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Patagonian toothfish (Dissostichus eleginoides) is a highly prized resource in markets due to the quality of its meat. The Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) implemented controls and regulations in response to the sharp rise in the illegal fishing of D. eleginoides in the 1990s. Today, four fisheries in waters close to the southern tip of South America are managed in accordance with stringent sustainability standards. Even though they are separate management units, both abundance assessments and annual catch allocations are conducted using different criteria regarding stock considerations across the region, leaving one of the fundamental premises of fisheries management unclear. This study examines historical data and recent research to explore the potential differentiation between Patagonian toothfish populations in South American waters, which is crucial for the management of diverse fisheries. Genetic studies, otolith microchemistry, morphometry, parasitic fauna, tagging programs, reproductive characteristics, and the impact of ocean circulation on dispersal and recruitment were analyzed. Tagging studies in the southern hemisphere oceans confirm the species’ affinity to specific habitats, suggesting minimal fish exchange between South American fishing grounds. From a fisheries perspective, this review suggests the existence of distinct stocks of the species structured along the shelf and slope of the southern cone of America based on reproduction areas along the continental shelves and slope, the diverse parasitic fauna, the variability in stable isotopes and trace elements of otoliths, and the little significant exchange of fish between current fishing grounds. All of this could lead to considering the D. eleginoides fishery as independent exploitation units.

Abstract Background Reference values for lung volumes are necessary to identify and diagnose restrictive lung diseases and hyperinflation, but the values have to be validated in the relevant population. Our aim was to investigate the Global Lung Function Initiative (GLI) reference equations in a representative healthy Austrian population and create population-derived reference equations if poor fit was observed. Methods We analysed spirometry and body plethysmography data from 5371 respiratory healthy subjects (6–80 years) from the Austrian LEAD Study. Fit with the GLI equations was examined using z-scores and distributions within the limits of normality. LEAD reference equations were then created using the LMS method and the generalized additive model of location shape and scale package according to GLI models. Results Good fit, defined as mean z-scores between + 0.5 and -0.5,was not observed for the GLI static lung volume equations, with mean z-scores > 0.5 for residual volume (RV), RV/TLC (total lung capacity) and TLC in both sexes, and for expiratory reserve volume (ERV) and inspiratory capacity in females. Distribution within the limits of normality were shifted to the upper limit except for ERV. Population-derived reference equations from the LEAD cohort showed superior fit for lung volumes and provided reproducible results. Conclusion GLI lung volume reference equations demonstrated a poor fit for our cohort, especially in females. Therefore a new set of Austrian reference equations for static lung volumes was developed, that can be applied to both children and adults (6–80 years of age).

A groundbreaking remote sensing approach that uses three Bastnäsite Indices (BI) to detect rare earth elements (REEs) was initially developed using ore samples from the Sulfide Queen mine in California and later applied to various well-studied ground-based, drone-based, airborne, and spaceborne imaging spectrometers across a wide range of scales, from micrometers to tens of meters. In this work, those same innovative techniques have revealed the existence of a potential site for extracting REEs. Data from AVIRIS-NG, AVIRIS-Classic, HISUI, DESIS, EnMAP, EO-1 Hyperion, PRISMA, and EMIT were utilized to map Ivanpah Dry Lake, which is located fourteen kilometers northeast of the Sulfide Queen mine. Although this area was not previously associated with REE deposits, BI maps have indicated the presence of a site that has remained enriched in REEs for decades, suggesting an opportunity for further exploration and mining. Historically, a pipeline transported wastewater from facilities at the Sulfide Queen mine to evaporation ponds on or near Ivanpah Dry Lake, where wastewater may have contained concentrated REEs. This research highlights imaging spectroscopy not only as a valuable tool for rapidly identifying and efficiently extracting REEs, but also as a means of recovering REEs from supposed waste.

Summary: Background: Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition. Methods: We analysed cross-sectional data from 33,983 adults (≥40 years), recruited between Jan 2, 2003 and Dec 26, 2016, in 41 sites (34 countries) from the Burden of Obstructive Lung Disease (BOLD) study. We estimated the prevalence of chronic cough for each site accounting for sampling design. To identify risk factors, we conducted multivariable logistic regression analysis within each site and then pooled estimates using random-effects meta-analysis. We also calculated the population attributable risk (PAR) associated with each of the identifed risk factors. Findings: The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job. Interpretation: Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors. Funding: Wellcome Trust.

Recent developments in biomimetic hydrogel research have expanded the scope of biomedical technologies that can be used to model, diagnose, and treat a wide range of medical conditions. Cancer presents one of the most intractable challenges in this arena due to the surreptitious mechanisms that it employs to evade detection and treatment. In order to address these challenges, biomimetic design principles can be adapted to beat cancer at its own game. Biomimetic design strategies are inspired by natural biological systems and offer promising opportunities for developing life-changing methods to model, detect, diagnose, treat, and cure various types of static and metastatic cancers. In particular, focusing on the cellular and subcellular phenomena that serve as fundamental drivers for the peculiar behavioral traits of cancer can provide rich insights into eradicating cancer in all of its manifestations. This review highlights promising developments in biomimetic nanocomposite hydrogels that contribute to cancer therapies via enhanced drug delivery strategies and modeling cancer mechanobiology phenomena in relation to metastasis and synergistic sensing systems. Creative efforts to amplify biomimetic design research to advance the development of more effective cancer therapies will be discussed in alignment with international collaborative goals to cure cancer.

Rationale Structural airway changes related to chronic cough (CC) are described in the literature, but so far reported data are rare and non-conclusive. Furthermore, they derive mainly from cohorts with small sample sizes. Advanced CT imaging not only allows airway abnormalities to be quantified, but also to count the number of visible airways. The current study evaluates these airway abnormalities in CC and assesses the contribution of CC in addition to CT findings on the progression of airflow limitation, defined as a decline in forced expiratory volume in 1 s (FEV1) over time.Methods A total of 1183 males and females aged ≥40 years with thoracic CT scans and valid spirometry from Canadian Obstructive Lung Disease, a Canadian multicentre, population-based study has been included in this analysis. Participants were stratified into 286 never-smokers, 297 ever-smokers with normal lung function and 600 with chronic obstructive pulmonary disease (COPD) of different severity grades. Imaging parameters analyses included total airway count (TAC), airway wall thickness, emphysema as well as parameters for functional small airway disease quantification.Results Irrespective of COPD presence, CC was not related to specific airway and lung structure features. Independent of TAC and emphysema score, CC was highly associated with FEV1 decline over time in the entire study population, particularly in ever-smokers (p

A principios de la década de 1990, la pesquería de merluza negra argentina ganó protagonismo gracias a la rápida expansión de las flotas de arrastre y palangre que se dirigían a esta especie. Esta zona de pesca cubre el talud y plataforma desde los 60° S hasta los 37° S en la Zona Económica Exclusiva argentina. El principal caladero se encuentra en la zona sur, colindando con las áreas marinas protegidas (AMP) Banco Namuncurá-Burdwood II (NBBII) y Yaganes (Y), establecidas en 2018. Para determinar el impacto que generan las AMP en la distribución del esfuerzo, se analizaron espacialmente 308 viajes de pesca realizados entre 2010 y 2020, que reportaron 82% del total del esfuerzo pesquero declarado de merluza negra argentina en ese período. El sector Y-AMP categorizado como Reserva Nacional Marina y ubicado al sur de Tierra del Fuego, reportó más de la mitad (58%) de la captura de merluza negra registrada durante ese período, mientras que el NBBII-AMP ubicado al este de Tierra del Fuego y sur de la Isla de los Estados representaron 17%. El sector NBBII-AMP establecido como Reserva Nacional Marina Estricta y ubicado al sur del Banco Burdwood representó el 25%. Con el establecimiento de las AMP se ha cumplido 7,11% del requerimiento internacional. En la actualidad, los efectos resultantes de la creación de AMP solo pueden especularse cualitativamente, pero deberían cuantificarse en un futuro próximo.

La merluza negra (Dissostichus eleginoides) es un pez demersal presente en el hemisferio sur, muy valioso comercialmente. Por ello, comprender los movimientos en diferentes escalas temporales y espaciales contribuiría a conocer más acerca del comportamiento que presenta la especie en la plataforma patagónica argentina y chilena. Desde 2004, el Instituto Nacional de Investigación y Desarrollo Pesquero (INIDEP, Argentina), inició un programa de marcado y recaptura de D. eleginoides. Un total de 5.907 ejemplares, en su mayoría juveniles (< 82 cm de largo total), fueron marcados y liberados en sectores ubicados en aguas del borde de la plataforma y talud de la Argentina entre 37° S y 47° S (Sector norte del caladero argentino), y al este de la Isla de los Estados y sur de Tierra del Fuego (54° S-57° S -Sector sur del caladero argentino). Actualmente, fueron recapturados 121 ejemplares, 25 (20,7%) se recuperaron en el Sector norte, 84 (69,4%) en el Sector sur y 12 (9,9%) en aguas del Océano Pacífico en Chile. El 67,5% fue recapturado a menos de 20 mn (37 km) del lugar de liberación y 15% recorrió distancias inferiores a las 120 mn. Una fracción menor (5%) recorrió distancias entre 120 y 400 mn y solo 12,5% se recapturó a más de 400 mn. Mediante un Modelo Aditivo Generalizado se determinó que las variables Días en libertad, Sector y Época de marcado influyeron en la distancia recorrida de los ejemplares. A partir del presente trabajo, parece evidente que la especie en el cono sur americano carece de desplazamientos migratorios regulares que involucren a una parte significativa del stock.

Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with targeted radioimmunotherapy (RIT).We studied two RCC models, analyzed Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) and AXL/MET expression and performed therapy studies in Balb/cnu/nu mice combining sunitinib and [177Lu]Lu-cG250 RIT (6.5 MBq/10 μg), specifically targeting RCC cells.pAXL and pMET were expressed in sunitinib-resistant SK-RC-52 and absent in sunitinib-sensitive NU12. NGS evaluation showed that expression of VEGFA, VEGFB, VEGFD, PGF and VEGFR1,2,3 was higher and expression of VEGFC and PDGFA was lower in NU12 than in SK-RC-52.Therapy studies combining sunitinib with [177Lu]Lu-cG250 RIT showed that the best response in mice with “resistant” SK-RC-52 tumors was observed with two cycles of Sunitinib and [177Lu]Lu-cG250 RIT, probably due to increased vascular permeability by sunitinib treatment. In the “sensitive” NU12 model, two cycles of [177Lu]Lu-cG250 RIT and two cycles of combination treatment were equally effective.Enhanced therapeutic efficacy was achieved when two agents ([177Lu]Lu-cG250 RIT and sunitinib) that on their own did not induce satisfactory response levels, are combined. Our findings provide a promising new therapeutic strategy for patients with advanced RCC.

Background and purpose: Tumor hypoxia is an important cause of radioresistance and is associated with poor outcome.SPECT (Single-photon emission computed tomography) imaging enables visualizing tumor characteristics. We investigated the SPECT-radiotracer [111In]-girentuximab-F(ab’)2 to image Carbonic Anhydrase IX (CAIX), an enzyme upregulated under hypoxic conditions. Materials and methods: Athymic mice with subcutaneous FaDu or SCCNij202 head and neck squamous cell carcinoma (HNSCC) xenografts were treated with atovaquone or were housed in a hypoxic chamber (8% O2). Next, [111In]-girentuximab-F(ab’)2 was injected and 24 h later mice were euthanized for ex vivo biodistribution, autoradiography of the tumor, and immunohistochemical staining of the tumor. Tumor sections were analyzed for hypoxia, CAIX expression, vessels, and perfusion. Also, the effect of atovaquone on microSPECT scans was determined in the FaDu model. Results: Atovaquone decreased CAIX expression by 69% (p = 0.017) compared with control tumors in FaDu, while in the SCCNij202 tumors no difference was observed. Hypoxic breathing did not increase CAIX expression or hypoxia staining in either tumor model, but did affect the necrotic tumor fraction. Ex vivo tracer uptake in the atovaquone treated group did not differ significantly from the control group, despite the difference in CAIX expression. Furthermore, SPECT imaging with [111In]-girentuximab-F(ab’)2 did not discriminate atovaquone-treated versus control tumors. Conclusion: Atovaquone decreased CAIX expression only in the FaDu tumor model. [111In]-girentuximab-F(ab’)2 specifically targets CAIX-expressing areas in HNSCC xenografts, but differences in vessel density and necrosis most likely affected tracer uptake in the tumors and therefore complicated quantification of changes in CAIX expression.

Abstract We analyzed SARS-CoV-2 seroprevalence in a large, well-described representative Viennese cohort after an early governmental lockdown with respect to the occurrence of symptoms and household transmission. Participants of the LEAD Study, a population-based cohort study from Vienna, Austria, were invited along with their household members (April 20th to May20th 2020). Sera were analyzed using anti-SARS-CoV-2 immunoassay including a neutralization test as a confirmatory assay. A total of 12,419 individuals participated (5984 LEAD participants; 6435 household members), 163 (1.31%; 59 LEAD cohort members) of whom were SARS-CoV-2 antibody positive. The estimated number of COVID-19 cases projected from our findings by age and sex for Vienna was 21,504 (1.13%). Cumulative number of positively tested cases in Vienna until May 20th 2020 was 3020, hence 7.1 times (95% confidence interval 5.5–9.1) lower than projected. Relative risk (RR) of seropositivity by age was highest for children aged 6–9 years [RR compared to age group 20–49: 1.21 (CI 0.37–4.01)], lowest for ≥ 65 years [RR 0.47 (CI 0.21–1.03)]. Half of the positive individuals developed no or mild symptoms. In a multivariate analysis, taste and smell disturbances were most strongly related to SARS-CoV-2 positivity. Infection probability within households with one confirmed SARS-CoV-2-specific antibody-positive person was 31%. Although seroprevalence was very low (1.13%) for a central European capital city, due to an early governmental lockdown, SARS-CoV-2 infections were more prevalent than officially reported polymerase chain reaction-positive cases. Of note, seroprevalence was highest in young children. Half of SARS-CoV-2 antibody-positive subjects had no or only mild symptoms. Taste and smell disturbances were most prominent, possibly guiding clinicians in diagnosing SARS-CoV-2 infection.

Rationale: Preserved ratio impaired spirometry (PRISm) is a recently recognized spirometric pattern defined by a ratio of forced expiratory volume in 1 second to forced vital capacity of at least 0.70 and a forced expiratory volume in 1 second  <80% of reference. For unclear reasons, PRISm is associated with increased cardiovascular (CV) morbidity and mortality. Arterial stiffness is a major mechanism of CV disease, which can be measured by carotid-femoral pulse-wave velocity (cfPWV). Objectives: We explored the hypothesis that cfPWV would be increased in individuals with PRISm and airflow limitation (AL). Methods: We measured forced spirometry, lung volumes by body plethysmography, and cfPWV in 9,466 subjects recruited from the general population in the Austrian cross-sectional LEAD (Lung, Heart, Social, Body) study and tested the association of arterial stiffness with PRISm and AL by multivariable linear regression analysis. Individuals younger than 18 years were excluded from the study. Results: Individuals with PRISm (n = 431; 4.6%) were of similar age to those with normal spirometry (n = 8,136; 85.9%) and significantly younger than those with AL (n = 899; 9.5%). Arterial hypertension, diabetes mellitus, coronary artery disease, heart failure, and peripheral arterial occlusive disease were significantly more common in individuals with PRISm than in those with normal lung function and similar to those with AL. There was a significant association between PRISm and arterial stiffness on bivariate linear regression analysis (crude model, β = 0.038; 95% confidence interval [CI], 0.016–0.058), which persisted after robust adjustment for clinical confounders upon multivariable analysis (final model, β = 0.017; 95% CI, 0.001–0.032). cfPWV was significantly higher in individuals with PRISm irrespective of the presence of established CV disease or pulmonary restriction. AL also showed a significant association with arterial stiffness on multivariable linear regression analysis (final model, β = 0.025; 95% CI, 0.009–0.042). Conclusions: Arterial stiffness measured by cfPWV is increased in individuals with PRISm independent of CV disease and risk factors. The pathobiological mechanisms underlying this association deserve further research. [ABSTRACT FROM AUTHOR]

Objective: We aim to provide a template structured report of fetal Magnetic Resonance Imaging in congenital diaphragmatic hernia (CDH) that was locally validated by the CDH study group in Mannheim. Methods: A selection of 50 fetal MRIs of patients with an isolated diaphragmatic hernia and associated radiology reports from five different senior radiologists from a single center resulted in a primary structured report, which was put into practice by using dedicated software. A questionnaire survey of the interdisciplinary CDH study group Mannheim was used to adapt the report to the clinical requirements. Results: There was a huge variability in how deep the free text reports go into detail. The side of the hernia was named in 94% of cases. In 58%, both the lung volume and the total lung volume were reported. A comparison with the expected lung volume was reported in 66% of cases. Additional findings, such as herniated organs, were reported in 96% of cases. Overall satisfaction with the newly established structured report was high within the CDH study group with a mean of 4.7. Conclusions: The use of the structured report of this study can optimize the interdisciplinary dialog, the standardization of report content, increase report completeness and improve quality. Key points: What's already known about this topic? Use of prenatal magnetic resonance imaging for diagnosis and prognosis assessment in congenital diaphragmatic hernia (CDH).Assessment of lung development in CDH is crucial for treatment and prognosis.Free text reports may lead to information gaps and loss of quality in rare diseases. What does this study add? The structured report improves the consistency and completeness of reports, leading to better communication and treatment planning.For less experienced radiologists, structured reporting can facilitate access to and reporting of rare diseases. [ABSTRACT FROM AUTHOR]

Recent developments in biomimetic hydrogel research have expanded the scope of biomedical technologies that can be used to model, diagnose, and treat a wide range of medical conditions. Cancer presents one of the most intractable challenges in this arena due to the surreptitious mechanisms that it employs to evade detection and treatment. In order to address these challenges, biomimetic design principles can be adapted to beat cancer at its own game. Biomimetic design strategies are inspired by natural biological systems and offer promising opportunities for developing life-changing methods to model, detect, diagnose, treat, and cure various types of static and metastatic cancers. In particular, focusing on the cellular and subcellular phenomena that serve as fundamental drivers for the peculiar behavioral traits of cancer can provide rich insights into eradicating cancer in all of its manifestations. This review highlights promising developments in biomimetic nanocomposite hydrogels that contribute to cancer therapies via enhanced drug delivery strategies and modeling cancer mechanobiology phenomena in relation to metastasis and synergistic sensing systems. Creative efforts to amplify biomimetic design research to advance the development of more effective cancer therapies will be discussed in alignment with international collaborative goals to cure cancer. [ABSTRACT FROM AUTHOR]

Background Increasing attention has been drawn on the assessment of body composition phenotypes, since the distribution of soft tissue influences cardio-metabolic risk. Dual-energy X-ray absorptiometry (DXA) is a validated technique to assess body composition. European reference values from population-based cohorts are rare. Aims To provide age- and sex-related reference values of body composition parameters and visceral adipose tissue (VAT) mass, and for lean mass index (LMI) with regard to fat mass index (FMI) quantities and BMI categories. Methods GE-Lunar Prodigy DXA scans of 10.894 participants, aged 18-81 years, recruited from 2011 to 2019 by the Austrian LEAD study, a population-based cohort study, have been used to construct reference curves using the LMS method. Parameters assessed are FMI, LMI, appendicular LMI, fat mass ratios android/gynoid and trunk/limbs, and VAT. Results All lean mass and fat mass parameters indicating central fat accumulation were higher in men, whereas other fat mass indices were higher in women. LMI differed between each FMI subgroup (low vs. normal, low vs. high, normal vs. high), and BMI category in all ages and LMI increased with FMI and BMI classes. VAT mass was higher in men compared with women and increased across all age groups within both sexes. Conclusion The present study provides age- and sex-related reference values for European adults aged 18-81 years for body composition parameters and VAT mass for Lunar Prodigy DXA. In addition, this study reports LMI reference values with regard to fat mass quantities, showing a positive association with increasing FMI percentiles and BMI categories., Author(s): Alina Ofenheimer [sup.1] [sup.2] [sup.3], Robab Breyer-Kohansal [sup.2] [sup.4], Sylvia Hartl [sup.2] [sup.3] [sup.4], Otto C. Burghuber [sup.2] [sup.3], Florian Krach [sup.5], Andrea Schrott [sup.2], Emiel F. M. Wouters [...]

A series of alkali metal- and nickel-exchanged Al-MCM-41 catalysts were prepared via aqueous ion exchange and then investigated for gas-phase oligomerization of propene at 453 K and near ambient pressures. All catalysts were active and produced oligomers with >98% selectivity. The highest activities per Ni2+ cation were observed when the cations were highly dispersed as a consequence of either lowering the Ni loading for a fixed MCM-41 Si/Al ratio or by decreasing the concentration of exchangeable sites within the material by increasing the MCM-41 Si/Al ratio at a fixed Ni loading. The identity of the alkali metal cation had no significant effect on the catalytic activity or degree of dimer branching, except for the sample containing Cs + cations, where the decreased pore volume resulted in a lower catalyst activity and slightly more linear dimer products. Comparison of Ni-MCM-41 prepared with and without Na+ cations showed that a higher yield of oligomers could be achieved when Na+ cations are present because of partial removal of strong Brønsted acid sites. For the same reaction conditions, Ni-Na-MCM-41 was more than twice as active as smaller-pored Ni-Na-X zeolites, demonstrating that the activity of Ni2+ cations increases with the increasing free volume near the site. This effect of free volume on the activity of Ni2+ cations was further confirmed by comparing the activities of Ni-Na-X, Ni-Na-MCM-41, Ni-Na-MCM-48, and Ni-Na-SBA-15 with respect to pore size. © 2013 American Chemical Society.

Abstract Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. Methods To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1 nu/nu ) with subcutaneously xenografted LoVo tumors. Results In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm2 and 0.5 μg/μL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. Conclusion Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo.

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR -mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR -mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies.

Immunotherapy aims to re-engage and revitalize the immune system in the fight against cancer. Research over the past decades has shown that the relationship between the immune system and human cancer is complex, highly dynamic, and variable between individuals. Considering the complexity, enormous effort and costs involved in optimizing immunotherapeutic approaches, clinically applicable tools to monitor therapy-induced immune responses in vivo are most warranted. However, the development of such tools is complicated by the fact that a developing immune response encompasses several body compartments, e.g., peripheral tissues, lymph nodes, lymphatic and vascular systems, as well as the tumor site itself. Moreover, the cells that comprise the immune system are not static but constantly circulate through the vascular and lymphatic system. Molecular imaging is considered the favorite candidate to fulfill this task. The progress in imaging technologies and modalities has provided a versatile toolbox to address these issues. This review focuses on the detection of therapy-induced anticancer immune responses in vivo and provides a comprehensive overview of clinically available imaging techniques as well as perspectives on future developments. In the discussion, we will focus on issues that specifically relate to imaging of the immune system and we will discuss the strengths and limitations of the current clinical imaging techniques. The last section provides future directions that we envision to be crucial for further development.