Jason B. Klapman

Clinical Impact of On-Site Cytopathology Interpretation on Endoscopic Ultrasound-Guided Fine Needle Aspiration

OBJECTIVES:Endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) is becoming a preferred modality for diagnosing and staging GI and mediastinal malignancies. Although experts advocate on-site cytopathology assessment for tissue sample adequacy, there are few data to support this claim. Our goal was to determine whether on-site cytopathology interpretation improves the diagnostic yield of EUS-guided FNA.METHODS:EUS-guided FNA results from two university hospital centers were reviewed and compared. At center 1, where EUS-guided FNA was performed with a cytopathologist on site, the results of 108 consecutive patients were evaluated. At center 2, where a cytopathologist is unavailable, the results of 87 consecutive patients were reviewed. One endoscopist performed all procedures at both institutions. Cytologic diagnoses were categorized as positive or negative for malignancy, suspicious for malignancy, atypical/indeterminate, or unsatisfactory. The number of repeat procedures, needle passes, medication use, target site, age, and sex were compared between the two sites.RESULTS:Patients at center 2 were older (p = 0.04) and predominantly female (p = 0.03). Pancreas was the most common target site at center 2, whereas thoraco-abdominal nodes were the most common at center 1 (p = 0.0001). Patients at center 1 had a diagnosis of positive or negative for malignancy more frequently (p = 0.001) and were less likely to have an unsatisfactory specimen (p = 0.035) or repeat procedure, although the latter was not significant (p = 0.156)CONCLUSION:On-site cytopathology interpretation improves the diagnostic yield of EUS-guided FNA. EUS centers should allocate resources to cover for on-site cytopathology evaluation.

Negative predictive value of endoscopic ultrasound in a large series of patients with a clinical suspicion of pancreatic cancer.

OBJECTIVES:Endoscopic ultrasound (EUS) has been shown to be very accurate in the diagnosis and staging of pancreatic cancer. The accuracy of EUS in predicting the absence of pancreatic cancer in a large series of patients with a clinical suspicion of pancreatic cancer is not well documented. Our aim was to determine the negative predictive value (NPV) of EUS in patients with a suspicion of pancreatic cancer.METHODS:We retrospectively reviewed, from our EUS database (between January 1999 and March 2003), 693 patients who were suspected of having pancreatic cancer and had EUS examinations. A total of 155 patients were found by EUS to have a completely normal pancreas. Indications for EUS in these patients included: weight loss/abdominal pain; and/or pancreatic enlargement/fullness on computed tomography (CT); and/or bile duct/pancreatic duct narrowing on endoscopic retrograde cholangiopancreatography; and/or an elevated CA 19-9. Follow-up information was obtained in 135/155 (87%) patients from patient phone calls and/or physician visits and/or CT scan. The mean follow-up period was 25 months (range 8–48 months).RESULTS:No patients developed pancreatic cancer during the follow-up period. Following the EUS examination, no work-up was required in 119/135 (88%) of patients. CT scan was performed in 16 patients at 6 months postprocedure, none of which showed a pancreatic mass. The NPV of EUS in excluding pancreatic cancer in those patients with follow-up was 100%.CONCLUSION:EUS is highly specific in the diagnosis of pancreatic cancer with a NPV of 100% and obviates the need for further diagnostic testing. In patients with a clinical suspicion of pancreatic cancer, EUS should be considered as the initial diagnostic modality.

Early detection of pancreatic cancer: why, who, and how to screen.

BACKGROUND Pancreatic cancer represents the fourth-leading cause of cancer death in the United States, with a dismal 5-year survival rate of less than 5%. Despite advancements in screening and early detection of other cancers such as breast and colon cancer, no reliable screening test exists for pancreatic cancer. Subsequently, the majority of patients present with advanced-stage disease leading to a poor prognosis. Because of the relatively low incidence, current efforts are focused on early detection and screening only in patients at high risk for the development of the disease. METHODS We discuss the practical considerations encountered when determining if an individual should be screened for pancreatic cancer. The current literature was reviewed regarding risk factors, genetic syndromes, screening modalities, and screening studies of pancreatic cancer. The current high-risk pancreatic screening program at our institute is also summarized. RESULTS Current efforts to detect pancreatic cancer at a curative phase are focused on screening individuals at high risk for the development of this disease. They include kindreds with two or more first-degree relatives affected with this disease and those with known hereditary pancreatic cancer syndromes. Hereditary pancreatic cancer syndromes include Peutz-Jeghers syndrome, familial breast cancer syndrome, and familial atypical multiple mole melanoma syndrome. Of all the screening modalities available, endoscopic ultrasound is the most sensitive and specific screening tool to evaluate the pancreas and has been proven to detect early precancerous and cancerous changes in clinical studies. CONCLUSIONS Early detection and screening for pancreatic cancer in the current state should be limited to high-risk patients, although hereditary/familial factors account for only 10% of patients with pancreatic cancer. Continued efforts are needed to discover effective test to identify patients with nonhereditary risk factors who will benefit from screening and also to develop less invasive and more cost-effective screening modalities aimed at controlling pancreatic cancer.

Randomized Phase III Multi-Institutional Study of TNFerade Biologic With Fluorouracil and Radiotherapy for Locally Advanced Pancreatic Cancer: Final Results

PURPOSE TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy. PATIENTS AND METHODS In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity. RESULTS The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05). CONCLUSION SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.

Colorectal Cancer Screening

During the past decade we have seen dramatic advances in colon cancer screening. Reduction in mortality in average risk screening for colorectal cancer has now been shown in multiple trials. Efforts to increase public awareness and compliance with evidence-based screening guidelines are underway. Recent guidelines have incorporated family history, as it has been identified as a common risk factor. The genes responsible for the inherited syndromes of colon cancer have been identified and genetic testing is available. Currently, screening the average risk population over the age of 50 would reduce mortality from colon cancer by 50%. Future advances will likely include improved screening tests, and the development of familial genetic testing.

Neoadjuvant GTX Chemotherapy and IMRT-Based Chemoradiation for Borderline Resectable Pancreatic Cancer

To improve the likelihood of achieving a margin‐free resection, neoadjuvant induction chemotherapy with GTX (gemcitabine, docetaxel, and capecitabine) followed by 5‐FU‐IMRT was administered to patients with borderline resectable pancreatic cancer. The utility of computed tomography (CT), endoscopic ultrasound (EUS), positron emission tomography (PET), and CA 19‐9 during diagnostic workup and assessment of response was also examined.

A lupus-like syndrome associated with infliximab therapy

Infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNF-alpha), is efficacious in the treatment of rheumatoid arthritis and Crohns disease. We report in detail an unusual adverse reaction to infliximab therapy, a drug-induced lupus-like clinical syndrome. A 45-year-old woman with steroid-dependent Crohns colitis, successfully managed with maintenance infliximab infusions and methotrexate, developed a lupus-like syndrome eight months after her initial infusion. This was characterized by inflammatory arthritis and an urticarial and papulosquamous rash and was accompanied by high titers of antinuclear, double-stranded DNA, glomerular-binding, and histone antibodies and by reduced levels of the C4 component of complement. After discontinuance of infliximab infusions and treatment of symptoms with intermittent courses of prednisone, the patients arthritis progressively improved, with accompanying decrements in autoantibody titers. One year later, she has minimal joint discomfort and no rash or gastrointestinal symptoms despite also discontinuing prednisone and methotrexate. Infliximab therapy may cause a lupus-like syndrome that is reversible upon discontinuing this agent. These findings support recent evidence identifying TNF-alpha as an inhibitor of autoantibody formation.

Management of persistent gastroesophageal anastomotic strictures with removable self-expandable polyester silicon-covered (Polyflex) stents: an alternative to serial dilation.

BACKGROUND A benign gastroesophageal anastomotic stricture occurs in up to 42% of patients after transhiatal esophagectomy for esophageal cancer. Management of anastomotic strictures may require extended periods of serial endoscopic dilation, with significant risk, cost, and inconvenience for the patient. OBJECTIVE To determine if placement of removable self-expandable polyester silicon-covered (Polyflex) stents (SEPSs) prolonged the interval between endoscopic interventions in the management of persistent anastomotic stricture. DESIGN Retrospective cohort study. SETTING National Cancer Institute designated comprehensive cancer center. PATIENTS Eight patients after a transhiatal esophagectomy referred for management of benign persistent anastomotic strictures. INTERVENTIONS Serial balloon and bougie dilations and SEPS placement. MAIN OUTCOME MEASUREMENT The interval between endoscopic interventions and the number of endoscopic interventions before and after SEPS placement. RESULTS Over a 365-day period, 13 SEPS were placed in 8 patients with benign persistent anastomotic strictures after a transhiatal esophagectomy. A SEPS placement delayed the interval between endoscopic interventions from a mean of 7 days before stent insertion to 62 days after insertion (P < .008). The median number of preinsertion interventions was 4 and was reduced to 1 after insertion (P < .005). LIMITATION The small number of patients. CONCLUSIONS A SEPS placement did not result in stricture resolution or stabilization after SEPS removal. The SEPS migration rate was much higher in our patients with postesophagectomy anastomotic strictures than previously reported for other types of strictures. However, a SEPS placement did significantly delay the interval between endoscopic interventions in patients with persistent gastroesophageal anastomotic strictures after transhiatal esophagectomy. SEPS placement should be considered as an alternative to continued serial dilation in patients with persistent anastomotic strictures after transhiatal esophagectomy.

Stability of endoscopic ultrasound-guided fiducial marker placement for esophageal cancer target delineation and image-guided radiation therapy

PURPOSE Fiducial markers have been integrated into the management of multiple malignancies to guide more precise delivery of radiation therapy (RT). Fiducials placed at the margins of esophageal tumors are potentially useful to facilitate both RT target delineation and image-guided RT (IGRT). In this study, we report on the stability of endoscopic ultrasound (EUS)-guided fiducial placement for esophageal cancers and utilization for radiation treatment planning and IGRT. METHODS An institutional review board-approved database was queried for patients treated for esophageal cancer with chemoradiotherapy (CRT). Patients included in the analysis had a diagnosis of esophageal cancer, were referred for treatment with CRT, and had fiducials placed under EUS guidance. Images acquired at time of radiation treatment planning, daily IGRT imaging, post-treatment restaging, and surveillance scans were analyzed to determine the stability of implanted markers. RESULTS We identified 60 patients who underwent EUS-guided fiducial marker placement near the margins of their esophageal tumors in preparation for RT treatment planning. A total of 105 fiducial markers were placed. At time of CT simulation, 99 markers were visualized. Fifty-seven patients had post-treatment imaging available for review. Of the 100 implanted fiducials in these 57 patients, 94 (94%) were visible at time of RT simulation. Eighty-eight (88%) fiducials were still present post-treatment imaging at a median of 107 days (range, 33-471 days) after implantation. CONCLUSIONS EUS-guided fiducial marker placement for esophageal cancer aids in target delineation for radiation planning and daily IGRT. Fiducial stability is reproducible and facilitates conformal treatment with image-guided RT techniques.

A randomized controlled cross-over trial and cost analysis comparing endoscopic ultrasound fine needle aspiration and fine needle biopsy *

Background and study aims: Techniques to optimize endoscopic ultrasound-guided tissue acquisition (EUS-TA) in a variety of lesion types have not yet been established. The primary aim of this study was to compare the diagnostic yield (DY) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) to endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for pancreatic and non-pancreatic masses. Patients and methods: Consecutive patients referred for EUS-TA underwent randomization to EUS-FNA or EUS-FNB at four tertiary-care medical centers. A maximum of three passes were allowed for the initial method of EUS-TA and patients were crossed over to the other arm based on on-site specimen adequacy. Results: A total of 140 patients were enrolled. The overall DY was significantly higher with specimens obtained by EUS-FNB compared to EUS-FNA (90.0 % vs. 67.1 %, P = 0.002). While there was no difference in the DY between the two groups for pancreatic masses (FNB: 91.7 % vs. FNA: 78.4 %, P = 0.19), the DY of EUS-FNB was higher than the EUS-FNA for non-pancreatic lesions (88.2 % vs. 54.5 %, P = 0.006). Specimen adequacy was higher for EUS-FNB compared to EUS-FNA for all lesions (P = 0.006). There was a significant rescue effect of crossover from failed FNA to FNB in 27 out of 28 cases (96.5 %, P = 0.0003). Decision analysis showed that the strategy of EUS-FNB was cost saving compared to EUS-FNA over a wide range of cost and outcome probabilities. Conclusions: Results of this RCT and decision analysis demonstrate superior DY and specimen adequacy for solid mass lesions sampled by EUS-FNB.