Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements.

The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.

Accuracy and effectiveness of laparoscopic vs open hepatic radiofrequency ablation.

BACKGROUND: The purpose of this study was to compare the accuracy (in terms of ultrasound-guided probe placement) and the effectiveness (in terms of pathologic tumor-free margin) of laparoscopic vs open radiofrequency (RF) ablation. METHODS: Using a previously validated tissue-mimic model, 1-cm simulated hepatic tumors were ablated in 10 pigs randomized to open or laparoscopic techniques. Energy was applied until tissue temperature reached 100 degrees C (warm-up) and thereafter for 8 min. A pathologist blinded to technique examined all specimens immediately after treatment. Analysis was by Fisher's exact test and the Mann-Whitney U test; p < 0.05 was considered significant. RESULTS: Off-center distance (3.5 +/- 1.6 vs 4.2 +/- 1.4 mm), size (24.7 +/- 3.1 vs 25.6 +/- 3.8 mm), symmetry (40% vs 73%), margin positivity (33% vs 9%), and margin distance (1.1 +/- 1.2 vs 2.2 +/- 1.6 mm) were not significantly different between laparoscopic (n = 15) and open (n = 11) ablations, respectively. The proportion of round/ovoid lesions (20% vs 64%) was lower (p = 0.043), and warm-up time (20.2 +/- 14.0 vs 10.7 +/- 7.5) was longer (p = 0.049) for the laparoscopic than for the open groups, respectively. CONCLUSION: Accurate probe placement can be achieved using laparoscopic and open RF ablation techniques. The physiologic effects of laparoscopy may alter ablation shape and warm-up time. Additional studies are needed to establish effective ways of achieving complete tumor destruction.

Long-term outcomes of renal transplantation: a result of the original endowment of the donor kidney and the inflammatory response to both alloantigens and injury.

Recent data suggest that long-term allograft survival might be affected by two factors. The first is the endowment of the allograft, which consists of two elements: the nephron mass and the ability of these nephrons to repair injuries sustained during the transplant process. The second factor is renal inflammation. Although inflammation is traditionally ascribed to alloreactivity, recent data have shown that there is also a renal inflammatory response to early injury after transplantation, to brain death in the donor, and as part of the maladaptive response to nephron loss. These two factors contribute to the detrimental effects of delayed graft function or acute rejection on the long-term survival seen in most studies, and the beneficial effects of anti-inflammatory agents on the maladaptive response to nephron loss.

Laparoscopic training on bench models: better and more cost effective than operating room experience?

BACKGROUND: Developing technical skill is essential to surgical training, but using the operating room for basic skill acquisition may be inefficient and expensive, especially for laparoscopic operations. This study determines if laparoscopic skills training using simulated tasks on a video-trainer improves the operative performance of surgery residents. STUDY DESIGN: Second- and third-year residents (n= 27) were prospectively randomized to receive formal laparoscopic skills training or to a control group. At baseline, residents had a validated global assessment of their ability to perform a laparoscopic cholecystectomy based on direct observation by three evaluators who were blinded to the residents' randomization status. Residents were also tested on five standardized video-trainer tasks. The training group practiced the video-trainer tasks as a group for 30 minutes daily for 10 days. The control group received no formal training. All residents repeated the video-trainer test and underwent a second global assessment by the same three blinded evaluators at the end of the 1-month rotation. Within-person improvement was determined; improvement was adjusted for differences in baseline performance. RESULTS: Five residents were unable to participate because of scheduling problems; 9 residents in the training group and 13 residents in the control group completed the study. Baseline laparoscopic experience, video-trainer scores, and global assessments were not significantly different between the two groups. The training group on average practiced the video-trainer tasks 138 times (range 94 to 171 times); the control group did not practice any task. The trained group achieved significantly greater adjusted improvement in video-trainer scores (five of five tasks) and global assessments (four of eight criteria) over the course of the four-week curriculum, compared with controls. CONCLUSIONS: Intense training improves video-eye-hand skills and translates into improved operative performance for junior surgery residents. Surgical curricula should contain laparoscopic skills training.

Nitric oxide inhibits INFgamma-induced increases in CIITA mRNA abundance and activation of CIITA dependent genes--class II MHC, Ii and H-2M. Class II TransActivator.

BACKGROUND: Nitric oxide (NO) has been recently implicated as a powerful inhibitor of immune responses during allograft rejection, and some autoimmune and infectious diseases. We previously showed that one potential regulatory effect of NO is inhibition of IFNgamma-stimulated expression of Class II MHC on macrophages. Activation of this gene is mediated by the "Class II TransActivator" (CIITA). We now ask whether NO inhibits CIITA and thus the family of genes regulated by CIITA--Class II MHC, Ii, and H-2M. The latter two genes participate in antigen processing and formation of the cell-surface peptide-Class II MHC complex. METHODS: Murine macrophages--both peritoneal macrophages and the RAW264.7 macrophage line--were stimulated in vitro with IFNgamma. NO production was measured by the Greiss reagent. Transcription of Class II MHC was measured by nuclear run-on assay. mRNA abundance of Class II MHC, Ii, H-2M, and CIITA was measured by Northern blotting and RT-PCR. RESULTS: NO inhibits IFNgamma-induced increases in the abundance and transcription of the Class II MHC Ab gene. The increases in mRNA abundance of CIITA, Ii, and H-2M are also inhibited. As a control, we found that NO did not inhibit LPS-induce increases in TNFalpha mRNA abundance. CONCLUSIONS: NO inhibits IFNgamma-induced increases in CIITA, and thus inhibits the CIITA-regulated genes: Class II MHC, Ii, and H-2M. Early during rejection, NO production by macrophages may result after stimulation by IFNgamma produced by CD4+ T cells, and be an effector of allograft damage. High concentrations of NO may then act as a feedback inhibitor which decreases antigen presentation by macrophages and thus decreases CD4 T cell activation.

Rare presentation of actinomycosis as an abdominal mass: report of a case.

PURPOSE: The purpose of this article was to report an unusual presentation of abdominal actinomycosis masquerading as a tumor. METHODS: The patient was a 54-year-old male who presented with vague abdominal discomfort and a palpable left lower quadrant mass defined on CT scan. Multiple intraoperative core biopsies were nondiagnostic, and he underwent en bloc resection of the mass and adjacent organs for a presumed tumor. RESULTS: Examination of tissue from deep within the excised specimen revealed sulfur granules diagnostic for actinomycosis. CONCLUSION: Abdominal actinomycosis is an extremely rare infection that can mimic multiple disease processes and requires accurate diagnosis for successful therapy. This novel presentation and a review of the literature are reported.

Docosahexaenoic acid decreases IRF-1 mRNA and thus inhibits activation of both the IRF-E and NFkappa d response elements of the iNOS promoter.

BACKGROUND: Nitric oxide produced by inducible nitric oxide synthase (iNOS) may be cytotoxic during cardiac, hepatic, and renal acute allograft rejection. Because the incidence of rejection is decreased by fish oils that contain docosahexaenoic acid (DHA), we investigated the effects of DHA on iNOS. Using nuclear run-on assays and iNOS-promoter constructs, we previously showed that docosahexaenoic acid (DHA) inhibits activation of the iNOS gene by murine macrophages that had been stimulated in vitro by IFNgamma plus lipopolysaccharide. METHODS: In our current investigation, our purpose has been to determine how DHA inhibits iNOS gene activation in murine macrophages, by using gel retardation and Northern blotting techniques. We studied the effects of DHA on the formation nuclear protein complexes that interact with the critical iNOS promoter's response elements for IRF-1 (IRF-E -923 to -913 bp) and NF-kappaB (NFkappa d -85 to -75 bp). RESULTS: We now show that DHA inhibited increases of IRF-1 mRNA abundance in response to IFNgamma plus lipopolysaccharide. As expected, we found that this prevented formation of the nuclear protein complex that binds to the IRF-E DNA response element. We also found that inhibition of IRF-1 inhibited formation of the nuclear protein complex that binds to the NFkappa d DNA response element. CONCLUSIONS: DHA decreases the abundance of IRF-1 mRNA in stimulated cells. That, in turn, results in the decreased nuclear protein binding to the major iNOS promoter response elements (IRF-E and NF-kappaB). We found that this occurred because IRF-1 is a component of both the nuclear protein complex that binds to IRF-E and the nuclear protein complex that binds to NFkappa d.

Transplant surgery injury recruits recipient MHC class II-positive leukocytes into the kidney.

BACKGROUND: CD4 T cells, which are stimulated by the "indirect pathway" of antigen-presentation, participate in rejection. These T cells are sensitized by recipient major histocompatibility complex (MHC) class II-positive leukocytes that migrate into the transplant. Therefore, an important early step in rejection is the immigration of these recipient MHC class II-positive leukocytes into the renal transplant. The regulation of this early step is not understood. We now test the hypothesis that such leukocytes immigrate into the renal transplant in response to ischemic injury occurring during the transplant procedure. METHODS: We transplanted Brown Norway (BN) kidneys into F1 Lewis/Brown Norway (L/BN) recipients. The F1 recipients are tolerant to the parental BN antigens, and any infiltration of recipient MHC class II-positive leukocytes results from injury occurring during transplantation surgery. In addition, ischemia/reperfusion injury was also induced by temporarily occluding the native renal arteries for 30 minutes. Transplanted kidneys and native kidneys, which suffered ischemia/reperfusion injury, were studied by immunohistochemistry on days 3, 7, 14, and 28 after surgery. Staining by the new monoclonal antibody (mAb) OX62 and antibodies to MHC class II identified dendritic cells. In addition, the following monoclonal antibodies identified: gamma/delta T cells, V65; B cells, OX33; cells that may be macrophages, dendritic cells, or dendritic cell precursors, ED1 (+) and OX62 (-); and recipient class II MHC, OX3. RESULTS: After transplantation, the serum creatinine increased to 4 mg/dl and then decreased, which was consistent with reversible injury during transplantation and the absence of rejection. We found that the injury of transplantation itself resulted in the infiltration of recipient MHC class II-positive leukocytes into the transplanted kidney. This infiltrate peaked at days 7 to 14 after surgery. The inflammation was peritubular and patchy and involved cortex and outer medulla. Double staining for OX62 and OX3 identified some of the infiltrating leukocytes as dendritic cells. Other recipient leukocytes were MHC class II positive, ED1 positive, and OX62 negative. We also found that MHC class II leukocytes, including dendritic cells, infiltrated native kidneys injured by ischemia/reperfusion injury. CONCLUSION: To our knowledge, this is the first demonstration that injury to the kidney during transplantation recruits recipient MHC class II-positive leukocytes into the kidney. Some of these leukocytes are dendritic cells.

Hypothesis: is renal allograft rejection initiated by the response to injury sustained during the transplant process?

Allograft rejection can be caused by numerous factors such as damage to the donor kidney during surgical removal or implantation, injury sustained during the transport process between the donor and recipient, and suboptimal allograft perfusion during the intra- and post-operative period. In cadaveric allografts, damage can occur during cold storage, during the transit stage between donor and recipient, and hemodynamic instability due to the initial damage that caused its removal from the donor (such as brain death or trauma). We hypothesize that rejection requires recognition of this injury in addition to recognition of alloantigens. If indeed injury proves to be one factor in acute rejection episodes, then therapeutic efforts can be made to reduce injury during the transplantation process.

Docosahexaenoic acid, a component of fish oil, inhibits nitric oxide production in vitro.

INTRODUCTION: Docosahexaenoic acid (DHA) has been shown to be immunosuppressive in the fetus, and fish oil diets are thought to be beneficial in autoimmune disease and transplantation. This effect may be mediated through nitric oxide (NO). Here, we investigate the effect of DHA on murine macrophages. METHODS: Peritoneal macrophages were subjected to stimulation with various concentrations of interferon gamma-(IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). NO production was assessed by measuring nitrite (Greiss reaction). RESULTS: At all doses of IFN-gamma and TNF-alpha, DHA was found to be inhibitory to NO production. CONCLUSIONS: DHA inhibits macrophage-stimulated NO production in response to IFN-gamma and TNF-alpha. As NO is thought to be important in several disease processes, DHA may be a useful agent in the treatment of conditions such as autoimmune disease.

Syngeneic renal transplantation increases the number of renal dendritic cells in the rat.

Dendritic cells participate in the regulation of CD4 and CD8 T cells during transplant rejection. Understanding what causes increased numbers of dendritic cells to appear in the renal transplant is therefore important. We performed syngeneic renal transplants between rats. We used the monoclonal antibody OX62 to detect dendritic cells, and OX6 to detect major histocompatability complex (MHC) Class II in the renal transplant. One week after transplant, dendritic cells appeared. This indicates that the injury of transplantation itself is sufficient to increase the number of dendritic cells in the kidney in a model where there is no alloreactivity.

Recurrent primary sclerosing cholangitis after orthotopic liver transplantation: is chronic rejection part of the disease process?

BACKGROUND: The possibility of primary sclerosing cholangitis (PSC) recurrence after liver transplantation has been debated. The aim of this study is to examine whether recurrent PSC and chronic rejection (CR) are different expressions of the same disease process. METHODS: One hundred consecutive patients receiving 118 grafts for the diagnosis of PSC were reviewed and placed into three groups: group A, recurrent disease, as evidenced by cholangiographic and pathologic findings with radiographic arterial flow to the liver (n=18; 15.7%); group B, those who developed CR (n=15; 13.0%); and group C, all others (n=82; 71.3%). Cholangiograms and histopathologic specimens were examined in a blinded fashion. RESULTS: Demographic factors were similar, except for age, with a significantly younger age and more episodes of rejection in groups A and B (P<0.03). Group A had a higher incidence of cytomegalovirus hepatitis (P=0.008). Five-year graft survivals for A, B, and C were 64.6%, 33.3%, and 76.1%, respectively (P=0.0001), 5-year patient survivals were 76.2%, 66.7%, and 89.1%, respectively (P=0.0001), and repeat transplantation rates were 27.8%, 46.7%, and 8.5%, respectively (P=0.005). Radiographically, 90% of cholangiograms in patients with recurrent disease showed at least multiple intrahepatic strictures. Histopathologically, patients with recurrent disease and CR shared many features. CONCLUSIONS: We have described a high incidence of recurrent PSC and CR in patients who received transplants for PSC. Histopathologic analysis suggests that CR and recurrent PSC could represent a spectrum of indistinguishable disease. However, the distinct difference in clinical outcome, as evidenced by an increased repeat transplantation rate and lower graft and patient survival in the CR group, clearly suggests that they are two distinct entities that require very different treatment strategies.

Liver and kidney transplantation for polycystic disease.

BACKGROUND: With the poor results of resective and fenestration procedures for polycystic liver disease (PCLD), we present the first series of patients receiving orthotopic liver transplantation for this condition. METHODS: Five of our six patients with PCLD had polycystic kidney disease also. Three of these five received combined organ transplants, while the other two required subsequent kidney transplants. RESULTS: Forty-eight and 52 months after orthotopic liver transplantation, all surviving patients had relief of their pain, distention, and anorexia. Two patients had succumbed to infectious complications and died at 15 and 24 months after transplant. CONCLUSIONS: We conclude that patients with PCLD can be transplanted safely for the relief of their distention and anorexia, with good results. Those patients with both PCLD and polycystic kidney disease who are not dialysis dependent can be managed for several years with isolated liver transplantation and then receive kidney transplantation if needed. Those who are dialysis dependent should receive combined liver-kidney transplantation. Unfortunately, patients with polycystic disease seem to be very susceptible to infectious complications after organ transplantation.

Is liver transplantation indicated for cholangiocarcinoma?

Liver transplantation (OLTx) has been investigated as a mode of therapy for malignancies. The efficacy of OLTx for the treatment of cholangiocarcinoma (CCA) has been somewhat controversial. We review the current literature on resective procedures for CCA and show that isolated intrahepatic CCA has a slightly better survival than extrahepatic disease. Results of OLTx for CCA are then reviewed, with specific attention to the experience at our center. Our results demonstrate that 1-year patient survival was 53%, and disease-free survival at 3 years was only 13%. Specific issues pertaining to the timing of OLTx in primary sclerosing cholangitis are then addressed. In summary, we believe that OLTx for known CCA results in a very poor patient survival. Those with incidental CCA found on explant histopathologic evaluation, without lymphatic involvement, may result in acceptable patient survival.

The safety of cardiac operations in the liver transplant recipient.

BACKGROUND: Advances in surgical techniques and immunosuppressive drugs have improved the survival of patients after orthotopic liver transplantation. Enhanced survival has resulted in an increased number of patients who require medical as well as surgical management of diseases. METHODS: To contribute to the sparse literature on the surgical aspects, we reviewed our experience with 15 patients who underwent cardiac operation (1.25%) from a total of 1,200 liver transplant recipients at our center. The variables studied included the pretransplant cardiac evaluation, the interval from transplantation to cardiac operation, postoperative complications, the management of immunosuppression, and follow-up. The patients had a mean age of 52.9 years (range, 39 to 69 years) and 13 of them (86.6%) were men. Multiple cardiac risk factors were present in all 15 patients and chronic renal insufficiency was present in 7 patients. Cardiac operation was undertaken a mean of 30.4 months (range, 9 days to 62 months) after myocardial ischemia and valvular regurgitation had been ruled out at the time of transplantation. Myocardial revascularization was performed in 12 patients, 2 of whom underwent concurrent valve operation and 3 of whom underwent valve repair or replacement. Most patients had their immunosuppression regimen continued at baseline levels. RESULTS: There were no early deaths. Three patients had major complications and 4 had minor complications. There were no bleeding, infection, or healing complications. Postoperative renal parameters were persistently elevated in 5 patients and transiently elevated in 3. Liver function parameters were transiently elevated in 6 patients after the cardiac operation. No patient had hepatic rejection. A transient elevation or decrease in immunosuppressive drug levels was seen in 3 patients. Follow-up, obtained on all 15 patients, ranged from 6 to 83 months (mean, 26.5 months). There were 2 late deaths (13.3%), and 3 patients (25%) who underwent myocardial revascularization had recurrent angina. CONCLUSIONS: Cardiac operations can be undertaken safely in liver transplant recipients with good intermediate-term results. The immunosuppression regimen can be continued at preoperative levels with no need for stress-dose steroids. There were no hepatic complications among our patients, although some patients can experience worsening of renal failure.

Hepatorenal syndrome: combined liver kidney transplants versus isolated liver transplant.

BACKGROUND: As many as 38% of combined liver-kidney transplant (LKTx) procedures performed nationally may be done for the renal diagnosis of hepatorenal syndrome (HRS). This study was designed to compare the national results with those at our medical center and to determine if combined LKTx provides any benefit over isolated liver transplant (LTx) to HRS patients. METHODS: Data on 29 combined LKTx and 79 HRS patients at our center were collected and compared with the national data on 414 LKTx and 2442 patients with serum creatinine >2.0 mg/dl receiving isolated LTx from 1988 to 1995. RESULTS: United Network of Organ Sharing data revealed 5-year patient survival of 62.2% for LKTx recipients and 50.4% for patients with serum creatinine >2.0 mg/dl receiving isolated LTx (P=0.0001). Our center results demonstrated 5-year patient survival of 48.1% for LKTx patients, 67.1% for HRS patients receiving isolated LTx, and 70.1% for patients with serum creatinine >2.0 mg/dl receiving isolated LTx (P not significant comparing all groups). Intensive care unit status and preoperative dialysis rates were similar in those HRS patients who did and those who did not need future KTx. CONCLUSION: National data would suggest a survival benefit of combined LKTx over isolated LTx for those patients with poor renal function, specifically those with HRS, whereas our center's results suggest otherwise. Unfortunately, we could not identify any preoperative risk factors in the HRS patients, or in the broader group of patients with renal insufficiency at our center, that would indicate the need for future renal transplantation. We believe that HRS patients can be successfully managed with isolated LTx.

Ten years of liver transplantation: an evolving understanding of late graft loss.

BACKGROUND: We undertook this study to understand the causes of late graft loss and long-term outcome in orthotopic liver transplantation (OLT) recipients. METHODS: Prospectively collected data of 1174 consecutive OLT in 1045 adult patients who received liver grafts between April 1985 and August 1995 were reviewed. The causes of graft loss, pretransplant patient characteristics, and posttransplant events were analyzed in patients who survived at least 1 year after OLT, in an attempt to establish a link between these factors and graft loss. RESULTS: One hundred fifty-nine (17.9%) grafts were lost after the first year. Of these, 132 grafts were lost by death and 27 by retransplantation. Recipients who survived the first year (n=884) had 5- and 10-year survivals of 81.4% and 67.2%, respectively. Death with a functioning graft occurred in 97 (61%) patients. The main causes of late graft loss were recurrent disease (n=48), cardiovascular and cerebral vascular accidents (n=28), infections (n=24), and chronic rejection (n = 15). Pretransplant heart disease and diabetes were found to be significant risk factors for late graft loss due to cardiovascular diseases and cerebral vascular accidents. CONCLUSIONS: Survival of OLT patients who live beyond the first posttransplant year is excellent. Some patient characteristics may be associated with late graft loss. Compared with previous reports, this study shows an increased incidence of late graft loss secondary to recurrent diseases, de novo malignancies, cardiovascular diseases, and cerebral vascular accidents. Chronic rejection seems to be a less frequent cause of late graft loss. The prevention of recurrent disease and better immunosuppression may further improve these results.