Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath.

BACKGROUND: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients. METHODS: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis. RESULTS: Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96). CONCLUSION: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.

Surgical removal of the index node marked using magnetic seed localization to assess response to neoadjuvant immunotherapy in patients with stage III melanoma.

This pilot study explored the value of localized index node removal after neoadjuvant immunotherapy in patients with stage III melanoma, for use as a response indicator to guide the extent of completion lymph node dissection. Promising technology.

Feasibility of magnetic marker localisation for non-palpable breast cancer.

OBJECTIVES: Accurate tumour localisation is essential for breast-conserving surgery of non-palpable tumours. Current localisation technologies are associated with disadvantages such as logistical challenges and migration issues (wire guided localisation) or legislative complexities and high administrative burden (radioactive localisation). We present MAgnetic MArker LOCalisation (MaMaLoc), a novel technology that aims to overcome these disadvantages using a magnetic marker and a magnetic detection probe. This feasibility study reports on the first experience with this new technology for breast cancer localisation. MATERIALS AND METHODS: Fifteen patients with unifocal, non-palpable breast cancer were recruited. They received concurrent placement of the magnetic marker in addition to a radioactive iodine seed, which is standard of care in our clinic. In a subset of five patients, migration of the magnetic marker was studied. During surgery, a magnetic probe and gammaprobe were alternately used to localise the markers and guide surgery. The primary outcome parameter was successful transcutaneous identification of the magnetic marker. Additionally, data on radiologist and surgeon satisfaction were collected. RESULTS: Magnetic marker placement was successful in all cases. Radiologists could easily adapt to the technology in the clinical workflow. Migration of the magnetic marker was negligible. The primary endpoint of the study was met with an identification rate of 100%. Both radiologists and surgeons reflected that the technology was intuitive to use and that it was comparable to radioactive iodine seed localisation. CONCLUSION: Magnetic marker localisation for non-palpable breast cancer is feasible and safe, and may be a viable non-radioactive alternative to current localisation technologies.

Comparative ex vivo study on humidifying function of three speaking valves with integrated heat and moisture exchanger for tracheotomised patients.

OBJECTIVE: Assessment of humidifying function of tracheotomy speaking valves with integrated heat and moisture exchanger. DESIGN: Ex vivo measurement of water exchange and storage capacity of three tracheotomy speaking valves: Humidiphon Plus, Spiro and ProTrach DualCare (with two different heat and moisture exchangers: XtraMoist and Regular). SETTING: Comprehensive Cancer Centre. PARTICIPANT: Healthy volunteer. MAIN OUTCOME MEASURES: Difference between end-inspiratory and end-expiratory weight as measure for water exchange capacity, weight after 10 min breathing as measure for water storage capacity, weighing at 1-min intervals to assess residual water exchange potential in speaking mode and absolute humidity in mg/L as measure for environmental and respiratory humidity. RESULTS: None of the tracheotomy speaking valves provides humidification while in speaking mode. Only the ProTrach DualCare allows blocking the speaking valve and breathing through the heat and moisture exchanger during inhalation and exhalation (heat and moisture exchanger mode). This leads to an increase in inspiratory humidity of 2.5 mg (XtraMoist) and 1.6 mg (Regular). There was no measurable water storage in speaking mode in any of the three tracheotomy speaking valves. In breathing mode, water storage in the DualCare heat and moisture exchangers was 47 and 37 mg, respectively. The remaining humidifying potential in speaking mode after 10 min breathing in heat and moisture exchanger mode for XtraMoist was 38%, 15% and 10% at 1, 2 and 3 min, respectively. For Regular, this was 47%, 24% and 13%, respectively. CONCLUSIONS: Tracheostoma valves with integrated heat and moisture exchanger have no humidification function in speaking mode. Only ProTrach DualCare, allowing blocking the speaking mode, in heat and moisture exchanger mode enables a significant increase in humidification. Regular switching between speaking and heat and moisture exchanger mode with this latter device prolongs the humidification in speaking mode.

Simultaneous use of an (125)I-seed to guide tumour excision and (99m)Tc-nanocolloid for sentinel node biopsy in non-palpable breast-conserving surgery.

PURPOSE: In the present study we describe patients with non-palpable breast lesions, in which an Iodine-125 ((125)I)-marker (or "seed") for excision of the primary tumour and Technetium-99m nanocolloid ((99m)Tc-nanocolloid) for sentinel node biopsy (SNB) are used simultaneously. The purpose was to investigate any interference between (125)I-seeds and (99m)Tc-nanocolloid by an in vitro and in vivo analysis. METHODS: Contrast/interference-ratios between (125)I and (99m)Tc count-rates were determined in vitro using a realistic simulation model. Measurements were performed with 3 gamma-probes with different crystal materials. In 25 consecutive patients (99m)Tc-nanocolloid was intratumourally administered at the site of a previously implanted (125)I-seed. Respectively, the (125)I-setting and (99m)Tc-setting of the gamma-probe guided the wide local excision and SNB and maximum counts-per-second (cps) were measured. RESULTS: In vitro the different probes varied in (125)I- and (99m)Tc-sensitivity. The contrast-ratio between (125)I and (99m)Tc in the (125)I-channel was 4.6 for a 3-month-old (125)I-seed using the most appropriate gamma-probe. In vivo the gamma-probe in the (125)I-setting measured a median of 16,300 cps at the tumour site compared to 4820 cps using the (99m)Tc-setting. The (125)I-seed could be well distinguished from the (99m)Tc-nanocolloid in 92% of the patients and 96% required a single operation. The SNB was successful in all patients. CONCLUSIONS: Simultaneous use of (125)I-seeds and (99m)Tc-nanocolloid is possible under well-standardised conditions. Non-palpable breast lesions can be safely excised using the (125)I-seed in combination with a SN procedure. Use of (125)I-seeds is a next step within fine-tuning breast-conserving surgery that should lead to further investigation to confirm its value.

Effects of heat and moisture exchangers on tracheal mucociliary clearance in laryngectomized patients: a multi-center case-control study.

After total laryngectomy, inspired air is no longer optimally conditioned by the upper airways. Impaired mucociliary clearance and histological changes of respiratory epithelium, such as loss of ciliated cells, have been described in laryngectomized patients. Heat and moisture exchangers (HMEs) are passive humidifiers that re-condition the inspired air. Aim of this study was to assess the effect of HMEs on tracheal epithelium and tracheal mucus transport velocity (TMV). Tracheal brush biopsies were collected in three groups of TLE patients: 21 long-term HME users, 10 non-HME users, and 16 non-HME users before and after 4-9 months HME use. Tracheal epithelium biopsies were assessed using a digital high-speed camera mounted onto a light microscope. TMV was determined by scintigraphy in the first two patient groups. Significantly more ciliated cells were found in HME users compared to non-HME users (p = 0.05). TMV was higher in HME users (median 2 mm/min; 0-7.9) compared to non-HME users (median 0.8 mm/min; 0-12.3), but this difference was not significant (p = 0.37). One-hour breathing without HME in long-term HME users did not measurably decrease TMV (p = 0.13). The long-term use of an HME restores/prevents the loss of tracheal ciliated cells. A significant improvement in TMV was not found. Short-term (one hour) detachment of an HME has no measurable effect on TMV.

Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum.

G protein-coupled receptors (GPCR) signal not only through heterotrimeric G proteins, but also through alternate pathways. Thus, dopamine D2 receptors in the striatum signal through Gαi/o and also by promoting formation of a multi-protein complex containing ß-arrestin2, protein phosphatase 2A (PP2A), and Akt in order to dephosphorylate Akt. Lithium, on the other hand, disrupts this complex to increase Akt phosphorylation. Rhes is a striatally enriched GTP-binding protein that has been shown to inhibit dopamine receptor-mediated behavior and signaling through heterotrimeric G proteins. Therefore, our objective was to test whether Rhes similarly affects signaling through the Akt/GSK3 pathway in the striatum. Rhes(-/-) mice showed basally increased Akt and GSK3ß phosphorylation relative to rhes(+/+) mice that was not further enhanced by lithium treatment. Furthermore, they responded to the D1/D2 agonist apomorphine with increased Akt and GSK3 phosphorylation. Co-immunoprecipitation experiments revealed that apomorphine treatment recruits PP 2A-C to Akt in both rhes(+/+) and rhes(-/-) mice. Lithium did not disrupt their interaction in rhes(-/-) mice as there was little basal interaction. Rhes co-immunoprecipitated with ß-arrestins, suggesting that it is integral to the multi-protein complex. Thus, Rhes is necessary for Akt dephosphorylation by the striatal multi-protein complex, and in its absence, a lithium-treated phenotype results.

Plasma blob generation due to cooperative elliptic instability.

Using fast-camera measurements the generation mechanism of plasma blobs is investigated in the linear device CSDX. During the ejection of plasma blobs the plasma is dominated by an m=1 mode, which is a counterrotating vortex pair. These flows are known to be subject to the cooperative elliptic instability, which is characterized by a cooperative disturbance of the vortex cores and results in a three-dimensional breakdown of two-dimensional flows. The first experimental evidence of a cooperative elliptic instability preceding the blob-ejection is provided in terms of the qualitative evolution of the vortex geometries and internal wave patterns.

Experimental investigation of the role of fluid turbulent stresses and edge plasma flows for intrinsic rotation generation in DIII-D H-mode plasmas.

The first measurements of turbulent stresses and flows inside the separatrix of a tokamak H-mode plasma are reported, using a reciprocating multitip Langmuir probe at the DIII-D tokamak. A strong co-current rotation layer at the separatrix is found to precede intrinsic rotation development in the core. The measured fluid turbulent stresses transport toroidal momentum outward against the velocity gradient and thus try to sustain the edge layer. However, large kinetic stresses must exist to explain the net inward momentum transport leading to co-current core plasma rotation. The importance of such kinetic stresses is corroborated by the success of a simple orbit loss model, representing a purely kinetic mechanism, in the prediction of features of the edge corotation layer.

Intrinsic rotation from a residual stress at the boundary of a cylindrical laboratory plasma.

An azimuthally symmetric radially sheared azimuthal flow is driven by a nondiffusive, or residual, turbulent stress localized to a narrow annular region at the boundary of a cylindrical magnetized helicon plasma device. A no-slip condition, imposed by ion-neutral flow damping outside the annular region, combined with a diffusive stress arising from turbulent and collisional viscous damping in the central plasma region, leads to net plasma rotation in the absence of momentum input.

Cross-field motion of plasma blobs in an open magnetic field line configuration.

The radial propagation of blobs generated from plasma instabilities is investigated in an open magnetic field line configuration. Blob cross-field velocities and sizes are obtained from internal probe measurements using pattern recognition. By varying the ion mass, the normalized vertical blob scale a[over] is scanned from a[over] < 1 to a[over] > 1. An analytical expression for the blob velocity including cross-field ion polarization currents, parallel currents to the sheath, and ion-neutral collisions is derived and shows good quantitative agreement with the experimental data. In agreement with previous theoretical studies, this scaling shows that, for a[over] < 1, the blob velocity is limited by cross-field ion polarization currents, while for a[over] > 1 it is limited by parallel currents to the sheath.

Endotracheal temperature and humidity measurements in laryngectomized patients: intra- and inter-patient variability.

UNLABELLED: This study assesses intra- and inter-patient variability in endotracheal climate (temperature and humidity) and effects of heat and moister exchangers (HME) in 16 laryngectomized individuals, measured repeatedly (N = 47). Inhalation Breath Length (IBL) was 1.35 s without HME and 1.05 s with HME (P < 0.0001). With HME, end-inspiratory (minimum) humidity values increased 5.8 mg H(2)O/L (P < 0.0001) and minimum temperature values decreased 1.6 degrees C (P < 0.0001). For the temperature and humidity minimums, the inter-patient variability was much smaller than the short- and long-term intra-patient variability. For exhalation breath length and full breath length, the opposite was the case. CONCLUSIONS: (1) Because inter-patient variability is smaller than intra-patient variability, investigating endotracheal climate in a limited number of laryngectomized subjects is justified, provided repeated measurements per patient are accomplished; (2) main contributor to intra-patient variability is the positioning of the catheter tip in the trachea; (3) an HME leads to a shortened IBL which enhances the HME effect.

The impact of preoperative MRI on breast-conserving surgery of invasive cancer: a comparative cohort study.

AIM: To assess whether preoperative contrast-enhanced magnetic resonance imaging (MRI) of the breast influences the rate of incomplete tumor excision. METHODS: In a cohort of 349 women with invasive breast cancer, patients eligible for breast-conserving therapy (BCT) on the basis of conventional imaging and palpation only (N = 176) were compared to those who had an additional preoperative MRI (N = 173). Multivariate analysis was applied to explore associations with incomplete tumor excision. RESULTS: MRI detected larger extent of breast cancer in 19 women (11.0%), leading to treatment change: mastectomy (8.7%) or wider excision (2.3%). Tumor excision was incomplete in 22/159 (13.8%) wide local excisions in the MRI group and in 35/180 (19.4%) in the non-MRI group (P = 0.17). Stratified to tumor type, incompletely excised infiltrating ductal carcinoma (IDC) was significantly associated with absence of MRI: 11/136 (8.1%) versus 2/126 (1.6%) (MRI present) (P = 0.02). No significant factors explained incomplete excision of other tumor types. CONCLUSION: Preoperative MRI did not significantly affect the overall rate of incomplete tumor excision, but it yielded significantly lower rate of incompletely excised IDC. The reduction of incomplete excisions after MRI was smaller than the rate of a prior treatment change incurred by MRI.

Dust measurements in tokamaks (invited).

Dust production and accumulation present potential safety and operational issues for the ITER. Dust diagnostics can be divided into two groups: diagnostics of dust on surfaces and diagnostics of dust in plasma. Diagnostics from both groups are employed in contemporary tokamaks; new diagnostics suitable for ITER are also being developed and tested. Dust accumulation in ITER is likely to occur in hidden areas, e.g., between tiles and under divertor baffles. A novel electrostatic dust detector for monitoring dust in these regions has been developed and tested at PPPL. In the DIII-D tokamak dust diagnostics include Mie scattering from Nd:YAG lasers, visible imaging, and spectroscopy. Laser scattering is able to resolve particles between 0.16 and 1.6 microm in diameter; using these data the total dust content in the edge plasmas and trends in the dust production rates within this size range have been established. Individual dust particles are observed by visible imaging using fast framing cameras, detecting dust particles of a few microns in diameter and larger. Dust velocities and trajectories can be determined in two-dimension with a single camera or three-dimension using multiple cameras, but determination of particle size is challenging. In order to calibrate diagnostics and benchmark dust dynamics modeling, precharacterized carbon dust has been injected into the lower divertor of DIII-D. Injected dust is seen by cameras, and spectroscopic diagnostics observe an increase in carbon line (CI, CII, C(2) dimer) and thermal continuum emissions from the injected dust. The latter observation can be used in the design of novel dust survey diagnostics.

Cross-field transport by instabilities and blobs in a magnetized toroidal plasma.

The mechanisms for anomalous transport across the magnetic field are investigated in a toroidal magnetized plasma. The role of plasma instabilities and macroscopic density structures (blobs) is discussed. Examples from a scenario with open magnetic field lines are shown. A transition from a main plasma region into a loss region is reproduced. In the main plasma, which includes particle and heat source locations, the transport is dominated by the fluctuation-induced particle and heat flux associated with a plasma instability. On the low-field side, the cross-field transport is ascribed to the intermittent ejection of macroscopic blobs propagating toward the outer wall. It is shown that instabilities and blobs represent fundamentally different mechanisms for cross-field transport.

Experimental observation of the blob-generation mechanism from interchange waves in a plasma.

The mechanism for blob generation in a toroidal magnetized plasma is investigated using time-resolved measurements of two-dimensional structures of electron density, temperature, and plasma potential. The blobs are observed to form from a radially elongated structure that is sheared off by the E x B flow. The structure is generated by an interchange wave that increases in amplitude and extends radially in response to a decrease of the radial pressure scale length. The dependence of the blob amplitude upon the pressure radial scale length is discussed.

Stage of breast cancers found during the surveillance of women with a familial or hereditary risk.

AIM: To compare the breast cancer stages found during MG alone surveillance in women at increased risk with those detected in a program where MRI was added. METHODS: Stage results of in a retrospective MG alone study of prospectively followed patients, compared with the pooled stage results of breast cancers MG/MRI surveillance. RESULTS: One hundred and-fifty-one patients were detected with a first or contralateral breast cancer. Interval cancers were diagnosed in 56% of the BRCA1, 42% of the BRCA2 and 28% of the non-BRCA carriers. A considerable proportion of the breast cancers were detected with breast self-examination alone: 41%, 27% and 31% respectively. Nevertheless the established goals for biennial population screening were reached, except for the BRCA2 carriers, but this group was small. Comparison with pooled data from published MG/MRI surveillance studies did not show significant differences in the stages, except for the BRCA2 carriers. CONCLUSION: Breast cancers detected in a MG alone surveillance program for women at increased risk fulfill most goals set for population screening except for the BRCA2 carriers. Breast self-examination appears to be a valuable additional detection method especially for BRCA1 carriers, who are at risk of developing a highly proliferating breast cancer.

Universal statistical properties of drift-interchange turbulence in TORPEX plasmas.

A unique parabolic relation is observed to link skewness and kurtosis of around ten thousand density fluctuation signals, measured over the whole cross section of a toroidal magnetized plasma for a broad range of experimental conditions. All the probability density functions of the measured signals, including those characterized by a negative skewness, are universally described by a special case of the Beta distribution. Fluctuations in the drift-interchange frequency range are necessary and sufficient to assure that probability density functions can be described by this specific Beta distribution.

A newly developed tool for intra-tracheal temperature and humidity assessment in laryngectomized individuals: the Airway Climate Explorer (ACE).

The aim of this study is to develop a postlaryngectomy airway climate explorer (ACE) for assessment of intratracheal temperature and humidity and of influence of heat and moisture exchangers (HMEs). Engineering goals were within-device condensation prevention and fast response time characteristics. The ACE consists of a small diameter, heated air-sampling catheter connected to a heated sensor house, containing a humidity sensor. Air is sucked through the catheter by a controlled-flow pump. Validation was performed in a climate chamber using a calibrated reference sensor and in a two-flow system. Additionally, the analyser was tested in vivo. Over the clinically relevant range of humidity values (5-42 mg H2O/l air) the sensor output highly correlates with the reference sensor readings (R2 > 0.99). The 1-1/e response times are all <0.5 s. A first in vivo pilot measurement was successful. The newly developed, verified, fast-responding ACE is suitable for postlaryngectomy airway climate assessment.

Tumor characteristics and detection method in the MRISC screening program for the early detection of hereditary breast cancer.

In the MRISC study, women with an inherited risk for breast cancer were screened by a 6-month clinical breast examination (CBE) and yearly MRI and mammography. We found that the MRISC screening scheme could facilitate early breast cancer diagnosis and that MRI was a more sensitive screening method than mammography, but less specific. In the current study we investigated the contribution of MRI in the early detection of breast cancer in relation to tumor characteristics. From November 1999 to October 2003, 1909 women were included and 50 breast cancers were detected, of which 45 were evaluable and included in the current study. We compared the characteristics of tumors detected by MRI-only with those of all other (non-palpable) screen-detected tumors. Further, we compared the sensitivity of mammography and MRI within subgroups according to different tumor characteristics. Twenty-two (49%) of the 45 breast cancers were detected by MRI and not visible at mammography, of which 20 (44%) were also not palpable (MRI-only detected tumors). MRI-only detected tumors were more often node-negative than other screen-detected cancers (94 vs. 59%; P=0.02) and tended to be more often