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Introduction: Sinonasal carcinomas (SNCs) are rare neoplasms that are often diagnosed at advanced stages due to asymptomatic growth of tumours in the spaces of the sinonasal complex. Treatment is associated with high morbidity, and outcomes have only improved slightly in the past few decades despite advancements in treatment modalities. The purpose of this study is to evaluate the efficacy and safety of treatment at our institution., Methods: This retrospective cohort study analysed patients who received definitive treatment at the Prince of Wales Hospital (POWH), Sydney, for non-metastatic SNC. Patients with non-carcinoma and olfactory neuroblastoma pathology were excluded. Data were collected from the POWH electronic patient database. Survival functions were calculated through Kaplan-Meier analysis, and multivariate analysis for prognostic factors was performed through Cox regression., Results: Seventy-five patients from 1994 to 2016 were eligible for analysis. Overall 5-year local control (LC), ultimate local control (ULC), overall survival (OS) and cancer-specific survival (CSS) were 76 ± 6%, 80 ± 5%, 69 ± 6% and 77 ± 5%, respectively. On multivariate analysis, clinical stage was prognostic for LC and primary site was prognostic for OS and CSS. Lymphovascular invasion and tumour inoperability were also predictive of CSS., Conclusion: Survival and local control rates at our centre were greater than those reported in the literature. Early-stage patients treated with surgery alone had excellent oncologic outcomes. Radical surgery with postoperative radiation provides the best outcome in the setting of advanced disease., (© 2020 The Royal Australian and New Zealand College of Radiologists.)

Microfluidic devices are widely used for applications such as cell isolation. Currently, the most common method to improve throughput for microfluidic devices involves fabrication of multiple, identical channels in parallel. However, this 'numbering up' only occurs in one dimension, thereby limiting gains in volumetric throughput. In contrast, macro-fluidic devices permit high volumetric flow-rates but lack the finer control of microfluidics. Here, we demonstrate how a micro-pore array design enables flow homogenization across a magnetic cell capture device, thus creating a massively parallel series of micro-scale flow channels with consistent fluidic and magnetic properties, regardless of spatial location. This design enables scaling in 2-dimensions, allowing flow-rates exceeding 100 mL/hr while maintaining >90% capture efficiencies of spiked lung cancer cells from blood in a simulated circulating tumor cell system. Additionally, this design facilitates modularity in operation, which we demonstrate by combining two different devices in tandem for multiplexed cell separation in a single pass with no additional cell losses from processing.

Background: Telemedicine is an emerging field with numerous applications within medicine. Previous review articles describe its use within plastic surgery and otolaryngology but none, to the authors' knowledge, within dermatologic surgery., Objective: To provide a review of the applications of telemedicine within dermatologic surgery., Materials and Methods: A PubMed search of articles published on teledermatology was conducted in July 2018. Articles were selected based on their relevance to dermatologic surgery and reviewed for their discussion of the applications of telemedicine in surgical and cosmetic dermatology., Results: The initial search resulted in 156 articles. Eleven ultimately met inclusion criteria: 2 in referral and consultation, 5 in telepathology, 2 in intraoperative uses, and 2 in postprocedural care., Conclusion: For preoperative consultation, teledermatology enables the surgeon to plan ahead and increases access to care by reducing the number of clinic visits. Telepathology has the potential to allow intraoperative consultation with a dermatopathologist to achieve accurate tumor clearance without delay. Smartglasses represent a promising technology for greater care coordination and a teaching tool. Postprocedural monitoring via text messaging provides convenient access to expert advice and early detection of postoperative complications. With increasing technologic advancements, telemedicine holds great potential to augment the dermatologic surgeon's daily practice.

Background: Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma., Methods: This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498., Findings: Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia., Interpretation: Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care., Funding: Regeneron Pharmaceuticals and Sanofi., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Purpose: The role of chemoradiation (CRT) in treating patients with early-stage glottic squamous cell carcinoma (SCC), especially for T2N0M0 glottic SCC with impaired vocal cord mobility, remains unexplored. We sought to evaluate the impact of CRT on survival in early-stage glottic SCC by using the SEER database., Patients and Methods: We included patients with localized (T1-4N0M0) glottic SCC (N = 4,743) diagnosed between 2004 and 2014 and treated with definitive radiotherapy (RT) alone, CRT, or laryngectomy alone in the SEER database. Disease-specific mortality (DSM) was evaluated via multivariable regression using a competing risk model that accounts for other-cause mortality as a competing risk event for DSM. One-to-one propensity score matching between CRT and RT cohorts was also performed to facilitate comparison of cumulative DSM and other-cause mortality incidences stratified by T stage., Results: After stratification by T stage, CRT was associated with increased DSM in T1-2N0M0 glottic SCC (adjusted hazard ratios [AHRs], 4.222 and 2.260 for T1 and T2 disease, respectively; P < .001 for both). For T2N0M0 glottic SCC with and without impaired vocal cord mobility, CRT resulted in significantly increased DSM compared with RT alone in both cohorts (AHR, 2.084; P = .046 and AHR, 2.412; P < .001, respectively). After propensity score matching, cumulative incidence plots demonstrated a statistically significant increase in DSM associated with CRT compared with RT alone for both T1 and T2 glottic SCC ( P < .001 and P = .003, respectively)., Conclusion: CRT for T1-2N0M0 glottic SCC was associated with increased DSM compared with RT alone. This pattern persisted upon further stratification on the basis of vocal cord mobility status for T2N0M0 glottic SCC. This finding warrants careful consideration of chemotherapy in early-stage glottic SCC.

Background: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours., Methods: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 μg/kg or 20 μg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449., Findings: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26·9 months (IQR 22·3-31·5) for patients with non-small-cell lung cancer, 33·0 months (29·2-35·1) for those with melanoma, and 22·7 months (20·9-27·0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma)., Interpretation: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma., Funding: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Risk factors predicting progression from low grade to severe mitral regurgitation (MR), which is a guideline criterion for surgical intervention, remain unknown. We hypothesized that abnormalities of cardiac structure and function may predict progression in MR severity. We followed 82 asymptomatic mitral valve prolapse (MVP) patients (65 ± 12 years, 51% men) with mild or moderate MR (36 mild, 46 moderate, mean LVEF: 62%), without significant co-morbidities. We examined clinical findings and 13 echo measurements. The primary end point was progression to severe MR. In a mean follow-up period of 4.5 ± 2.7 years, mortality and heart failure development were similar for mild and moderate MR. No mild MR patient progressed to severe, but 23 moderate MR patients (50.0%) progressed to severe with 9 patients (39.1%) who underwent surgery. No clinical variables were predictive for progression. Only mean mitral annulus diameter (apical 4 and 2 chamber) was predictive for progression to severe MR (hazards ratio 1.14, 95% confidence interval 1.03 to 1.26, p = 0.01). A cut-off annulus diameter of 39.6 mm had a good accuracy (area under the curve 0.78, sensitivity 100%, and specificity 63.8%) for progression to severe. In conclusion, over a 4.5-year period, 50% of asymptomatic MVP patients with moderate MR, but none with mild, progressed to severe MR. Only mitral annular dimension predicted progression of moderate to severe MR, and values >39.6 mm predicted progression accurately. Mitral annulus diameter may be of value in identifying asymptomatic MVP patients at risk of developing severe MR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Since the introduction of the first anti-tumor necrosis factor antibodies in the late 1990s, biologic therapy has revolutionized the medical treatment of patients with inflammatory bowel disease (IBD). Nevertheless, surgery continues to play a significant role in treating IBD patients. Rates of intestinal resection in patients with Crohn's disease or colectomy in ulcerative colitis are reducing but not substantially over the long term. An increasing variety of biologic medications are now available to treat IBD patients in various clinical situations. Consequently, a number of questions persist about how biologic medications affect the need for surgery and overall course in IBD patients. Given the trend for earlier and more frequent use of biologic medications in IBD patients, a working knowledge of the effects of these medications on surgical decision-making and outcomes is essential for the practicing colorectal surgeon and gastroenterologist. This review seeks to summarize the relevant literature surrounding biologic use and IBD surgery with a focus on the effect of biologics on the frequency, type and complications of surgery in this 'age of biologics'.

Background: To date, there are few studies comparing the outcomes of robotic hepatectomy (RH) versus open hepatectomy (OH). We report the first systematic review and meta-analysis comparing the outcomes of RH versus OH., Methods: A systemic review was performed of all comparative studies of RH versus OH that reported the perioperative outcome(s) of interest., Results: Seven retrospective cohort studies were included. There was no significant difference in patients' baseline characteristics. RH was associated with a longer operation time (mean difference (MD) 61.47 min; 95% confidence interval (CI) (7.03, 115.91); P = 0.03), shorter hospital stay (MD -2.57 days; 95% CI (-3.31, -1.82); P < 0.001), lower costs, less overall (risk ratio (RR) 0.63; 95% CI (0.46, 0.86); P = 0.004), minor (RR 0.64; 95% CI (0.43, 0.95); P = 0.03) and major (RR 0.45; 95% CI (0.22, 0.94); P = 0.03) post-operative complications compared to OH., Conclusion: RH had superior perioperative outcomes and was not cost prohibitive compared to OH, but had longer operation times., (© 2018 Royal Australasian College of Surgeons.)

Immune checkpoint inhibitors (ICIs) have demonstrated promising results in a variety of advanced cancer types. The phenomenon of hyperprogressive disease (HPD) has only been documented in recent years, however, there have been no reports of HPD in hepatocellular carcinoma. We present a case series of six patients with advanced hepatocellular carcinoma treated with ICIs who demonstrated rapid radiological progression, this was confirmed by comparing tumor growth rates before and during treatment with HPD defined as tumor growth rate ratio ≥2. Although ICIs have demonstrated profound efficacy in advanced cancer, they might also be responsible for HPD in a small subset of patients. The ability to predict treatment response to ICI is thus of importance in protecting patients from the deleterious effects of HPD.

Tumor-reactive T cell exhaustion prevents the success of immune therapies. Pegilodecakin activates intratumoral CD8 + T cells in mice and induces objective tumor responses in patients. Here we report that pegilodecakin induces hallmarks of CD8 + T cell immunity in cancer patients, including elevation of interferon-γ and GranzymeB, expansion and activation of intratumoral CD8 + T cells, and proliferation and expansion of LAG-3 + PD-1 + CD8 + T cells. On pegilodecakin, newly expanded T cell clones, undetectable at baseline, become 1%-10% of the total T cell repertoire in the blood. Elevation of interleukin-18, expansion of LAG-3 + PD-1 + T cells and novel T cell clones each correlated with objective tumor responses. Combined pegilodecakin with anti-PD-1 increased the expansion of LAG-3 + PD-1 + CD8 + T cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We assessed the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with previously treated metastatic adrenocortical carcinoma (mACC)., Methods: In this phase 1b expansion cohort, patients with mACC and prior platinum-based therapy received avelumab at 10 mg/kg intravenously every 2 weeks. Continuation of mitotane was permitted; however, mitotane levels during the study were not recorded. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors v1.1., Results: Fifty patients received avelumab and were followed for a median of 16.5 months. Prior treatment included ≥2 lines in 74.0%; mitotane was continued in 50.0%. The objective response rate (ORR) was 6.0% (95% CI, 1.3% to 16.5%; partial response in 3 patients). Twenty-one patients (42.0%) had stable disease as best response (disease control rate, 48.0%). Median progression-free survival was 2.6 months (95% CI, 1.4 to 4.0), median overall survival (OS) was 10.6 months (95% CI, 7.4 to 15.0), and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). In evaluable patients with PD-L1+ (n = 12) or PD-L1- (n = 30) tumors (≥5% tumor cell cutoff), ORR was 16.7% vs 3.3% (P = .192). Treatment-related adverse events (TRAEs) occurred in 82.0%; the most common were nausea (20.0%), fatigue (18.0%), hypothyroidism (14.0%), and pyrexia (14.0%). Grade 3 TRAEs occurred in 16.0%; no grade 4 to 5 TRAEs occurred. Twelve patients (24.0%) had an immune-related TRAE of any grade, which were grade 3 in 2 patients (4.0%): adrenal insufficiency (n = 1), and pneumonitis (n = 1)., Conclusions: Avelumab showed clinical activity and a manageable safety profile in patients with platinum-treated mACC., Trial Registration: Clinicaltrials.gov NCT01772004 ; registered January 21, 2013.

Importance: Innovative, online models of specialty-care delivery are critical to improving patient access and outcomes., Objective: To determine whether an online, collaborative connected-health model results in equivalent clinical improvements in psoriasis compared with in-person care., Design, Setting, and Participants: The Patient-Centered Outcomes Research Institute Psoriasis Teledermatology Trial is a 12-month, pragmatic, randomized clinical equivalency trial to evaluate the effect of an online model for psoriasis compared with in-person care. Participant recruitment and study visits took place at multicenter ambulatory clinics from February 2, 2015, to August 18, 2017. Participants were adults with psoriasis in Northern California, Southern California, and Colorado. The eligibility criteria were an age of 18 years or older, having physician-diagnosed psoriasis, access to the internet and a digital camera or mobile phone with a camera, and having a primary care physician. Analyses were on an intention-to-treat basis., Interventions: Participants were randomized 1:1 to receive online or in-person care (148 randomized to online care and 148 randomized to in-person care). The online model enabled patients and primary care physicians to access dermatologists online asynchronously. The dermatologists provided assessments, recommendations, education, and prescriptions online. The in-person group sought care in person. The frequency of online or in-person visits was determined by medical necessity. All participants were exposed to their respective interventions for 12 months., Main Outcomes and Measures: The prespecified primary outcome was the difference in improvement in the self-administered Psoriasis Area and Severity Index (PASI) score between the online and in-person groups. Prespecified secondary outcomes included body surface area (BSA) affected by psoriasis and the patient global assessment score., Results: Of the 296 randomized participants, 147 were women, 149 were men, 187 were white, and the mean (SD) age was 49 (14) years. The adjusted difference between the online and in-person groups in the mean change in the self-administered PASI score during the 12-month study period was -0.27 (95% CI, -0.85 to 0.31). The difference in the mean change in BSA affected by psoriasis between the 2 groups was -0.05% (95% CI, -1.58% to 1.48%). Between-group differences in the PASI score and BSA were within prespecified equivalence margins, which demonstrated equivalence between the 2 interventions. The difference in the mean change in the patient global assessment score between the 2 groups was -0.11 (95% CI, -0.32 to 0.10), which exceeded the equivalence margin, with the online group displaying greater improvement., Conclusions and Relevance: The online, collaborative connected-health model was as effective as in-person management in improving clinical outcomes among patients with psoriasis. Innovative telehealth delivery models that emphasize collaboration, quality, and efficiency can be transformative to improving patient-centered outcomes in chronic diseases., Trial Registration: ClinicalTrials.gov Identifier: NCT02358135.

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8 + T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions. Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250-7. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195 ., (©2018 American Association for Cancer Research.)

Background: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy., Methods: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment-related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune-related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion-related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms., Results: Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%)., Conclusions: Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010-7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., (© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Single-cell characterization techniques, such as mRNA-seq, have been applied to a diverse range of applications in cancer biology, yielding great insight into mechanisms leading to therapy resistance and tumor clonality. While single-cell techniques can yield a wealth of information, a common bottleneck is the lack of throughput, with many current processing methods being limited to the analysis of small volumes of single cell suspensions with cell densities on the order of 107 per mL. In this work, we present a high-throughput full-length mRNA-seq protocol incorporating a magnetic sifter and magnetic nanoparticle-antibody conjugates for rare cell enrichment, and Smart-seq2 chemistry for sequencing. We evaluate the efficiency and quality of this protocol with a simulated circulating tumor cell system, whereby non-small-cell lung cancer cell lines (NCI-H1650 and NCI-H1975) are spiked into whole blood, before being enriched for single-cell mRNA-seq by EpCAM-functionalized magnetic nanoparticles and the magnetic sifter. We obtain high efficiency (> 90%) capture and release of these simulated rare cells via the magnetic sifter, with reproducible transcriptome data. In addition, while mRNA-seq data is typically only used for gene expression analysis of transcriptomic data, we demonstrate the use of full-length mRNA-seq chemistries like Smart-seq2 to facilitate variant analysis of expressed genes. This enables the use of mRNA-seq data for differentiating cells in a heterogeneous population by both their phenotypic and variant profile. In a simulated heterogeneous mixture of circulating tumor cells in whole blood, we utilize this high-throughput protocol to differentiate these heterogeneous cells by both their phenotype (lung cancer versus white blood cells), and mutational profile (H1650 versus H1975 cells), in a single sequencing run. This high-throughput method can help facilitate single-cell analysis of rare cell populations, such as circulating tumor or endothelial cells, with demonstrably high-quality transcriptomic data.

In patients with locally advanced squamous cell cancer of the head and neck, a multimodality treatment approach is recommended. The addition of platinum-based systemic therapy concurrently with radiation has been shown to be superior to radiation alone and is considered standard therapy for locally advanced disease. No study has shown superiority of induction therapy followed by chemoradiotherapy versus chemoradiotherapy alone. In the adjuvant setting only patients with nodal extracapsular extension or positive margins seem to benefit from chemoradiotherapy versus radiotherapy alone. In the recurrent or metastatic setting, systemic treatment with chemotherapy is palliative. A subset of patients treated with PD-1 immunotherapy may achieve durable responses., (Published by Elsevier Inc.)

Numerous techniques for isolating circulating tumor cells (CTCs) have been developed. Concurrently, single-cell techniques that can reveal molecular components of CTCs have become widely available. We discuss how the combination of isolation and multigene profiling of single CTCs in our platform can facilitate eventual translation to the clinic.

Circulating tumor cells (CTCs) are currently widely studied for their potential application as part of a liquid biopsy. These cells are shed from the primary tumor into the circulation, and are postulated to provide insight into the molecular makeup of the actual tumor in a minimally invasive manner. However, they are extremely rare in blood, with typical concentrations of 1-100 in a milliliter of blood; hence, a need exists for a rapid and high-purity method for isolating CTCs from whole blood. Here, we describe the application of a microfabricated magnetic sifter toward isolation of CTCs from whole blood at volumetric flow rates of 10 mL/h, along with the use of a PDMS-based nanowell system for single-cell gene expression profiling. This method allows rapid isolation of CTCs and subsequent integration with downstream genetic profiling methods for clinical applications such as targeted therapy, therapy monitoring, or further biological studies.

Introduction: Two of the 4 hospitals designated as major trauma centers in London, UK, currently operate on-site helicopter landing pads. King's College Hospital (KCH) is constructing a third. We evaluate current trauma services at King's College Hospital, before the helipad entering service, establishing baseline workload and mortality measures., Methods: We retrospectively analyzed data from patients admitted January 1, 2014, to December 31, 2015, to KCH after major trauma with on-scene helicopter emergency medical services involvement (N = 427) using the Trauma Audit and Research Network database., Results: The median Injury Severity Score of the cohort was 22 (interquartile range [IQR], 13-30). The median length of stay was 11 days (IQR, 5-24). Fifty-seven percent of the patients received intensive care unit (ICU) admission, with a median ICU length of stay (LOS) of 5 days (IQR, 2-12) in this subgroup. There was no significant difference in Injury Severity Score, LOS, or ICU LOS between 2014 and 2015. One hundred ninety-three patients (45.2%) underwent ≥ 1 operation, accounting for 1,276.5 hours of operating room time in total. Cox proportional hazards regression showed no difference in survival outcomes between 2014 and 2015., Conclusion: Baseline workload and mortality measures were obtained, forming the basis of future service evaluation to assess the impact of helipad construction., (Copyright © 2016 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring., Competing Interests: S.X.W. holds two issued patents on MagSifter, which are owned by Stanford University and outlicensed for possible commercialization. S.-m.P., D.J.W., C.C.O., S.S.G., V.S.N., and S.X.W. are coinventors of a pending patent filed by Stanford University on the subject of this work.

Background: Right ventricular function is impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) have been shown to help assess right ventricular function in pulmonary hypertension. Our goal was to (1) assess TAPSE and RVFAC before and after PTE, and (2) assess correlation of these variables with right heart catheterization data and PVR., Methods: We evaluated 67 consecutive patients with CTEPH for pulmonary thromboendarterectomy (PTE). Of these 67 patients, 48 were deemed surgical candidates. Preoperative right heart catheterization was performed within 1.3±1.2 days of the preoperative echocardiogram. All postoperative right heart catheterizations were performed on the first postoperative day., Results: TAPSE dropped from 18±6 to 10±3 mm after PTE (P<.0001). RVFAC remained the same (25%±10% vs 30%±12%). Mean pulmonary artery (mPAP) pressure dropped from 45±12 to 28±6 mm Hg after PTE, and pulmonary vascular resistance (PVR) decreased from 757±406 to 306±147 dyne-s/cm 5 (P<.0001 for both). Before PTE, TAPSE correlated inversely with PVR (r=-.57, P<.0001, TAPSE=-5.904×ln[PVR]+56.318). RVFAC did not correlate well with PVR or mean pulmonary artery pressure. After PTE, both TAPSE and RVFAC correlated poorly with PVR (r=-.12 and .01, respectively)., Conclusion: In patients with CTEPH, TAPSE paradoxically decreased by 50% early after PTE. TAPSE correlated inversely with PVR prior to PTE, but this correlation was lost completely after PTE. Thus, despite the immediate and marked decrease in afterload postoperatively, TAPSE did not improve; thus, TAPSE cannot be used as an early marker for surgical success., (© 2016, Wiley Periodicals, Inc.)

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Introduction: Clinical deterioration (ICU transfer and cardiac arrest) occurs during approximately 5-10% of hospital admissions. Existing prediction models have a high false positive rate, leading to multiple false alarms and alarm fatigue. We used routine vital signs and laboratory values obtained from the electronic medical record (EMR) along with a machine learning algorithm called a neural network to develop a prediction model that would increase the predictive accuracy and decrease false alarm rates., Design: Retrospective cohort study., Setting: The hematologic malignancy unit in an academic medical center in the United States., Patient Population: Adult patients admitted to the hematologic malignancy unit from 2009 to 2010., Intervention: None., Measurements and Main Results: Vital signs and laboratory values were obtained from the electronic medical record system and then used as predictors (features). A neural network was used to build a model to predict clinical deterioration events (ICU transfer and cardiac arrest). The performance of the neural network model was compared to the VitalPac Early Warning Score (ViEWS). Five hundred sixty five consecutive total admissions were available with 43 admissions resulting in clinical deterioration. Using simulation, the neural network outperformed the ViEWS model with a positive predictive value of 82% compared to 24%, respectively., Conclusion: We developed and tested a neural network-based prediction model for clinical deterioration in patients hospitalized in the hematologic malignancy unit. Our neural network model outperformed an existing model, substantially increasing the positive predictive value, allowing the clinician to be confident in the alarm raised. This system can be readily implemented in a real-time fashion in existing EMR systems.

Background: Vein bypass is an essential therapy for patients with advanced peripheral and coronary artery disease despite development of neointimal hyperplasia. We have shown that stimulation of the receptor tyrosine kinase ephrin type-B receptor 4 (Eph-B4) with its ligand ephrin-B2 prevents neointimal hyperplasia in murine vein grafts. This study determines whether Eph-B4 in adult human veins is capable of phosphorylation and activation of downstream signaling pathways, as well as functional to release nitric oxide (NO) and prevent neointimal hyperplasia in vitro., Methods: Discarded human saphenous veins were taken from the operating room and placed in organ culture without or with ephrin-B2/Fc (2 μg/mL) for 14 days, and the neointima/media ratio was measured in matched veins. Primary human umbilical vein endothelial cells were treated with ephrin-B2/Fc (2 μg/mL) and examined with quantitative polymerase chain reaction, Western blot, immunoassays, and for release of NO. Ephrin-B2/Fc (2 μg/mL) was placed on the adventitia of saphenous veins treated with arterial shear stress for 24 hours in a bioreactor and activated Eph-B4 examined with immunofluorescence., Results: The baseline intima/media ratio in saphenous vein rings was 0.456 ± 0.097, which increased to 0.726 ± 0.142 in untreated veins after 14 days in organ culture but only to 0.630 ± 0.132 in veins treated with ephrin-B2/Fc (n = 19, P = .017). Ephrin-B2/Fc stimulated Akt, endothelial NO synthase and caveolin-1 phosphorylation, and NO release (P = .007) from human umbilical vein endothelial cells (n = 6). Ephrin-B2/Fc delivered to the adventitia stimulated endothelial Eph-B4 phosphorylation after 24 hours of arterial stress in a bioreactor (n = 3)., Conclusions: Eph-B4 is present and functional in adult human saphenous veins, with intact downstream signaling pathways capable of NO release and prevention of neointimal hyperplasia in vitro. Adventitial delivery of ephrin-B2/Fc activates endothelial Eph-B4 in saphenous veins treated with arterial shear stress in vitro. These results suggest that stimulation of Eph-B4 function may be a candidate strategy for translation to human clinical trials designed to inhibit venous neointimal hyperplasia., (Published by Elsevier Inc.)

Objective: To evaluate the outcomes after cochlear implantation (CI) in the elderly population, with a particular emphasis on perioperative complications, dizziness, and speech perception outcomes., Study Design: A retrospective cohort study of elderly cochlear implant patients., Setting: Tertiary referral center (Cochlear Implant Clinic, Royal Victorian Eye and Ear Hospital, Melbourne)., Patients: All patients aged 75 and above at the time of first cochlear implant (N = 150). Comparison was made between groups aged 85+ to 80-84, and 75-79., Interventions: All patients received Nucleus devices (either CI512 or CI24RE(CA))., Main Outcome Measures: Speech recognition scores both pre- and postimplantation, symptomatic dizziness and effects upon independent living after surgery, and the incidence of perioperative medical and surgical complications. Complications were classified as major (intrinsic device failure, device migration, extracochlear insertion, meningitis, surgical site infection requiring reoperation, wound breakdown, permanent facial nerve paralysis) and minor (tinnitus, transient facial nerve palsy, facial nerve stimulation, taste disturbance, delayed wound healing)., Results: All three cohorts had poor preoperative speech perception. There was significant improvement in postoperative word scores at 3 and 12 months across all groups. There was no statistically significant difference between the three cohorts in terms of speech recognition outcomes at 3 and 12 months. After surgery, more than 20% of patients at all ages experienced transient imbalance, although the incidence did not differ significantly between age groups (p = 0.71). In total, there were 13 major complications in 7 patients (4.7%), and 28 minor complications in 25 patients (16.7%)., Conclusion: Postoperative disequilibrium was commonly observed in this elderly population, yet patients still benefited with improved speech perception after cochlear implantation. Elderly patients can benefit from cochlear implantation, and age should not be a limitation for CI surgery. Cochlear implantation can be done safely and provides significant patient benefits.

Vemurafenib and dabrafenib, two potent tyrosine kinase inhibitors (TKIs) of the BRAF(V600E) kinase, are highly effective in the treatment of a BRAF (V600) -mutant metastatic melanoma. These are selective type I inhibitors (functional against the active conformation of the kinase) of the RAF kinases, which are key players in the mitogen-activated protein kinase (MAPK) pathway. BRAF (V600) mutations are present in approximately 7 % of all cancers, including high frequencies of mutations reported in 50 % of advanced melanomas and 100 % of hairy cell leukemias. As with most targeted therapies, resistance to BRAF inhibitors is an issue, and mechanisms of resistance are varied. Combining BRAF inhibitors with MEK inhibitors such as trametinib delays the development of resistance. Rationally combining targeted therapies to address the mechanism of resistance or combining BRAF inhibitors with other effective therapies such as immunotherapy may result in further improvement in outcomes for patients.

A 59-year-old woman was admitted three times over a six-month period with recurrent upper extremity deep venous thrombosis (UEDVT). It was determined that this patient was suffering from an unusual presentation of Paget-Schröetter syndrome secondary to a 20-year-old non-union of a midshaft clavicle fracture. Following thrombolysis the patient underwent resection and plate fixation of the clavicle fracture non-union. Despite the anatomic proximity of the subclavian vessels to the clavicle, vascular complications from fracture are rare. Treatment of midshaft clavicle fractures is often non-operative. Non-union rates are generally less than 10%, and easily treated secondarily without complication. Clavicular pseudo-arthroses from trauma have been implicated in the development of the thoracic outlet syndromes, however, onset 20 years after fracture has never before been reported., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Approximately 20% of melanomas contain a mutation in NRAS. However no direct inhibitor of NRAS is available. One of the main signaling pathways downstream of NRAS is the MAPK pathway. In this study we investigated the possibility of blocking oncogenic signaling of NRAS by inhibiting two signaling points in the MAPK pathway., Methods: Fourteen NRAS mutated human melanoma cell lines were treated with a pan-RAF inhibitor (PRi, Amgen Compd A), a MEK inhibitor (MEKi, trametinib) or their combination and the effects on proliferation, cell cycle progression, apoptosis, transcription profile and signaling of the cells were investigated., Results: The majority of the cell lines showed a significant growth inhibition, with high levels of synergism of the PRi and MEKi combination. Sensitive cell lines showed induction of apoptosis by the combination treatment and there was a correlation between p-MEK levels and synergistic effect of the combination treatment. Proliferation of sensitive cell lines was blocked by the inhibition of the MAPK pathway, which also blocked expression of cyclin D1. However, in resistant cell lines, proliferation was blocked by combined inhibition of the MAPK pathway and cyclin D3, which is not regulated by the MAPK pathway. Resistant cell lines also showed higher levels of p-GSK3β and less perturbation of the apoptotic profile upon the treatment in comparison with the sensitive cell lines., Conclusions: The combination of PRi + MEKi can be an effective regimen for blocking proliferation of NRAS mutant melanomas when there is higher activity of the MAPK pathway and dependence of proliferation and survival on this pathway.

Background: The aim of this study is to identify the predictors of hospital readmission or early unplanned return to clinic within 30 days of discharge after pulmonary lobectomy., Methods: The medical records of patients undergoing lobectomy by the thoracic surgery service between January 2009 and July 2012 were reviewed. All lobectomies were included irrespective of the etiology of disease. Multivariate logistic regression methods were used to identify predictors of readmission and or early unplanned return to clinic., Results: Two hundred thirteen patients underwent a pulmonary lobectomy during the study period (median age, 67 years). Pathologic diagnosis was malignant in 94% of the patients and benign in 6%. Minimally invasive approaches were used in 69% of the patients, whereas open thoracotomy was used in 31%. Median hospital length of stay was 4 days, and postoperative mortality occurred in 1 patient (0.5%). The Charlson comorbidity index was 1 ± 1. Predicted postoperative forced expiratory volume in 1 second and diffusing capacity of the lung for carbon monoxide were 68% ± 18% and 64% ± 17%, respectively. Postoperative complications occurred in 31% of patients; 13% required readmission to the hospital within 30 days of discharge or early unplanned return to clinic. Predictors of readmission or early unplanned return to clinic were unplanned transfer to the intensive care unit (odds ratio, 10.4; 95% confidence interval, 1.1 to 103.5; p = 0.04) and Charlson comorbidity index greater than 0 (odds ratio, 1.5; 95% confidence interval, 1.04 to 2.03; p = 0.03). Readmission or early unplanned return to clinic was independent of surgical approach (p = 0.32)., Conclusions: Patients who require a postoperative transfer to the intensive care unit or with higher Charlson comorbidity index are at higher risk for hospital readmission after pulmonary lobectomy. Readmission was not affected by the surgical approach. Whether a different strategy to follow-up for these high-risk patients can prevent readmission remains to be determined., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We describe the presentation, treatment, clinical outcome, and targeted genome analysis of a metastatic salivary acinic cell carcinoma (AciCC). A 71-year-old male presented with a 3 cm right tail of a parotid lesion, first detected as a nodule by the patient seven months earlier. He had a right total parotidectomy with cranial nerve VII resection, right facial nerve resection and grafting, resection of the right conchal cartilage, and right modified radical neck dissection. The primary tumor revealed AciCC with two distinct areas: a well-differentiated component with glandular architecture and a dedifferentiated component with infiltrative growth pattern associated with prominent stromal response, necrosis, perineural invasion, and cellular pleomorphism. Tumor staging was pT4 N0 MX. Immunohistochemistry staining showed pankeratin (+), CD56 (-), and a Ki67 proliferation index of 15%. Upon microscopic inspection, 49 local lymph nodes resected during parotidectomy were negative for cancer cells. Targeted sequencing of the primary tumor revealed deletions of CDKN2A and CDKN2B, a nonsense mutation in ARID2, and single missense mutations of unknown significance in nine other genes. Despite postoperative localized radiation treatment, follow-up whole body PET/CT scan showed lung, soft tissue, bone, and liver metastases. The patient expired 9 months after resection of the primary tumor.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have revolutionized the treatment of HER2-positive breast cancer, both in the metastatic and early stage settings. While trastuzumab and lapatinib had been the mainstays of treatment in combination with chemotherapy, innate and acquired resistance to these therapies occur. More recently, two additional HER2-directed therapies have been approved for HER2-positive breast cancer. Pertuzumab is a humanized monoclonal antibody that binds to the extracellular portion of the receptor on a domain distinct from the binding site of trastuzumab. The addition of pertuzumab to trastuzumab results in synergistic tumor cell inhibition and has been shown to significantly improve clinical outcomes for patients with HER2-positive metastatic breast cancer (MBC) compared to trastuzumab plus chemotherapy alone. In addition, ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate linking trastuzumab with the cytotoxic maytansinoid, DM1, is an effective treatment for HER2-positive breast cancer that has progressed on other HER2-directed therapies. Both pertuzumab and T-DM1 are relatively well tolerated. This review presents the mechanisms of action as well as phase I, II and III clinical data describing the safety and efficacy of pertuzumab and T-DM1 for HER2-positive breast cancer.

Background: Carotid endarterectomy (CEA) is an effective surgical option for stroke prophylaxis for most patients. Restenosis after CEA can lead to additional interventions and adverse outcomes, but the factors that predict restenosis are poorly understood. This study examined which risk factors, such as metabolic syndrome (MetS), are associated with restenosis after CEA., Study Design: This retrospective study examined the records of all patients who underwent CEA at the Veterans Affairs Connecticut Healthcare System during a 4-year period. Metabolic syndrome was defined as the presence of 3 or more of the following: hypertension (blood pressure ≥130 mmHg/≥85 mmHg); serum triglycerides ≥150 mg/dL; high-density lipoprotein ≤40 mg/dL; BMI ≥25 kg/m(2); and fasting blood glucose ≥110 mg/dL. Major adverse events were defined as death, stroke, or MI. Restenosis was defined as >50% stenosis on follow-up imaging., Results: Seventy-eight patients underwent 79 CEAs during the study period. All patients were male and 76% were white. Mean patient age was 72.6 years. The mean duration of follow-up was 5.2 years. Sixty-seven percent of patients had MetS. Patients with MetS were comparable with those without MetS in demographics and preoperative comorbidities, except for increased hypertension and diabetes, as expected, and chronic renal insufficiency (p = 0.05). There was no significant difference in long-term survival or freedom from MAE between patients with and without MetS. Restenosis was significantly higher in patients with MetS (p = 0.02) and occurred 2 years after CEA in patients with MetS only, with a large increase in restenosis after 5 years (p = 0.018). MetS was an independent predictor of restenosis in multivariable analysis (p = 0.01)., Conclusions: Metabolic syndrome is an independent predictor for restenosis after CEA in a high-risk population. More frequent and/or long-term surveillance might be warranted in patients with MetS after CEA., (Published by Elsevier Inc.)

Vein graft adaptation to the arterial environment is characterized by loss of venous identity, with reduced Ephrin type-B receptor 4 (Eph-B4) expression but without increased Ephrin-B2 expression. We examined changes of vessel identity of human saphenous veins in a flow circuit in which shear stress could be precisely controlled. Medium circulated at arterial or venous magnitudes of laminar shear stress for 24 hours; histologic, protein, and RNA analyses of vein segments were performed. Vein endothelium remained viable and functional, with platelet endothelial cell adhesion molecule (PECAM)-expressing cells on the luminal surface. Venous Eph-B4 expression diminished (p = .002), Ephrin-B2 expression was not induced (p = .268), and expression of osteopontin (p = .002) was increased with exposure to arterial magnitudes of shear stress. Similar changes were not found in veins placed under venous flow or static conditions. These data show that human saphenous veins remain viable during ex vivo application of shear stress in a bioreactor, without loss of the venous endothelium. Arterial magnitudes of shear stress cause loss of venous identity without gain of arterial identity in human veins perfused ex vivo. Shear stress alone, without immunologic or hormonal influence, is capable of inducing changes in vessel identity and, specifically, loss of venous identity.

Background: In melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma., Methods: The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined., Results: Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis., Conclusions: Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.

Background: Despite low peri-operative mortality after major lower extremity amputation, long-term mortality remains substantial. Metabolic syndrome is increasing in incidence and prevalence at an alarming rate in the USA., Aim: This study was to determine whether metabolic syndrome predicts outcome after major lower extremity amputation., Patients and Methods: A retrospective review of charts between July 2005 and June 2010., Results: Fifty-four patients underwent a total of 60 major lower extremity amputations. Sixty percent underwent below-knee amputation and 40% underwent above-knee amputation. The 30-day mortality was 7% with no difference in level (below-knee amputation, 8%; above-knee amputation, 4%; P = 0.53). The mean follow-up time was 39.7 months. The 5-year survival was 54% in the whole group, and was independent of level of amputation (P = 0.24) or urgency of the procedure (P = 0.51). Survival was significantly decreased by the presence of underlying chronic kidney disease (P = 0.04) but not by other comorbidities (history of myocardial infarction, P = 0.79; metabolic syndrome, P = 0.64; diabetes mellitus, P = 0.56)., Conclusion: Metabolic syndrome is not associated with increased risk of adverse outcomes after lower extremity amputation. However, patients with chronic kidney disease constitute a sub-group of patients at higher risk of postoperative long-term mortality and may be a group to target for intervention.

Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition., Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated., Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1-exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines., Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1-exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies., (©2014 American Association for Cancer Research.)

Histone deacetylase inhibitors (HDACi) have been reported to increase tumor antigen expression, and have been successfully tested as adjuvants for melanoma immunotherapy in mouse models. In this work, we tested the effects of a pan-HDACi on human lymphocytes and melanoma cell lines. Effects of the pan-HDACi panobinostat (LBH589) on cell viability, cell cycle, apoptosis, and DNA damage were determined in peripheral blood mononuclear cells (PBMC) from 2 healthy donors, 13 patients with metastatic melanoma, 2 bone marrow samples from patients with different malignances, and 12 human melanoma cell lines. Intracellular signaling in lymphocytes, with or without cytokine stimulation, was analyzed by phospho-flow cytometry in one of each type. The IC50 in PBMCs was <20 nmol/L compared with >600 nmol/L in melanoma cell lines; >40% apoptotic cell death in PBMCs versus <10% in melanoma cell lines was seen at the same concentration. Phospho-histone variant H2A.X (pH2A.X) increased 2-fold in healthy donor PBMCs at 1 nmol/L, whereas the same effect in the melanoma cell line M229 required 10 nmol/L. pH2A.X was inhibited slightly in the PBMCs of 3 patients with metastatic melanoma at 1 nmol/L and in the melanoma cell line M370 at 10 nmol/L. Panobinostat inhibited phospho-STAT1/3/5/6, -p38, -ERK, -p53, -cyclin D3, and -histone H3 in flow cytometry-gated healthy donor B and T cells, whereas it induced up to 6-fold activation in patients with metastatic melanoma and bone marrow samples. In human lymphocytes, panobinostat alters key lymphocyte activation signaling pathways and is cytotoxic at concentrations much lower than those required for melanoma antitumor activity, resulting in an adverse therapeutic window.