Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.

Partially Covered Versus Uncovered Self-Expandable Metal Stents: Coating Nor Diameter Affect Clinical Outcomes.

INTRODUCTION: Jaundice is a common initial presentation of malignant biliary stricture. In patients with life expectancies that are greater than 3 months, self-expanding metal stents (SEMS) offer a larger diameter stent with longer patency and fewer complications compared to plastic stents. There have been conflicting results in the published literature as to efficacy and safety between the various SEMS types and diameters. We compared stent coating (PCSEMS vs USEMS) and diameter on clinical outcomes regarding management of malignant biliary obstruction. METHODS: A retrospective cohort study was conducted using a database of consecutive patients who underwent an ERCP with biliary SEMS placement (only 8 and 10 mm) between 2009 and 2017. RESULTS: In total, 278 patients who had SEMS at ERCP for malignant biliary obstruction were included (213 PCSEMS vs 65 USEMS). The groups were demographically evenly matched. Clinical success rates and patency duration were not statistically significant between PCSEMS and USEMS (98.1% vs 95.5%, P = 0.36, and 302.5 vs 225.5 days, P = 0.72, respectively). Adverse event rates were similar between both PCSEMS and USEMS with regard to overall adverse events. Stent diameter did not have an impact on overall clinical success (98.9% vs 95.3%, P = 0.11) or patency duration (239 days vs 336 days, P = 0.51). CONCLUSIONS: Our comparison of PCSEMS versus USEMS and 8 mm versus 10 mm showed no difference in clinical efficacy or adverse events between the two SEMS coatings and diameter, illustrating that coating and size do not matter in regard to stent choice, despite prior suggestive data.

Perceptions of risk and therapy among patients with Barrett's esophagus: a patient survey study.

Nondysplastic Barrett's esophagus has a risk of progression to esophageal adenocarcinoma as low as 0.18-0.3% per person per year, and low-grade dysplasia as low as 0.5%. While adherence to guidelines and selection of management options varies, little is known about what modifies patient decision-making. This study aims to evaluate and identify factors that influence patient perceptions of risk and decisions about management. An independently developed and piloted survey was administered to patients at an academic hospital. Risk perception and desire for therapy were assessed using a standard reference gamble paradigm, and responses were stratified based on patient and disease characteristics. Data were analyzed with Student's t and chi-squared tests. A total of 42 of 50 patients with Barrett's esophagus and no prior endoscopic therapy participated (84% response; 76% nondysplastic Barrett's esophagus, 22% low-grade dysplasia, 2% indeterminate for dysplasia; mean age 61 years, 29% female). On average, patients perceived their risk of developing esophageal adenocarcinoma in the next year, 10 years and lifetime as 6, 14, and 19%, respectively. Nearly half viewed their lifetime risk of developing esophageal adenocarcinoma to be the same or higher than diabetes, heart disease, or colon cancer. Although 92% of patients felt surveillance beneficial, only 54% believed endoscopic therapy to be effective in most or all cases. As many as 83% of patients were willing to undergo endoscopic therapy with a hypothetical success rate as low as 70%, and a majority (64%) accepted complication rates up to 30%. Compared to patients with low risk perception of developing esophageal adenocarcinoma, those with high risk perception more often believed their risk for developing esophageal adenocarcinoma was greater than diabetes (p = 0.04) or colon cancer (p = 0.002). Those with lifetime low risk perception were less likely to accept modest complication rates (<10%) of therapy (P < 0.05). Age, gender, degree of dysplasia, lifetime endoscopies and duration of symptoms had no impact on perceived effectiveness of surveillance or therapy, and did not correlate with desire for treatment at varying levels of risk and effectiveness. Patients with Barrett's esophagus overestimate their risk of developing esophageal adenocarcinoma and will accept low success rates and high risk of complications to undergo endoscopic therapy. Baseline risk perception correlates with the desire for endoscopic therapy.

Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.

BACKGROUND: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. PATIENTS AND METHODS: A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. RESULTS: The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. CONCLUSION: Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.

Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study.

BACKGROUND: Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. PATIENTS AND METHODS: HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. RESULTS: Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. CONCLUSIONS: In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma.

The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients.

Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI95): weight-normalized volume of distribution: 0.65-0.73 L/kg; t(1/2): 122-147 min; weight-normalized clearance (CL(n)): 3.4-4.3 mL/min/kg; and area under the curve: 1835-2180 mmol × min/L. From these results, a steady state concentration was calculated with CI95 between 628-746 ng/mL. Comparison between recipients ≤4 vs >4 years old revealed significant differences in t(1/2) (mean: 115 vs 146 min, P=0.008) and CL(n) (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing.

New techniques in imaging in Barrett's esophagus.

The presence of dysplasia in patients with Barrett's esophagus identifies who is at increased risk for the development of esophageal adenocarcinoma and who may most benefit from intervention. Several technologies have emerged as potent tools to identify subtle or occult neoplasia in the gastrointestinal tract. Detailed inspection of the mucosa with high resolution white light endoscopy is the most critical tool to detect subtle neoplasia. This review also chromoendoscopy, narrow band imaging, autofluorescence imaging, optical coherence tomography, confocal laser endomicroscopy, and spectroscopy in the context of detection of neoplasia in Barrett's esophagus.

A pilot study of reduced toxicity conditioning with BU, fludarabine and alemtuzumab before the allogeneic hematopoietic SCT in children and adolescents.

We report the results of a pilot study of a BU-fludarabine-alemtuzumab (BFA)-reduced toxicity conditioning (RTC) followed by allogeneic hematopoietic SCT (AlloHSCT) in 12 children and adolescents (<21 years) with malignant and non-malignant diseases. Stem cell sources were: two unrelated cord blood, one unrelated BM, two related and seven unrelated PBSC. Positive CD34 selection was performed in five unrelated PBSC grafts. RCT was carried out with BFA, and GVHD prophylaxis was FK506 and mycophenolate mofetil. The median time for neutrophil and platelet engraftment was 16 and 31 days, respectively. The P of developing ≥ grade II, ≥ grade III aGVHD and cGVHD was 41.6, 25 and 9%, respectively. Only 1 out of 12 developed ≥ grade III toxicity. There was one primary and no secondary graft failure. Mixed donor chimerism on day 100 and 1 year was median 99 and 96%, respectively; ≥ 90% of recipients achieved ≥ 80% donor chimerism. The 3-year overall survival (OS) in all patients was 91.7 ± 8% (100% for malignant vs. 80% for non-malignant diseases, ns). In all, 11 (91%) patients remain alive at median 2.8 (0.3-6.8) years. RTC followed by AlloHSCT, based on BFA conditioning, is feasible and tolerable in children and adolescents, and results in prompt achievement of durable mixed donor chimerism and excellent OS.

New directions in endoscopic therapy of Barrett' s esophagus.

The key to prevention and early treatment of esophageal adenocarcinoma is the detection and eradication of neoplasia found in patients with Barrett's esophagus (BE). The approach to the management in BE has rapidly evolved based on the paradigm shift towards endoscopic therapy, on improved detection of neoplasia with increased appreciation for subtle lesions and enhanced endoscopic imaging modalities, and on a new set of endoscopic therapeutic modalities. This review briefly outlines the evolution of the current approach to neoplasia in BE, the appreciation for improved techniques and technologies to detect neoplasia, and the specific modalities currently used in the endoscopic treatment of Barrett's neoplasia. The goals of endoscopic therapy of Barrett's neoplasia are to preserve the esophagus while ablating or removing the entire Barrett's segment. The therapeutic modalities highlighted are endoscopic resection (endoscopic mucosal resection and endoscopic submucosal dissection), photodynamic therapy, radiofrequency ablation, and cryotherapy. Endoscopic resection is a tool to accurately provide a histological diagnosis of lesions in addition to treat neoplasia. In addition, to treating the known neoplasia, it is also important to treat the remainder of the at-risk Barrett's epithelium to address synchronous and metachronous lesions. This treatment of the entire Barrett's epithelium may be achieved with one or more modalities. With multiple endoscopic tools available, it is important to appreciate how to optimally address neoplasia in BE.

Confocal laser endomicroscopy: potential in the management of Barrett's esophagus.

Confocal laser endomicroscopy (CLE) can serve as a useful adjunct imaging modality for targeted endoscopic biopsies during surveillance of Barrett's esophagus (BE). In addition, CLE may also have potential roles during therapeutic procedures that include localization of pathology, targeting of resections, guiding which therapy to use, and determining adequacy of treatment. This case series illustrates a range of cases in which endomicroscopy was performed during the procedure and offers possibilities of real-time decision-making to select specific therapies in patients with known high-grade dysplasia (HGD) and intramucosal carcinoma in the setting of BE presented for endoscopic treatment or follow-up. Patients with BE with HGD and intramucosal carcinoma presented for management for initial treatment or follow-up. Examinations were performed sequentially with detailed white light endoscopy, narrow band imaging (NBI), acetic acid, and CLE. This is a retrospective case series describing the characteristics of the exam findings and illustrating the role of endomicroscopy on real-time case management. Seven patients with Barrett-associated neoplasia underwent endomicroscopy as part of their endoscopic examination. CLE confirmed findings of neoplasia seen with red flag techniques such as NBI, and in one case independently suggested findings of neoplasia. In the majority of cases, these findings were incorporated into the decision of which modality of treatment was used. Future prospective studies should be done to validate the role of endomicroscopy in BE.

Long-term follow-up of complete Barrett's eradication endoscopic mucosal resection (CBE-EMR) for the treatment of high grade dysplasia and intramucosal carcinoma.

BACKGROUND AND STUDY AIMS: In patients with Barrett's esophagus (BE), targeted endoscopic mucosal resection (EMR) of visible lesions of high grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) is effective, but carries the risk of leaving in place synchronous lesions and Barrett's epithelium with the potential for recurrent disease. We evaluated the safety and long-term efficacy of complete Barrett's eradication EMR (CBE-EMR) for the treatment of patients with HGD or IMC, independently of the presence of macroscopically visible lesions or surgical risk. PATIENTS AND METHODS: 26 consecutive patients with BE and HGD or IMC underwent CBE-EMRs, which were performed with the endoscopic cap suction method and/or a 2.3-mm monofilament mucosectomy snare. Endoscopic follow up after completion of resection was carried out to assess the rate of residual or recurrent BE with or without HGD or IMC. RESULTS: 24 patients completed the study. They underwent a total of 44 EMR sessions with a median of 3 pieces (range 1-8) removed per session. Two patients with immediate bleeding were successfully managed endoscopically. Three patients developed an early esophageal stricture that was completely resolved with a single endoscopic dilation. After a median follow-up of 28 months (range 15-51 months), persistent endoscopic and histologic eradication of BE was demonstrated in 21 patients (87.5 %). In two patients, Barrett's epithelium was detected beneath the neosquamous epithelium 3 months after completion of the resection. In the remaining patient, IMC was found in a nodule seen and removed by EMR at 12-month surveillance endoscopy. CONCLUSIONS: CBE-EMR is a safe and highly effective long-term treatment that should be offered to all patients with Barrett's esophagus with HGD and IMC.

Clinical impact of conventional endosonography and endoscopic ultrasound-guided fine-needle aspiration in the assessment of patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma who have been referred for endoscopic ablation therapy.

BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection and photodynamic therapy are exciting, minimally invasive curative techniques that represent an alternative to surgery in patients with Barrett's esophagus and high-grade dysplasia or intramucosal adenocarcinoma. However, there is lack of uniformity regarding which staging method should be used prior to therapy, and some investigators even question whether staging is required prior to ablation. We report our experience with a protocol of conventional endoscopic ultrasound staging prior to endoscopic therapy. PATIENTS AND METHODS: A total of 25 consecutive patients with a diagnosis of high-grade dysplasia or intramucosal adenocarcinoma in Barrett's esophagus who had been referred to the University of Chicago for staging in preparation for endoscopic therapy between March 2002 and November 2004 were included in the study. All 25 patients underwent repeat diagnostic endoscopy and conventional endosonography with a radial echo endoscope. Any suspicious lymph nodes that were detected were sampled using endoscopic ultrasound-guided fine-needle aspiration. RESULTS: Baseline pathology in the 25 patients (mean age 70, range 49-85) revealed high-grade dysplasia in 12 patients and intramucosal carcinoma in 13 patients. Five patients were found to have submucosal invasion on conventional endosonography. Seven patients had suspicious adenopathy, six regional (N1) and one metastatic to the celiac axis (M1a). Fine-needle aspiration confirmed malignancy in five of these seven patients. Based on these results, five patients (20%) were deemed to be unsuitable candidates for endoscopic therapy. CONCLUSIONS: By detecting unsuspected malignant lymphadenopathy, conventional endosonography and endoscopic ultrasound with fine-needle aspiration dramatically changed the course of management in 20% of patients referred for endoscopic therapy of Barrett's esophagus with high-grade dysplasia or intramucosal carcinoma. Based on our results, we believe that conventional endosonography and endoscopic ultrasound with fine-needle aspiration when nodal disease is present should be performed routinely in all patients referred for endoscopic therapy in this setting.

Subcapsular hepatic hematoma after guide wire injury during endoscopic retrograde cholangiopancreatography: management and review.

Complications of endoscopic retrograde cholangiopancreatography (ERCP) that are associated with the guide wire are fortunately rare, but may be more common than is reported. We describe the case of a 43-year-old woman with obstructive jaundice from metastatic pancreatic cancer who underwent an elective ERCP for biliary stent placement. This was complicated by guide wire-associated injury that resulted in the development and eventual rupture of a subcapsular hepatic hematoma and which was successfully treated with nonsurgical management. If identified and treated rapidly, using a multidisciplinary approach (i. e., with medical, interventional radiology, and surgical input), such patients can be conservatively managed.

Endoscopic ultrasound-guided fine needle aspiration in esophageal cancer.

Esophageal cancer has a poor prognosis since it is often diagnosed in the symptomatic and incurable state. Accurate staging at initial diagnosis is imperative as it determines prognosis and influences treatment. Computed tomography (CT) scan is sensitive for identifying metastatic disease but is insensitive for detecting the extent of wall involvement or nodal disease. Endoscopic ultrasound (EUS) has emerged as a powerful tool in staging esophageal cancer with an impressive accuracy. Use of endoscopic ultrasound-guided fine needle aspiration as an adjunct further improves accuracy in nodal staging and allows for histologic confirmation. The impact of this invaluable staging modality in the management of esophageal cancer continues to grow.

Serous cystadenoma of the pancreas with papillary features: a diagnostic pitfall on fine-needle aspiration biopsy.

Serous cystadenoma of the pancreas is an uncommon neoplasm that occasionally exhibits papillary differentiation. The cytomorphologic structure of pancreatic serous cystadenoma has been rarely described, and, to our knowledge, such papillary morphologic structure has never been reported on fine-needle aspiration cytologic examination. We present a case of serous cystadenoma of the pancreas in a 77-year-old woman. Endoscopic ultrasonography showed a well-demarcated solid/cystic mass in the midbody of the pancreas, suggestive of solid pseudopapillary tumor. Aspiration cytologic examination, performed under endoscopic ultrasound guidance, showed a predominantly papillary epithelial neoplasm consistent with the radiologic impression. Gross and histologic examination of the excised specimen revealed a pancreatic serous cystadenoma with multifocal papillae. This case illustrates the cytomorphologic structure of serous cystadenoma that presents with prominent papillary differentiation on aspiration cytologic examination. The unusual cytologic appearance of this tumor introduces significant diagnostic challenges to the pathologist. Serous cystadenoma must be included in the differential diagnosis of pancreatic neoplasms with papillary morphologic structure as evaluated by fine-needle aspiration cytologic examination.