Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions.

BACKGROUND & AIMS: Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS: We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker's performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS: The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS: We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.

Should Patients With Cystic Lesions of the Pancreas Undergo Long-term Radiographic Surveillance?: Results of 3024 Patients Evaluated at a Single Institution.

OBJECTIVE: In 2015, the American Gastroenterological Association recommended the discontinuation of radiographic surveillance after 5 years for patients with stable pancreatic cysts. The current study evaluated the yield of continued surveillance of pancreatic cysts up to and after 5 years of follow up. METHODS: A prospectively maintained registry of patients evaluated for pancreatic cysts was queried (1995-2016). Patients who initially underwent radiographic surveillance were divided into those with <5 years and ≥5 years of follow up. Analyses for the presence of cyst growth (>5 mm increase in diameter), cross-over to resection, and development of carcinoma were performed. RESULTS: A total of 3024 patients were identified, with 2472 (82%) undergoing initial surveillance. The ≥5 year group (n = 596) experienced a greater frequency of cyst growth (44% vs. 20%; P < 0.0001), a lower rate of cross-over to resection (8% vs 11%; P = 0.02), and a similar frequency of progression to carcinoma (2% vs 3%; P = 0.07) compared with the <5 year group (n = 1876). Within the ≥5 year group, 412 patients (69%) had demonstrated radiographic stability at the 5-year time point. This subgroup, when compared with the <5 year group, experienced similar rates of cyst growth (19% vs. 20%; P= 0.95) and lower rates of cross-over to resection (5% vs 11%; P< 0.0001) and development of carcinoma (1% vs 3%; P= 0.008). The observed rate of developing cancer in the group that was stable at the 5-year time point was 31.3 per 100,000 per year, whereas the expected national age-adjusted incidence rate for this same group was 7.04 per 100,000 per year. CONCLUSION: Cyst size stability at the 5-year time point did not preclude future growth, cross-over to resection, or carcinoma development. Patients who were stable at 5 years had a nearly 3-fold higher risk of developing cancer compared with the general population and should continue long-term surveillance.

Recurrence and Survival After Resection of Small Intraductal Papillary Mucinous Neoplasm-associated Carcinomas (≤20-mm Invasive Component): A Multi-institutional Analysis.

BACKGROUND: Early invasive carcinoma may be encountered in association with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The natural history of these early invasive lesions is unknown. METHODS: Pancreatic surgical databases from 4 high-volume centers were queried for IPMNs, with invasive components measuring 20 mm or less. All cases were reviewed by GI gastrointestinal pathologists, and pathologic features were analyzed to identify predictors of recurrence and survival. RESULTS: A total of 70 small IPMN-associated invasive carcinomas (≤20-mm invasion) were identified, comprising 25% of resected IPMN-associated carcinomas (n = 280). Most of these small invasive cancers were multifocal (66%), less than 10 mm in size (73%), and arose in the setting of a main duct IPMN (96%). The most common adenocarcinoma subtypes were tubular (57%) and colloid (29%). Lymph node metastases were present in 19% of cases and 23% were T3 lesions. The overall recurrence rate was 24% (n = 17), and the median time to recurrence was 16 months (range: 4-132 months). Median and 5-year survival rates were 99 months and 59%. Recurrence patterns of invasive disease were local in 35%, distant in 47%, and both in 18%. Lymphatic spread and T3 stage were predictive of recurrence (univariate, P = 0.006), whereas tubular carcinoma type was the most predictive of poor overall survival (multivariate hazard ratio = 3.7, P = 0.04). CONCLUSIONS: This study represents the largest multi-institutional experience of resected small IPMN-associated carcinoma. Although these malignancies may frequently be cured with resection, recurrence risk is significant. Lymphatic spread, increased T stage, and tubular type carcinoma were associated with the poorest outcome.

Antiangiogenic therapy for primary liver cancer: correlation of changes in dynamic contrast-enhanced magnetic resonance imaging with tissue hypoxia markers and clinical response.

BACKGROUND: This study utilized the imaging data of primary liver cancer (PLC) treated with floxuridine (FUDR) and bevacizumab to test the hypothesis that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters correlate with tissue hypoxia markers and treatment outcome. METHODS: Seventeen patients with PLC were treated with hepatic artery infusional (HAI) FUDR for 14 days followed by systemic bevacizumab therapy. DCE-MRI images were obtained at baseline and after HAI FUDR and bevacizumab therapy. The parameters (K(trans), AUC) pertaining to perfusion and vascular permeability of the tumor and adjacent liver parenchyma were measured with DCE-MRI. Tissue obtained at baseline was stained for hypoxia markers (anti-hypoxia inducible factor-1α, anti-carbonic anhydrase IX, and vascular endothelial growth factor). Changes in DCE-MRI parameters were correlated with tissue hypoxia and time to progression (TTP). RESULTS: The median TTP was 8.8 months. Significant decreases in AUC90 (P = 0.004), AUC180 (P = 0.004), and K(trans) (P = 0.05) were noted in tumors after bevacizumab but not in nontumor areas. TTP correlated inversely with changes in AUC90 and AUC180 after bevacizumab (P = 0.002 and P = 0.0001). Reductions in tumor perfusion (AUC90 and AUC180) were greater in tumors expressing anti-hypoxia inducible factor-1α (P = 0.02 and 0.03), vascular endothelial growth factor (P = 0.01 and P = 0.01), and anti-carbonic anhydrase IX (P = 0.009 and P = 0.009). CONCLUSIONS: In patients with PLC, bevacizumab induces a reduction in tumor perfusion measured by DCE-MRI. These changes correlate with TTP and tissue markers of tumor hypoxia.

Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results?

OBJECTIVES: This study investigated the efficacy and safety of adding systemic (IV) bevacizumab (Bev) to hepatic arterial infusion (HAI) with floxuridine (FUDR)/dexamethasone (Dex) in unresectable primary liver cancer. METHODS: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) were treated with HAI FUDR/Dex plus IV Bev. Results were compared to a recent study of HAI without Bev in a similar patient population. RESULTS: Twenty-two patients (18 ICC, 4 HCC) were treated with HAI FUDR/Dex plus Bev; 7 (31.8%) had partial response and 15 (68.2%) had stable disease. Median survival was 31.1 months (CI 14.14-33.59), progression-free survival (PFS) 8.45 months (CI 5.53-11.05), and hepatic PFS 11.3 months (CI 7.93-15.69). In the previous trial with HAI alone (no Bev), the response was 50%; median survival, PFS, and hepatic PFS were 29.5, 7.3, and 10.1 months. In the present trial, bilirubin elevation (>2 mg/dl) was seen in 24% of patients and biliary stents were placed in 13.6%, versus 5.8 and 0%, respectively, in the HAI trial without Bev. Due to increased biliary toxicity, the trial was prematurely terminated. CONCLUSION: Adding Bev to HAI FUDR/Dex appeared to increase biliary toxicity without clear improvement in outcome (median PFS 8.45 vs. 7.3 months, and median survival 31.1 vs. 29.5 months, for HAI + Bev vs. HAI alone groups, respectively).

Response to neoadjuvant chemotherapy does not predict overall survival for patients with synchronous colorectal hepatic metastases.

OBJECTIVE: We investigated the relation between response to neoadjuvant chemotherapy and overall survival (OS) in patients with colorectal liver metastases (CLM). BACKGROUND: It has previously been reported that patients with synchronous CLM whose disease progresses while receiving neoadjuvant chemotherapy or who do not receive neoadjuvant chemotherapy experience worse survival than patients whose disease responds to neoadjuvant chemotherapy. METHODS: By means of a prospectively maintained surgical database, between 1995 and 2003, we identified 111 patients with a synchronous CLM who received neoadjuvant chemotherapy before hepatic resection. The disease of all 111 patients was deemed resectable, and patients underwent hepatic resection with curative intent. RESULTS: The median OS after liver resection was 62 months, with a median follow-up of 63 months. Median OS was similar between the three study groups classified by response to neoadjuvant chemotherapy (complete or partial response, 58 months; stable disease, 65 months; and disease progression, 61 months; P = .98). By univariate analysis, carcinoembryonic antigen level after liver resection of <5 ng/dL, size of metastatic lesion of 5 cm in size than patients in the complete or partial response group and the stable disease group. Patients whose tumor progressed but who received postoperative hepatic arterial infusion had a trend toward improved survival compared with those who did not receive hepatic arterial infusion (70% vs. 50% at 3 years, permutation log rank test P = .12). CONCLUSIONS: Response to neoadjuvant chemotherapy did not correlate with OS even after controlling for margins, stage of primary tumor, and postoperative carcinoembryonic antigen level. Postoperative salvage treatment may have helped the survival of some patients.

A phase I study of gemcitabine given via intrahepatic pump for primary or metastatic hepatic malignancies.

PURPOSE: To determine the maximum tolerated dose and duration of hepatic arterial infusion (HAI) gemcitabine in patients with unresectable hepatic metastases from colorectal cancer or primary hepatic malignancies. METHODS: Patients received weekly gemcitabine via the side-port of an implantable HAI pump for 3 weeks in a 28-day cycle. During the dose escalation phase, increasing doses of HAI gemcitabine (800, 1,000, 1,200, and 1,500 mg/m(2)) were given at a fixed dose-rate of 10 mg/(m(2) min). This was followed by the infusion duration escalation (IDE) phase, in which HAI gemcitabine at 1,000 mg/m(2) was given over increasing lengths of time (200, 300, and 400 min). To estimate hepatic drug extraction, the pharmacokinetics of HAI gemcitabine was compared with those of intravenous gemcitabine given at the same dose-rate to the same patient in the IDE phase. RESULTS: Twenty-eight of 30 patients were evaluable. HAI gemcitabine was well tolerated up to 1,500 mg/m(2) given at 10 mg/(m(2) min) and up to 1,000 mg/m(2) infused over 400 min. There were no protocol-defined dose-limiting toxicities. One patient with cholangiocarcinoma had a partial response. Hepatic extraction of gemcitabine seems highly variable among patients and does not correlate with the length of HAI infusion. CONCLUSIONS: Hepatic arterial infusion of gemcitabine given at doses higher or longer than the recommended systemic dose of 1,000 mg/m(2) over 30 min is well tolerated. For future studies, we recommend an infusion of 1,500 mg/m(2) at a fixed dose-rate of 10 mg/(m(2) min).