Lymphopenia following pancreaticoduodenectomy is associated with pancreatic fistula formation.

BACKGROUNDS/AIMS: Post-operative pancreatic fistulas (POPF) are a major source of morbidity following pancreaticoduodenectomy (PD). This study aims to investigate if persistent lymphopenia, a known marker of sepsis, can act as an additional marker of POPF with clinical implications that could help direct drain management. METHODS: A retrospective chart review of all patients who underwent PD in a single hospital network from 2008 to 2018. Persistent lymphopenia was defined as lymphopenia beyond post-operative day #3. RESULTS: Of the 201 patients who underwent PD during the study period 161 patients had relevant laboratory data, 81 of whom had persistent lymphopenia. 17 patients with persistent lymphopenia went on to develop a POPF, compared to 7 patients without. Persistent lymphopenia had a negative predictive value of 91.3%. Multivariate analysis revealed only persistent lymphopenia as being independently associated with POPF (HR 2.57, 95% CI 1.07-6.643, p=0.039). Patients with persistent lymphopenia were more likely to have a complication requiring intervention (56.8% vs 35.0%, p<0.001). CONCLUSIONS: Persistent lymphopenia is a readily available early marker of POPF that holds the potential to identify clinically relevant POPF in patients where no surgical drain is present, and to act as an adjunct of drain amylase helping to guide drain management.

Comparisons of oral, intestinal, and pancreatic bacterial microbiomes in patients with pancreatic cancer and other gastrointestinal diseases.

Background: Oral microbiota is believed to play important roles in systemic diseases, including cancer. Methods: We collected oral samples (tongue, buccal, supragingival, and saliva) and pancreatic tissue or intestinal samples from 52 subjects, and characterized 16S rRNA genes using high-throughput DNA sequencing. Results: Bray-Curtis plot showed clear separations between bacterial communities in the oral cavity and those in intestinal and pancreatic tissue samples. PERMANOVA tests indicated that bacterial communities from buccal samples were similar to supragingival and saliva samples, and pancreatic duct samples were similar to pancreatic tumor samples, but all other samples were significantly different from each other. A total of 73 unique Amplicon Sequence Variants (ASVs) were shared between oral and pancreatic or intestinal samples. Only four ASVs showed significant concordance, and two specific bacterial species (Gemella morbillorum and Fusobacterium nucleatum subsp. vincentii) showed consistent presence or absence patterns between oral and intestinal or pancreatic samples, after adjusting for within-subject correlation and disease status. Lastly, microbial co-abundance analyses showed distinct strain-level cluster patterns among microbiome members in buccal, saliva, duodenum, jejunum, and pancreatic tumor samples. Conclusions: Our findings indicate that oral, intestinal, and pancreatic bacterial microbiomes overlap but exhibit distinct co-abundance patterns in patients with pancreatic cancer and other gastrointestinal diseases.

Improving the value of palliative surgery by optimizing patient selection: The role of long-term survival on high impact palliative intent operations.

BACKGROUND: In order to better characterize outcomes of palliative surgery (PS), we evaluated patients that experienced top quartile survival to elucidate predictors of high impact PS. METHODS: All PS performed on advanced cancer patients from 2003 to 2017 were identified from a PS database. RESULTS: 167 patients were identified. Multivariate analysis demonstrated the ability to rise from a chair was independently associated with top quartile survival (HR 7.61, 95% CI 2.12-48.82, p=0.008) as was the need for re-operation (HR 2.81, 95% CI 1.26-6.30, p=0.0012). Patients who were able to rise from a chair had significantly prolonged overall survival (320 vs 87 days, p < 0.001). CONCLUSIONS: Although not the primary goal, long-term survival can be achieved following PS and is associated with re-operation and the ability to rise from a chair. These patients experience the benefits of PS for a longer period of time, which in turn maximizes value and positive impact. SUMMARY: Long-term survival and symptom control can be achieved in highly selected advanced cancer patients following palliative surgery. The ability of the patient to independently rise from a chair and the provider to offer a re-operation when indicated are associated with long-term survival following a palliative operation.

Adjuvant FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Pancreatic Cancer: A Brown University Oncology Research Group Phase II Study (BrUOG295).

OBJECTIVES: Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival. RESULTS: Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea. CONCLUSIONS: Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX.

Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.

To demonstrate multifaceted contribution of aspartate ß-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's ß-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.

An Assessment of Fine Surgical KnotTying.

OBJECTIVE: Operating room simulation exercises have been well established as an effective means of improving confidence, task engagement, and learning retention among surgical residents. We have established a cost-effective model and scoring system assessing resident skills to tie secure surgical knots with minimal tension. DESIGN: A circular grid divided into 18 segments was placed underlying an aluminum can. Trainees tie 20 surgical square knots scored for time and total knot length. Movement of the can outside the grid served as a scoring penalty. Recorded were time, length of the 20 knots, and number of segments exposed at exercise end. A score was developed to identify a progression of skills with PGY level. All outcomes were compared between classes using ANOVA. SETTING: Brown University/Rhode Island Hospital Department of Surgery. PARTICIPANTS: Surgical residents (PGY1-PGY5) and participating attending surgeons employed by Rhode Island Hospital. RESULTS: Knot length and exposed segments showed trends of improved scores with ascending PGY level. Only average time attained statistical significance. Overall scores improved with PGY level: Composite scores significantly improved when comparing PGY1 to PGY3, PGY5, and Attending surgeons (p = 0.016, 0.011, and 0.011, respectively). Time significantly improved when comparing PGY1 to PGY3 and Attending surgeons (77vs. 50 and 47 seconds, p = 0.019 and 0.022 respectively). Composite scores were not significantly different above PGY3. CONCLUSIONS: A low fidelity, high impact knot tying model has been developed to assess the ability to securely tie surgical knots while minimizing tension, with linear increases in scores that appear to plateau at the PGY3 level.

The Microbiomes of Pancreatic and Duodenum Tissue Overlap and Are Highly Subject Specific but Differ between Pancreatic Cancer and Noncancer Subjects.

BACKGROUND: In mice, bacteria from the mouth can translocate to the pancreas and impact pancreatic cancer progression. In humans, oral bacteria associated with periodontal disease have been linked to pancreatic cancer risk. It is not known if DNA bacterial profiles in the pancreas and duodenum are similar within individuals. METHODS: Tissue samples were obtained from 50 subjects with pancreatic cancer or other conditions requiring foregut surgery at the Rhode Island Hospital (RIH), and from 34 organs obtained from the National Disease Research Interchange. 16S rRNA gene sequencing was performed on 189 tissue samples (pancreatic duct, duodenum, pancreas), 57 swabs (bile duct, jejunum, stomach), and 12 stool samples. RESULTS: Pancreatic tissue samples from both sources (RIH and National Disease Research Interchange) had diverse bacterial DNA, including taxa typically identified in the oral cavity. Bacterial DNA across different sites in the pancreas and duodenum were highly subject specific in both cancer and noncancer subjects. Presence of genus Lactobacillus was significantly higher in noncancer subjects compared with cancer subjects and the relative abundance of Fusobacterium spp., previously associated with colorectal cancer, was higher in cancer subjects compared with noncancer subjects. CONCLUSIONS: Bacterial DNA profiles in the pancreas were similar to those in the duodenum tissue of the same subjects, regardless of disease state, suggesting that bacteria may be migrating from the gut into the pancreas. Whether bacteria play a causal role in human pancreatic cancer needs to be further examined. IMPACT: Identifying bacterial taxa that differ in cancer patients can provide new leads on etiologically relevant bacteria.

Aspartate ß-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway.

BACKGROUND: Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate ß-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. METHODS: To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's ß-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. RESULTS: ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). CONCLUSION: Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

A comparison of outcomes between open, laparoscopic and robotic pancreaticoduodenectomy.

BACKGROUND: The advantages and comparison of minimally invasive techniques for pancreaticoduodenectomies have not been fully explored using large national multicenter data. STUDY DESIGN: A retrospective review of NSQIP targeted data from 2014 to 2015 was performed. Demographics and outcomes were compared between open (OPD), laparoscopic (LPD) and robotic pancreaticoduodenectomies (RPD). RESULTS: Of 6827 pancreaticoduodenectomies, 6336 (92.8%) were OPD, 280 (4.1%) were LPD, and 211 (3.1%) were RPD. Compared to OPD, LPD required more post-operative drainage procedures (18.4% vs 13.2%, p = 0.013), had less SSI (3.2% vs 9%, p = 0.001), and had fewer discharges to a new facility (8.1% vs 13%, p = 0.018). Compared to OPD, RPD had less perioperative transfusions (14.2% vs 20.5%, p = 0.026) and more readmissions (23.2% vs 16.7%, p = 0.013). After controlling for differences, LPD was independently associated with decreased 30-day morbidity compared to OPD (OR 0.75, 95% CI 0.56-0.99). There was no difference in 30-day mortality. CONCLUSIONS: This is the first study to compare the outcomes of laparoscopic and robotic pancreaticoduodenectomies to open using the NSQIP database. After controlling for differences between groups, LPD is independently associated with less morbidity. In experienced hands, it appears safe and valuable to pursue refinement of minimally invasive techniques for pancreaticoduodenectomies.

Irreversible electroporation of hepatocellular carcinoma: patient selection and perspectives.

Irreversible electroporation (IRE) is a novel form of tissue ablation that uses high-current electrical pulses to induce pore formation of the cell lipid bilayer, leading to cell death. The safety of IRE for ablation of hepatocellular carcinoma (HCC) has been established. Outcome data for ablation of HCC by IRE are limited, but early results are encouraging and suggest equivalency to the outcomes obtained for thermal ablation for appropriately selected, small (<3 cm) tumors. Long-term oncologic efficacy and histopathologic response data have not been published, and therefore, application of IRE for the treatment of HCC should still be viewed with caution.

FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study.

BACKGROUND: The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel. METHODS: Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil 2400 mg/m with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity. RESULTS: Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months. CONCLUSIONS: The maximum tolerated dose of nab-paclitaxel is 150 mg/m every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.

What Shape is Your Resident in? Using a Radar Plot to Guide a Milestone Clinical Competency Discussion.

OBJECTIVE: One of the challenges for program directors (PDs) is to sort and weight the tidal wave of assessments that training programs create in the modern Milestone era. We evaluated whether the use of a radar plot (RP) would be helpful in sorting data and providing a graphic representation of each resident's progress. DESIGN: Using at least 2 different types of assessments for each of the 16 surgical Milestones, the data were ranked and weighted by a predetermined method embedded in a computerized workbook (Excel). This process created a unique 16-spoked RP for each resident (Fig. below). The RP allowed the faculty to see areas of weakness (shown by concavity) and allowed an overall grade calculated as a ratio of the area of the smooth outer circle (faculty expectations, triangles) and the resident's unique radar shape (resident performance, squares). To help us validate our new tool, we looked at whether residents with recent remedial issues "looked" different from residents without remedial issues. RESULTS: Of our 30 categorical residents, 8 had significant areas of concavities, suggesting possible areas of improvement. Of these 8 residents, 4 had been on a remediation program in the last 18 months. The average ratio of performance/expectations was 0.709. The 4 residents on recent remediation had a ratio of 0.616 when compared with 0.723 for the residents without remedial issues (p < 0.009). CONCLUSIONS: Many exciting challenges await PDs, as we evolve to a competency-based evaluation system. The use of an evaluation summary tool using RPs may aid PDs in leading clinical competency discussions and in monitoring a resident's progress over time.

Microwave ablation of focal hepatic malignancies regardless of size: A 9-year retrospective study of 64 patients.

PURPOSE: To retrospectively evaluate the safety and efficacy of microwave ablation (MWA) as treatment for single, focal hepatic malignancies. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study. From December 2003 to May 2012, 64 patients were treated with MWA for a single hepatic lesion, in 64 sessions. Hepatocellular carcinoma (HCC) was treated in 25 patients (geometric mean tumor size, 3.33-cm; 95% CI, 2.65-4.18-cm; range, 1.0-12.0-cm), metastatic colorectal cancer (CRC) was treated in 27 patients (geometric mean tumor size, 2.7-cm; 95% CI, 2.20-3.40-cm; range, 0.8-6.0-cm), and other histological-types were treated in 12 patients (geometric mean tumor size, 3.79-cm; 95% CI, 2.72-5.26-cm; range, 1.7-8.0-cm). Kaplan-Meier (K-M) method was used to analyze time event data. Chi-square and correlation evaluated the relationship between tumor size and treatment parameters. RESULTS: Technical success rate was 95.3% (61/64). Treatment parameters were tailored to tumor size; as size increased more antennae were used (p<0.001), treatment with multiple activations increased (p<0.028), and treatment time increased (p<0.001). There was no statistically significant relationship between time to recurrence and tumor size, number of activations, number of antennae, and treatment time. At one-year, K-M analysis predicted a likelihood of local recurrence of 39.8% in HCC patients, 45.7% in CRC metastases patients, and 70.8% in patients with other metastases. Median cancer specific survivals for patients were 38.3 months for HCC patients, 36.3 months for CRC metastases, and 13.9 months for other histological-types. Complications occurred in 23.4% (15/64) of sessions. CONCLUSION: In our sample, tumor size did not appear to impact complete ablation rates or local recurrence rates for focal hepatic malignancies treated with MWA.

Aspartate-ß-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a poor prognosis due to high recurrence rate. Aspartate-ß-hydroxylase (ASPH) is a highly conserved transmembrane protein, which is over expressed in HCC and promotes a malignant phenotype. The capability of ASPH protein-derived HLA class I and II peptides to generate antigen specific CD4(+) and CD8(+) immune responses is unknown. Therefore, these studies aim to define the epitope specific components required for a peptide based candidate vaccine. Monocyte-derived dendritic cells (DCs) generated from the peripheral blood mononuclear cells (PBMCs) of HCC patients were loaded with ASPH protein. Helper CD4(+) T cells and CD8(+) cytotoxic T lymphocytes (CTLs) were co-incubated with the DCs; T cell activation was evaluated by flow cytometric analysis. Immunoinformatics tools were used to predict HLA class I- and class II-restricted ASPH sequences, and the corresponding peptides were synthesized. The immunogenicity of each peptide in cultures of human PBMCs was determined by IFN-γ ELISpot assay. ASPH protein-loaded DCs activated both CD4(+) and CD8(+) T cells contained within the PBMC population derived from HCC patients. Furthermore, the predicted HLA class I- and class II-restricted ASPH peptides were significantly immunogenic. Both HLA class I- and class II-restricted peptides derived from ASPH induce T cell activation in HCC. We observed that ASPH protein and related peptides were highly immunogenic in patients with HCC and produce the type of cellular immune responses required for generation of anti-tumor activity.

Identification of Nonalcoholic Fatty Liver Disease following Pancreatic Surgery in a Western Cohort Using a Novel Radiographic Technique.

BACKGROUND AND AIMS: While traditional risk factors for the development of nonalcoholic fatty liver disease (NAFLD) relate to metabolic syndrome, several Asian studies have suggested a high rate of de novo NAFLD following pancreaticoduodenectomy (PD). The aim of this study is to identify de novo NAFLD after pancreatic surgery and its associated risk factors. METHODS: A retrospective cohort of patients at a single center that underwent PD or distal pancreatectomy (DP) over 7 years was identified. Pre- and postoperative contrast-enhanced computed tomography scans of the abdomen were reviewed, including attenuation measurements of the liver, spleen, and muscle. Primary outcomes included hepatic attenuation, liver to muscle ratio (LMR), and liver to spleen ratio (LSR). RESULTS: Of the 96 patients (mean age 64.3) included, 70% underwent PD, and 30% underwent DP. The mean LMR decreased significantly from 1.81 to 1.66 (p=0.02), noted only in men. No interaction effect with LMR was observed with surgical type, chemotherapy, blood loss, pancreatic enzyme replacement, or transaminases. LMR decreased in 55% of subjects. CONCLUSIONS: Increased fatty infiltration, as evidence by decreased LMR, was found among men that underwent PD and DP within a year of surgery. This may be related to weight loss and malabsorption and deserves further investigation.

Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study.

PURPOSE: To assess the activity and toxicity of lenalidomide for patients with advanced hepatocellular cancer (HCC) previously treated with sorafenib. MATERIALS AND METHODS: Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Patients received lenalidomide 25 mg orally for 1 to 21 days in a 28-day cycle until disease progression or unacceptable toxicities. RESULTS: Forty patients were enrolled and were classified according to the Child-Pugh score: 19 were Child-Pugh A, 16 patients were Child-Pugh B, and 5 were Child-Pugh C. Seventeen patients had extrahepatic disease. Grade 4 neutropenia occurred in 1 of 40 patients (2.5%). Grade 3 fatigue (n=3) and rash (n=4) were the most common nonhematologic toxicities attributable to lenalidomide. Six of 40 patients (15%) had a partial response. Two patients (5%) have not progressed at 36 and 32 months. The median progression-free survival was 3.6 months and the median overall survival was 7.6 months. CONCLUSIONS: Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction. Promising, and in a small percentage of patients, durable activity has been demonstrated. Investigations are needed to explore the mechanism of action of lenalidomide in HCC.

Assessment of surgical residents in a vascular anastomosis laboratory.

BACKGROUND: We designed a simple, low-cost workshop to teach surgical residents the basic skills of vascular anastomosis. We studied our ability to identify objective procedural and end-product metrics that could be used to measure improvement in vascular anastomotic skill before and after training. MATERIALS AND METHODS: Ten postgraduate year 2 residents without previous vascular surgery experience and four attending surgeons (expert) performed end-to-side anastomosis using a synthetic graft. The residents were taught the basic skills of vascular anastomosis during three didactic workshops. The objective metrics included volume leakage after saline perfusion (leak) and the time needed to complete the anastomosis. Penalty points were assigned for broken sutures, air knots, locking sutures, and failure to maintain an outside-in to inside-out technique. The leak, time, and penalties before and after training were compared. RESULTS: The mean leak was 70.4 ± 13.7 mL and the mean completion time was 18.7 ± 3 min for the pretraining group versus 45.3 ± 10.6 mL (P < 0.01) and 8.5 ± 1 min (P < 0.001), respectively, for the attending group. After training, significant improvement was seen in resident leak (46.7 ± 6.8 mL; P < 0.001) and completion time (14.4 ± 3 min; P < 0.01). Leak was similar between the post-training and expert groups (46.7 ± 6.8 mL and 45.3 ± 10.6 mL, respectively; P = 0.77); however, a significant difference for the completion time remained (14.4 ± 3.0 min and 8.5 ± 1 min, respectively; P < 0.01). The mean number of technical errors improved from 2.7 in the pretraining group to zero for the post-training group after completing the workshop. CONCLUSIONS: We have reported an easy to implement workshop for teaching surgical residents the basic skills of performing vascular anastomosis.

Intra-operative microwave ablation of liver malignancies with tumour permittivity feedback control: a prospective ablate and resect study.

BACKGROUND: Tumour permittivity feedback control is a novel method for microwave ablation (MWA) that theoretically allows for larger, more predictable ablations. This prospective case series evaluates the feasibility and efficacy of MWA of liver malignancies using a device with tumour permittivity feedback control. METHODS: Ten consecutive patients initially determined to be candidates for surgical resection of a liver malignancy underwent intra-operative MWA with tumour permittivity feedback control followed by a surgical resection. A 14-gauge Medwaves microwave antenna was used to deliver a single treatment according to the manufacturer's recommendations. Tumours were assessed grossly as well as by haematoxylin and eosin (H&E) and tetrazolium chloride staining. The primary end point was per cent tumour necrosis. RESULTS: The median maximum ablation diameter measured was 4.1 cm (range 3.0-6.8). The median ablation volume was 8.7 cm(3) (range 4.84-17.55). Six of the 10 tumours demonstrated a pathological complete response (CR). Six of seven tumours ≤ 3 cm demonstrated a pathological CR. Zero of the three tumours ≥ 3 cm had a pathological CR, but all had ≥ 50% tumour necrosis. All patients survived and there were no ablation-related morbidities. DISCUSSION: MWA of liver tumours with tumour permittivity feedback control is feasible and appears effective for the treatment of small (< 3 cm) liver tumours.

Irreversible electroporation for the ablation of liver tumors: are we there yet?

OBJECTIVE: To explore irreversible electroporation (IRE) as a novel, nonthermal form of tissue ablation using high-voltage electrical current to induce pores in the lipid bilayer of cells, resulting in cell death. DATA SOURCES: PubMed searches were performed using the keywords electroporation, IRE, and ablation. The abstracts for the 2012 meetings of both the American Hepato-Pancreato-Biliary Association and the Society for Interventional Radiology were also searched. All articles and abstracts with any reference to electroporation were identified and reviewed. STUDY SELECTION: All studies and abstracts pertaining to electroporation. DATA EXTRACTION: All data pertaining to the safety and efficacy of IRE were extracted from preclinical and clinical studies. Preclinical data detailing the theory and design of IRE systems were also extracted. DATA SYNTHESIS: Preclinical studies have suggested that IRE may have advantages over conventional forms of thermal tumor ablation including no heat sink effect and preservation of the acellular elements of tissue, resulting in less unwanted collateral damage. The early clinical experience with IRE demonstrates safety for the ablation of human liver tumors. Short-term data regarding oncologic outcome is now emerging and appears encouraging. CONCLUSION: Irreversible electroporation is likely to fill a niche void for the ablation of small liver tumors abutting a major vascular structure and for ablation of tumors abutting a major portal pedicle where heat sink and collateral damage must be avoided for maximum efficacy and safety. Studies are still needed to define the short-term and long-term oncologic efficacy of IRE.

Tumor progression-related transmembrane protein aspartate-ß-hydroxylase is a target for immunotherapy of hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-ß-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed in both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion. METHODS: Dendritic cells (DCs), expanded and isolated from the spleen, were incubated with a cytokine cocktail to optimize IL-12 secretion and co-stimulatory molecule expression, then subsequently loaded with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC tumor cells followed by subcutaneous inoculation with 5-10×10(5) ASPH loaded DCs using a prophylactic and therapeutic experimental approach. Tumor infiltrating lymphocytes (TILs) were characterized, and their role in producing anti-tumor effects determined. The immunogenicity of ASPH protein with respect to activating antigen specific CD4+ T cells derived from human peripheral blood mononuclear cells (PBMCs) was also explored. RESULTS: We found that immunotherapy with ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically. Ex-vivo re-stimulation experiments and in vivo depletion studies demonstrated that both CD4+ and CD8+ cells contributed to anti-tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, we showed that ASPH stimulation led to significant development of antigen-specific CD4+ T-cells. CONCLUSIONS: Immunization with ASPH-loaded DCs has substantial anti-tumor effects which could reduce the risk of HCC recurrence.