Faculty Bibliography

PURPOSE/OBJECTIVE:Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer. EXPERIMENTAL DESIGN/METHODS:We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum. RESULTS:We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%). CONCLUSIONS:Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.

PURPOSE/OBJECTIVE:To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences. METHODS AND MATERIALS/METHODS:Consecutive patients with resectable PDA undergoing PD and 1 or more computed tomography (CT) scans more than 60 days after PD at our institution were reviewed. Patients were divided into 3 groups: no adjuvant treatment (NA), chemotherapy alone (CTA), or chemoradiation (CRT). Cross-sectional scans were centrally reviewed, and local recurrences were plotted to scale with respect to the celiac axis (CA), superior mesenteric artery (SMA), and renal veins on 1 CT scan of a template post-PD patient. An adjuvant clinical treatment volume comprising 90% of local failures based on standard expansions of the CA and SMA was created and simulated on 3 post-PD CT scans to assess the feasibility of this planning approach. RESULTS:Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume. CONCLUSIONS:Modified PTVs targeting high-risk areas may improve local control while minimizing toxicities, allowing dose escalation with intensity-modulated or stereotactic body radiation therapy.

OBJECTIVE:We sought to quantify the use of and analyze factors predictive of receipt of surgical therapy for early hepatocellular carcinoma (HCC). BACKGROUND:The incidence of HCC is increasing, and the options for surgical therapy for early HCC have expanded, but the use of surgical therapy for early HCC has not been examined in a modern cohort. METHODS:A retrospective cohort study was performed using data from the 1998-2007 Surveillance, Epidemiology, and End Results-Medicare linked database. Data were analyzed for patients 66 years of age and older with early HCC (tumors ≤5 cm without metastatic disease, nodal metastasis, extrahepatic extension, or major vascular invasion). Both Surveillance, Epidemiology, and End Results and Medicare data were used to ascertain receipt of therapy as well as comorbidity burden and other patient and hospital variables. Multivariable logistic regression models were used to analyze factors associated with receipt of therapy. RESULTS:Our selection criteria identified 1745 patients for this study. Most patients had tumors between 2 and 5 cm in size (n = 1440, 83%). Solitary tumors (n = 1121, 64%) were more common than multiple tumors (n = 624, 36%). A total of 820 patients (47%) with early HCC received no surgical therapy. Among 741 patients with solitary, unilobar tumors and microscopic confirmation of HCC, 246 (33%) received no surgical therapy. Of 535 patients with no liver-related comorbidities, 273 (51%) did not receive surgical therapy. In multivariable analysis, patient age, income, tumor factors, liver-related comorbidities, and hospital factors were associated with receipt of surgical therapy. CONCLUSIONS:Although some patients with early HCC may not be candidates for surgical therapy, these data suggest that there is a significant missed opportunity to improve survival of patients with early HCC through the use of surgical therapy.

BACKGROUND:Assessment of patient performance status is often subjective. Sarcopenia--measurement of muscle wasting--may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT). METHODS:Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors. RESULTS:Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm(2)/m(2)) was greater than women (413 mm(2)/m(2)). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR = 1.84) and Child's score (HR = 2.15) (all P < 0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR = 1.84; P = 0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients. CONCLUSIONS:Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.

INTRODUCTION/BACKGROUND:Pancreatoblastoma is an extremely rare pancreatic neoplasm in adults. The aim of this study is to report our experience with adult pancreatoblastoma as well as review the cases reported in the literature in order to provide guidelines for the management of patients with this rare neoplasm. METHODS:We have encountered three cases of pancreatoblastoma in adults at our institution in addition to the 30 cases reported to date in literature. RESULTS:The median age of pancreatoblastoma in adults is 37 years (range, 18-78 years); men and women are similarly affected (male/female = 16/17). The behavior of pancreatoblastoma is clearly that of a malignant neoplasm, with local invasion, recurrence, and metastasis. Among the adult reported cases, at diagnosis or operation, metastasis and/or local invasion was found in 14 of 31 adult patients (46 %) (2 patients had no data) The survival was significantly higher in patients with resected tumor (resection only and resection + adjuvant chemo/radiotherapy) when compared to unresected patients (palliative chemo/radiotherapy and no treatment), (p = 0.008, HR = 0.20). CONCLUSION/CONCLUSIONS:When disease is localized, the treatment of choice is a complete surgical resection. The role of adjuvant chemotherapy or radiotherapy is still unclear based on the very small number of patients treated.