Ferga C. Gleeson

Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience

Background There is a paucity of data on long-term management of type 1 autoimmune pancreatitis (AIP), a relapsing steroid-responsive disorder. Objective We describe our experience with treatment of relapses and maintenance of remission using steroid-sparing immunomodulators (IMs) and induction of remission using rituximab (RTX). Methods We obtained details of disease relapse and treatment in 116 type 1 AIP patients from clinic visits, medical records and telephone interviews. We compared relapse free survival in those treated with IMs versus those treated with steroids alone, assessed patients’ response to RTX, and identified treatment-related complications. Results During a median follow-up of 47 months, 52/116 AIP patients experienced 76 relapse episodes. The first relapse was treated with another course of steroids in 24 patients, and with steroids plus IM in another 27 patients; subsequent relapse-free survival until a second relapse was similar in the two groups (p=0.23). 38 patients received an IM for >2 months; failure or intolerance of IM therapy occurred in 17 (45%). 12 patients with steroid or IM intolerance/resistance were treated with RTX, an antiCD20 antibody; 10 (83%) experienced complete remission and had no relapses while on maintenance therapy. Treatment-limiting side effects related to RTX were uncommon. Conclusions In type 1 AIP relapses are common. Relapse-free survival is similar in those treated with steroids plus IM compared to those treated with steroids alone. Nearly half the patients on IMs will relapse during treatment. RTX is effective in the treatment of both IM resistant and steroid intolerant patients.

Initial evaluation of the efficacy and safety of endoscopic ultrasound-guided direct ganglia neurolysis and block

BACKGROUND:Celiac plexus neurolysis and block are considered safe but provide limited pain relief. Standard techniques target the region of the celiac plexus but do not attempt injections directly into celiac ganglia. The recent recognition that celiac ganglia can be visualized by endoscopic ultrasound (EUS) now allows direct injection into celiac ganglia for neurolysis (CGN) and block (CGB).AIMS:To determine the safety and initial efficacy (at 2–4 wk) of direct ganglia injection in patients with moderate to severe pain secondary to unresectable pancreatic carcinoma or chronic pancreatitis.METHODS:An EUS database was reviewed to identify patients undergoing CGN and CGB. Data were retrieved from the medical records and phone follow-up.RESULTS:Thirty-three patients underwent 36 direct celiac ganglia injections for unresectable pancreatic cancer (CGN N = 17, CGB N = 1) or chronic pancreatitis (CGN N = 5, CGB N = 13) with bupivacaine (0.25%) and alcohol (99%) for CGN, or Depo-Medrol (80 mg/2 cc) for CGB. Cancer patients reported pain relief in 16/17 (94%) when alcohol was injected and 0/1 (00%) when steroid was injected. For chronic pancreatitis, 4/5 (80%) who received alcohol reported pain relief versus 5/13 (38%) receiving steroids. Thirteen (34%) patients experienced initial pain exacerbation, which correlated with improved therapeutic response (P < 0.05). Transient hypotension and diarrhea developed in 12 and 6 patients, respectively.CONCLUSIONS:Initial experience suggests that EUS-guided direct celiac ganglion block or neurolysis is safe. Alcohol injection into ganglia appears to be effective in both cancer and chronic pancreatitis. Prospective trials are needed to confirm the efficacy of this new approach.

Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients

BackgroundCancer risk and Lhermitte-Duclos disease (LDD) risk estimates for Cowden syndrome (CS) are broad and based on a small number of patients. Risk estimates are vital to the development of diagnostic criteria, genetic counseling, and cancer surveillance. To further elaborate and estimate the risks associated with CS, a large cohort of patients was evaluated.MethodsCS patients were identified from the medical literature and the Mayo Clinics records. All patients met accepted diagnostic criteria for CS.ResultsA total of 211 CS patients (age 44 ± 16 years, 64% female, 46% PTEN mutation) were included (published literature 90% and Mayo Clinic series 10%). The cumulative lifetime (age 70 years) risks were 89% for any cancer diagnosis (95% confidence interval (CI) = 80%,95%), breast cancer [female] 81% (CI = 66%,90%), LDD 32% (CI = 19%,49%), thyroid cancer 21% (CI = 14%,29%), endometrial cancer 19% (CI = 10%,32%), and renal cancer 15% (CI = 6%,32%). A previously unreported increased lifetime risk for colorectal cancer was identified (16%, CI = 8%,24%). Male CS patients had fewer cancers diagnosed than female patients and often had cancers not classically associated with CS. Seven percent of breast and thyroid cancers occurred in patients who were younger than the recommended age to commence radiographic cancer screening. There was a trend for patients with a family history of CS and PTEN mutations to have a lower cancer risk than those without.ConclusionsThis study confirms CS patients are at increased risk for cancer and quantitative data is provided to guide clinical care. Based on a different tumor spectrum, separate male and female clinical CS diagnostic criteria may be indicated.

False positive endoscopic ultrasound fine needle aspiration cytology: incidence and risk factors

Objective It is broadly accepted that the false positive (FP) rate for endoscopic ultrasound fine needle aspiration (EUS FNA) is 0–1%. It was hypothesised that the FP and false suspicious (FS) rates for EUS FNA are greater than reported. A study was undertaken to establish the rate and root cause of discordant interpretation. Design Using a prospectively maintained endoscopic database, cytohistological discordant EUS FNA examinations from 30 July 1996 to 31 December 2008 were identified retrospectively. Setting Tertiary referral centre. Main outcome measures Discordant FNA was defined by positive or suspicious FNA cytology in the absence of malignancy or neoplasm in the subsequent surgical pathology specimen, specifically in the absence of neoadjuvant therapy. Three cytopathologists conducted a blinded review of randomised discordant and matched specimens. Results FNA was performed in 5667/18 066 (31.4%) patients undergoing EUS, of whom 2547 had cytology results interpreted as ‘positive’ or ‘suspicious’ or ‘atypical’ for malignancy or neoplasm. Subsequent surgical resection without prior neoadjuvant therapy was performed in 377 patients with positive or suspicious cytology. The FP rate was 20/377 (5.3%) and increased to 27/377 (7.2%) when FS cases were included. The incidence of discordance was consistent over time (1996–2002: 10/118 (8.6%) vs 2003–2008: 17/259 (6.6%); p=0.5) and was higher in non-pancreatic FNA (15%) than pancreatic FNA (2.2%; p=0.0001). Two-thirds of the non-pancreatic FP cases involved sampling of perioesophageal or perirectal nodes in patients with luminal neoplasms or Barretts oesophagus. Following pathological re-review, discordance was attributed to translocated cell contamination/sampling error (50%) or cytopathologist interpretive error (50%). Conclusions These findings refute the accepted paradigm that FP cytology rarely occurs with EUS FNA. Further investigation revealed that FP FNA developed secondary to endosonographer technique or initial cytological misinterpretation, and is particularly likely when perioesophageal or perirectal nodes are aspirated in the setting of a luminal neoplasm or Barretts oesophagus. Further study is needed to determine the significance of these findings and potential impact on the performance of FNA and patient outcomes.

Histologic and Imaging Features of Mural Nodules in Mucinous Pancreatic Cysts

BACKGROUND & AIMS Mural nodules predict malignancy within pancreatic cysts, but it is not clear whether endoscopic ultrasound (EUS) and computed tomography (CT) accurately identify nodules. We assessed images and the histology of mural nodules in branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) and mucinous cystic neoplasms (MCNs) and identified criteria to distinguish mural nodules from mucus. METHODS We reviewed pathology specimens and EUS and CT images from consecutive patients with resected BD-IPMNs or MCNs. A blinded interobserver study of the EUS images was then conducted to identify features that distinguished nodules from mucus. After education about these features, the raters interpreted the EUS images again. RESULTS On the basis of histologic analysis, 22 of 57 cases had epithelial nodules. Cancer or high-grade dysplasia was found in 23% of cysts with nodules versus 3% without nodules (P = .02). On the basis of reports, EUS detected epithelial nodules with 75% sensitivity and 83% specificity, whereas these values were 24% and 100%, respectively, for CT. Mucus accounted for 65% of intracystic lesions detected by EUS and was often diagnosed by using change in body position and fine-needle aspiration. Interobserver analysis identified 3 features that were detected by EUS (echogenicity, edge, and rim) that distinguished mucus from epithelial nodules. The diagnostic accuracy of the raters improved from a mean of 57% to 79% after education about these features (P = .004); accuracy was 90% when all 3 features of mucus were present. CONCLUSIONS Malignancy is associated with epithelial nodules in BD-IPMNs and MCNs, but most echogenic lesions detected in cysts by EUS are mucus. Knowledge of features that discriminate mucus from mural nodules improves the diagnostic accuracy of EUS.

Diagnostic Accuracy of Interleukin-6 and Interleukin-8 in Predicting Severe Acute Pancreatitis: A Meta-Analysis

Objectives: The early identification of patients at risk for severe acute pancreatitis (SAP) is crucial. Serum markers of disease severity have been assessed including interleukin (IL)-6 and IL-8; however, their predictive accuracy has varied significantly across studies. We conducted a meta-analysis to assess the accuracy of IL-6 and IL-8 at predicting SAP. Methods: We identified relevant published articles and calculated pooled sensitivities, specificities and likelihood ratios using the random-effect model. We included values for days 1, 2 and 3 of presentation for IL-6 and for days 1 and 2 for IL-8. We also constructed summary receiver-operating curves and assessed the area under the curve (AUC) and the diagnostic odds ratios (DORs) as measures of diagnostic accuracy. Results: For IL-6, we included 7 reports for day 1 and 4 reports for days 2 and 3. For IL-8, we analyzed 5 studies for day 1 and 4 for day 2. The pooled IL-6 sensitivities ranged between 81.0 and 83.6% and specificities between 75.6 and 85.3% with positive likelihood ratios of 3.43, 4.90 and 4.40 for days 1, 2 and 3, respectively. The IL-8 pooled sensitivities were 65.8 and 70.9% with specificities of 66.5 and 91.3% for days 1 and 2 with positive likelihood ratios of 1.96 and 8.15. The IL-6 AUCs were 0.75, 0.88 and 0.85 for days 1, 2 and 3. The IL-8 AUCs were 0.73 and 0.91 for days 1 and 2. The DOR for IL-6 was higher than that of IL-8 on day 1. Conclusion: IL-6 and IL-8 seem to perform at an acceptable level in predicting SAP. Larger confirmatory studies formally comparing this performance with that of more commonly used markers are needed.

EUS-guided pancreatic duct intervention: outcomes of a single tertiary-care referral center experience.

BACKGROUND EUS can provide access to the main pancreatic duct (MPD) for therapeutic intervention. The long-term clinical success of EUS-guided MPD interventions is unknown. OBJECTIVE To determine technical and clinical success rates, predictors of success, and long-term outcomes of EUS-guided MPD intervention. DESIGN Retrospective, single-center study. SETTING Tertiary-care referral center. PATIENTS Forty-five patients. INTERVENTION EUS-guided MPD stent retrieval or placement. MAIN OUTCOME MEASUREMENTS Technical and clinical success rates, adverse events, and long-term clinical outcomes. RESULTS Among the 45 patients, 37 had undergone failed ERCP, and 29 had surgically altered anatomy. Median follow-up after initial EUS-guided intervention was 23 months. Two patients underwent EUS for stent removal, and EUS-guided MPD stent placement was attempted in 43 patients. Technical success was achieved in 32 of 43 patients (74%) with antegrade (n = 18) or retrograde (n = 14) stent insertion. Serious adverse events occurred in 3 patients (6%). Patients underwent a median of 2 (range 1-6) follow-up procedures for revision or removal of stents, without adverse events. Complete symptom resolution occurred in 24 of 29 patients (83%) while stents were in place, including all 6 with nondilated ducts. Stents were removed in 23 patients, who were then followed for an additional median of 32 months; 4 patients had recurrent symptoms. Among the 11 failed cases, most had persistent symptoms or required surgery. LIMITATIONS Retrospective study design, individualized patient management. CONCLUSION EUS-guided MPD intervention is feasible and safe, with long-term clinical success in the majority of patients. EUS provides important treatment options, particularly in patients who would otherwise undergo surgery.

Prospective Cytological Assessment of Gastrointestinal Luminal Fluid Acquired During EUS: A Potential Source of False-Positive FNA and Needle Tract Seeding

OBJECTIVES:Endoscopic ultrasound (EUS) fine needle aspiration (FNA) can result in false-positive cytology and can also cause needle tract seeding. Our goal was to evaluate a potential cause, namely, the presence of malignant cells within gastrointestinal (GI) luminal fluid, either as a result of tumor sloughing from luminal cancers or secondary to FNA of extraluminal sites.METHODS:During EUS, luminal fluid that is usually aspirated through the echoendoscope suction channel and discarded was instead submitted for cytological analysis among patients with cancer and benign disease. Pre- and post-FNA luminal fluid samples were collected to discern the role of FNA in inducing a positive cytology. When not performing FNA, one sample was collected for the entire examination. The final diagnosis was based on strict clinicopathological criteria and ≥2-year follow-up. This study was conducted in a tertiary referral center.RESULTS:We assessed the prevalence of luminal fluid-positive cytology among patients with luminal (e.g., esophageal), extraluminal (e.g., pancreatic), and benign disease. Among the 140 patients prospectively enrolled with sufficient sampling and follow-up, an examination of luminal fluid cytology showed positive results for malignancy in luminal and extraluminal cancer patients, 48 and 10%, respectively. This included 8 out of 23 esophageal, 4 of 5 gastric, and 9 of 15 rectal cancers. The positive luminal fluid cytology rate with luminal cancers was not affected by performing FNA. Post-FNA luminal fluid cytology was positive in 3 out of 26 with pancreatic cancers. Cytological examination of luminal fluid aspirates did not demonstrate malignant cells in any patient with nonmalignant disease.CONCLUSIONS:Malignant cells are commonly present in the GI luminal fluid of patients with luminal cancers and can also be found in patients with pancreatic cancer after EUS FNA. Further study is needed to determine the impact of these findings on cytological interpretation, staging, risk of needle tract seeding, and patient care and outcomes.

Lung cancer adrenal gland metastasis: Optimal fine‐needle aspirate and touch preparation smear cellularity characteristics for successful theranostic next‐generation sequencing

Multigene molecular testing to guide personalized therapy for oncology patients is of increasing clinical relevance. Molecular testing of fine‐needle aspiration samples is underused, but when acquired with minimally invasive techniques could become the standard of care to obtain theranostic specimens. The aims of the current study were to identify key cytology specimen selection criteria suitable for next‐generation sequencing (NGS) and to determine the prevalence and spectrum of pathogenic alterations in a cohort of patients with AJCC stage IV lung cancer.

Prospective assessment of EUS criteria for lymphadenopathy associated with rectal cancer.

BACKGROUND There are few data that assess the accuracy of echo characteristics for predicting lymph-node (LN) metastases in patients with rectal cancer. OBJECTIVE To identify nodal echo characteristics and size predictive of malignant infiltration and to determine if any combination of standard nodal criteria has sufficient predictive value to preclude FNA. DESIGN Prospective uncontrolled study. SETTING Tertiary-referral hospital. PATIENTS Seventy-six patients (68% men) with untreated rectal cancer; 52 had visualized LNs. INTERVENTION EUS-guided FNA. MAIN OUTCOME MEASUREMENTS Evaluation of perirectal nodal morphology accuracy that corresponds to malignant cytology and identification of echo criteria, including LN size, to have sufficient predictive value to predict malignancy. RESULTS Forty-three of 52 patients (83%) underwent FNA of a visualized LN. Nodal hypoechogenicity and short-axis length >or=5 mm were factors independently predictive of malignancy. The number of malignant nodal echo features per node did not distinguish benign from malignant pathology, except when all 4 features were present. Only 68% of malignant LN had >or=3 echo characteristics. An optimum LN short-axis or long-axis length cutoff value of 6 mm or 9 mm were 90% and 95% specific, respectively, for the presence of malignancy by receiver operating characteristic analysis. LIMITATIONS FNA was performed in a subset of identified LNs. CONCLUSIONS Nodal echo features alone are often inadequate to establish the presence of locoregional metastatic disease by EUS. These data support the value of FNA to confirm the presence of malignancy in place of relying on imaging criteria.