Mark A. Schattner

A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

BACKGROUND & AIMS The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Cystic Lesions of the Pancreas: Changes in the Presentation and Management of 1,424 Patients at a Single Institution over a 15-year Time Period

BACKGROUND Cystic lesions of the pancreas are being identified more frequently, and a selective approach to resection is now recommended. The aim of this study was to assess the change in presentation and management of pancreatic cystic lesions evaluated at a single institution over 15 years. STUDY DESIGN A prospectively maintained registry of patients evaluated between 1995 and 2010 for the ICD-9 diagnosis of pancreatic cyst was reviewed. The 539 patients managed from 1995 to 2005 were compared with the 885 patients managed from 2005 to 2010. RESULTS A total of 1,424 patients were evaluated, including 1,141 with follow-up >6 months. Initial management (within 6 months of first assessment) was operative in 422 patients (37%) and nonoperative in 719 patients (63%). Operative mortality in patients initially submitted to resection was 0.7% (n = 3). Median radiographic follow-up in patients initially managed nonoperatively was 28 months (range 6 to 175 months). Patients followed radiographically were more likely to have cysts that were asymptomatic (72% versus 49%, p < 0.001), smaller (1.5 versus 3 cm, p < 0.001), without solid component (94% versus 68%, p < 0.001), and without main pancreatic duct dilation (88% versus 61%, p < 0.001). Changes prompting subsequent operative treatment occurred in 47 patients (6.5%), with adenocarcinoma identified in 8 (17%) and pancreatic endocrine neoplasm in 4 (8.5%). Thus, of the 719 patients initially managed nonoperatively, invasive malignancy was identified in 12 (1.7%), with adenocarcinoma seen in 1.1%. CONCLUSION Cystic lesions of the pancreas are being identified more frequently, yet are less likely to present with concerning features of malignancy. Carefully selected patients managed nonoperatively had a risk of malignancy that was equivalent to the risk of operative mortality in those patients who initially underwent resection.

Feasibility and yield of screening in relatives from familial pancreatic cancer families

OBJECTIVES:Pancreatic adenocarcinoma is a lethal disease. Over 80% of patients are found to have metastatic disease at the time of diagnosis. Strategies to improve disease-specific outcome include identification and early detection of precursor lesions or early cancers in high-risk groups. In this study, we investigate whether screening at-risk relatives of familial pancreatic cancer (FPC) patients is safe and has significant yield.METHODS:We enrolled 309 asymptomatic at-risk relatives into our Familial Pancreatic Tumor Registry (FPTR) and offered them screening with magnetic resonance cholangiopancreaticogram (MRCP) followed by endoscopic ultrasound (EUS) with fine needle aspiration if indicated. Relatives with findings were referred for surgical evaluation.RESULTS:As of 1 August 2009, 109 relatives had completed at least one cycle of screening. Abnormal radiographic findings were present on initial screening in 18/109 patients (16.5%), 15 of whom underwent EUS. A significant abnormality was confirmed in 9 of 15 patients, 6 of whom ultimately had surgery for an overall diagnostic yield of 8.3% (9/109). Yield was greatest in relatives >65 years old (35%, 6/17) when compared with relatives 55–65 years (3%, 1/31) and relatives <55 years (3%, 2/61).CONCLUSIONS:Screening at-risk relatives from FPC families has a significant diagnostic yield, particularly in relatives >65 years of age, confirming prior studies. MRCP as initial screening modality is safe and effective.

EUS-guided fiducial placement for image-guided radiation therapy in GI malignancies by using a 22-gauge needle (with videos )

BACKGROUND Image-guided radiation therapy (IGRT) is dependent on the presence of fiducial markers for target localization and tracking. EUS-guided placement of fiducial markers with a 19-gauge needle has been reported. However, the size and stiffness of the 19-gauge needle may compromise the safety and ease of fiducial placement. OBJECTIVE The aim of this study was to evaluate the safety and feasibility of EUS-guided placement of thin flexible gold coil fiducials by using a 22-gauge needle. DESIGN Retrospective study. SETTING Memorial Sloan-Kettering Cancer Center, between December 2008 and November 2009. PATIENTS A total of 30 patients with GI malignancies of the mediastinum and upper abdomen who were to undergo IGRT. INTERVENTIONS EUS evaluation with a curvilinear-array echoendoscope was performed. The target lesion was identified, a 22-gauge needle preloaded with a gold coil fiducial was inserted into the lesion, and the fiducial was deployed under EUS guidance. MAIN OUTCOME MEASUREMENTS Technical success was defined as the ability to place fiducials in the desired location. Immediate and delayed complications were also noted. RESULTS A total of 69 fiducials were placed in 12 different sites in the mediastinum and upper abdomen. Technical success was achieved in 29 out of 30 cases (97%). No intraprocedural complications were encountered. One patient developed a fever and abnormal liver function tests 12 hours after fiducial placement. LIMITATIONS Retrospective design, small case series. CONCLUSIONS EUS-guided placement of thin flexible gold coil fiducials by using a 22-gauge needle is both safe and feasible for upper GI malignancies.

Cyst Fluid Interleukin-1β (IL1β) Levels Predict the Risk of Carcinoma in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Purpose: Biomarkers for high-grade dysplasia in patients with radiographically identified intraductal papillary mucinous neoplasms (IPMN) have not been described. We hypothesized that dysplasia in IPMN invokes an immunogenic/proinflammatory microenvironment that can be identified by cyst fluid cytokine levels. Experimental Design: Pancreatic cyst fluid aspirates were collected at resection (2005–2009). Samples were grouped into low-risk [low-grade (n = 6) or moderate dysplasia (n = 15)] and high-risk groups [high-grade dysplasia (n = 13) or carcinoma (n = 6)]. Cytokine expression was determined using a multiplex sandwich immunoassay. Differences in cytokine expression were evaluated using the 2-sample t test. Sample classification was performed using a logistic regression adjusting for sample covariates. Results: IL5 and IL8 concentrations were higher in the cyst fluid from patients in the high-risk group than the low-risk group. Interleukin (IL)-1β concentrations were also higher in the cyst fluid from patients with high-grade dysplasia or cancer (n = 19) than those with low- or moderate-grade dysplasia (n = 21, 539 ± 255 pg/mL vs. 0.2 ± 0.1 pg/mL; P < 0.0001). IL1β remained a significant predictor of high-risk cysts after multivariate analysis. There was no significant difference in levels of IL2, IL4, IL10, IL12, IL13, TNF-α, or IFN-γ between the groups. That IL1β levels identified cysts at a high risk of malignancy was confirmed in an independent validation set. Conclusions: Cyst fluid levels of IL1β can differentiate low- from high-risk IPMN. This study introduces IL1β as a potential biomarker for validation in larger clinical studies. Clin Cancer Res; 17(6); 1502–8. ©2011 AACR.

Quality of Life and Symptom Control after Stent Placement or Surgical Palliation of Malignant Colorectal Obstruction

BACKGROUND Emergent surgical management of malignant large bowel obstruction (LBO) carries a high rate of morbidity and mortality. Self-expanding metal stents have emerged as an alternative for palliation of malignant LBO. However, there are few long-term studies documenting the effect of surgical palliation or colonic stents on symptoms or quality of life (QoL). STUDY DESIGN Between 2003 and 2006, patients with unresectable-for-cure malignancies presenting with LBO were enrolled in this prospective study. Patients elected to undergo stent placement or surgical palliation. Patients completed a symptom questionnaire and a QoL instrument (Functional Assessment of Cancer Therapy-Colorectal [FACT-C]) at weeks 1, 2, 4, 8, 12, and 24 after palliation. Symptoms were assessed using the Colon Obstruction Score, a novel instrument comprising nausea, vomiting, pain, distension, and bowel movement frequency scores. RESULTS Thirty patients had successful stent placement; 14 underwent surgical diversion. Colon Obstruction Scores immediately improved after both stent placement and surgery (p < 0.05 for all time points). Composite FACT-C scores progressively improved after stent placement (p = NS), with the colon symptoms subscale improving after 1 month (p < 0.05). FACT-C scores declined initially after surgery and then returned to baseline, with modest improvements seen in the Colon Symptoms subscale (p = NS). CONCLUSIONS Both stent placement and surgical diversion provide durable improvement in symptoms from LBO, as readily assessed by the Colon Obstruction Score. QoL is difficult to assess in terminal cancer patients, but colon stent placement is associated with improved overall QoL and QoL related to gastrointestinal symptoms.

Enteral Nutrition Support of Head and Neck Cancer Patients

Patients with head and neck cancer are at high risk for malnutrition due to dysphagia from the tumor and treatment. Despite difficulty with oral intake, these patients usually have a normal stomach and lower gastrointestinal tract. Enteral nutrition support via percutaneous endoscopic gastrostomy (PEG) administered in the home by the patient helps to prevent weight loss, dehydration, nutrient deficiencies, treatment interruptions, and hospitalizations. It also improves quality of life. Successful management of these patients requires orderly care and follow-up by a multidisciplinary nutrition team.

The Role of Pretreatment Percutaneous Endoscopic Gastrostomy in Facilitating Therapy of Head and Neck Cancer and Optimizing the Body Mass Index of the Obese Patient

BACKGROUND Chemoradiation of head and neck cancer induces severe dysphagia and malnutrition, which may lead to interruptions in therapy and reduction in its efficacy. Percutaneous endoscopic gastrostomy (PEG) feedings bypass the oropharynx, allowing administration of nutrients and medications into the stomach, thus preventing malnutrition, dehydration, and treatment interruption. METHODS Medical records of 161 patients treated for head and neck cancer who had PEGs placed prior to chemoradiation and 2 PEGs placed during chemoradiation were reviewed from the date of PEG placement throughout treatment and utilization. The objective was to determine the contribution of pretreatment PEGs to the therapy of patients with head and neck cancer and to optimize their body mass index. RESULTS Severe chemoradiation-induced dysphagia developed in 160 patients (98%), necessitating PEG utilization for feeding and hydration. PEGs were used for a mean 251 +/- 317 days. Significant complications related to PEG placement and utilization were infrequent. PEG feeding allowed chemoradiation to continue without interruption in 93% of patients. Individualized feeding regimens optimized body mass index in obese and overweight patients with a decline from 33.0 +/- 3.4 to 28.4 +/- 4.8 kg/m(2) (P < .001) and 27.3 +/- 1.5 to 24.6 +/- 2.7 kg/m(2) (P < .001), respectively. Radiation-induced strictures developed in 12% of patients, requiring endoscopic dilatation. CONCLUSIONS Enteral feeding through prechemoradiation-placed PEGs is an effective and safe method for nutrition and hydration of patients with head and neck cancer undergoing chemoradiation. PEGs allowed chemoradiation to proceed with minimal interruptions despite severe dysphagia, which excluded oral intake for prolonged periods.

Carcinomatosis is not a contraindication to enteral stenting in selected patients with malignant gastric outlet obstruction

BACKGROUND Endoscopically inserted self-expandable metal stents (SEMSs) are used to palliate malignant gastric outlet obstruction (GOO). Peritoneal disease is considered a relative contraindication to SEMS placement given the risk of multifocal obstruction. OBJECTIVE To evaluate the success of SEMSs placed in patients with GOO with carcinomatosis. DESIGN Retrospective review of patients who underwent SEMS placement for malignant GOO. SETTING Large, urban cancer center. PATIENTS A total of 215 patients who were scheduled for SEMS placement for GOO. INTERVENTIONS SEMS placement. MAIN OUTCOME MEASUREMENTS Technical success, clinical success, early and late SEMS failure, and complications. RESULTS Technical success was achieved in 192 of 201 patients (95.5%). Of the 9 patients who did not achieve technical success, 6 had carcinomatosis. Among the 116 patients (60%) with carcinomatosis, clinical success was achieved 94 of them (81%). Of these 94 patients, 17 (18%) required reinterventions: 4 for early SEMS failure and 13 for late SEMS failure. Among the 76 patients (40%) without carcinomatosis, clinical success was achieved in 64 of them (84%). Of these 64 patients, 17 (27%) required reinterventions: 4 for early SEMS failure and 13 for late SEMS failure. Complication rates were similar for both groups. LIMITATIONS This was a retrospective review with experienced clinicians selecting patients whom they thought would benefit from SEMS placement. CONCLUSIONS This is the first study to evaluate the effect of carcinomatosis on the technical and clinical success of SEMSs in the palliation of malignant GOO. We found clinical outcomes comparable to those without peritoneal disease. Carcinomatosis should not be considered a contraindication to SEMS placement in selected patients with malignant GOO.

A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma.

Background:The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined. Objective:We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma. Methods:Eligible patients were screened using computed tomography–pancreas angiography, laparoscopy, endoscopic ultrasonography, and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m2 intravenously over 100 minutes and oxaliplatin 80 mg/m2 intravenously over 2 hours, every 2 weeks. Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine (1000 mg/m2 intravenously over 30 minutes days 1, 8, and 15 every 4 weeks). The primary endpoint was 18-month overall survival and secondary endpoints included radiological, tumor marker and pathological response to neoadjuvant therapy, time to recurrence, patterns of failure, and feasibility of obtaining preoperative core biopsies. Results:Thirty-five of 38 patients (92%) completed neoadjuvant therapy. Twenty-seven patients underwent tumor resection (resectability rate 71%), of which 26 initiated adjuvant therapy for a total of 23 patients (60.5%) who completed all planned therapy. The 18-month survival was 63% (24 patients alive). The median overall survival for all 38 patients was 27.2 months (95% confidence interval: 17–NA) and the median disease-specific survival was 30.6 months (95% confidence interval: 19–NA). Conclusions:This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma. Improved patient selection and more active systemic regimens are key. Clinical trials identification: NCT00536874.