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.

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.

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.

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.

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.

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.

Percutaneous transhepatic cholecystoduodenal stent for empyema of the gallbladder.

Acute cholecystitis is treated by antibiotics and cholecystectomy. When the gallbladder neck is obstructed in the presence of infection, preventing pus from draining via the cystic duct, an empyema of the gallbladder develops. Under these circumstances, treatment may be either cholecystectomy or, in the presence of significant comorbidity, by drainage via percutaneous cholecystostomy, followed at a later date by cholecystectomy. We present the case of a patient who presented acutely with an attack of cholecystitis and refused to undergo a cholecystectomy owing to previous respiratory arrest following general anaesthesia. She settled with intravenous antibiotic treatment and was discharged. However, she presented shortly afterwards with a further attack of cholecystitis that was refractory to intravenous antibiotics and so was treated initially with percutaneous drainage. This was subsequently replaced with interno-external drainage of the gallbladder (transpapillary cholecystoduodenal stent) with the use of a J-J ureteric stent, which was then fully internalised. She remained well following this procedure and was discharged home. The long-term patency of the stent is not known and we hope that no further intervention will be required, but if necessary the stent could be exchanged endoscopically, by a percutaneous route, or via a combined approach.

Pancreas-sparing distal duodenectomy for infrapapillary neoplasms.

INTRODUCTION: For neoplasms that arise in the third and fourth parts of the duodenum (D(3), D(4)), a duodenectomy that preserves the pancreas can provide adequate tumour clearance while avoiding the additional dissection and risk of the common alternative, pancreatoduodenectomy. PATIENTS AND METHODS: Pancreas-sparing distal duodenectomy (PSDD) was performed in 14 patients with infrapapillary duodenal neoplasms between 1991-2002, and the clinical outcome is reviewed. The operation entails careful separation of the lower pancreatic head from D(3), complete mobilisation of the ligament of Treitz and end-to-end duodenojejunal anastomosis 1-3 cm below the major duodenal papilla. RESULTS: There were 9 men and 5 women of median age 56 years, who presented with iron-deficiency anaemia (n = 8), gastric outlet obstruction (n = 4), anaemia and gastric outlet obstruction (n = 1), epigastric pain or mass (1 each). There were 11 malignant neoplasms (adenocarcinoma 5, stromal tumour 4, recurrent seminoma 1, plasmacytoma 1), 2 benign neoplasms (villous adenoma, lipoma) and 1 patient with steroid-induced ulceration. In addition to D(3) and D(4), resection included the distal part of D(2) in 5 patients, while 4 required concomitant partial colectomy. Median operation time was 240 min and median blood loss 1197 ml, being greater for malignant than benign lesions (1500 ml versus 700 ml). There was one death from gangrenous cholecystitis, one early re-operation for anastomotic bleeding and one late re-operation for delayed gastric emptying secondary to anastomotic stricture, but no pancreatic complications. At a median follow-up of 47 months, three patients had died of recurrent disease while the other 10 were alive and well with no upper gastrointestinal symptoms. CONCLUSIONS: Provided there is a minimum 1-cm clearance at the papilla, PSDD is a useful alternative to formal pancreatoduodenectomy in patients with unusual neoplasms arising from the third and fourth parts of the duodenum. Although a major undertaking in its own right, it avoids the extra time of a pancreatic resection and the extra risk of a pancreatic anastomosis.

Bloodless hepatectomy technique.

BACKGROUND: Surgical resection remains the gold standard in dealing with liver tumours. Blood loss, biliary leak and postoperative liver function are still the main concerns of surgeons operating on the liver, even though different techniques have been developed to allow safer liver resection. A novel concept for liver resection is described using a radiofrequency energy (RF) assisted technique. METHOD: A patient with a large colorectal liver metastasis located in segments VI, VII, VIII underwent a right hepatectomy using this technique. At laparotomy the tumour was staged with intraoperative ultrasonography, and a 'cooled tipped' radiofrequency probe was used to achieve a 'zone of desiccation' in the liver parenchyma 2 cm away from the edge of the tumour. Liver parenchyma was subsequently divided with a surgical scalpel. RESULTS: The resection time was 80 min with a blood loss of 30 ml. The patient was discharged on the ninth postoperative day without complications. DISCUSSION: Liver resection assisted by RF energy is feasible and safe. This technique could offer a new method for 'transfusion-free' resection without the need for sutures, ties, staples, tissue glue or admission to the intensive care unit.

Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2.

Described herein is the design and synthesis of indazolylaminopyridopyrimidines and quinazolines as inhibitors of the class 1 tyrosine kinase receptor family. Data is presented for N(4)-(1-benzyl-1H-indazol-5-yl)-N(6),N(6)-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine 3B. This compound inhibited EGFr and c-erbB-2 enzymes selectively over other kinases. It inhibited the proliferation of a range of tumour cell lines in vitro and the growth of BT474 xenografts in SCID mice.

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.

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.

Evaluation of pyrazole and ethanol induced S9 fraction in bacterial mutagenicity testing.

A major constitutive enzyme in the liver of the uninduced rat is cytochrome P450-2E1. This isozyme has been shown to metabolize a number of carcinogens, including low molecular weight nitrosamines and a number of compounds normally regarded as non-mutagenic in the Ames test, e.g. aniline, urethane and benzene. Using the standard induction procedures [Aroclor 1254 or a combination of phenobarbitone (PB) and beta-naphthoflavone (beta-NF)] the level of CYP2E1 in rat liver is actually suppressed and it has been suggested that this may account for the negative findings with these compounds in the Ames test. S9 fractions were prepared from rats pre-treated with pyrazole or ethanol (inducers of CYP2E1) and then used in the Ames test (or pre-incubation modification) with urethane, acetaminophen, aniline, benzene, procarbazine and N-nitrosopyrrolidine. Both pyrazole and ethanol induced S9 were superior to PB/beta-NF-S9 and uninduced-S9 for the activation of N-nitrosopyrrolidine, a known CYP2E1 substrate. However, there was no evidence of mutagenic activity with urethane, aniline, benzene, procarbazine or acetaminophen. As these compounds have demonstrated genotoxicity in vivo, additional important metabolic pathways must be required which are not present in rat liver S9 fraction.

Pre-pre-B cells containing only cytoplasmic B220 can be induced by dendritic cells and T cells to differentiate in vitro.

We have derived from spleens of nude mice early B lineage cells that were phenotypically compatible with a pre-pre-B cell stage of differentiation. Although these cells containing large basophilic granules had the B lymphocyte antigen B220, in the cytoplasm, they had no surface B220, no cytoplasmic or surface immunoglobulin heavy or light chains, no surface Thy-1, and no surface Ia. In addition, they appeared to have little or no heavy chain gene rearrangements, including the D to J that occurs on both chromosomes prior to the VH rearrangement that forms the code for the C mu heavy chain polypeptide. Cells at even this early stage of differentiation could be induced by DC-T to express B220 on the surface and to synthesize and then to secrete immunoglobulins. These phenotypic changes were associated with a morphologic change in the cells to a lymphoblastoid appearance. Different patterns of immunoglobulin secretion resulted when pre-pre-B cells were cocultivated with DC-T from different tissues; SP DC-T induced the secretion of only IgM, PP DC-T induced the secretion of IgM as well as IgG and IgA. The early inductive event(s) appeared to occur during cell-cell contact in aggregates of the inducing DC-T and the pre-pre-B cells.

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.

Many different levels of maturation and commitment are present in nontransformed cells identified serologically as pre-B cells.

The pre-B cell stage of B lymphocyte development is characterized by the presence of immunoglobulin heavy chains of the IgM isotype in the cytoplasm and no other heavy or light chains in the cytoplasm or on the surface. We established several cell lines that were identical in their serologically defined pre-B cell phenotypes and in their dependence upon interleukin 3 for growth, but which differed in their levels of cytoplasmic RNA from immunoglobulin constant region genes, in their rates of differentiation in vitro, and in the isotype profile of the antibodies that they secreted upon differentiation. The two cell lines that we have analyzed in detail, PF1 and PF1C, both contained RNA from the C mu and C delta heavy chain genes and from both the C kappa and C lambda light chain genes, even though they were not producing detectable polypeptide products from the C delta, C kappa, or C lambda genes. However, PF1C had higher levels of C gamma and C alpha RNA transcripts and differentiated in vitro under the influence of dendritic cells and T lymphocytes (DC-T) more rapidly than did PF1. If the DC-T were derived from spleens, all cell lines secreted only IgM. However, under the influence of DC-T from Peyer's patches PF1C secreted predominantly IgM, PF1 secreted primarily IgA, and a third line, PF3, secreted primarily IgG. Therefore, within the population of cells described as pre-B cells on the basis of their immunoglobulin gene polypeptide products, there are subpopulations that probably represent different levels of maturation and different levels of commitment to particular pathways of B lymphocyte development.