Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial.

BACKGROUND AND AIMS: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial. APPROACH AND RESULTS: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Defining the Disparity: A Multi-Institutional Analysis of Factors Associated With Decreased Resident Operative Experience.

INTRODUCTION: Technical learning in surgical training is multifaceted and existing literature suggests a positive relationship between case volume and proficiency. Little is known about factors associated with a decreased volume of operative experience. This study aimed to identify resident and program factors associated with general surgery residents (GSR) in the bottom quartile of logged case volume upon program completion. METHODS: A post hoc analysis of a multicenter study was used to examine case logs for categorical GSR. Participants included graduates between 2010 and 2020 from 20 programs. Residents below and above the 25th percentile for total operative volume were compared. RESULTS: The present study includes 1343 GSR who graduated over the 11-y period. In total, 336 residents were below the 25th percentile and 1007 residents were above the 25th percentile. Those below the 25th percentile were more likely to be female (41% versus 34%, P = 0.02), identify as underrepresented in medicine (22% versus 14%, P < 0.01), and pursue fellowship (86% versus 80%, P = 0.01) compared to those above the 25th percentile. Residents below the 25th percentile were more likely to have graduated from a low volume program (55% versus 25%, P < 0.01) and from top National Institutes of Health funded institutions (57% versus 52%, P = 0.01). CONCLUSIONS: This study identified individual and program characteristics associated with lower operative volume of GSR. Understanding such characteristics will aid surgical educators to achieve better equity in training.

A National Assessment of T2 Staging for Intrahepatic Cholangiocarcinoma and the Poor Prognosis Associated with Multifocality.

BACKGROUND: T2 intrahepatic cholangiocarcinoma (ICC) is defined as a solitary tumors with vascular invasion or multifocal tumors including satellite lesions, multiple lesions, and intrahepatic metastases. This study aimed to evaluate the prognosis associated with multifocal tumors. METHODS: The National Cancer Database was queried from 2004 to 2017 for patients with non-metastatic ICC. The patients were grouped based on T2 staging, multifocality, and lymph node involvement. RESULTS: The study enrolled and classified 4887 patients into clinical (c) stage groups as follows: 15.2% with solitary T2N0 (sT2N0) tumors, 21.3% with multifocal T2N0 (mT2N0) tumors, and 63.5% with node-positive (TxN1) disease. Patients with (c)sT2N0 tumors had higher rates of surgical resection than those with (c)mT2N0 or (c)TxN1 disease (33.5% vs 19.7% vs 15.0%; p < 0.01). Median overall survival (OS) was better for the patients with (c)sT2N0 tumors than for those with multifocal and node-positive disease (15.4 vs 10.4 vs 10.4 months; p < 0.01). On multivariate analysis, (c)sT2N0 tumors were associated with better OS than (c)mT2N0 tumors [hazard ratio (HR), 1.31; 95% confidence interval (CI), 1.17-1.46; p < 0.01] or (c)TxN1 disease (HR,1.41; 95% CI 1.28-1.56; p < 0.01). In a subset analysis based on pathologic (p) staging of patients who underwent surgical resection with regional lymphadenectomy, multivariate analysis demonstrated that (p)sT2N0 tumors were associated with better OS than (p)mT2N0 tumors (HR,1.40; 95% CI 1.03-1.92; p = 0.03) or (p)TxN1 disease (HR, 2.05; 95% CI 1.62-2.58; p < 0.01). CONCLUSIONS: Multifocal T2N0 ICC is associated with poor OS and has a disparate prognosis compared with solitary T2N0 disease, even among patients who undergo resection. Future staging criteria should account for the poor outcomes associated with multifocal ICC.

Hypothermic machine perfusion in liver transplantation.

A finite supply of donor organs has led many transplant centers to accept marginal liver allografts with increasing frequency. These allografts may be at higher risk of primary nonfunction, early allograft dysfunction, and other recipient complications following liver transplantation. Machine perfusion preservation is an emerging technology that limits ischemia/reperfusion injury associated with preservation and may lead to improved outcomes following transplantation. Increased used of machine perfusion in liver preservation may permit an expansion of the donor pool. In this review, we examine the major clinical experience of hypothermic machine perfusion in human liver transplantation.Liver Transplantation 24 276-281 2018 AASLD.

Not all operative experiences are created equal: a 19-year analysis of a single center's case logs.

BACKGROUND: Although national operative volumes have remained stable, surgical educators should appreciate the changing experience of today's surgical residents. We set out to evaluate operative volume trends at our institution and study the impact of resident learning styles on operative experience. MATERIALS AND METHODS: The Accreditation Council for Graduate Medical Education operative log data from 1999 to 2017 for a single general surgery residency program were examined. All residents completed the Kolb Learning Style Inventory. Statistical analyses were performed using linear regression analysis, Student's t-test, and Fischer's exact test. RESULTS: Over the study period, 106 general surgery residents graduated from our program. There were 87% action learners and 13% observation learners. Although there was no change in total major, total chief, or total non-chief cases, a decrease in teaching assistant cases was observed. Subcategory analysis revealed that there was an increase in operative volume on graduation in the following categories: skin, soft tissue, and breast; alimentary tract; abdomen; pancreas; operative trauma; pediatric; basic laparoscopy; complex laparoscopy; and endoscopy with a concurrent decrease in liver, vascular, and endocrine. Learning style analysis found that action learners completed significantly more cases than observation learners in most domains in which operative volume increased. CONCLUSIONS: While the operative volume at our center remained stable over the study period, the experience of general surgery residents has become narrowed toward a less subspecialized, general surgery experience. These shifts may disproportionally impact trainees as observation learners operate less than action learners. Residency programs should therefore incorporate methods such as learning style assessment to identify residents at risk of a suboptimal experience.

Variation by center and economic burden of readmissions after liver transplantation.

The rate and causes of hospital readmissions after liver transplantation (LT) remain largely unknown in the United States. Adult patients (n = 11,937; 43.1% of all LT cases) undergoing LT from 2007 to 2011 were examined with a linkage of the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases to determine the incidence and risk factors for 30-day readmissions and utilization metrics 90 days after LT. The overall 30-day hospital readmission rate after LT was 37.9%, with half of patients admitted within 7 days after discharge. Readmitted patients had worse overall graft and patient survival with a 2-year follow-up. Multivariate analysis identified risk factors associated with 30-day hospital readmission, including a higher Model for End-Stage Liver Disease score, diabetes at LT, dialysis dependence, a high donor risk index allograft, and discharge to a rehabilitation facility. After adjustments for donor, recipient, and geographic factors in a hierarchical model, we found significant variation in readmission rates among hospitals ranging from 26.3% to 50.8% (odds ratio, 0.53-1.90). In the 90-day analysis after LT, readmissions accounted for $43,785 of added costs in comparison with patients who were not readmitted in the first 90 days. This is the first national report showing that more than one-third of LT recipients are readmitted to their center within 30 days and that readmissions are associated with center variation and increased resource utilization.

Impact of recipient morbid obesity on outcomes after liver transplantation.

The aim of this study was to analyze the impact of morbid obesity in recipients on peritransplant resource utilization and survival outcomes. Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 12 445 patients who underwent liver transplantation (LT) between 2007 and 2011 and divided them into two cohorts based on recipient body mass index (BMI; <40 vs. ≥40 kg/m²). Recipients with BMI ≥40 comprised 3.3% (n = 416) of all LTs in the studied population. There were no significant differences in donor characteristics between two groups. Recipients with BMI ≥40 were significant for being female, diabetic, and with NASH cirrhosis. Patients with a BMI ≥40 had a higher median MELD score, limited physical capacity, and were more likely to be hospitalized at LT. BMI ≥40 recipients had higher post-LT length of stay and were less often discharged to home. With a median follow-up of 2 years, patient and graft survival were equivalent between the two groups. In conclusion, morbidly obese LT recipients appear sicker at time of LT with an increase in resource utilization but have similar short-term outcomes.

Neighborhood level effects of socioeconomic status on liver transplant selection and recipient survival.

BACKGROUND & AIMS: Previous studies have reported that patients of higher socioeconomic status (SES) have increased access to liver transplantation and reduced waitlist mortality than patients of lower SES. However, little is known about the association between SES and outcomes after liver transplantation. METHODS: By using a link between the University HealthSystem Consortium and the Scientific Registry of Transplant Recipients databases, we identified 12,445 patients who underwent liver transplantation from 2007 through 2011. We used a proportional hazards model to assess the effect of SES on patient survival, controlling for characteristics of recipients, donors, geography, and center. RESULTS: Compared with liver recipients in the lowest SES quintile, those in the highest quintile were more likely to be male, Caucasian, have private insurance, and undergo transplantation when they had lower Model for End-Stage Liver Disease scores. In proportional hazards model analysis, liver recipients of the lowest SES were at an increased risk for death within a median of 2 years after transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02-1.35). CONCLUSIONS: Patients of lower SES appear to face barriers to liver transplantation, but perioperative outcomes (length of stay, in-hospital mortality, or 30-day readmission) do not differ significantly from those of patients of higher SES. However, fewer patients of low SES survive for 2 years after transplantation, independent of features of the recipient, donor, surgery center, or location.

Is liver transplantation safe and effective in elderly (≥70 years) recipients? A case-controlled analysis.

BACKGROUND: Elderly patients are evaluated for liver transplantation (LT) with increasing frequency, but outcomes in this group have not been well defined. METHODS: A linkage of the Scientific Registry of Transplant Recipients (SRTR) and the University HealthSystem Consortium (UHC) databases identified 12,445 patients who underwent LT during 2007-2011. Two cohorts were created consisting of, respectively, elderly recipients aged ≥70 years (n = 323) and recipients aged 18-69 years (n = 12,122). A 1:1 case-matched analysis was performed based on propensity scores. RESULTS: Elderly recipients had lower Model for End-stage Liver Disease (MELD) scores at LT (median 15 versus 19; P < 0.0001), more often underwent transplantation at high-volume centres (46% versus 33%; P < 0.0001) and more often received grafts from donors aged >60 years (24% versus 15%; P < 0.0001). The two cohorts had similar hospital lengths of stay, in-hospital mortality, hospital costs and 30-day readmission rates. There were no differences in graft survival between the two cohorts (P = 0.10), but elderly recipients had worse longterm overall survival (P = 0.009). However, a case-controlled analysis confirmed similar perioperative hospital outcomes, graft survival and longterm patient survival in the two matched cohorts. CONCLUSIONS: Elderly LT recipients accounted for <3% of all LTs performed during 2007-2011. Selected elderly recipients have perioperative outcomes and survival similar to those in younger adults.

Cost effectiveness after a pancreaticoduodenectomy: bolstering the volume argument.

BACKGROUND: The cost implication of variability in pancreatic surgery is not well described. It was hypothesized that for a pancreaticoduodenectomy (PD), lower volume centres demonstrate worse peri-operative outcomes at higher costs. METHODS: From 2009-2011, 9883 patients undergoing a PD were identified from the University HealthSystems Consortium (UHC) database and stratified into quintiles by annual hospital case volume. A decision analytic model was constructed to assess cost effectiveness. Total direct cost data were based on Medicare cost/charge ratios and included readmission costs when applicable. RESULTS: The lowest volume centres demonstrated a higher peri-operative mortality rate (3.5% versus 1.3%, P < 0.001) compared with the highest volume centres. When both index and readmission costs were considered, the per-patient total direct cost at the lowest volume centres was $23,005, or 10.9% (i.e. $2263 per case) more than at the highest volume centres. One-way sensitivity analyses adjusting for peri-operative mortality (1.3% at all centres) did not materially change the cost effectiveness analysis. Differences in cost were largely recognized in the index admission; readmission costs were similar across quintiles. CONCLUSIONS: For PD, low volume centres have higher peri-operative mortality rates and 10.9% higher cost per patient. Performance of PD at higher volume centres can lead to both better outcomes and substantial cost savings.

Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice.

UNLABELLED: Interleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. In the current study, we sought to determine whether IL-33 is an important regulator in the hepatic response to ischemia/reperfusion (I/R). Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia, followed by up to 8 hours of reperfusion. Some mice received recombinant IL-33 (IL-33) intraperitoneally (IP) before surgery or anti-ST2 antibody IP at the time of reperfusion. Primary hepatocytes and Kupffer cells were isolated and treated with IL-33 to assess the effects of IL-33 on inflammatory cytokine production. Primary hepatocytes were treated with IL-33 to assess the effects of IL-33 on mediators of cell survival in hepatocytes. IL-33 protein expression increased within 4 hours after reperfusion and remained elevated for up to 8 hours. ST2L protein expression was detected in healthy liver and was up-regulated within 1 hour and peaked at 4 hours after I/R. ST2L was primarily expressed by hepatocytes, with little to no expression by Kupffer cells. IL-33 significantly reduced hepatocellular injury and liver neutrophil accumulation at 1 and 8 hours after reperfusion. In addition, IL-33 treatment increased liver activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinase (MAPK), cyclin D1, and B-cell lymphoma 2 (Bcl-2), but reduced serum levels of CXC chemokines. In vitro experiments demonstrated that IL-33 significantly reduced hepatocyte cell death as a result of increased NF-κB activation and Bcl-2 expression in hepatocytes. CONCLUSION: The data suggest that IL-33 is an important endogenous regulator of hepatic I/R injury. It appears that IL-33 has direct protective effects on hepatocytes, associated with the activation of NF-κB, p38 MAPK, cyclin D1, and Bcl-2 that limits liver injury and reduces the stimulus for inflammation.

Microsatellite instability is associated with worse overall survival in resectable colorectal liver metastases.

BACKGROUND: Microsatellite instability (MSI) has been associated with improved overall survival (OS) in locoregional colorectal cancer; however, the effects on colorectal liver metastases (CRLM) have not been studied. METHODS: The National Cancer Database (NCDB) was queried for patients with CRLM that underwent metastasectomy. Patients with microsatellite stable tumors (MSS) (n = 2,316, 84.4%) were compared those with MSI (n = 427, 15.6%). RESULTS: Baseline characteristics, including sex, race, and underlying comorbidities, were similar between groups. MSS patients had lower rates of high-risk pathologic features and higher rates of receiving multi-agent chemotherapy. On Kaplan-Meier analysis, median OS in the MSS group was improved compared with the MSI group (41.1 mo vs. 33.2 mo, p < 0.01). On multivariate analysis MSI status remained associated with worse OS (HR: 1.21 95% CI: 1.01-1.46, p = 0.04). CONCLUSIONS: This national analysis of CRLM validates MSI status as a biomarker to guide clinical decision-making due to the associated poor prognosis.

Experience of surgical subspecialty residents on general surgery rotations.

BACKGROUND: Surgical subspecialty residents complete 5-6 years of training which includes general surgery rotations. A lack of data exists evaluating these rotations. This study aims to identify discrepancies in subspecialty training and improve the quality of surgical education. METHODS: Case logs for surgical subspecialty residents and general surgery residents at our institution were analyzed and queried for cases performed on general surgery rotations. A survey was distributed to subspecialty residents regarding their perceptions of these rotations. RESULTS: 50 residents were included in the study and the majority were male (n = 27, 54%). Subspecialty residents perform fewer cases per month compared to general surgery residents (13 vs 21, p < 0.001). 75% of subspecialty residents were satisfied with their experience on general surgery rotations. CONCLUSIONS: Subspecialty residents perform fewer operations on general surgery rotations. Despite this, most are satisfied with off-service rotations and believe they are an important part of their education.

Utilization and effectiveness of the organ procurement and transplantation network "safety-net" policy.

BACKGROUND: Liver transplant recipients with persistent renal dysfunction may be prioritized on the kidney transplant waitlist based on the Organ Procurement and Transplantation Network "safety-net" policy implemented in 2017. The aim of this study was to evaluate the utilization of kidney transplant and posttransplant outcomes, of liver transplant recipients with persistent renal dysfunction before and after implementation of the Organ Procurement and Transplantation Network kidney safety-net policy and standardization of simultaneous liver-kidney requirements. METHODS: Using the United Network for Organ Sharing database from January 2015 to March 2019, outcomes of liver transplant recipients listed for kidney transplant and the subset who received kidney after liver transplants were compared before and after policy implementation. RESULTS: Liver transplant recipients listed for kidney transplant increased from 58 to 200, and kidney after liver transplants increased from 29.3% to 42.5% after safety-net policy implementation. Post-policy kidney after liver transplants received more local organs (91.8% vs 70.6%, P = .03) and trended toward shorter waitlist time (47 [17-123] vs 84 [37-226] days, P = .051). The pre- and post-policy cohorts had similar (P > .05) kidney donor profile index (0.43 [0.27-0.69] vs 0.42 [0.28-0.58]) and delayed graft function (11.8% vs 14.1%). Patient, kidney graft, and liver graft survival were similar (P > .05) between pre and post-policy cohorts. Patient and kidney graft survival were similar between kidney after liver transplants and propensity score-matched kidney transplant alone recipients. Patient, kidney, and liver graft survival were similar between kidney after liver transplants and propensity score-matched simultaneous liver-kidney transplant recipients. CONCLUSION: This study demonstrates that after Organ Procurement and Transplantation Network "safety-net" policy implementation, there has been an increase in liver transplant recipients with renal dysfunction who are listed for and undergo kidney transplant with excellent short-term results.

Impact of Integrated Thoracic Residency on General Surgery Residents' Thoracic Operative Volume.

BACKGROUND: Integrated thoracic surgery (I-6) programs have become popular over traditional general surgery (GS) pathways since their inception in 2007. However the effect of I-6 programs on GS resident training remains unknown. The purpose of this study was to evaluate the effect of I-6 programs on the thoracic operative experience of co-located GS residents. METHODS: Thoracic surgery cases recorded by residents in GS programs co-located with I-6 programs until 2019 were analyzed. Cases were reviewed 5 years before (TSR-5) through 5 years after (TSR-5) the matriculation of the first thoracic resident in the co-located I-6 program. To contextualize the overall trends in the field Accreditation Council for Graduate Medical Education GS resident case logs from 1990 to 2018 were analyzed and total thoracic surgery cases recorded. Statistical analysis was performed with linear regression. RESULTS: Residents in 19 GS programs with co-located I-6 programs showed an increase in total thoracic cases from 3710 to 4451 (Δ/year of +85.05 cases a year; P = .03) balanced by an increase in GS residents from 107 to 126 (Δ/year of +1.45; P = .01) with no significant overall change in the median thoracic operative case volume (31.00 at both thoracic residency before and after 5 years). Nationally from 1990 to 2018 there was no change in the total thoracic operative experience for GS graduates. CONCLUSIONS: The introduction of I-6 programs did not negatively impact thoracic operative experience for residents in co-located GS programs. Adequate training of both I-6 and GS residents at the same institution is feasible.

Where Has All the Complexity Gone? An Analysis of the Modern Surgical Resident Operative Experience.

OBJECTIVES: The operative experience of today's general surgery (GS) residents are changing. The Surgical Council on Resident Education (SCORE) was founded to provide a standardized, competency-based curriculum. We set out to evaluate resident operative experience in core and advanced operations. DESIGN: Accreditation Council for Graduate Medical Education (ACGME) national operative log reports from 2010 to 2018 were reviewed. Operative volume data for 344 operations were extracted and analyzed. Operations were designated as core, advanced, or undefined as listed by SCORE, and stratified as GS or subspecialty. SETTING: National analysis utilizing ACGME operative log reports. PARTICIPANTS: All graduating general surgery residents between 2010 and 2018. RESULTS: A total of 10,118 residents completed GS training with an average of 1121.5 ± 29.3 total cases. Core operations comprised 80.5% of total volume while advanced comprised only 8.0%. The total core experience increased (+7.0 cases/year), while total advanced experience decreased (-1.4 cases/year) (p < 0.01 each). Compositional analysis among core operations revealed an increase in 9/13 GS domains and a decrease in 8/10 subspecialty domains (all p < 0.05). CONCLUSIONS: There has been an increase in core operative experience with a concurrent decrease in advanced operative experience of graduating GS residents. These findings highlight the continued narrowing of the operative experience for trainees, with increasing focus on GS and less on subspecialty domains. Ongoing efforts to look beyond operative volume to ensure competency of graduates will prove beneficial.

An analysis of applicant competitiveness to general surgery, surgical subspecialties, and integrated programs.

BACKGROUND: General surgery was once the gateway into a career in surgery. Over time, surgical subspecialties developed separate residency programs, and recently, integrated programs have emerged. It is unknown what impact the presence of surgical subspecialties and integrated programs have had on general surgery. Our objective was to evaluate match trends and quantify competitiveness of the general surgery, integrated programs, and surgical subspecialties matches. METHODS: National Residency Matching Program match data and applicant characteristics from 2010 through 2020 were analyzed for US senior allopathic applicants. Integrated programs were defined as plastic and vascular surgery, and surgical subspecialties were defined as otolaryngology, orthopedic surgery, and neurosurgery. Trends were evaluated using linear regression, programs were compared on 10 metrics by Wilcoxon rank-sum tests, and a logistic regression was used to rank each specialty match. RESULTS: The number of US senior applicants per position to integrated programs decreased and approached that of general surgery and surgical subspecialties, but the median number of applicants per position to general surgery was lower than to surgical subspecialties or integrated programs (1.21 interquartile range). Our logistic regression showed United States Medical Licensing Examination scores, research experience, Alpha Omega Alpha Honor Society membership, and graduation from a top medical school to be the most important factors in the match, and our weighted rank score found general surgery (2.85) to be less competitive than surgical subspecialties (1.92) or integrated programs (1.17). CONCLUSION: Throughout the last decade, integrated programs and surgical subspecialties have matched more competitive applicants based on the most significant predictors of the match. Moving forward, it is important that general surgery strives to attract the best and brightest out of medical school.