Evolution of the Surgical Residency System in Switzerland: An In-Depth Analysis Over 15 Years.

BACKGROUND: The landscape of surgical training has been subject to many changes over the past 15 years. This study examines resident satisfaction, determinants of satisfaction, demographics, working hours and the teaching rate of common operations in a longitudinal fashion with the aim to identify trends, shortcomings and possible ways to improve the current training system. METHODS: The Swiss Medical Association administers an annual survey to all Swiss residents to evaluate the quality of postgraduate medical training (yearly respondents: 687-825, response rate: 68-72%). Teaching rates for general surgical procedures were obtained from the Swiss association for quality management in surgery. RESULTS: During the study period (2003-2018), the number of surgical residents (408-655 (+61%)) and graduates in general surgery per year (42-63 (+50%)) increased disproportionately to the Swiss population. While the 52 working hour restriction was introduced in 2005 reported average weekly working hours did not decline (59.9-58.4 h (-3%)). Workplace satisfaction (6 being highest) rose from 4.3 to 4.6 (+7%). Working climate and leadership culture were the main determinants for resident satisfaction. The proportion of taught basic surgical procedures fell from 24.6 to 18.9% (-23%). CONCLUSIONS: The number of residents and graduates in general surgery has risen markedly. At the same time, the proportion of taught operations is diminishing. Despite the introduction of working hour restrictions, the self-reported hours never reached the limit. The low teaching rate combined with the increasing resident number represents a major challenge to the maintenance of the current training quality.

JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice.

BACKGROUND & AIMS: To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (associating liver partition and portal vein ligation for staged hepatectomy [coined ALPPS]) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. METHODS: ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. c-Jun N-terminal kinase (JNK1 [Mapk8]) activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK1 diminution to substantiate their relationship during accelerated liver regeneration. RESULTS: Transcriptomic analysis linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in alpha-smooth muscle actin-positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. CONCLUSIONS: JNK1-mediated induction of IHH paracrine signaling from hepatic stellate cells is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. LAY SUMMARY: Associating liver partition and portal vein ligation for staged hepatectomy (so called ALPPS), is a new two-staged approach to hepatectomy, which induces an unprecedented acceleration of liver regeneration, enabling treatment of patients with liver tumors that would otherwise be considered unresectable. Herein, we demonstrate that JNK1-IHH signaling from stellate cells is a key mechanism underlying the regenerative acceleration that is induced by ALPPS.

PTEN Down-Regulation Promotes ß-Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice.

In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration-associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is a key inhibitor of the protein kinase B/mammalian target of rapamycin axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, whereas its role in regenerating liver remains unknown. Here, we show that PTEN down-regulation promotes liver growth in a TRAS-dependent way. In wild-type mice, PTEN reduction occurred after TRAS formation, persisted during its disappearance, and correlated with up-regulated ß-oxidation at the expense of lipogenesis. Pharmacological modulation revealed an association of PTEN with TRAS turnover and hypertrophic liver growth. In liver-specific Pten-/- mice shortly after induction of knockout, hypertrophic regeneration was accelerated and led to hepatomegaly. The resulting surplus liver mass was functional, as demonstrated by raised survival in a lethal model of resection-induced liver failure. Indirect calorimetry revealed lipid oxidation as the primary energy source early after hepatectomy. The shift from glucose to lipid usage was pronounced in Pten-/- mice and correlated with the disappearance of TRAS. Partial inhibition of ß-oxidation led to persisting TRAS in Pten-/- mice and abrogated hypertrophic liver growth. PTEN down-regulation may promote ß-oxidation through ß-catenin, whereas hypertrophy was dependent on mammalian target of rapamycin complex 1. CONCLUSION: PTEN down-regulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017;66:908-921).

Hedgehog pathway mediates early acceleration of liver regeneration induced by a novel two-staged hepatectomy in mice.

BACKGROUND & AIMS: ALPPS, a novel two-staged approach for the surgical removal of large/multiple liver tumors, combines portal vein ligation (PVL) with parenchymal transection. This causes acceleration of compensatory liver growth, enabling faster and more extensive tumor removal. We sought to identify the plasma factors thought to mediate the regenerative acceleration following ALPPS. METHODS: We compared a mouse model of ALPPS against PVL and additional control surgeries (n=6 per group). RNA deep sequencing was performed to identify candidate molecules unique to ALPPS liver (n=3 per group). Recombinant protein and a neutralizing antibody combined with appropriate surgeries were used to explore candidate functions in ALPPS (n=6 per group). Indian hedgehog (IHH/Ihh) levels were assessed in human ALPPS patient plasma (n=6). RESULTS: ALPPS in mouse confirmed significant acceleration of liver regeneration relative to PVL (p<0.001). Ihh mRNA, coding for a secreted ligand inducing hedgehog signaling, was uniquely upregulated in ALPPS liver (p<0.001). Ihh plasma levels rose 4h after surgery (p<0.01), along with hedgehog pathway activation and subsequent cyclin D1 induction in the liver. When combined with PVL, Ihh alone was sufficient to induce ALPPS-like acceleration of liver growth. Conversely, blocking Ihh markedly inhibited the accelerating effects of ALPPS. In the small cohort of ALPPS patients, IHH tended to be elevated early after surgery. CONCLUSIONS: Ihh and hedgehog pathway activation provide the first mechanistic insight into the acceleration of liver regeneration triggered by ALPPS surgery. The accelerating potency of recombinant Ihh, and its potential effect in human ALPPS may lead to a clinical role for this protein. LAY SUMMARY: ALPPS, a novel two-staged hepatectomy, accelerates liver regeneration, thereby helping to treat patients with otherwise unresectable liver tumors. The molecular mechanisms behind this accelerated regeneration are unknown. Here, we elucidate that Indian hedgehog, a secreted ligand important for fetal development, is a crucial mediator of the regenerative acceleration triggered by ALPPS surgery.

ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration.

OBJECTIVES: To develop a reproducible animal model mimicking a novel 2-staged hepatectomy (ALPPS: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy) and explore the underlying mechanisms. BACKGROUND: ALPPS combines portal vein ligation (PVL) with liver transection (step I), followed by resection of the deportalized liver (step II) within 2 weeks after the first surgery. This approach induces accelerated hypertrophy of the liver remnant to enable resection of massive tumor load. To explore the underlying mechanisms, we designed the first animal model of ALPPS in mice. METHODS: The ALPPS group received 90% PVL combined with parenchyma transection. Controls underwent either transection or PVL alone. Regeneration was assessed by liver weight and proliferation-associated molecules. PVL-treated mice were subjected to splenic, renal, or pulmonary ablation instead of hepatic transection. Plasma from ALPPS-treated mice was injected into mice after PVL. Gene expression of auxiliary mitogens in mouse liver was compared to patients after ALPPS or PVL. RESULTS: The hypertrophy of the remnant liver after ALPPS doubled relative to PVL, whereas mice with transection alone disclosed minimal signs of regeneration. Markers of hepatocyte proliferation were 10-fold higher after ALPPS, when compared with controls. Injury to other organs or ALPPS-plasma injection combined with PVL induced liver hypertrophy similar to ALPPS. Early initiators of regeneration were significantly upregulated in human and mice. CONCLUSIONS: ALPPS in mice induces an unprecedented degree of liver regeneration, comparable with humans. Circulating factors in combination with PVL seem to mediate enhanced liver regeneration, associated with ALPPS.

Impact of restrictive intravenous fluid replacement and combined epidural analgesia on perioperative volume balance and renal function within a Fast Track program.

BACKGROUND AND OBJECTIVE: Key factors of Fast Track (FT) programs are fluid restriction and epidural analgesia (EDA). We aimed to challenge the preconception that the combination of fluid restriction and EDA might induce hypotension and renal dysfunction. METHODS: A recent randomized trial (NCT00556790) showed reduced complications after colectomy in FT patients compared with standard care (SC). Patients with an effective EDA were compared with regard to hemodynamics and renal function. RESULTS: 61/76 FT patients and 59/75 patients in the SC group had an effective EDA. Both groups were comparable regarding demographics and surgery-related characteristics. FT patients received significantly less i.v. fluids intraoperatively (1900 mL [range 1100-4100] versus 2900 mL [1600-5900], P < 0.0001) and postoperatively (700 mL [400-1500] versus 2300 mL [1800-3800], P < 0.0001). Intraoperatively, 30 FT compared with 19 SC patients needed colloids or vasopressors, but this was statistically not significant (P = 0.066). Postoperative requirements were low in both groups (3 versus 5 patients; P = 0.487). Pre- and postoperative values for creatinine, hematocrit, sodium, and potassium were similar, and no patient developed renal dysfunction in either group. Only one of 82 patients having an EDA without a bladder catheter had urinary retention. Overall, FT patients had fewer postoperative complications (6 versus 20 patients; P = 0.002) and a shorter median hospital stay (5 [2-30] versus 9 d [6-30]; P< 0.0001) compared with the SC group. CONCLUSIONS: Fluid restriction and EDA in FT programs are not associated with clinically relevant hemodynamic instability or renal dysfunction.

Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the model for end-stage liver disease era.

OBJECTIVES: To design a new score on risk assessment for orthotopic liver transplantation (OLT) based on both donor and recipient parameters. BACKGROUND: The balance of waiting list mortality and posttransplant outcome remains a difficult task in the era of the model for end-stage liver disease (MELD). METHODS: Using the United Network for Organ Sharing database, a risk analysis was performed in adult recipients of OLT in the United States of America between 2002 and 2010 (n = 37,255). Living donor-, partial-, or combined-, and donation after cardiac death liver transplants were excluded. Next, a risk score was calculated (balance of risk score, BAR score) on the basis of logistic regression factors, and validated using our own OLT database (n = 233). Finally, the new score was compared with other prediction systems including donor risk index, survival outcome following liver transplantation, donor-age combined with MELD, and MELD score alone. RESULTS: Six strongest predictors of posttransplant survival were identified: recipient MELD score, cold ischemia time, recipient age, donor age, previous OLT, and life support dependence prior to transplant. The new balance of risk score stratified recipients best in terms of patient survival in the United Network for Organ Sharing data, as in our European population. CONCLUSIONS: The BAR system provides a new, simple and reliable tool to detect unfavorable combinations of donor and recipient factors, and is readily available before decision making of accepting or not an organ for a specific recipient. This score may offer great potential for better justice and utility, as it revealed to be superior to recent developed other prediction scores.

A fast-track program reduces complications and length of hospital stay after open colonic surgery.

BACKGROUND & AIMS: A fast-track program is a multimodal approach for patients undergoing colonic surgery that combines stringent regimens of perioperative care (fluid restriction, optimized analgesia, forced mobilization, and early oral feeding) to reduce perioperative morbidity, hospital stay, and cost. We investigated the impact of a fast-track protocol on postoperative morbidity in patients after open colonic surgery. METHODS: A randomized trial of patients in 4 teaching hospitals in Switzerland included 156 patients undergoing elective open colonic surgery who were assigned to either a fast-track program or standard care. The primary end point was the 30-day complication rate. Secondary end points were severity of complications, hospital stay, and compliance with the fast-track protocol. RESULTS: The fast-track protocol significantly decreased the number of complications (16 of 76 in the fast-track group vs 37 of 75 in the standard care group; P = .0014), resulting in shorter hospital stays (median, 5 days; range, 2-30 vs 9 days, respectively; range, 6-30; P < .0001). There was a trend toward less severe complications in the fast-track group. A multiple logistic regression analysis revealed fluid administration greater than the restriction limits (odds ratio, 4.198; 95% confidence interval, 1.7-10.366; P = .002) and a nonfunctioning epidural analgesia (odds ratio, 3.365; 95% confidence interval, 1.367-8.283; P = .008) as independent predictors of postoperative complications. CONCLUSIONS: The fast-track program reduces the rate of postoperative complications and length of hospital stay and should be considered as standard care. Fluid restriction and an effective epidural analgesia are the key factors that determine outcome of the fast-track program.

Kidney transplantation in mice using left and right kidney grafts.

BACKGROUND: Mouse kidney transplantation is a powerful tool for scientific research. The conventional method uses only the left donor kidney for grafting because of shorter renal vessels on the right side. MATERIALS AND METHODS: We developed a new technique of harvesting both left and right kidneys from one donor mouse, and separately transplanted them into two recipients. Forty-six kidney grafts (23 left, 23 right kidneys) were transplanted to 46 recipient mice. Life-supporting kidney transplantation (in which both recipient kidneys were removed) was performed in 12 recipients (six of each group). RESULTS: Cold ischemia times were considerably longer for the second kidney graft (2.5-3 versus 1 h), which resulted in reduced graft function at early time points. However, the 14 d survival rate was comparable with 80% for right and 70% for left kidney grafts. Recipient animals were sacrificed between 1 and 6 wk after transplantation. Histologic examination of surviving grafts showed intact renal parenchyma, whereas total necrosis was usually seen in failed grafts. The causes of graft failure were thrombosis of the renal artery, narrow outflow of the renal vein, and fistula of the ureter. In a subgroup of animals, specific staining for apoptosis was performed. A tendency for a higher rate of apoptosis was seen at 1 wk compared with 6 wk post-transplant, but no correlation with cold ischemia time was found. CONCLUSION: We report a new microsurgical technique of mouse kidney transplantation using both right and left donor kidneys as grafts for two recipient mice. Right kidney grafts showed equal survival compared with left kidney grafts. Thus, this technique reduces overall operating time and costs for microsurgery experiments.

The Clavien-Dindo classification of surgical complications: five-year experience.

BACKGROUND AND AIMS: The lack of consensus on how to define and grade adverse postoperative events has greatly hampered the evaluation of surgical procedures. A new classification of complications, initiated in 1992, was updated 5 years ago. It is based on the type of therapy needed to correct the complication. The principle of the classification was to be simple, reproducible, flexible, and applicable irrespective of the cultural background. The aim of the current study was to critically evaluate this classification from the perspective of its use in the literature, by assessing interobserver variability in grading complex complication scenarios and to correlate the classification grades with patients', nurses', and doctors' perception. MATERIAL AND METHODS: Reports from the literature using the classification system were systematically analyzed. Next, 11 scenarios illustrating difficult cases were prepared to develop a consensus on how to rank the various complications. Third, 7 centers from different continents, having routinely used the classification, independently assessed the 11 scenarios. An agreement analysis was performed to test the accuracy and reliability of the classification. Finally, the perception of the severity was tested in patients, nurses, and physicians by presenting 30 scenarios, each illustrating a specific grade of complication. RESULTS: We noted a dramatic increase in the use of the classification in many fields of surgery. About half of the studies used the contracted form, whereas the rest used the full range of grading. Two-thirds of the publications avoided subjective terms such as minor or major complications. The study of 11 difficult cases among various centers revealed a high degree of agreement in identifying and ranking complications (89% agreement), and enabled a better definition of unclear situations. Each grade of complications significantly correlated with the perception by patients, nurses, and physicians (P < 0.05, Kruskal-Wallis test). CONCLUSIONS: This 5-year evaluation provides strong evidence that the classification is valid and applicable worldwide in many fields of surgery. No modification in the general principle of classification is warranted in view of the use in ongoing publications and trials. Subjective, inaccurate, or confusing terms such as "minor or major" should be removed from the surgical literature.

Radiomics of liver MRI predict metastases in mice.

BACKGROUND: The purpose of this study was to investigate whether any texture features show a correlation with intrahepatic tumor growth before the metastasis is visible to the human eye. METHODS: Eight male C57BL6 mice (age 8-10 weeks) were injected intraportally with syngeneic MC-38 colon cancer cells and two mice were injected with phosphate-buffered saline (sham controls). Small animal magnetic resonance imaging (MRI) at 4.7 T was performed at baseline and days 4, 8, 12, 16, and 20 after injection applying a T2-weighted spin-echo sequence. Texture analysis was performed on the images yielding 32 texture features derived from histogram, gray-level co-occurrence matrix, gray-level run-length matrix, and gray-level size-zone matrix. The features were examined with a linear regression model/Pearson correlation test and hierarchical cluster analysis. From each cluster, the feature with the lowest variance was selected. RESULTS: Tumors were visible on MRI after 20 days. Eighteen features from histogram and the gray-level-matrices exhibited statistically significant correlations before day 20 in the experiment group, but not in the control animals. Cluster analysis revealed three distinct clusters of independent features. The features with the lowest variance were Energy, Short Run Emphasis, and Gray Level Non-Uniformity. CONCLUSIONS: Texture features may quantitatively detect liver metastases before they become visually detectable by the radiologist.

Indicating ALPPS for Colorectal Liver Metastases: A Critical Analysis of Patients in the International ALPPS Registry.

OBJECTIVES: In the international associating liver partition and portal vein ligation for staged hepatectomy registry, more than 50% of patients underwent associating liver partition and portal vein ligation for staged hepatectomy with a right hepatectomy. This study evaluated the necessity of two-stage hepatectomies being performed as right hepatectomy associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases versus right trisectionectomy associating liver partition and portal vein ligation for staged hepatectomy. PATIENTS AND METHODS: All patients registered between 2012 and 2017 undergoing associating liver partition and portal vein ligation for staged hepatectomy for colorectal liver metastases were included. A liver to body weight index of 0.5 or less prior to stage I in the presence of liver damage was used as an internationally accepted standard to justify a two-stage hepatectomy. RESULTS: Four-hundred and three patients with colorectal liver metastases with right hepatectomy associating liver partition and portal vein ligation for staged hepatectomy (n = 183) or right trisectionectomy associating liver partition and portal vein ligation for staged hepatectomy (n = 220) were analyzed. Presence of metastases in segments II/III, liver damage, number of patients on chemotherapy, and cycles were comparable, and there was a comparable response to chemotherapy. Liver to body weight index was different prior to stage 1 (right trisectionectomy associating liver partition and portal vein ligation for staged hepatectomy: 0.33 ± 0.12 versus right hepatectomy associating liver partition and portal vein ligation for staged hepatectomy: 0.40 ± 0,14; P < .001) and prior to stage 2 (right trisectionectomy associating liver partition and portal vein ligation for staged hepatectomy: 0.58 ± 0.17 versus right hepatectomy associating liver partition and portal vein ligation for staged hepatectomy: 0.66 ± 0,18; P < .001). Hypertrophy rates were similar between groups. As much as 16.9% and 7.2% of patients in right hepatectomy associating liver partition and portal vein ligation for staged hepatectomy and right trisectionectomy associating liver partition and portal vein ligation for staged hepatectomy had no apparent justification for a two-stage hepatectomy based on LBWI prior to stage 1 and absence of chemotherapy (<12 cycles). CONCLUSION: More than 15% of associating liver partition and portal vein ligation for staged hepatectomy procedures were performed in patients who may have had no indication for a two-stage hepatectomy, especially in the group of patients with right hepatectomy. Thus, it appears that there is a risk of the overuse of associating liver partition and portal vein ligation for staged hepatectomy because of its great potential to induce volume growth. Due to the high perioperative risk of associating liver partition and portal vein ligation for staged hepatectomy, indications should be carefully reconsidered.

Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results.

BACKGROUND: Liver transplantation (LTX) recipients with renal dysfunction may benefit from mycophenolate mofetil (MMF) and reduction or discontinuation of nephrotoxic calcineurin inhibitors (CNI). The authors report the first randomized, multicenter pilot studies of this approach (one study for patients on cyclosporine [CsA] and one for those on tacrolimus [Tac]). METHODS: Patients 3 to 27 months post-LTX with greater than 20% reduced renal function since LTX, and creatinine 1.8 to 4.0 mg/dL, creatinine clearance 20 to 60 mL/min, or both, were randomized to discontinuation (group 1) or 50% reduction (group 2) of CNI dose, together with MMF 1.5 g administered twice daily and prednisone. Endpoints included measured glomerular filtration rate (GFR) 52 weeks after study entry and biopsy-proven rejection. RESULTS: In the CsA and Tac trials, 15 and 12 patients, respectively, completed the 52-week follow-up. In the CsA trial, the mean GFR at baseline and week 52 were 35.0 and 57.8 mL/min (>15% improvement, five of six; unchanged, one of six) for group 1 and 46.0 and 63.8 mL/min (>15% improvement, four of nine; unchanged, three of nine; >15% deterioration, two of nine) for group 2. In the Tac trial, GFRs were 55.4 and 56.0 mL/min (>15% improvement, two of five; unchanged, three of five) for group 1 and 46.7 and 60.2 mL/min (>15% improvement, four of seven; unchanged, three of seven) for group 2. Mild or moderate rejection occurred in 38% and 9% of patients in groups 1 and 2 of the CsA trial and in 14% of each group of the patients in the Tac trial. CONCLUSIONS: These pilot studies show that in LTX recipients with renal dysfunction, MMF allows CNI dose reduction or discontinuation, improving or stabilizing GFR in most patients.