Citations

Objective: To define benchmark values for adult-to-adult living-donor liver transplantation (LDLT). Background: LDLT utilizes living-donor hemiliver grafts to expand the donor pool and reduce waitlist mortality. Although references have been established for donor hepatectomy, no such information exists for recipients to enable conclusive quality and comparative assessments. Methods: Patients undergoing LDLT were analyzed in 15 high-volume centers (≥10 cases/year) from 3 continents over 5 years (2016–2020), with a minimum follow-up of 1 year. Benchmark criteria included a Model for End-stage Liver Disease ≤20, no portal vein thrombosis, no previous major abdominal surgery, no renal replacement therapy, no acute liver failure, and no intensive care unit admission. Benchmark cutoffs were derived from the 75th percentile of all centers’ medians. Results: Of 3636 patients, 1864 (51%) qualified as benchmark cases. Benchmark cutoffs, including posttransplant dialysis (≤4%), primary nonfunction (≤0.9%), nonanastomotic strictures (≤0.2%), graft loss (≤7.7%), and redo-liver transplantation (LT) (≤3.6%), at 1-year were below the deceased donor LT benchmarks. Bile leak (≤12.4%), hepatic artery thrombosis (≤5.1%), and Comprehensive Complication Index (CCI ® ) (≤56) were above the deceased donor LT benchmarks, whereas mortality (≤9.1%) was comparable. The right hemiliver graft, compared with the left, was associated with a lower CCI ® score (34 vs 21, P < 0.001). Preservation of the middle hepatic vein with the right hemiliver graft had no impact neither on the recipient nor on the donor outcome. Asian centers outperformed other centers with CCI ® score (21 vs 47, P < 0.001), graft loss (3.0% vs 6.5%, P = 0.002), and redo-LT rates (1.0% vs 2.5%, P = 0.029). In contrast, non-benchmark low-volume centers displayed inferior outcomes, such as bile leak (15.2%), hepatic artery thrombosis (15.2%), or redo-LT (6.5%). Conclusions: Benchmark LDLT offers a valuable alternative to reduce waitlist mortality. Exchange of expertise, public awareness, and centralization policy are, however, mandatory to achieve benchmark outcomes worldwide.

Abstract Background HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes. Methods A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses. Results Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates. Conclusions While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients.

Abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10− 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

11005 Background: Despite progress in the enrollment of underrepresented in medicine (UIM) individuals in medical schools, hematology/oncology (HO) remains one of the least diverse medical subspecialties. We evaluated current recruitment efforts and barriers to the inclusion of UIM individuals in HO fellowship programs. Methods: We conducted a national online survey of program directors (PDs) and associate PDs (reported in aggregate as PDs) of adult and pediatric HO fellowships. Each PD received a unique survey link via email and 4 email reminders over the 8-week study period. Interim results at 4-weeks are presented and summarized with descriptive statistics. Results: At a pre-defined interim time point of 4 weeks, 78 HO PDs participated (18% response rate) and 69 completed the survey (88% completion rate). Most self-identified as women (57%, n = 38) and White (55%, n = 37), were affiliated with an academic program (79%, n = 53), and led an adult HO fellowship (73%, n = 49). Most PDs reported under or no representation of UIM faculty in their divisions; 9% (n = 6) self-identified as UIM. PDs reported their HO fellowships matched a median of 3 UIM fellows over the last 5 years (IQR 2-5 over 5 years); 46% (n = 32) reported UIM recruitment was unchanged and 4% (n = 3) decreased during this period. About half of PDs (51%, n = 35), matched a UIM candidate in the 2023 match. Of the 21% (n = 14) of PDs whose programs had no UIM fellows, 0% matched a UIM applicant in the 2023 match. 52% (n = 36) of PDs endorsed an inability to match UIM applicants despite consistently ranking them highly. PDs perceive the top 3 barriers to UIM recruitment as: low number of UIM applicants (53%, n = 41), geographic program location (50%, n = 39), and lack of diverse faculty/fellows in their program (42%, n = 31). 10% (n = 7) also reported meeting resistance about DEI initiatives. While 53% (n = 41) of PDs believe fellow demographics should reflect the local population, 23% (n = 16) don’t know how to increase diversity and 11% (n = 8) do not believe their program’s diversity needs to increase. In answers to open ended questions, some PDs expressed disagreement with the definition of UIM and reported a perceived limited number of qualified UIM applicants. Almost all institutions provide DEI training (96%, n = 72) for faculty and most PDs believe it has improved recruitment and inclusion of diverse individuals (52% and 65%, respectively). Yet, 34% (n = 23) agree that UIM fellows in their program are treated differently because of their race/ethnicity and 22% (n = 15) agree that UIM fellows repress their identity or background to be respected by faculty, peers, and staff. Conclusions: Historically and currently excluded populations remain underrepresented in the HO workforce. PDs face multiple barriers to the recruitment of diverse fellows, including differing views on the definition of UIM and perception of the value of diversity in the physician workforce.

AbstractPurposeThis study aimed to comprehensively review the existing evidence concerning surgical treatment of inferior pole fractures of the patella and to report the outcomes and complications of different fixation techniques.MethodThis systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Searches of PubMed, Scopus, and Web of Science were conducted in March 2023. Studies were screened against predecided inclusion and exclusion criteria. The extracted data included fracture characteristics, surgical techniques, and radiographic and functional outcomes. The Methodological Index for Non‐Randomized Studies (MINORS) quality assessment tool was used to assess the eligible literature. The primary outcome was postoperative range of motion of different surgical methods, and the secondary outcomes were other clinical results and complications.ResultsA total of 42 studies satisfied all the inclusion criteria and were deemed suitable for review. Fourteen case–control studies and 28 case series were selected, for a total of 1382 patients with a mean age of 51.0 years (range = 11–90). The follow‐up period ranged from 6 to 300 months. The surgical techniques were categorized based on the device used as follows: (1) rigid fixation device; (2) tensile fixation device; (3) mixed device; and (4) extra‐patella device.ConclusionRegarding the outcomes following surgical treatment of inferior pole fractures of the patella, the postoperative range of motion (ROM) of each technique ranged from 120° to 135°, with the exception of that involving the patellotibial wire which had poorer outcomes. The lowest functional score was also found in those using the patellotibial wire. Complications after surgery are rare, but approximately half of the patients required additional surgery for implant removal, particularly those whose initial surgery involved rigid fixation devices. It's worth noting that bony fragment excision is no longer recommended, and the combined use of multiple surgical devices is now more common.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Background: Our understanding of the risk factors for and effectiveness of prophylactic measures against shoulder periprosthetic joint infections (PJIs) continues to evolve. This study’s objective was to study patient characteristics, procedural characteristics, and various infection prophylactic measures and their effects on the risk of shoulder PJI after primary arthroplasty. Methods: Nine hundred and ninety-eight patients in a longitudinally maintained, single-institution shoulder arthroplasty database who had at least 2 years of clinical follow-up were retrospectively reviewed. Patient and procedural characteristics were collected. Perioperative variables, including the use of intraoperative antibiotics, topical antibiotics, antibiotic-containing irrigation solution, and a postoperative drain, were collected. Patients who developed shoulder PJI were compared with those without shoulder PJI to identify any association with patient or procedural characteristics. Results: Of the 998 patients, 20 (2.0%) met the criteria for shoulder PJI. Cutibacterium was identified as the causative organism in 19 (95%) of 20 culture-positive reoperations. On univariate analysis, patients in the PJI group were more likely to be younger (p < 0.001), to be male (p = 0.014), to have commercial insurance (p = 0.003), to use alcohol (p = 0.048), and to have had a ream-and-run or hemiarthroplasty procedure (p = 0.005). On multivariable analysis, older age was independently associated with a lower risk of PJI (odds ratio [OR] per year = 0.95; 95% confidence interval [CI], 0.91 to 0.99; p = 0.014). Reverse total shoulder arthroplasty (OR, 10.32; 95% CI, 0.92 to 116.33; p = 0.059) and hemiarthroplasty (OR, 8.59; 95% CI, 0.86.30 to 85.50; p = 0.067) trended toward a higher risk of PJI. Conclusions: Younger patients and patients undergoing procedures other than anatomic total shoulder arthroplasty are at higher risk for shoulder PJI. The majority of culture-positive reoperations were a result of Cutibacterium species. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as “cytotoxic lymphocytes,” or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

OBJECTIVE The American Spine Registry (ASR) is a collaborative effort between the American Academy of Orthopaedic Surgeons and the American Association of Neurological Surgeons. The goal of this study was to evaluate how representative the ASR is of the national practice with spinal procedures, as recorded in the National Inpatient Sample (NIS). METHODS The authors queried the NIS and the ASR for cervical and lumbar arthrodesis cases performed during 2017–2019. International Classification of Diseases, 10th Revision and Current Procedural Terminology codes were used to identify patients undergoing cervical and lumbar procedures. The two groups were compared for the overall proportion of cervical and lumbar procedures, age distribution, sex, surgical approach features, race, and hospital volume. Outcomes available in the ASR, such as patient-reported outcomes and reoperations, were not analyzed due to nonavailability in the NIS. The representativeness of the ASR compared to the NIS was assessed via Cohen’s d effect sizes, and absolute standardized mean differences (SMDs) of < 0.2 were considered trivial, whereas > 0.5 were considered moderately large. RESULTS A total of 24,800 arthrodesis procedures were identified in the ASR for the period between January 1, 2017, and December 31, 2019. During the same time period, 1,305,360 cases were recorded in the NIS. Cervical fusions comprised 35.9% of the ASR cohort (8911 cases) and 36.0% of the NIS cohort (469,287 cases). The two databases presented trivial differences in terms of patient age and sex for all years of interest across both cervical and lumbar arthrodeses (SMD < 0.2). Trivial differences were also noted in the distribution of open versus percutaneous procedures of the cervical and lumbar spine (SMD < 0.2). Among lumbar cases, anterior approaches were more common in the ASR than in the NIS (32.1% vs 22.3%, SMD = 0.22), but the discrepancy among cervical cases in the two databases was trivial (SMD = 0.03). Small differences were illustrated in terms of race, with SMDs < 0.5, and a more significant discrepancy was identified in the geographic distribution of participating sites (SMDs of 0.7 and 0.74 for cervical and lumbar cases, respectively). For both of these measures, SMDs in 2019 were smaller than those in 2018 and 2017. CONCLUSIONS The ASR and NIS databases presented a very high similarity in proportions of cervical and lumbar spine surgeries, as well as similar distributions of age and sex, and distribution of open versus endoscopic approach. Slight discrepancies in anterior versus posterior approach among lumbar cases and patient race, and more significant discrepancies in geographic representation were also identified, yet decreasing trends in differences suggested the improving representativeness of the ASR over the course of time and its progressive growth. These conclusions are important to underline the external validity of quality investigations and research conclusions to be drawn from analyses in which the ASR is used.

Background: Ream-and-run arthroplasty can improve pain and function in patients with glenohumeral arthritis while avoiding the complications and activity restrictions associated with a prosthetic glenoid component. However, stiffness is a known complication after ream-and-run arthroplasty and can lead to repeat procedures such as a manipulation under anesthesia (MUA) or open surgical revision. The objective of this study was to determine risk factors associated with repeat procedures indicated for postoperative stiffness after ream-and-run arthroplasty. Methods: We conducted a retrospective review of our shoulder arthroplasty database to identify patients who underwent ream-and-run arthroplasty and determined which patients underwent subsequent repeat procedures (MUA and/or open revision) indicated for postoperative stiffness. The minimum follow-up was 2 years. We collected baseline demographic information and preoperative and 2-year patient-reported outcome scores and analyzed preoperative radiographs. Univariate and multivariate analyses determined the factors significantly associated with repeat procedures to treat postoperative stiffness. Results: There were 340 patients who underwent ream-and-run arthroplasty. The mean Simple Shoulder Test (SST) scores for all patients improved from 5.0 ± 2.4 preoperatively to 10.2 ± 2.6 postoperatively (p < 0.001). Twenty-six patients (7.6%) underwent open revision for stiffness. An additional 35 patients (10.3%) underwent MUA. Univariate analysis found younger age (p = 0.001), female sex (p = 0.034), lower American Society of Anesthesiologists (ASA) class (p = 0.045), posterior decentering on preoperative radiographs (p = 0.010), and less passive forward elevation at the time of discharge after ream-and-run arthroplasty (p < 0.001) to be significant risk factors for repeat procedures. Multivariate analysis found younger age (p = 0.040), ASA class 1 compared with class 3 (p = 0.020), and less passive forward elevation at discharge (p < 0.001) to be independent risk factors for repeat procedures. Of the patients who underwent open revision for stiffness, 69.2% had multiple positive cultures for Cutibacterium. Conclusions: Younger age, ASA class 1 compared with class 3, and less passive forward elevation in the immediate postoperative period were independent risk factors for repeat procedures to treat postoperative stiffness after ream-and-run arthroplasty. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.