A Case-matched Comparative Study of Laparoscopic Versus Open Distal Pancreatectomy.

INTRODUCTION: Although the laparoscopic approach to distal pancreatectomy for benign and malignant diseases is largely replacing open surgery in some centers, well-designed studies comparing these approaches are limited. We present a case-matched study that compares the outcomes of laparoscopic distal pancreatectomy (LDP) to open distal pancreatectomy (ODP). METHODS: Of 112 patients (51 female) who underwent surgery between January 2002 and December 2011, 44 patients were matched on a 1:1 basis (22 LDP, 22 ODP) according to age, sex, and tumor size. Outcomes were compared on an intention-to-treat basis. Data shown represent median where appropriate. RESULTS: The laparoscopic and open groups were comparable for age (57 vs. 59.9 y, P=0.980), sex distribution (P=1.000), tumor size (3 vs. 4 cm, P=0.904), and the frequency of benign versus malignant disease (P=0.920). LDP was associated with significantly lower blood loss (100 vs. 500 mL, P=0.001), higher spleen preservation rate (45% vs. 18%, P=0.029), as well as shorter high dependency unit stay (1 vs. 5 d, P=0.001) and postoperative hospital stay (5 vs. 14 d, P=0.017). There was no significant difference in operating time (245 vs. 240 min, P=0.602) and postoperative morbidity (13.6% vs. 27.2%, P=0.431). In patients with malignant disease, there were no differences in R0 resection margin status (90% vs. 85.7%, P=0.88), the numbers of lymph nodes retrieved (12.7 vs. 14.1, P=0.82), the 1- and 2-year survival rates (89% vs. 81%, P=0.54 and 74.2% vs. 71.5%, P=0.63, respectively), and the mean duration of survival (45 vs. 31 mo, P=0.157). CONCLUSIONS: The laparoscopic approach to distal pancreatectomy offers advantages over open surgery in terms of reductions in operative trauma and duration of postoperative recovery without compromising the oncologic resection.

Perioperative Enteral Immunonutrition Modulates Systemic and Mucosal Immunity and the Inflammatory Response in Patients With Periampullary Cancer Scheduled for Pancreaticoduodenectomy: A Randomized Clinical Trial.

OBJECTIVES: Nutritional deficiencies and immune dysfunction in cancer patients may contribute to postoperative septic morbidity. This trial compared the effects of perioperative enteral immunonutrition (EIN) versus standard enteral nutrition (SEN) on systemic and mucosal immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer. METHODS: Thirty-seven patients were randomized (EIN, n = 17; SEN, n = 20) to receive feed for 14 days preoperatively and 7 days postoperatively. Mediators of systemic immunity (interleukin 1α, tumor necrosis factor α, lymphocytes subsets, and complement components) and of mucosal immunity in duodenal biopsies, nutritional markers and parameters were evaluated. RESULTS: The groups were comparable for demographics, the concentrations of mediators of systemic and mucosal immunity at time of recruitment, and for the duration and amount of feed received. Preoperative EIN rather than SEN was associated with significant reductions in plasma tumor necrosis factor α and total hemolytic complement. Enteral immunonutrition-fed patients had significantly higher total lymphocyte count on the third postoperative day and significantly greater rise in CD4/CD8 ratio from day 3 to day 7 postoperatively compared with SEN-fed patients. CONCLUSIONS: The perioperative administration of EIN rather than SEN is associated with a favorable modulation of the inflammatory response and enhancement of systemic immunity in patients undergoing pancreaticoduodenectomy for periampullary cancer.

Source of nitrogen associated with recovery of relative growth rate in Arabidopsis thaliana acclimated to sustained cold treatment.

To determine (1) whether acclimation of carbon metabolism to low temperatures results in recovery of the relative growth rate (RGR) of plants in the cold and (2) the source of N underpinning cold acclimation in Arabidopsis thaliana, we supplied plants with a nutrient solution labelled with (15) N and subjected them to a temperature shift (from 23 to 5 °C). Whole-plant RGR of cold-treated plants was initially less than 30% of that of warm-maintained control plants. After 14 d, new leaves with a cold-acclimated phenotype emerged, with the RGR of cold-treated plants increasing by 50%; there was an associated recovery of root RGR and doubling of the net assimilation rate (NAR). The development of new tissues in the cold was supported initially by re-allocation of internal sources of N. In the longer term, the majority (80%) of N in the new leaves was derived from the external solution. Hence, both the nutrient status of the plant and the current availability of N from external sources are important in determining recovery of growth at low temperature. Collectively, our results reveal that both increased N use efficiency and increases in nitrogen content per se play a role in the recovery of carbon metabolism in the cold.

Laparoscopic versus open cystgastrostomy for pancreatic pseudocysts: a case-matched comparative study.

BACKGROUND: Cystgastrostomy is the commonest method of internal drainage of pancreatic pseudocysts (PPs). While large and persistent retrogastric pancreatic pseudocysts are amenable to laparoscopic cystgastrostomy, the potential benefits of this minimally invasive laparoscopic approach over open surgery remain to be demonstrated. The aim of this study was to compare the outcomes of the laparoscopic and open approaches for cystgastrostomy. METHODS: Patients who underwent laparoscopic cystgastrostomy (LCG) were matched on a 3:1 basis to those who underwent open cystgastrostomy (OCG) according to age, sex distribution, and size of pseudocyst. The outcomes of the two approaches were compared on an intention-to-treat basis. Data shown represent medians. RESULTS: A total of 54 patients underwent cystgastrostomy (35 LCG, 19 OCG) between 1997 and 2011. The final case matched cohort consisted of 40 patients (12 female and 28 male) of which 30 underwent LCG (two converted to open surgery) and 10 underwent OCG. The laparoscopic and open groups were comparable for age (55 vs. 59 years, P = 0.80), sex distribution, and size of pseudocyst (10 vs. 13 cm, P = 0.51). The laparoscopic approach had a significantly shorter operating time (62 vs. 95 min, P = 0.035) and carried a significantly lower risk of postoperative morbidity (10% vs. 60%, P = 0.024) and shorter postoperative hospital stay (6.2 vs. 11 days, P = 0.038). There was one operative death after OCG (10%). CONCLUSION: The laparoscopic approach to cystgastrostomy for large and persistent retrogastric pancreatic pseudocysts is associated with a shorter operating time, smoother and more rapid recovery, and a shorter hospital stay compared with open surgery. The laparoscopic approach should be considered the preferable approach where expertise is available.

Excess adiposity and survival in patients with colorectal cancer: a systematic review.

Excess adiposity is an established risk factor for incident colorectal cancer (CRC) but whether this association extrapolates to poorer survival is unclear. We undertook a systematic review to examine relationships between measures of adiposity and survival in patients with CRC. For distinction, we included pre-diagnosis exposure and CRC-related mortality. We performed dose-response meta-analyses and assessed study quality using eight domains of bias. Six study categories were identified based on (i) timing of adiposity measurement relative to survival analysis time zero and (ii) clinical setting. Several types of adiposity measurements were reported; body mass index (BMI) was the commonest. For pre-diagnosis cohorts, baseline BMI negatively impacted on CRC-related mortality in men only (risk estimate per 5 kg m(-2) = 1.19, 95% confidence intervals: 1.14-1.25). The other groups were pre-diagnosis BMI but diagnosis as time zero; population-based cohorts; treatment cohorts; observational analyses within adjuvant chemotherapy trials; patients with metastatic CRC - each had several biases (e.g. treatment selection, reverse causality) and sources of confounding (e.g. chemotherapy 'capping'). Overall, there was insufficient evidence for a strong link between adiposity and survival. These findings demonstrate an important principle: an established link between an exposure (here, adiposity) and increased cancer incidence does not necessarily extrapolate into an inferior post-treatment outcome.

Early Experience with a Hepatobiliary and Pancreatic Quality Improvement Program.

This project aims to assess the impact of the introduction of a hepatobiliary and pancreatic (HPB) Quality Improvement Program (QIP) on postoperative complications following liver, biliary and pancreatic surgery. A prospective analysis of postoperative complications over a six month period was performed. Complications were analysed and graded according to internationally agreed definitions. Justification was sought and errors identified. Weekly meetings were performed to review each complication enabling an action plan to be created to prevent future recurrence. Rates were compared with previously audited and published results, using the chi-square test. A total of 326 procedures were performed over the six months including 30 pancreatectomies, 45 liver resections and 251 other procedures. 37 patients developed complications (11.3%) with 47 complications in total including two deaths. Using the ISGPS grading, eight complications were identified; two grade A, four grade B and two grade C. There were three grade A ISGLS complications and one grade B. 30 complications were justified as unavoidable, 16 as avoidable and one as indeterminate. Action plans included continued monitoring (n=41), formulation of new policy (n=3), individual counselling (n=4), educational offering (n=4). When compared with 2010 complication rates, 114 complications occurred in 233 liver operations during the baseline period, compared with 17 complications in 45 liver operations during the QIP period, OR=0.63 (95% CI: 0.33 to 1.22), p=0.17 and 86 complications occurred in 99 pancreatic resections during the baseline period, compared with 20 complications in 30 pancreatic resections during the QIP period OR=0.30 (95% CI: 0.12 to 0.79), p=0.01 The HPB QIP is a rigorous approach to grade every complication and death. A statistically significant reduction in pancreas related complications has already been obtained. Further work is required to determine the persistence and magnitude of this quality improvement.

Complications arising in simple and polycystic liver cysts.

Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study.

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.

Pancreatoduodenectomy as a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue.

A clear understanding of oral drug absorption is an important aspect of the drug development process. The permeability of drug compounds across intact sections of small intestine from numerous species, including man, has often been investigated using modified Ussing chambers. The maintenance of viable, intact tissue is critical to the success of this technique. This study therefore aimed to assess the viability and integrity of tissue from patients undergoing pancreatoduodenectomy, for use in cross-species Ussing chamber studies. Electrical parameters (potential difference, mV; short-circuit current, µA.cm(-2) ; resistance, Ω.cm(2) ) were monitored over the duration of each experiment, as was the permeability of the paracellular marker atenolol. The permeability values (Papp; cm/s × 10(-6) ) for a training-set of compounds, displaying a broad range of physicochemical properties and known human fraction absorbed values, were determined in both rat and human jejunum, as well as Caco-2 cell monolayers. The results indicate that human jejunum sourced from pancreatoduodenectomy remained viable and intact for the duration of experiments. Permeability values generated in rat and human jejunum correlate well (R(2) = 0.86), however the relationship between permeability in human tissue and Caco-2 cells was comparatively weak (R(2) = 0.58). Relating permeability to known human fraction absorbed (hFabs) values results in a remarkably similar relationship to both rat and human jejunum Papp values. It can be concluded that human jejunum sourced from pancreatoduodenectomy is a suitable source of tissue for Ussing chamber permeability investigations. The relationship between permeability and hFabs is comparable to results reported using alternative test compounds.

Eotaxin-2 and colorectal cancer: a potential target for immune therapy.

PURPOSE: To study the production of chemokines by colorectal hepatic metastases. EXPERIMENTAL DESIGN: Biopsies of resected colorectal hepatic metastases and nonneoplastic adjacent liver tissue were screened for chemokines using protein arrays and results were confirmed by ELISA and immunohistochemistry. RESULTS: Two chemokines, eotaxin-2 and MCP-1, were found at elevated levels within the tumor biopsy compared with adjacent liver. The relative increase in expression from tumor was much higher for eotaxin-2 than MCP-1, with 10 of 25 donors having a >100-fold increase in expression compared with 0 of 24 donors for MCP-1. In a parallel analysis, eotaxin-2 was also found at elevated levels in the tumor region of primary colorectal cancer biopsies. Immunohistochemical staining indicated that carcinoembryonic antigen-positive tumor cells stained strongly for eotaxin-2, implicating these cells as the predominant source of the chemokine. In vitro studies confirmed that several colorectal tumor lines produce eotaxin-2 and that secretion of this chemokine could be depressed by IFN-gamma and enhanced by the Th2-type cytokines interleukin-4 and interleukin-13. Jurkat T cells were engineered to express the receptor for eotaxin-2 (CCR3). These cells effectively migrated in response to eotaxin-2 protein, suggesting that immune cells gene modified to express a chemokine receptor may have improved abilities to home to tumor. CONCLUSIONS: Taken together, these observations confirm eotaxin-2 as a chemokine strongly associated with primary and metastatic tumors of colorectal origin. Furthermore, the importance of this result may be a useful tool in the development of targeted therapeutic approaches to colorectal tumors.

Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases.

PURPOSE: The overall aim of this study was to develop a novel treatment for colorectal cancer based on the use of gene therapy. Genetic modification of T lymphocytes has been used to specifically target and kill tumor cell lines directly. To test the efficacy of this method with clinically relevant materials, this study investigated the potential of T lymphocytes derived from patients with advanced colorectal disease to target autologous primary tumor material. METHODS T lymphocytes isolated preoperatively were modified genetically with recombinant retroviruses encoding CD3zeta-based chimeric immune receptors and were tested for functional activity against freshly isolated autologous tumor cells harvested from hepatic colorectal metastases. RESULTS: Patient-derived T cells were successfully transduced, and chimeric immune receptor expression was confirmed. Carcinoembryonic antigen expression on freshly isolated colorectal tumor cells was also demonstrated by molecular and immunohistochemical techniques. T cells expressing the anticarcinoembryonic antigen receptor were specifically activated by coculture with disaggregated or intact, diced tumor, whereas control non-carcinoembryonic antigen-targeted T-cell populations failed to activate. CONCLUSIONS: These results indicate that gene-targeted primary T lymphocytes depict specific functional activity against autologous colorectal tumor cells. This evidence indicates that chimeric immune receptor-expressing T cells may be able to circumvent the mechanisms used by tumor cells to avoid immune cell activity in vivo. This study emphasizes the potential of this approach as a therapy for carcinoembryonic antigen-expressing primary colorectal tumor and its metastases.

Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial.

BACKGROUND: The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver. METHODS: We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat. FINDINGS: 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival. INTERPRETATION: Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

Cryoablation for liver tumors - is there clinical utility?

The large majority of liver tumors are metastatic, of which colorectal deposits are the most common. Resection is the preferable mode of treatment because it offers the possibility of prolonged survival, but this strategy is only viable in about 25% of patients. This is due to either the proximity of the disease to the portal structures or to the number of metastases. Other treatment options are therefore required for liver tumors, such as chemotherapy, radiofrequency ablation, laser photocoagulation, chemoembolization, and cryotherapy. This article focuses on cryotherapy as a method of treating unresectable hepatic tumors.

Unusual bony colorectal metastases in post-hepatometastasectomy patients.

Colorectal cancer metastases occur predominantly in the liver, with extrahepatic sites being far less common and equally distributed in the lung, brain, skin, and bone. We report two cases of unusual bony metastases of colorectal cancer. A 55-year-old man underwent an abdominoperineal resection for a Dukes B carcinoma of the rectum, followed 17 months later by a right hemihepatectomy for metachronous liver metastases. He subsequently presented 11 months later with a solitary metastatic deposit in the mandible. Seven months after resection and reconstruction, he remained well and disease-free. A 67-year-old man underwent a right hemicolectomy and right hemihepatectomy for carcinoma of the cecum and synchronous liver metastases. He presented 16 months later with a lesion suspicious of metastases in his clavicle. He subsequently died 18 months after his original operation. The prolongation of survival after hepatic metastasectomy results in the presentation of metastases at sites not commonly seen in colorectal malignancy. Postoperative surveillance after apparently curative hepatectomy should be directed to the evaluation of any unusual new symptoms.

Conformational Preference and Donor Atom Interaction Leading to Hexacoordination vs Pentacoordination in Bicyclic Tetraoxyphosphoranes(1).

New bicyclic tetraoxyphosphoranes all containing a six-membered oxaphosphorinane ring, C(6)H(8)(CH(2)O)(2)P(OC(12)H(8))(OXyl) (1), (C(6)H(4)O)(2)P(OC(12)H(8))(OXyl) (2), CH(2)[(t-Bu)(2)C(6)H(2)O](2)P(OC(12)H(8))(OXyl) (3), O(2)S[(t-Bu)MeC(6)H(2)O](2)P(OC(12)H(8))(OXyl) (4), and S[(t-Bu)MeC(6)H(2)O](2)P(OC(12)H(8))(OXyl) (5), were synthesized by the oxidative addition reaction of the cyclic phosphine P(OC(12)H(8))(OXyl) (6) with an appropriate diol in the presence of N-chlorodiisopropylamine. X-ray analysis revealed trigonal bipyramidal (TBP) geometries for 1-4 where the dioxa ring varied in size from six- to eight-membered. With a sulfur donor atom as part of an eight-membered ring in place of a potential oxygen donor atom of a sulfone group as in 4, the X-ray study of 5 showed the formation of a hexacoordinated structure via a P-S interaction. Ring constraints are evaluated to give an order of conformational flexibility associated with the (TBP) tetraoxyphosphoranes 4 > 3 approximately 1 > 2 which parallels the degree of shielding from (31)P NMR chemical shifts: 4 > 3 > 1 > 2. The six- and seven-membered dioxa rings in 1 and 2, respectively, are positioned at axial-equatorial sites, whereas the eight-membered dioxa ring in 3 and 4 occupies diequatorial sites of a TBP. V-T (1)H NMR data give barriers to xylyl group rotation about the C-OXyl bond. The geometry of 5 is located along a coordinate from square pyramidal toward octahedral to the extent of 60.7%. Achieving hexacoordination in bicyclic tetraoxyphosphoranes of reduced electrophilicity relative to bicyclic pentaoxyphosphoranes appears to be dependent on the presence of a sufficiently strong donor atom.