Risk factors and outcomes of conversion in minimally invasive distal pancreatectomy: a systematic review.

PURPOSE: The reported conversion rates for minimally invasive distal pancreatectomy (MIDP) range widely from 2 to 38%. The identification of risk factors for conversion may help surgeons during preoperative planning and patient counseling. Moreover, the impact of conversion on outcomes of MIDP is unknown. METHODS: A systematic review was conducted as part of the 2019 Miami International Evidence-Based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR). The PubMed, Cochrane, and Embase databases were searched for studies concerning conversion to open surgery in MIDP. RESULTS: Of the 828 studies screened, eight met the eligibility criteria, resulting in a combined dataset including 2592 patients after MIDP. The overall conversion rate was 17.1% (range 13.0-32.7%) with heterogeneity between studies associated with the definition of conversion adopted. Only one study divided conversion into elective and emergency conversion. The main indications for conversion were vascular involvement (23.7%), concern for oncological radicality (21.9%), and bleeding (18.9%). The reported risk factors for conversion included a malignancy as an indication for surgery, the proximity of the tumor to vascular structures in preoperative imaging, higher BMI or visceral fat, and multi-organ resection or extended resection. Contrasting results were seen in terms of blood loss and length of stay in comparing converted MIDP and completed MIDP patients. CONCLUSION: The identified risk factors for conversion from this study can be used for patient selection and counseling. Surgeon experience should be considered when contemplating MIDP for a complex patient. Future studies should divide conversion into elective and emergency conversion.

The role of older age and obesity in minimally invasive and open pancreatic surgery: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The aim of this study was to assess the impact of older age (≥70 years) and obesity (BMI ≥30) on surgical outcomes of minimally invasive pancreatic resections (MIPR). Subsequently, open pancreatic resections or MIPR were compared for elderly and/or obese patients. METHODS: A systematic review was conducted as part of the 2019 Miami International Evidence-Based Guidelines on MIPR (IG-MIPR). Study quality assessment was according to The Scottish Intercollegiate Guidelines Network (SIGN). A meta-analysis was performed to assess the impact of MIPR or open pancreatic resections in elderly patients. RESULTS: After screening 682 studies, 13 observational studies with 4629 patients were included. Elderly patients undergoing laparoscopic distal pancreatectomy (LDP) had less blood loss (117 mL, p < 0.001) and a shorter hospital stay (3.5 days p < 0.001) than elderly patients undergoing open distal pancreatectomy (ODP). Postoperative pancreatic fistula (POPF) B/C, major complication and reoperation rate were not significantly different in elderly patients undergoing either laparoscopic or open pancreatoduodenectomy (OPD). One study compared robot PD with OPD in obese patients, indicating that patients with robotic surgery had less blood loss (mean 250 ml vs 500 ml, p = 0.001), shorter operative time (mean 381 min vs 428 min, p = 0.003), and lower rate of POPF B/C (13% vs 28%, p = 0.039). CONCLUSION: The current available limited evidence does not suggest that MIPR is contraindicated in elderly or obese patients. Additionally, outcomes in MIPR are equal or more beneficial compared to the open approach when applied in these patient groups.

Pancreatic Head Resection Following Roux-en-Y Gastric Bypass: Operative Considerations and Outcomes.

PURPOSE: This study aimed to identify optimal management decisions for surgeons preforming pancreatic head resection on patients with altered anatomy due to a previous Roux-en-Y gastric bypass (RYGB). METHODS: A multi-national (4), multi-center (28) collaborative of 55 pancreatic surgeons who have performed pancreatoduodenectomy or total pancreatectomy following RYGB for obesity (2005-2018) was created. Demographics, operative details, and perioperative outcomes from this cohort were analyzed and compared in a propensity-score matched analysis with a multi-center cohort of 5533 pancreatoduodenectomies without prior RYGB. RESULTS: Ninety-six patients with a previous RYGB undergoing pancreatic head resection were assembled. Pathologic indications between the RYGB and normal anatomy cohorts did not differ. Propensity score matching of RYGB vs. patients with unaltered anatomy demonstrated no differences in major postoperative outcomes. In total 20 distinct reconstructions were employed (of 37 potential options); the three most frequent reconstructions accounted for 52.1%, and none demonstrated superior outcomes. There were no differences in outcomes observed between original biliopancreatic limb use (66.7%) and those where a secondary Roux limb was created for biliopancreatic reconstruction. Remnant stomachs were removed in 54.7% of cases, with no outcome differences between resected and retained stomachs. Venting gastrostomy tubes were used in 36.2% of retained stomachs without obvious outcome benefits. Jejunostomy tubes were used infrequently (11.7%). CONCLUSIONS: Pancreatic head resection after RYGB is an infrequently encountered, unique and challenging scenario for any given surgeon. These patients do not appear to suffer higher morbidity than those with unaltered anatomy. Various technical reconstructive options do not appear to confer distinct benefits.

Analysis of the Eurotransplant Kidney Allocation Algorithm: How Should We Balance Utility and Equity?

BACKGROUND: Since 2014, expected graft and recipient survival are matched by the U.S. kidney allocation system to improve organ utility. This mechanism is based on the kidney donor profile index (KDPI) and the estimated posttransplant survival score (EPTS). Here we analyzed 1. the transferability of these scores into the Eurotransplant (ET) region and 2. the extent to which the ET kidney allocation algorithm promotes utility. METHODS: We studied data of 262 kidney transplantations performed at the University Hospital Kiel between 2000 and 2009 (median follow-up, 9.94 years). RESULTS: Multivariable Cox regression analysis revealed that only the variables donor age of the KDPI and recipient's age of the EPTS have a significant value as predictors of posttransplant graft and recipient survival. The other variables showed no additional predictive value. Analyzing all kidneys allocated in the ET kidney allocation system and the European Senior Program, we found that donor and recipient's age and KDPI and EPTS were weakly correlated (rage-age = 0.5, P < .001; rKDPI-EPTS = 0.4, P < .01). If both programs were analyzed separately, no correlation between donor and recipient's age and between KDPI and EPTS was detected. CONCLUSION: The ET kidney allocation algorithm poorly matched predicted graft and recipient survival at our center. A better age-matching may improve organ utility.

Severity of polymicrobial sepsis modulates mitochondrial function in rat liver.

Mitochondrial dysfunction is assumed to be an important contributor to multi organ dysfunction syndrome. Here, the effects of varying degrees of sepsis on hepatic mitochondrial function were investigated. Moderate or more severe sepsis was induced in rats using a colon ascendens stent peritonitis (CASP)-model (16 G and 14 G stent respectively). Respiratory control ratio (RCR) was significantly higher in the 16 G-group and unchanged in the 14 G-group compared with healthy controls. The ADP/O ratio was similar in all groups. Our results indicate that different severities of sepsis differently influence the mitochondrial function, which could be a sign of adaptive reaction.

Histological and Molecular Subclassification of Pancreatic and Nonpancreatic Periampullary Cancers: Implications for (Neo) Adjuvant Systemic Treatment.

The benefit of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC) has been confirmed in randomized controlled trials. For nonpancreatic periampullary cancers (NPPC) originating from the distal bile duct, duodenum, ampulla, or papilla of Vater, the role of adjuvant therapy remains largely unclear. This review describes methods for distinguishing PDAC from NPPC by means of readily available and recently developed molecular diagnostic methods. The difficulties of reliably determining the exact origin of these cancers pathologically also is discussed. The review also considers the possibility of unintentional inclusion of NPPC in the most important adjuvant trials on PDAC and the subsequent implications for interpretation of the results. The authors conclude that correct determination of the origin of periampullary cancers is essential for clinical management and should therefore be systematically incorporated into clinical practice and future studies.

Hypothermia improves oral and gastric mucosal oxygenation during hypoxic challenges.

BACKGROUND: Therapeutic hypothermia, used primarily for protective effects after hypoxia, improves oral and gastric mucosal microvascular oxygenation (µHbO2) during additional haemorrhage. Therefore, we questioned whether hypothermia likewise improves µHbO2 during hypoxic challenges. Since both hypothermia and hypoxia reduce cardiac output (e.g. by myofilament Ca(2+) desensitization), and modulate vasomotor tone via K(+) ATP channels, we hypothesized that the Ca(2+) sensitizer levosimendan and K(+) ATP channel blocker glibenclamide would support the cardiovascular system. METHODS: The effects of mild hypothermia (34°C) on µHbO2 during hypoxia [Formula: see text] were analysed in a cross-over study on five anaesthetized dogs and compared with normothermia (37.5°C) and hypoxia. During hypothermia, but before hypoxia, glibenclamide (0.2 mg kg(-1)) or levosimendan (20 µg kg(-1)+0.25 µg kg(-1) min(-1)) was administered. Systemic haemodynamic variables, gastric and oral mucosal microvascular oxygenation (reflectance spectrophotometry), and perfusion (laser Doppler flowmetry) were recorded continuously. Data are presented as mean (sem), P<0.05. RESULTS: Hypoxia during normothermia reduced gastric µHbO2 by 27 (3)% and oral µHbO2 by 28 (3)% (absolute change). During hypothermia, this reduction was attenuated to 16 (3)% and 13 (1)% (absolute change). This effect was independent of microvascular flow that did not change during hypoxia and hypothermia. Additional administration of levosimendan during hypothermia restored reduced cardiac output but did not change flow or µHbO2 compared with hypothermia alone. Glibenclamide did not exert any additional effects during hypothermia. CONCLUSIONS: Hypothermia attenuates the decrease in µHbO2 during additional hypoxic challenges independent of systemic or regional flow changes. A reduction in cardiac output during hypothermia is prevented by Ca(2+) sensitization with levosimendan but not by K(+) ATP channel blockade with glibenclamide.

Potential roles of ATP and local neurons in the monitoring of blood O2 content by rat aortic bodies.

Aortic bodies are arterial chemoreceptors presumed to monitor blood O2 content by unknown mechanisms, in contrast to their well-studied carotid body counterparts, which monitor PO2 and /pH. We recently showed that rat aortic body chemoreceptors (type I cells), located at the left vagus-recurrent laryngeal nerve bifurcation, responded to PO2 and PCO2 /pH in a manner similar to carotid body type I cells. These aortic bodies are uniquely associated with a group of local neurons, which are also sensitive to these stimuli. Here, we hypothesized that these local neurons may contribute to monitoring blood O2 content. During perforated patch recordings, ATP, known to be released from (carotid body) type I cells and red blood cells during hypoxia, induced inward currents and excited ≈ 45% of local neurons (EC50 ≈ 1 µm), mainly via heteromeric P2X2/3 purinoceptors. While ATP also induced a rise in intracellular [Ca(2+)] in a subpopulation of these neurons, almost all of them responded to nicotinic cholinergic agonists. During paired recordings, several juxtaposed neurons showed strong bidirectional electrical coupling, suggesting a local co-ordination of electrical activity. Perfusion with Evans Blue dye resulted in labelling of aortic body paraganglia, suggesting they have ready access to circulatory factors, e.g. ATP released from red blood cells during hypoxia. When combined with confocal immunofluorescence, the dye-labelled regions coincided with areas containing tyrosine hydroxylase-positive type I cell clusters and P2X2-positive nerve endings. We propose a working model whereby local neurons, red blood cells, ATP signalling and low blood flow contribute to the unique ability of the aortic body to monitor blood O2 content.

Characterization of L-type voltage-gated Ca(2+) channel expression and function in developing CA3 pyramidal neurons.

Voltage-gated calcium channels (VGCCs) play a major role during the development of the central nervous system (CNS). Ca(2+) influx via VGCCs regulates axonal growth and neuronal migration as well as synaptic plasticity. Specifically, L-type VGCCs have been well characterized to be involved in the formation and refinement of the connections within the CA3 region of the hippocampus. The majority of the growth, formation, and refinement in the CNS occurs during the third trimester of human pregnancy. An equivalent developmental time period in rodents occurs during the first 2weeks of post-natal life, and the expression pattern of L-type VGCCs during this time period has not been well characterized. In this study, we show that Cav1.2 channels are more highly expressed during this developmental period compared to adolescence (post-natal day 30) and that L-type VGCCs significantly contribute to the overall Ca(2+) currents. These findings suggest that L-type VGCCs are functionally expressed during the crucial developmental period.

Complications of a buried penis in an extremely obese patient.

The buried penis syndrome in adults is a rare condition of different aetiologies. Today extreme obesity is considered as a major contributor. We present a case of a 30-year-old extremely obese patient (BMI 65 kg/m(2)) with purulent infection of the penile cavity, a phlegmon of the mons pubis and urinary retention due to a buried penis. Whereas acute complications of a buried penis in obese patients include local infection and urinary retention, chronic problems are undirected voiding, disturbed vaginal penetration and erectile dysfunction. Even though several surgical techniques are described, weight reduction should be primarily preferred.

TEM foil preparation of sub-micrometre sized individual grains by focused ion beam technique.

Analysis of presolar silicate grains provides new knowledge on interstellar and circumstellar environments and can be used to test models of the Galactic chemical evolution. However, structural information of these grains is rare because sample preparation for transmission electron microscopy is very difficult due to the small dimensions of these grains (<0.5 mum). With the use of the focused ion beam technique thin foils from these grains for transmission electron microscopy analysis can be prepared. Nevertheless, reaching the required precision of some tens of nanometres for the preparation of the transmission electron microscopy foil in the place of interest is not trivial. Furthermore, in the current samples, the grain of interest can only be identified by its different isotopic composition; i.e. there is no contrast difference in scanning electron microscopy or transmission electron microscopy images which allow the identification of the grain. Therefore, the grain has to be marked in some way before preparing the transmission electron microscopy foil. In the present paper, a method for transmission electron microscopy foil preparation of grains about 200 to 400 nm in diameter is presented. The method utilizes marking of the grain by Pt deposition and milling of holes to aid in the exact orientation of the transmission electron microscopy foil with respect to the grain. The proposed method will be explained in detail by using an example grain.

The latent presentation of pancreatic fistulas.

BACKGROUND: Pancreatic fistula is traditionally suspected on the basis of increased drain amylase activity. However, some patients have a low amylase level but later manifest clinical evidence of a fistula. This study investigated the prevalence and significance of these presentations. METHODS: Severity of fistula was determined according to the International Study Group on Pancreatic Fistula criteria for 405 consecutive pancreatic resections. Latent fistulas, initially lacking amylase-rich effluent but ultimately clinically relevant (grades B or C), were examined to determine their impact and significance. RESULTS: Fistula of any extent occurred in 107 patients (26.4 per cent). Latent fistulas occurred in 20 patients (4.9 per cent of all resections, 18.7 per cent of all fistulas and 36 per cent of all clinically relevant fistulas). Initial amylase activity was consistently low (range 3-235 units/l), but these fistulas subsequently manifested clinical relevance (abdominal pain, radiographic evidence, fever, sinister effluent, wound infection). Latent presentations had twice the infection rate of evident fistulas, required more aggressive interventions, resulted in longer hospitalizations and incurred greater hospital costs. CONCLUSION: A considerable proportion of patients with pancreatic fistula do not initially demonstrate an amylase-rich effluent. These patients have significantly worse outcomes. In fistula definition, the clinical course is important as well as biochemical parameters.

Meta-analysis of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy is the primary treatment for periampullary cancer. Associated morbidity is high and often related to pancreatic anastomotic failure. This paper compares rates of pancreatic fistula, morbidity and mortality after pancreaticoduodenectomy in patients having reconstruction by pancreaticogastrostomy with those in patients having reconstruction by pancreaticojejunostomy. METHODS: A meta-analysis was performed of all large cohort and randomized controlled trials carried out since 1990. RESULTS: Eleven articles were identified for inclusion: one prospective randomized trial, two non-randomized prospective trials and eight observational cohort studies. The meta-analysis revealed a higher rate of pancreatic fistula associated with pancreaticojejunostomy reconstruction (relative risk (RR) 2.62 (95 per cent confidence interval (c.i.) 1.91 to 3.60)). A higher overall morbidity rate was also demonstrated in this group (RR 1.43 (95 per cent c.i. 1.26 to 1.61)), as was a higher mortality rate (RR 2.51 (95 per cent c.i. 1.61 to 3.91)). CONCLUSION: Current literature suggests that the safer means of pancreatic reconstruction after pancreaticoduodenectomy is pancreaticogastrostomy, but much of the evidence comes from observational cohort study data.

Management of a solid pseudopapillary tumor of the pancreas with liver metastases.

BACKGROUND: Solid pseudopapillary tumor, otherwise known as solid and cystic tumor or Frantz tumor, is an unusual form of pancreatic carcinoma. Its natural history differs from the more common pancreatic adenocarcinoma in that it has a female predilection, is more indolent, and carries a better prognosis. Metastatic disease can occur, usually involving the liver, and its management is not well defined. CASE OUTLINE: A young woman was found to have a tumor situated in the pancreatic tail with seven synchronous hepatic metastases. Segments II and III were free of metastatic disease. A needle biopsy of the pancreatic lesion was non-diagnostic but suggested that the lesion was unlikely to be a typical adenocarcinoma. Initial treatment consisted of a distal pancreatectomy, which confirmed the diagnosis of a solid pseudopapillary tumor. Given the indolent nature of this pathologic entity as well as the patient's youth, an aggressive approach to treatment of the hepatic metastases was recommended. Because the liver was fatty, the right portal vein was embolized to produce hypertrophy of the left hemiliver. Six weeks later an extended right hepatectomy cleared the hepatic disease. The patient had an uncomplicated recovery, and she remains disease-free at 22 months. DISCUSSION: Solid pseudopapillary tumor of the pancreas is a rare malignancy. Survival following primary resection approaches 95% at 5 years. Metastatic disease, although rare, usually involves the liver and/or peritoneum. Given the paucity of reported cases, the management of metastatic disease is, to date, poorly defined. This case demonstrates a favorable short-term outcome with aggressive surgical treatment of both the primary and metastatic tumor.

Sclerosing pancreatitis presenting as a periampullary tumour.

BACKGROUND: Sclerosing lesions of the pancreatic duct are rare and may be secondary to primary sclerosing cholangitis (PSC) or the result of a primary sclerosing process (the recently described lymphoplasmacystic sclerosing pancreatitis, LSP). Occasionally this process may present as a mass lesion. CASE OUTLINE: A 21 -year-old man presented with abdominal pain and jaundice, giving a high index of suspicion for a periampullary malignancy. There were minimal symptoms suggestive of PSC. The resected head of the pancreas demonstrated changes of chronic pancreatitis with a fibro-inflammatory process of the pancreatic duct suggesting an underlying ductal sclerosing process. DISCUSSION: Clinical presentation and imaging characteristics of PSC involving the pancreas are often misleading and may suggest a neoplasm as the underlying disorder. Conclusive diagnosis is usually not determined until after surgical intervention. Although racial differences in pancreatic duct involvement have been suggested, the underlying histopathology is the same as in PSC involving the biliary ducts.

Expression of P2X2 and P2X3 receptor subunits in rat carotid body afferent neurones: role in chemosensory signalling.

1. Hypoxic chemotransmission in the rat carotid body (CB) is mediated in part by ATP acting on suramin-sensitive P2X purinoceptors. Here, we use RT-PCR, cloning and sequencing techniques to show P2X2 and P2X3 receptor expression in petrosal neurones, some of which develop functional chemosensory units with CB receptor clusters in co-culture. 2. Single-cell RT-PCR revealed that hypoxia-responsive neurones, identified electrophysiologically in co-culture, expressed both P2X2 and P2X3 mRNA. 3. Isohydric hypercapnia (10 % CO(2); pH 7.4) caused excitation of chemosensory units in co-culture. This excitation depended on chemical transmission, with ATP acting as a co-transmitter, since it was inhibited by reduction of the extracellular Ca(2+):Mg(2+) ratio and by the purinoceptor blocker suramin (50-100 microM). 4. Hypoxia and isohydric hypercapnia could separately excite the same chemosensory unit, and together the two stimuli interacted synergistically. 5. Using confocal immunofluorescence, co-localization of P2X2 and P2X3 protein was demonstrated in many petrosal somas and CB afferent terminals in situ. Taken together, these data indicate that ATP and P2X2-P2X3 purinoceptors play important roles in the peripheral control of respiration by carotid body chemoreceptors.

T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein.

alpha fetoprotein (AFP)-derived peptide epitopes can be recognized by human T cells in the context of MHC class I. We determined the identity of AFP-derived peptides, presented in the context of HLA-A*0201, that could be recognized by the human (h) T cell repertoire. We screened 74 peptides and identified 3 new AFP epitopes, hAFP(137-145), hAFP(158-166), and hAFP(325-334), in addition to the previously reported hAFP(542-550.) Each possesses two anchor residues and stabilized HLA-A*0201 on T2 cells in a concentration-dependent class I binding assay. The peptides were stable for 2-4 h in an off-kinetics assay. Each peptide induced peptide-specific T cells in vitro from several normal HLA-A*0201 donors. Importantly, these hAFP peptide-specific T cells also were capable of recognizing HLA-A*0201(+)/AFP(+) tumor cells in both cytotoxicity assays and IFN-gamma enzyme-linked immunospot assays. The immunogenicity of each peptide was tested in vivo with HLA-A*0201/K(b)-transgenic mice. After immunization with each peptide emulsified in CFA, draining lymph node cells produced IFN-gamma on recognition of cells stably transfected with hAFP. Furthermore, AFP peptide-specific T cells could be identified in the spleens of mice immunized with dendritic cells transduced with an AFP-expressing adenovirus (AdVhAFP). Three of four AFP peptides could be identified by mass spectrometric analysis of surface peptides from an HLA-A*0201 human hepatocellular carcinoma (HCC) cell line. Thus, compelling immunological and physiochemical evidence is presented that at least four hAFP-derived epitopes are naturally processed and presented in the context of class I, are immunogenic, and represent potential targets for hepatocellular carcinoma immunotherapy.

Adenovirus-interleukin-12-mediated tumor regression in a murine hepatocellular carcinoma model is not dependent on CD1-restricted natural killer T cells.

The cytokine interleukin-12 (IL-12) has shown potent antitumor activity in several tumor models. Recently, natural killer (NK) T cells have been proposed to mediate the antitumor effects of IL-12. In this study, the antitumor response of IL-12 was investigated in a gene therapeutic model against s.c. growing mouse hepatocellular carcinomas using an adenoviral vector expressing murine IL-12 (AdVmIL-12). An adenoviral-based system was chosen because of the ability of adenoviruses to transduce dividing and nondividing cells and because of their high transduction efficiencies. Our goals were to examine the efficacy of AdVmIL-12 in a hepatocellular carcinoma model and to investigate the mechanism of the AdVmIL-12-mediated antitumor response with specific interest in the role of NK T cells. Our studies demonstrate that intratumoral AdVmIL-12-mediated regression of s.c. hepatocellular tumors is associated with rapid antitumor responses. AdVmIL-12 treatment was associated with an immune cellular infiltrate consisting of CD4 and CD8 T lymphocytes, macrophages, NK cells, and NK T cells. Antibody ablation of CD4 and CD8 T cells and use of NK cell-defective beige mice failed to abrogate the response to AdVmIL-12. Studies in T-cell- and B-cell-deficient severe combined immunodeficient and recombinase activating gene-2-deficient mice and T-cell-, B-cell-, and NK cell-defective severe combined immunodeficient/beige mice also failed to abrogate this response. AdVmIL-12 retained potent antitumor activity in mice with specific genetic defects in immune cellular cytotoxicity (perforin knockout mice) and costimulation (CD28 knockout mice). Use of mice with specific NK T cell deficiencies, Valpha14 T-cell receptor and CD1 knockout mice, also failed to abrogate the response to AdVmIL-12. Histological and immunohistochemical studies of AdVmIL-12-treated tumors showed extensive inhibition of neovascularization and a marked decrease in factor VIII-stained endothelial cells. Our studies indicate that the antitumor response of AdVmIL-12 is independent of direct cytotoxic cellular immunity (specifically, the function of NK T cells) and suggest that the initial mechanisms of AdVmIL-12-mediated tumor regression involve inhibition of angiogenesis.