10 years, 100 robotic major hepatectomies: a single-center experience.

INTRODUCTION: Adoption of robotic liver resections has been gradually increasing throughout the HPB surgical community over the past decade. Currently there is limited literature which demonstrates a significant benefit of robotic surgery for major hepatectomies over open or laparoscopic. As one of the first centers to develop a robotic HPB program, we have experienced improved outcomes over time with increasing utilization of robotics. Herein, we present our 10-year experience and outcomes for major robotic liver resections. METHODS: From 2012 to 2022, 361 robotic liver procedures were performed, including 100 major hepatectomies. A retrospective data review of the electronic medical record was performed evaluating outcomes after robotic major hepatectomy. Outcomes for the first 50 cases (Group A) and second 50 cases (Group B) were compared to identify any improvements in practice. Demographic and clinical outcome variables were analyzed. Data were assessed for normality, and Wilcoxon rank-sum, χ2 tests, and a logistic regression model were performed appropriate for the data. Stata v.17 was utilized, and significance was set as p < .05. RESULTS: There was no difference in median operative time (258 vs 256 min), EBL (500 vs 500 mL), median LOS (5 vs 3.5 days), 90-day readmission (14% vs 24%), major complications (14% vs 20%), and 90-day mortality (6% vs 4%) between early and late cases, respectively. ICU admissions and conversion rates were significantly lower in group B (14.0% vs 48.0%), while expert level difficulty indices were higher (82% vs 58%). CONCLUSION: Development of a robotic liver program with good outcomes is feasible over time. Our data suggest that our institutional learning curve for robotic major hepatectomy plateaued at approximately 50 cases.

Expanding the utility of robotics for pancreaticoduodenectomy: a 10-year review and comparison to international benchmarks in pancreatic surgery.

BACKGROUND: Robotic pancreaticoduodenectomy (RPD) is an emerging alternative to open pancreaticoduodenectomy (OPD). Although RPD offers various theoretical advantages, it is used in less than 10% of all pancreaticoduodenectomies. The aim of this study was to report our 10-year experience and compare RPD outcomes with international benchmarks for OPD. METHODS: A retrospective review of a prospectively maintained institutional database was performed of consecutive patients who underwent RPD between January 2011 and December 2021. Patients were categorized into low-risk and high-risk groups according to the selection criteria set by the benchmark study. Their outcomes were compared to the international benchmark cut off values. Outcomes were then evaluated over time to identify improvements in practice and establish a learning curve. RESULTS: Of 201 RPDs, 36 were low-risk and 165 high-risk patients. Compared to the OPD benchmarks, outcomes of low-risk patients were within the cutoff values. High-risk patients were outside the cutoff for blood transfusions (26% vs. ≤ 23%), overall complications (78% vs. ≤ 73%), grade I-II complications (68% vs. ≤ 62%), and readmissions (22% vs ≤ 21%). Oncologic outcomes for high-risk patients were within benchmark cutoffs. Cases at the end of the learning curve included more pancreatic cancer (42% from 17%) and fewer low-risk patients (10% from 24%) than those at the beginning. After 41 RPD there was a decline in conversion rates and operative time. Between 95 and 143 cases operative time, transfusion rates, and LOS declined significantly. Complications did not differ over time. CONCLUSION: RPD yields results comparable to the established benchmarks in OPD in both low- and high-risk patients. Along the learning curve, RPD evolved with the inclusion of more high-risk cases while outcomes remained within benchmarks. Addition of a robotic HPB surgery fellowship did not compromise outcomes. These results suggest that RPD may be an option for high-risk patients at specialized centers.

External validation of the Japanese difficulty score for laparoscopic hepatectomy in patients undergoing robotic-assisted hepatectomy.

INTRODUCTION: The Japanese difficulty score (JDS) categorizes laparoscopic hepatectomy into low, intermediate, and high complexity procedures, and correlates with operative and postoperative outcomes. We sought to perform a validation study to determine if the JDS correlates with operative and postoperative indicators of surgical complexity for patients undergoing robotic-assisted hepatectomy. METHODS: Retrospective review of 657 minimally invasive hepatectomy procedures was performed between January 2008 through March 2019. Outcomes included operative time, estimated blood loss (EBL), blood transfusion, complications, post-hepatectomy liver failure (PHLF), length of stay, 30-day readmission, and 30-day and 90-day mortality. Patients were grouped based on JDS defined as: low (< 4), intermediate (4-6), and high (7 +) complexity procedures. Statistical comparisons were analyzed by ANOVA or χ2 test. RESULTS: 241 of 657 patients underwent robotic-assisted resection. Of these patients, 137 were included in the analysis based on JDS: 25 low, 58 intermediate, and 54 high. High JDS was associated with more major resections (≥ 4 contiguous segments) versus minor resections (median JDS 8 vs. 5, P < 0.0001). High JDS was associated with significantly longer operative times, higher EBL, and more blood transfusions. High JDS was associated with higher rates of PHLF at 16.7%, compared with 5.2% intermediate and 0.0% low, (P = 0.018). Complication rates, 30-day readmissions, and mortality rates were similar between groups. Median LOS was longer in patients with high JDS compared with intermediate and low (4 days vs. 3 days vs. 2 days; P = 0.0005). DISCUSSION: Higher JDS was associated with multiple indicators of operative complexity, including greater extent of resection, increased operative time, EBL, blood transfusion, PHLF, and LOS. This validation study supports the ability of the JDS to categorize patients undergoing robotic-assisted hepatectomy by complexity.

Robotic pancreatic necrosectomy and internal drainage for walled-off pancreatic necrosis.

BACKGROUND: Pancreatic necrosectomy with concomitant internal drainage is a single-stage treatment option for walled-off pancreatic necrosis (WOPN). However, an optimal minimally invasive technique has not been established. We evaluated the safety and single-intervention success rate of robotic pancreatic necrosectomy and internal drainage. METHODS: Patients with WOPN undergoing robotic pancreatic necrosectomy and internal drainage at a single institution from 2011-2022 were identified. The primary outcome was the rate of clinical symptom resolution following the index surgical intervention. RESULTS: 57 patients underwent robotic pancreatic necrosectomy and internal drainage, consisting of robotic cystgastrostomy (RCG, n = 37), robotic cystjejunostomy (RCJ, n = 13) and robotic fistulojejunostomy (RFJ, n = 7). Surgery was performed a median of 102 (range 28-1153) days following the onset of necrotizing pancreatitis. The median operative time was 187 (91-344) minutes and there were 2 (3.5%) conversions. The median length of hospital stay was 4 (2-38) days. Postoperative morbidity was 11%, and there was one (1.8%) 90-day mortality. At a median follow-up of 5.5 months, 53 (93%) patients had clinical symptom resolution after their index procedure and did not require any reintervention. CONCLUSION: In select patients, robotic pancreatic necrosectomy and internal drainage is safe and achieves a high single-intervention success rate.

Hepatocellular carcinoma as predominant cancer subgroup accounting for sex differences in post-hepatectomy liver failure, morbidity and mortality.

BACKGROUND: Experimental evidence suggests sex dependent differences in liver regeneration. Limited evidence is available examining sex differences in post-hepatectomy liver failure (PHLF) and postoperative outcomes. Our aim was to assess the influence of sex on the outcomes after liver resection. METHODS: The hepatectomy targeted National Surgical Quality Improvement Program (NSQIP) database was assessed for associations between sex and outcomes. RESULTS: A total of 13,401 patients underwent elective hepatic resection between 2014-2017. PHLF was highest among male patients with hepatocellular carcinoma (HCC) (OR = 2.81,95%CI:1.40-5.62). Male sex was independently associated with increased PHLF (OR = 1.47,95%CI:1.15-1.88), major complications (OR = 1.25,95%CI:1.08-1.45), mortality (OR = 1.61,95%CI:1.03-2.50), and if only major resections were assessed (OR = 1.38,95%CI:1.03-1.84). Diagnosis specific subgroup analyses revealed that effects of sex were predominantly HCC associated. CONCLUSIONS: This is the largest series investigating the effects of gender on outcomes after hepatic resection. We documented that women undergoing liver resection have significantly lower risk of PHLF. This difference seemed influenced by the striking increase of PHLF in male HCC patients. These hypothesis suggest that sex might play a role in preoperative risk stratification.

A Propensity-Matched Analysis of the Postoperative Venous Thromboembolism Rate After Pancreatoduodenectomy Based on Operative Approach.

BACKGROUND: The use of minimally invasive approaches for pancreatoduodenectomy has increased in recent years, but the risk of postoperative VTE is undefined. We aimed to compare venous thromboembolism (VTE) rates after open and minimally invasive pancreatoduodenectomy using an administrative dataset. METHODS: Patients who underwent pancreatoduodenectomy within the National Surgical Quality Improvement Program targeted pancreatectomy database (2016-2018) were identified. VTE was compared between patients who underwent open or minimally invasive pancreatoduodenectomy directly and after propensity score matching 1:1 for demographics, comorbidities, and peri-/intra-operative factors. RESULTS: A total of 12,227 patients underwent pancreatoduodenectomy during the study period (open: n = 11,217; minimally invasive: n = 1010). Before matching, the VTE rate was higher among patients who underwent minimally invasive pancreatoduodenectomy (5.2% vs. 3.8%, p = 0.033), and minimally invasive resection was independently associated with VTE (OR = 1.46, 95%CI = 1.09-2.06). After matching, there were 916 patients per group without differences in demographics or comorbidities. Patients who underwent minimally invasive pancreatoduodenectomy had longer median operative times (422 vs. 348 min). The VTE rate remained higher following minimally invasive pancreatoduodenectomy after matching (5.1% vs. 2.9%, p = 0.018), mainly driven by a higher DVT rate (3.9% vs. 1.7%, p = 0.005). CONCLUSIONS: Minimally invasive pancreatoduodenectomy is associated with a higher postoperative VTE rate compared to open pancreatoduodenectomy.

Synchronous resection of colorectal cancer primary and liver metastases: an outcomes analysis.

BACKGROUND: Concurrent resection of the primary cancer and synchronous colorectal cancer liver metastases (CRCLM) was evaluated for differences in outcomes following stratification of both the liver and colorectal resection. METHODS: Consecutive cases of synchronous resection of both the CRC primary and CRCLM were reviewed retrospectively at a single, high-volume institution over a 17-year period (2000-2017). RESULTS: 273 patients underwent simultaneous resection of CRCLM. The distribution of the primary lesion was similar between the colon (52.4%) and rectum (47.6%), while 46.9% of patients had bilobar liver disease. Major liver/major colorectal resection (n = 24) were significantly more likely to experience colorectal specific morbidity (OR 3.98, 95% CI 1.56-10.15, p = 0.004), liver specific morbidity (OR 7.4, 95% CI 2.22-24.71, p = 0.001), total morbidity (OR 2.91, 95% CI 1.18-7.18, p = 0.020) and 90-day mortality (OR 5.50, 95% CI 1.27-23.81, p = 0.023). Failure to receive adjuvant chemotherapy secondary to postoperative morbidity was associated with significantly worsened survival (HR for death 5.91, 95% CI 1.59-22.01, p = 0.008). CONCLUSIONS: Postoperative morbidity precluding the administration of adjuvant chemotherapy is associated with an increase in mortality. Combining a major liver with major colorectal resection is associated with a significant increase in major morbidity and 90-day mortality, and should be avoided.

Finding the Balance: General Surgery Resident Versus Fellow Training and Exposure in Hepatobiliary and Pancreatic Surgery.

BACKGROUND: Institutions training both General Surgery (GS) residents and Hepato-Pancreatico-Biliary (HPB) fellows must strive for adequate case volumes for each trainee cohort. METHODS: Six academic years of graduating ACGME Residency and HPB Fellowship Council case logs (July 2011-June 2017) and institutional administrative faculty billing data were examined at a single high-volume center with a formal HPB Surgical Division with both GS Residency and HPB Surgery Fellowship trainees. RESULTS: During the 6-year period, 7482 operations were performed by HPB faculty (5.5 total full-time equivalent (FTE)) and included 2419 major liver, 375 major biliary, and 1591 major pancreas cases. Residents/fellows performed 1102 (50%)/1101 (50%) of all major liver operations, 165 (49.7%)/163 (50.3%) major biliary operations, and 843 (59.2%)/581 (40.8%) major pancreas operations, with significantly different case mix of pancreas for resident versus fellow, p < 0.0001. The overall relative proportion of total HPB cases performed by residents versus fellows was 53%/47%, respectively, and this was stable over time, with no significant decrease in resident exposure/cases with dedicated HPB fellowship. CONCLUSIONS: Our experience in training both GS residents and HPB fellows with a formal HPB Surgical Division suggests that a high volume HPB Division allows for more than adequate exposure for both groups of trainees.

Consequences of Perioperative Serotonin Reuptake Inhibitor Treatment During Hepatic Surgery.

BACKGROUND AND AIMS: Platelet-stored serotonin critically affects liver regeneration in mice and humans. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenalin reuptake inhibitors (SNRIs) reduce intraplatelet serotonin. As SSRIs/SNRIs are now one of the most commonly prescribed drugs in the United States and Europe and given serotonin's impact on liver regeneration, we evaluated whether perioperative use of SSRIs/SNRIs affects outcome after hepatic resection. APPROACH AND RESULTS: Consecutive patients undergoing hepatic resection (n = 754) were retrospectively included from prospectively maintained databases from two European institutions. Further, an independent cohort of 495 patients from the United States was assessed to validate our exploratory findings. Perioperative intake of SSRIs/SNRIs was recorded, and patients were followed up for postoperative liver dysfunction (LD), morbidity, and mortality. Perioperative intraplatelet serotonin levels were significantly decreased in patients receiving SSRI/SNRI treatment. Patients treated with SSRIs/SNRIs showed a higher incidence of morbidity, severe morbidity, LD, and LD requiring intervention. Associations were confirmed in the independent validation cohort. Combined cohorts documented a significant increase in deleterious postoperative outcome (morbidity odds ratio [OR], 1.56; 95% confidence interval [CI], 1.07-2.31; severe morbidity OR, 1.86; 95% CI, 1.22-2.79; LD OR, 1.96; 95% CI, 1.23-3.06; LD requiring intervention OR, 2.22; 95% CI, 1.03-4.36). Further, multivariable analysis confirmed the independent association of SSRIs/SNRIs with postoperative LD, which was closely associated with postoperative 90-day mortality and 1-year overall survival. CONCLUSIONS: We observed a significant association of perioperative SSRI/SNRI intake with adverse postoperative outcome after hepatic resection. This indicates that SSRIs/SNRIs should be avoided perioperatively in patients undergoing hepatic resections.

Factors Associated with Treatment and Survival of Early Stage Pancreatic Cancer in the Era of Modern Chemotherapy: An Analysis of the National Cancer Database.

Background: Underutilization of operative management of early stage pancreatic cancer is associated with sociodemographic variables, including age, race, facility type, insurance, and education. It is currently unclear how these variables are associated with survival in patients who undergo surgery. Methods: Patients with clinical stage I pancreatic adenocarcinoma were identified within the National Cancer Database (2010-2016). Utilization of surgery and nonoperative management was determined. Nonclinical factors associated with nonoperative management were identified by multivariable analysis. The association between nonclinical factors and survival was assessed in patients who received operative management. Results: A total of 17,833 patients with clinical stage I pancreatic cancer were identified, and 41.2% underwent operative intervention. Approximately 46% of nonoperatively managed patients lacked a contraindication. Operatively managed patients had longer overall survival (OS) than those who were nonoperatively managed or untreated (25.1 months vs. 11.1 months vs. 5.1 months, p < 0.0001). Factors associated with nonoperative management included age, black/Hispanic race, nonacademic facilities, nonprivate health insurance, lower education level, and lower income. In operatively managed patients, nonclinical factors associated with lower OS included Medicaid (hazard ratio [HR] 1.27) and treatment at nonacademic facilities (HR 1.20-1.22). Patients on Medicaid received less adjuvant therapy and had higher 30- and 90-day mortality rates. Patients treated at nonacademic facilities received less neoadjuvant therapy, had worse pathologic outcomes, and had higher 30- and 90-day mortality rates. Conclusions: Surgical management is underutilized in clinical stage I pancreatic cancer. Primary insurance payor and facility type appear to be associated with OS in patients who undergo operative management.

Emergent pancreatectomy for neoplastic disease: outcomes analysis of 534 ACS-NSQIP patients.

BACKGROUND: While emergent pancreatic resection for trauma has been previously described, no large contemporary investigations into the frequency, indications, and outcomes of emergent pancreatectomy (EP) secondary to complications of neoplastic disease exist. Modern perioperative outcomes data are currently unknown. METHODS: ACS-NSQIP was reviewed for all non-traumatic pancreatic resections (DP - distal pancreatectomy, PD - pancreaticoduodenectomy, or TP- total pancreatectomy) in patients with pancreatico-biliary or duodenal-ampullary neoplasms from 2005 to 2013. Patients treated for complications of pancreatitis were specifically excluded. Emergent operation was defined as NSQIP criteria for emergent case and one of the following: ASA Class 5, preoperative ventilator dependency, preoperative SIRS, sepsis, or septic shock, or requirement of > 4 units RBCs in 72 h prior to resection. Chi-square tests, Fisher's exact tests were performed to compare postoperative outcomes between emergent and elective cases as well as between pancreatectomy types. RESULTS: Of 21,452 patients who underwent pancreatectomy for neoplastic indications, we identified 534 (2.5%) patients who underwent emergent resection. Preoperative systemic sepsis (66.3%) and bleeding (17.9%) were most common indications for emergent operation. PD was performed in 409 (77%) patients, DP in 115 (21%), and TP in 10 (2%) patients. Overall major morbidity was significantly higher (46.1% vs. 25.6%, p < 0.001) for emergent vs. elective operations. Emergent operations resulted in increased transfusion rates (47.6% vs. 23.4%, p < 0.001), return to OR (14.0% vs. 5.6%, p < 0.001), organ-space infection (14.6 vs. 10.5, p = 0.002), unplanned intubation (9.% vs. 4.1%, p < 0.001), pneumonia (9.6% vs. 4.2%, p < 0.001), length of stay (14 days vs. 8 days, p < 0.001), and discharge to skilled facility (31.1% vs. 13.9%). These differences persisted when stratified by pancreatic resection type. The 30-day operative mortality was higher in the emergent group (9.4%vs. 2.7%, p < 0.001) and highest for emergent TP (20%). CONCLUSION: Emergent pancreatic resection is markedly uncommon in the setting of neoplastic disease. Although these operations result in increased morbidity and mortality compared to elective resections, they can be life-saving in specific circumstances. The results of this large series of modern era national data may assist surgeons as well as patients and their families in making critical decisions in select cases of acutely complicated neoplastic disease.

Surgical Transgastric Necrosectomy for Necrotizing Pancreatitis: A Single-stage Procedure for Walled-off Pancreatic Necrosis.

OBJECTIVE: The aim of this study was to evaluate the role of surgical transgastric necrosectomy (TGN) for walled-off pancreatic necrosis (WON) in selected patients. BACKGROUND: WON is a common consequence of severe pancreatitis and typically occurs 3 to 5 weeks after the onset of acute pancreatitis. When symptomatic, it can require intervention. METHODS: A retrospective review of patients with WON undergoing surgical management at 3 high-volume pancreatic institutions was performed. Surgical indications, intervention timing, technical methodology, and patient outcomes were evaluated. Patients undergoing intervention <30 days were excluded. Differences across centers were evaluated using a P value of <0.05 as significant. RESULTS: One hundred seventy-eight total patients were analyzed (mean WON diameter = 14 cm, 64% male, mean age = 51 years) across 3 centers. The majority required inpatient admission with a median preoperative length of hospital stay of 29 days (25% required preoperative critical care support). Most (96%) patients underwent a TGN. The median duration of time between the onset of pancreatitis symptoms and operative intervention was 60 days. Thirty-nine percent of the necrosum was infected. Postoperative morbidity and mortality were 38% and 2%, respectively. The median postoperative length of hospital length of stay was 8 days, with the majority of patients discharged home. The median length of follow-up was 21 months, with 91% of patients having complete clinical resolution of symptoms at a median of 6 weeks. Readmission to hospital and/or a repeat intervention was also not infrequent (20%). CONCLUSION: Surgical TGN is an excellent 1-stage surgical option for symptomatic WON in a highly selected group of patients. Precise surgical technique and long-term outpatient follow-up are mandatory for optimal patient outcomes.

"Oh the weather outside is frightful": Severe injury secondary to falls while installing residential Christmas lights.

INTRODUCTION: Falls are an increasingly common source of severe traumatic injury. They now account for approximately 40% of both overall trauma volumes and injury-related deaths within Canada. In northern climates, the risk of all types of falls may increase during the fall/winter months when conditions become increasingly dangerous. The purpose of this study was to define the injury and patient demographics of severe trauma that occurs during falls associated with the installation of Christmas lights. PATIENTS AND METHODS: All patients who were admitted to a referral level 1 trauma center (2002-2012) with severe injuries (ISS≥12) caused during Christmas light installation were retrospectively reviewed. Standard statistical methodology was utilised (p<0.05=significant). RESULTS: A total of 40 patients were severely injured (95% male; mean age=55 years; mean ISS=25.7 (range: 12-75)) while installing Christmas lights. Injuries included: neurologic (68%), thoracic (68%), spinal (43%), extremity (40%), and multiple other sites. Fall mechanisms were: ladder (65%), roof (30%), ground (3%) and railing (3%). Interventions included intubation and critical care (20%), as well as orthopaedic and neurosurgical operative repairs (30%). The median length of hospital stay was 15.6 days (range: 2-165). The fall-related morbidity (28%) and mortality (5%) were significant with a total of 12.5% patients requiring transfer to a long-term care or rehabilitation facility. CONCLUSIONS: Falls while installing Christmas lights during the fall/winter seasons can result in severe life-altering injuries with considerable morbidity and mortality. Caution should be employed when installing lights at any height.

Disruption of lipid domain organization in monolayers of complex yeast lipid extracts induced by the lysophosphatidylcholine analogue edelfosine in vivo.

The lysophosphatidylcholine analogue edelfosine is a potent antitumor and antiparasitic drug that targets cell membranes. Previous studies have shown that edelfosine alters membrane domain organization inducing internalization of sterols and endocytosis of plasma membrane transporters. These early events affect signaling pathways that result in cell death. It has been shown that edelfosine preferentially partitions into more rigid lipid domains in mammalian as well as in yeast cells. In this work we aimed at investigating the effect of edelfosine on membrane domain organization using monolayers prepared from whole cell lipid extracts of cells treated with edelfosine compared to control conditions. In Langmuir monolayers we were able to detect important differences to the lipid packing of the membrane monofilm. Domain formation visualized by means of Brewster angle microscopy also showed major morphological changes between edelfosine treated versus control samples. Importantly, edelfosine resistant cells defective in drug uptake did not display the same differences. In addition, co-spread samples of control lipid extracts with edelfosine added post extraction did not fully mimic the results obtained with lipid extracts from treated cells. Altogether these results indicate that edelfosine induces changes in membrane domain organization and that these changes depend on drug uptake. Our work also validates the use of monolayers derived from complex cell lipid extracts combined with Brewster angle microscopy, as a sensitive approach to distinguish between conditions associated with susceptibility or resistance to lysophosphatidylcholine analogues.

The diagnostic pathway for solid pancreatic neoplasms: are we applying too many tests?

BACKGROUND: The single best diagnostic and staging test for pancreatic cancer remains a contrast-enhanced computed tomography scan. It is frequently the only imaging test required before surgical resection for solid pancreatic lesions. Unfortunately, many patients undergo additional testing that often delays definitive care. MATERIALS AND METHODS: A retrospective review of all patients with solid pancreatic lesions concerning for adenocarcinoma referred to a high volume Hepato-Pancreato-Biliary (HPB) service over 4 y (2008-2012) was completed. The time intervals between the initial imaging test and both consultation with HPB surgery and operative intervention, as well as the number of additional tests, were evaluated. Standard statistical methodology was used (P < 0.05). RESULTS: Among 130 patients with solid pancreatic lesions, the index imaging modality was ultrasonography and computed tomography for 75 (58%) and 52 (40%), respectively. Patients underwent a mean of 1.3 diagnostic tests after the index study and before consultation with HPB surgery (range: 0-5). There was a significant increase in time to HPB consultation and operative intervention with an increasing number of interval imaging tests. The mean time to surgical consultation and operation if 0 interval diagnostic tests were performed was 15.9 and 45.4 d, respectively. If four interval tests were conducted, the mean was 69.4 and 122.6 d, respectively. Sixty-two patients (48%) were initially referred to a nonsurgical service. The mean time to surgical consultation and operation if an intervening referral occurred was 36.6 and 66.8 d, respectively. This compares to 19.8 and 48.1 d, respectively, in cases of direct referral to an HPB surgeon. The mean number of diagnostic tests performed before HPB consultation if a nonsurgical referral occurred was 2.1 (versus 0.7 if direct HPB surgeon referral). CONCLUSIONS: Despite a relatively simple algorithm for the investigation of solid pancreatic lesions, considerable heterogeneity remains in how these patients are evaluated before referral to HPB surgery. As the number of investigations increases after the index imaging test, there is increasing delay to both surgical consultation and definitive intervention. Education is required to expedite care and mitigate excess diagnostic tests.

Importance of Arg-599 of ß-galactosidase (Escherichia coli) as an anchor for the open conformations of Phe-601 and the active-site loop.

Structural and kinetic data show that Arg-599 of ß-galactosidase plays an important role in anchoring the "open" conformations of both Phe-601 and an active-site loop (residues 794-803). When alanine was substituted for Arg-599, the conformations of Phe-601 and the loop shifted towards the "closed" positions because interactions with the guanidinium side chain were lost. Also, Phe-601, the loop, and Na+, which is ligated by the backbone carbonyl of Phe-601, lost structural order, as indicated by large B-factors. IPTG, a substrate analog, restored the conformations of Phe-601 and the loop of R599A-ß-galactosidase to the open state found with IPTG-complexed native enzyme and partially reinstated order. ᴅ-Galactonolactone, a transition state analog, restored the closed conformations of R599A-ß-galactosidase to those found with ᴅ-galactonolactone-complexed native enzyme and completely re-established the order. Substrates and substrate analogs bound R599A-ß-galactosidase with less affinity because the closed conformation does not allow substrate binding and extra energy is required for Phe-601 and the loop to open. In contrast, transition state analog binding, which occurs best when the loop is closed, was several-fold better. The higher energy level of the enzyme•substrate complex and the lower energy level of the first transition state means that less activation energy is needed to form the first transition state and thus the rate of the first catalytic step (k2) increased substantially. The rate of the second catalytic step (k3) decreased, likely because the covalent form is more stabilized than the second transition state when Phe-601 and the loop are closed. The importance of the guanidinium group of Arg-599 was confirmed by restoration of conformation, order, and activity by guanidinium ions.