Dissemination of UTC(NIST) over 20 km of commercial optical fiber with active phase stabilization.

We demonstrate the transfer of a cesium frequency standard steered to UTC(NIST) over 20 km of dark telecom optical fiber. Our dissemination scheme uses an active stabilization technique with a phase-locked voltage-controlled oscillator. Out-of-loop characterization of the optical fiber link performance is done with dual-fiber and single-fiber transfer schemes. We observe a fractional frequency instability of 1.5 × 10-12 and 2 × 10-15 at averaging intervals of 1 s and 105 s, respectively, for the link. Both schemes are sufficient to transfer the cesium clock reference without degrading the signal, with nearly an order of magnitude lower fractional frequency instability than the cesium clocks over all time scales. The simplicity of the two-fiber technique may be useful in future long-distance applications where higher stability requirements are not paramount, as it avoids technical complications involved with the single-fiber scheme.

Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Tyre particle exposure affects the health of two key estuarine invertebrates.

Tyre wear particles may be the largest source of microplastic to the natural environment, yet information on their biological impacts is inadequate. Two key estuarine invertebrates; the clam Scrobicularia plana and the ragworm Hediste diversicolor were exposed to 10% tyre particles in sediment for three days. Both species consumed the particles, although S. plana consumed 25x more than H. diversicolor (967 compared with 35 particles.g-1 wet weight, respectively). We then investigated the impact of 21 days exposure to different concentrations of tyre particles in estuarine sediments (0.2, 1, and 5% dry weight sediment) on aspects of the health of S. plana and H. diversicolor. Reductions in feeding and burial rates were observed for S. plana but not H. diversicolor, whilst both species showed a decrease in protein content in response to the greatest tyre particle concentration (5%), linked to an 18% decrease in energy reserves for H. diversicolor. Five percent tyre particle exposure led to an increase in total glutathione in the tissues of H. diversicolor, whilst lipid peroxidation decreased in the digestive glands of S. plana, possibly due to an increase in cell turnover. This study found that S. plana's health was impacted at lower concentrations than H. diversicolor, likely due to its consumption of large quantities of sediment. At the high exposure concentration (5%), the health of both invertebrates was impacted. This study did not separate the effects caused by the microplastic particles versus the effects of the chemical additives leaching from these particles, but our results do indicate that future studies should investigate effects in isolation and in combination, to determine the main drivers of toxicity.

Regulation of gene expression during ontogeny of physiological function in the brackishwater amphipod Gammarus chevreuxi.

Embryonic development is a complex process involving the co-ordinated onset and integration of multiple morphological features and physiological functions. While the molecular basis of morphological development in embryos is relatively well known for traditional model species, the molecular underpinning of the development of physiological functions is not. Here, we used global gene expression profiling to investigate the transcriptional changes associated with the development of morphological and physiological function in the amphipod crustacean Gammarus chevreuxi. We compared the transcriptomes at three timepoints during the latter half of development, characterised by different stages of the development of heart form and function: 10 days post fertilisation (dpf, Early: no heart structure visible), 15 dpf (Middle: heart present but not fully functional), and 18 dpf (Late: regular heartbeat). Gene expression profiles differed markedly between developmental stages, likely representing a change in the activity of different processes throughout the latter period of G. chevreuxi embryonic development. Differentially expressed genes belonged to one of three distinct clusters based on their expression patterns across development. One of these clusters, which included key genes relating to cardiac contractile machinery and calcium handling, displayed a pattern of sequential up-regulation throughout the developmental period studied. Further analyses of these transcripts could reveal genes that may influence the onset of a regular heartbeat. We also identified morphological and physiological processes that may occur alongside heart development, such as development of digestive caeca and the cuticle. Elucidating the mechanisms underpinning morphological and physiological development of non-model organisms will support improved understanding of conserved mechanisms, addressing the current phylogenetic gap between relatively well known model species.

Facing up to climate change: Community composition varies with aspect and surface temperature in the rocky intertidal.

Marine rocky intertidal organisms are amongst those most affected by climate change with regional distributional changes observed for many species. Although often ascribed to increased sea surface temperatures, precise assessment of the local habitat conditions underpinning observed and predicted changes in community assembly is lacking. Here we examine how aspect (i.e. north-south orientation) affects intertidal community composition and how rock surface temperatures and stress responses of two dominant grazer species (Patella spp.) elucidate emergent differences. We quantified year-round temperature variation and surveyed intertidal community composition on paired natural rock gullies with Equator- (EF) and Pole-facing (PF) surfaces. We also investigated variation in limpet (Patella spp.) reproductive phenology and osmotic stress. Average annual temperatures were 0.8 °C (1.6 °C at low tide) higher, with six-fold more frequent extremes (i.e. > 30 °C) on EF than PF surfaces. Intertidal community composition varied with aspect across trophic levels with greater overall species richness, abundance of primary producers and grazers on PF-surfaces, and greater barnacle abundance on EF-surfaces. Although species richness of organisms from different biogeographical origins ('Boreal' or 'Lusitanian') did not vary, the Lusitanian limpet Patella depressa exhibited earlier reproductive development on EF-surfaces and both limpet species exhibited greater thermal stress on EF-surfaces. We argue that our study system provides a good model for understanding how temperature variation at local scales can affect community composition, as well as ecophysiological and ecological responses to climate change and so better inform and predict regional range shifts over coming decades.

A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity. PATIENTS AND METHODS: PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0-1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses. RESULTS: Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected [hazard ratio = 1.06, 95% confidence interval (CI): 0.73-1.53; P = 0.76], and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1-4.2), compared with 3.4 (2.2-4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 [17.5 months: (14.8-19.7)], no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74-1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS. CONCLUSION: This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.

Consensus statement: summary of the Quebec Lung Cancer Network recommendations for prioritizing patients with thoracic cancers in the context of the COVID-19 pandemic.

Background: The emergence of covid-19 has the potential to change the way in which the health care system can accommodate various patient populations and might affect patients with non-covid-19 problems. The Quebec Lung Cancer Network, which oversees thoracic oncology services in the province of Quebec under the direction of the Ministère de la Santé et des Services sociaux, convened to develop recommendations to deal with the potential disruption of services in thoracic oncology in the province of Quebec. The summary provided here has been adapted from the original document posted on the Programme québécois du cancer Web site at: https://www.msss.gouv.qc.ca/professionnels/documents/coronavirus-2019-ncov/PJ1_Recommandations_oncologie-thoracique-200415.pdf. Methods: Plans to optimize the health care system and potentially to prioritize services were discussed with respect to various levels of activity. For each level-of-activity scenario, suggestions were made for the services and treatments to prioritize and for those that might have to be postponed, as well as for potential alternatives to care. Results: The principal recommendation is that the cancer centre executive committee and the multidisciplinary tumour board always try to find a solution to maintain standard-of-care therapy for all patients with thoracic tumours, using novel approaches to treatment and the adoption of a network approach to care, as needed. Conclusions: The effect of the covid-19 pandemic on the health care system remains unpredictable and requires that cancer teams unite and offer the most efficient and innovative therapies to all patients under the various conditions that might be forced upon them.

Dynamic Alteration of Neutrophil-to-Lymphocyte Ratio over Treatment Trajectory is Associated with Survival in Esophageal Adenocarcinoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been identified as a biomarker for multiple malignancies. There is emerging evidence that implicates neutrophils in cancer progression. Alterations of neutrophil counts and NLR during treatment may reflect a change in oncologic outcome that is more important than baseline values. The aim of this study is to investigate the prognostic role of NLR changes during the treatment trajectory of patients with esophageal adenocarcinoma. PATIENTS AND METHODS: NLR values of patients with esophageal adenocarcinoma who underwent surgery between 2005 and 2016 were measured at baseline and in the late postoperative period. Primary outcomes were overall survival (OS) and disease-free survival (DFS). The secondary outcome was pathological response to neoadjuvant chemotherapy. RESULTS: 330 patients were included; mean age was 65.6 years, and 82% were male. Most patients had cT3 (74.8%), cN-positive (59.7%) disease. Two-thirds (65.2%) received neoadjuvant chemotherapy. The independent predictors of OS were pathological N-stage, size of primary tumor, and delta NLR (late - baseline NLR). Patients with persistently elevated NLR did worse than those with decreasing NLR trends between baseline and postoperative time points (3-year OS 43.4% versus 71.3%, p < 0.0001, 3-year DFS 29.7% versus 61.9%, p < 0.0001). High baseline and postoperative NLR were associated with significantly worse OS and DFS. Patients with complete pathological response had lower mean baseline NLR. CONCLUSION: Dynamic changes in NLR during treatment are associated with survival and may be more informative than static baseline values.

Toll-like receptors: exploring their potential connection with post-operative infectious complications and cancer recurrence.

Cancer is the leading cause of death in North America. Despite modern advances in cancer therapy, many patients will ultimately develop cancer metastasis resulting in mortality. Surgery to resect early stage solid malignancies remains the cornerstone of cancer treatment. However, surgery places patients at risk of developing post-operative infectious complications that are linked to earlier cancer metastatic recurrence and cancer mortality. Toll-like receptors (TLRs) are evolutionarily-conserved sentinel receptors of the innate immune system that are activated by microbial products present during infection, leading to activation of innate immunity. Numerous types of solid cancer cells also express TLRs, with their activation augmenting their ability to metastasize. Similarly, healthy host-tissue TLRs activated during infection induce a prometastatic environment in the host. Cancer cells additionally secrete TLR activating ligands that activate both cancer TLRs and host TLRs to promote metastasis. Consequently, TLRs are an attractive therapeutic candidate to target infection-induced cancer metastasis and progression.

Multivisceral Resection for Locally Advanced Gastric and Gastroesophageal Junction Cancers-11-Year Experience at a High-Volume North American Center.

INTRODUCTION: The oncologic benefit of multivisceral en bloc resections for T4 gastroesophageal tumors has been questioned, given the increased morbidity associated. We thus sought to investigate the surgical and oncologic outcomes of curative-intent en bloc multivisceral resections for T4 gastroesophageal carcinomas. METHODS: Between 2005 and 2016, 35 of the 525 patients who had gastric or EGJ carcinomas underwent curative-intent multivisceral resections for direct invasion or adhesion to adjacent organs. RESULTS: Postoperative complications occurred in 16(46%), 10 of which were Clavien-Dindo ≥ 3 (29%). Ninety-day mortality was 3%. The R0 resection rate was 94% (33). Direct organ invasion (pT4b) was confirmed on pathological analysis in 14 (40%) and did not affect survival. The majority (28, 80%) had lymph node involvement with a high nodal disease burden and was associated with decreased survival. Overall 5-year survival rate was 34%, and the vast majority of recurrences were distant/peritoneal (81%). On multivariate analysis, positive lymph nodes (H.R. 21.2; 95%CI 2.34-192) and R1 resection (H.R. 5.6; 95%CI 1.02-30.9) were predictors of survival. CONCLUSION: Multivisceral resections for T4 gastric and GEJ adenocarcinomas, in combination with effective systemic therapy, result in prolonged long-term survival with acceptable morbidity. Complete resection to negative margins should remain a mainstay of curative-intent treatment in carefully selected patients.

Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis.

CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts.

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.

An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE.

BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.

Does plasticity in thermal tolerance trade off with inherent tolerance? The influence of setal tracheal gills on thermal tolerance and its plasticity in a group of European diving beetles.

In the face of global warming, both the absolute thermal tolerance of an ectotherm, and its ability to shift its tolerance level via acclimation, are thought to be fundamentally important. Understanding the links between tolerance and its plasticity is therefore critical to accurately predict vulnerability to warming. Previous studies in a number of ectotherm taxa suggest trade-offs in the evolution of thermal tolerance and its plasticity, something which does not, however, apply to Deronectes diving beetles, where these traits are instead positively correlated. Here we revisit the relationship between thermal tolerance and plasticity in these beetles, paying attention to a recently discovered morphological adaptation supporting under water respiration - setal tracheal gills. Hollow setae on the elytra interconnect with the beetle's tracheal system, providing a gas exchange surface that allows oxygen to be extracted directly from the water. This enables individuals to stay submerged for longer than their subelytral air stores would allow. We show that hypoxia reduced heat tolerance, especially when individuals were denied access to air, forcing them to rely solely on aquatic gas exchange. Species with higher densities of these gas-exchanging setae exhibited improved cold tolerance, but reduced heat tolerance and lower plasticity of heat tolerance. Differences in setal tracheal gill density across species were also related to habitat use: species with low gill density were found mainly in intermittent, warmer rivers, where underwater gas exchange is more problematic and risks of surfacing may be smaller. Moreover, when controlling for differences in gill density we no longer found a significant relationship between heat tolerance and its plasticity, suggesting that the previously reported positive relationship between these variables may be driven by differences in gill density. Differences in environmental conditions between the preferred habitats could simultaneously select for characteristic differences in both thermal tolerance and gill density. Such simultaneous selection may have resulted in a non-causal association between cold tolerance and gill density. For heat tolerance, the correlations with gill density could reflect a causal relationship. Species relying strongly on diffusive oxygen uptake via setal tracheal gills may have a reduced oxygen supply capacity and may be left with fewer options for matching oxygen uptake to oxygen demand during acclimation, which could explain their reduced heat tolerance and limited plasticity. Our study helps shed light on the mechanisms that underpin thermal tolerance and plasticity in diving air-breathing ectotherms, and explores how differences in thermal tolerance across species are linked to their selected habitat, morphological adaptations and evolutionary history.

Perforated esophageal intervention focus (PERF) study: a multi-center examination of contemporary treatment.

The treatment of esophageal perforation (EP) remains a significant clinical challenge. While a number of investigators have previously documented efficient approaches, these were mostly single-center experiences reported prior to the introduction of newer technologies: specifically endoluminal stents. This study was designed to document contemporary practice in the diagnosis and management of EP at multiple institutions around the world and includes early clinical outcomes. A five-year (2009-2013) multicenter retrospective review of management and outcomes for patients with thoracic or abdominal esophageal perforation was conducted. Demographics, etiology, diagnostic modalities, treatments, subsequent early outcomes as well as morbidity and mortality were captured and analyzed. During the study period, 199 patients from 10 centers in the United States, Canada, and Europe were identified. Mechanisms of perforation included Boerhaave syndrome (60, 30.1%), iatrogenic injury (65, 32.6%), and penetrating trauma (25, 12.6%). Perforation was isolated to the thoracic segment alone in 124 (62.3%), with 62 (31.2%) involving the thoracoabdominal esophagus. Mean perforation length was 2.5 cm. Observation was selected as initial management in 65 (32.7%), with only two failures. Direct operative intervention was initial management in 65 patients (32.6%), while 29 (14.6%) underwent esophageal stent coverage. Compared to operative intervention, esophageal stent patients were significantly more likely to be older (61.3 vs. 48.3 years old, P < 0.001) and have sustained iatrogenic mechanisms of esophageal perforation (48.3% vs.15.4%). Secondary intervention requirement for patients with perforation was 33.7% overall (66). Complications included sepsis (56, 28.1%), pneumonia (34, 17.1%) and multi-organ failure (23, 11.6%). Overall mortality was 15.1% (30). In contemporary practice, diagnostic and management approaches to esophageal perforation vary widely. Despite the introduction of endoluminal strategies, it continues to carry a high risk of mortality, morbidity, and need for secondary intervention. A concerted multi-institutional, prospectively collected database is ideal for further investigation.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

BACKGROUND: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. PATIENTS AND METHODS: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. RESULTS: Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. CONCLUSIONS: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01046266 (ClinicalTrials.gov).

AllergoOncology - the impact of allergy in oncology: EAACI position paper.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.