Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC.

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.

Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer.

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.

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

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.

Does interaction occur between risk factors for revision total knee arthroplasty?

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.

Generation of Orthotopic Patient-Derived Xenografts in Humanized Mice for Evaluation of Emerging Targeted Therapies and Immunotherapy Combinations for Melanoma.

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.

Co-Clinical Imaging Metadata Information (CIMI) for Cancer Research to Promote Open Science, Standardization, and Reproducibility in Preclinical Imaging.

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.

PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in Patients with Myelofibrosis.

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.

Statistical and Methodological Considerations for Randomized Controlled Trial Design in Physical Medicine and Rehabilitation.

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.

Risk of Revision Shoulder Arthroplasty After Anatomic and Reverse Total Shoulder Arthroplasty.

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.

Incidence and Clinical Risk Factors of Post-Operative Complications following Primary Total Hip Arthroplasty: A 10-Year Population-Based Cohort Study.

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.

The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes.

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).

Safety and Efficacy of Avelumab in Small Bowel Adenocarcinoma.

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.

Proximity of immune and tumor cells underlies response to BRAF/MEK-targeted therapies in metastatic melanoma patients.

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.

Risk factors for degenerative, symptomatic rotator cuff tears: a case-control study.

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.

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade.

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 BRAFwt and BRAFmut 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).

Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer.

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.

Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.

Characteristics of ambulatory spine care visits in the United States, 2009-2016.

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.

Factors Associated With Symptomatic Rotator Cuff Tears: The Rotator Cuff Outcomes Workgroup Cohort Study.

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.