Adherence to vaccination guidelines post splenectomy: A five year follow up study.

Following a splenectomy patients are at increased risk of significant infections. In its most severe form, overwhelming post-splenectomy infection (OPSI) has a mortality rate of up to 80%. In this study we aim to establish the adherence to vaccination and antibiotic national guidelines in splenectomised patients. A retrospective study of 100 patients who underwent splenectomy (21 emergency, 79 elective), in two teaching hospitals was undertaken over a five-year period. Patients were followed up for five years. Hospital and GP records were reviewed for adherence to pre, intra and postoperative vaccination, thromboprophylaxis and antibiotic guidance. Eighty-six eligible patients (91.5%) received their Haemophilus influenzae B, meningococcal C and pneumococcus vaccinations peri-operatively. Eighty-one (86%) received post-operative antibiotics. Ninety-nine percent of patients received thromboprophylaxis treatment. Eighty-nine (95%) were treated with long-term antibiotic prophylaxis. Only 20 patients (23%) had an emergency supply of antibiotics. Ninety-five percent of patients were administered an annual influenza vaccination and 84% of eligible patients received a five-year pneumococcal booster vaccination. Improvement in the management of this patient cohort can be achieved by a multidisciplinary approach involving adherence to national guidelines, standardised trust protocols, patient information leaflets and advice detailing risk of infection, standardised GP letters and a splenectomy register to monitor and manage this vulnerable group of patients.

Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy.

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.

Characterization and propagation of tumor initiating cells derived from colorectal liver metastases: trials, tribulations and a cautionary note.

Tumor initiating cells (TIC) are increasingly being put forward as a potential target for intervention within colorectal cancer. Whilst characterisation and outgrowth of these cells has been extensively undertaken in primary colorectal cancers, few data are available describing characteristics within the metastatic setting. Tissue was obtained from patients undergoing surgical resection for colorectal liver metastases, and processed into single cell suspension for assessment. Tumor initiating cells from liver metastases were characterised using combinations of EPCAM, Aldehyde dehydrogenase activity, CD133 and CD26. CD133 expression was significantly lower in patients who had received chemotherapy, but this was accounted for by a decrease observed in the male patient cohort only. ALDHhigh populations were rare (0.4 and 0.3% for EPCAM+/ALDHhigh/CD133- and EPCAM+/ALDHhigh/CD133+ populations respectively) and below the limits of detection in 28% of samples. Spheroid outgrowth of metastatic tumor cells across all samples could not be readily achieved using standard spheroid-formation techniques, thus requiring further method validation to reliably propagate cells from the majority of tissues. Spheroid formation was not enhanced using additional growth factors or fibroblast co-culture, but once cells were passaged through NOD-SCID mice, spheroid formation was observed in 82% samples, accompanied by a significant increase in CD26. Order of spheroid forming ability was ALDHhigh>CD133>CD26. Samples sorted by these markers each had the ability to reform ALDHhigh, CD133 and CD26 positive populations to a similar extent, suggestive of a high degree of plasticity for each population. Ex vivo TIC models are increasingly being utilised to assess efficacy of therapeutic interventions. It is therefore essential that such investigations use well-characterised models that are able to sustain TIC populations across a large patient cohort in order that the inherent heterogeneity observed in cancer populations is maintained.

Advances in membrane emulsification. Part B: recent developments in modelling and scale-up approaches.

Membrane emulsification is a promising process for formulating emulsions and particulates. It offers many advantages over conventional 'high-shear' processes with narrower size distribution products, higher batch repeatability and lower energy consumption commonly demonstrated at a small scale. Since the process was first introduced around 25 years ago, understanding of the underlying mechanisms involved during microstructure formation has advanced significantly leading to the development of modelling approaches that predict processing output; e.g. emulsion droplet size and throughput. The accuracy and ease of application of these models is important to allow for the development of design equations which can potentially facilitate scale-up of the process and meet the manufacturer's specific requirements. Part B of this review considers the advantages and disadvantages of a variety of models developed to predict droplet size, flow behaviour and other phenomena (namely droplet-droplet interactions), with presentation of the appropriate formulae where necessary. Furthermore, the advancement of the process towards an industrial scale is also highlighted with additional recommendations by the authors for future work.

Advances in membrane emulsification. Part A: recent developments in processing aspects and microstructural design approaches.

Modern emulsion processing technology is strongly influenced by the market demands for products that are microstructure-driven and possess precisely controlled properties. Novel cost-effective processing techniques, such as membrane emulsification, have been explored and customised in the search for better control over the microstructure, and subsequently the quality of the final product. Part A of this review reports on the state of the art in membrane emulsification techniques, focusing on novel membrane materials and proof of concept experimental set-ups. Engineering advantages and limitations of a range of membrane techniques are critically discussed and linked to a variety of simple and complex structures (e.g. foams, particulates, liposomes etc.) produced specifically using those techniques.

Ganglia arising from the transverse acetabular ligament: a report of two cases.

Ganglia arising from the hip are rare. Its diagnosis is difficult owing to the anatomic location. A high index of suspicion and high-resolution imaging is essential to make the diagnosis. Treatment depends on the size, location, and symptoms. This report is of 2 patients with ganglia arising from the transverse acetabular ligament.

Histological changes during extracorporeal perfusions of the porcine liver: implications for temporary support during acute liver failures.

Ex vivo perfused porcine livers have been used for temporary support during acute liver failure. The aim of this study was to assess both the histological changes and temporal pattern of the changes that occur during extracorporeal liver perfusions and to correlate these with factors that may influence them. Five porcine livers were harvested, preserved in cold ice and reperfused for 6 h in an extracorporeal circuit using autologous normothermic blood. Tissue biopsies were collected hourly. The Ishak score was used to quantify hepatic necrosis, and immunohistochemistry was used to evaluate apoptosis and regeneration. Liver weight, perfusion parameters, arterial blood gases and blood samples were also collected. The Ishak score peaked immediately before and 4 h after the start of reperfusion. Scattered necrosis, microvesicular steatotic vacuolization, sinusoidal dilatation and red cell extravasation were present. Anion gap acidosis was associated with the Ishak score. An inverse correlation was present between liver regeneration and necrosis, and between liver weight and regeneration. No changes were observed for apoptosis. Among the inflammatory cytokines evaluated, interleukin-6 and -8 levels increased significantly during the perfusions. Hepatic necrosis was always present during the extracorporeal perfusions, followed a definite pattern and was inversely correlated with regeneration. Apoptosis did not increase over baseline levels. The meaning of these findings and their correlation with clinical outcomes during acute hepatic failures deserve further investigation.

Steps for the autologous ex vivo perfused porcine liver-kidney experiment.

The use of ex vivo perfused models can mimic the physiological conditions of the liver for short periods, but to maintain normal homeostasis for an extended perfusion period is challenging. We have added the kidney to our previous ex vivo perfused liver experiment model to reproduce a more accurate physiological state for prolonged experiments without using live animals. Five intact livers and kidneys were retrieved post-mortem from sacrificed pigs on different days and perfused for a minimum of 6 hr. Hourly arterial blood gases were obtained to analyze pH, lactate, glucose and renal parameters. The primary endpoint was to investigate the effect of adding one kidney to the model on the acid base balance, glucose, and electrolyte levels. The result of this liver-kidney experiment was compared to the results of five previous liver only perfusion models. In summary, with the addition of one kidney to the ex vivo liver circuit, hyperglycemia and metabolic acidosis were improved. In addition this model reproduces the physiological and metabolic responses of the liver sufficiently accurately to obviate the need for the use of live animals. The ex vivo liver-kidney perfusion model can be used as an alternative method in organ specific studies. It provides a disconnection from numerous systemic influences and allows specific and accurate adjustments of arterial and venous pressures and flow.

The autologous normothermic ex vivo perfused porcine liver-kidney model: improving the circuit's biochemical and acid-base environment.

BACKGROUND: The ex vivo porcine liver perfused model isolates the organ from extrinsic regulatory mechanisms, facilitating an improved understanding of the organ physiology and reaction to various conditions. We have assessed the influence of the addition of a porcine kidney to the circuit. METHODS: Eight livers were harvested and perfused for 6 hours. In 5 additional experiments a kidney also was connected in parallel. Hourly arterial blood gases were collected to analyze glucose, acid base, and renal parameters. The primary end point was an evaluation of the influence of the kidney on glucose, pH, and electrolyte levels. RESULTS: In the combined porcine liver-kidney circuit all the parameters significantly improved compared with the liver circuit alone. This was particularly evident for glucose values because normoglycemia was reached by the end of the perfusion, and for pH and electrolyte values that were maintained at initial levels. CONCLUSIONS: The addition of a porcine kidney to the perfusion circuit improves the biochemical milieu. This might produce more consistent and reliable results, particularly during studies requiring a steady-state environment.

Targeted microbubbles in the experimental and clinical setting.

BACKGROUND: Microbubbles have improved ultrasonography imaging techniques over the past 2 decades. Their safety, versatility, and easiness of use have rendered them equal or even superior in some instances to other imaging modalities such as computed tomography and magnetic resonance imaging. Herein, we conducted a literature review to present their types, general behavior in tissues, and current and potential use in clinical practice. METHODS: A literature search was conducted for all preclinical and clinical studies involving microbubbles and ultrasonography. RESULTS: Different types of microbubbles are available. These generally improve the enhancement of tissues during ultrasonography imaging. They also can be attached to ligands for the target of several conditions such as inflammation, angiogenesis, thrombosis, apoptosis, and might have the potential of carrying toxic drugs to diseased sites, thereby limiting the systemic adverse effects. CONCLUSIONS: The use of microbubbles is evolving rapidly and can have a significant impact on the management of various conditions. The potential for their use as targeting agents and gene and drug delivery vehicles looks promising.

Patterns of histological changes following hepatic electrolytic ablation in an ex-vivo perfused model.

Electrolytic ablation (EA) destroys the liver by releasing toxic radicles and producing modifications in the local pH without increasing the tissue temperature. We assessed the histological changes produced by EA using an ex-vivo perfused model. Five porcine livers were harvested, preserved in ice and reperfused for six hours in an extracorporeal circuit using autologous normothermic blood. One hour after reperfusion EA was performed and liver biopsies collected at the end of the experiments. The main necrotic zone consisted of coagulative necrosis, sinusoidal dilatation and haemorrhage with an unusual morphological pattern. The coagulative necrosis and haemorrhage affected mainly the peripheral area of the lobule with relative sparing of the area surrounding the centrilobular vein. Contrasting with this sinusoidal dilatation appeared to be more prominent in the centrilobular area. EA produces patterns of tissue destruction that have not been observed with the more commonly used thermal techniques. Further studies should obtain more information about the influence of adjacent biliary and vascular structures so that appropriate clinical trials can be designed.

Addition of a kidney to the normothermic ex vivo perfused porcine liver model does not increase cytokine response.

The addition of a kidney to the ex vivo liver perfused model may facilitate the circuit homeostatic balance of important biochemical parameters (i.e. pH changes, urea and creatinine, or glucose levels) but might also increase the inflammatory reaction produced. In this study, we compared the production of various cytokines between liver-kidney and liver-alone circuits. Seven livers were harvested from female pigs and perfused for 6 h. In five additional experiments, a kidney was also harvested and connected in parallel. Blood samples for interleukins (IL) 1, 2, 4, 6, 8, 10, and 12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were collected before perfusion and at hours 1, 2, 4 and 6 postperfusion. In the combined liver-kidney circuit, a significant increase was present only for IL-6 and IL-8, but this did not differ significantly from those recorded in the liver-alone circuit. All other cytokines were not modified from baseline levels. The addition of a kidney to the perfusion circuit does not stimulate a greater inflammatory reaction than that of the liver alone and therefore further confirms the safety of the experimental setups in view of more delicate experiments requiring strict homeostatic conditions.

Evaluation of nurse-led discharge following laparoscopic surgery.

INTRODUCTION: The United Kingdom's Department of Health has identified reducing delays in patient discharge as a key aim for Health Service development. Laparoscopic cholecystectomy and laparoscopic inguinal hernia repair may be safely performed on a short stay basis, but day case rates remain low, with delays in discharge identified as a major contributing factor. Nurse-led discharge has been widely advocated to speed patient discharge across varied specialities, but objective evidence to support its use is lacking. This study aimed to assess the effectiveness of nurse-led discharge following laparoscopic surgery. METHODS: A retrospective comparison of doctor-led and nurse-led discharge following laparoscopic surgery was performed by analysis of two consecutive 4-month periods, prior to and following the introduction of nurse-led discharge by a laparoscopic nurse specialist. Outcomes assessed included time to discharge, reasons for delayed discharge, hospital readmissions and primary care episodes following discharge. RESULTS: A total of 128 patients were included in the study, with each discharge group containing 64 patients. Patients in the nurse-led discharge group were significantly more likely to be discharged on the day of surgery than patients in the doctor-led discharge group (17.2% vs. 4.7%; P = 0.023), with a highly significant difference in same day discharge rates noted among patients operated on during morning theatre lists (44.0% vs. 10.7%; P = 0.006). There was no significant difference between the discharge groups in readmission rates or in the number of patients seeking primary care attention following discharge. CONCLUSIONS: Nurse-led discharge may speed discharge following laparoscopic surgery with no apparent detriment to patient care.

Heat shock protein 70 expression following hepatic radiofrequency ablation is affected by adjacent vasculature.

BACKGROUND: Heat shock proteins are a highly conserved family of stress response proteins. Members of the heat shock protein 70 (Hsp70) family prevent protein misfolding and aggregation. Following radiofrequency ablation of unresectable liver tumors an interface appears between the irreversibly damaged and normal liver. The fate of this transition zone is critical and is believed to be responsible for local recurrences. Hsp70 is expressed in response to thermal stress and may influence the fate of cells in this transitional zone. It is also recognized that the presence of large vessels or a perivascular location of tumors also influences the recurrence rate. The aim of this study is to examine the transition zone and observe the effect of local blood flow on ablation morphology and Hsp70 expression. METHODS: Radiofrequency ablation was performed in 25 rats at various distances from the liver hilum. Tissue was retrieved and analysed at time points 0, 4, 24, 48 h, and 2 wk following treatment. Tissue was analyzed histologically with hematoxylin and eosin staining (H and E,) and immunohistochemically for Hsp70 expression. RESULTS: All rats survived the procedure. H and E staining revealed previously unreported foci of apoptosis at the ablation edge and deep in the normal hepatic parenchyma. Hsp70 was expressed in the transition zone at 4 h and peaked at 24 h. The degree of Hsp70 expression was significantly influenced by the distance from surrounding vasculature. CONCLUSIONS: This study reports several previously unreported findings. There is increased apoptosis distal to the ablated zone suggests leakage of radiofrequency (RF) current down blood vessels originating in the ablation zone. The degree of Hsp70 expression in the transition zone correlates with time after treatment and the size and location of any adjacent vasculature. These findings suggest that heat shock proteins may play a role in the ability of damaged cells to recover and survive at the periphery of an ablation zone.

Changes in acid-base balance during electrolytic ablation in an ex vivo perfused liver model.

BACKGROUND: Electrolytic ablation (EA) destroys tissues through extreme pH changes in the local microenvironment. An ex vivo perfused liver model was used to assess the systemic effects of EA on the acid-base balance without the influence of compensatory organs (lungs and kidneys). METHODS: Eleven pigs were perfused extracorporeally at 39°C with autologous blood; 4 also underwent EA after 1 hour of reperfusion. Arterial blood samples were obtained hourly. RESULTS: pH and CO(2) levels did not change throughout the experiments. A significant increase of HCO(3)-, anion gap, base excess, and lactate was present after the third hour. No differences were observed between EA experiments and controls. CONCLUSIONS: EA does not alter the acid-base balance even when the confounding influence of compensatory organs is removed. Such findings should be considered when planning ablations in patients with renal failure or respiratory diseases in which EA could avoid undesirable metabolic changes.

Is intraoperative confirmation of malignancy during pancreaticoduodenectomy mandatory?

INTRODUCTION: Differentiating between chronic pancreatitis and pancreatic adenocarcinoma can be difficult due to considerable overlap in disease presentation and radiological signs and the frequent co-existence of the two conditions. In this situation, surgeons may have to proceed to "blind" pancreaticoduodenectomy or attempt to confirm malignancy intraoperatively with frozen section (FS) histology. METHODS: This study attempted to ascertain the false-negative and false-positive rates of undertaking pancreaticoduodenectomies (PD) based on clinical suspicion (CS) or after intraoperative confirmation of malignancy using FS histology. RESULTS: Of patients, 13.6% (nine out of 66) underwent a benign PD in the CS group; 6.7% of patients had a missed malignancy in the FS group (n = 62), but intraoperative histology prevented PD in 35% of patients with benign disease in the FS group. Specificity and sensitivity of intraoperative FS in detecting malignancy was 100% and 89.7%, respectively. Sensitivity of clinical assessment in detecting malignancy was 86.4%. CONCLUSIONS: In experienced hands, intraoperative confirmation of malignancy is effective and will avoid resection in patients with benign disease. However, for many surgeons the chance of missing a small tumour with a false-negative biopsy will be unacceptable and they would prefer to undertake a "blind" resection and accept the mortality risk of pancreaticoduodenectomy for benign disease.

International multicentre prospective study on microwave ablation of liver tumours: preliminary results.

BACKGROUND: Microwave ablation (MWA) is increasingly utilized in the treatment of hepatic tumours. Promising single-centre reports have demonstrated its safety and efficacy, but this modality has not been studied in a prospective, multicentre study. METHODS: Eighteen international centres recorded operative and perioperative data for patients undergoing MWA for tumours of any origin in a voluntary Internet-based database. All patients underwent operative MWA using a 2.45-GHz generator with a 5-mm antenna. RESULTS: Of the 140 patients, 114 (81.4%) were treated with MWA alone and 26 (18.6%) were treated with MWA combined with resection. Multiple tumours were treated with MWA in 40.0% of patients. A total of 299 tumours were treated in these 140 patients. The median size of ablated lesions was 2.5 cm (range: 0.5-9.5 cm). Tumours were treated with a median of one application (range: 1-6 applications) for a median of 4 min (range: 0.5-30.0 min). A power setting of 100 W was used in 78.9% of cases. Major morbidity was 8.3% and in-hospital mortality was 1.9%. CONCLUSIONS: These multi-institution data demonstrate rapid ablation time and low morbidity and mortality rates in patients undergoing operative MWA with a high rate of multiple ablations and concomitant hepatic resection. Longterm follow-up will be required to determine the efficacy of MWA relative to other forms of ablative therapy.

The porcine hepatic arterial supply, its variations and their influence on the extracorporeal perfusion of the liver.

BACKGROUND: Variations in the porcine hepatic vasculature may contribute to the outcome of experiments based on liver perfusion models. We studied the hepatic artery (HA), variations of its branches, and the correlation with the resultant perfusion. MATERIALS AND METHODS: Nineteen animals were used. After 6 h of perfusion, dissection of the HA and its branches was conducted up to the insertion in the liver parenchyma. Data about the macroscopic appearance of lobes and the pattern of branching were recorded. RESULTS: In all cases, the HA bifurcated into two constant branches, one for the LL/LM lobes (further divided in two vessels for each lobe) and one for the RM lobe. Five main patterns were identified involving vessels for the RL and the CL lobes. Two variations produced complete and uniform perfusion of the entire liver in all cases, while in the remaining cases, only part of them were completely perfused. CONCLUSIONS: Some variants of the porcine HA and its branches are associated with the risk of incomplete perfusion if the perfusion cannula placement does not take the individual hepatic arterial anatomy into account. Understanding of the hepatic arteries branching patterns is essential when ex vivo perfusion models are being established.

Radiofrequency ablation versus resection for liver tumours: an evidence-based approach to retrospective comparative studies.

BACKGROUND: Recently randomized controlled trials have been advocated to compare radiofrequency ablation (RFA) and hepatic resection (HR) in resectable tumours and determine whether differences in observed survivals result from the heterogeneity in previous studies between RFA (treating unresectable lesions) and HR (treating lesions deemed resectable). We reviewed the literature that directly compares the treatments and employed an evidence-based approach to examine the data. MATERIALS AND METHODS: All studies comparing RFA and HR were included. Primary outcomes were the overall survival (OS) and disease-free survival (DFS) at 3 and 5 years. A subgroup analysis was conducted for solitary or small tumors (<4 cm for colorectal metastases (CRM) or <5 cm for hepatocellular carcinoma (HCC)). RESULTS: Most studies were retrospective. For CRM, HR was markedly superior to RFA in respect of 3- and 5-year OS as well as 5-year DFS including tumours smaller than 4 cm and solitary lesions. For HCC, HR was markedly superior to RFA for 3- and 5-year OS as well as 3-year DFS, and produced a better OS at 3 years for solitary lesions and DFS at 3 years for small tumours. CONCLUSIONS: Multiple factors determine outcomes following treatment of liver tumours. Small or solitary lesions seem the most appropriate ones to study as this reduces the number of confounding variables, but even in these cases HR confers a better OS and DFS than RFA for both CRM and HCC. If our data are confirmed it will be important to examine other factors influencing the response.