for early reoperation and readmission after hepatectomy. STUDY DESIGN Perioperative outcomes of 1,281 patients undergoing hepatic resection at an academic center from 1996 to 2009 were analyzed. The indications for early reoperation and readmission (90 days) were reviewed. Multivariate logistic regression analysis was performed to determine variables associated with reoperation and readmission. A scoring system was generated to predict the need for readmission after hepatectomy. RESULTS Eighty-seven patients (6.8%) required reoperation. The perioperative mortality in patients requiring reoperation was significantly higher than for those not requiring reoperation (23.0% vs 3.4%; p < 0.001). Variables associated with reoperation included male sex, performance of concomitant major nonhepatic procedures, and greater intraoperative blood loss. One hundred and eighty-four patients (14.4%) required readmission. Variables associated with readmission included major hepatectomy, development of major postoperative complications, and index hospitalization >7 days. A Readmission Prediction Score ranging from 0 to 4 was generated and directly correlated with need for readmission. CONCLUSIONS In the current era of hepatic surgery, early reoperation and readmission remain relatively frequent. As we care for patients who are increasingly receiving regionalized care far from home, we must be mindful of patients at increased risk for readmission. The development of strategies to minimize the complications that necessitate reoperation and readmission is critical to improving patient care.

Bevacizumab-Induced Alterations in Vascular Permeability and Drug Delivery: A Novel Approach to Augment Regional Chemotherapy for In-Transit Melanoma

Purpose: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). Experimental Design: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evans blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO2 were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Results: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO2 decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Conclusions: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma. Clin Cancer Res; 18(12); 3328–39. ©2012 AACR.

Laparoscopic Versus Open Hartmann Procedure for the Emergency Treatment of Diverticulitis: A Propensity-matched Analysis

BACKGROUND: A laparoscopic approach has been proposed to reduce the high morbidity and mortality associated with the Hartmann procedure for the emergency treatment of diverticulitis. OBJECTIVE: The objective of our study was to determine whether a laparoscopic Hartmann procedure reduces early morbidity or mortality for patients undergoing an emergency operation for diverticulitis. DESIGN: This is a comparative effectiveness study. A subset of the entire American College of Surgeons National Surgical Quality Improvement Program patient sample matched on propensity for undergoing their procedure with the laparoscopic approach were used to compare postoperative outcomes between laparoscopic and open groups. SETTING: This study uses data from the American College of Surgeons National Surgical Quality Improvement Program Participant User Files from 2005 through 2009. PATIENTS: All patients who underwent an emergency laparoscopic or open partial colectomy with end colostomy for colonic diverticulitis were reviewed. MAIN OUTCOME MEASURES: The main outcome measures were 30-day mortality and morbidity. RESULTS: Included in the analysis were 1186 patients undergoing emergency partial colectomy with end colostomy for diverticulitis. Among the entire cohort, the laparoscopic group had fewer overall complications (26% vs 41.7%, p = 0.008) and shorter mean length of hospitalization (8.9 vs 11.6 days, p = 0.0008). Operative times were not significantly different between groups. When controlling for potential confounders, a laparoscopic approach was not associated with a decrease in morbidity or mortality. In comparison with a propensity-match cohort, the laparoscopic approach did not reduce postoperative morbidity or mortality. LIMITATIONS: This study is limited by its retrospective nature and the absence of pertinent variables such as postoperative pain indices, time for return of bowel function, and rates of readmission. CONCLUSIONS: A laparoscopic approach to the Hartmann procedure for the emergency treatment of complicated diverticulitis does not significantly decrease postoperative morbidity or mortality in comparison with the open technique.

Hepatic Resection for Metastatic Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era

Before the advent of tyrosine kinase inhibitors (TKIs), surgical resection was the primary treatment for hepatic gastrointestinal stromal tumor (GIST) metastases. Although TKIs have improved survival in the metastatic setting, outcomes after multimodal therapy comprised of hepatectomy and TKIs for GIST are unknown. The objective of this study was to determine whether combination therapy for hepatic GIST metastases is associated with improved overall survival compared with reported outcomes from surgery or TKI therapy alone.