The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program.

BACKGROUND: Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population. METHODS: The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12 months. RESULTS: Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow-up of 25 months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p < 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1-13, p = 0.03). CONCLUSIONS: In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

Optimizing cytological specimens of EUS-FNA of solid pancreatic lesions: A pilot study to the effect of a smear preparation training for endoscopy personnel on sample quality and accuracy.

BACKGROUND: In the absence of rapid on-side pathological evaluation, endoscopy staff generally "smears" endoscopic ultrasound guided fine needle aspiration (EUS-FNA) specimens on a glass slide. As this technique is vulnerable to preparation artifacts, we assessed if its quality could be improved through a smear-preparation-training for endoscopy staff. METHODS: In this prospective pilot study, 10 endosonographers and 12 endoscopy nurses from seven regional EUS-centers in the Netherlands were invited to participate in a EUS-FNA smear-preparation-training. Subsequently, post training slides derived from solid pancreatic lesions were compared to pre-training "control" slides. Primary outcome was to assess if the training positively affects smear quality and, consequently, diagnostic accuracy of EUS-FNA of solid pancreatic lesions. RESULTS: Participants collected and prepared 71 cases, mostly pancreatic head lesions (48%). Sixty-eight controls were selected from the pretraining period. The presence of artifacts was comparable for smears performed before and after training (76% vs 82%, P = .36). Likewise, smear cellularity (≥50% target cells) before and after training did not differ (44% (30/68) vs 49% (35/71), P = .48). Similar, no difference in diagnostic accuracy for malignancy was detected (P = .10). CONCLUSION: In this pilot EUS-FNA smear-preparation-training for endoscopy personnel, smear quality and diagnostic accuracy were not improved after the training. Based on these results, we plan to further study other training programs and possibilities.

Diagnostic yield and agreement on fine-needle specimens from solid pancreatic lesions : comparing the smear technique to liquid-based cytology.

Background and study aims The traditional "smear technique" for processing and assessing endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is sensitive to artifacts. Processing and evaluation of specimens collected in a liquid medium, liquid-based cytology (LBC) may be a solution. We compared the diagnostic value of EUS-FNA smears to LBC in pancreatic solid lesions in the absence of rapid on-site evaluation (ROSE). Patients and methods Consecutive patients who required EUS-FNA of a solid pancreatic lesion were included in seven hospitals in the Netherlands and followed for at least 12 months. Specimens from the first pass were split into two smears and a vial for LBC (using ThinPrep and/or Cell block). Smear and LBC were compared in terms of diagnostic accuracy for malignancy, sample quality, and diagnostic agreement between three cytopathologists. Results Diagnostic accuracy for malignancy was higher for LBC (82 % (58/71)) than for smear (66 % (47/71), P  = 0.04), but did not differ when smears were compared to ThinPrep (71 % (30/42), P  = 0.56) or Cell block (62 % (39/63), P  = 0.61) individually. Artifacts were less often present in ThinPrep (57 % (24/42), P  = 0.02) or Cell block samples (40 % (25/63), P  < 0.001) than smears (76 % (54/71)). Agreement on malignancy was equally good for smears and LBC (ĸ = 0.71 versus ĸ = 0.70, P  = 0.98), but lower for ThinPrep (ĸ = 0.26, P  = 0.01) than smears. Conclusion After a single pass, LBC provides higher diagnostic accuracy than the conventional smear technique for EUS-FNA of solid pancreatic lesions in the absence of ROSE. Therefore, LBC, may be an alternative to the conventional smear technique, especially in centers lacking ROSE.

Radiological Position and Clinical Outcome of Preoperative Self-Expanding Metal Stents for Obstructing Colonic Cancer: A Single-Centre Cohort Study.

BACKGROUND: Preoperative placement of self-expanding metal stents is used in patients with obstructing colon carcinoma to prevent an emergency operation. The perceived benefits remain the subject of discussion. The data-evaluating function and complications of stents in relation to radiological position are limited. METHODS: Patients receiving a preoperative stent between 2003 and 2013 were retrospectively analysed in this single-centre study. We analysed radiological deployment, eccentricity and angulation of the stent directly after placement. Endpoints were clinical success (resolution of ileus), complications needing non-elective surgery (blow-out, perforation, persistent ileus, dislocation) and other complications (bleeding, infiltrate). Associations were corrected for other potential influences. RESULTS: Eighty-two patients were included. In 22 patients (26.8%), the stent was placed proximal to the splenic flexure. Clinical success was present in 85.4%. Twenty-two patients (26.8%) had a complication of which 16 (19.5%) underwent urgent surgery for insufficient functioning of the stent; there were two blow-outs (2.4%). A more symmetrically placed stent was associated with clinical success (p = 0.042), with large overlap between groups. However, no association was found with non-elective surgery or complications. Also, angulation and deployment were unassociated with these outcomes. CONCLUSIONS: We could not establish an association between symmetry, angulation or deployment of self-expandable colonic stents with clinical success and complications.

Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7.

BACKGROUND: ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients. METHODS: The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy. RESULTS: Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-α and IFN-γ inducible protein (IP)-10 levels were observed only in virological responders (≥1 log(10) IU/ml reduction of HCV RNA levels upon ANA773 treatment), but were absent in virological non-responders. In vitro stimulation of peripheral blood mononuclear cells from virological responders showed a high frequency of IFN-α-producing plasmacytoid DC upon stimulation in vitro with ANA773, whereas no IFN-α was induced in non-responders. CONCLUSIONS: These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-α and IP-10) upon TLR7 ligation.

Continuous interferon-α2b infusion in combination with ribavirin for chronic hepatitis C in treatment-experienced patients.

BACKGROUND: Sustained virological response (SVR) rates in previous non-responders to pegylated interferon (PEG-IFN)-α and ribavirin for chronic HCV remain low (~10%). We hypothesize that continuous subcutaneous delivery of fully potent interferon (IFN)-α2b via an external pump will lead to stable blood concentrations and thereby prevent subtherapeutic trough levels associated with viral breakthrough. The aims of the study were to assess safety, tolerability and virological response in patients who were previous PEG-IFN-α/ribavirin non-responders. METHODS: We randomized 30 HCV genotype 1 (n=24) and genotype 4 (n=6) patients to receive 6, 9 or 12 million units (MU) IFN-α2b daily by continuous subcutaneous administration using an insulin pump (MiniMed(®) 508; Medtronic Inc., Minneapolis, MN, USA) in combination with ribavirin (1,000-1,600 mg) for 48 weeks. RESULTS: The magnitude of viral decline in the 12 MU group after 4 weeks of treatment was 2.67 log HCV RNA compared with 1.21 and 1.27 log HCV RNA in the 9 and 6 MU groups, respectively (P=0.001). In the intention-to-treat analysis, the SVR rate was 20% (6/30). The per-protocol SVR rate was 25% (6/24), of which four out of six patients in the high-dose arm achieved SVR. Adverse events appeared dose-dependent, were mostly mild-to-moderate and were typical of IFN therapy. Five patients developed irritation and/or abscesses at the injection site. Six serious adverse events were reported in five patients. CONCLUSIONS: Continuous delivery of IFN-α2b can induce a strong dose-dependent viral suppression. This could be an effective approach in conjunction with, or as lead-in therapy prior to, treatment with a direct antiviral agent.

Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients.

UNLABELLED: Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log10 in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥ 60%) patients had undetectable HCV-RNA (< 25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated. CONCLUSION: Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients.

Safety and antiviral activity of JTK-652: a novel HCV infection inhibitor.

BACKGROUND: Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK-652, a novel pyrrolopyridazin-derived HCV infection inhibitor. METHODS: JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1x10(5) IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks. RESULTS: JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment. CONCLUSIONS: Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level.

Gamma-glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon-alpha-2b in chronic hepatitis C non-responders.

BACKGROUND: High-dose peginterferon-alpha (PegIFN-alpha) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-alpha may intensify side effects. METHODS: We randomized 53 patients, who previously failed with standard IFN-alpha+/-ribavirin, to a high-dose induction and an extended regimen with PegIFN-alpha-2b [3.0 microg/kg once weekly (q.w.) 12 weeks-->2.0 microg/kg q.w. 12 weeks-->1.5 microg/kg q.w. 48 weeks] or a standard regimen (1.5 microg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). RESULTS: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P=0.01] and gamma-glutamyltransferase (GGT) levels <2 x ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 x ULN (OR: 7.3, 95% CI: 1.4-38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P<0.001) were independently predictive for SVR. CONCLUSION: Retreatment with PegIFN-alpha-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome.