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Unter extrakorporaler Membranoxygenierung (ECMO) bzw. Extracorporeal life support (ECLS) versteht man den Einsatz einer miniaturisierten Herz-Lungen-Maschine, der bei respiratorischem (ECMO) bzw. kardialem (ECLS) Versagen erfolgt, wenn konservative therapeutische Masnahmen gescheitert sind. Die ECMO/ ECLS kann als Uberbruckung bis zur Erholung, bis zur Transplantation bzw. bis zur Implantation eines definitiven Unterstutzungssystems oder bis zu einer endgultigen therapeutischen Entscheidung (z. B. bei unklarer neurologischer Situation) eingesetzt werden. Die Maschine wird entweder venoarteriell (v.a.) oder venovenos (v.v.) angeschlossen. Venoarteriell besteht die Moglichkeit des zentralen Zugangs uber die Aorta ascendens und den rechten Vorhof oder peripher uber die Hals- bzw. Femoralgefase. Venovenos konnen entweder beide Vv. femorales, eine Femoralvene und die rechtsseitige V. jugularis oder nur die V. jugularis interna kanuliert werden. Indikationen, Kanulierungstechniken und intensivmedizinisches Management unterscheiden sich bei Kindern und Erwachsenen in einigen wichtigen Details. Bei angeborenen Herzfehlern konnen die venosen Konnexionen mit dem Herzen vor- oder auch nach kinderherzchirurgischen Operationen von der normalen Situation abweichen. Daher sollte die padiatrische ECMO-Therapie ausschlieslich von Kinder-Teams (Kinderherzchirurgen, Kinderkardiologen/Neonatologen und speziell geschulten Kardiotechnikern) durchgefuhrt werden. Im Folgenden werden die institutionelle Philosophie und die Techniken des ECMO-Programms der Autoren beispielhaft dargestellt. Die padiatrische ECMO-Therapie wird aufgrund der geringen Fallzahlen immer eine Therapie bleiben, die auf das jeweilige Kind masgeschneidert sein muss und sich von Zentrum zu Zentrum im Detail unterscheidet.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

PURPOSE The objective response rate (ORR) for single-agent anti–programmed death receptor 1 (anti–PD-1) therapy is modest in patients with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). We aimed to test whether radiotherapy may act synergistically with anti–PD-1 therapy to improve response through the abscopal effect. PATIENTS AND METHODS We conducted a single-center, randomized, phase II trial of nivolumab (anti–PD-1 therapy) versus nivolumab plus stereotactic body radiotherapy (SBRT) in patients with metastatic HNSCC. Patients had at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Patients were randomly assigned (1:1), stratified by human papillomavirus status, to nivolumab (3 mg/kg intravenously every 2 weeks) or nivolumab (same dose) plus SBRT (9 Gy × 3) to 1 lesion. The primary end point was ORR in nonirradiated lesions, which was assessed by RECIST in patients with at least one available set of on-treatment images; safety was assessed in a per-protocol population. RESULTS Between March 11, 2016, and June 22, 2018, 62 patients were randomly assigned to nivolumab (n = 30) or nivolumab plus SBRT (n = 32). There was no statistically significant ORR difference between arms (34.5% [95% CI, 19.9% to 52.7%] v 29.0% [95% CI, 16.1% to 46.6%]; P = .86). There was no significant difference in overall survival ( P = .75), progression-free survival ( P = .79), or response duration ( P = .26). Grade 3-5 toxicities were similar (13.3% v 9.7%; P = .70). CONCLUSION We found no improvement in response and no evidence of an abscopal effect with the addition of SBRT to nivolumab in unselected patients with metastatic HNSCC.

Workplace participatory ergonomics (PE) programs may foster the prevention of injuries and illnesses as well as promote healthier behaviors and productivity among employees. Facilitating leadership has been identified as a critical component to the implementation of PE programs. Several contemporary leadership styles and theories have been proposed in the Industrial and Organizational (I/O) Psychology literature. A bibliometric mapping analysis was performed to assess the extent to which contemporary leadership styles have been studied in relation to PE programs in the ergonomics and public, environmental, and occupational health literature categories of the Clarivate Analytics Web of Science (WoS). Results indicated that while production in the collective areas of PE programs and leadership has increased significantly in recent decades, the study of contemporary leadership styles and/or theories in PE programs has been limited. The results highlight an opportunity for additional interdisciplinary research that may lead to more effective PE program implementation.

Die Urologie ist aufgrund ihrer Vielseitigkeit und der Haufigkeit der urologischen Erkrankungen eine medizinische Schlusseldisziplin fur beide Geschlechter und Kinder, was grosen Teilen der Bevolkerung unbekannt ist. 2016 wurde als Initiative zur Gesundheitsforderung der Deutschen Gesellschaft fur Urologie (DGU) die „Triple F-Kampagne“ gegrundet mit dem Ziel, sowohl uber die Bedeutung des Faches als auch uber die Wichtigkeit rechtzeitiger urologischer Untersuchungen inklusive PSA-gestutzter (prostataspezifisches Antigen) Fruherkennung aufzuklaren. Mit den Roth-Brudern als Gesichter der Kampagne wurde eine Homepage erstellt mit Informationen uber die wichtigsten urologischen Erkrankungen, Flyer und Poster fur Arzte und Patienten an 3500 Arzte verschickt, ein Urologensuchportal fur Patienten mit bislang 2200 registrierten Kollegen eingerichtet etc. Geplant sind weitere Aktivitaten, u. a. mit dem Ziel einer immer weiter wachsenden Beteiligung der deutschen Urologen und ihrer Patienten.

Objective The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. Methods In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously. Results We identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later. Conclusion Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Background CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations. Methods Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function. Findings FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02–0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09–0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = −0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = −0.16, 95% CI -0.48–0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089). Interpretation FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.

Purpose Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration–approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. Methods and Materials This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. Results Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. Conclusions The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.

Purpose To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with Results Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. Conclusion The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

BACKGROUND Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients. METHODS Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT. RESULTS The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P

Background Early blindness secondary to incurable retinal detachment is one of the main complications of incontinentia pigmenti (IP). The efficiency of ophthalmological management for preventing such evolution has not been proven. The objective of this retrospective study was to report a screening and treatment strategy of the vascular retinopathy in newborns and infants with IP. Results All files of patients diagnosed with IP within the two first months of life in a single tertiary referral center, between 2010 and 2015, were retrospectively included. The minimum follow-up duration was three years. Patients had undergone systematic indirect ophthalmoscopy examination, looking for signs of peripheric retinal vasculopathy, according to a standardized schedule: at diagnosis, at age 1, 2, 3, 6, 9, 12, 18 and 24 months, and then once a year. Urgent laser therapy was performed under anesthesia in case of signs of retinal ischemia. Nineteen children files (17 girls) were studied. Median age at IP diagnosis was 1 day [0–44]; median age at first retinal evaluation was 25 days. Retinal manifestations occurred in 7 patients (n = 10/38 eyes, 26.3%); they were diagnosed at median age 19 days [3–59]. These patients underwent one or two ablative session per eye (mean 1.7, median 2), under general anaesthesia. No retinal detachment or fold occurred during the follow-up (median 6 years [3–9.8]). Conclusion Ocular screening should be performed in all cases of IP as soon as possible after diagnosis. A strict ophthalmological monitoring and prophylactic treatment of retinal vasculopathy can efficiently prevent the early blinding complications of the disease.

Purpose: The purpose of this study was to analyze national trends and disparities in proton therapy use among patients with head and neck cancer receiving radiotherapy to primary disease sites. Patients and Methods: Using the National Cancer Database, we identified patients diagnosed with any nonmetastatic head and neck primary malignancy between 2005 and 2014 who were treated with radiation therapy or proton therapy directed specifically at the primary disease site. Distributions of patient and clinical factors between the two groups were evaluated. Multivariable logistic regression was used to correlate factors associated with proton therapy use compared with other modalities of radiation therapy. Results: There were 220 491 patients who received any radiation therapy as part of their initial treatment course, only 417 (0.2%) of whom received proton therapy. The use of protons underwent a small increase from 0.13% in 2005-06 to 0.41% by 2013-14 (P $63 000; OR, 2.52; P = .002) were associated with an increased likelihood of receiving proton therapy. Conclusion: Proton use has undergone an incremental increase in the United States but remains an uncommon modality for the treatment of primary head and neck cancer.

As demonstrated in Part I of this contribution, the precise and full prediction of the cracking patterns and concrete’s global behaviour in ageing structures is a complex task. Though the suggested modelling strategy allows the prediction of the main cracking patterns, its drawbacks are mainly related to (a) the use of the so-called Statistical Size Effect Law requiring various random field realizations (more than 30) and (b) the identification of a consequent number of Thermo-Hydro-Mechanical parameters (more than 50) which variations may also affect the computed cracking patterns and ageing behaviour. In part II of this contribution, the aim is to evaluate the effect of such uncertainty-related variations on concrete’s early age and long term behaviours (in comparison with the effect of the intrinsic spatial variation of mechanical properties in part I). With that regard, a 1st order sensitivity analysis to the various input’s variation is performed using the OFAT method. Throughout the study, the robustness (model’s convergence) and predictiveness (physical representativeness of numerical results) of the suggested model in Part I are evaluated within the identified inputs’ variation domains. The obtained results, in terms of the 1st order global sensitivity indexes, provide a subjectively quantitative and objectively qualitative ordering of the most influential parameters within the model’s associated physical hypotheses. In particular, the obtained results show (a) the relevance of the Gaussian function to describe the spatial correlation of the Young’s modulus property (b) the dependence of early age behaviour on, both, the spatial scattering of the mechanical properties and the maturity process; but mostly, on the structural size effect assessment (c) the main dependence of long term behaviour on the drying history and applied prestressing loads and (d) the importance of uncertainties propagation through the Thermo-Hydro-Mechanical calculations and through the operational lifespan of ageing concrete structures.

Background: Patients with hematologic conditions have a high mortality rate when infected with SARS-CoV-2 (Williamson, Nature 2020). Protection of this group from severe COVID-19 is therefore important. However, according to available vaccination guidelines, one should consider to postpone vaccination of patients on or early after chemotherapy, hematopoietic progenitor cell transplantation (HCT) or with graft versus host disease, because of anticipated poor efficacy. Based on previous (non-COVID-19) vaccination studies among hematology patients, we hypothesized that a significant group of patients may acquire sufficient protection following COVID-19 vaccination, despite disease and therapy related immunodeficiencies. Methods: We conducted a prospective cohort study with 17 cohorts of hematology patients of particular risk for severe COVID-19 who are considered to have no or limited benefit from vaccination. We evaluated humoral immune responses following 2 doses (28 days apart) of the mRNA-1273 vaccine (Moderna/Spikevax) in 722 patients, at baseline and 28 days after each vaccination as SARS-COV-2 S1- (spike)-specific serum IgG antibody concentrations by bead-based multiplex immune assay. The threshold for adequate antibody response is set at ≥300 binding antibody units (BAU)/ml according to the international WHO standard, and is associated with virus plaque reducing neutralization test titers of ≥40 PRNT 50. This study is registered as EudraCT 2021-001072-41, NL76768.029.21. Results: Patient cohorts and corresponding vaccine responses are depicted in Table 1. Vaccine efficacy, as measured by antibody concentration, 4 weeks after the 2 nd mRNA-1273 vaccination was available for 691 out of 722 participants. The majority of patients (389/691; 56%) obtained an S1 antibody titer that is considered adequate (≥300 BAU/ml). Twenty-nine percent of patients (198/691) did not seroconvert (S1 antibody titer Conclusion: Vaccination with mRNA-1273 had significant efficacy in severely immunocompromised hematology patients. Adequate humoral immune responses after two dose vaccination were reached in the majority of patients receiving therapy for sickle cell disease, MPD, MM, CML and AML, in patients early after HCT and in patients with GvHD. We are currently evaluating clinical and immunologic parameters that correlate with sufficient antibody responses, pseudovirus neutralization and SARS-COV-2-specific B and T cell numbers, phenotype and function. Per study design, all participants with absent or insufficient antibody responses ( Figure 1 Figure 1. Disclosures Mutsaers: AstraZeneca: Research Funding; BMS: Consultancy. Van Meerten: Janssen: Consultancy; Kite, a Gilead Company: Honoraria. Kater: BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nijhof: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Crowdsourcing is an increasingly popular method for organizational and occupational health research. Amazon’s Mechanical Turk (MTurk) is at the forefront of this trend, but few studies have examined the labor market characteristics of MTurk workers (Turkers) or results of organizational and occupational health data as compared to published benchmarks. To address these gaps, we review the current MTurk literature and present the results of a multi-wave study of Turker labor characteristics and organizational and occupational health variable relationships. We found Turkers to be broadly distributed across the labor market, indicating MTurk is a viable option for both generalizable and understudied samples, as well as a source for targeted occupational sectors. Additionally, we found effect size magnitudes to be comparable to published benchmarks, and data displayed high levels of test-retest reliability and stability of relationships across time. Our results support the use of MTurk as a viable source for organizational and occupational health research assuming general methodological concerns and validity threats are addressed (see Cheung et al. Journal of Business and Psychology 1–15, 2016).

Burnout is a growing concern among primary care providers (PCPs). The condition may lead to diminished quality of patient care as well as reduced quality of life. Although self-reported musculoskeletal pain is common among healthcare providers, the relationship between burnout and musculoskeletal pain among PCPs has been studied very little. We describe a cross-sectional pilot survey conducted among 38 PCPs (MDs, DOs, PAs, and NPs) in the Midwestern United States. Self-reported feelings of burnout and musculoskeletal pain in different body regions were analyzed using regression models. Results suggested that increasing number of hours worked per day, severity of pain in the neck / shoulder area, and severity of pain in the right wrist were associated with an increased risk of burnout. On the contrary, burnout decreased with increasing age. The findings suggest that additional research is needed to understand the risk factors for burnout among PCPs, particularly during the early stages of their career.

La Presse Medicale - In Press.Proof corrected by the author Available online since samedi 29 avril 2017

Background & Aim HepaStem is composed of human autologous liver-derived progenitor cells (HALPC) manufactured under GMP conditions and developed by Promethera Biosciences for the treatment of fibro-inflammatory disorders such as acute-on-chronic liver failure (ACLF). ACLF is a life-threatening complication of cirrhosis characterized by an acute liver decompensation associated with multiple organ failure and a very low survival rate. ACLF is linked to multiple cell type dysfunction, immunological imbalance and increased local (liver) and systemic inflammation. Preclinical data demonstrated that HepaStem has immunomodulatory properties. It is expected that HepaStem exerts immunomodulatory effects by interactions with immune cells of the patient and by paracrine effects through the various factors they secrete. It is expected that HepaStem will play a favorable role in treating the immunological disturbances observed in patients with ACLF and ultimately will be able to restore liver homeostasis. Methods, Results & Conclusion After a phase IIa clinical trial showing that IV administration of HepaStem was safe in ACLF patients, Promethera Biosciences initiated beginning of 2020 an efficacy study across multiple centres in Europe. In this context, the strategy followed by Promethera to develop the potency assay for release testing of batches that will be used in clinical trial is based on the immunomodulatory properties as main mechanism of action targeted for this pathology with (1) the development of an in vitro cell-based-assay that directly measures a biological activity of HepaStem representative of the biological effect expected in clinics and (2) then the development of non-biological analytical assay(s) used as surrogate markers to allow robust and easy routine evaluation of the potency. After identification of several well described soluble mediators with immunomodulatory properties, loss- and gain- of function experiments were performed to identify PGE2 as the main mediator associated with the suppression of APC-induced CD4+ T cell proliferation as well as inhibition of pro-inflammatory cytokine secretion such as TNFa. A very good correlation between the concentration of PGE2 in HepaStem conditioned medium after pro-inflammatory stimulation and the ability to inhibit APC-induced CD4+ T cell proliferation in vitro allowed together with the method validation to determine a first specification for the potency assay that will be later refined based on clinical data.

SUMMARYBackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate.MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (NCT02296684), and is ongoing but closed to accrual.FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR ≥10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-γ pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%).ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical.FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

Aim To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data. Methods 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations. Results Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7–15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01–0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy. Conclusion Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

Objectives Patients with prior irradiated head and neck cancer (HNC) who are ineligible for definitive retreatment have limited local palliative options. We report the largest series of the use of the Quad Shot (QS) regimen as a last-line local palliative therapy. Materials and Methods We identified 166 patients with prior HN radiation therapy (RT) treated with QS regimen (3.7 Gy twice daily over 2 consecutive days at 4 weeks intervals per cycle, up to 4 cycles). Palliative response defined by symptom(s) relief or radiographic tumor reduction, locoregional progression free survival (LPFS), overall survival (OS) and radiation-related toxicity were assessed. Results Median age was 66 years. Median follow-up for all patients was 6.0 months and 9.7 months for living patients. Overall palliative response rate was 66% and symptoms improved in 60% of all patients. Predictors of palliative response were > 2 year interval from prior RT and 3–4 QS cycles. Median LPFS was 5.1 months with 1-year LPFS 17.7%, and median OS was 6.4 months with 1-year OS 25.3%. On multivariate analysis, proton RT, KPS > 70, presence of palliative response and 3–4 QS cycles were associated with improved LPFS and improved OS. The overall Grade 3 toxicity rate was 10.8% (n = 18). No Grade 4–5 toxicities were observed. Conclusion Palliative QS is an effective last-line local therapy with minimal toxicity in patients with previously irradiated HNC. The administration of 3–4 QS cycles predicts palliative response, improved PFS, and improved OS. KPS > 70 and proton therapy are associated with survival improvements.

Background High-grade inflammation may play a pivotal role in the pathogenesis of left ventricular (LV) dysfunction. Evidence to support a role of systemic inflammation in mediating impaired LV function in experimental models of rheumatoid arthritis (RA) remains limited. The aim of the present study was to determine the effects of high-grade systemic inflammation on LV diastolic and systolic function in collagen-induced arthritis (CIA). Methods To induce CIA, bovine type-II collagen emulsified in incomplete Freund’s adjuvant was injected at the base of the tail into 21 three-month old Sprague Dawley rats. Nine-weeks after the first immunisation, LV function was assessed by pulsed Doppler, tissue Doppler imaging and Speckle tracking echocardiography. Cardiac collagen content was determined by picrosirius red staining; circulating inflammatory markers were measured using ELISA. Results Compared to controls (n = 12), CIA rats had reduced myocardial relaxation as indexed by lateral e’ (early diastolic mitral annular velocity) and e’/a’ (early-to-late diastolic mitral annular velocity) and increased filling pressures as indexed by E/e’. No differences in ejection fraction and LV endocardial fractional shortening between the groups were recorded. LV global radial and circumferential strain and strain rate were reduced in CIA rats compared to controls. Higher concentrations of circulating inflammatory markers were associated with reduced lateral e’, e’/a’, radial and circumferential strain and strain rate. Greater collagen content was associated with increased concentrations of circulating inflammatory markers and E/e’. Conclusion High-grade inflammation is associated with impaired LV diastolic function and greater myocardial deformation independent of haemodynamic load in CIA rats.

The loss of p16 is a signature event in Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) that leads to increased Cyclin Dependent Kinase 4/6 (CDK) signaling. Palbociclib, a CDK4/6 inhibitor, is active for the treatment of a subset of HNSCC. In this study, we analyzed patient response data from a phase I clinical trial of palbociclib in HNSCC and observed an association between prior cisplatin exposure and CDK inhibitor resistance. We studied the effects of palbociclib on cisplatin-sensitive and -resistant HNSCC cell lines. We found that while palbociclib is highly effective against chemo-naive HNSCC cell lines and tumor xenografts, prior cisplatin exposure induces intrinsic resistance to palbociclib in vivo, a relationship that was not observed in vitro. Mechanistically, in the course of provoking a DNA damage-resistance phenotype, cisplatin exposure upregulates both c-Myc and cyclin E, and combination treatment with palbociclib and the c-Myc bromodomain inhibitor JQ1 exerts a synergistic anti-growth effect in cisplatin-resistant cells. These data show the benefit of exploiting the inherent resistance mechanisms of HNSCC to overcome cisplatin- and palbociclib resistance through the use of c-Myc inhibition.

Background Patients who experienced myocardial infarction (MI) at a young age are of special medical and socioeconomic interest; cardiovascular risk factor control to prevent recurrent events is crucial in this specific cohort. Objectives The purpose of the study was to evaluate long-term risk factor control in young MI-patients in clinical practice and investigate the effects of a modern intensive prevention program in a prospective randomized trial. In a genetic substudy it was analyzed if prevention effects were depending on individual genetic risk. Methods Patients who had MI at age of ≤45 years were revisited after a mean period of 5.7±4.0 years to evaluate long-term risk factor control. Furthermore a 12-months intensive prevention program in young MI-patients (IPP-Y), coordinated by non-physician prevention assistants and including personal teachings, telephone contacts, clinical and telemetric control of risk factors, was compared to usual care in a randomized trial. Primary endpoint of the randomized trial was prevention success, defined as improvement of one of the risk factors smoking, LDL cholesterol or physical inactivity without deterioration of the others. As the opposite prevention failure was defined as deterioration of one of the risk factors without improvement of the others. Genetic risk was assessed by polygenetic risk scores, based on 163 SNPs. Results Only a minority of the 277 young patients after MI achieved guideline-recommended risk factor targets at long-term follow-up visits: mean body mass index was 29.9±5.1 kg/m2, just 14.8% had a body mass index However, the long-term prevention program IPP-Y led to a higher rate of the primary endpoint prevention success (IPP-Y: 49% vs. UC: 27%, p In the genetic subanalysis prevention effects were found in both, patients with high genetic risk as well as patients with low genetic risk assessed by polygenetic risk scores (p=0.79 high vs. low genetic risk). Effects of IPP-Y during 12 months Conclusions To our knowledge this is the first study on young patients with MI that demonstrates insufficient long-term risk factor control in clinical practice and significant effects of an intensive prevention program. Prevention effects were independent from individual genetic risk. Acknowledgement/Funding This work was supported by the Stiftung Bremer Herzen, Bremen, Germany and the Stiftung Bremer Wertpapierbörse, Bremen, Germany

Background Current guidelines on the management of patients with ST-elevation myocardial infarction (STEMI) recommend the preferred use of the modern P2Y12-inhibitors ticagrelor or prasugrel regardless of the presence of chronic kidney disease (CKD), although patients with advanced stages of CKD were excluded from randomized trials. Aim of the present study was therefore to evaluate the potential benefit of modern P2Y12-inhibitors in patients with and without advanced renal disease at admission. Methods All patients admitted with STEMI between 2006–2017 from a large german heart center treated with primary percutaneous coronary intervention (PCI) entered analysis. Initial CKD was estimated with the initial glomerular filtration rate (GFR), calculated with the CKD-EPI-equation, assigning them to the groups G1-G5. Results Of 7227 patients with STEMI and primary PCI 2669 (37%) showed no relevant reduction in GFR at admission (≥90 ml/min/1.73 m2, G1), 2976 pts. (41%), a slight reduction (GFR 60–89 ml/min/1.73 m2, G2), 880 pts. (12%) a moderate reduction (GFR 45–59 ml/min/1.73 m2, G3a) and 702 pts. (10%) a moderate to severe reduction (GFR Impact of CKD-stage on outcome CKD-stage G1 CKD-stage G2 CKD-stage G3a CKD-stage G3b-G5 1-year-MACCE-rate (%) Ticagrelor/prasugrel 4.5 11.0 27.4 47.3 Clopidogrel 9.9 15.6 26.6 50.4 Significance Conclusions These data from a large STEMI-registry demonstrate, that modern P2Y12-inhibitors were less often used in patients with CKD and their benefit regarding MACCE disappeared in advanced stages of CKD while bleeding rates increased. These results underline the special role of patients with advanced stage-CKD in STEMI and the necessity of specialized randomized trials for these patients.

We report on the development of an induction based low temperature high frequency ac susceptometer capable of measuring at frequencies up to 3.5 MHz and at temperatures between 2 K and 300 K. Careful balancing of the detection coils and calibration have allowed a sample magnetic moment resolution of $5\times10^{-10} Am^2$ at 1 MHz. We will discuss the design and characterization of the susceptometer, and explain the calibration process. We also include some example measurements on the spin ice material CdEr$_2$S$_4$ and iron oxide based nanoparticles to illustrate functionality.

Chronic pain states have resulted in an overreliance on opioid pain relievers, which can carry significant risks when used long term. As such, alternative pain treatments are increasingly desired. Although emerging research suggests that cannabinoids have therapeutic potential regarding pain, results from studies across pain populations have been inconsistent. To provide meta-analytic clarification regarding cannabis's impact on subjective pain, we identified studies that assessed drug-induced pain modulations under cannabinoid and corresponding placebo conditions. A literature search yielded 25 peer-reviewed records that underwent data extraction. Baseline and end-point data were used to compute standardized effect size estimates (Cohen's d) across cannabinoid administrations (k = 39) and placebo administrations (k = 26). Standardized effects were inverse-variance weighted and pooled across studies for meta-analytic comparison. Results revealed that cannabinoid administration produced a medium-to-large effect across included studies, Cohen's d = -0.58, 95% confidence interval (CI) [-0.74, -0.43], while placebo administration produced a small-to-medium effect, Cohen's d = -0.39, 95% CI [-0.52, -0.26]. Meta-regression revealed that cannabinoids, β = -0.43, 95% CI [-0.62, -0.24], p < .05, synthetic cannabinoids, β = -0.39, 95% CI [-0.65, -0.14], p < .05, and sample size, β = 0.01, 95% CI [0.00, 0.01], p < .05, were associated with marked pain reduction. These outcomes suggest that cannabinoid-based pharmacotherapies may serve as effective replacement/adjunctive options regarding pain, however, additional research is warranted. Additionally, given demonstrated neurocognitive side effects associated with some constituent cannabinoids (i.e., THC), subsequent work may consider developing novel therapeutic agents that capitalize on cannabis's analgesic properties without producing adverse effects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background Glycoprotein-A repetitions predominant (GARP) regulates membrane-bound transforming growth factor β1 (TGFβ1), an immunosuppressive cytokine. ABBV-151 is a first-in-class monoclonal antibody (mAb) that binds to the GARP-TGFβ1 complex and blocks TGFβ1 release. Preclinical data demonstrated that targeting both GARP-TGFβ1 and programmed cell death protein 1 (PD-1) improved antitumor effects compared with anti-PD-1 alone. Combining ABBV-151 with the anti-PD-1 mAb budigalimab (ABBV-181) may enable a more effective antitumor immune response by reducing the immunosuppressive effect of TGFβ1. Trial design This is a multicenter phase 1, dose escalation and dose expansion study (NCT03821935) in patients (pts; ≥18 yr, Eastern Cooperative Oncology Group performance status 0-1) with locally advanced or metastatic solid tumors. The primary objective of dose escalation is to determine the recommended phase 2 dose (RP2D) of ABBV-151 as monotherapy or with budigalimab; dose expansion will assess the objective response rate of ABBV-151 ± budigalimab. Secondary/exploratory objectives include assessing preliminary efficacy, safety, tolerability, pharmacokinetics (PK), and evaluating potential pharmacodynamic and predictive biomarkers. Dose escalation of ABBV-151, guided by a Bayesian optimal interval design, will assess dose-limiting toxicities during the first 28-day cycle and will be utilized until the RP2D is defined. ABBV-151 + budigalimab (fixed dose) will start ≥2 dose levels below that proven safe for ABBV-151. Adverse events will be evaluated per National Cancer Institute Common Terminology Criteria v5.0. Response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and iRECIST every 8 weeks. PK of ABBV-151 will be characterized. Saturation of GARP-TGFβ1 on platelets and PD-1 on CD4 T cells will be determined. Modulation of cytokines, chemokines, lymphocyte activity, and gene expression will be assessed in blood, while gene signatures and protein markers will be explored in tumor tissues. Baseline tumor characteristics will be retrospectively related to response. Enrollment initiated Mar 2019, with 37 pts enrolled as of May 2020. Citation Format: John Powderly, Toshio Shimizu, Patricia LoRusso, Albiruni Razak, Kathy Miller, Arjun Balar, Jordi Bruix, Loren Michel, Martha Blaney, Xiaowen Guan, Susan Lacy, Satwant Lally, Stacie Lambert, Rachel Leibman, Gregory Vosganian, Talia Golan, Anthony Tolcher. Phase 1 first-in-human study of ABBV-151 as monotherapy or in combination with budigalimab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT207.

Key Points Question Is intensity-modulated proton therapy (IMPT) associated with fewer treatment-related adverse events and comparable oncologic outcomes for patients with nonmetastatic nasopharyngeal carcinoma (NPC) compared with patients treated with intensity-modulated radiation therapy (IMRT)? Findings In this cohort study of 77 patients with nonmetastatic NPC treated with curative-intent radiotherapy, IMPT treatment was associated with significantly fewer acute adverse events compared with standard-of-care IMRT, with rare late complications. Propensity score–matched analysis demonstrated equally excellent oncologic outcomes in both groups, including 100% locoregional control rate at 2 years in the IMPT group. Meaning These findings suggest that IMPT should be discussed with patients as the potential primary radiotherapy modality for nonmetastatic NPC when it is available because it was associated with less acute toxicity burden compared with IMRT, with potential oncologic benefit in locoregional control., This cohort study compares toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic nasopharyngeal carcinoma (NPC) when treated with intensity-modulated proton therapy (IMPT) vs intensity-modulated radiation therapy (IMRT) with or without chemotherapy., Importance Patients with nonmetastatic nasopharyngeal carcinoma (NPC) are primarily treated by radiotherapy with curative intent with or without chemotherapy and often experience substantial treatment-related toxic effects even with modern radiation techniques, such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) may improve the toxicity profile; however, there is a paucity of data given the limited availability of IMPT in regions with endemic NPC. Objective To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic NPC when treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants This retrospective cohort study included 77 patients with newly diagnosed nonmetastatic NPC who received curative-intent radiotherapy with IMPT or IMRT at a tertiary academic cancer center from January 1, 2016, to December 31, 2019. Forty-eight patients with Epstein-Barr virus (EBV)–positive tumors were included in a 1:1 propensity score–matched analysis for survival outcomes. The end of the follow-up period was March 31, 2021. Exposures IMPT vs IMRT with or without chemotherapy. Main Outcomes and Measures The main outcomes were the incidence of acute and chronic treatment-related adverse events (AEs) and oncologic outcomes, including locoregional failure-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Results We identified 77 patients (25 [32.5%] women; 52 [67.5%] men; median [interquartile range] age, 48.7 [42.2-60.3] years), among whom 28 (36.4%) were treated with IMPT and 49 (63.6%) were treated with IMRT. Median (interquartile range) follow-up was 30.3 (17.9-41.5) months. On multivariable logistic regression analyses, IMPT was associated with lower likelihood of developing grade 2 or higher acute AEs compared with IMRT (odds ratio [OR], 0.15; 95% CI, 0.03-0.60; P = .01). Only 1 case (3.8%) of a chronic grade 3 or higher AE occurred in the IMPT group compared with 8 cases (16.3%) in the IMRT group (OR, 0.21; 95% CI, 0.01-1.21; P = .15). Propensity score matching generated a balanced cohort of 48 patients (24 IMPT vs 24 IMRT) and found similar PFS in the IMPT and IMRT groups (2-year PFS, 95.7% [95% CI, 87.7%-100%] vs 76.7% [95% CI, 60.7%-97.0%]; hazard ratio [HR], 0.31; 95% CI, 0.07-1.47; P = .14). No locoregional recurrence or death was observed in the IMPT group from the matched cohort. Two-year LRFS was 100% (95% CI, 100%-100%) in the IMPT group and 86.2% (95% CI, 72.8%-100%) in the IMRT group (P = .08). Three-year OS was 100% (95% CI, 100%-100%) in the IMPT group and 94.1% (95% CI, 83.6%-100%) in the IMRT group (P = .42). Smoking history was the only clinical factor significantly associated with both poor LRFS (HR, 63.37; 95% CI, 3.25-1236.13; P = .006) and poor PFS (HR, 6.33; 95% CI, 1.16-34.57; P = .03) on multivariable analyses. Conclusions and Relevance In this study, curative-intent radiotherapy with IMPT for nonmetastatic NPC was associated with significantly reduced acute toxicity burden in comparison with IMRT, with rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years. Prospective trials are warranted to direct the optimal patient selection for IMPT as the primary radiotherapy modality for nonmetastatic NPC.

6002 Background: R/M SGCs are a diverse group of malignant neoplasms arising from the major or minor salivary glands and have no standard treatment. The impact of combining PD-1/CTLA-4 checkpoint blockade in R/M SGCs is unknown. Methods: In a Simon's two-stage minimax phase II trial, pts with progressive R/M SGCs (any histology except adenoid cystic carcinoma (ACC)) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was best overall response (BOR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable BOR of 5% and a desirable BOR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with ACC was analyzed and reported separately. Results: From 7/25/2017-7/16/2020, 32 pts were enrolled and evaluable for the primary endpoint. There was 3 confirmed PRs in the first 18 pts, therefore enrollment of the second stage continued. BOR rate was 16% (5/32). Seven pts never reached a first disease assessment and were classified as non-responders: 5 due to clinical PD, 1 due to toxicity, and 1 pt withdrew. Four pts discontinued the trial for toxicities: pancytopenia (1), blurry vision (1), cardiomyopathy/hyperglycemia (1), and neutropenic sepsis (1), and mucositis (1). The 5 confirmed responders had regressions ranging from -66% to -100% in target lesions, with a duration of therapy ranging from 15.7 to 29.5 months (treatment ongoing for one as of 2/6/20). Conclusions: This cohort met its primary endpoint, and the responses observed were dramatic and durable. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.

6019 Background: Our previously published proof-of-concept trial using functional imaging to select patient with human papillomavirus (HPV) oropharyngeal carcinoma (OPC) for radiation de-escalation showed promising results. Here we report the outcome of a larger validation trial using the same paradigm where select HPV+ OPC patients received a definitive dose of 30Gy concurrently with chemotherapy and were subsequently observed. Methods: The trial enrolled patients who had p16+, T0-2, N1-N2c, M0 OPC by AJCC 7th TNM. Patients were required to have resection of the primary site (negative margin not required) or core biopsy of lymph node if unknown primary. In addition to standard positron emission tomography (PET), a pre-radiation dynamic 18F-FMISO (fluoromisonidazole) PET was performed to identify hypoxia in gross nodal disease. Patients with evidence of hypoxia ( > 1.2 tumor to muscle standard uptake value on 18F-FMISO) underwent repeat18F-FMISO PET around 2 weeks into radiation. Patients without pre-radiation hypoxia or with resolution of hypoxia on 18F-FMISO PET received 30Gy with 2 cycles of concurrent chemotherapy (cisplatin 100mg/m2 or carboplatin AUC 1.25 x 4 with 5-fluorouracil 2400 mg/m2). Results: From 11/2/17-1/4/21, 158 HPV+ OPC patients consented and were enrolled on trial. Patient characteristics were as follows: male (90%); ages 36-80 years; T-stage T0(26), T1(77), T2(55); N stage N1(19), N2a(15), N2b(95), N2c(29). Of the 114 patients with pre-treatment hypoxia, 24 had persistent hypoxia and received 70Gy. 128 patients were de-escalated to 30Gy and chemotherapy (86% cisplatin). 6 patients withdrew from trial [3 decided to receive standard of care; 3 refused 18F-FMISO PET]. Acute mucositis rates were 11% grade 0, 59% grade 1, and 30% grade 2, respectively. Acute xerostomia rates were 92% grade 1 and 8% grade 2, respectively. Weight loss was infrequent and only 19% complained of grade 1 and 5% complained of grade 2 weight loss. Six patients experienced grade 3 adverse events (diarrhea (2), syncope (2), vasovagal (1), dysphagia (1)). No patients required PEG tubes. With a median follow-up is 12 months (range: 2 months to 40 months), the 1-year locoregional control, distant metastasis-free overall survival rates were 94%, 100%, and 100%, respectively. Among the 30Gy de-escalated patients, none failed in the primary site. 8 patients had recurrent nodal disease underwent successful salvage surgery of which no additional therapy was given to 4 patients. Conclusions: Major de-escalation to 30Gy using patient specific treatment response based on hypoxia resolution resulted in excellent locoregional control with significant toxicity reduction. Updated results along with detailed correlative analysis will be presented. Clinical trial information: NCT03323463.

6060 Background: Patients with ER after surgery and prior to postoperative radiation (RT) for SCC of the OC have aggressive biology and poor prognosis. After the introduction of a PET/CT simulator in our department, we incorporated post-operative PET/CT as part of RT planning. We hypothesized PET/CT would improve detection of macroscopic disease before postoperative RT. Methods: We reviewed the medical records of patients treated with postoperative radiotherapy between 2005 and 2019 for OC SCC. Clinicopathologic risk factors were recorded. Intermediate risk factors (IRFs) included pT3-4 disease, nodal disease, perineural invasion (PNI), lymphovascular invasion (LVI), and close ( < 5mm) surgical margins (SM); extranodal extension (ENE) and positive SM were considered high-risk factors (HRF). Patients were stratified into risk groups based upon the number and type of risk factors: 0-1 IRFs, 2 IRFs, ≥3 IRFs, and any HRF. Patients were considered to have ER if they had biopsy confirmed recurrence, or if the imaging or exam was sufficiently suspicious, after discussion with the head and neck team, to warrant treatment to definitive doses of RT (70 Gy). Results: Our cohort included 391 patients with SCC of the OCC who were treated with postoperative radiotherapy. 61% of patients were male, 35% had pT3-4 disease, 36% had pN2a-3 disease, 53% had PNI, 20% had LVI, 30% had ENE, and 14% had positive SM. The most common sites were oral tongue (46%), alveolar ridge (18%), and buccal mucosa (13%). 237 (61%) patients underwent postoperative PET/CT planning, and 165 patients (41%) were planned with CT only. Patients screened with post-operative PET/CT were more likely to be diagnosed with ER (46/237, 19.4%) than those simulated with CT only (6/154, 3.9%, p < 0.0001). Among patients simulated with PET/CT, 7%, 9%, 14%, and 35% of patients were diagnosed with ER for patients with 0-1 IRFs, 2 IRFs, ≥3 IRFs, and any HRF, respectively. Median follow-up was 4.1 years (95% CI 3.6 – 4.5). Among 52 patients with ER, 24 (49.0%) had local, 41 (83.7%) had regional, and 5 (10.2%) had distant recurrence. 17 (33%) of ER were biopsy proven. For patients with ER, 3-year freedom from locoregional recurrence, distant-metastasis free survival, and overall survival were 45.2% (95% CI 32% - 64%), 55% (95% CI 42% – 72%), and 43% (95% CI 30% - 61%), respectively. For patients without ER, use of postoperative PET/CT was associated with improved disease-free survival (HR 0.68, 95% CI 0.46 – 0.98, p = 0.041) and overall survival (HR 0.59, 95% CI 0.38 – 0.91, p = 0.019). Conclusions: Postoperative PET/CT may increase detection ER compared to CT simulation alone and improve risk stratification. Patients with ER are at high risk of locoregional failure, distant metastases, and mortality, despite salvage therapy. A prospective trial is underway at our institution to systemically study the role of PET/CT for detection of ER.

In term breech deliveries, vaginal delivery can be safely envisioned in some conditions (related to patient selection and obstetrician experience). Very few data are currently available, however, about the possibility of inducing labor in these situations.To assess the effectiveness and safety of induction of labor for breech presentations.Retrospective comparative hospital-based study of a continuous series of term breech deliveries from 2000 to 2010. The condition of term breech newborns delivered vaginally after induction of labor was compared to that of their counterparts delivered vaginally after spontaneous labor.During the study period, 96 women with term fetuses in breech presentations had labor induced and 501 in spontaneous labor had attempted vaginal deliveries. Compared with spontaneous labor, induction was not associated with a significantly higher rate of cesarean delivery during labor (20.8 vs 14.8%, P=0.14), nor with poorer neonatal condition, defined either as moderate acidosis (pH7.15; 21.6 vs 19.8%, P=0.71) or composite neonatal morbidity (2.1 vs 0.6%, P=0.16).Our data indicate that, compared with spontaneous labor, neither cervical ripening nor oxytocin induction of labor is associated with either a poorer neonatal prognosis or an excess rate of obstetric complications in term breech births, and that the success rate of induction is satisfactory.

Iron deficiency (ID) has been identified as an important co-morbidity in patients with heart failure (HF). Intravenous iron therapy reduced symptoms and rehospitalizations of iron-deficient patients with HF in randomized trials. The present multicenter study investigated the "real-world" management of iron status in patients with HF. Consecutive patients with HF and ejection fraction ≤40% were recruited and analyzed from December 2010 to October 2015 by 11 centers in Germany and Switzerland. Of 1,484 patients with HF, iron status was determined in only 923 patients (62.2%), despite participation of the centers in a registry focusing on ID and despite guideline recommendation to determine iron status. In patients with determined iron status, a prevalence of 54.7% (505 patients) for ID was observed. Iron therapy was performed in only 8.5% of the iron-deficient patients with HF; 2.6% were treated with intravenous iron therapy. The patients with iron therapy were characterized by a high rate of symptomatic HF and anemia. In conclusion, despite strong evidence of beneficial effects of iron therapy on symptoms and rehospitalizations, diagnostic and therapeutic efforts on ID in HF are low in the actual clinical practice, and the awareness to diagnose and treat ID in HF should be strongly enforced.

More students than ever before are combining the experience of higher education with paid employment, but relatively little research has been done exploring how students manage these roles. In the current study, we explored the association between personality (i.e. core self-evaluations) and support, both specific to the school context. The relationship between support for school and both work–school conflict (WSC) and work-school enrichment (WSE) were also studied, and in turn, associated outcomes (i.e. grade point average, job satisfaction, general psychological health, and school burnout) of inter-role conflict and enrichment. In a two-wave study of 291 employed college students, we found that individuals high in school-specific core self-evaluations perceived greater organizational support and family support for school, which was associated with decreased WSC and increased WSE (through organizational support). In turn, WSC was related to lower general psychological health and higher school bur...

Rheumatoid arthritis (RA) impacts arterial and diastolic function. This study examined whether arterial properties can determine diastolic function in RA. In 173 RA patients, arterial function measures including carotid femoral pulse wave velocity (PWV), central systolic and pulse pressure, pulse pressure amplification, and the magnitude and timing of the forward and reflected waves were measured using applanation tonometry. Diastolic function parameters including the ratio of early-to-late transmitral velocity (E/A) and ratio of E to the mean of the lateral and septal wall myocardial tissue lengthening (e') were measured using echocardiography. The timing of the reflected wave was associated with E/A; PWV was related to E/e'. The timing of the reflected wave, forward wave magnitude, and pulse pressure amplification were associated with impaired relaxation; PWV was related to increased left ventricular (LV) filling pressure. Early wave reflection and PWV are associated with LV-impaired relaxation and increased filling pressure, respectively, in RA.

6541 Background: Despite overexpression of EGFR in HNSCC, cetuximab monotherapy has limited benefit. Fibroblast growth factor receptor (FGFR) signaling is a known resistance mechanism to EGFR inhibition. Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor (RTKI) and has unique activity against FGFR 1,2,3, and 4. We are evaluating inhibition of EGFR and RTKs including FGFR through the combination of cetuximab and lenvatinib in patients (pts) with R/M HNSCC. Methods: In this phase I/Ib, single-institution study, pts with measurable disease per RECIST v1.1 that is incurable with surgery and radiation are eligible regardless of prior cetuximab therapy. The dose de-escalation phase included pts with HNSCC and cutaneous squamous cell carcinoma (cSCC) treated with standard cetuximab dosing and lenvatinib in 3 potential dose levels (DL): (0) 24mg, (-1) 20mg, (-2) 14mg oral daily in a standard 3+3 design. The primary objective was to determine the MTD of lenvatinib in combination with cetuximab. The expansion phase included an additional 5 pts with HNSCC treated at the MTD. Exploratory endpoints include ORR and PFS in HNSCC pts treated at the MTD. Results: 12 evaluable pts were treated on the dose de-escalation phase. There were no DLTs on DL 0; however, 3/6 pts were removed immediately following the 28-day DLT period due to toxicity that included extensive thrombotic events and athlerosclerotic disease. On DL -1, 0/6 pts (5 HNSCC/1 cSCC) had a DLT establishing lenvatinib 20mg daily as the MTD. 7 pts were enrolled onto the expansion phase; 4 are currently evaluable for response and 2 are unevaluable because of withdrawal due to a cetuximab reaction and required surgery. Of the 9 evaluable HNSCC pts treated with lenvatinib 20mg daily, 6 pts had a PR with a 67% ORR. For the 8 pts who have completed treatment, the median PFS is 3.6 months (range 1.6-10.4). Grade 3 AEs regardless of attribution included hypertension (3), oral mucositis (3) and oral cavity fistula (1). The most common AEs were acneiform rash (7), fatigue (6), and hypertension/hypothyroidism/oral mucositis (5 each). Conclusions: The MTD of lenvatinib 20mg daily with cetuximab appears to be active in R/M HSNCC with an impressive preliminary ORR, warranting further evaluation of the efficacy of this combination. Clinical trial information: NCT03524326 .

6587 Background: Immune checkpoint blockade (ICB) has limited efficacy for radioiodine-refractory thyroid cancer. The high incidence of autoimmune thyroid disease and ICB-induced hypothyroidism suggests that loss of T cell tolerance to thyroid protein epitopes is common and can be activated by ICB to induce immune responses. We hypothesize that RAI can enhance presentation of thyroid protein immunogens and putative neoantigens in thyroid cancers to amplify the effectiveness of ICB. We studied the safety and efficacy of RAI plus the anti-PD-L1 agent durvalumab (durva) in recurrent/metastatic (R/M) patients (pts). Methods: Pts. had at least one RAI-avid tumor on the most recent RAI scan or one tumor on FDG PET with an SUVmax < 10. RECIST measurable disease was required. Any number of prior therapies was allowed. Pts were treated with durva 1500 mg IV every 4 weeks with recombinant human TSH (rhTSH)-stimulated RAI (100 mCi) administered in Cycle 1. Treatment beyond progression was allowed. The primary objective was to assess safety. Durva related dose limiting toxicities (DLTs) were monitored for 6 weeks after the first dose. Since no durva DLTs were observed in the first 6 pts, per protocol rules the trial accrued 11 pts total. Secondary objectives were assessing best overall response (BOR) per RECIST and progression-free survival (PFS). Results: 11 pts (7 female) were enrolled. Eight had prior drug therapy. No DLTs or > Grade 3 durva related adverse events (AEs) were observed. The most common non-laboratory AEs (regardless of attribution) were cough (7), hypertension (7), pain (6), edema (5), and fatigue/nausea/diarrhea/arthralgia/dry skin/dyspnea/edema (4 each). As of 2/6/20, 2 had partial response, 7 stable disease, and 2 progression of disease as BOR. Six pts had tumor regression. Four pts received treatment for > 6 months. Six are still on treatment. Analyses of research biopsies (bxs) (8 had pre-treatment bxs, 6 had an additional on-treatment bx) will be presented. Conclusions: Durva plus RAI is safe and well tolerated. The preliminary efficacy signal in this small cohort is promising. Understanding how RAI plus PD-L1 targeting impacts the tumor immune microenvironment may guide how RAI should be evaluated in future ICB trials. Clinical trial information: NCT03215095 .

TPS3648 Background: Trophoblast cell surface antigen (Trop-2) is highly expressed in many epithelial cancers (non–small-cell lung cancer [NSCLC], endometrial cancer, urothelial carcinoma [UC], and triple-negative breast cancer [TNBC]) and has been linked to aggressive disease and poor prognosis. SG is a Trop-2–directed antibody drug conjugate containing SN-38 (active metabolite of irinotecan) with a 7.5:1 drug-to-antibody ratio and unique hydrolyzable linker that allows for extracellular bystander effect. The phase 1/2 IMMU-132-01 basket study reported clinical activity with SG in patients with multiple tumor types not selected for Trop-2 expression including NSCLC (objective response rate [ORR]: 17%), TNBC (ORR: 33%), and UC (ORR: 31%).1-3 Results from the overall safety population (N=420) from this study found that SG was tolerable, with a predictable and manageable safety profile, and low discontinuation rates due to AEs. Methods: To test a biomarker-enrichment strategy with Trop-2, the TROPiCS-03 (TROP-2 Investigations in Cancer with SG) study was initiated. TROPiCS-03 (NCT03964727) is a multi-cohort, open-label, phase 2 study in patients with metastatic solid tumors - presently NSCLC (adenocarcinoma and squamous cell carcinoma), head and neck squamous cell carcinoma, and endometrial cancer - selected based on elevated Trop-2 expression by a validated IHC assay. Patients receive SG (10 mg/kg IV, days 1 and 8 every 21 days) and continue treatment until lack of clinical benefit or unacceptable toxicity. The primary endpoint is objective response rate (local assessment) and additional endpoints include clinical benefit rate, duration of response, progression-free survival, and safety. Females or males ≥18 years old who are histologically documented to have locally advanced or metastatic (M1, stage 4) solid tumors of the above types are eligible. Patients must have ECOG 0 or 1 and adequate clinical laboratory results to be enrolled. All subjects will have progressed after prior platinum-based chemotherapy and programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) directed therapy. Patients who have previously received topoisomerase I inhibitors and those with known active CNS metastases are excluded. Approximately 160 patients will be enrolled in the trial overall; enrollment in the NSCLC cohort is currently in progress. References: Heist RS et al. J Clin Oncol. 2017;35:2790-7, Bardia A et al., NEJM. 2019;380:741-51.,Tagawa ST et al., Oral presentation; ASCO-GU 2019, San Francisco, CA. Clinical trial information: NCT03964727 .