Impact of Obesity on the CCR6-CCL20 Axis in Epidermal γδ T Cells and IL-17A Production in Murine Wound Healing and Psoriasis.

Obesity is associated with comorbidities including type 2 diabetes, chronic nonhealing wounds and psoriasis. Normally skin homeostasis and repair is regulated through the production of cytokines and growth factors derived from skin-resident cells including epidermal γδ T cells. However epidermal γδ T cells exhibit reduced proliferation and defective growth factor and cytokine production during obesity and type 2 diabetes. One of the genes modulated in epidermal γδ T cells during obesity and type 2 diabetes is CCR6, which is the receptor for CCL20. CCL20 is elevated in the skin during obesity and type 2 diabetes. Here we identify a subset of murine epidermal γδ T cells that expresses CCR6 in response to activation in vitro and post-wounding or psoriasis induction with imiquimod in vivo. We show that CCL20 stimulates epidermal γδ T cells to produce IL-17 suggesting CCR6 regulates the IL-17 axis as in dermal γδ T cells. Further, epidermal γδ T cells upregulate CCR6 and produce IL-17 during murine models of wound repair and psoriasis. Obesity increases CCR6 and IL-17 expression by epidermal γδ T cells during wound repair but has less of an effect during psoriasis. These findings have novel implications for the regulation of a specific population of IL-17-producing epidermal γδ T cells during skin damage and inflammation.

Compression asphyxia and other clinicopathological findings from the Hillsborough Stadium disaster.

Ninety-six people died following a crowd crush at the Hillsborough Football Stadium, Sheffield, UK in 1989. The cause of death in nearly all cases was compression asphyxia. The clinical and pathological features of deaths encountered in crowds are discussed with a particular focus on the Hillsborough disaster.

Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer.

BACKGROUND: Luminespib (AUY922) is a second-generation heat shock protein 90 (HSP90) inhibitor with demonstrated activity in non-small cell lung cancer (NSCLC). Since luminespib reduces levels of dihydrofolate reductase (DHFR), a key enzymatic target of pemetrexed, we assessed the safety and tolerability of luminespib in combination with pemetrexed in patients with previously treated metastatic non-squamous non-small cell lung cancer (NSCLC). We also sought to study the pharmacokinetics and correlate tumor dihydrofolate reductase (DHFR) expression with clinical response. METHODS: Patients received weekly luminespib at either 40 mg/m2, 55 mg/m2, or 70 mg/m2 according to a standard 3 + 3 dose-escalation design along with pemetrexed at 500 mg/m2 followed by an expansion at the maximum tolerated dose (MTD). RESULTS: Two-dose limiting toxicities (DLTs) were experienced in the 70 mg/m2 cohort, therefore the MTD was determined to be 55 mg/m2. 69% (N = 9) of patients experienced ophthalmologic toxicity related to luminespib. Maximum serum concentration (Cmax) of luminespib was associated with increased grade 2 drug related adverse events (DRAEs) (rs = 0.74, P < 0.01), with volume of distribution (VD) inversely associated with the number of DRAEs (rs = - 0.81, P = 0.004) and ophthalmologic related DRAEs (rs = - 0.65, P = 0.04). The best response was partial response in one patient for 20 months, prior to expiration of all luminespib. Amongst patients treated at the MTD, the objective response rate was 14%. CONCLUSION: In patients with previously treated metastatic NSCLC, the MTD of luminespib in combination with pemetrexed was 55 mg/m2 per week. The combination of luminespib and pemetrexed demonstrated clinical activity. Tolerability of luminespib with pemetrexed is limited by ocular toxicity.

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non-Small-Cell Lung Cancer.

BACKGROUND: Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. METHODS: Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics. RESULTS: Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%). CONCLUSION: Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

Quantitative measurement of HER2 expression in breast cancers: comparison with 'real-world' routine HER2 testing in a multicenter Collaborative Biomarker Study and correlation with overall survival.

INTRODUCTION: Accurate assessment of HER2 status is critical in determining appropriate therapy for breast cancer patients but the best HER2 testing methodology has yet to be defined. In this study, we compared quantitative HER2 expression by the HERmark™ Breast Cancer Assay (HERmark) with routine HER2 testing by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and correlated HER2 results with overall survival (OS) of breast cancer patients in a multicenter Collaborative Biomarker Study (CBS). METHODS: Two hundred and thirty-two formalin-fixed, paraffin-embedded breast cancer tissues and local laboratory HER2 testing results were provided by 11 CBS sites. HERmark assay and central laboratory HER2 IHC retesting were retrospectively performed in a blinded fashion. HER2 results by all testing methods were obtained in 192 cases. RESULTS: HERmark yielded a continuum of total HER2 expression (H2T) ranging from 0.3 to 403 RF/mm2 (approximately 3 logs). The distribution of H2T levels correlated significantly (P<0.0001) with all routine HER2 testing results. The concordance of positive and negative values (equivocal cases excluded) between HERmark and routine HER2 testing was 84% for local IHC, 96% for central IHC, 85% for local FISH, and 84% for local HER2 status. OS analysis revealed a significant correlation of shorter OS with HER2 positivity by local IHC (HR=2.6, P=0.016), central IHC (HR=3.2, P=0.015), and HERmark (HR=5.1, P<0.0001) in this cohort of patients most of whom received no HER2-targeted therapy. The OS curve of discordant low (HER2 positive but H2T low, 10% of all cases) was aligned with concordant negative (HER2 negative and H2T low, HR=1.9, P=0.444), but showed a significantly longer OS than concordant positive (HER2 positive and H2T high, HR=0.31, P=0.024). Conversely, the OS curve of discordant high (HER2 negative but H2T high, 9% of all cases) was aligned with concordant positive (HR=0.41, P=0.105), but showed a significantly shorter OS than concordant negative (HR=41, P<0.0001). CONCLUSIONS: Quantitative HER2 measurement by HERmark is highly sensitive, accurately quantifies HER2 protein expression and correlates well with routine HER2 testing. When HERmark and local HER2 results were discordant, HERmark more accurately predicted overall survival.

Walk and die: an unusual presentation of head injury.

We report three deaths in young adult males following closed blunt trauma to the head and face where the affected individuals were able to walk away from the incident, before subsequently collapsing and dying a short distance from the site of the assault. In each case, due to the rapidity of the posttrauma collapse, the pathologist was faced with a diagnostic difficulty at autopsy; the external examination revealed multiple injuries to the head and face, but internal examinations showed limited findings with no structural explanation for the death. We discuss possible mechanisms that could account for this scenario, the implications of alcohol consumption with a concussive head injury, and parallels that can be drawn with the so-called "talk and die,""talk and deteriorate," and "second impact syndrome." Finally, the possible role of so-called "postexercise peril" is discussed in relation to these deaths.