Dustin M. Walters

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.

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.

The impact of portal vein resection on outcomes for hilar cholangiocarcinoma: a multi-institutional analysis of 305 cases.

BACKGROUND. Surgical strategy for hilar cholangiocarcinoma often includes hepatectomy, but the role of portal vein resection (PVR) remains controversial. In this study, the authors sought to identify factors associated with outcome after surgical management of hilar cholangiocarcinoma and examined the impact of PVR on survival.

Inhibition of Focal Adhesion Kinase by PF-562,271 Inhibits the Growth and Metastasis of Pancreatic Cancer Concomitant with Altering the Tumor Microenvironment

Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA, and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small-molecule inhibitor of FAK/PYK2) on (i) in vitro migration, invasion, and proliferation; (ii) tumor proliferation, invasion, and metastasis in a murine model; and (iii) stromal cell composition in the PDA microenvironment. Migration assays were conducted to assess tumor and stromal cell migration in response to cellular factors, collagen, and the effects of PF-562,271. An orthotopic murine model was used to assess the effects of PF-562,271 on tumor growth, invasion, and metastasis. Proliferation assays measured PF-562,271 effects on in vitro growth. Immunohistochemistry was used to examine the effects of FAK inhibition on the cellular composition of the tumor microenvironment. FAK and PYK2 were activated and expressed in patient-derived PDA tumors, stromal components, and human PDA cell lines. PF-562,271 blocked phosphorylation of FAK (phospho-FAK or Y397) in a dose-dependent manner. PF-562,271 inhibited migration of tumor cells, cancer-associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis, or apoptosis, but it did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts than control or gemcitabine. These data support a role for FAK in PDA and suggest that inhibitors of FAK may contribute to efficacious treatment of patients with PDA. Mol Cancer Ther; 10(11); 2135–45. ©2011 AACR.

Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis.

Information on the clinicopathologic characteristics of invasive carcinomas arising from mucinous cystic neoplasms (MCNs) is limited, because in many early studies they were lumped and analyzed together with noninvasive MCNs. Even more importantly, many of the largest prior studies did not require ovarian-type stroma (OTS) for diagnosis. We analyzed 178 MCNs, all strictly defined by the presence of OTS, 98% of which occurred in perimenopausal women (mean age, 47 y) and arose in the distal pancreas. Twenty-nine (16%) patients had associated invasive carcinoma, and all were female with a mean age of 53. Invasion was far more common in tumors with grossly visible intracystic papillary nodule formation ≥1.0 cm (79.3% vs. 8.7%, P=0.000) as well as in larger tumors (mean cyst size: 9.4 vs. 5.4 cm, P=0.006); only 4/29 (14%) invasive carcinomas occurred in tumors that were <5 cm; however, none were <3 cm. Increased serum CA19-9 level (>37 U/L) was also more common in the invasive tumors (64% vs. 23%, P=0.011). Most invasive carcinomas (79%) were of tubular type, and the remainder (5 cases) were mostly undifferentiated carcinoma (2, with osteoclast-like giant cells), except for 1 with papillary features. Interestingly, there were no colloid carcinomas; 2 patients had nodal metastasis at the time of diagnosis, and both died of disease at 10 and 35 months, respectively. While noninvasive MCNs had an excellent prognosis (100% at 5 y), tumors with invasion often had an aggressive clinical course with 3- and 5-year survival rates of 44% and 26%, respectively (P=0.000). The pT2 (>2 cm) invasive tumors had a worse prognosis than pT1 (⩽2 cm) tumors (P=0.000), albeit 3 patients with T1a (<0.5 cm) disease also died of disease. In conclusion, invasive carcinomas are seen in 16% of MCNs and are mostly of tubular (pancreatobiliary) type; colloid carcinoma is not seen in MCNs. Serum CA19-9 is often higher in invasive carcinomas, and invasion is typically seen in OTS-depleted areas with lower progesterone receptor expression. Invasion is not seen in small tumors (<3 cm) and those lacking intracystic papillary (mural) nodules of ≥1 cm, thus making the current branch-duct intraductal papillary mucinous neoplasm management protocols also applicable to MCNs.

Primary payer status affects outcomes for cardiac valve operations

BACKGROUND Disparities in health care have been reported among various patient populations, and the uninsured and Medicaid populations are a major focus of current health care reform. The objective of this study was to examine the influence of primary payer status on outcomes after cardiac valve operations in the United States. METHODS From 2003 to 2007, 477,932 patients undergoing cardiac valve operations were evaluated using discharge data from the Nationwide Inpatient Sample database. Records were stratified by primary payer status: Medicare (n = 57,249, age = 74.0 ± 0.02 years), Medicaid (n = 5,868, age = 41.2 ± 0.13 years), uninsured (n = 2,349, age = 49.7 ± 0.15 years), and private insurance (n = 31,808, age = 53.3 ± 0.04 years). Multivariate regression models were applied to assess the independent effect of payer status on in-hospital outcomes. RESULTS Preoperative patient risk factors were more common among Medicare and Medicaid populations. Unadjusted mortality and complication rates for Medicare (6.9%, 36.6%), Medicaid (5.7%, 31.4%) and uninsured (5.2%, 31.4%) patient groups were higher compared with private insurance groups (2.9%, 29.9%; p < 0.001). In addition, mortality was lowest for patients with private insurance for all types of valve operations. Medicaid patients accrued the longest unadjusted hospital length of stay and highest total hospital costs compared with other payer groups (p < 0.001). Importantly, after risk adjustment, uninsured and Medicaid payer status conferred the highest odds of risk-adjusted mortality and morbidity compared with private insurance status, which were higher than those for Medicare. CONCLUSIONS Uninsured and Medicaid payer status is associated with increased risk-adjusted in-hospital mortality and morbidity among patients undergoing cardiac valve operations compared with Medicare and private insurance. In addition, Medicaid patients accrued the longest hospital stays and highest total costs. Primary payer status should be considered as an independent risk factor during preoperative risk stratification and planning.

Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury

OBJECTIVE Adenosine and the activation of specific adenosine receptors are implicated in the attenuation of inflammation and organ ischemia-reperfusion injury. We hypothesized that activation of A(1), A(2A), or A(3) adenosine receptors would provide protection against lung ischemia-reperfusion injury. METHODS With the use of an isolated, ventilated, blood-perfused rabbit lung model, lungs underwent 18 hours of cold ischemia followed by 2 hours of reperfusion. Lungs were administered vehicle, adenosine, or selective A(1), A(2A), or A(3) receptor agonists (CCPA, ATL-313, or IB-MECA, respectively) alone or with their respective antagonists (DPCPX, ZM241385, or MRS1191) during reperfusion. RESULTS Compared with the vehicle-treated control group, treatment with A(1), A(2A), or A(3) agonists significantly improved function (increased lung compliance and oxygenation and decreased pulmonary artery pressure), decreased neutrophil infiltration by myeloperoxidase activity, decreased edema, and reduced tumor necrosis factor-alpha production. Adenosine treatment was also protective, but not to the level of the agonists. When each agonist was paired with its respective antagonist, all protective effects were blocked. The A(2A) agonist reduced pulmonary artery pressure and myeloperoxidase activity and increased oxygenation to a greater degree than the A(1) or A(3) agonists. CONCLUSION Selective activation of A(1), A(2A), or A(3) adenosine receptors provides significant protection against lung ischemia-reperfusion injury. The decreased elaboration of the potent proinflammatory cytokine tumor necrosis factor-alpha and decreased neutrophil sequestration likely contribute to the overall improvement in pulmonary function. These results provide evidence for the therapeutic potential of specific adenosine receptor agonists in lung transplant recipients.

Clinical, Molecular and Genetic Validation of a Murine Orthotopic Xenograft Model of Pancreatic Adenocarcinoma Using Fresh Human Specimens

Background Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC. Methods Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression. Results Fifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines. Conclusions The orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.

Use of a falciform ligament pedicle flap to decrease pancreatic fistula after distal pancreatectomy.

Objectives: Postoperative pancreatic fistula (POPF) remains a significant source of morbidity after distal pancreatectomy (DP). We describe a technique for coverage of the pancreatic stump after DP using a pedicled falciform ligament flap with a low POPF rate. Methods: A retrospective review of clinical, radiographic, and pathologic variables of patients undergoing open DP between November 2005 and August 2009 was performed. After standardized DP, the pancreatic stump was closed using a pedicled falciform ligament flap. Postoperative pancreatic fistula was defined using the International Study Group classification for pancreatic fistula definition. Results: Twenty-three consecutive patients underwent open DP and splenectomy with closure of the pancreatic stump using a pedicled falciform ligament flap. Pancreatic transection and stump closure was performed in a uniform fashion in all patients. Eight patients (35%) had additional organs resected. Two patients (8.7%) developed grade C POPFs, which were successfully managed with percutaneous drain placement. No additional patients developed a POPF or abdominal abscess. The median length of stay was 5 days. There were no perioperative mortalities. Conclusions: We conclude that use of a pedicled falciform ligament flap for coverage of the pancreatic stump is associated with a low incidence of POPF. Continued investigation of this technique is warranted.

Severe Traumatic Head Injury Affects Systemic Cytokine Expression

BACKGROUND The neuroimmunologic effect of traumatic head injury remains ill-defined. This study aimed to characterize systemic cytokine profiles among traumatically injured patients to assess the effect of traumatic head injury on the systemic inflammatory response. STUDY DESIGN For 5 years, 1,022 patients were evaluated from a multi-institutional Trauma Immunomodulatory Database. Patients were stratified by presence of severe head injury (SHI; head Injury Severity Score ≥4, n = 335) vs nonsevere head injury (NHI; head Injury Severity Score ≤3, n = 687). Systemic cytokine expression was quantified by ELISA within 72 hours of admission. Patient factors, outcomes, and cytokine profiles were compared by univariate analyses. RESULTS SHI patients were more severely injured with higher mortality, despite similar ICU infection and ventilator-associated pneumonia rates. Expression of early proinflammatory cytokines, interleukin-6 (p < 0.001) and tumor necrosis factor-α (p = 0.02), was higher among NHI patients, and expression of immunomodulatory cytokines, interferon-γ (p = 0.01) and interleukin-12 (p = 0.003), was higher in SHI patients. High tumor necrosis factor-α levels in NHI patients were associated with mortality (p = 0.01), increased mechanical ventilation (p = 0.02), and development of ventilator-associated pneumonia (p = 0.01). Alternatively, among SHI patients, high interleukin-2 levels were associated with survival, decreased mechanical ventilation, and absence of ventilator-associated pneumonia. CONCLUSIONS The presence of severe traumatic head injury significantly alters systemic cytokine expression and exerts an immunomodulatory effect. Early recognition of these profiles can allow for targeted intervention to reduce patient morbidity and mortality.