Jeffrey H. Lee

Preoperative Gemcitabine and Cisplatin Followed by Gemcitabine-Based Chemoradiation for Resectable Adenocarcinoma of the Pancreatic Head

PURPOSE We conducted a phase II trial of preoperative gemcitabine and cisplatin chemotherapy in addition to chemoradiation (Gem-Cis-XRT) and pancreaticoduodenectomy (PD) for patients with stage I/II pancreatic adenocarcinoma. PATIENTS AND METHODS Chemotherapy consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given every 2 weeks for four doses. Chemoradiation consisted of four weekly infusions of gemcitabine (400 mg/m(2)) combined with radiation therapy (30 Gy in 10 fractions administered over 2 weeks) delivered 5 days per week. Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery. RESULTS The study enrolled 90 patients; 79 patients (88%) completed chemo-chemoradiation. Sixty-two (78%) of 79 patients were taken to surgery and 52 (66%) of 79 underwent PD. The median overall survival of all 90 patients was 17.4 months. Median survival for the 79 patients who completed chemo-chemoradiation was 18.7 months, with a median survival of 31 months for the 52 patients who underwent PD and 10.5 months for the 27 patients who did not undergo surgical resection of their primary tumor (P < .001). CONCLUSION Preoperative Gem-Cis-XRT did not improve survival beyond that achieved with preoperative gemcitabine-based chemoradiation (Gem-XRT) alone. The longer preoperative interval required more durable biliary decompression (metal stents) but was not associated with local tumor progression. The gemcitabine-based chemoradiation platform is a reasonable foundation on which to build future phase II multimodality trials for stage I/II pancreatic cancer incorporating emerging systemic therapies.

Clinical outcome of the use of enteral stents for palliation of patients with malignant upper GI obstruction

BACKGROUND The endoscopically placed enteral stent has emerged as a reasonable alternative to palliative surgery for malignant intestinal obstruction. This is a report of our experience with the use of enteral stents for nonesophageal malignant upper GI obstruction. METHODS Data on all patients who had undergone enteral stent placement were reviewed. Those with a diagnosis of pancreatic cancer were compared with another similar cohort of patients who underwent palliative gastrojejunostomy. RESULTS Thirty-one procedures were performed on 29 patients (mean age 67.7 years). Thirteen (45%) were men and 16 (55%) women. The diagnoses were gastric (13.8%), duodenal (10.3%), pancreatic (41.4%), metastatic (27.6%), and other malignancies (6.9%). Malignant obstruction occurred at the pylorus (20.7%), first part of duodenum (37.9%), second part of duodenum (27.6%), third part of duodenum (3.5%), and anastomotic sites (10.3%). Twenty-nine (93.5%) procedures were successful and good clinical outcome was achieved in 25 (80.6%). Re-obstruction by tumor ingrowth occurred in 2 patients after a mean of 183 days. The median survival time for patients with pancreatic cancer who underwent enteral stent placement compared with those who underwent surgical gastrojejunostomy was 94 and 92 days, charges were

Gene Expression Profiling of Localized Esophageal Carcinomas: Association With Pathologic Response to Preoperative Chemoradiation

9921 and

Association of Activated Transcription Factor Nuclear Factor κB With Chemoradiation Resistance and Poor Outcome in Esophageal Carcinoma

28,173, and duration of hospitalization was 4 and 14 days, respectively (latter 2 differences with p value < 0.005). CONCLUSION Endoscopic enteral stent placement of nonesophageal malignant upper GI obstruction is a safe, efficacious, and cost-effective procedure with good clinical outcome, lower charges, and shorter hospitalization period than the surgical alternative.

Intraductal papillary mucinous neoplasms of the pancreas : Effect of invasion and pancreatic margin status on recurrence and survival

PURPOSE Patients with localized esophageal carcinoma have a 5-year survival rate of less than 20%. Patients are often treated similarly (ie, with preoperative chemoradiotherapy) but the outcomes vary greatly. Chemoradiotherapy and surgery can result in significant undesirable consequences. Currently, however, there are no tools to help select optimum therapy. We hypothesized that gene expression profiling could provide clues and biomarkers for selection of therapy. METHODS Pretreatment endoscopic cancer biopsies from 19 patients (16 with adenocarcinoma, two with squamous cell carcinoma, and one with adenosquamous carcinoma) enrolled onto a preoperative chemoradiotherapy protocol were profiled using oligonucleotide microarrays. Surgical specimens following therapy were assessed for the degree of pathologic response. On the basis of array data, selected genes were analyzed by polymerase chain reaction. RESULTS Unsupervised hierarchical cluster analysis segregated the cancers into two molecular subtypes, each consisting 10 and nine specimens, respectively. Most cancers (five of six) that had pathologic complete response (pathCR) clustered in molecular subtype I. Subtype II, with one exception, consisted cancers that had less than pathCR (< pathCR). Using a combination marker approach, levels of PERP, S100A2, and SPRR3 allowed discrimination of pathCR from < pathCR with high sensitivity and specificity (85%). Pathway analysis identified apoptotic pathway as one of the key functions downregulated in molecular type II in comparison with type I. CONCLUSION These encouraging, albeit preliminary, data suggest that expression profiling may distinguish cancers with different pathologic outcome. This is the first report to show subtypes of esophageal cancers with distinct molecular signatures. The potential of PERP, S100A2, and SPRR3 as biomarkers of pathCR warrants further validation.

Endoscopic ultrasound and fine-needle aspiration of unexplained bile duct strictures.

PURPOSE The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor kappaB (NF-kappaB), a transcriptional factor, is constitutively activated or treatment induced in esophageal cancer and may influence treatment outcomes. PATIENTS AND METHODS Pre- and post-treatment cancer specimens from patients enrolled onto a clinical trial were studied for the expression of activated NF-kappaB protein and it was correlated with histologic features, pathologic response, metastatic potential, overall survival (OS), and disease-free survival (DFS). RESULTS Forty-three patients undergoing the same therapy on a protocol were studied. Twenty-one (72%) of 29 patients achieving less than complete pathologic response (pathCR) had NF-kappaB positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-kappaB positive cancer (P = < .001). Activated NF-kappaB was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-kappaB positive patients developed metastases compared to none of 22 NF-kappaB negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-kappaB positive patients had died compared to only one (5%) of 22 NF-kappaB negative patients (P = .0013). Observations were similar for DFS (P = .0006). In a multivariate model (using baseline stage, pathCR or less than pathCR, age, presence of metastatic lymph nodes in the surgical specimen, and NF-kappaB expression) NF-kappaB activation was the only independent predictor of DFS (P = .010) and OS (P = .015). CONCLUSION Our data suggest that esophageal cancers with activated NF-kappaB have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-kappaB regulated pathways may uncover potential therapeutic targets.

Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts

BackgroundThe natural history and prognosis for patients with intraductal papillary mucinous neoplasms (IPMN) with and without invasion remain poorly defined. This study evaluated the outcome after pancreatectomy for IPMN according to the pancreatic transection margin status and the presence or absence of invasive carcinoma.MethodsData from a prospective pancreatic tumor database and medical records were reviewed for all patients who underwent pancreatic resection for IPMN at our institution between July 1990 and July 2003. Surgical specimens were re-reviewed by a single pathologist.ResultsIPMN was diagnosed in 35 (26%) of 137 patients who underwent pancreatic resection for cystic neoplasms. Invasive IPMN was confirmed in 13 (37%) of 35 patients. Noninvasive IPMN was found in 22 (63%) of 35 patients; pathology re-review changed the original diagnosis from invasive to noninvasive IPMN in 6 patients. Noninvasive IPMN was found at the final pancreatic margin in eight patients; none developed recurrent disease at a median follow-up of 34 months. Recurrent disease was identified in 7 (58%) of 13 patients with invasive IPMN and in none with noninvasive IPMN. The median overall survival was 22.9 and 84.9 months in patients with invasive and noninvasive IPMN, respectively (P = .0009).ConclusionsDistinction between invasive and noninvasive IPMN is essential in estimating prognosis and determining the need for adjuvant therapy and the frequency of follow-up surveillance. Noninvasive IPMN, even if present at the pancreatic margin, was not associated with recurrent disease. In contrast, invasive IPMN was associated with early recurrence and short survival.

Use of expandable metallic biliary stents in resectable pancreatic cancer

OBJECTIVES:The aim of this study was to assess the utility of endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) in patients with unexplained common bile duct strictures after endoscopic retrograde cholangiopancreatography (ERCP) and intraductal tissue sampling.METHODS:Records were reviewed for all subjects undergoing EUS for evaluation of unexplained bile duct strictures at our institution. 40 subjects had either a final histologic diagnosis (24) or no evidence of malignancy after at least 1 yr of follow-up (16).RESULTS:The finding of a pancreatic head mass and/or an irregular bile duct wall had sensitivity for malignancy of 88%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 84%. Bile duct wall thickness ≥3 mm had a sensitivity for malignancy of 79%, specificity of 79%, positive predictive value of 73%, and negative predictive value of 80%. Sensitivity of EUS FNA for malignancy was 47% with specificity 100%, positive predictive value 100%, and negative predictive value 50%.CONCLUSIONS:Sonographic features may be more sensitive than EUS FNA for diagnosis of unexplained bile duct strictures and include presence of a pancreatic mass, an irregular bile duct wall, or bile duct wall thickness > 3 mm. EUS FNA cytology is specific but insensitive for diagnosis. EUS improves the diagnosis of otherwise unexplained bile duct strictures.

Pancreaticoduodenectomy After Placement of Endobiliary Metal Stents

Objective Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. Design Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ∼66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. Results GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. Conclusion Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.

Imaging of Pancreatic Adenocarcinoma: Update on Staging/Resectability

AIM:To compare the efficacy of metal versus plastic stents for biliary strictures in patients with surgically resectable pancreatic cancer.METHODS:The medical records at MD Anderson Caner Center from September 2001 to May 2004 were reviewed. Fifty-five patients were identified to have either a metal biliary stent (13 patients, group A) or a plastic biliary stent (42 patients, group B) and subsequently went to surgery. These two groups were compared with regards to number of stents placed prior to surgery, time period between the last stent and surgery, and operative and postoperative complications.RESULTS:Of the 13 patients in group A, 12 had pancreaticoduodenectomy performed and one had exploration only due to the peritoneal metastatses discovered at the time of surgery. Of the 12 patients with pancreaticoduodenectomy, 10 had pancreatic adenocarcinoma, 1 intraductal papillary mucinous tumor, and 1 ampullary cancer. Only 2 patients required an additional endoscopic retrograde cholangiopancreatography (ERCP) after initial metal stent placement until surgery. The average time between last stent placement and surgery was 106.5 days. Of the 42 patients in group B, 35 had pancreaticoduodenectomy and 7 had either palliative surgery or exploration due to metastatic diseases discovered at the time of surgery. Of the 35 patients, 27 had pancreatic adenocarcinoma, 5 ampullary cancer, 1 neuroendocrine tumor, 1 microcystic adenoma, and 1 autoimmune pancreatitis. Sixteen patients (38%) in group B required 3 or more ERCPs with plastic stents prior to surgery. The average time between last stent placement and surgery was 56.4 days. Preoperative chemoradiation was given to all 13 patients in group A and 31 of 42 patients in group B. There were no stent-related intra- or postoperative complications in both groups. Two of 13 patients (15%) with metal stents versus 39 of 42 patients (93%) with plastic stents, however, developed either cholangitis or cholestasis due to stent occlusion while waiting for surgery.CONCLUSIONS:Contrary to the belief that metal stents are contraindicated for patients with surgically resectable pancreatic cancer, our study demonstrated that metal stents provided a longer patency rate, fewer ERCP sessions, and fewer episodes of cholangitis without adding any intra- or postoperative complications. Therefore, metal stents should be considered for patients with resectable pancreatic cancer, especially if surgery is not immediately planned as more patients are now receiving preoperative chemoradiation.