Comparative analysis of whole cell-derived vesicular delivery systems for photodynamic therapy of extrahepatic cholangiocarcinoma.

This first-in-its-class proof-of-concept study explored the use of bionanovesicles for the delivery of photosensitizer into cultured cholangiocarcinoma cells and subsequent treatment by photodynamic therapy (PDT). Two types of bionanovesicles were prepared: cellular vesicles (CVs) were fabricated by sonication-mediated nanosizing of cholangiocarcinoma (TFK-1) cells, whereas cell membrane vesicles (CMVs) were produced by TFK-1 cell and organelle membrane isolation and subsequent nanovesicularization by sonication. The bionanovesicles were loaded with zinc phthalocyanine (ZnPC). The CVs and CMVs were characterized (size, polydispersity index, zeta potential, stability, ZnPC encapsulation efficiency, spectral properties) and assayed for tumor (TFK-1) cell association and uptake (flow cytometry, confocal microscopy), intracellular ZnPC distribution (confocal microscopy), dark toxicity (MTS assay), and PDT efficacy (MTS assay). The mean ±â€¯SD diameter, polydispersity index, and zeta potential were 134 ±â€¯1 nm, -16.1 ±â€¯0.9, and 0.220 ±â€¯0.013, respectively, for CVs and 172 ±â€¯3 nm, -16.4 ±â€¯1.1, and 0.167 ±â€¯0.022, respectively, for CMVs. Cold storage for 1 wk and incorporation of ZnPC increased bionanovesicular diameter slightly but size remained within the recommended range for in vivo application (136-220 nm). ZnPC was incorporated into CVs and CMVs at an optimal photosensitizer:lipid molar ratio of 0.006 and 0.01, respectively. Both bionanovesicles were avidly taken up by TFK-1 cells, resulting in homogenous intracellular ZnPC dispersion. Photosensitization of TFK-1 cells did not cause dark toxicity, while illumination at 671 nm (35.3 J/cm2) produced LC50 values of 1.11 µM (CVs) and 0.51 µM (CMVs) at 24 h post-PDT, which is superior to most LC50 values generated in tumor cells photosensitized with liposomal ZnPC. In conclusion, CVs and CMVs constitute a potent photosensitizer platform with no inherent cytotoxicity and high PDT efficacy in vitro.

Photoactive imaging and therapy for colorectal cancer using a CEA-Affimer conjugated Foslip nanoparticle.

Theranostic nanoparticles hold promise for simultaneous imaging and therapy in colorectal cancer. Carcinoembryonic antigen can be used as a target for these nanoparticles because it is overexpressed in most colorectal cancers. Affimer reagents are synthetic proteins capable of binding specific targets, with additional advantages over antibodies for targeting. We fabricated silica nanoparticles using a water-in-oil microemulsion technique, loaded them with the photosensitiser Foslip, and functionalised the surface with anti-CEA Affimers to facilitate fluorescence imaging and photodynamic therapy of colorectal cancer. CEA-specific fluorescence imaging and phototoxicity were quantified in colorectal cancer cell lines and a LS174T murine xenograft colorectal cancer model. Anti-CEA targeted nanoparticles exhibited CEA-specific fluorescence in the LoVo, LS174T and HCT116 cell lines when compared to control particles (p < 0.0001). No toxicity was observed in LS174T cancer mouse xenografts or other organs. Following photo-irradiation, the anti-CEA targeted particles caused significant cell death in LoVo (60%), LS174T (90%) and HCT116 (70%) compared to controls (p < 0.0001). Photodynamic therapy (PDT) at 24 h in vivo showed a 4-fold reduction in tumour volume compared to control mouse xenografts (p < 0.0001). This study demonstrates the efficacy of targeted fluorescence imaging and PDT using Foslip nanoparticles conjugated to anti-CEA Affimer nanoparticles in in vitro and in vivo colorectal cancer models.

Photodynamic Stromal Depletion in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies, with a five-year survival of less than 10%. The resistance of the disease and the associated lack of therapeutic response is attributed primarily to its dense, fibrotic stroma, which acts as a barrier to drug perfusion and permits tumour survival and invasion. As clinical trials of chemotherapy (CT), radiotherapy (RT), and targeted agents have not been successful, improving the survival rate in unresectable PDAC remains an urgent clinical need. Photodynamic stromal depletion (PSD) is a recent approach that uses visible or near-infrared light to destroy the desmoplastic tissue. Preclinical evidence suggests this can resensitise tumour cells to subsequent therapies whilst averting the tumorigenic effects of tumour-stromal cell interactions. So far, the pre-clinical studies have suggested that PDT can successfully mediate the destruction of various stromal elements without increasing the aggressiveness of the tumour. However, the complexity of this interplay, including the combined tumour promoting and suppressing effects, poses unknowns for the clinical application of photodynamic stromal depletion in PDAC.

Aortoiliac graft-enteric fistula presenting as gastrointestinal hemorrhage: A report on a complex case management.

Key Clinical Message: Iliac artery-enteric fistula is a rare cause of lower GI bleeding and can cause life-threatening consequences. A high degree of clinical suspicion is needed in patients with previous aortic surgery to allow early multidisciplinary intervention. Abstract: This case study discusses the staged management of a 78-year-old patient presenting with life-threatening lower gastrointestinal (GI) bleeding secondary to an aortoiliac graft-enteric fistula (GEF) into the sigmoid colon on the background of an adenocarcinoma and diverticular disease. The patient had an aorto bi-iliac synthetic dacron graft repair of an abdominal aortic aneurysm (AAA) some 20 years ago. Here, we present a case of successful endovascular treatment of massive hemorrhage as a bridge to definitive second-stage dacron graft explant and autologous vein reconstruction with a simultaneous anterior resection.

Affimer Tagged Cubosomes: Targeting of Carcinoembryonic Antigen Expressing Colorectal Cancer Cells Using In Vitro and In Vivo Models.

Nanomedicines, while having been approved for cancer therapy, present many challenges such as low stability, rapid clearance, and nonspecificity leading to off-target toxicity. Cubosomes are porous lyotropic liquid crystalline nanoparticles that have shown great premise as drug delivery vehicles; however, their behavior in vivo is largely underexplored, hindering clinical translation. Here, we have engineered cubosomes based on the space group Im3m that are loaded with copper acetylacetonate as a model drug, and their surfaces are functionalized for the first time with Affimer proteins via copper-free click chemistry to actively target overexpressed carcinoembryonic antigens on LS174T colorectal cancer cells. Unlike nontargeted cubosomes, Affimer tagged cubosomes showed preferential accumulation in cancer cells compared to normal cells not only in vitro (2D monolayer cell culture and 3D spheroid models) but also in vivo in colorectal cancer mouse xenografts, while exhibiting low nonspecific absorption and toxicity in other vital organs. Cancerous spheroids had maximum cell death compared to noncancerous cells upon targeted delivery. Xenografts subjected to targeted drug-loaded cubosomes showed a 5-7-fold higher drug accumulation in the tumor tissue compared to the liver, kidneys, and other vital organs, a significant decrease in tumor growth, and an increased survival rate compared to the nontargeted group. This work encompasses the first thorough preclinical investigation of Affimer targeted cubosomes as a cancer therapeutic.

Matched Case-Control Comparative Study of Laparoscopic Versus Open Pancreaticoduodenectomy for Malignant Lesions.

INTRODUCTION: Advances in surgical technologies allowed safe laparoscopic pancreaticoduodenectomy (LPD). The aim of this study is to compare the oncologic outcomes of LPD to open pancreaticoduodenectomy (OPD) in terms of safety and recurrence rate. MATERIALS AND METHODS: A cohort of 30 patients were matched for age, sex, American Society of Anaesthesiologists, tumor size, pancreatic duct diameter, and histopathologic diagnosis on a 1:1 basis (15 LPD, 15 OPD). Comparison between groups was performed on intention-to-treat basis. Survival following resection was compared using the Kaplan-Meier survival analysis. RESULTS: The median operating time for LPD group was longer than for OPD group (470 vs. 310 min; P=0.184). However, estimated blood loss (300 vs. 620 mL; P=0.023), high dependency unit stay (2.0 vs. 6.0 d; P=0.013) and postoperative hospital stay (9.0 vs. 17.4 d; P=0.017) were significantly lower in the LPD group. There was no significant difference in postoperative rates of morbidity (40% vs. 67%; P=0.431) and mortality (0% vs. 6.7%; P=0.99). The surgical resection margins R0 status (87% vs. 73%; P=0.79) and the number of lymph nodes (18 vs. 20; P=0.99) in the resected specimens were comparable between the 2 groups. There was no significant difference in overall survival outcomes. CONCLUSIONS: In selected patients, the laparoscopic approach to pancreaticoduodenectomy in the hands of the experienced offers advantages over open surgery without compromising the oncologic resection.

Outcome of long interval radiological surveillance of side branch pancreatic duct-involved intraductal papillary mucinous neoplasm in selected patients.

INTRODUCTION: Side branch IPMN (SB-IPMN) of the pancreas has a malignancy rate between 10 and 20%. We hypothesized that surveillance at longer intervals on selected patients with SB-IPMN might be indicated. METHODS: This is a retrospective study of prospectively collected data of 276 patients presenting from 2000 to 2010. After 2007, we opted to screen our patients with longer intervals, initially at 12 months then 24 months using MR if no "worrisome features" were present. RESULTS: Complete data sets for 261 patients were analysed and patients were aged 78 (40-91) years. 232 patients had sole SB-IPMN while 92% were incidental (n = 209) and 8% were symptomatic (n = 24). Single SB-IPMN accounted for 84% (n = 195) of all cases; maximum diameter of 15.5 (5-60) mm. The median follow up duration was 46 (32-53) months. Short interval radiological surveillance (3-9 months) was 39% (n = 90), while long interval surveillance (12-36 months) was performed in 61% (n = 142). The rate of pancreatic resection, due to concern for the development of pancreatic cancer, in the short and long interval surveillance groups was 4.4% (n = 4) and 3.5% (n = 5) respectively; p = 0.78. CONCLUSION: Our data suggests no difference in outcome between long and short interval MR surveillance of SB-IPMN patients.

Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients.

Regulatory T cells (Tregs) comprise numerous heterogeneous subsets with distinct phenotypic and functional features. Identifying Treg markers is critical to investigate the role and clinical impact of various Treg subsets in pathological settings, and also for developing more effective immunotherapies. We have recently shown that non-activated FoxP3-Helios+ and activated FoxP3+/-Helios+ CD4+ T cells express GARP/LAP immunosuppressive markers in healthy donors. In this study we report similar observations in the peripheral blood of patients with pancreatic cancer (PC) and liver metastases from colorectal cancer (LICRC). Comparing levels of different Treg subpopulations in cancer patients and controls, we report that in PC patients, and unlike LICRC patients, there was no increase in Treg levels as defined by FoxP3 and Helios. However, defining Tregs based on GARP/LAP expression showed that FoxP3-LAP+ Tregs in non-activated and activated settings, and FoxP3+Helios+GARP+LAP+ activated Tregs were significantly increased in both groups of patients, compared with controls. This work implies that a combination of Treg-specific markers could be used to more accurately determine expanded Treg subsets and to understand their contribution in cancer settings. Additionally, GARP-/+LAP+ CD4+ T cells made IL-10, and not IFN-γ, and levels of IL-10-secreting CD4+ T cells were elevated in LICRC patients, especially with higher tumor staging. Taken together, our results indicate that investigations of Treg levels in different cancers should consider diverse Treg-related markers such as GARP, LAP, Helios, and others and not only FoxP3 as a sole Treg-specific marker.

Anti-cancer effects of oncolytic viral therapy combined with photodynamic therapy in human pancreatic cancer cell lines.

BACKGROUND: Oncolytic viral therapy and photodynamic therapy are potential therapies for inoperable or advanced pancreatic cancer. Our aim was to investigate the anti-cancer killing effects of reovirus therapy combined with protoporphyrin IX (PpIX)-mediated photodynamic therapy on a variety of human pancreatic cancer cell lines. METHODS: Pancreatic cancer cell lines (PsPC-1 and BXPC-3) and a non-cancer control cell line (HEK293) were infected with reovirus serotype 3 strain Dearing (T3D) at 0, 0·1, 1, and 10 plaque-forming units (PFU) per cell for 48 h. Cells were incubated with PpIX pro-drug 5-aminolevulinic acid (5-ALA) at 0, 1, 2, 3, and 4 mM for 4 h. Then, cells were photo-irradiated for 15 min with visible red light-emitting diodes with a light-fluence of 0·54 J/cm(2) of 653 nm (PpIX optimal excitation wavelength). The killing effects of reovirus combined with PpIX-mediated photodynamic therapy were analysed in methylthiazoltetrazolium (MTT) and trypan blue assays. The effect of adding reovirus after photodynamic therapy was also assessed. The statistical significance of the difference between groups was assessed with the two-tailed Student's t test. p<0·05 was considered statistically significant. FINDINGS: Reovirus monotherapy induced cell death in the two pancreatic lines (mean 57% [SE 10·2] at 10 PFU per cell). PpIX-mediated PDT monotherapy induced cell death in a dose-dependent manner (mean 10% [SE 2·2], 30 [6·4], 50 [8·2], and 70 [13·2] after 1, 2, 3, and 4 mM 5-ALA, respectively). Reovirus with PpIX-mediated photodynamic therapy resulted in a significantly increased cytotoxic effect compared with reovirus monotherapy and photodynamic therapy (p=0·042) with 100% cell death observed across pancreatic cell lines with 10 PFU per cell combined with 1 and 2 mM 5-ALA. There was no difference in cytotoxicity observed between added reovirus before or after photodynamic therapy. INTERPRETATION: To our knowledge, this is the first in-vitro study to combine reovirus oncolytic viral therapy with PpIX-mediated photodynamic therapy to treat pancreatic cancer. These results show a significant additive effect in cell killing and they provide initial evidence for a novel combined therapeutic intervention. FUNDING: National Institute for Health Research.

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.

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.

Increased levels of granulocytic myeloid-derived suppressor cells in peripheral blood and tumour tissue of pancreatic cancer patients.

Pancreatic cancer (PC) often presents late with poor survival. While role of immunosuppressive cells in preclinical studies provided help to develop immunotherapeutic agents, these cells remain under investigation in PC. The aim of this study was to characterise the different subsets of myeloid-derived suppressor cells (MDSCs) and evaluate their level and function in the circulation and tissue of PC patients. Significant increases in circulating and tumour-infiltrating granulocytic (Lin-HLA-DR-CD33+CD11b+CD15+), but not monocytic (Lin-HLA-DR-CD14+), MDSCs were detected in PC patients when compared with healthy donors and patients with chronic pancreatitis. The circulating MDSCs from PC patients expressed arginase 1, which represents their functional state. Blood levels of MDSCs showed no association with PC stage or preoperative levels of tumour markers. These findings provide a first characterisation of the phenotype of different subsets of peripheral and local MDSCs in PC patients and suggest that the frequency and contribution of these cells are predominantly granulocytic. This information demonstrates that MDSCs play a role in pancreatic cancer and future large validation studies may help in the development of new immunotherapeutic strategies to inhibit or eliminate MDSC function.

Laparoscopic lateral pancreaticojejunostomy and laparoscopic Berne modification of Beger procedure for the treatment of chronic pancreatitis: the first UK experience.

BACKGROUND: Pancreatic resection and/or ductal drainage are common surgical options in the management of unremitting abdominal pain of chronic pancreatitis (CP). We describe the results of the largest UK series of laparoscopic approach to pancreatic duct drainage and head resection for CP. METHODS: Patients with CP and intractable abdominal pain requiring duodenum-preserving pancreatic head resection (Berne modification of Beger procedure) or Puestow procedure were offered laparoscopic surgery by a single surgeon. The results shown represent median (range). RESULTS: Six patients (3 males) with CP (alcohol induced, n=4; idiopathic, n=2) underwent surgery between 2009 and 2012. The pancreatic duct diameter was 8.75 (6 to 11) mm. Five patients have had lateral pancreaticojejunostomy and 1 patient underwent Berne modification of Beger procedure, all of which were completed laparoscopically. The operating time was 277.5 (250 to 360) minutes. There were no deaths and 1 patient was readmitted 10 days postoperatively and had laparotomy for pancreatic bleeding after pancreaticojejunostomy (morbidity, 17%). The hospital stay was 5 (5 to 8) days. At a follow-up of 14.2 (10 to 35) months, 4 of the patients were pain free, whereas 2 patients required one third and half of the preoperative oral opioid dose for pain control. CONCLUSIONS: The laparoscopic approach to pancreatic duct drainage and duodenum-preserving head resection in carefully selected patients and in experienced hands is feasible and safe with good short-term results and potential advantages. Further expansion of experience and longer follow-up is required.

Congenital insensitivity to pain in a child attending a paediatric fracture clinic.

Congenital insensitivity to pain is a rare condition that is often undiagnosed until patients present with a variety of musculoskeletal problems. A major sequel of these orthopaedic manifestations is the development of heterotopic ossification and callus formation following fractures, eventually leading to the development of a Charcot's joint. This case reports on a 7-year-old child who was diagnosed with congenital insensitivity to pain type V, after he presented in our clinic with fractures of the metatarsals in his left foot while continuing to weight bear, without any discomfort. The patient failed to attend the follow-up in paediatric neurology clinic despite multiple invitations. This case highlights the importance of establishing an early diagnosis and keeping a close eye on this rare entity, which can present for the first time in a paediatric fracture clinic.

Salmonella osteomyelitis of the calcaneum bone in an immunocompetent child.

Salmonella osteomyelitis occurs infrequently in healthy children and can manifest in the subacute form. This condition has only been reported in few cases previously. We report the first case of primary subacute haematogenous osteomyelitis of the calcaneum in a healthy 12-year-old child. The patient made uneventful recovery following surgical drainage and antibiotic therapy. Histology of the tissue biopsy confirmed a diagnosis of Salmonella livingstone infection. Although the diagnosis of Salmonella osteomyelitis of the calcaneum can be difficult to establish, it should be considered as an aetiological factor even in healthy children.

Neuropilin 1: function and therapeutic potential in cancer.

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.

Myeloid-derived suppressor cells in cancer: recent progress and prospects.

Immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs) and T regulatory cells, downregulate antitumour immunity and cancer immunotherapy. MDSCs are a heterogeneous group of immature myeloid cells that negatively regulate the immune responses during tumour progression, inflammation and infection. Whilst there have been extensive laboratory investigations aimed at characterising the MDSC subsets in cancer, there remains a significant gap in our understanding of their phenotypical and functional heterogeneity. In this article, we review data concerning the phenotypical and functional role of MDSCs in cancers. Importantly, we analyse the value of MDSCs as a prognostic factor in various clinical settings and the possible therapeutic approaches towards elimination of their immunosuppressive activity and enhancement of beneficial antitumour immune responses. MDSCs promote tumour immune evasion by inhibiting T-cell responses, as well as by supporting tumour progression. Accumulation of MDSCs is associated with the progression of human cancers, and their elimination was shown to improve anti-tumour immune responses. Phenotypical characterisation of MDSCs has been poorly investigated in many human cancers and lacks comprehensive clinicopathological correlation data. Although the need for effective therapeutic agents to eliminate the MDSC suppressive effect is immense, their role has been examined only in a few clinical settings.

Laparoscopic bile duct exploration via choledochotomy followed by primary duct closure is feasible and safe for the treatment of choledocholithiasis.

BACKGROUND: The common bile duct traditionally is managed with T-tube drainage after choledochotomy and removal of common bile duct (CBD) stones, but this approach carries an associated tube-related morbidity rate, including bile leak, of 10.5-20 %. This study examined the safety and effectiveness of laparoscopic CBD exploration (LCBDE) followed by primary duct closure. METHODS: This is a retrospective analysis of 120 consecutive patients (81 female) who underwent LCBDE between October 2002 and October 2012. The duct primarily was closed in all patients. The results are given as median (range). RESULTS: Trans-CBD exploration was performed in 120 patients and all cases were successfully completed laparoscopically. The maximum diameter of the CBD was 9.4 (3-30) mm and the number of CBD stones detected was 3 (0-20). The biliary tree was clear at the end of exploration in 116 patients (96.7 %). The operating time was 122 (70-360) min. The mortality rate, morbidity rate, postoperative bile leak rate, rate of retained CBD stones after the primary procedure, and CBD stricture rate at a follow-up of 39.2 (2-82) months were 0, 8.3, 2.5, 3.3, and 0.8 %, respectively. The postoperative hospital stay was 2.1 (1-29) days. CONCLUSION: Primary duct closure following LCBDE is safe, can be employed routinely as an alternative to T-tube insertion, and has a short hospital stay and low morbidity rate.

Macrophage inhibitory cytokine-1: a review of its pleiotropic actions in cancer.

BACKGROUND AND AIMS: The macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor-ß (TGF-ß) superfamily that can serve as a potential immune-therapeutic target and/or a prognostic biomarker for the treatment of some cancers. This article reviews the current published data on the molecular and clinical application of MIC-1 in cancer. METHODS: Literature review was conducted using Medline, PubMed, Embase and Cochrane databases. RESULTS: MIC-1 is the only known secreted p53-regulated cytokine and therefore can serve as a biomarker for p53 activation both in vitro and in vivo. MIC-1 gene can be activated by cyclooxygenase inhibitors and has pro-apoptotic and anti-tumour activities. Although MIC-1 may induce anti-tumour role in the early stages of cancer, it can promote the invasiveness and metastatic behaviour in advanced stages. Greater concentration of MIC-1 was associated with the induction of cancer-related anorexia and weight loss in animals and humans. Of clinical interest, MIC-1 out-performs all available biomarkers including CA19-9 in the differentiation of patients with resectable pancreatic cancer from patients with benign pancreatic disease. MIC-1 gene was over-expressed in colorectal cancer (CRC), and a progressive rise of MIC-1 serum levels was noted in patients with adenomatous polyps and further in patients with CRC. CONCLUSIONS: MIC-1 cytokine has the potential characteristics for a new diagnostic biomarker and a target for cancer treatment. Further research however is required to characterise MIC-1 receptors and to revalidate its diagnostic power in larger and better-standardised clinical studies.