Management of patients with pancreatic cystic lesions: A case-based survey.

BACKGROUND: Pancreatic cystic lesions (PCL), including intraductal papillary mucinous neoplasia (IPMN), harbor different malignant potential and the optimal management is often challenging. The present study aims to depict the compliance of experts with current consensus guidelines and the accuracy of treatment recommendations stratified by the medical specialty and hospital volume. METHODS: An international survey was conducted using a set of 10 selected cases of PCL that were presented to a cohort of international experts on pancreatology. All presented cases were surgically resected between 2004 and 2015 and histopathological examination was available. Accuracy of the treatment recommendations was based on the European and international consensus guideline algorithms, and the histopathological result. RESULTS: The response rate of the survey was 26% (46 of 177 contacted experts), consisting of 70% surgeons and 30% gastroenterologists/oncologists (GI/Onc). In the case of main-duct IPMN (MD-IPMN), surgeons preferred more often the surgical approach in comparison with the GI/Onc (55 versus 44%). The mean accuracy rate based on the European and international consensus guidelines, and the histopathological result, were 71/76/38% (surgeons), and 70/73/34% (GI/Onc), respectively. High-volume centers achieved insignificantly higher accuracy scores with regard to the histopathology. Small branch-duct IPMN with cysts <2 cm and malignant potential were not identified by the guideline algorithms. CONCLUSION: The survey underlines the complexity of treatment decisions for patients with PCL; less than 40% of the recommendations were in line with the final histopathology in this selected case panel. Experts and consensus guidelines may fail to predict malignant potential in small PCL.

Endoscopic ultrasound-guided fine needle aspiration training: evaluation of a new porcine lymphadenopathy model for in vivo hands-on teaching and training, and review of the literature.

BACKGROUND AND STUDY AIMS: Adequate training is required to achieve successful endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA). Of the variety of training models currently available, none offers verisimilitude to the tactile feel of puncturing a human lymph node. The aim of the current study was to evaluate a new porcine lymph node model for EUS-FNA training and to evaluate its impact on trainees' performance in patients compared with the literature of other models available. METHODS: Two trainees each performed EUS-FNA of 96 lymph nodes in 18 animals with induced lymphadenopathy (mean 1.6 cm [range 0.9-3.5 cm]). Accuracy, speed, adequacy of sampling, and trainees' performance pre- and post-training were measured. Using a questionnaire, data were gathered regarding the effect of training and comfort level in patients. Results were compared with those in the literature. RESULTS: Trainees progressed from hands-on assistance to occasional verbal guidance toward the end of animal training. There was good correlation between puncture time and number of EUS-FNA procedures performed in all but the subcarinal location (r = - 0.17). Comparison of trainee performance in patients before and after training showed a reduction in puncture time (P = 0.0014). Questionnaire analysis revealed increased confidence in echoendoscope- and needle-handling. Comparison with other published models supports these results. CONCLUSION: Results from the literature and the current study showed that animal training improves trainee performance, confidence, and procedural comfort when returning to patient examinations. The new model produces a realistic response that is similar to EUS-FNA in patients; this experience provides a benefit to endoscopists in terms of improved performance in patients and could be considered for use in accreditation. Due to the small numbers of trainees, larger experiences are needed to confirm training efficacy.

Prospective evaluation of malignant cell seeding after percutaneous endoscopic gastrostomy in patients with oropharyngeal/esophageal cancers.

BACKGROUND AND STUDY AIMS: Insertion of a percutaneous endoscopic gastrostomy (PEG) is standard care for many patients with oropharyngeal (ENT) and esophageal malignancies in order to ensure enteral feeding. The current pull-through insertion technique involves direct contact with the tumor and case reports have demonstrated the presence of metastases at insertion sites. The aim of the current study was to prospectively evaluate the risk of malignant cell seeding and the development of abdominal wall metastases after PEG placement. PATIENTS AND METHODS: A total of 50 consecutive patients with ENT/esophageal tumors were included. After PEG placement (40 pull-through technique, 10 direct insertion), brush cytology was taken from the PEG tubing and the transcutaneous incision site. A second cytological assessment was performed after a follow-up period of 3 - 6 months. RESULTS: In total, 26 patients with ENT cancer, 13 with esophageal cancer, and one with esophageal infiltration of lung cancer underwent pull-through PEG placement with no immediate complications. Cytology following brushing of tubing and incision sites demonstrated malignant cells in 9 /40 cases (22.5 %). Correlation analyses revealed a higher rate of malignant seeding in older patients and in those with higher tumor stages. At follow-up, cytology was undertaken in 32 /40 patients who had undergone pull-through PEG placement. Malignant cells were present in three on cytology, resulting in a metastatic seeding rate of 9.4 %. CONCLUSION: This study showed that malignant cells were present in 22.5 % of patients immediately after pull-through PEG placement; local metastases were verified at follow-up in 9.4 %, all of which were from esophageal squamous cell carcinoma. This risk is particularly high in the older age group and in patients with higher tumor stages. Therefore, pull-through PEG placement should be avoided in these patients and direct access PEG favored instead.

Induction of human ß-defensins and psoriasin in vulvovaginal human papillomavirus-associated lesions.

BACKGROUND: Infections with a low-risk type of human papillomavirus (HPV) may lead to genital warts. HPV targets the basal cell layer of epithelial cells. The first line of defense is the innate immune system, which provides nonspecific protection against a variety of pathogens. The antimicrobial peptides (AMPs) α- and ß-defensins, cathelicidins, psoriasin, and RNase7 are central mediators. METHODS: The expression of various α- and ß-defensins, cathelicidin LL-37, psoriasin, and RNase7 was studied in biopsy samples from 35 patients with genital warts and 25 healthy women using quantitative real-time polymerase chain reaction and immunohistochemical analysis. RESULTS: We found a significantly higher expression of the ß-defensins hBD-1 (P = .03), hBD-2 (P < 0.01), and hBD-3 (P < .001), and psoriasin (P = .001) in condylomata acuminata, compared with normal controls. The RNA and protein levels of RNase7 did not differ between infected and uninfected samples (P = .55). The α-defensins HNP 1-3, HD5, and HD6 and the cathelicidin LL-37 were scarcely detectable in normal and infected tissue. CONCLUSIONS: The differing expression of AMPs in HPV-infected, compared with noninfected, vulvovaginal biopsy samples suggests that these peptides are important in the local immune response. Curiously, hBD-1 shows a significant induction whereas RNase7 does not, which suggests differing regulation of AMPs over the course of bacterial and viral infections.

Granulomatous mediastinal adenopathy: can endoscopic ultrasound-guided fine-needle aspiration differentiate between tuberculosis and sarcoidosis?

BACKGROUND AND STUDY AIMS: Mediastinal lymphadenopathy may indicate diseases such as tuberculosis or sarcoidosis, and it is often difficult to establish a diagnosis when standard medical work-up is inconclusive. In this study we investigated the diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the differentiation between tuberculosis and sarcoidosis. PATIENTS AND METHODS: In this prospective study, 72 consecutive patients with mediastinal lymphadenopathy, negative endoscopic investigations including bronchoscopic procedures, and no radiological evidence of lung cancer or other malignancies on computed tomography were enrolled. EUS-FNA and subsequent cytology, microscopy for acid-fast bacilli, and culture were performed. At least 12 months' follow-up including further investigations was included to exclude tuberculosis. RESULTS: Adequate samples were obtained from 71/72 patients (36 male; mean age 50.2 years). No complications occurred. The final diagnosis included 30 cases of sarcoidosis, 28 of tuberculosis, four malignancies, one abscess, and nine benign lymphadenopathies. The size of lymph nodes on EUS varied from 0.5 cm to 4.2 cm. Tuberculosis nodes were significantly smaller than those in sarcoidosis. Unrelated nodes were significantly smaller than in either tuberculosis or sarcoidosis. The sensitivity, specificity, and positive and negative predictive values of EUS - FNA for tuberculosis were 86 %, 100 %, 100 %, and 91 %, respectively; those for sarcoidosis were 100 %, 93 %, 91 %, and 100 %, respectively. For culture of tuberculosis, they were 71 %, 100 %, 100 %, and 84 %, respectively. EUS - FNA led to a definite diagnosis in 64/72 cases (89 %) that had not been previously diagnosed by routine methods. CONCLUSION: EUS - FNA offers a high diagnostic yield for the differential diagnosis of tuberculosis and sarcoidosis that have not been diagnosed by conventional methods.

Endoscopic transesophageal vs. thoracoscopic removal of mediastinal lymph nodes: a prospective randomized trial in a long term animal survival model.

BACKGROUND AND STUDY AIMS: In cases where biopsies remain inconclusive, removal of mediastinal lymph nodes for further analysis requires surgical means. Natural orifice transluminal endoscopic surgery (NOTES) procedures allow incision/closure of the gut wall, which might enable endoscopic excision of pre-marked nodes. The aims of the current study were to investigate the feasibility, safety, and reproducibility of lymph node generation in an animal model to enable endoscopic ultrasound-guided (EUS) lymph node removal (ELR) using transesophageal NOTES access/closure and to compare this procedure with thoracoscopic lymph node removal (TLR) in a randomized long term survival animal study. PATIENTS AND METHODS: Lymph node creation using graphite injection was performed in 12 pigs. After randomization into ELR and TLR groups, lymph nodes were marked with newly developed anchors under EUS guidance and removed using either ELR or TLR. ELR included incision of the esophageal wall and closure after lymph node removal. The main outcome measures were success in lymph node generation, technical success of lymph node removal, complications, and comparability of ELR and TLR. RESULTS: Generation of lymph nodes proved successful in all animals in 46/48 sites injected (96 %). Anchors were placed through the selected nodes in a mean of 9.4 minutes. TLR and ELR were successful in all cases. One bleeding occurred during esophageal incision in ELR, which was stopped endoscopically. After lymph node removal, endoscopic suturing of the incision took a mean of 18 minutes. Procedure time was longer for ELR than TLR (mean 48 vs. 42 minutes). All animals survived the procedures. Autopsy after 4 weeks showed two thoracic wall abscesses in the TLR group and none in the ELR group.  Microscopic analysis revealed well healed esophageal scars. CONCLUSION: ELR proved to be feasible in this limited sample size and complications were not observed more frequently in this group than in the TLR group.

Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils.

Alpha-Synuclein (alpha-Syn) accounts, as a major component of Lewy bodies (LB), for the filamentous deposits in many cases of neurodegenerative diseases. Yet, little is known about the molecular mechanisms of neuronal loss in these diseases. The correlation between alpha-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of alpha-Syn (i.e. monomeric alpha-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucleinopathies. We show that human alpha-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERK1/2 MAP kinases and NF-kappaB) in microglial cells in vitro. Furthermore, stereotactic injection of alpha-Syn PFs into the substantia nigra of adult rats leads to a profound activation of microglia and adjacent neuronal cell loss, which can be attenuated by the MAP kinase inhibitor semapimod. We propose that the neurodegenerative process of alpha-synucleinopathies involves microglial activation through alpha-Syn released or extruded from cells with pathogenic alpha-Syn metabolism. Compounds that inhibit the MAPK/NF-kappaB pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucleinopathies including PD.

NF-kappaB as a molecular target in the therapy of pancreatic carcinoma.

The constitutive activation of the transcription factor nuclear-factor kappa B (NF-kappaB) is a hallmark of many highly malignant tumours such as the pancreatic ductal adenocarcinoma and accounts for profound chemoresistance. Inhibition of NF-kappaB activation has been shown to be a useful strategy for increasing the sensitivity towards cytostatic drug treatment in vitro and in vivo. Moreover, various pharmacological substances (e.g. thalidomide, bortezomib, sulphasalazine) have already entered clinical studies partially showing promising results for certain types of cancer. Further studies will be needed, in particular for pancreatic ductal adenocarcinoma, to evaluate the therapeutic efficacy of appropriate combinations of a NF-kappaB inhibitor and cytostatic drugs.

Fatal pneumocystis jirovecii pneumonia in a case of ectopic Cushing's syndrome due to neuroendocrine carcinoma of the kidney.

Immunosuppression with subsequent opportunistic infections is a well-recognized complication of severe hypercortisolism. We report a case of fatal pneumocystis jirovecii pneumonia (formerly pneumocystis carinii pneumonia) in a case of ectopic Cushing's syndrome caused by a neuroendocrine carcinoma of the kidney. The 36-year old male patient had consulted a physician because of weight gain. Further endocrine diagnostic work-up revealed ACTH-dependent hypercortisolism of non-pituitary origin. Because of rapid clinical deterioration therapy with metyrapone was initiated. A neuroendocrine carcinoma of the right kidney with regional lymph node infiltration was identified and was suspected to be the source of the ACTH excess. Before any causal therapy could be initiated, the patient developed severe pneumocystis jirovecii pneumonia and died shortly thereafter from multiorgan failure one month after he first consulted a physician. Pneumocystosis has been reported in only a few cases of Cushing's syndrome. There seems to be a relationship between the degree of hypercortisolism and the susceptibility to opportunistic infections. Since ACTH concentrations may be excessively high in ectopic Cushing's syndrome and pneumocystosis may deteriorate as a consequence of decreasing circulating cortisol levels under adrenolytic therapy, prophylaxis against pneumocystis jirovecii infection should be considered.