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Purpose: The objective of this study is to determine the reproducibility of static 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT), and [(18)F]-fluoromisonidazole ((18)F-FMISO) microPET measurements, as well as kinetic parameters returned from analyses of dynamic (18)F-FLT and (18)F-FMISO data.Procedures: HER2+ xenografts were established in nude mice. Dynamic data were acquired for 60 min, followed by a repeat injection and second scan 6 h later. Reproducibility was assessed for the percent-injected dose per gram (%ID/g) for each radiotracer, and with kinetic parameters (K (1) -k (4) , K ( i )) for (18)F-FLT and (18)F-FMISO.Results: The value needed to reflect a change in tumor physiology is given by the 95 % confidence interval (CI), which is ±14, ±5, and ±6 % for (18)F-FDG (n = 12), (18)F-FLT (n = 11), and (18)F-FMISO (n = 11) %ID/g, respectively. V ( d ) (=K (1) /k (2)), k (3), and K (FLT) are the most reproducible (18)F-FLT (n = 9) kinetic parameters, with 95 % CIs of ±18, ±10, and ±18 %, respectively. V ( d ) and K (FMISO) are the most reproducible (18)F-FMISO kinetic parameters (n = 7) with 95 % CIs of ±16 and ±14 %, respectively.Conclusions: Percent-injected dose per gram measurements are reproducible and appropriate for detecting treatment-induced changes. Kinetic parameters have larger threshold values, but are potentially sufficiently reproducible to detect treatment response. [ABSTRACT FROM AUTHOR]

In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010 and 2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). A literature search identified phase I studies in adults with solid tumors published January 1, 2000- December 31, 2020 from 12 journals. We included only studies enrolling between 2010 and 2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized., (© 2024. The Author(s).)

Triple-negative breast cancer (TNBC) is a heterogeneous and challenging-to-treat breast cancer subtype. The clinical introduction of immune checkpoint inhibitors (ICI) for TNBC has had mixed results, and very few patients achieved a durable response. The PI3K/AKT pathway is frequently mutated in breast cancer. Given the important roles of the PI3K pathway in immune and tumor cell signaling, there is an interest in using inhibitors of this pathway to increase the response to ICI. This study sought to determine if AKT inhibition could enhance the response to ICI in murine TNBC models. We further sought to understand underlying mechanisms of response or non-response to AKT inhibition in combination with ICI. Using four murine TNBC-like cell lines and corresponding orthotopic mouse tumor models, we found that hyperactivity of the PI3K pathway, as evidenced by levels of phospho-AKT rather than PI3K pathway mutational status, was associated with response to AKT inhibition alone and in combination with ICI. Additional mutations in other growth regulatory pathways could override the response of PI3K pathway mutant tumors to AKT inhibition. Furthermore, we observed that AKT inhibition enhanced the response to ICI in an already sensitive model. However, AKT inhibition failed to convert ICI-resistant tumors, to responsive tumors. These findings suggest that analysis of both the mutational status and phospho-AKT protein levels may be beneficial in predicting which TNBC tumors will respond to AKT inhibition in combination with ICI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC., (© 2024. The Author(s).)

Background: Total hip arthroplasty (THA) has become a growing treatment procedure for debilitating hip pathologies. Patients experienced post-operative complications and revision surgeries according to large THA registries. To fully understand the short-term and long-term post-operative outcomes following THA, the purpose of this study is to examine the incidence of post-operative complications following primary THA and to examine how this trend has changed over 10 years within community hospitals in the US using large databases. Methods: This study queried the State Inpatient Database (SID) for primary THA between 2006 and 2015. Individual patients were followed forward in time until the first instance of a post-operative complication. The multivariable logistic regression analyses were computed to examine which post-operative complications were independent predictors of pre-operative comorbidities. Results: Median age of patients was 67 years, and 56% of patients were female. Females with avascular necrosis (AVN) as an indication for THA had a 27% higher risk of complication. Females with osteoarthritis (OA) as an indication for THA had a 6% higher risk of complication. Post-operative complications occurred with higher frequencies in the first two months of THA and the highest risks of THA complications within the first 6 months. Conclusion: The most common indication is OA in elders with primary THA. Females and those of black ethnicity showed the greatest risks of THA complications. Data from our large study can be used to understand post-operative complications and readmissions after THA. Our study also provides data on risk factors associated with these complications.

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments., Competing Interests: Declaration of interests C.N.H. is an employee of Regeneron Pharmaceuticals. M.J.S. receives funding from Janssen. B.C. is an employee of Genentech. E.T.M. is an employee of GlaxoSmithKline. Y.Q. and T.S. are stockholders and employees of Incendia Therapeutics. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Several risk factors for revision TKA have previously been identified, but interactions between risk factors may occur and affect risk of revision. To our knowledge, such interactions have not been previously studied. As patients often exhibit multiple risk factors for revision, knowledge of these interactions can help improve risk stratification and patient education prior to TKA., Materials and Methods: The State Inpatient Databases (SID), part of the Healthcare Cost and Utilization Project (HCUP), were queried to identify patients who underwent TKA between January 1, 2006 and December 31, 2015. Risk factors for revision TKA were identified, and interactions between indication for TKA and other risk factors were analyzed., Results: Of 958,944 patients who underwent TKA, 33,550 (3.5%) underwent revision. Age, sex, race, length of stay, Elixhauser readmission score, urban/rural designation, and indication for TKA were significantly associated with revision (p < 0.05). Age was the strongest predictor (p  < 0.0001), with younger patients exhibiting higher revision risk. Risks associated with age were modified by an interaction with indication for TKA (p < 0.0001). There was no significant interaction between sex and indication for TKA (p = 0.535) or race and indication for TKA (p = 0.187)., Conclusions: Age, sex, race, length of stay, Elixhauser readmission score, urban/rural designation, and indication for TKA are significantly associated with revision TKA. Interaction occurs between age and indication., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Well-designed randomized controlled clinical trials assessing treatments in the field of physical medicine and rehabilitation are essential for evidence-based patient care. However, there are challenges unique to clinical trials in physical medicine and rehabilitation due to complex health interventions in this field. We highlight routinely encountered empirical challenges and provide evidence-based recommendations on statistical and methodological approaches for the design and conduct of randomized controlled trials. Some of the issues addressed include challenges with blinding treatment groups in a rehabilitation setting, heterogeneity in treatment therapy, heterogeneity of treatment effects, uniformity in patient-reported outcome measures, and effect on power with varying scales of information. Furthermore, we discuss challenges with estimation of sample size and power, adaption to poor compliance with treatment and missing outcomes, and preferred statistical approaches for longitudinal data analysis., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME., Cme Objectives: Upon completion of this article, the reader should be able to: (1) Appraise the complexities of interventions in physical medicine and rehabilitation and how these challenges impact the conduct of clinical trials; (2) Develop an analytical strategy for poor treatment compliance and missing outcomes that can compromise the causal effect sought in a randomized clinical trial; and (3) Recognize the role of a data and safety monitoring board in a clinical trial., Level: Advanced., Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™. Physicians should only claim credit commensurate with the extent of their participation in the activity., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.

Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines., Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas., Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up., Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued., (©2023 American Association for Cancer Research.)

Background: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established., Methods: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf V600E /Pten -/- /Cxcr2 -/- and NRas Q61R /INK4a -/- /Cxcr2 -/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in Braf V600E /Pten -/- and NRas Q61R /INK4a -/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA)., Results: Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1, a key tumor suppressive transcription factor, was the only gene significantly induced with a log 2 fold-change greater than 2 in these three different melanoma models., Conclusions: Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an enabling technology for translational imaging research. Unlike clinical imaging, where equipment manufacturers strive to meet standards in practice at clinical sites, standards are neither fully developed nor implemented in preclinical imaging. This fundamentally limits the collection and reporting of metadata to qualify preclinical imaging studies, thereby hindering open science and impacting the reproducibility of co-clinical imaging research. To begin to address these issues, the NCI co-clinical imaging research program (CIRP) conducted a survey to identify metadata requirements for reproducible quantitative co-clinical imaging. The enclosed consensus-based report summarizes co-clinical imaging metadata information (CIMI) to support quantitative co-clinical imaging research with broad implications for capturing co-clinical data, enabling interoperability and data sharing, as well as potentially leading to updates to the preclinical Digital Imaging and Communications in Medicine (DICOM) standard.

Introduction: The objective of this study was to determine the survivorship of anatomic total shoulder arthroplasty (aTSA) and reverse TSA (rTSA) over a medium-term follow-up in a large population-based sample and to identify potential risk factors for revision surgery., Methods: The State Inpatient Database from the Healthcare Cost and Utilization Project was used to identify patients who underwent aTSA or rTSA from 2011 through 2015 using ICD9 codes. We modeled the primary outcome of time to revision or arthroplasty using the Cox proportional hazards model. The predictors of revision surgery in the model include aTSA versus rTSA, indication for surgery, age, sex, race, urban versus rural residence, hospital length of stay zip code-based income quartile classification, and Elixhauser comorbidity readmission score., Results: Among 43,990 patients in this study, 1,141 (4.0%) underwent revision or implant removal over the 4-year study period. The median age was 71 years, and 57% of patients were female. Indications for the index surgery included primary osteoarthritis (75.2%), cuff tear (8.5%), acute fracture (7.0%), malunion/nonunion (1.4%), and other (7.8%). Among these indications for surgery, the risk of revision or removal was greatest in patients who underwent the primary procedure for malunion/nonunion (hazard ratio [HR] 2.39, 95% confidence interval [CI] 1.69 to 3.39) compared with the reference of primary osteoarthritis. Male patients who underwent aTSA were less likely to need revision surgery than male patients who underwent rTSA (HR: 0.59, 95% CI 0.49 to 0.71), and the opposite relationship was observed in female patients (HR: 1.41, 95% CI 1.18 to 1.69). Age, length of stay, and Elixhauser comorbidity score were predictive of revision surgery (P < 0.0001, P = 0.0005, P < 0.0001, respectively), whereas race, urban versus rural, and zip code-based income quartile were not., Discussion: aTSA and rTSA showed excellent 4-year survivorship of 96.0% in a large population-based sample. aTSA and rTSA survivorships were similar at the 4-year follow-up., (Copyright © 2022 by the American Academy of Orthopaedic Surgeons.)

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response., Methods: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability., Discussion: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population., Trial Registration: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421)., (© 2022. The Author(s).)

Introduction: Small bowel adenocarcinomas (SBAs) are rare and frequently treated like large intestinal adenocarcinomas. However, SBAs have a very different microenvironment and could respond differently to the same therapies. Our previous data suggested that SBAs might benefit from targeting the PD-1/PD-L1 axis based on PD-L1 staining in almost 50% of SBA tissue samples tested. Thus, we designed a phase 2 study to explore safety and efficacy of avelumab in SBA., Patients and Methods: Patients with advanced or metastatic disease were enrolled; ampullary tumors were considered part of the duodenum and allowed. Prior PD-1/PD-L1 inhibition was not allowed. Avelumab (10 mg/kg) was given every 2 weeks, and imaging was performed every 8 weeks. Primary endpoint was response rate., Results: Eight patients (n = 5, small intestine; n = 3, ampullary) were enrolled, with a majority (88%) being male and a median age of 61 years. Of 7 efficacy-evaluable patients, 2 (29%) experienced partial responses; stable disease occurred in 3 additional patients (71%). Median progression-free survival was 3.35 months. Most frequent, related toxicities were anemia, fatigue, and infusion-related reaction (25% each), mostly grade ≤2; grade 3 hypokalemia and hyponatremia occurred in one patient, and another reported grade 4 diabetic ketoacidosis., Conclusions: Despite the observed benefit, accrual was slower than expected and the study was closed early due to feasibility. A general clinic observation was that patients were receiving immunotherapy off-label as the availability of these agents increased. Off-label availability and disease rarity were likely drivers of insufficient accrual., Competing Interests: Disclosure JB is an advisory board member of Insmed, Bayer, Mirati, Ipsen, QED, Oxford Biotherapeutics DSMB: Novocure, Pancreatic Cancer Action Network, Karyopharm, and his institution has received research funding from I-Mab, Dragonfly, Astellas, Atreca, AbbVie, Pfizer, Karyopharm, Boston biomedical, PsiOxus, EMD Serono, BMS. The other authors do not have any relevant conflicts to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Despite the considerable public health burden of rotator cuff tears, there is no consensus on risk factors associated with symptomatic rotator cuff tears. In this study, a large data source was used to identify factors associated with symptomatic rotator cuff tears. We defined cases of rotator cuff tears as those verified by imaging or operative reports and controls as symptomatic shoulders without rotator cuff tears as verified by imaging or operative reports., Methods: We performed a case-control study of patients with and without symptomatic rotator cuff tears by use of the Vanderbilt University Medical Center de-identified electronic medical record system, the Synthetic Derivative, with records on >2.5 million patients from 1998 to 2017. Cases and controls were confirmed by individual chart review and review of imaging and/or operative notes. A final set of 11 variables were analyzed as potential risk factors for cuff tears: age, sex, body mass index (BMI), race, smoking history, hypertension, depression/anxiety, dyslipidemia, carpal tunnel syndrome, overhead activity, and affected side. Multivariable logistic regression was used to estimate the association between predictor variables and the risk of having a rotator cuff tear., Results: A total of 2738 patients were selected from the Synthetic Derivative, which included 1731 patients with rotator cuff tears and 1007 patients without rotator cuff tears. Compared with individuals without tears, those with rotator cuff tears were more likely to be older (odds ratio [OR], 2.44; 95% confidence interval [CI], 2.12-2.89), to have a higher BMI (OR, 1.45; 95% CI, 1.24-1.69), to be of male sex (OR, 1.56; 95% CI, 1.32-1.85), and to have carpal tunnel syndrome (OR, 1.41; 95% CI, 1.03-1.93). Patients with rotator cuff tears were less likely to have left shoulder symptoms (OR, 0.68; 95% CI, 0.57-0.82) and to have depression/anxiety (OR, 0.77; 95% CI, 0.62-0.95) compared with the control group, which had symptomatic shoulder pain without rotator cuff tears., Conclusions: In a large imaging and operative report-verified case-control study, we identified advancing age, male sex, higher BMI, and diagnosis of carpal tunnel syndrome as risk factors significantly associated with an increased risk of rotator cuff tears. Left shoulder symptoms and depression/anxiety were less likely to be associated with rotator cuff tears compared with symptomatic shoulders without rotator cuff tears. Contrary to some prior reports in the literature, smoking was not associated with rotator cuff tears., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Acquired resistance to BRAF/MEK-targeted therapy occurs in the majority of melanoma patients that harbor BRAF mutated tumors, leading to relapse or progression and the underlying mechanism is unclear in many cases. Using multiplex immunohistochemistry and spatial imaging analysis of paired tumor sections obtained from 11 melanoma patients prior to BRAF/MEK-targeted therapy and when the disease progressed on therapy, we observed a significant increase of tumor cellularity in the progressed tumors and the close association of SOX10 + melanoma cells with CD8 + T cells negatively correlated with patient's progression-free survival (PFS). In the TCGA-melanoma dataset (n = 445), tumor cellularity exhibited additive prognostic value in the immune score signature to predict overall survival in patients with early-stage melanoma. Moreover, tumor cellularity prognoses OS independent of immune score in patients with late-stage melanoma., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases., (© 2022. The Author(s).)

Background: While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy., Methods: Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF wt and BRAF mut melanoma and analyzed in reference to patient data., Results: RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8 + cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40 + SOX10 + melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB., Conclusions: Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone., Trial Registration: NCT01205815 (Sept 17, 2010).

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI., Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS., Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8 + T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8 + T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8 + T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors., Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

Background: A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort., Research Question: The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis., Study Design and Methods: In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses., Results: The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24)., Interpretation: Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Although rotator cuff tear is one of the most common musculoskeletal disorders, its etiology is poorly understood. We assessed factors associated with the presence of rotator cuff tears in a cohort of patients with shoulder pain., Design: From February 2011 to July 2016, a longitudinal cohort of patients with shoulder pain was recruited. Patients completed a detailed questionnaire in addition to a magnetic resonance imaging scan and a clinical shoulder evaluation. The association of multiple factors associated with rotator cuff tears was assessed using multivariate logistic regression., Results: In our cohort of 266 patients, 61.3% of patients had a rotator cuff tear. Older age (per 1 yr: odds ratio = 1.03, 95% confidence interval = 1.02-1.07), involvement of the dominant shoulder (odds ratio = 2.02, 95% confidence interval = 1.16-3.52), and a higher body mass index (per 1 kg/m2: odds ratio = 1.06, 95% confidence interval = 1.03-1.12) were independently associated with rotator cuff tears. Sex, depression, smoking status, shoulder use at work, hypertension, and diabetes were not significantly associated with rotator cuff tear., Conclusions: In a cohort of patients with shoulder pain, we identified older age, involvement of the dominant shoulder, and a higher body mass index to be independently associated with rotator cuff tear. The mechanism of how these factors possibly lead to rotator cuff tears needs further research., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME., Cme Objectives: Upon completion of this article, the reader should be able to: (1) Identify factors associated with an increased risk of developing rotator cuff tears in adults; (2) Describe the current epidemiological trends of rotator cuff tears in the United States; and (3) Discuss the pathophysiological role of aging in the development of nontraumatic rotator cuff tears., Level: Advanced., Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity., Competing Interests: GDA receives all of his funding from the NIH or NCI grants. Ten percent of his effort is funded through the Center of Quantitative Sciences at Vanderbilt, which has a contractual agreement with a principle investigator who has a funding arrangement with Incyte Corporation. GDA is a journal editor for Journal of Elbow and Shoulder Surgery, receiving a stipend for his reviews. LDH is an employee of Arthrex, Inc. KMB receives speaking and consulting fees from Wright Medical and speaking fees from Arthrex (potential conflicts of interest are not directly related to this research). Others authors have no disclosures to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment (TME) contributes to cancer immune evasion. MDSCs express the chemokine receptor CXCR2, and inhibiting CXCR2 suppresses the recruitment of MDSCs into the tumor and the premetastatic niche. Here, we compared the growth and metastasis of melanoma and breast cancer xenografts in mice exhibiting or not exhibiting targeted deletion of Cxcr2 in myeloid cells (CXCR2 myeΔ/Δ vs. CXCR2 myeWT ). Detailed analysis of leukocyte populations in peripheral blood and in tumors from CXCR2 myeΔ/Δ mice revealed that loss of CXCR2 signaling in myeloid cells resulted in reduced intratumoral MDSCs and increased intratumoral CXCL11. The increase in intratumoral CXCL11 was derived in part from tumor-infiltrating B1b cells. The reduction in intratumoral MDSCs coupled with an increase in intratumoral B1b cells expressing CXCL11 resulted in enhanced infiltration and activation of effector CD8 + T cells in the TME of CXCR2 myeΔ/Δ mice, accompanied by inhibition of tumor growth in CXCR2 myeΔ/Δ mice compared with CXCR2 myeWT littermates. Treatment of tumor-bearing mice with a CXCR2 antagonist (SX-682) also inhibited tumor growth, reduced intratumoral MDSCs, and increased intratumoral B1b cells expressing CXCL11, leading to an increase in activated CD8 + T cells in the tumor. Depletion of B220 + cells or depletion of CD8 + T cells reversed the tumor-inhibitory properties in CXCR2 myeΔ/Δ mice. These data revealed a mechanism by which loss of CXCR2 signaling in myeloid cells modulates antitumor immunity through decreasing MDSCs and enriching CXCL11-producing B1b cells in the TME, which in turn increases CD8 + T-cell recruitment and activation in tumors., (©2020 American Association for Cancer Research.)

Background: Back pain is a leading reason for seeking care in the United States (US), and is a major cause of morbidity., Objective: To analyze demographic, patient, and visit characteristics of adult ambulatory spine clinic visits in the United States from 2009-2016., Methods: Data from the National Ambulatory Medical Care Survey from 2009-2016 were used and were sample weighted., Results: Most patients presenting for ambulatory spine care were 45-64 years (45%), were most commonly female (56.8%), and private insurance (45%) and Medicare (26%) were most common payors. The percentage of visits for spine care done at a primary care setting was 50.1% in 2009-2010 and 48.3% in 2014-2015. Approximately 15.5% were seen in orthopedic surgery clinics in 2009-2010 and 7.3% in 2015-2016. MRI was utilized in 11.7% in 2009-2010 and 11.0% in 2015-2016. Physical therapy was prescribed in 13.2% and narcotic analgesic medications were prescribed in 36.2% of patients in 2015-2016., Conclusions: MRI was used more frequently than guidelines recommended, and physical therapy was less frequently utilized despite evidence. A relatively high use of opiates in treatment of back pain was reported and is concerning. Although back pain represents a substantial public health burden in the United States, the delivery of care is not evidence-based.

Background: The treatment of patients who sustain a first-time anterior glenohumeral dislocation (FTAGD) is controversial. The purpose of this study was to find consensus among experts using a validated iterative process in the treatment of patients after an FTAGD., Methods: The Neer Circle is an organization of shoulder experts recognized for their service to the American Shoulder and Elbow Surgeons. Consensus among 72 identified experts from this group was sought with a series of surveys using the Delphi process. The first survey used open-ended questions designed to identify patient-related features that influence treatment decisions after an FTAGD. The second survey used a Likert scale to rank each feature's impact on treatment decisions. The third survey used highly impactful features to construct 162 clinical scenarios. For each scenario, experts recommended surgery or not and reported how strongly they made their recommendation. These data were analyzed to find clinical scenarios that had >90% consensus for recommending treatment. These data were also used in univariate and multivariate mixed-effects models to identify odds ratios (ORs) for different features and to assess how combining these features influenced the probability of surgery for specific populations., Results: Of the 162 scenarios, 8 (5%) achieved >90% consensus for recommending surgery. All of these scenarios treated athletes with meaningful bone loss at the end of their season. In particular, for contact athletes aged > 14 years who were at the end of the season and had apprehension and meaningful bone loss, there was >90% consensus for recommending surgery after an FTAGD, with surgeons feeling very strongly about this recommendation. Of the scenarios, 22 (14%) reached >90% consensus for recommending nonoperative treatment. All of these scenarios lacked meaningful bone loss. In particular, surgeons felt very strongly about recommending nonoperative treatment after an FTAGD for non-athletes lacking apprehension without meaningful bone loss. The presence of meaningful bone loss (OR, 6.85; 95% confidence interval, 6.24-7.52) and apprehension (OR, 5.60; 95% confidence interval, 5.03-6.25) were the strongest predictors of surgery. When these 2 features were combined, profound effects increasing the probability of surgery for different populations (active-duty military, non-athletes, noncontact athletes, and contact athletes) were noted, particularly non-athletes., Conclusion: Consensus for recommending treatment of the FTAGD patient was not easily achieved. Certain combinations of patient-specific factors, such as the presence of meaningful bone loss and apprehension, increased the probability of surgery after an FTAGD in all populations. Over 90% of shoulder instability experts recommend surgery after an FTAGD for contact athletes aged > 14 years at the end of the season with both apprehension and meaningful bone loss. Over 90% of experts would not perform surgery after a first dislocation in patients who are not athletes and who lack apprehension without meaningful bone loss., (Copyright © 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Purpose: Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic "incidentalomas," particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions., Experimental Design: Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. In vivo imaging was performed with [ 18 F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated., Results: TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [ 18 F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS., Conclusions: We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery., (©2020 American Association for Cancer Research.)

Background: A lack of studies with large sample sizes of patients with rotator cuff tears is a barrier to performing clinical and genomic research., Objective: To develop and validate an electronic medical record (EMR)-based algorithm to identify individuals with and without rotator cuff tear., Design: We used a deidentified version of the EMR of more than 2 million subjects. A screening algorithm was applied to classify subjects into likely rotator cuff tear and likely normal rotator cuff groups. From these subjects, 500 likely rotator cuff tear and 500 likely normal rotator cuff were randomly chosen for algorithm development. Chart review of all 1000 subjects confirmed the true phenotype of rotator cuff tear or normal rotator cuff based on magnetic resonance imaging and operative report. An algorithm was then developed based on logistic regression and validation of the algorithm was performed., Results: The variables significantly predicting rotator cuff tear included the number of times a Current Procedural Terminology code related to rotator cuff procedures was used (odds ratio [OR] = 3.3; 95% confidence interval [CI]: 1.6-6.8 for ≥3 vs 0), the number of times a term related to rotator cuff lesions occurred in radiology reports (OR = 2.2; 95% CI: 1.2-4.1 for ≥1 vs 0), and the number of times a term related to rotator cuff lesions occurred in physician notes (OR = 4.5; 95% CI: 2.2-9.1 for 1 or 2 times vs 0). This phenotyping algorithm had a specificity of 0.89 (95% CI: 0.79-0.95) for rotator cuff tear, area under the curve (AUC) of 0.842, and diagnostic likelihood ratios (DLRs), DLR+ and DLR- of 5.94 (95% CI: 3.07-11.48) and 0.363 (95% CI: 0.291-0.453)., Conclusion: Our informatics algorithm enables identification of cohorts of individuals with and without rotator cuff tear from an EMR-based data set with moderate accuracy., (© 2020 American Academy of Physical Medicine and Rehabilitation.)

Purpose: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN , and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy., Experimental Design: To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein-phosphoprotein changes, were analyzed., Results: One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAF V600WT tumors responded to KRT-232 treatment alone while BRAF V600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors., Conclusions: KRT-232 is an effective therapy for the treatment of either BRAF WT or PAN WT (BRAF WT , NRAS WT ) TP53 WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAF V600 -mutant tumors., (©2020 American Association for Cancer Research.)

Background: Comparative time to recovery after operative and nonoperative treatment for rotator cuff tears is an important consideration for patients. Hence, we compared the time to achieve clinically meaningful reduction in shoulder pain and function after treatment., Methods: From February 2011 to June 2015, a multicenter cohort of patients with rotator cuff tears undergoing operative or nonoperative treatment was recruited. After propensity score weighting, the Kaplan-Meier method was used to estimate the time to achieve a minimal clinically important difference (MCID), >30% reduction, and >50% reduction in the Shoulder Pain and Disability Index (SPADI) and the American Shoulder and Elbow Surgeons (ASES) scores. (In our analysis, both ASES and SPADI were coded such that a lower number corresponded to a better outcome; thus, the word "reduction" was used to indicate improvement in both ASES and SPADI scores.) A 2-stage test was conducted to detect a difference between the 2 groups., Results: In this cohort, 96 patients underwent nonoperative treatment and 73 patients underwent a surgical procedure. The surgical treatment group and the nonoperative treatment group were significantly different with respect to SPADI and ASES scores (p < 0.05). The maximum difference between groups in achievement of the MCID for the SPADI scores was at 3.25 months, favoring the nonoperative treatment group. The probability to achieve the MCID was 0.06 (95% confidence interval [CI], 0.00 to 0.12) for the surgical treatment group compared with 0.40 (95% CI, 0.29 to 0.50) for the nonoperative treatment group. The surgical treatment group had a greater probability of achieving >50% reduction in SPADI scores at 15.49 months (0.20 [95% CI, 0.12 to 0.29] for the surgical treatment group compared with 0.04 [95% CI, 0.00 to 0.09] for the nonoperative treatment group). The surgical treatment group had a greater probability of achieving >50% reduction in ASES scores at 24.74 months (0.96 [95% CI, 0.84 to 0.99] for the surgical treatment group compared with 0.66 [95% CI, 0.53 to 0.75] for the nonoperative treatment group). The differences for >30% reduction in SPADI and ASES scores and the MCID for ASES scores were not significant., Conclusions: Patients undergoing nonoperative treatment had significantly better outcomes in the initial follow-up period compared with patients undergoing a surgical procedure, but this trend reversed in the longer term. These data can be used to inform expectations for nonoperative and operative treatments for rotator cuff tears., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Importance: Although rates of arthroscopy have substantially increased, recent data question its comparative effectiveness., Objectives: To assess time trends and geographical variations among several US states in arthroscopy rates and to assess the association of orthopedist density with arthroscopy rates., Design, Setting, and Participants: In this cross-sectional study, procedure rates were calculated for knee arthroscopy, shoulder arthroscopy, and arthroscopic rotator cuff repair using data from the State Ambulatory Surgery and Services Databases for 2006 to 2016 (as available) for the states of California, Colorado, Florida, Iowa, Kentucky, Maryland, Maine, Michigan, Minnesota, North Carolina, Nebraska, New Jersey, Nevada, New York, Oregon, Utah, Vermont, and Wisconsin. Data were analyzed from June 2017 to October 2019., Main Outcomes and Measures: Rates of knee arthroscopy, shoulder arthroscopy, and arthroscopic rotator cuff repair., Results: The combined data sets included 4 856 385 records with 2 530 840 female patients (47%); mean (SD) patient age was 49.13 (16.34) years. Rates per 100 000 persons showed large geographical variations for knee arthroscopy (from 63.31 [95% CI, 5.92-198.95] to 721.72 [95% CI, 633.41-806.20]), shoulder arthroscopy (from 53.02 [95% CI, 2.80-164.36] to 438.25 [95% CI, 399.00-476.78]), and arthroscopic rotator cuff repair (from 11.94 [95% CI, 1.30-56.98] to 185.35 [95% CI, 143.84-226.20]) across US states and years. There were significant downward time trends in knee arthroscopy rates in California, Florida, Iowa, Maryland, Michigan, Nebraska, and New Jersey and upward trends for arthroscopic rotator cuff repair in Colorado, Florida, Kentucky, Maine, and North Carolina. Orthopedist density was not associated with knee arthroscopy rates (slope = 3.07; 95% CI, -9.88 to 16.03; P = .54), shoulder arthroscopy rates (slope = 2.74; 95% CI, -6.53 to 12.01; P = .47), or rates of arthroscopic rotator cuff repair (slope = 1.15; 95% CI, -2.77 to 5.05; P = .49)., Conclusions and Relevance: There is large geographical variation in arthroscopy rates despite the questionable comparative effectiveness of these procedures. The reasons for increasing rates of rotator cuff surgery should be further examined.

Background: The evidence to support operative versus nonoperative treatment for rotator cuff tears is sparse and inconclusive., Purpose: To assess pain and functional outcomes in patients undergoing operative and nonoperative treatments for rotator cuff tears., Study Design: Cohort study; Level of evidence, 3., Methods: From March 2011 to February 2015, a multicenter cohort of patients with rotator cuff tears undergoing operative and nonoperative treatments was recruited. Patients completed a detailed history questionnaire, the Shoulder Pain and Disability Index (SPADI), and the American Shoulder and Elbow Surgeons (ASES) standardized form and underwent magnetic resonance imaging. In addition to baseline assessments, patients received follow-up questionnaires at 3, 6, 12, and 18 months. Propensity score weighting was used to balance differences in characteristics of the operative and nonoperative groups., Results: Adjusted for propensity scores, the operative (n = 50) and nonoperative (n = 77) groups had similar characteristics, as evidenced by the small standardized mean differences between the groups. Adjusted mean differences in the SPADI and ASES scores between the operative and nonoperative groups were -22.0 points (95% CI, -32.1 to -11.8) and -22.2 points (95% CI, -32.8 to -11.6) at 18 months, respectively. The operative group had a significantly higher proportion of patients who showed ≥30% ( P = .002) and ≥50% ( P < .0001) improvement in SPADI and ASES scores as compared with the nonoperative group., Conclusion: In this prospective cohort study, patients undergoing operative treatment had significantly better pain and functional outcomes as compared with patients undergoing nonoperative treatment for rotator cuff tears. Differences between the 2 groups in SPADI and ASES scores at the 6- to 18-month time points met the minimal clinically important difference (depending on the threshold used). A large randomized controlled trial is needed to answer this question more definitively.

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Importance: Rotator cuff disorders remain the most common cause of shoulder pain and are among the most common reasons for patients to seek care in primary and specialty settings. Although operative and nonoperative treatments are offered to patients with atraumatic rotator cuff tears, there is a lack of evidence to support operative vs nonoperative treatment. This paucity of evidence has been highlighted by several professional agencies and experts., Objective: To perform a pragmatic randomized clinical trial, the Arthroscopic Rotator Cuff trial, comparing pain and functional outcomes in patients undergoing operative vs nonoperative treatment for atraumatic rotator cuff tears, and assessing heterogeneity of treatment effects by age and tear size., Design, Setting, and Participants: Trial protocol of the Arthroscopic Rotator Cuff trial. This pragmatic randomized clinical trial of an estimated 700 patients is adequately powered to accomplish its aims with 488 patients. Primary analysis will be conducted on an intent-to-treat population in the context of a mixed model. The multicenter trial started recruitment in 2018 with a 1-year follow-up duration. Patients aged 50 years or older to younger than 85 years with magnetic resonance imaging-confirmed atraumatic rotator cuff tears that are suitable for either operative or nonoperative treatment will be enrolled. Block randomization will be performed and stratified by site, age, and tear size., Intervention: Nonoperative treatment consists of an approximately 3-month standardized physical therapy program, whereas operative treatment consists of rotator cuff surgery followed by approximately 4 months of postoperative rehabilitation., Main Outcomes and Measures: The primary outcome is patient-reported Shoulder Pain and Disability Index score, and the secondary outcome is American Shoulder and Elbow Surgeons Standardized Shoulder Form score measured at 1 year of follow-up., Discussion: The Arthroscopic Rotator Cuff trial is ongoing, and 12 sites with more than 40 physicians are currently recruiting patients. Although there is variation by site, as of May 2, 2019, 13% of all patients screened (787 of 6293) were eligible for the trial, and 9% of eligible patients (74 of 787) were recruited. Results of this study may help patients, clinicians, and policy makers assess the comparative effectiveness of operative vs nonoperative treatment for atraumatic rotator cuff tears., Trial Registration: ClinicalTrials.gov identifier: NCT03295994.

Background: The American Shoulder and Elbow Surgeons Standardized Shoulder Form (ASES), the Shoulder Pain and Disability Index (SPADI), and the shortened Disability of the Arm, Shoulder, and Hand (quickDASH) are patient-reported upper extremity-specific outcome scales currently used to evaluate patients with rotator cuff tears. This heterogeneity does not allow for a uniform metric for research and patient care., Questions/purposes: Our objective was to determine psychometric properties (reliability, convergent and discriminant validity, and responsiveness) of five commonly used outcome instruments (the ASES, the SPADI, the quickDASH, the SF-12, and the EuroQol-5D) in a longitudinal study of patients undergoing treatment for rotator cuff tears., Methods: From February 2011 through June 2015, 120 patients completed a standardized history, the five outcome scales under study, a physical examination, and an MRI. Of these, 47 (39%) were lost to followup before 18 months, and another 24 (20%) were accounted for at 18 months but had missing data at one or more of the earlier prespecified followup intervals (3, 6, or 12 months). Reliability (the reproducibility of an outcome instrument between subjects; tested by Cronbach's alpha), convergent and discriminant validity (determining which outcome measures correlate most strongly with others; tested by Spearman's correlation coefficients), and responsiveness (the change in outcome scales over time based on percent improvement in shoulder functionality using the minimal clinically important difference [MCID] and the subjective shoulder value) were calculated., Results: All outcomes measures had a Cronbach's alpha above 0.70 (range, 0.74-0.94) and therefore were considered reliable. Convergent validity was demonstrated as the upper extremity-specific measures (SPADI, ASES, and quickDASH) were more strongly correlated with each other (rho = 0.74-0.81; p < 0.001) than with any of the other measures. Discriminant validity was demonstrated because the Spearman's correlation coefficients were stronger for the relationships between upper extremity measures compared with the correlations between upper extremity measures and general health measures for 53 of the 54 correlations that were compared. Both internal and external responsiveness of the measures was supported. Patients who achieved the MCID and at least a 30% change on the subjective shoulder value had more positive change in scores over time compared with those who did not. Mixed model linear regressions revealed that all three upper extremity-specific measures had a group by time interaction for the MCID, indicating that patients who achieved the MCID had greater change over time compared with those who did not achieve the MCID. Results showed that the measure with the best discrimination between groups, or best internal responsiveness, was the ASES (beta = -8.26, 95% confidence interval [CI], -11.39 to -5.14; p < 0.001; η = 0.089) followed by the SPADI (beta = 6.88, 95% CI, 3.78-9.97; p < 0.001; η = 0.088) then the quickDASH (beta = 3.43, 95% CI, 0.86-6.01; p = 0.009, η = 0.027). Measures with the best external responsiveness followed the same pattern of results., Conclusions: All the upper extremity-specific scales had acceptable psychometric properties. Correlations were high and thus only one upper extremity-specific instrument is needed for outcome assessment. Given the overall psychometric assessment, we recommend SPADI be the shoulder-specific instrument used to assess outcomes in patients with rotator cuff tears., Level of Evidence: Level III, diagnostic study.

Background: We compared the outcomes of patients who performed physical therapy versus those who did not in a longitudinal cohort of patients undergoing nonoperative treatment of rotator cuff tears. We also assessed whether there was a dose effect in which the pain and functional outcomes in patients performing physical therapy plateaued., Methods: From February 2011 to June 2015, a multicenter cohort of patients with rotator cuff tears undergoing nonoperative treatment completed a detailed health and demographic questionnaire and the Shoulder Pain and Disability Index (SPADI) at baseline and 3, 6, 12, and 18 months. Longitudinal mixed models were used to assess whether physical therapy in the first 3 months predicted SPADI scores and dose effect., Results: Among the 55 patients in our cohort, the performance of physical therapy within the first 3 months predicted better SPADI scores versus nonperformance of physical therapy at 3 months (P = .02). Scores were similar between groups at 6, 12, and 18 months. A threshold of 16 physical therapy sessions was observed for pain and functional improvement during follow-up, after which significant improvement was not seen., Conclusions: Patients who performed physical therapy within the first 3 months had statistically significant improvements in pain and function as measured by the SPADI score at 3 months compared with patients who did not report performing physical therapy. Depending on the minimal clinically important difference used for the SPADI score, our results could be interpreted as meeting the minimal clinically important difference threshold or not. Improvement in outcomes was observed up to 16 sessions of physical therapy, after which outcomes plateaued., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML. See related commentary by Leber et al., p. 1511 . This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)

The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4 MyeΔ/Δ ) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4 MyeΔ/Δ mice exhibited slowed tumor progression compared with CXCR4 WT mice in an inducible melanocyte Braf V600E /Pten -/- mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4 MyeΔ/Δ mice as compared with myeloid cells from CXCR4 WT mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4 MyeΔ/Δ mice. NK cells from CXCR4 MyeΔ/Δ mice also exhibited increased tumor cell killing capacity in vivo , based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4 MyeΔ/Δ neutrophils. Furthermore, enhanced NK cell activity in CXCR4 MyeΔ/Δ mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4 WT mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. Cancer Immunol Res; 6(10); 1186-98. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1 + CD4 + T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4 + T cells. PD-1 + T helper 17 cells are the predominant CD4 + T cell subset expressing TGF-β. Coculture of PD-1 + CD4 + T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4 + T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1 + CD4 + T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Optimal patient selection is key to the success of nonoperative treatment for rotator cuff tears., Purpose: To assess the predictors of pain and functional outcomes in a longitudinal cohort of patients undergoing nonoperative treatment., Study Design: Cohort study; Level of evidence, 2., Methods: A multicenter cohort of patients with rotator cuff tears undergoing nonoperative treatment was recruited from March 2011 to February 2015. Patients completed a detailed health questionnaire, completed standardized shoulder questionnaires including the Shoulder Pain and Disability Index (SPADI), and underwent magnetic resonance imaging. In addition to baseline assessments, patients received follow-up questionnaires at 3, 6, 12, and 18 months. Longitudinal mixed models were used to test predictors of the SPADI score, and interactions with time were assessed., Results: In our cohort of 70 patients, being married as compared with being single/divorced/widowed ( P = .02), a shorter duration of symptoms ( P = .02), daily shoulder use at work that included light or no manual labor versus moderate or heavy manual labor ( P = .04), alcohol use of 1 to 2 times per week or more as compared with 2 to 3 times per month or less ( P = .007), and absence of fatty infiltration ( P = .0009) were significantly associated with decreased SPADI scores (improved shoulder pain and disability) over time. When interactions with time were assessed, having a college level of education or higher compared with less than a college education showed a differential effect over time, with those with a college level of education or more having lower SPADI scores ( P = .004). Partial-thickness tear versus full-thickness tear also had an interaction with follow-up duration, such that those with a partial-thickness tear had lower SPADI scores ( P = .0002)., Conclusion: Longitudinal predictors of better outcomes of the nonoperative treatment of rotator cuff tears included being married, having at least a college education, shorter duration of symptoms, light or manual labor in daily work, alcohol use of 1 to 2 times per week or more, partial-thickness tear, and absence of fatty infiltration of the rotator cuff. Our results suggest that nonoperative treatment should be performed early for optimal outcomes. These data can be used to select optimal candidates for the nonoperative treatment of rotator cuff tears and to assist with patient education and expectations before treatment., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This project was supported by the Clinical and Translational Science Awards program (CTSA No. UL1TR000445) from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. N.B.J. is supported by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (1K23AR059199 and 1U34AR069291). K.B. has received consulting fees from Wright Medical Group and educational support from Arthrex. E.M. has received educational support from NuVasive and Smith & Nephew. L.D.H. has received educational support from Arthrex and Ethicon.

Background: Embryonal tumors arise typically in infants and young children and are often massive at presentation. Operative resection is a cornerstone in the multimodal treatment of embryonal tumors but potentially disrupts therapeutic timelines. When used appropriately, minimally invasive surgery can minimize treatment delays. The oncologic integrity and safety attainable with minimally invasive resection of embryonal tumors, however, remains controversial., Methods: Query of the Vanderbilt Cancer Registry identified all children treated for intracavitary, embryonal tumors during a 15-year period. Tumors were assessed radiographically to measure volume (mL) and image-defined risk factors (neuroblastic tumors only) at time of diagnosis, and at preresection and postresection. Patient and tumor characteristics, perioperative details, and oncologic outcomes were compared between minimally invasive surgery and open resection of tumors of comparable size., Results: A total of 202 patients were treated for 206 intracavitary embryonal tumors, of which 178 were resected either open (n = 152, 85%) or with minimally invasive surgery (n = 26, 15%). The 5-year, relapse-free, and overall survival were not significantly different after minimally invasive surgery or open resection of tumors having a volume less than 100 mL, corresponding to the largest resected with minimally invasive surgery (P = .249 and P = .124, respectively). No difference in margin status or lymph node sampling between the 2 operative approaches was detected (p = .333 and p = .070, respectively). Advantages associated with minimally invasive surgery were decreased blood loss (P < .001), decreased operating time (P = .002), and shorter hospital stay (P < .001). Characteristically, minimally invasive surgery was used for smaller volume and earlier stage neuroblastic tumors without image-defined risk factors., Conclusion: When selected appropriately, minimally invasive resection of pediatric embryonal tumors, particularly neuroblastic tumors, provides acceptable oncologic integrity. Large tumor volume, small patient size, and image-defined risk factors may limit the broader applicability of minimally invasive surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Heat shock protein 90 regulates multiple signaling proteins involved in key pathways of pancreatic cancer pathogenesis. Ganetespib binds to heat shock protein 90 and interferes with its binding to client proteins thus leading to inactivation and degradation of the signaling proteins that promote cancer progression. This phase II study was designed to evaluate the efficacy of ganetespib in patients with refractory metastatic pancreatic cancer (rMPC)., Methods: Patients with rMPC received 175 mg/m ganetespib intravenously once weekly for 3 weeks in 4-week cycles. Primary endpoint was disease control rate at 8 weeks, with a goal of 70%. Secondary endpoints were progression-free survival, overall survival, and safety. Simon's 2-stage design was used to assess futility and efficacy. Ganetespib was considered inactive if ≤8 patients among the first 15 treated had disease control after 8 weeks of treatment., Results: Fourteen patients were treated on study. Grade 3 treatment-related toxicities were diarrhea, abdominal pain, fatigue, nausea, vomiting, and hyponatremia. Disease control rate at 8 weeks was 28.6%, and median progression-free survival and overall survival were 1.58 months and 4.57 months, respectively. Early stopping rules for lack of clinical efficacy led to study closure., Conclusions: Single-agent ganetespib was tolerable with only modest disease control in rMPC. This disease is resistant to chemotherapy, and given the emerging data in lung and rectal cancers, as well as in pancreatic cancer cell lines, suggesting improved activity of ganetespib in combination with cytotoxic agents, studies combining this agent with chemotherapy in rMPC are more likely to yield success.

Background: Optimal patient selection is key to success of operative treatment for cuff tears. We assessed predictors of pain and functional outcomes in a longitudinal cohort of patients undergoing operative treatment., Methods: From March 2011 to January 2015, a cohort of patients with rotator cuff tears undergoing rotator cuff surgery was recruited. Patients completed a detailed health and demographic questionnaire, standardized shoulder questionnaires, including the Shoulder Pain and Disability Index (SPADI), and underwent a magnetic resonance imaging scan. Patients received follow-up questionnaires at 3, 6, 12, and 18 months. We assessed longitudinal predictors of SPADI using longitudinal mixed models. Interactions with follow-up duration after surgery were also assessed., Results: In our analysis (n = 50), a lower Fear-Avoidance Beliefs Questionnaire physical activity score (P = .001) predicted a lower SPADI score (better shoulder pain and function). Those consuming alcohol 1 to 2 times per week or more had lower SPADI scores than those consuming alcohol 2 to 3 times per month or less (P = .017). Both of these variables had a significant interaction with duration of follow-up. Variables that were not significant predictors of SPADI included sociodemographic characteristics, magnetic resonance imaging characteristics, such as tear size and muscle quality, shoulder strength, and variations in surgical techniques/performance of adjuvant surgical procedures., Conclusions: Those with higher fear avoidance behavior and alcohol use of 1 to 2 times per week had worse shoulder pain and function at 18 months of follow-up. These data can be used to select optimal candidates for operative treatment of rotator cuff tears and assist with patient education and expectations before treatment., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Rotator cuff tears are the leading cause of shoulder pain and disability. However, the diagnosis of a rotator cuff tear based on patient characteristics, symptoms, and physical examination findings remains a challenge because of a lack of data. Moreover, data on the predictive ability of a combination of these characteristics and tests are not available from a large cohort of patients. Consequently, clinicians rely on expensive imaging, such as magnetic resonance imaging (MRI), to make a diagnosis., Purpose: To model patient characteristics, symptoms, and physical examination findings that predict a rotator cuff tear. We present a nomogram based on our predictive model that can be used in patients with shoulder pain to determine the probability of the diagnosis of a rotator cuff tear without the need for imaging., Study Design: Cohort study (diagnosis); Level of evidence, 2., Methods: We recruited patients from outpatient clinics who were ≥45 years of age and who had shoulder pain of at least 4 weeks' duration. A rotator cuff tear was diagnosed based on expert clinical impression and the presence/absence of a tear on a blinded review of MRI. Ultimately, 301 patients were included in the analysis., Results: A total of 123 patients (41%) had rotator cuff tears, and 178 patients (59%) did not. The predictors of the diagnosis of a rotator cuff tear included external rotation strength ratio of the affected versus unaffected shoulder (odds ratio [OR], 1.20 [95% CI, 1.08-1.34]), male sex (OR, 1.98 [95% CI, 1.10-3.56]), positive lift-off test result (OR, 4.33 [95% CI, 1.46-12.86]), and positive Jobe test result (OR, 9.19 [95% CI, 4.69-17.99]). A nomogram based on these predictor variables was plotted., Conclusion: Presented is a model that can accurately predict the diagnosis of a rotator cuff tear with satisfactory discrimination and calibration based on 4 variables: sex, lift-off test, Jobe test, and external rotation strength ratio. Data from this study can be used to aid in the diagnosis of a rotator cuff tear in day-to-day clinical practice in outpatient settings without the need for expensive imaging such as MRI., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by a Clinical and Translational Science Award (No. UL1TR000445) from the National Center for Advancing Translational Sciences. N.B.J. has grants/grants pending from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants 1K23AR059199 and 1U34AR069201). L.D.H. has received educational support from Arthrex and Ethicon.

Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations., (Copyright © 2017. Published by Elsevier B.V.)

Purpose: Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity. Experimental Design: The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kγ -null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice and PI3Kγ null versus PI3Kγ WT mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice. Results: Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of PI3Kγ in the host. The antitumor effect of PI3Kγ loss in host, but not tumor, was partially reversed by CD8 + T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone. Conclusions: PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer. Clin Cancer Res; 23(13); 3371-84. ©2016 AACR ., (©2016 American Association for Cancer Research.)