Massimo Raimondo

Minimally invasive endoscopic staging of suspected lung cancer.

CONTEXT In patients with suspected lung cancer, the presence of mediastinal lymph node metastasis is a critical determinant of therapy and prognosis. Invasive staging with pathologic confirmation is recommended. Many methods for staging exist; mediastinoscopy, an invasive procedure requiring general anesthesia, is currently regarded as the diagnostic standard. OBJECTIVE To compare the diagnostic accuracy of 3 methods of minimally invasive endoscopic staging (and their combinations): traditional transbronchial needle aspiration (TBNA), endobronchial ultrasound-guided fine-needle aspiration (EBUS-FNA), and transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). In particular, we aimed to compare EBUS-FNA with TBNA. DESIGN, SETTING, AND PARTICIPANTS Invasive staging of the mediastinum among consecutive patients with suspected lung cancer at a US academic medical center from November 2004 through October 2006. INTERVENTION TBNA, EBUS-FNA, and EUS-FNA performed sequentially as a single combined procedure. MAIN OUTCOME MEASURE Sensitivity for detecting mediastinal lymph node metastases, using pathologic confirmation and 6- to 12-month clinical follow-up as the criterion standard. RESULTS Among 138 patients who met all study criteria, 42 (30%) had malignant lymph nodes. EBUS-FNA was more sensitive than TBNA, detecting 29 (69%) vs 15 (36%) malignant lymph nodes (P = .003). The combination of EUS-FNA and EBUS-FNA (EUS plus EBUS) had higher estimated sensitivity (93% [39/42]; 95% confidence interval, 81%-99%) and negative predictive value (97% [96/99]; 95% confidence interval, 91%-99%) compared with either method alone. EUS plus EBUS also had higher sensitivity and higher negative predictive value for detecting lymph nodes in any mediastinal location and for patients without lymph node enlargement on chest computed tomography. CONCLUSIONS These findings suggest that EBUS-FNA has higher sensitivity than TBNA and that EUS plus EBUS may allow near-complete minimally invasive mediastinal staging in patients with suspected lung cancer. These results require confirmation in other studies but suggest that EUS plus EBUS may be an alternative approach for mediastinal staging in patients with suspected lung cancer.

Comparison of Probe-Based Confocal Laser Endomicroscopy With Virtual Chromoendoscopy for Classification of Colon Polyps

BACKGROUND & AIMS Probe-based confocal laser endomicroscopy (pCLE) allows in vivo imaging of tissue at micron resolution. Virtual chromoendoscopy systems, such as Fujinon intelligent color enhancement and narrow band imaging, also have potential to differentiate neoplastic colorectal lesions. The accuracy of these systems in clinical practice is, however, unknown. Our primary aim was to compare sensitivity and specificity of pCLE to virtual chromoendoscopy for classification of colorectal polyps using histopathology as a gold standard. A secondary aim was to compare sensitivity and specificity of pCLE to virtual chromoendoscopy using a modified gold standard that assumed that all polyps >/=10 mm had malignant potential and were considered neoplastic or high risk. METHODS Patients underwent colonoscopy using high-resolution colonoscopes. The surface pit pattern was determined with NBI or FICE in all patients. Confocal images were recorded and subsequently analyzed offline, blinded to the endoscopic characteristics and histopathology. Each polyp was diagnosed as benign or neoplastic based on confocal features according to modified Mainz criteria. RESULTS A total of 119 polyps (81 neoplastic, 38 hyperplastic) from 75 patients was assessed. The pCLE had higher sensitivity compared to virtual chromoendoscopy when considering histopathology as gold standard (91% vs 77%; P = .010) and modified gold standard (88% vs 76%; P = .037). There was no statistically significant difference in specificity between pCLE and virtual chromoendoscopy when considering histopathology or modified gold standard. CONCLUSIONS Confocal endomicroscopy demonstrated higher sensitivity with similar specificity in classification of colorectal polyps. These new methods may replace the need for ex vivo histological confirmation of small polyps, but further studies are warranted.

Seasonal distribution in newly diagnosed cases of eosinophilic esophagitis in adults.

OBJECTIVES:The etiology of eosinophilic esophagitis (EoE) is not well understood. It has been proposed that eosinophils migrate to the esophagus in response to various ingested and inhaled allergens. Recent reports in children found an increased proportion of cases of EoE during months with higher outdoor aeroallergens. To our knowledge, this has not been evaluated in adults. We aimed to determine whether there is a seasonal distribution in the number of newly diagnosed cases of EoE in an adult population.METHODS:We conducted a retrospective review of consecutive adult cases newly diagnosed with EoE in 1 year. Cases were grouped based on the index month when the diagnosis was made at endoscopy. To test the consistency of the observations, a second cohort of consecutive cases of similar sample size diagnosed at a different period in time was also analyzed.RESULTS:In total, 41 patients were diagnosed with EoE at our center during the study period, providing an annual prevalence of 0.98%. More cases were diagnosed with EoE during the months of April and May than any other month (P<0.001). When patients were grouped seasonally, there was a significant increase of EoE cases in spring and summer months (n=28) when compared with the fall and winter months (n=13) (P=0.019). Analysis of the second cohort of cases (n=37) from 2002 to 2006 confirmed a similar seasonal diagnostic pattern for EoE during the outdoor seasons.CONCLUSIONS:Our data demonstrate that EoE has a seasonal prevalence in adults. The seasonal variation pattern found in newly diagnosed EoE cases in adults supports the potential role of aeroallergens in the pathogenesis of EoE.

CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer

Angiogenesis is essential for tumor growth and metastasis. Although ELR+‐CXC‐chemokines and their corresponding receptor, CXC‐receptor 2 (CXCR2), are known mediators of angiogenesis, little is known about their role in pancreatic cancer (PaCa). The aim of our study was to determine the role of ELR+‐CXC‐chemokine/CXCR2 biological axis in promoting PaCa angiogenesis. We prospectively collected secretin‐stimulated exocrine pancreatic secretions (SSEPS) from normal individuals (NP) and PaCa patients. We showed that summed concentrations of ELR+‐CXC‐chemokines in SSEPS from PaCa patients were significantly higher than in those from NP (p = 0.002). We measured ELR+‐CXC‐chemokine levels in supernatants from multiple PaCa cell lines and confirmed that BxPC‐3, Colo‐357 and Panc‐28 had significantly higher expression compared with an immortalized human pancreatic ductal epithelial (HPDE) cell line. After confirming lack of autocrine effects of ELR+‐CXC‐chemokines on PaCa cells (due to absence of CXCR2 expression), we investigated paracrine effects of these chemokines on human umbilical vein endothelial cells (HUVEC). Both recombinant ELR+‐CXC‐chemokines and co‐culturing with BxPC‐3 significantly enhanced proliferation, invasion, and tube formation of HUVEC (p < 0.05). These biological effects were significantly inhibited by treatment with a neutralizing antibody against CXCR2 (anti‐CXCR2 Ab) (p < 0.05). Finally, anti‐CXCR2 Ab significantly reduced tumor volume (p < 0.05), Ki‐67 proliferation index (p = 0.043) and Factor VIII+ microvessel density (p = 0.004) in an orthotopic nude mouse PaCa model. Our results show that ELR+‐CXC‐chemokines promote PaCa tumor‐associated angiogenesis through CXCR2, suggesting that CXCR2 is an anti‐angiogenic target in PaCa.

High-Definition Colonoscopy Detects Colorectal Polyps at a Higher Rate Than Standard White-Light Colonoscopy

BACKGROUND & AIMS Adenoma detection rates might be improved through use of high-definition colonoscopy, which can detect subtle mucosal changes. We investigated whether the use of high-definition white-light (HDWL) colonoscopy resulted in a higher rate of adenoma detection than standard-definition white-light (SDWL) colonoscopy in a clinical practice setting. METHODS This retrospective study included 2430 patients who underwent colonoscopies from September 2006 to December 2007; 1226 received SDWL colonoscopy and 1204 received HDWL colonoscopy. We analyzed data from consecutive screening, surveillance, and diagnostic colonoscopies, comparing adenoma and overall polyp detection between procedures. Potentially confounding variables were controlled using multivariable logistic regression analysis. RESULTS The adenoma detection rate was higher among patients who underwent HDWL compared with SDWL colonoscopies (28.8% vs 24.3%; P = .012), as was the polyp detection rate (42.2% vs 37.8%; P = .026). These findings remained after adjustments for potentially confounding variables (P = .018 and .022, respectively). CONCLUSIONS In a general clinical practice setting, HDWL colonoscopy resulted in a higher adenoma detection rate compared with SDWL colonoscopy. The use of SDWL colonoscopy could reduce the number of missed adenomas and the subsequent risk for colorectal cancer.

Invasive cancer and survival of intraductal papillary mucinous tumors of the pancreas

OBJECTIVES:Intraductal papillary mucinous tumor (IPMT) is frequently associated with pancreatic cancer. We hypothesized that IPMT progresses to invasive cancer with K-ras mutations as an early event, and that invasive cancer affects survival. We compared survival after resection and determined whether K-ras mutations predicted survival in IPMT patients without or with invasive cancer.METHODS:Records of 47 patients with IPMT who were seen between 1983 and 1998 were reviewed retrospectively in 15 cases and prospectively in 32. All histological material was reviewed to confirm the diagnosis of IPMT and to assess invasion. Kaplan-Meier survival curves were analyzed by the log-rank test. The χ2 test was used for differences in K-ras between groups.RESULTS:There were 30 men and 17 women, with a mean age of 65 yr (range 36–90 yr). Of the patients, 26 had IPMT without invasive cancer and 19 had IPMT with invasion. Tissue diagnosis was available in 45 patients. K-ras was analyzed in 40 patients. Mutations were present in 15 of 23 patients (65%) without invasive cancer and in 14 of 17 patients (82%) with invasive cancer (p = ns). At 2.5 yr, the overall cumulative survival of IPMT patients without invasive cancer was 94% compared to 24% of patients with invasive cancer (p < 0.001). The 5-yr survival of IPMT patients without invasive cancer was 94%. K-ras mutations did not correlate with survival.CONCLUSIONS:Invasive cancer in IPMT reduces the 2.5-yr survival after surgery from 93% to 24%. K-ras mutations occur before invasive cancer, and do not predict postoperative survival.

Photodynamic Therapy for Dysplastic Barrett Esophagus and Early Esophageal Adenocarcinoma

OBJECTIVE To evaluate our results using photodynamic therapy (PDT) for the treatment of dysplasia or superficial cancer (T1 N0 M0) in patients with Barrett esophagus. PATIENTS AND METHODS We retrospectively reviewed our clinical experience with 48 patients (34 patients with high-grade dysplasia and 14 patients with superficial cancer in Barrett esophagus) who had been referred for PDT. Initial evaluation included computed tomography and standard and high-frequency catheter endosonography. Follow-up endoscopy was performed 4 to 6 weeks after PDT with ablation of any residual glandular mucosa, using the argon plasma coagulator. Patients were then followed up indefinitely every 3 to 6 months with computed tomography, endosonography, and endoscopic surveillance. RESULTS The median series follow-up was 18.5 months (range, 1-56 months). Apparent complete photoablation of Barrett mucosa and/or superficial neoplasm was documented in 47 of 48 cases. Complications included symptomatic strictures (11 patients), photosensitivity (7 patients), atrial fibrillation (1 patient) or recurrent congestive heart failure (1 patient), and self-limited esophageal perforation (1 patient). Failure to ablate T1 N0 M0 adenocarcinoma occurred in 1 patient. CONCLUSIONS Porfimer sodium PDT appears to eradicate dysplastic Barrett mucosa and neoplasia. These results are promising; however, long-term studies are needed to document the efficacy of PDT in reducing the morbidity and mortality in such patients.

Diagnostic Accuracy of Probe-Based Confocal Laser Endomicroscopy and Narrow Band Imaging for Small Colorectal Polyps: A Feasibility Study

OBJECTIVES:Probe-based confocal laser endomicroscopy (pCLE) allows real-time in-vivo microscopic imaging of tissue. Narrow band imaging (NBI) can also classify colorectal lesions. Both systems may allow accurate optical diagnosis of small (6–9 mm) and diminutive (1–5 mm) polyps without histopathology. This study assesses the accuracy of pCLE and NBI for prediction of histology.METHODS:Participants underwent high-definition colonoscopy. The surface pit pattern of all polyps (1–9 mm) was determined in vivo using NBI. Confocal videos were obtained after administration of IV fluorescein. Recorded videos were subsequently analyzed offline, blinded to endoscopic characteristics, and histopathology. Confocal images were classified as neoplastic and non-neoplastic according to the Miami classification system.RESULTS:A total of 130 polyps (58 neoplastic, 72 non-neoplastic, mean size 4.6 mm) from 65 patients were assessed. Assuming histopathology as gold standard, pCLE had higher sensitivity than NBI (86% vs. 64%, P=0.008), with lower specificity (78% vs. 92%, p=0.027) and similar overall accuracy (82% vs. 79%, P=0.59). When 65 high-confidence cases were analyzed (polyps diagnosed identically with pCLE and NBI and with high-quality confocal videos), sensitivity and specificity were 94 and 97%.CONCLUSIONS:pCLE demonstrated higher sensitivity in predicting histology of small polyps compared with NBI, whereas NBI had higher specificity. When used in combination, the accuracy of pCLE and NBI was extremely high, approaching the accuracy of histopathology. Together, they may reduce the need for histological examination. However, further studies are warranted to evaluate the role of these techniques, especially in the population-based colon cancer screening.

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.

Economic analysis of combined endoscopic and endobronchial ultrasound in the evaluation of patients with suspected non-small cell lung cancer.

Lung cancer remains the most common cause of cancer-related death in the United States. This study evaluated the costs of alternative diagnostic evaluations for patients with suspected non-small cell lung cancer (NSCLC). Researchers used a cost-minimization model to compare various diagnostic approaches in the evaluation of patients with NSCLC. It was less expensive to use an initial endoscopic ultrasound (EUS) with fine needle aspiration (FNA) to detect a mediastinal lymph node metastasis (