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.

Failing to Make the Grade: Conventional Cardiac Allograft Rejection Grading Criteria Are Inadequate for Predicting Rejection Severity.

BACKGROUND: Cardiac allograft rejection is the leading cause of early graft failure and is a major focus of postheart transplant patient care. While histological grading of endomyocardial biopsy samples remains the diagnostic standard for acute rejection, this standard has limited diagnostic accuracy. Discordance between biopsy rejection grade and patient clinical trajectory frequently leads to both overtreatment of indolent processes and delayed treatment of aggressive ones, spurring the need to investigate the adequacy of the current histological criteria for assessing clinically important rejection outcomes. METHODS: N=2900 endomyocardial biopsy images were assigned a rejection grade label (high versus low grade) and a clinical trajectory label (evident versus silent rejection). Using an image analysis approach, n=370 quantitative morphology features describing the lymphocytes and stroma were extracted from each slide. Two models were constructed to compare the subset of features associated with rejection grades versus those associated with clinical trajectories. A proof-of-principle machine learning pipeline-the cardiac allograft rejection evaluator-was then developed to test the feasibility of identifying the clinical severity of a rejection event. RESULTS: The histopathologic findings associated with conventional rejection grades differ substantially from those associated with clinically evident allograft injury. Quantitative assessment of a small set of well-defined morphological features can be leveraged to more accurately reflect the severity of rejection compared with that achieved by the International Society of Heart and Lung Transplantation grades. CONCLUSIONS: Conventional endomyocardial samples contain morphological information that enables accurate identification of clinically evident rejection events, and this information is incompletely captured by the current, guideline-endorsed, rejection grading criteria.

Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology.

Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.

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.

Orthopedic surgery residents reported increased shoulder procedure volumes during the COVID-19 pandemic.

Background: The purpose of this study is to evaluate the impact of the COVID-19 pandemic on shoulder procedure volumes reported to the Accreditation Council for Graduate Medical Education by orthopedic surgery residents. Methods: We performed a retrospective review of Accreditation Council for Graduate Medical Education case logs reporting data from graduating orthopedic surgery residents during the academic years of 2006-2022. Data were queried for all patients for the following shoulder Current Procedural Terminology codes: incision, excision, intro or removal, repair/revision/reconstruction, fracture and/or dislocation, manipulation, arthroscopy, trauma, and total procedures performed. Individual t-tests were used to compare case log trends of graduating academic years before (classes of 2018 and 2019) and during (classes of 2020, 2021, and 2022) the COVID-19 pandemic. Statistical significance was established to be P <.05 for total procedure types, but at P <.005 during category comparisons to protect against alpha errors. Results: Reported mean total shoulder procedures per resident steadily increased each year from 2017 to 2022, but the only significant increase was seen when comparing the graduating classes of 2020 to 2021 (157.9 vs. 165.7, P =.02). Stratification of these procedures by subgroup revealed a significant increase in manipulation procedures from 2021 to 2022 (7.3 vs. 8.8, P =.001). Discussion/Conclusion: COVID-19 did not have a negative impact on logged shoulder procedure volume. Orthopedic surgery residents graduating during the COVID-19 pandemic reported more shoulder procedures than those graduating prepandemic. However, shoulder procedure log trends should be longitudinally investigated, as preceding years of procedural opportunities may underestimate the pandemic's impact.

A metagenomic analysis of the virome of inverted papilloma and squamous cell carcinoma.

INTRODUCTION: Inverted papilloma (IP) is a sinonasal tumor with a well-known potential for malignant transformation. The role of human papillomavirus (HPV) in its pathogenesis has been controversial. The purpose of this study was to determine the virome associated with IP, with progression to carcinoma in situ (CIS), and invasive carcinoma. METHODS: To determine the HPV-specific types, a metagenomics assay that contains 62,886 probes targeting viral genomes in a microarray format was used. The platform screens DNA and RNA from fixed tissues from eight controls, 16 IP without dysplasia, five IP with CIS, and 13 IP-associated squamous cell carcinoma (IPSCC). Paired with next-generation sequencing, 48 types of HPV with 857 region-specific probes were interrogated against the tumors. RESULTS: The prevalence of HPV-16 was 14%, 42%, 70%, and 73% in control tissue, IP without dysplasia, IP with CIS, and IPSCC, respectively. The prevalence of HPV-18 had a similar progressive increase in prevalence, with 14%, 27%, 67%, and 74%, respectively. The assay allowed region-specific analysis, which identified the only oncogenic HPV-18 E6 to be statistically significant when compared with control tissue. The prevalence of HPV-18 E6 was 0% in control tissue, 25% in IP without dysplasia, 60% in IP with CIS, and 77% in IPSCC. CONCLUSIONS: There are over 200 HPV types that infect human epithelial cells, of which only a few are known to be high-risk. Our study demonstrated a trend of increasing prevalence of HPV-18 E6 that correlated with histologic severity, which is novel and supports a potential role for HPV in the pathogenesis of IP.

Computational pathology improves risk stratification of a multi-gene assay for early stage ER+ breast cancer.

Prognostic markers currently utilized in clinical practice for estrogen receptor-positive (ER+) and lymph node-negative (LN-) invasive breast cancer (IBC) patients include the Nottingham grading system and Oncotype Dx (ODx). However, these biomarkers are not always optimal and remain subject to inter-/intra-observer variability and high cost. In this study, we evaluated the association between computationally derived image features from H&E images and disease-free survival (DFS) in ER+ and LN- IBC. H&E images from a total of n = 321 patients with ER+ and LN- IBC from three cohorts were employed for this study (Training set: D1 (n = 116), Validation sets: D2 (n = 121) and D3 (n = 84)). A total of 343 features relating to nuclear morphology, mitotic activity, and tubule formation were computationally extracted from each slide image. A Cox regression model (IbRiS) was trained to identify significant predictors of DFS and predict a high/low-risk category using D1 and was validated on independent testing sets D2 and D3 as well as within each ODx risk category. IbRiS was significantly prognostic of DFS with a hazard ratio (HR) of 2.33 (95% confidence interval (95% CI) = 1.02-5.32, p = 0.045) on D2 and a HR of 2.94 (95% CI = 1.18-7.35, p = 0.0208) on D3. In addition, IbRiS yielded significant risk stratification within high ODx risk categories (D1 + D2: HR = 10.35, 95% CI = 1.20-89.18, p = 0.0106; D1: p = 0.0238; D2: p = 0.0389), potentially providing more granular risk stratification than offered by ODx alone.

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

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".

Epithelial cell size dysregulation in human lung adenocarcinoma.

Human cells tightly control their dimensions, but in some cancers, normal cell size control is lost. In this study we measure cell volumes of epithelial cells from human lung adenocarcinoma progression in situ. By leveraging artificial intelligence (AI), we reconstruct tumor cell shapes in three dimensions (3D) and find airway type 2 cells display up to 10-fold increases in volume. Surprisingly, cell size increase is not caused by altered ploidy, and up to 80% of near-euploid tumor cells show abnormal sizes. Size dysregulation is not explained by cell swelling or senescence because cells maintain cytoplasmic density and proper organelle size scaling, but is correlated with changes in tissue organization and loss of a novel network of processes that appear to connect alveolar type 2 cells. To validate size dysregulation in near-euploid cells, we sorted cells from tumor single-cell suspensions on the basis of size. Our study provides data of unprecedented detail for cell volume dysregulation in a human cancer. Broadly, loss of size control may be a common feature of lung adenocarcinomas in humans and mice that is relevant to disease and identification of these cells provides a useful model for investigating cell size control and consequences of cell size dysregulation.

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.

Spatial interplay patterns of cancer nuclei and tumor-infiltrating lymphocytes (TILs) predict clinical benefit for immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) show prominent clinical activity across multiple advanced tumors. However, less than half of patients respond even after molecule-based selection. Thus, improved biomarkers are required. In this study, we use an image analysis to capture morphologic attributes relating to the spatial interaction and architecture of tumor cells and tumor-infiltrating lymphocytes (TILs) from digitized H&E images. We evaluate the association of image features with progression-free (PFS) and overall survival in non-small cell lung cancer (NSCLC) (N = 187) and gynecological cancer (N = 39) patients treated with ICIs. We demonstrated that the classifier trained with NSCLC alone was associated with PFS in independent NSCLC cohorts and also in gynecological cancer. The classifier was also associated with clinical outcome independent of clinical factors. Moreover, the classifier was associated with PFS even with low PD-L1 expression. These findings suggest that image analysis can be used to predict clinical end points in patients receiving ICI.

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.

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: 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!

Clinical Commentary: Rehabilitation Using Acute Dry Needling for Injured Athletes Returning to Sport and Improving Performance.

Dry needling is most commonly used in the subacute and chronic phases of an injury; therefore, it is imperative to understand the use of dry needling in the acute phases of an injury. There are four main reasons to use dry needling during the acute phase of injury: to relieve pain, decrease edema, increase range of motion and flexibility, and increase strength and power. Dry needling can be used pregame, postgame, during half time or an intermission, or following an injury. Although further research is needed, acute dry needling can be used to bolster athletes' health and possibly improve sports performance.

Rehabilitation Using a Systematic and Holistic Approach for the Injured Athlete Returning to Sport.

The purpose of this article is to identify gold standards of care for return to sport following athletic injury, investigate overlooked aspects of return to sport rehabilitation, and provide expert opinion regarding current practices. The article was written by performing a literature review, then providing editorial expert opinion regarding current standards of return to sport. We concluded, through literature review and expert consensus, that a three-pronged approach to return to sport is recommended for therapists. These three prongs are ROM, strength, and hop testing. Cardiovascular readiness and psychological readiness for return to sport must also be assessed."

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.

An automated COVID-19 triage pipeline using artificial intelligence based on chest radiographs and clinical data.

While COVID-19 diagnosis and prognosis artificial intelligence models exist, very few can be implemented for practical use given their high risk of bias. We aimed to develop a diagnosis model that addresses notable shortcomings of prior studies, integrating it into a fully automated triage pipeline that examines chest radiographs for the presence, severity, and progression of COVID-19 pneumonia. Scans were collected using the DICOM Image Analysis and Archive, a system that communicates with a hospital's image repository. The authors collected over 6,500 non-public chest X-rays comprising diverse COVID-19 severities, along with radiology reports and RT-PCR data. The authors provisioned one internally held-out and two external test sets to assess model generalizability and compare performance to traditional radiologist interpretation. The pipeline was evaluated on a prospective cohort of 80 radiographs, reporting a 95% diagnostic accuracy. The study mitigates bias in AI model development and demonstrates the value of an end-to-end COVID-19 triage platform.

PROTEIN KINASE C ALPHA IS A CENTRAL NODE FOR TUMORIGENIC TRANSCRIPTIONAL NETWORKS IN HUMAN PROSTATE CANCER.

Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different members of the PKC family control cellular events associated with cancer development and progression. Whereas the classical/conventional PKCα isozyme has been linked to tumor suppression in most cancer types, here we demonstrate that this kinase is required for the mitogenic activity of aggressive human prostate cancer cells displaying aberrantly high PKCα expression. Immunohistochemical analysis showed abnormal up-regulation of PKCα in human primary prostate tumors. Interestingly, silencing PKCα expression from aggressive prostate cancer cells impairs cell cycle progression, proliferation and invasion, as well as their tumorigenic activity in a mouse xenograft model. Mechanistic analysis revealed that PKCα exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell cycle progression and E2F transcription factors. PKCα RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of pro-inflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent down-regulation of the immune checkpoint ligand PD-L1. This PKCα-dependent gene expression profile was corroborated in silico using human prostate cancer databases. Our studies established PKCα as a multifunctional kinase that plays pleiotropic roles in prostate cancer, particularly by controlling genetic networks associated with tumor growth and progression. The identification of PKCα as a pro-tumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches towards targeting PKCα or its effectors.