Endoscopic resection of early squamous neoplasia of the oesophagus: long-term follow-up in a UK population from a tertiary hospital.

AIM: To review the efficacy and outcomes of endoscopic resection in the diagnosis and treatment of oesophageal squamous dysplasia and early neoplasia. METHODS: This was a retrospective study between May 2012-2018. Twenty-one patients were treated with or considered for treatment with endoscopic resection at a tertiary hospital in the UK. The primary outcome was curative resection, defined as histologically proven complete resection of the lesion with deep/vertical margin ≥1 mm from neoplasia. Secondary outcomes were changes in staging from endoscopic resection histology, whether there was a complete reversal of dysplasia at 12-months or the latest endoscopic follow-up and 5-year overall survival rate. RESULTS: Seventeen patients (mean age = 66.5 years) with 20 lesions (35% en-bloc; 65% piecemeal resections) had endoscopic resection performed. Complete resection was achieved in 90% of lesions by endoscopic criteria, but this was confirmed in fewer lesions histologically. Curative resection was achieved histologically in 60% of lesions (11 patients) and noncurative resection in 40% of lesions (6 patients). Changes in staging from endoscopic resection histology were found in 79.2% of lesions (41.7% upstaged; 37.5% downstaged). No patients were found to have recurrence at their 12-month endoscopic follow-up. Eight of the 11 patients (72.7%) with curative resection remained clear of dysplasia/neoplasia throughout their follow-up (mean, 24.3 months; median, 19 months). The five-year overall survival rate was 64%. CONCLUSION: In UK, endoscopic resection is useful in the management of early squamous neoplasia both for staging and (by piecemeal endoscopic resection in elderly unfit) for medium- to long-term disease clearance.

Accuracy of the revised Vienna Classification for predicting postendoscopic resection outcomes for gastric and oesophageal neoplasms: a retrospective cohort study of patients from a UK tertiary referral centre.

AIMS: To review the effectiveness of the revised Vienna classification (rVC) at predicting histological outcome and defining the postendoscopic resection (ER) clinical management plan of gastro-oesophageal dysplasia and early neoplasia in a UK tertiary-centre population. METHODS: This was a retrospective cohort study between November 2011 and May 2018. 157 patients from Salford Royal NHS Foundation Trust in the UK were included. The primary outcome was the histological results of postsurgical resection (SR) specimens compared with their post-ER rVC. The secondary outcome was overall survival rates of patients with category 4.4 and 5 of the rVC. RESULTS: One-hundred and thirteen patients were diagnosed with category ≥4 of the rVC. 23 patients (20.4%) were referred for additional surgery, whereas 69 patients (61.1%) were on endoscopic surveillance only. 60.9% of post-SR specimens (14/23) revealed no residual neoplasia. 78.6% of these cancer-free specimens were classed as category 5 rVC. The overall 7-year survival rate of 25 patients with category ≥4.4 was 68% with causes of mortality not linked to upper gastrointestinal neoplasia. The overall 7-year and 3-year survival rates of category 4.4 and 5 were 73.6% and 50%, respectively, although age and comorbid state played a role. CONCLUSIONS: This study provides evidence of outcomes comparable to other reported cohorts for cases after ER in a single-centre UK population even at rVC 4.4/5. It suggests surgery may not be necessary in all cases due to the lack of residual disease and further refinement of the rVC category 5 may help guide management.

What Factors Influence Delayed Referral to Spinal Surgeon in Adolescent Idiopathic Scoliosis?

STUDY DESIGN: Retrospective review with qualitative phone interview. OBJECTIVE: This study aims to identify the factors leading to delayed diagnosis or referral to a spinal surgeon in patients who subsequently require surgery for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: AIS can be effectively treated with bracing to prevent curve progression in skeletally immature patients. Australia currently has in place a national self-detection screening program to diagnose AIS. METHODS: A retrospective review was performed for patients who underwent surgery for scoliosis at Princess Margaret Hospital for Children and Royal Perth Hospital between June 1, 2010 and May 27, 2014. Data were retrieved from the digital medical record and a semistructured phone interview was used to determine path to diagnosis and referral. RESULTS: Mean Cobb angle at first specialist review was 49.5°â€Š±â€Š14.0° for patients who subsequently required surgery for AIS. These patients experienced an average interval of 20.7 months from detection of symptoms to review in a specialist clinic. CONCLUSION: In a condition in which early detection and intervention may halt progression of disease, AIS is detected relatively late and there are specific delays to diagnosis and referral to specialist clinics. LEVEL OF EVIDENCE: 4.

Gastric endoscopic submucosal dissection as a treatment for early neoplasia and for accurate staging of early cancers in a United Kingdom Caucasian population.

AIM: To investigate the efficacy of endoscopic submucosal dissection (ESD) at diagnosing and treating superficial neoplastic lesions of the stomach in a United Kingdom Caucasian population. METHODS: Data of patients treated with or considered for ESD at a tertiary referral center in the United Kingdom were retrieved for a period of 2 years (May 2015 to June 2017) from the electronic patient records of the hospital. Only Caucasian patients were included. Primary outcomes were curative resection (CR) and were defined as ESD resections with clear horizontal and vertical margin and an absence of lympho-vascular invasion, poor differentiation and submucosal involvement on histological evaluation of the resected specimen. Secondary end-points were reversal of dysplasia at 12 mo endoscopic follow-up and/or at the latest follow up. Change in histological diagnosis pre and post ESD was also analysed. RESULTS: Twenty-four patients were initially identified with intention to treat. 19 patients were eligible after mapping gastroscopy and ESD was attempted on a total of 25 ESD lesions, 4 of which failed and had to be aborted mid-procedure. Out of 21 ESD performed, en-bloc resection was achieved in 71.4% of cases. Resection was considered complete on endoscopy in 90.5% of cases compared to only 38.1% on histology. A total of 6 resections were considered curative (28%), 5 non-curative (24%) and 10 indefinite for CR or non-CR (24%). ESD changed the histological diagnosis in 66.6% of cases post ESD. Endoscopic follow-up in the "indefinite" group and CR group showed that 50% and 80% of patients were clear of dysplasia at the latest follow-up respectively; 2 cases of recurrence were observed in the "indefinite"group. Survival rate for the entire cohort was 91.7%. CONCLUSION: This study provides early evidence for the efficacy of ESD as a therapeutic and diagnostic intervention in Caucasian populations and supports its application in the United Kingdom.

Hepatitis e infection in a renal transplant recipient.

An asymptomatic 35-year-old renal transplant recipient was noted to have deranged liver function tests. Liver biopsy revealed a portal inflammatory process with mild lobular activity and portal fibrous expansion, consistent with a virally mediated process. An extensive viral screen confirmed infection with Hepatitis E virus genotype 3 (HEV-3). There is increased awareness about locally acquired Hepatitis E virus (HEV) infection in the transplant population in the UK. The important implications of this infection are becoming more apparent as progression to liver cirrhosis can occur. However, the incidence, natural history, and treatment of HEV infection in the transplant population are not well established. This report illustrates a case of delayed spontaneous clearance of the HEV infection.

Identification and characterization of lactococcal-prophage-carried superinfection exclusion genes.

Superinfection exclusion (Sie) proteins are prophage-encoded phage resistance systems. In this study, genes encoding Sie systems were identified on the genomes of Lactococcus lactis subsp. cremoris MG1363 and L. lactis subsp. lactis IL1403. These Sie systems are genetically distinct and yet were shown to act specifically against a particular subset of the 936 phage group. Each of the systems allows normal phage adsorption while affecting plasmid transduction and intracellular phage DNA replication, which points to the blocking of phage DNA injection as their common mode of action. Sie-specifying genes found on the MG1363 prophages are also present in various lactococcal strains, whereas the prophage-encoded Sie systems of IL1403 do not appear to be as widely disseminated.

Metastatic transitional cell carcinoma causing a unilateral pleural effusion: a case report.

BACKGROUND: Transitional cell carcinoma (TCC) is a common neoplasm, but it is only rarely associated with serous effusions. The cytologic features of metastatic TCC in pleural effusions have been described only in occasional studies. One feature that raises the possibility of metastatic TCC in this setting is the presence of eosinophilic cytoplasmic inclusions (ECIs). CASE: Metastatic TCC was diagnosed in a pleural fluid from a 50-year-old man with a unilateral effusion. Two years previously he had been diagnosed with a poorly differentiated TCC of the urinary bladder (WHO grade 3, stage pT2 at least), and more recently he had also been diagnosed with an omental metastasis. Cytologic examination of the pleural fluid sample revealed numerous pleomorphic malignant cells, many of which were vacuolated. Numerous eosinophilic inclusions were identified within the malignant cells in the liquid based cytology (ThinPrep) preparation. Examination of the omental cake biopsy revealed similar appearances. CONCLUSION: ECIs within malignant pleural effusion fluid specimens should, if detected, raise the possibility of metastatic transitional cell carcinoma.

Histopathological assessment of lymph nodes in upper gastrointestinal cancer: does triple levelling detect significantly more metastases?

BACKGROUND: For cancers of the upper gastrointestinal tract it is standard to examine one section/level, from paraffin blocks containing lymph node tissue, for metastatic tumour. AIMS: To determine whether significantly more metastases can be detected by assessing two additional levels. METHODS: 101 archival upper gastrointestinal cancers were evaluated. All negative lymph nodes were examined at two additional levels separated by 100 microm and stained by H&E. The slides were examined for the presence of metastases. RESULTS: 1143 lymph nodes, that were originally clear of metastases, were examined at a further two levels (three levels in total); 23 additional metastases were identified in 17 patients. Eleven of these patients were already stage N1 before examination of the additional levels. However, six patients were originally N0, and were therefore upgraded to N1. CONCLUSIONS: Examining lymph nodes at three levels did detect more metastatic deposits than examination of one section/level. In six patients this changed the N stage from N0 to N1. This would have significant prognostic and management implications.

A terrestrial biotic ligand model. 1. Development and application to Cu and Ni toxicities to barley root elongation in soils.

A Terrestrial Biotic Ligand Model (TBLM) was developed using noncalcareous soils from Europe based on Cu and Ni speciation and barley (Hordeum vulgare cv. Regina) root elongation bioassays. Free metal ion (M2+) activity was computed by the WHAM VI model using inputs of soil metal, soil organic matter, and alkali and alkaline earth metals concentrations, and pH in soil solution. The TBLM assumes that metal in soil and in the solution are in equilibrium. Metal ions react with the biotic ligand, the receptor site, and inhibit root elongation. Other ions, principally H+, Ca2+ and Mg2+, compete with M2+ and, therefore, affect its toxicity. Toxicity is correlated only to the fraction of the total biotic ligand sites occupied by M2+. Compared to other models using either the soil metal concentration or M2+ activity as the toxic dose, the TBLM provides a more consistent method to normalize and compare Cu and Ni toxicities to root elongation among different soils. The TBLM was able to predictthe EC50 soil Cu and Ni concentrations generally within a factor of 2 of the observed values, a level of precision similar to that for the aquatic Biotic Ligand Model, indicating its potential utility in metals risk assessment in soils.

Terrestrial biotic ligand model. 2. Application to Ni and Cu toxicities to plants, invertebrates, and microbes in soil.

The Terrestrial Biotic Ligand Model (TBLM) is applied to a number of noncalcareous soils of the European Union for Cu and Ni toxicities using organisms and endpoints representing three levels of terrestrial organisms: higher plants, invertebrates, and microbes. A comparison of the TBLM predictions to soil metal concentration or free metal ion activity in the soil solution shows that the TBLM is able to achieve a better normalization of the wide variation in toxicological endpoints among soils of disparate properties considered in this study. The TBLM predictions of the EC50s were generally within a factor of 2 of the observed values. To our knowledge, this is the first study that incorporates Cu and Ni toxicities to multiple endpoints associated with higher plants, invertebrates, and microbes for up to eleven noncalcareous soils of disparate properties, into a single theoretical framework. The results of this study clearly demonstrate that the TBLM can provide a general framework for modeling metals ecotoxicity in soils.

Comparative genomics and transcriptional analysis of prophages identified in the genomes of Lactobacillus gasseri, Lactobacillus salivarius, and Lactobacillus casei.

Lactobacillus gasseri ATCC 33323, Lactobacillus salivarius subsp. salivarius UCC 118, and Lactobacillus casei ATCC 334 contain one (LgaI), four (Sal1, Sal2, Sal3, Sal4), and one (Lca1) distinguishable prophage sequences, respectively. Sequence analysis revealed that LgaI, Lca1, Sal1, and Sal2 prophages belong to the group of Sfi11-like pac site and cos site Siphoviridae, respectively. Phylogenetic investigation of these newly described prophage sequences revealed that they have not followed an evolutionary development similar to that of their bacterial hosts and that they show a high degree of diversity, even within a species. The attachment sites were determined for all these prophage elements; LgaI as well as Sal1 integrates in tRNA genes, while prophage Sal2 integrates in a predicted arginino-succinate lyase-encoding gene. In contrast, Lca1 and the Sal3 and Sal4 prophage remnants are integrated in noncoding regions in the L. casei ATCC 334 and L. salivarius UCC 118 genomes. Northern analysis showed that large parts of the prophage genomes are transcriptionally silent and that transcription is limited to genome segments located near the attachment site. Finally, pulsed-field gel electrophoresis followed by Southern blot hybridization with specific prophage probes indicates that these prophage sequences are narrowly distributed within lactobacilli.

Bacteriophage Tuc2009 encodes a tail-associated cell wall-degrading activity.

Tuc2009 is a P335-type member of the tailed-phage supergroup Siphoviridae and was originally identified as a resident prophage of the gram-positive bacterium Lactococcus lactis UC509. A Tuc2009 gene designated tal2009 which is located within the morphogenic module was shown to specify a lytic activity within the 3' portion of its coding region. Comparative sequence analysis indicated that the cell wall-degrading part of Tal2009 is a member of the M37 protein family and that Tal2009 lacks a cell-binding domain, a finding supported by binding studies. Tal2009 appears to undergo self-mediated posttranslational processing in both L. lactis and Escherichia coli. Antibodies directed against a purified C-terminal portion of Tal2009 were used for immunoelectron microscopy, which showed that Tal2009 is located at the tail tip of Tuc2009. Antibody neutralization studies demonstrated that Tal2009-directed antibodies inhibited the ability of phage to mediate host lysis by more than 100-fold. These data indicate that tal2009 encodes a tail-associated lysin involved in localized cell wall degradation, thus allowing the Tuc2009 DNA injection machinery access to the membrane of its bacterial host.

The impact of bacteriophage genomics.

The discovery of (bacterio)phages revolutionised microbiology and genetics, while phage research has been integral to answering some of the most fundamental biological questions of the twentieth century. The susceptibility of bacteria to bacteriophage attack can be undesirable in some cases, especially in the dairy industry, but can be desirable in others, for example, the use of bacteriophage therapy to eliminate pathogenic bacteria. The relative ease with which entire bacteriophage genome sequences can now be elucidated has had a profound impact on the study of these bacterial parasites.

Dueling quorum sensing systems in Pseudomonas aeruginosa control the production of the Pseudomonas quinolone signal (PQS).

The opportunistic human pathogen Pseudomonas aeruginosa regulates the production of numerous virulence factors via the action of two separate but coordinated quorum sensing systems, las and rhl. These systems control the transcription of genes in response to population density through the intercellular signals N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C(12)-HSL) and N-(butanoyl)-L-homoserine lactone (C(4)-HSL). A third P. aeruginosa signal, 2-heptyl-3-hydroxy-4-quinolone [Pseudomonas quinolone signal (PQS)], also plays a significant role in the transcription of multiple P. aeruginosa virulence genes. PQS is intertwined in the P. aeruginosa quorum sensing hierarchy with its production and bioactivity requiring the las and rhl quorum sensing systems, respectively. This report presents a preliminary transcriptional analysis of pqsA, the first gene of the recently discovered PQS biosynthetic gene cluster. We show that pqsA transcription required pqsR, a transcriptional activator protein encoded within the PQS biosynthetic gene cluster. It was also found that the transcription of pqsA and subsequent production of PQS was induced by the las quorum sensing system and repressed by the rhl quorum sensing system. In addition, PQS production was dependent on the ratio of 3-oxo-C(12)-HSL to C(4)-HSL, suggesting a regulatory balance between quorum sensing systems. These data are an important early step toward understanding the regulation of PQS synthesis and the role of PQS in P. aeruginosa intercellular signaling.

Identification and characterization of phage-resistance genes in temperate lactococcal bacteriophages.

The sie2009 gene, which is situated between the genes encoding the repressor and integrase, on the lysogeny module of the temperate lactococcal bacteriophage Tuc2009, was shown to mediate a phage-resistance phenotype in Lactococcus lactis against a number of bacteriophages. The Sie2009 protein is associated with the cell membrane and its expression leaves phage adsorption, transfection and plasmid transformation unaffected, but interferes with plasmid transduction, as well as phage replication. These observations indicate that this resistance is as a result of DNA injection blocking, thus representing a novel superinfection exclusion system. A polymerase chain reaction (PCR)-based strategy was used to screen a number of lactococcal strains for the presence of other prophage-encoded phage-resistance systems. This screening resulted in the identification of two such systems, without homology to sie2009, which were shown to mediate a phage-resistance phenotype similar to that conferred by sie2009. To our knowledge, this is the first description of a phage-encoded super-infection exclusion/injection blocking mechanism in the genus Lactococcus.