Robotic versus laparoscopic distal pancreatectomy: multicentre analysis.

BACKGROUND: The role of minimally invasive distal pancreatectomy is still unclear, and whether robotic distal pancreatectomy (RDP) offers benefits over laparoscopic distal pancreatectomy (LDP) is unknown because large multicentre studies are lacking. This study compared perioperative outcomes between RDP and LDP. METHODS: A multicentre international propensity score-matched study included patients who underwent RDP or LDP for any indication in 21 European centres from six countries that performed at least 15 distal pancreatectomies annually (January 2011 to June 2019). Propensity score matching was based on preoperative characteristics in a 1 : 1 ratio. The primary outcome was the major morbidity rate (Clavien-Dindo grade IIIa or above). RESULTS: A total of 1551 patients (407 RDP and 1144 LDP) were included in the study. Some 402 patients who had RDP were matched with 402 who underwent LDP. After matching, there was no difference between RDP and LDP groups in rates of major morbidity (14.2 versus 16.5 per cent respectively; P = 0.378), postoperative pancreatic fistula grade B/C (24.6 versus 26.5 per cent; P = 0.543) or 90-day mortality (0.5 versus 1.3 per cent; P = 0.268). RDP was associated with a longer duration of surgery than LDP (median 285 (i.q.r. 225-350) versus 240 (195-300) min respectively; P < 0.001), lower conversion rate (6.7 versus 15.2 per cent; P < 0.001), higher spleen preservation rate (81.4 versus 62.9 per cent; P = 0.001), longer hospital stay (median 8.5 (i.q.r. 7-12) versus 7 (6-10) days; P < 0.001) and lower readmission rate (11.0 versus 18.2 per cent; P = 0.004). CONCLUSION: The major morbidity rate was comparable between RDP and LDP. RDP was associated with improved rates of conversion, spleen preservation and readmission, to the detriment of longer duration of surgery and hospital stay.

Risk of conversion to open surgery during robotic and laparoscopic pancreatoduodenectomy and effect on outcomes: international propensity score-matched comparison study.

BACKGROUND: Minimally invasive pancreatoduodenectomy (MIPD) is increasingly being performed because of perceived patient benefits. Whether conversion of MIPD to open pancreatoduodenectomy worsens outcome, and which risk factors are associated with conversion, is unclear. METHODS: This was a post hoc analysis of a European multicentre retrospective cohort study of patients undergoing MIPD (2012-2017) in ten medium-volume (10-19 MIPDs annually) and four high-volume (at least 20 MIPDs annually) centres. Propensity score matching (1 : 1) was used to compare outcomes of converted and non-converted MIPD procedures. Multivariable logistic regression analysis was performed to identify risk factors for conversion, with results presented as odds ratios (ORs) with 95 per cent confidence intervals (c.i). RESULTS: Overall, 65 of 709 MIPDs were converted (9.2 per cent) and the overall 30-day mortality rate was 3.8 per cent. Risk factors for conversion were tumour size larger than 40 mm (OR 2.7, 95 per cent c.i.1.0 to 6.8; P = 0.041), pancreatobiliary tumours (OR 2.2, 1.0 to 4.8; P = 0.039), age at least 75 years (OR 2.0, 1.0 to 4.1; P = 0.043), and laparoscopic pancreatoduodenectomy (OR 5.2, 2.5 to 10.7; P < 0.001). Medium-volume centres had a higher risk of conversion than high-volume centres (15.2 versus 4.1 per cent, P < 0.001; OR 4.1, 2.3 to 7.4, P < 0.001). After propensity score matching (56 converted MIPDs and 56 completed MIPDs) including risk factors, rates of complications with a Clavien-Dindo grade of III or higher (32 versus 34 per cent; P = 0.841) and 30-day mortality (12 versus 6 per cent; P = 0.274) did not differ between converted and non-converted MIPDs. CONCLUSION: Risk factors for conversion during MIPD include age, large tumour size, tumour location, laparoscopic approach, and surgery in medium-volume centres. Although conversion during MIPD itself was not associated with worse outcomes, the outcome in these patients was poor in general which should be taken into account during patient selection for MIPD.

Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study.

BACKGROUND: A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. METHODS: An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007-2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. RESULTS: Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13 days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien-Dindo grade ≥ III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20 months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. CONCLUSION: The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP.

Predictors for Survival in an International Cohort of Patients Undergoing Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical factors, including resection of Gerota's fascia, R0-resection, and lymph node yield, may be associated with survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC), but evidence from large multicenter studies is lacking. This study aimed to identify predictors for overall survival after DP for PDAC, especially those related to surgical technique. PATIENTS AND METHODS: Data from an international retrospective cohort including patients from 11 European countries and the USA who underwent DP for PDAC (2007-2015) were analyzed. Cox proportional hazard analyses were performed and included Gerota's fascia resection, R0 resection, lymph node ratio, extended resection, and a minimally invasive approach. RESULTS: Overall, 1200 patients from 34 centers with median follow-up of 15 months [interquartile range (IQR) 5-31 months] and median survival period of 30 months [95% confidence interval (CI), 27-33 months] were included. Gerota's fascia resection [hazard ratio (HR) 0.74; p = 0.019], R0 resection (HR 0.70; p = 0.006), and decreased lymph node ratio (HR 0.28; p < 0.001) were associated with improved overall survival, whereas extended resection (HR 1.75; p < 0.001) was associated with worse overall survival. A minimally invasive approach did not improve survival as compared with an open approach (HR 1.14; p = 0.350). Adjuvant chemotherapy (HR 0.67; p = 0.003) was also associated with improved overall survival. CONCLUSIONS: This international cohort identified Gerota's fascia resection, R0 resection, and decreased lymph node ratio as factors associated with improved overall survival during DP for PDAC. Surgeons should strive for R0 resection and adequate lymphadenectomy and could also consider Gerota's fascia resection in their routine surgical approach.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Expert consensus on a train-the-trainer curriculum for robotic colorectal surgery.

AIM: Robotic techniques are being increasingly used in colorectal surgery. There is, however, a lack of training opportunities and structured training programmes. Robotic surgery has specific problems and challenges for trainers and trainees. Ergonomics, specific skills and user-machine interfaces are different from those in traditional laparoscopic surgery. The aim of this study was to establish expert consensus on the requirements for a robotic train-the-trainer curriculum amongst robotic surgeons and trainers. METHOD: This is a modified Delphi-type study involving 14 experts in robotic surgery teaching. A reiterating 19-item questionnaire was sent out to the same group and agreement levels analysed. A consensus of 0.8 or higher was considered to be high-level agreement. RESULTS: Response rates were 93-100% and most items reached high levels of agreement within three rounds. Specific requirements for a robotic faculty development curriculum included maximizing dual-console teaching, theatre team training, nontechnical skills training, patient safety, user-machine interface training and telementoring. CONCLUSION: A clear need for the development of a train-the-trainer curriculum has been identified. Further research is needed to assess feasibility, effectiveness and clinical impact of a robotic train-the-trainer curriculum.

Modulation of Autophagy Influences the Function and Survival of Human Pancreatic Beta Cells Under Endoplasmic Reticulum Stress Conditions and in Type 2 Diabetes.

Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n = 17; age 65 ± 21 years; gender: 5 M/12 F; BMI 23.4 ± 3.3 kg/m2) and T2D (n = 9; age 76 ± 6 years; 4 M/5 F; gender: BMI 25.4 ± 3.7 kg/m2) organ donors. Nine ND organ donors were treated for hypertension and 1 for both hypertension and hypercholesterolemia. T2D organ donors were treated with metformin (1), oral hypoglycemic agents (2), diet + oral hypoglycemic agents (3), insulin (3) or insulin plus metformin (3) as for antidiabetic therapy and, of these, 3 were treated also for hypertension and 6 for both hypertension and hypercholesterolemia. Two days after isolation, they were cultured for 1-5 days with 10 ng/ml rapamycin (autophagy inducer), 5 mM 3-methyladenine or 1.0 nM concanamycin-A (autophagy blockers), either in the presence or not of metabolic (0.5 mM palmitate) or chemical (0.1 ng/ml brefeldin A) ER stressors. In ND islets palmitate exposure induced a 4 to 5-fold increase of beta cell apoptosis, which was significantly prevented by rapamycin and exacerbated by 3-MA. Similar results were observed with brefeldin treatment. Glucose-stimulated insulin secretion from ND islets was reduced by palmitate (-40 to 50%) and brefeldin (-60 to 70%), and rapamycin counteracted palmitate, but not brefeldin, cytotoxic actions. Both palmitate and brefeldin induced PERK, CHOP and BiP gene expression, which was partially, but significantly prevented by rapamycin. With T2D islets, rapamycin alone reduced the amount of p62, an autophagy receptor that accumulates in cells when macroautophagy is inhibited. Compared to untreated T2D cells, rapamycin-exposed diabetic islets showed improved insulin secretion, reduced proportion of beta cells showing signs of apoptosis and better preserved insulin granules, mitochondria and ER ultrastructure; this was associated with significant reduction of PERK, CHOP and BiP gene expression. This study emphasizes the importance of autophagy modulation in human beta cell function and survival, particularly in situations of ER stress. Tuning autophagy could be a tool for beta cell protection.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET.

BACKGROUND: Non-functioning (NF) pancreatic neuroendocrine tumors (pNET) often have an indolent outcome. A consensus to submit patients with large (>2 cm) NF-pNET to surgery already exists; but a conservative approach for small (≤2 cm) NF neoplasms has been proposed. AIM: To identify prognostic factors for survival and progression free survival (PFS) of NF-pNET, evaluating whether surgery may be avoided for small NF-pNET. SUBJECTS AND METHODS: Retrospective study of 77 consecutive patients with pNET submitted to surgery, of which 60 were NF. Pathological tissues were revised according to the 2000 and 2010 WHO classifications. Risk factors for survival and PFS were evaluated using the Kaplan-Meier method and the Cox regression model. RESULTS: The 8-year cause-specific survival of NF-pNET was 79.3%. At univariate analysis, high grading, high staging, large tumors, angioinvasion and peri-pancreatic infiltration were significantly associated with a shorter survival; at multivariate analysis only peri-pancreatic infiltration was significantly associated with a shorter NF-pNET survival. Most small NF-pNET were grade 1 (74%), compared to large NF-pNET (27%). Distant metastases were present in 29.7% (n = 11) and 17.4% (n = 4) of patients with large or small NF-pNET, respectively; among the 19 small NF-pNET without metastasis, five had a local malignancy (lymph node metastasis or local infiltration); thus, 39% of the 23 NF-pNET, turned out to have a malignant potential. CONCLUSIONS: Among NF-pNET, large neoplasms were associated with worse outcomes; however, small NF-pNET do not seem to have an invariable benign behavior. Whether surgery should be avoided in all patients with small NF-pNET is questionable.

A multicenter survey on distal pancreatectomy in Italy: results of minimally invasive technique and variability of perioperative pathways.

No data are available about distal pancreatectomy (DP) in Italy, regarding variability of care among centers, and outcome of minimally invasive distal pancreatectomy (MIDP) in a multicenter setting. Hence, a survey was conducted among 20 institutions experienced in pancreatic surgery by the Italian Association for Study of Pancreas. Centers were asked to fill in two questionnaires about (1) general approach and perioperative protocols for DP and MIDP; (2) detailed operative results of MIDP in the period 2010-2011. Results of questionnaire 1: a great variability in perioperative approach was observed: octreotide was used in 50 % of centers, enzyme supplementation in 35 %, postoperative gastric suction in 80 % and oral liquids on day 1 in 55 %. All hospitals used at least one drain and its removal ranged between days 3-5 (in absence of fistula). Differences in type and timing of post-splenectomy vaccinations were recorded. As regards MIDP, 17/20 centers performed laparoscopic or robotic DP. MIDP rate on overall DP varied among centers (range 0-82 %) and it doubled from 2007 (14 %) to 2011 (28 %). Results of questionnaire 2: in the period 2010-2011, 171 MIDP were performed (140 laparoscopic, 31 robotic). Overall conversion rate was 17 %, mean operative time was 230 min and blood loss 285 ml. Mortality was nil and morbidity was 62 %, with 4 % relaparotomies. Pancreatic fistula occurred in 49 % (grade A 35 %, B 14 %). Mean postoperative stay was 9.8 days with 10 % readmission rate. The results indicated a great variability in DP management among Italian centers. Most centers performed MIDP, but MIDP rate on overall DP largely varied among centers. As regards MIDP conversion rate and hospital stay were found to be worse than those in single-institution series.

Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP/ADP ratio.

AIM: We have explored whether the insulin secretory defects induced by glucotoxicity in human pancreatic islets could be prevented by metformin and investigated some of the possible mechanisms involved. METHODS: Human pancreatic islets and INS-1E cells were cultured for 24h with or without high glucose (16.7mM) concentration in the presence or absence of therapeutical concentration of metformin and then glucose-stimulated insulin release, adenine nucleotide levels and mitochondrial complex I and II activities were measured. Islet ultrastructure was analyzed by electron microscopy. RESULTS: Compared to control islets, human islets cultured with high glucose showed a reduced glucose-stimulated insulin secretion that was associated with lower ATP levels and a lower ATP/ADP ratio. These functional and biochemical defects were significantly prevented by the presence of metformin in the culture medium, that was also able to significantly inhibit the activity of mitochondrial complex I especially in beta cells exposed to high glucose. Ultrastructural observations showed that mitochondrial volume density was significantly increased in high glucose cultured islets. The critical involvement of mitochondria was further supported by the observation of remarkably swollen organelles with dispersed matrix and fragmented cristae. Metformin was able to efficiently prevent the appearance of all these ultrastructural alterations in human islets exposed to high glucose. CONCLUSIONS: Our results show that the functional, biochemical and ultrastructural abnormalities observed in human islet cells exposed to glucotoxic condition can be significantly prevented by metformin, further highlighting a direct beneficial effect of this drug on the insulin secreting human pancreatic beta cells.

MET as a potential target for the treatment of upper gastrointestinal cancers: characterization of novel c-Met inhibitors from bench to bedside.

The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) plays a pivotal role in regulation of cell proliferation and migration. Abnormal expression of c-Met has been associated with poor prognosis in several cancer types, including upper gastrointestinal malignancies. Moreover, c-Met interaction with multiple signalling pathways involved in tumor growth and invasive/metastatic phenotype has gained substantial attention in the last few years, suggesting the therapeutic potential of this target. This has led to the development and evaluation of a number of c-Met inhibitors. Here we describe the critical role of the HGF/c-Met pathway in cancer, as well as the preclinical and clinical investigations on c-Met inhibitors in solid tumors, with particular emphasis on recent findings with small-molecule inhibitors in gastrointestinal cancers. Clinical trials with several of these novel inhibitors have been encouraging and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung cancers with ALK-rearrangement. There are accumulating evidences on the therapeutic potential of this and other c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic and environmental alterations affecting c-Met and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity of current and future anticancer strategies targeting c-Met.

Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia.

BACKGROUND: Hypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells. METHODS: Lactate dehydrogenase A levels were studied by quantitative RT-PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS. RESULTS: Lactate dehydrogenase A was significantly increased under hypoxic conditions (1% O2), where the novel LDH-A inhibitors proved to be particularly effective (e.g., with IC50 values of 0.9 vs 16.3 µM for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites. CONCLUSION: Lactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.

ß-Cell inflammation in human type 2 diabetes and the role of autophagy.

ß-Cell failure is crucial for the onset and progression of human type 2 diabetes, and a few studies have suggested that inflammation may play a role. Immune cell infiltration has been reported in subpopulations of islets in some cases of human type 2 diabetes, and altered gene expression of a few cytokines and chemokines has been observed in isolated islets and laser captured ß-cells from diabetic subjects. Recent observations on the links between inflammation, apoptosis and autophagy are putting the focus on the possibility that modulating the autophagic processes could protect the ß-cells from cytotoxicity induced by inflammatory mediators.

Feasibility of robotic pancreaticoduodenectomy.

BACKGROUND: Laparoscopic pancreaticoduodenectomy is feasible, but requires adaptations to established surgical techniques. The improved dexterity offered by robotic assistance provides the opportunity to see whether laparoscopic pancreaticoduodenectomy can be performed safely when faithfully reproducing the open operation. METHODS: Patients were selected for robotic pancreaticoduodenectomy when generally suitable for laparoscopy. Obese patients were excluded, and those with pancreatic cancer were highly selected. A prospectively designed database was used for data collection and analysis. RESULTS: Of 238 patients undergoing pancreaticoduodenectomy, 34 (14·3 per cent) were operated on robotically. No procedure was converted to conventional laparoscopy or open surgery, despite three patients requiring segmental resection of the superior mesenteric/portal vein and reconstruction. The mean duration of operation was 597 (range 420-960) min. The mean number of lymph nodes retrieved and analysed from patients with neoplasia was 32 (range 15-76). Four patients required blood transfusions and five developed postoperative complications exceeding Clavien-Dindo grade II. There were four grade B pancreatic fistulas. One patient died on postoperative day 40. Excess mean operative cost compared with open resection was €6193. CONCLUSION: Selected patients can safely undergo robotic pancreaticoduodenectomy. The main downsides are high costs and prolonged operating times compared with open resection.