A distinct group of individuals in a nonselected population demonstrates a persistently low lung function trajectory that may be partly established at birth and predisposes them to chronic obstructive pulmonary disease later in life.

Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs) in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP) studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP).F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested F-FDG PET andF-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Patients with bone-dominant MBC were imaged withF-FDG PET and F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUV) and lean body mass adjusted standardized uptake (SUL) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and F-FDG PET andF-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Twenty-eight patients were evaluated. HigherF-FDG SUL at scan2 predicted shorter time to tSRE ( = <0.001) and TTP ( = 0.044). Higher F-FDG SUV at scan2 predicted a shorter time to tSRE ( = <0.001). A multivariable model using F-FDG SUV of the index lesion at scan1 plus the difference in SUV of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) ( = 0.007, 0.028, respectively), with a trend toward improved survival ( = 0.1). An increase in the uptake between scans of up to 5 lesions by F-NaF PET was associated with longer OS ( = 0.027). Changes inF-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC.

PURPOSE: Lung cancer remains the leading cause of cancer death in the United States, with outcomes likely worsened by the presence of poorer outcomes among vulnerable populations such as the homeless. We hypothesized that homeless patients experience delays in biopsy, decreased appointment adherence, and increased overall mortality rates. METHODS: We conducted a retrospective electronic medical record–based review of all patients with non–small-cell lung cancer (NSCLC; N = 133) between September 2012 and September 2018 at an academic county hospital in Seattle, Washington. RESULTS: Of the 133 patients treated for NSCLC, 22 (17%) were homeless at the time of their treatment. Among homeless patients with localized lung cancer, the mean time from radiographic finding to biopsy was 248 days, compared with 116 days among housed patients ( P = .37). Homeless patients with advanced disease missed a mean of 26% of appointments in the year after diagnosis, compared with 16% among housed patients ( P = .03). Homeless patients with advanced NSCLC had a median survival of 0.58 years, versus 1.30 years in housed patients ( P = .48). CONCLUSION: To our knowledge, this is the first US study comparing outcomes among homeless and housed patients with NSCLC within the same institution; we found homeless patients had longer delays to biopsy, increased rates of missed appointments, and a trend toward decreased survival. This study shows potential areas where interventions could be implemented to improve lung cancer outcomes in this patient population.

Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D+ cancer cells have stem-like capacities, and provide formal in vivo evidence linking NKG2D stimulation with the development and maintenance of these functional states. NKG2D+ ovarian cancer cell populations harbor substantially greater capacities for self-renewing in vitro sphere formation and in vivo tumor initiation in immunodeficient (NOD scid gamma) mice than NKG2D− controls. Sphere formation and tumor initiation are impaired by NKG2D silencing or ligand blockade using antibodies or a newly designed pan ligand-masking NKG2D multimer. In further support of pathophysiological significance, a prospective study of 47 high-grade serous ovarian cancer cases revealed that the odds of disease recurrence were significantly greater and median progression-free survival rates higher among patients with above and below median NKG2D+ cancer cell frequencies, respectively. Collectively, our results define cancer cell NKG2D as an important regulator of tumor initiation in ovarian cancer and presumably other malignancies and thus challenge current efforts in immunotherapy aimed at enhancing NKG2D function.