Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.

Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.

Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.

Editorial Commentary: Biceps Management During Rotator Cuff Tear: Confounding Variables Result in Unclear Indications.

Is "killing the biceps" during rotator cuff repair a capital crime or a lawful act? One of the most passionately debated topics in shoulder surgery is what to do with the biceps during rotator cuff repair: save it, tenotomize it, or perform tenodesis. Results of repair are not very successful, and given that repair of massive rotator cuff tears shows a 40% to 57% failure rate, there is renewed interest in sparing the biceps tendon as a humeral head depressor-or so that it may be used as a local graft for revision rotator cuff repair. The literature regarding tenodesis versus biceps sparing during rotator cuff repair is controversial. There are so many confounding variables affecting rotator cuff repair outcomes (tear size, comorbidities, age, tissue quality, etc.) that we do not believe that anything less than a randomized, prospective study that matches groups is likely to provide a conclusive verdict.

Clinically Significant Outcome Scores in Orthopaedic Sports Medicine Shoulder and Knee Surgery Are Increasing in Prevalence but Often Reported Incorrectly.

PURPOSE: To study the prevalence and quality of application of minimal clinically important difference (MCID), substantial clinical benefit (SCB), patient-acceptable symptomatic state (PASS), and maximum outcome improvement (MOI), reported in the orthopaedic sports medicine knee and shoulder literature in recent years and to bring awareness of proper use of such metrics. METHODS: A literature review of all shoulder and knee articles published from the American Journal of Sports Medicine (AJSM), Journal of Shoulder and Elbow Surgery (JSES), and Arthroscopy from 2016 to 2020 was performed, specifically investigating whether MCID, SCB, PASS, or MOI were used or reported. Additionally, the way these metrics were reported and interpreted was recorded. RESULTS: Out of 5,039 studies, 889 shoulder and knee studies met the inclusion criteria. Overall, 16.7% reported either MCID, PASS, or SCB. MCID was the most reported across all 3 journals. MCID was reported 12.4% of the time throughout the 5 years. PASS was reported 3.2% and SCB 1.1% of the time over the 5 years. MOI was not reported by any of the journals during this period. There was a statistically significant increase in MCID reporting in 2 of the 3 journals over the 5-year course, Arthroscopy (P = .02) and AJSM (P = .05). There was no statistically significant increase in PASS or SCB reporting rates in all 3 journals. Only 39.1% of studies reported MCID correctly (i.e., defined as the number of individual patients meeting MCID/total patients in the study). CONCLUSIONS: This study shows an increasing trend in the use of clinically significant outcome metrics, such as MCID, for interpretation of patient-reported outcomes; however, these individual metrics are often not being used on the individual level and subsequently not reported accurately. We recommend determining whether the specific metric met the threshold per individual patient and then reporting those as a percentage of the sample population to achieve the full potential of these metrics and translate them accurately across various studies. CLINICAL RELEVANCE: As the usage of clinically significant outcome metrics rises, so does the need for accurate reporting. These findings will encourage future studies to follow a more standardized format.

Computational Analysis of Routine Biopsies Improves Diagnosis and Prediction of Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality for heart transplant recipients. Although clinical risk factors for CAV have been established, no personalized prognostic test exists to confidently identify patients at high versus low risk of developing aggressive CAV. This investigation aimed to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies (EMBs) to develop a precision medicine tool for predicting CAV years before overt clinical presentation. METHODS: Clinical data from 1 year after transplant were collected on 302 transplant recipients from the University of Pennsylvania, including 53 patients with early-onset CAV and 249 no early-onset CAV controls. These data were used to generate a clinical model (Clinical Risk Factor Future Cardiac Allograft Vasculopathy Prediction Model [ClinCAV-Pr]) for predicting future CAV development. From this cohort, 183 archived EMBs were collected for CD31 and modified trichrome staining and then digitally scanned. These included 1-year posttransplant EMBs from 50 patients with early-onset CAV and 82 patients with no early-onset CAV, as well as 51 EMBs from disease control patients obtained at the time of definitive coronary angiography confirming CAV. Using biologically inspired, handcrafted features extracted from digitized EMBs, quantitative histological models for differentiating no early-onset CAV from disease controls (Histological Cardiac Allograft Vasculopathy Diagnostic Model [HistoCAV-Dx]) and for predicting future CAV from 1-year posttransplant EMBs were developed (Histological Future Cardiac Allograft Vasculopathy Prediction Model [HistoCAV-Pr]). The performance of histological and clinical models for predicting future CAV (ie, HistoCAV-Pr and ClinCAV-Pr, respectively) were compared in a held-out validation set before being combined to assess the added predictive value of an integrated predictive model (Integrated Histological/Clinical Risk Factor Future Cardiac Allograft Vasculopathy Prediction Model [iCAV-Pr]). RESULTS: ClinCAV-Pr achieved modest performance on the independent test set, with an area under the receiver operating curve (AUROC) of 0.70. The HistoCAV-Dx model for diagnosing CAV achieved excellent discrimination, with an AUROC of 0.91, whereas the HistoCAV-Pr model for predicting CAV achieved good performance with an AUROC of 0.80. The integrated iCAV-Pr model achieved excellent predictive performance, with an AUROC of 0.93 on the held-out test set. CONCLUSIONS: Prediction of future CAV development is greatly improved by incorporation of computationally extracted histological features. These results suggest morphological details contained within regularly obtained biopsy tissue have the potential to enhance precision and personalization of treatment plans for patients after heart transplant.

Editorial Commentary: Indications for Shoulder SLAP Lesion Repair Versus Biceps Tenodesis Depend on Patient Age, Tear Type and Location, and Quality of Tissue.

Whether to repair a shoulder SLAP lesion or perform a biceps tenodesis depends on a multitude of factors: patient age, activity or work level, type of SLAP tear, location of SLAP tear, and quality of labral tissue. Determining which procedure to perform does not have such a simple, one-size-fits-all solution. For patients younger than 40 years, repair of type 2 SLAP tears that do not directly affect the biceps anchor (i.e., those tears from the 12:30 clock-face position to the 2-o'clock position or from the 10-o'clock position to the 11:30 clock-face position) is generally successful. For tears at the biceps anchor in patients younger than 40 years, repair the SLAP tear but perform tenodesis of the biceps. For type 3 SLAP tears, debride the bucket-handle component and spare the biceps because it usually is not involved. For type 4 tears, perform tenodesis. In patients older than 40 years, type 2 and type 4 SLAP tears are predominantly treated with biceps tenodesis with debridement of the SLAP tear, if indicated. SLAP repair is rarely indicated in patients older than 40 years because the tissue is usually degenerative and frayed.

Editorial Commentary: Interposition Graft Bridging Reconstruction: Good Mid-Term Outcomes for Massive Irreparable Rotator Cuff Tears.

Massive irreparable rotator cuff tears without glenohumeral arthritis are a common cause of shoulder pain and disability. Many surgical treatment options have been proposed, including debridement, partial repair, tendon transfer, superior capsule reconstruction, balloon spacer placement, bursal acromial reconstruction, and reverse shoulder arthroplasty. Interposition graft bridging reconstruction, as evidenced by the mid-term results of the current study, may also be considered, at least for now. However, let's see if this procedure will truly stand the test of time because all orthopaedic surgeons know that the one thing that ruins good results is long-term follow-up!

Editorial Commentary: Magnetic Resonance Imaging Is Generally Superior to Ultrasound for Evaluation of Rotator Cuff Pathology: If Unrecognized Subscapularis Pathology Is Suspected After Magnetic Resonance Imaging, Ultrasound Can Then Be Performed.

The advantages of using ultrasound over magnetic resonance imaging (MRI) in the diagnosis of rotator cuff pathology include patient and technical factors. Patient factors include the lack of claustrophobia or positioning constraints. Technical considerations include dynamic and real-time assessment, absence of contraindications due to implants, decreased cost, and portability. However, the limitations of ultrasound include operator dependency and skill, limited availability of experienced ultrasonographers, decreased sensitivity for other shoulder pathology, and possible less sensitivity for some types of rotator cuff pathology. In my practice, MRI, when indicated, is still the test of choice, as it is readily available, more versatile in diagnosing a wide range of shoulder pathologies, and not dependent on the availability of a skilled ultrasound operator. Should there still be concern for an unrecognized partial subscapularis tendon injury after MRI, ultrasound can then be performed.

Editorial Commentary: Magnetic Resonance Imaging Is Helpful in Predicting High-Grade Knee Rotatory Instability: But When in Doubt, Always Examine the Patient.

Unrecognized rotatory instability as evidenced by a high-grade pivot shift is well known to compromise anterior cruciate ligament (ACL) reconstruction results. By measuring which patients have anterior tibial subluxation of the lateral compartment ≥ 6 mm on a preoperative MRI, surgeons may be better able to counsel patients on postoperative expectations, as well as prepare for additional procedures to treat high-grade rotatory instability. Additionally, as there is an increased incidence of lateral meniscus tears in high-grade rotatory ACL lesions, surgeons should be vigilant and prepared to repair lateral meniscus root and ramp lesions. Furthermore, early identification of those patients with anterior tibial subluxation of the lateral compartment ≥6 mm will provide the opportunity for early surgery, as it is known that patients with high-grade rotatory instability are likely to sustain further intra-articular damage and have poorer outcomes if surgery is delayed. However, when there is doubt of high-grade rotatory instability after an ACL injury, examining the patient with a pivot shift maneuver should still be the "gold standard".

Editorial Commentary: Free Bone Block With Remplissage Provides Less Translation Than Free Bone Block Alone in Shoulder Instability Patients With Bipolar Bone Loss.

It would stand to reason that, in shoulder instability patients with bipolar bone loss, the combination of a bone block procedure and a remplissage procedure would provide better results than each one alone. Why would this be the case? When performing these procedures in the lateral decubitus position for patients with critical bipolar bone loss, the humeral head is anteriorly and inferiorly subluxed. This is most likely due to the incompetent restraints when in traction. A bone block procedure alone doesn't necessarily reduce the glenohumeral center of rotation; rather, it increases the "jump distance," making it more difficult for the humerus to dislocate over the bone block. However, the remplissage procedure not only makes the Hill-Sachs lesion extra-articular and prevents the defect from levering out the humerus, but also seems to pull the humeral head posteriorly centering it in the glenoid. This provides a posterior tether to the humeral head while increasing the jump distance over the bone block even further. In the future, one can anticipate a significant increase in remplissage-augmented bone block procedures in patients with bipolar bone loss.

An automated computational image analysis pipeline for histological grading of cardiac allograft rejection.

AIM: Allograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists. METHODS AND RESULTS: The study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The 'Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader' pipeline was trained using an interpretable, biologically inspired, 'hand-crafted' feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the 'grade of record', testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement [95% confidence interval (CI): 55.2-66.0%] with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0-65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4-68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3-64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001). CONCLUSION: These results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.

A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.

BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS: A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS: A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

Editorial Commentary: Anterior Cruciate Ligament Hamstring Autografts Should Be Avoided in Patients Younger Than 25 Years Old: Autograft-Allograft Hybrids Remain Controversial.

Some studies have reported no difference between autograft and hybrid anterior cruciate ligament reconstructions. However, other studies have shown a significantly greater revision rate. Consequently, surgeons are reluctant to perform hybrid reconstructions in younger patients with diminutive hamstring autografts and have turned to other autograft graft sources (e.g., quadriceps tendon, patellar tendon). Until we can perform high-quality prospective studies that can definitively answer this question, we should consider avoiding autograft hamstring reconstructions in patients younger than 25 years old so that we are not faced with the dilemma of implanting an undersized autograft or a hybrid graft, as both may be at increased risk for failure.

Editorial Commentary: Big Databases Are Not All Created Equal: Interpret Their Studies With Caution.

"Big Data" studies are extremely important in orthopedic research, as randomized controlled trials with extremely large sample sizes are nearly impossible to perform. But, as always, the devil is in the details. Databases are only as good as the information that is put into them. And when evaluating these studies, let's not forget how to interpret them. Many factors-patient insurance status, age, socioeconomic status, ethnicity, and comorbidities; regional variations; hospital status (inpatient/outpatient); clerical errors, recording biases, and omission of relevant orthopedic outcome measures; temporal changes in billing codes; payer mix; population demographics and catchment area; and data collection methodology-mean that the results of a specific big data study may or may not be generalizable to other populations.

Editorial Commentary: Suture Button-Anchor Fixation Is Preferable to Hook Plate Fixation for Acute Acromioclavicular Joint Dislocations: Form and Function Need to Be United.

Both hook plate fixation and suture button-anchor fixation have been reported to yield good results in the treatment of acute acromioclavicular joint reconstruction. In addition to a mandatory secondary procedure, hook plate fixation clearly has an increased prevalence of post-traumatic acromioclavicular arthritis in the short term that is likely to progress in the long term. Conversely, suture button-anchor fixation-a minimally invasive technique that creates less soft-tissue disruption, does not require hardware removal, and does not violate the acromioclavicular joint-is more likely to promote primary healing of the coracoclavicular ligaments, reduce the risk of late displacement, and minimize the development of post-traumatic acromioclavicular arthritis. As stated by the noted architect Frank Lloyd Wright, it is not only about form (i.e., alignment), it is about function as well.

Editorial Commentary: Should We Consider Early Retirement for Adolescent Pitchers and Catchers With Osteochonditis Dissecans of the Capitellum?

Repetitive throwing in the adolescent athlete often leads to long-term problems. Strict pitch counts and limitation of pitches (e.g., curve balls) that place extreme stress on the immature elbow must be monitored closely. And until our outcomes for osteochondritis dissecans of the capitellum in adolescent baseball players improve, it may be wise to counsel those pitchers and catchers who are symptomatic to consider switching to another position or sport.

Editorial Commentary: Perfecting Practice: Can We Train Residents to Be Proficient Arthroscopists Before Actually Treating Patients?

Although a spaced retraining schedule improved resident arthroscopic task completion time and camera path length on a virtual simulator, it did not improve the degree of cartilage injury. To quote former Green Bay Packer Head Coach Vince Lombardi: "Practice does not make perfect. Only perfect practice makes perfect."

Editorial Commentary: Arthroscopic Ankle Arthrodesis Requires Intraoperative Deformity Correction: Size of the Deformity Is Not the Primary Determinant of Outcome.

Traditional teaching has told us that arthroscopic ankle arthrodesis is reserved for those patients with severe osteoarthrosis but minimal deformity. However, it is not the size of the deformity that matters; rather, it is the ability to correct the deformity intraoperatively that leads to satisfactory results. Preoperative identification of those patients with significant deformity that can be corrected with an arthroscopic approach would allow for improved selection and likely lead to better patient-reported outcomes and fewer complications.

Editorial Commentary: Taking the Time to Teach the Next Generation of Orthopaedic Sports Medicine Physicians.

Most everything in life has a cost, and for the academic orthopaedic sports medicine physician, it is time. But if it is to improve the skill set of the next generation of arthroscopic or sports medicine surgeons (who someday may perform surgery on me!), then I believe it is worth it.