Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig.

Genetic modification of porcine donors, combined with optimized immunosuppression, has been shown to improve outcomes of experimental xenotransplant. However, little is known about outcomes in sensitized recipients, a population that could potentially benefit the most from the clinical implementation of xenotransplantation. Here, five highly allosensitized rhesus macaques received a porcine kidney from GGTA1 (α1,3-galactosyltransferase) knockout pigs expressing the human CD55 transgene (1KO.1TG) and were maintained on an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen. These recipients developed de novo xenoreactive antibodies and experienced xenograft rejection with evidence of thrombotic microangiopathy and antibody-mediated rejection (AMR). In comparison, three highly allosensitized rhesus macaques receiving a kidney from GGTA1, CMAH (cytidine monophospho-N-acetylneuraminic acid hydroxylase), and b4GNT2/b4GALNT2 (ß-1,4-N-acetyl-galactosaminyltransferase 2) knockout pigs expressing seven human transgenes including human CD46, CD55, CD47, THBD (thrombomodulin), PROCR (protein C receptor), TNFAIP3 (tumor necrosis factor-α-induced protein 3), and HMOX1 (heme oxygenase 1) (3KO.7TG) experienced significantly prolonged graft survival and reduced AMR, associated with dampened post-transplant humoral responses, early monocyte and neutrophil activation, and T cell repopulation. After withdrawal of all immunosuppression, recipients who received kidneys from 3KO.7TG pigs rejected the xenografts via AMR. These data suggest that allosensitized recipients may be suitable candidates for xenografts from genetically modified porcine donors and could benefit from an optimized immunosuppression regimen designed to target the post-transplant humoral response, thereby avoiding AMR.

Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS: Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION: Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

Neurocysticercosis Presenting as Migraine in the United States.

BACKGROUND Cysticercosis is a condition caused by infection with the larval form of Taenia solium, a pork tapeworm that uses pigs as an intermediate host. Humans become infected when they ingest water or food contaminated with tapeworm cysts. Cysticercosis is increasing in frequency in developed countries due to increased access to travel. Neurocysticercosis occurs when Taenia solium cysts embed within the nervous system. The clinical presentation of neurocysticercosis ranges from asymptomatic to life-threatening, largely depending on the brain parenchymal involvement. The diagnosis is typically made with a combination of clinical evaluation, serology, and neuroimaging. Treatment for parenchymal neurocysticercosis may involve anthelmintic agents, symptomatic agents, surgery, or a combination of methods. CASE REPORT A 52-year-old man with a medical history of migraine headaches, complicated type 2 diabetes mellitus, and obesity presented with a 4-month change in his migraines becoming severe, worse over his occiput bilaterally, and unresponsive to abortive therapy. His exposure history was unremarkable except for a habit of eating undercooked bacon, by which he would have developed neurocysticercosis via autoinfection. Neuroimaging and serology confirmed a diagnosis of neurocysticercosis and he was treated accordingly with antiparasitic and anti-inflammatory medications. CONCLUSIONS This presentation is nonspecific and can easily be overlooked, especially if there is an underlying known neurological condition such as migraine. This case illustrates that neurocysticercosis should be considered when an existing neuropathological condition displays a change in presentation or requires a change in therapeutic management, even without obvious risk factors.

Peripheral neuropathies after shoulder arthroscopy: a systematic review.

Purpose: Peripheral neuropathies after shoulder arthroscopy are rare, though likely under-reported. Many resolve spontaneously, but some patients are left with permanent neurological deficits. The purpose of this study was to review the literature to better characterize this patient population, diagnostic tests performed, the timing and type of surgical intervention, and report clinical outcomes. Methods: A systematic literature review was performed. Articles in English were identified from PubMed, EMBASE, and CINAHL in August 2021. Article titles and abstracts were screened for relevance by two authors and discordant abstracts were resolved by the senior author. Data were subsequently extracted from the included articles. Results: Seventeen articles were identified yielding a total of 91 patients. The average age was 53 ± 12 years, and most patients were male (72%). Rotator cuff repair (62%) was the most common procedure performed. A peripheral neuropathy was identified an average of 80 ± 81 days from the index procedure (range, 0-240 days). Most commonly, peripheral nerve injury presented as a mononeuropathy, with the median nerve (39%) and ulnar nerve (17%) affected predominantly. Seventeen percent of patients underwent a secondary surgery at an average of 232 ± 157 days after the index procedure. At the final follow-up, 55% of neuropathies had resolved, 14% partially improved, and 22% showed no clinical improvement. The most proposed etiologies were postoperative immobilization (29%) and intraoperative positioning (20%), but several possible etiologies have been suggested. Conclusions: Peripheral neuropathies after arthroscopic shoulder procedures are rare. While most spontaneously resolve, up to 1 in 5 patients may have persistent neuropathic symptoms. A high index of suspicion should be maintained throughout the postoperative period. When neurologic deficits are identified, patients should undergo a thorough diagnostic workup and be referred to a subspecialist in a timely manner.

A Rare Case of Severe Stevens-Johnson Syndrome Triggered by Topical Ofloxacin.

BACKGROUND Stevens-Johnson syndrome (SJS) is a rare dermatologic disorder that is characterized by nonspecific flu-like prodrome with fever, malaise, myalgia, cough, rhinitis, and sore eyes, followed by a characteristic rash and mucocutaneous manifestations. It is triggered by medications in up to 80% of cases in adults. In each of these cases, the medication is oral or parenteral. Severe and progressive SJS can result in life-threatening complications. Adult-onset medication-induced SJS presents within 8 weeks of exposure to the offending substance, lasting 8 to 12 days. Recovery of denuded skin generally is complete within a month. There is no consensus on treatment, but supportive care with corticosteroids is often the initial intervention. CASE REPORT A 36-year-old woman with a flare of allergic rhinitis and tearing resistant to over-the-counter options was treated with topical ophthalmic ofloxacin. She began experiencing a diffuse mucocutaneous rash, with oral desquamation, tongue swelling, vaginal desquamation, and rash of the palms and soles within 24 h, which suggested the possibility of SJS. A skin biopsy was obtained, and pathology confirmed this suspicion. She was treated with parenteral antibiotics, corticosteroids, and supportive care, and after 10 days was discharged from the hospital. She had a complete recovery in 30 days. CONCLUSIONS The clinical course of SJS induced by the ophthalmic application of medication can be just as severe as the oral or parenteral routes. This is, to the best of our knowledge, the first documented case of SJS being triggered by topical ofloxacin.

Special Report: The Moore Pediatric Surgery Center: An Evolving Model for Pediatric Orthopaedic Surgical Care in a Limited Resource Environment.

ABSTRACT: The authors describe their 11-year experience with 1 model for providing short-term (about 1 wk/y in country) pediatric orthopaedic surgical care in a limited resource environment. This paper provides a detailed narrative of 1 team's pediatric orthopaedic work at the Moore Pediatric Surgery Center in Guatemala City, how it has evolved over these 11 years, financial aspects of the model, and examines patient follow-up data for a consecutive 8-year period. The authors have reviewed financial records, case lists, patient charts from 2014 to 2022, and patient photographic records from The Moore Center and as provided via internet by a local contracted Guatemalan pediatric orthopaedic fellowship-trained surgeon to present a complete picture of how the service functions. Specific follow-up data included: last follow-up date, date discharged from follow-up, and major complications including infection, surgical wound dehiscence, return for unplanned surgery, major nerve injury, and recurrent hip dislocation for cases of closed or open reduction of developmental hip dislocation. A total of 297 consecutive pediatric orthopaedic surgical patients were identified from 2014 to 2022. Of these, charts were found for 235 patients (135 female, 110 male), of which 43% were from the urban Guatemala City region. Two hundred sixteen (72%) had at least 1 follow-up clinic visit, and 87 (37%) had at least 1-year follow-up or were discharged. All complications identified by this retrospective chart review included 4 recurrent hip dislocations (3 after closed reduction), 1 femur fracture after implant removal, 1 superficial infection requiring antibiotics, 1 partial dehiscence treated only with dressings, 1 thumb subluxation, and 1 failed graft with internal fixation for congenital pseudoarthrosis of tibia. CONCLUSIONS: The Moore Pediatric Surgery Center is a financially viable, sustainable, safe, and effective model for delivering short-term surgical care for many pediatric orthopaedic conditions in a limited resource environment. LEVEL OF EVIDENCE: None (descriptive).

Return to Play After Shoulder Surgery in Professional Baseball Players: A Systematic Review and Meta-analysis.

Background: The current literature lacks an updated review examining return to play (RTP) and return to prior performance (RTPP) after shoulder surgery in professional baseball players. Purpose: To summarize the RTP rate, RTPP rate, and baseball-specific performance metrics among professional baseball players who underwent shoulder surgery. Study Design: Systematic review; Level of evidence, 4. Methods: A literature search was performed utilizing the PubMed, MEDLINE, and CINAHL databases and according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria were English-language studies reporting on postoperative RTP and/or RTPP in professional baseball players who underwent shoulder surgery between 1976 and 2016. RTP rates, RTPP rates, and baseball-specific performance metrics were extracted from qualifying studies. A total of 2034 articles were identified after the initial search. Meta-analysis was performed where applicable, yielding weighted averages of RTP and RTPP rates and comparisons between pitchers and nonpitchers for each type of surgery. Baseball-specific performance metrics were reported as a narrative summary. Results: Overall, 26 studies featuring 1228 professional baseball players were included. Patient-level outcome data were available for 529 players. Surgical interventions included rotator cuff debridement (n = 197), rotator cuff repair (RCR; n = 43), superior labrum from anterior to posterior repair (n = 124), labral repair (n = 103), latissimus dorsi/teres major (LD/TM) repair (n = 21), biceps tenodesis (n = 17), coracoclavicular ligament reconstruction (n = 15), anterior capsular repair (n = 5), and scapulothoracic bursectomy (n = 4). Rotator cuff debridement was the most common surgical procedure, while scapulothoracic bursectomy was the least common (37.2% and 0.8% of interventions, respectively). Meta-analysis revealed that the RTP rate was highest for LD/TM repair (84.5%) and lowest for RCR (53.5%), while the RTPP rate was highest for LD/TM repair (100.0%) and lowest for RCR (27.9%). RTP and RTPP rates were generally higher for position players than for pitchers. Nonvolume performance metrics were unaffected by shoulder surgery, while volume statistics decreased or remained similar. Conclusion: RTP and RTPP rates among professional baseball players were modest after most types of shoulder surgery. Among surgical procedures commonly performed on professional baseball players, RTP and RTPP rates were highest for LD/TM repair and lowest for RCR.

Textbook Outcome: Definition and Analysis of a Novel Quality Measure in Lung Transplantation.

OBJECTIVE: To define textbook outcome (TO) for lung transplantation (LTx) using a contemporary cohort from a high-volume institution. SUMMARY BACKGROUND DATA: TO is a standardized, composite quality measure based on multiple postoperative endpoints representing the ideal "textbook" hospitalization. METHODS: Adult patients who underwent LTx at our institution between 2016 and 2019 were included. TO was defined as freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay >75th percentile of LTx patients, 90 day mortality, 30-day acute rejection, grade 3 primary graft dysfunction at 48 or 72 hours, postoperative extracorporeal membrane oxygenation, tracheostomy within 7 days, inpatient dialysis, reintubation, and extubation >48 hours post-transplant. Recipient, operative, financial characteristics, and post-transplant outcomes were recorded from institutional data and compared between TO and non-TO groups. RESULTS: Of 401 LTx recipients, 97 (24.2%) achieved TO. The most common reason for TO failure was extubation >48 hours post-transplant (N = 119, 39.1%); the least common was mortality (N = 15, 4.9%). Patient and graft survival were improved among patients who achieved versus failed TO (patient survival: log-rank P < 0.01; graft survival: log-rank P < 0.01). Rejection-free and chronic lung allograft dysfunction-free survival were similar between TO and non-TO groups (rejection-free survival: log-rank P = 0.07; chronic lung allograft dysfunction-free survival: log-rank P = 0.3). On average, patients who achieved TO incurred approximately $638,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in LTx was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer providers and patients new insight into transplant center quality of care and highlight areas for improvement.

Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Belatacept-Based Maintenance Immunosuppression Controls the Post-Transplant Humoral Immune Response in Highly Sensitized Nonhuman Primates.

Preexisting donor-specific antibodies (DSA) to MHC antigens increase the risk of antibody-mediated rejection (AMR) in sensitized transplant recipients and reduces graft survival. Pretransplant desensitization with costimulation blockade and proteasome inhibition has facilitated transplantation in our preclinical nonhuman primate (NHP) model. However, long-term graft survival is limited by rebound of DSA after transplantation. In this study, we performed kidney transplants between highly sensitized, maximally MHC-mismatched NHPs (n=14). At kidney transplantation, primates received T cell depletion with rhesus-specific anti-thymocyte globulin (rhATG; n=10) or monoclonal anti-CD4 and anti-CD8 antibodies (n=4). Maintenance immunosuppression consisted of belatacept and tacrolimus (n=5) or belatacept and rapamycin (n=9) with steroids. Rebound of DSA post-kidney transplantation was significantly reduced compared with maintenance immunosuppression with tacrolimus, mycophenolate, and steroids. Protocol lymph node biopsy specimens showed a decrease in germinal center activity, with low frequencies of T follicular helper cells and class-switched B cells after kidney transplantation. Combined belatacept and rapamycin was superior in controlling viral reactivation, enabling weaning of ganciclovir prophylaxis. Tacrolimus was associated with increased morbidity that included cytomegalovirus and parvovirus viremia and post-transplant lymphoproliferative disorder. All primates in the tacrolimus/belatacept group failed discontinuation of antiviral therapy. Overall, belatacept-based immunosuppression increased AMR-free graft survival by controlling post-transplant humoral responses in highly sensitized NHP recipients and should be further investigated in a human clinical trial.

Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.

Cellular Therapies in Solid Organ Allotransplantation: Promise and Pitfalls.

Donor specific transfusions have been the basis of tolerance inducing protocols since Peter Medawar showed that it was experimentally feasible in the 1950s. Though trials of cellular therapies have become increasingly common in solid organ transplantation, they have not become standard practice. Additionally, whereas some protocols have focused on cellular therapies as a method for donor antigen delivery-thought to promote tolerance in and of itself in the correct immunologic context-other approaches have alternatively focused on the intrinsic immunosuppressive properties of the certain cell types with less emphasis on their origin, including mesenchymal stem cells, regulatory T cells, and regulatory dendritic cells. Regardless of intent, all cellular therapies must contend with the potential that introducing donor antigen in a new context will lead to sensitization. In this review, we focus on the variety of cellular therapies that have been applied in human trials and non-human primate models, describe their efficacy, highlight data regarding their potential for sensitization, and discuss opportunities for cellular therapies within our current understanding of the immune landscape.

Detection of Leptomeningeal Disease Using Cell-Free DNA From Cerebrospinal Fluid.

Importance: Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions. Objective: To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis. Design, Setting, and Participants: This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018. Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection. Results: In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients. Conclusions and Relevance: This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted.

Reexamining Risk Aversion: Willingness to Pursue and Utilize Nonideal Donor Livers Among US Donation Service Areas.

BACKGROUND: Livers from "nonideal" but acceptable donors are underutilized; however, organ procurement organization (OPO) metrics do not assess how OPO-specific practices contribute to these trends. In this analysis, we evaluated nonideal liver donor avoidance or risk aversion among OPOs and within US donation service areas (DSAs). METHODS: Adult donors in the United Network for Organ Sharing registry who donated ≥1 organ for transplantation between 2007 and 2019 were included. Nonideal donors were defined by any of the following: age > 70, hepatitis C seropositive, body mass index > 40, donation after circulatory death, or history of malignancy. OPO-specific performance was evaluated based on rates of nonideal donor pursuit and consent attainment. DSA performance (OPO + transplant centers) was evaluated based on rates of nonideal donor pursuit, consent attainment, liver recovery, and transplantation. Lower rates were considered to represent increased donor avoidance or increased risk aversion. RESULTS: Of 97 911 donors, 31 799 (32.5%) were nonideal. Unadjusted OPO-level rates of nonideal donor pursuit ranged from 88% to 100%. In a 5-tier system of overall risk aversion, tier 5 DSAs (least risk-averse) and tier 1 DSAs (most risk-averse) had the highest and lowest respective rates of non-ideal donor pursuit, consent attainment, liver recovery, and transplantation. On average, recovery rates were over 25% higher among tier 5 versus tier 1 DSAs. If tier 1 DSAs had achieved the same average liver recovery rate as tier 5 DSAs, approximately 2100 additional livers could have been recovered during the study period. CONCLUSION: Most OPOs aggressively pursue nonideal liver donors; however, recovery practices vary widely among DSAs. Fair OPO evaluations should consider early donation process stages to best disentangle OPO and center-level practices.

A simple scoring system to estimate perioperative mortality following liver resection for primary liver malignancy-the Hepatectomy Risk Score (HeRS).

BACKGROUND: Selection of the optimal treatment modality for primary liver cancers remains complex, balancing patient condition, liver function, and extent of disease. In individuals with preserved liver function, liver resection remains the primary approach for treatment with curative intent but may be associated with significant mortality. The purpose of this study was to establish a simple scoring system based on Model for End-stage Liver Disease (MELD) and extent of resection to guide risk assessment for liver resections. METHODS: The 2005-2015 NSQIP database was queried for patients undergoing liver resection for primary liver malignancy. We first developed a model that incorporated the extent of resection (1 point for major hepatectomy) and a MELD-Na score category of low (MELD-Na =6, 1 point), medium (MELD-Na =7-10, 2 points) or high (MELD-Na >10, 3 points) with a score range of 1-4, called the Hepatic Resection Risk Score (HeRS). We tested the predictive value of this model on the dataset using logistic regression. We next developed an optimal multivariable model using backwards sequential selection of variables under logistic regression. We performed K-fold cross validation on both models. Receiver operating characteristics were plotted and the optimal sensitivity and specificity for each model were calculated to obtain positive and negative predictive values. RESULTS: A total of 4,510 patients were included. HeRS was associated with increased odds of 30-day mortality [HeRS =2: OR =3.23 (1.16-8.99), P=0.025; HeRS =3: OR =6.54 (2.39-17.90), P<0.001; HeRS =4: OR =13.69 (4.90-38.22), P<0.001]. The AUC for this model was 0.66. The AUC for the optimal multivariable model was higher at 0.76. Under K-fold cross validation, the positive predictive value (PPV) and negative predictive value (NPV) of these two models were similar at PPV =6.4% and NPV =97.7% for the HeRS only model and PPV =8.4% and NPV =98.1% for the optimal multivariable model. CONCLUSIONS: The HeRS offers a simple heuristic for estimating 30-day mortality after resection of primary liver malignancy. More complicated models offer better performance but at the expense of being more difficult to integrate into clinical practice.

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis.

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.

Definition and Analysis of Textbook Outcome: A Novel Quality Measure in Kidney Transplantation.

BACKGROUND: "Textbook outcome" (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal "textbook" hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. METHODS: Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay > 75th percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. RESULTS: A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N = 157, 50%) and hospital readmission within 30 days (N = 155, 50%); the least common was mortality within 90 days (N = 6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.