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// May Abd Al Samid 1, 2, * , Belal Chaudhary 1, * , Yazan S. Khaled 3 , Basil J. Ammori 3 , Eyad Elkord 1, 2, 3 1 Biomedical Research Centre, School of Environment and Life Sciences, University of Salford, Manchester, United Kingdom 2 College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates 3 Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom * These authors contributed equally to this work Correspondence to: Eyad Elkord, e-mail: eelkord@uaeu.ac.ae , e.elkord@salford.ac.uk and eyad.elkord@manchester.ac.uk Keywords: regulatory T cells, markers, GARP/LAP, FoxP3, Helios Received: December 09, 2015 Accepted: January 29, 2016 Published: February 11, 2016 ABSTRACT 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.

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 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.

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.

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.

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.

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.

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.

Background and aims The macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the transforming growth factor-β (TGF-β) 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.

Background Laparoscopic surgery has extended its applications to resection of malignancies with favorable results. We report the first successful simultaneous laparoscopic subtotal colectomy and pancreaticoduodenectomy (PD) in a patient with familial adenomatous polyposis (FAP). Case report A 37-year-old man presented with obstructive jaundice. Gastroscopy and biopsies revealed a large ampullary tubulovillous adenoma with mild dysplasia (Spigelman stage III). A colonoscopy for suspicion of FAP revealed numerous right-sided polyps with left-sided sparing. Computed tomography showed a double duct sign. A simultaneous laparoscopic subtotal colectomy and PD was performed successfully. The operative time was 225 minutes for the colectomy and 390 minutes for the PD. Histology showed an R0 resection of ampullary adenocarcinoma (20 negative nodes) and colonic polyps with low-grade dysplasia. Genetic screening confirmed a diagnosis of FAP. Conclusions A simultaneous laparoscopic subtotal colectomy and PD in patients with FAP and ampullary neoplasia seems safe with favorable clinical and oncologic outcomes.

Introduction Ductal carcinoma in-situ (DCIS) is a heterogeneous entity with an elusive natural history. The objective of radiological, histological and molecular characterisation remains to reliably predict the biological behaviour and optimise clinical management strategies. Increases in diagnostic frequency have followed the introduction of mammographic screening and increased utility of magnetic resonance imaging. However, progress remains limited in distinguishing non-progressive incidental lesions from their progressive and clinically relevant counterparts. This article reviews current management strategies for DCIS in the context of recent randomized trials, including the role of sentinel lymph node biopsy (SLNB), adjuvant radiotherapy (RT) and endocrine treatment. Methods Literature review facilitated by Medline, PubMed, Embase and Cochrane databases. Results DCIS should be managed in the context of a multidisciplinary team. Local control depends upon adequate surgical clearance with margins of at least 2 mm. SLNB is not routinely indicated and should be reserved for those with concurrent or recurrent invasive disease. SLNB can be considered in patients undergoing mastectomy (MX) and those with risk factors for invasion such as palpability, comedo morphology, necrosis or recurrent disease. RT following BCS significantly reduces local recurrence (LR), particularly in those at high-risk. There remains a lack of level-1 evidence supporting the omission of adjuvant RT in selected low-risk cases. Large, multi-centric or recurrent lesions (particularly in cases of prior RT) should be treated by MX with the opportunity for immediate reconstruction. Adjuvant Tamoxifen may reduce the risk of LR in selected cases with hormone sensitive disease. Conclusion Further research is required to determine the role of contemporary RT regimes and endocrine therapies. Biological profiling and molecular analysis represent an opportunity to improve our understanding of the tumour biology of this condition and rationalise its treatment. Reliable identification of low-risk lesions could allow treatment to be less radical or safely omitted.

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 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.

Introduction: May–Thurner Syndrome (MTS) usually presents with signs and symptoms of deep vein thrombosis or chronic venous insufficiency. We report the first case of MTS in a previously healthy adolescent female associated with a large intra-abdominal cyst arising from the right ovary. Case Report: The patient presented with signs and symptoms suggestive of deep vein thrombosis. Imaging confirmed extensive deep vein thromboses extending into the common iliac vein. Further imaging successfully diagnosed MTS and also identified a cyst arising from the right ovary. Catheter-directed thrombolysis followed by removal of the cyst and the right ovary was performed. Following re-thromboses few days later, the patient underwent further management with surgical thrombectomy with left common iliac vein stenting and IVC filter placement. Conclusion: The present case identifies an unusual presentation of a previously undiagnosed MTS in an adolescent female. In this case, anticoagulation alone was found to be ineffective and required the assistance of endovascular intervention.

Introduction While large and persistent pancreatic pseudocysts are amenable to internal drainage by laparoscopic techniques, the benefits of this minimally invasive approach remain to be demonstrated. The aim of this study was to compare the open and laparoscopic approaches for internal drainage of large and persistent pancreatic pseudocysts. Methods Patients who underwent cystgastrostomy were selected, and the demographic features, clinical characteristics and outcomes of those who had the surgery performed laparoscopically were compared to those who had open surgery. The two approaches were compared on an intention-to-treat basis. Data shown represent medians. Results Between 1997 and 2010, 42 patients (15 female and 27 male) underwent 45 surgical internal drainage procedures for pancreatic pseudocysts (36 laparoscopic with two conversions to open surgery, and nine open). The laparoscopic and open groups were comparable for age (56 vs 53 years, p = 0.448), sex distribution, and size of pseudocyst (12 vs 13 cm, p = 0.305). The two approaches had comparable operating times (90 vs 75 min, p=0.630) but laparoscopic surgery carried a significantly lower risk of postoperative morbidity (5.8% vs 54.5%, p=0.001) and shorter postoperative hospital stay (2 vs 10.5 days, p = 0.065). There was one death in the open group (11.1%) but none in the laparoscopic group. Conclusion The laparoscopic approach to cystgastrostomy for large and persistent retrogastric pancreatic pseudocysts is associated with a smoother and more rapid recovery and a shorter hospital stay compared with open surgery. Competing interests None declared.

Introduction Advances in technology and techniques facilitated the development of laparoscopic liver resection (LLR). The study is aimed at the evaluation of the feasibility and effectiveness of LLR for benign and malignant pathology. Methods This is a retrospective study of 61 patients (27 female) aged 63 (25–83) years who underwent LLR for benign (n=9) and malignant (n=52) between 2003 and 2011 in a single UK tertiary centre. The results shown represent median (range). Results Surgery was completed laparoscopically in 60 patients (98.3%) and converted to open due to extensive abdominal adhesions in one patient. The procedures performed included the resection of one segment ( n =16), two segments (n=36) and three segments (n=9). The overall operative morbidity was 8.5% and there was no mortality. The operating time was 162 (50–300) min. The estimated blood loss was 110 (25–1100) ml and two patients received blood transfusion. The postoperative hospital stay was 3.6 (1–14) days. The resected malignancy in 52 patients included metastases in 47 patients (44 colorectal adenocarcinoma, three others) and hepatocellular carcinoma (n=5), and the R0 resection rate was 86.6% (n=45). At 42 (6–108) months follow-up, 77% were disease-free, 19% showed recurrent metastasis (1 hepatic, 4 hepatic and elsewhere, 5 extra-hepatic) and 4% failed to attend the follow-up. Conclusion Our results support the expanding evidence that LLR is safe and efficient for the treatment of benign and malignant liver lesions in carefully selected patients. Competing interests None declared.

Introduction The common bile duct is traditionally 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 examines the safety and effectiveness of laparoscopic CBD exploration (LCBDE) followed by primary duct closure. Methods This is a retrospective analysis of 94 consecutive patients (27 male) who underwent LCBDE between October 2002 and December 2011. The duct was primarily closed in all patients. The results shown represent the median (range). Results All procedures were completed laparoscopically. The maximum diameter of the CBD was 9.7 (3–30) mm, and it was dilated in 93% of patients. The number of CBD stones was 2 (0–20). The exploration was transcystic in 14 patients and trans-CBD in 80 patients. The biliary tree was clear at the end of exploration with no subsequent evidence of retained stones in 92 patients (97.8%). The operating time was 117 (22–395) min. Postoperative bile leak occurred in four patients (4.5%) who were managed successfully with re-laparoscopy and suturing of the choledochotomy (n=2), laparoscopic insertion of biliary stent (n=1) and conservatively (n=1). The overall morbidity rate was 8% and included pulmonary complications (n=3), cholangitis (n=2), myocardial infarction (n=1) and wound infection (n=1). There were no operative deaths, and the postoperative hospital stay was 1 (0–51) day. At a follow-up of 48.2 (24–82) months, 92.5% of patients (n=87) had no biliary symptoms, one patient required endoscopic extraction of a retained stone, one developed bile duct stricture that was managed successfully by endoscopic balloon dilatation, and four patients (4.5%) failed to attend the follow-up. Conclusion Primary duct closure following LCBDE is safe, and can be employed as an alternative to T-tube insertion with short hospital stay and lower morbidityrate. Competing interests None declared.