Percutaneous biliary stone clearance: is there still a need? A 10-year single-centre experience.

AIM: To evaluate the safety and efficacy of percutaneous biliary stone clearance in a single hepatopancreaticobiliary (HPB) centre. MATERIALS AND METHODS: All patients who underwent percutaneous biliary stone clearance between 2010 and 2020 at a HPB centre were identified from the radiology information system. Their demographic data, presentation, previous surgery, number/size of biliary calculi, success and complications were collected from patient records. Unpaired student's t-test was used to compare numerical variables and the Chi-square test was used to compare categorical data. RESULTS: Sixty-eight patients aged between 58.5-91.1 years underwent the procedure, and 42.6% (29/68) had the procedure due to surgically altered anatomy precluding endoscopic retrograde cholangiopancreatography (ERCP). The most common presentation was cholangitis (62%). The success rate of percutaneous stone clearance was 92.7%. The average number of calculi was two (range 1-12). Of the patients included, 4.4% developed pancreatitis, 4.4% developed cholangitis, and 1.5% had hepatic artery branch pseudoaneurysm successfully treated with transarterial embolisation. There was no significant difference in success or complication rates between the different access sites (right lobe, left lobe, roux-loop, T-tube, p=0.7767). CONCLUSION: Percutaneous biliary stone clearance is safe and effective and will continue to play an important role where ERCP fails or is impossible due surgically altered anatomy.

Profile of exhaled-breath volatile organic compounds to diagnose pancreatic cancer.

BACKGROUND: Pancreatic cancer has a very poor prognosis as most patients are diagnosed at an advanced stage when curative treatments are not possible. Breath volatile organic compounds (VOCs) have shown potential as novel biomarkers to detect cancer. The aim of the study was to quantify differences in exhaled breath VOCs of patients with pancreatic cancers compared with cohorts without cancer. METHODS: Patients were recruited to an initial development cohort and a second validation cohort. The cancer group included patients with localized and metastatic cancers, whereas the control group included patients with benign pancreatic disease or normal pancreas. The reference test for comparison was radiological imaging using abdominal CT, ultrasound imaging or endoscopic ultrasonography, confirmed by histopathological examination as appropriate. Breath was collected from the development cohort with steel bags, and from the validation cohort using the ReCIVA™ system. Analysis was performed using gas chromatography-mass spectrometry. RESULTS: A total of 68 patients were recruited to the development cohort (25 with cancer, 43 no cancer) and 64 to the validation cohort (32 with cancer, 32 no cancer). Of 66 VOCs identified, 12 were significantly different between groups in the development cohort on univariable analysis. Receiver operating characteristic (ROC) curve analysis using significant volatile compounds and the validation cohort produced an area under the curve of 0·736 (sensitivity 81 per cent, specificity 58 per cent) for differentiating cancer from no cancer, and 0·744 (sensitivity 70 per cent, specificity 74 per cent) for differentiating adenocarcinoma from no cancer. CONCLUSION: Breath VOCs may distinguish patients with pancreatic cancer from those without cancer.

Meta-analysis of drain amylase content on postoperative day 1 as a predictor of pancreatic fistula following pancreatic resection.

BACKGROUND: Drain amylase content in the days immediately after major pancreatic resection has been investigated previously as a predictor of postoperative pancreatic fistula (POPF). Its accuracy, however, has not been determined conclusively. The purpose of this study was to evaluate the accuracy of drain amylase content on the first day after major pancreatic resection in predicting the occurrence of POPF. METHODS: A literature search of the MEDLINE, Embase and Scopus(®) databases to 13 May 2015 was performed to identify studies evaluating the accuracy of drain amylase values on day 1 after surgery in predicting the occurrence of POPF. The area under the hierarchical summary receiver operating characteristic (ROC) curve (AUChSROC ) was calculated as an index of accuracy, and pooled estimates of accuracy indices (sensitivity and specificity) were calculated at different cut-off levels. Subgroup and meta-regression analyses were performed to test the robustness of the results. RESULTS: Thirteen studies involving 4416 patients were included. The AUChSROC was 0·89 (95 per cent c.i. 0·86 to 0·92) for clinically significant POPF and 0·88 (0·85 to 0·90) for POPF of any grade. Pooled estimates of sensitivity and specificity were calculated for the different cut-offs: 90-100 units/l (0·96 and 0·54 respectively), 350 units/l (0·91 and 0·84) and 5000 units/l (0·59 and 0·91). Accuracy was independent of the type of operation, type of anastomosis performed and octreotide administration. CONCLUSION: Evaluation of drain amylase content on the first day after surgery is highly accurate in predicting POPF following major pancreatic resection. It may allow early drain removal and institution of an enhanced recovery pathway.

Neoadjuvant chemotherapy and primary-first approach for rectal cancer with synchronous liver metastases.

AIM: Up to a quarter of patients with rectal cancer have synchronous liver metastases at the time of diagnosis. This is a predictor of poor outcome. There are no standardized guidelines for treatment. We reviewed the outcomes of our patients with synchronous rectal liver metastases treated with a curative intent by neoadjuvant chemotherapy with or without chemoradiotherapy followed by resection of the primary tumour and then liver metastases. METHOD: Between 2004 and 2012, patients who presented with rectal cancer and synchronous liver metastasis were treated with curative intent with peri-operative systemic chemotherapy as the first line of treatment. Responders to chemotherapy underwent resection of the primary tumour with or without preoperative chemoradiotherapy followed by hepatic resection. RESULTS: Fifty-three rectal cancer patients with 152 synchronous liver lesions were identified. After a median follow-up of 29.6 months, the median survival was 41.4 months. Overall survival was 59.0% at 3 years and 39.0% at 5 years. CONCLUSION: Rectal resection before hepatic resection combined with neoadjuvant chemotherapy is associated with promising clinical outcome. It allows downstaging of liver lesions and removal of the primary tumour before the progression of further micrometastases. Furthermore, patients who do not respond to chemotherapy can be identified and may avoid major surgical intervention.

Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease.

BACKGROUND: Neuroendocrine neoplasias (NEN) of the gastroenteropancreatic (GEP) system frequently present with metastatic deposits. The proliferation marker Ki-67 is used for diagnosis and to assess the prognosis of disease. The aim of our study was to evaluate the usefulness of Ki-67 % in the assessment of NEN patients with regard to their disease stage in clinical practice. Additionally, a comparative analysis of Ki-67 levels among different sites of disease was performed. METHODS: This retrospective study included patients with GEP NEN referred to our center from 2010 to 2012. The NEN diagnosis was confirmed by standard histopathology. Ki-67 immunohistochemistry was done on paraffin-embedded sections using an automated Leica immunohistochemistry machine. NEN grading was carried out according to European Neuroendocrine Tumor Society recommendations (low grade [G1] to intermediate grade [G2], well to moderately differentiated neuroendocrine neoplasms; high-grade [G3], moderately to poorly differentiated neuroendocrine neoplasms). Results of tumor staging and grading were correlated. In a subgroup of cases, comparative analysis of Ki-67 levels in different sites of disease was carried out. RESULTS: One hundred sixty-one GEP NEN patients were included in the study. Metastatic disease was seen in 46.1 % (53/115) of G1 tumors, 77.8 % (28/36) of G2 tumors, and 100 % of (10/10) G3 tumors (p = 0.0002). When stratified according to primary tumor site, metastatic disease was documented in 42.9 % (36/84) of patients with pancreatic NEN and in 91.9 % (34/37) of those with small intestinal primary. Stage IV metastatic disease was present in 27.8 % (32/115) and 72.2 % (26/36) of the G1 and G2 tumors, respectively, and in 90 % (9/10) of the G3 tumors. Assessment of the Ki-67 index for a subset of cases at metastatic sites as well as the primary tumor site showed discrepancies in 35.3 % cases. In 7/9 (77.8 %) patients with liver metastases, Ki-67 % was higher in the liver lesions than in the primary tumor. CONCLUSIONS: Patients with GEP NEN exhibiting a high Ki-67 proliferation index present with metastatic disease in the vast majority of cases. Depending upon the primary tumor site, metastases are to be expected also in tumors with low Ki-67 %, although they are considered less aggressive. Different disease sites may express heterogeneous Ki-67 levels.

Pancreatobiliary cytology in the multidisciplinary setting.

This review article discusses the role of endoscopic ultrasound-guided fine needle aspiration (EUS FNA) cytology in the clinical management of patients with pancreatic tumours in the setting of a multidisciplinary team (MDT). The commonest diagnosis encountered is pancreatic adenocarcinoma, which is seldom diagnosed early enough for surgical resection. Thus, cytology is likely to be the only form of diagnosis in the majority of cases. Nevertheless, about half the lesions discussed at the MDT meeting are lesions other than primary adenocarcinoma and a wide differential diagnosis must be considered in order to identify tumours, including neuroendocrine tumours, that are amenable to surgical resection. Cytology is not always definitive and the diagnosis may be helped by categorizing results according to whether they are malignant, suspicious, atypical/indeterminate, benign or inadequate. Discussion at MDT meetings and correlation with clinical and imaging findings along with review of cytology slides may allow equivocal results to be clarified before treatment is decided. Inadequate cytology results are avoided by rapid on-site evaluation of slides; although this is cost-effective in terms of overall patient care, attendance of cytopathologists on-site may not be feasible. At Imperial College NHS Trust, specially trained biomedical scientists successfully carry out rapid on-site evaluation.

Preferential induction of polyclonal IgA secretion by murine Peyer's patch dendritic cell-T cell mixtures.

Polyclonal IgA secretion is inducible in murine B cells when DC-T from Peyer's patches (PP) provide the inducing stimulus. PP DC-T, which are composed predominantly of dendritic cells and Lyt-1+ T cells, are capable of dramatic augmentation of IgA secretion by PP or spleen B cells with minimal induction of IgM secretion. DC-T from spleen, however, are incapable of augmenting IgA secretion by either PP or spleen B cells. The level of IgA secretion is dependent upon the dose of DC-T providing the inducing stimulus and reaches a plateau with DC-T:B ratios of less than 1:1. This system for preferential induction of IgA responses should permit elucidation of cellular mechanisms involved in regulation of IgA secretion.

Accessory cells in murine Peyer's patch. I. Identification and enrichment of a functional dendritic cell.

Previous studies have suggested that in vitro and in vivo immune responses are defective in Peyer's patch (PP) as a result of a deficiency in accessory cell number or function. However, we report here that enzymatic dissociation of PP does release a cell population with accessory activity in oxidative mitogenesis, i.e., the proliferation of periodate-modified T cells. The accessory activity present in PP is quantitatively similar to that of spleen. Accessory function is mediated by a cell type(s) that has the following characteristics: low buoyant density, lack of adherence to plastic or glass surfaces, lack of Fc receptors, and presence of surface Ia and the 33D1 dendritic cell (DC)-specific determinants. This PP accessory cell was markedly enriched by a novel technique. PP cells formed large aggregates when cultured for 16 h with irradiated, periodate-treated spleen cells. From the clusters we obtained a low density cell population that was 60% Ia positive, 33D1 positive, non-T and non-B, Fc receptor-negative, and dendritic in morphology. The DC-enriched populations were 60-80-fold enriched in accessory function relative to unfractionated PP. We can now compare PP accessory cells with accessory cells from other organs, and try to determine how PP dendritic cells contribute to the unique functions of this lymphoid organ.

Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats.

BACKGROUND AND PURPOSE: Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs. EXPERIMENTAL APPROACH: The pharmacokinetics of diclofenac and rofecoxib was characterized in male rats following intravenous, intraperitoneal and oral administration. Blood samples were collected at pre-defined time points after dosing to determine plasma concentrations over time. A parametric approach using nonlinear mixed effects modelling was applied to describe EHC, whilst simulations were used to evaluate its impact on PGE(2) inhibition. KEY RESULTS: For diclofenac, EHC was described by a compartmental model with periodic transfer rate and metabolite formation rate. For rofecoxib, EHC modelling required a conversion compartment with first-order recycling rate and lag time. Based on model predictions, EHC causes an increase of 95% in the systemic exposure to diclofenac and of 15% in the exposure to rofecoxib. In addition, EHC prolongs the inhibition of PGE(2) and increases the duration of the anti-inflammatory effect (24 h for rofecoxib 10 mg kg(-1)) without affecting maximum inhibition. CONCLUSIONS AND IMPLICATIONS: Our findings show the relevance of exploring EHC in a quantitative manner to accurately interpret pharmacodynamic findings in vivo, in particular when scaling across species.

Absence of a stratum corneum antigen in disorders of epidermal cell proliferation: detection with an anti-ganglioside GM3 antibody.

We have investigated the distribution of ganglioside GM3 in normal skin with 8G9D8, a monoclonal antibody against GM3, and found binding to the stratum corneum. By electron microscopy, strong deposition of antibody was seen at the corneocyte envelope/"plasma membrane" region. Significantly decreased to absent binding to the stratum corneum was shown in a variety of disorders of excessive keratinocyte proliferation, including squamous cell carcinomas, psoriasis, and bullous and non-bullous forms of congenital ichthyosiform erythrodermas, as well as in the hyperplastic cornoid lamellae of porokeratosis. The 8G9D8 antibody recognizes the carbohydrate sequence N-acetylneuraminic acid alpha 2----3 galactose beta 1----4 glucose (or N-acetylglucosamine). Thus, in addition to ganglioside GM3, 8G9D8 may bind to glycoproteins or another glycolipid of the stratum corneum with a shared carbohydrate sequence. The carbohydrate sequence recognized by 8G9D8, whether attached to an epidermal glycoprotein or glycolipid, may prove to be important in keratinocyte proliferation and differentiation.

Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1.

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.

Exquisite sensitivity of dendritic cells to ultraviolet radiation and temperature changes.

Recent data suggest that dendritic cells (DC) are the critical passenger leukocytes in allograft rejection. Moreover, previous studies suggest that ultraviolet radiation (UVR) abrogates many in vivo and in vitro immune responses in which DC function as potent accessory cells (AC); however, the mechanism(s) underlying the suppressive effect of UVR on these responses is unclear. To address this mechanism, the hypothesis was tested that loss of DC viability (hence function) accounts for the suppressive effect of UVR on these responses. To this end, in vitro effects of UVR on murine splenic DC viability were addressed using two types of UVR (ultraviolet B [UVB] and ultraviolet C [UVC]) over a UVR dose range of 0-864 J/m2. DC viability was exquisitely sensitive to UVR when compared with other AC populations and UVC was 4-fold more effective in decreasing DC viability than UVB when doses of equal energy were compared. It was found that both UVR types induced marked decreases in DC viability beginning 4-6 hr post-UVR-treatment, that UVR- and non-UVR-induced death were temperature-dependent, and that decreases in DC viability induced by UVR were compatible with interphase death. Our findings indicate that DC are sensitive to temperature changes and exquisitely sensitive to UVR, and suggest that UVR-induced abrogation of murine immune responses is likely attributable to UVR-induced DC death.

Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids.

The N-demethylation of ethylmorphine was studied in liver microsomes from human fetuses and adult patients as well as from human fetal adrenals and kidneys. Unexpectedly the reaction was catalysed at the same rate in fetal (42.3-1277.4 pmol/mg/min in 11 individuals) and adult microsomes (414-1617.8 pmol/mg/min in two individuals), which also had similar values of the apparent Km (1.50, 1.72 mM respectively) and Vmax (1.33, 1.81 nmol/mg/min respectively) in studies of the enzyme kinetics. There was a close correlation (r = 0.96) between the semiquantitative immunoblotting assessment of cytochrome P-450 HL-p in fetal liver microsomes (with the use of a monoclonal antibody against pregnenolone-16-alpha-carbonitrile induced rat hepatic cytochrome P-450) and the catalytic activity. The fetal adrenal microsomal N-demethylation was only 11-30% of the hepatic activity when compared within three fetuses in which such a comparison was possible. No activity was measurable in the kidneys. Two drugs that are believed to be substrates of the cytochrome P-450 HLp were tested as inhibitors of the ethylmorphine N-demethylation in human fetal and adult liver microsomes and in rat liver microsomes. Midazolam was a potent inhibitor (100% at 0.4 mM) of the reaction in all specimens, whereas cyclosporin A inhibited the reaction clearly only in adult liver microsomes. Endogenous steroids of importance in the fetal circulation were also tested as inhibitors. Progesterone and dehydroepiandrosterone inhibited the reaction by 75-80% at a concentration of 0.4 mM, whereas pregnenolone and 17-alpha-hydroxyprogesterone were almost devoid of inhibitory potency. These results are of interest in the discussion about the physiological role of the human fetal cytochrome P-450 HLp which has an unprecedented relative abundance in the liver.

Localization of telomerase hTERT protein and hTR in benign mucosa, dysplasia, and squamous cell carcinoma of the cervix.

Telomerase has been detected by telomerase repeat amplification protocol (TRAP) assay in cervical dysplasia and squamous cell carcinoma but not in most normal cervical tissues. In the present study, the cellular localization of the protein catalytic subunit of telomerase (hTERT) and the RNA component (hTR) were investigated by a sensitive immunohistochemical technique and by in situ hybridization, respectively. hTERT protein was detected in all diagnostic categories of cervical specimens. hTERT was localized predominantly to the lower suprabasal levels of normal squamous mucosa but was detected throughout virtually all levels of the lesional epithelium in low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and squamous cell carcinoma (SCC). Telomerase expression correlated with hTERT detection in SCC and HSIL but was not detected by TRAP assay in most samples of normal mucosa or LSIL. The distribution of hTR correlated with the localization of hTERT in HSIL and SCC but was restricted to the basal and suprabasal cell layers in normal mucosa and LSIL.

Modelling the muscles of the scapula morphometric and coordinate data and functional implications.

Modelling of the shoulder mechanism is dependent upon reliable data on the morphometry and points of attachment of the relevant muscles. In this paper, the authors present coordinate data which have been derived from the radiography of dissected cadavers. All of the coordinates have been normalised with respect to reference dimensions of the relevant segments (humerus, scapula, clavicle and trunk). Similarly the measurements of physiological cross-section area (PCSA) have been normalised with respect to that of deltoid. The measurements of PCSA have been shown to agree largely with the work of Veeger et al. [J. Biomechanics 24, 615-629 (1991)] and Karlsson and Peterson [J. Biomechanics 25, 189-199 (1992)]. While the majority of the descriptions of morphometry concur with accepted texts there are some notable disagreements, particularly concerning trapezius.

A novel pre-B cell precursor: phenotypic characterization and differentiation induction by dendritic cell-T cell mixtures.

We have derived from spleens of nude mice early B lineage cell lines that are dependent upon factor(s) in supernatants of the WEHI-3B cell line. The cells are phenotypically at the pre-pre-B cell stage of differentiation. These cells are large and have basophilic granules in the cytoplasm. They are negative for cytoplasmic and surface immunoglobulin heavy or light chain, surface B220, surface Thy 1.2 and surface Ia but are positive for cytoplasmic B220. These cells at this early stage of maturation can be induced by mixtures of DC-T cells to express B220 on their surfaces and later to synthesize and ultimately to secrete immunoglobulin. These events are associated with morphologic changes in the cells to a lymphoblastoid appearance. Different pattern of immunoglobulin secretion were induced by DC-T from different tissues. The inductive event appears to occur during cell contact of pre-pre-B cells with the inducing DC-T cell mixture, but it does not appear to require IL-3. These data indicate that DC-T cell mixtures can provide signals for B cell differentiation at pre-pre-B cell stage as well as pre-B and mature B cell stage.

Laparoscopic resection of liver metastasis using a harmonic scalpel.

We report successful laparoscopic resection of a solitary liver metastasis from a colorectal carcinoma in an obese man, using a harmonic scalpel.

Surgical resection of hepatic and cardiac neuroendocrine metastases from a caecal primary tumour.

A 66-year-old patient had an incidentally detected caecal neuroendocrine tumour that had metastasised to the liver and left atrium. He was asymptomatic with regard to this tumour and did not have carcinoid syndrome. Resection of the primary tumour and the metastatic deposits (with the ablation of one lesion) is thought to be curative.

Radiofrequency assisted liver resection: analysis of 604 consecutive cases.

BACKGROUND: Intraoperative blood loss is an important factor contributing to morbidity and mortality in liver surgery. To address this we developed a bipolar radiofrequency (RF) device, the Habib 4X, used specifically for hepatic parenchymal transection. The aim of this study was to prospectively assess the peri-operative data using this technique. METHODS: Between 2001 and 2010, 604 consecutive patients underwent liver resections with the RF assisted technique. Clinico-pathological and outcome data were collected and analysed. RESULTS: There were 206 major and 398 minor hepatectomies. Median intraoperative blood loss was 155 (range 0-4300)ml, with a 12.6% rate of transfusion. There were 142 patients (23.5%) with postoperative complications; none had bleeding from the resection margin. Only one patient developed liver failure and the mortality rate was 1.8%. CONCLUSIONS: RF assisted liver resection allows major and minor hepatectomies to be performed with minimal blood loss, low blood transfusion requirements, and reduced mortality and morbidity rates.

Pancreatic and peripancreatic somatostatinomas.

BACKGROUND: Somatostatinomas are rare neuroendocrine tumours with an annual incidence of 1 in 40 million. They arise in the pancreas or periampullary duodenum. Most are clinically non-secretory and do not cause the somatostatinoma syndrome. Many are metastatic at presentation and their management is typically multimodal. CASE HISTORIES: Four cases of somatostatinoma are described. Two patients with periampullary disease presented with biliary obstruction, one with frank jaundice and one with incidental bile duct obstruction on investigation of hepatitis B. Each patient had type 1 neurofibromatosis and resection of the somatostatinoma by means of a pylorus-preserving proximal pancreaticoduodenectomy has resulted in long-term survival. Another two patients with metastatic pancreatic somatostatinomas presented with abdominal pain. Contrasting management illustrates current treatment strategies that are dependent in part on the distribution of the disease. DISCUSSION: The pathophysiology, presentation, clinical associations and role of diagnostic imaging are discussed for periampullary and pancreatic neuroendocrine tumours. Operative treatment has an important role in both the curative and palliative settings in conjunction with appropriate medical treatments and these are described. Management options depend on the extent of the disease and the cases are used to illustrate the rationale of such strategies.