Efficacy of ipilimumab and nivolumab in patients with high-grade neuroendocrine neoplasms.

BACKGROUND: Dual checkpoint inhibitor therapy with anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein 4 therapy has shown promising results in patients with high-grade neuroendocrine neoplasms (NENs), demonstrating varying response rates of 9%-44%. More data are needed to evaluate the true response in a real-world cohort of patients. PATIENTS AND METHODS: We conducted a retrospective study of all patients with high-grade NENs treated at the Moffitt Cancer Center and Mayo Clinic between September 2017 and July 2020 who received combination therapy with ipilimumab and nivolumab. RESULTS: Thirty-four patients met the eligibility criteria. Patients had received an average of two prior lines of therapy, including at least one cytotoxic chemotherapy regimen. Twenty-seven (79.4%) patients had poorly differentiated neuroendocrine carcinomas, and seven (20.6%) had well-differentiated high-grade neuroendocrine tumors. The most common primary site (10, 29.4%) was pancreas; other primary sites of disease included colon (n = 5), endometrium (n = 3), anorectum (n = 2), esophagus (n = 2), cervix (n = 1), stomach (n = 1), small intestine (n = 1), and unknown primary (n = 9). Five patients (14.7%) exhibited a best response of partial response as per RECIST 1.1 criteria, 9 (26.5%) stable disease, and 17 (50%) progressive disease: 3 patients did not have a follow-up scan as they discontinued treatment shortly after initiation due to clinical progression. The objective response rate was 14.7%, and disease control rate was 41.2%. Median progression-free survival was 1 month [95% confidence interval (CI), 0.54-1.46 months]; median overall survival (OS) from time of treatment initiation was 5.0 months (95% CI, 4.07-5.93 months), and median OS from diagnosis was 14.0 months (95% CI, 11.79-16.21 months). The median duration of treatment was 1 month (range 0-10 months). Twenty-eight patients discontinued treatment for progression, four patients for toxicity, and two remain on treatment at the time of data cut-off. Twelve patients (35%) experienced grade 3 and 4 treatment-emergent toxicities. CONCLUSIONS: The ipilimumab and nivolumab regimen has modest activity in aggressive and heavily pretreated high-grade NENs who have progressed on prior cytotoxic chemotherapy.

Particle clearance from the airways of subjects with bronchial hyperresponsiveness and with chronic obstructive pulmonary disease.

The aim of this study was to determine particle clearance and retention from non-alveolated airways of 14 healthy subjects (HS), 10 subjects with asymptomatic bronchial hyperresponsiveness (BHR), and 23 patients with chronic obstructive pulmonary disease (COPD). Monodisperse iron oxide particles of 1.6 micro m geometric and 3.5 micro m aerodynamic diameter labeled with (99m)Tc were delivered to the airways by inspiration of small aerosol boli into shallow volumetric lung depths. In each subject the penetration front depth of the aerosol boli was adjusted to 55% of the Fowler dead space of the airways. Particle deposition was enhanced by about 7 seconds of breath-holding after bolus inhalation. Retention of the particles in the airways during the 48 hours after their administration was assessed by measuring the decline in lung activity with a sensitive gamma counter. Particle deposition was not significantly different among study groups. Twenty-four hour particle retention in the airways was not different among study groups. Sixty-one percent of the particles were retained at 24 hours in HS, 58% in BHR, and 64% in COPD. However, subjects with BHR showed accelerated mucociliary clearance compared to healthy subjects, whereas clearance was retarded in COPD patients. This long-term particle retention in the airways has to be taken into account in aerosol toxicology risk assessment and aerosol therapy dose evaluation.

Negligible clearance of ultrafine particles retained in healthy and affected human lungs.

Ambient particles are believed to be a specific health hazard, although the underlying mechanisms are not fully understood. There are data in the literature indicating fast and substantial systemic uptake of particles from the lung. The present authors have developed an improved method to produce ultrafine particles with more stable radiolabelling and defined particle size range. Fifteen subjects inhaled technetium 99m (99mTc)-labelled carbonaceous particles of 100 nm in size. Radioactivity over the lung was followed for 70 h. The clearance of these ultrafine particles from the lungs and specifically translocation to the circulation was tested. Lung retention for all subjects at 46 h was mean+/-sd 99+/-4.6%. Cumulative leaching of 99mTc activity from the particles was 2.6+/-0.96% at 70 h. The 24-h activity leaching in urine was 1.0+/-0.55%. No evidence of a quantitatively important translocation of 100-nm particles to the systemic circulation from the lungs was found. More research is needed to establish if the approximately 1% cleared activity originates from leached activity or insoluble translocated particles, and whether a few per cent of translocated particles is sufficient to cause harmful effects.

Inhaling to mitigate exhaled bioaerosols.

Humans commonly exhale aerosols comprised of small droplets of airway-lining fluid during normal breathing. These "exhaled bioaerosols" may carry airborne pathogens and thereby magnify the spread of certain infectious diseases, such as influenza, tuberculosis, and severe acute respiratory syndrome. We hypothesize that, by altering lung airway surface properties through an inhaled nontoxic aerosol, we might substantially diminish the number of exhaled bioaerosol droplets and thereby provide a simple means to potentially mitigate the spread of airborne infectious disease independently of the identity of the airborne pathogen or the nature of any specific therapy. We find that some normal human subjects expire many more bioaerosol particles than other individuals during quiet breathing and therefore bear the burden of production of exhaled bioaerosols. Administering nebulized isotonic saline to these "high-producer" individuals diminishes the number of exhaled bioaerosol particles expired by 72.10 +/- 8.19% for up to 6 h. In vitro and in vivo experiments with saline and surfactants suggest that the mechanism of action of the nebulized saline relates to modification of the physical properties of the airway-lining fluid, notably surface tension.

Deposition of Foradil P in human lungs: comparison of in vitro and in vivo data.

In order to characterize the efficacy of dry powder inhalers, in vitro measurements are much easier to perform than human deposition studies, especially in early stages of drug development. In this study, lung deposition and delivered dose of radiolabeled Foradil P inhaled with the Aerolizer were measured in 10 healthy subjects. These data were then compared with data derived from an in vitro assessment of the device output and particle size distribution combined with mathematical modeling of lung deposition (modified ICRP-model). Delivered dose and lung deposition increased slightly but statistically significant with the inhalation peak flow in both the in vivo data and the in vitro data. The delivered dose ranged from 60% to 80% and lung deposition, relative to the fill weight, from 13% to 28%. Differences between the in vitro and in vivo data were slight and statistically not significant. This study indicates that in vitro assessment of device performance, in combination with lung deposition delivery data, are in good agreement with deposition data measured in healthy subjects. Since there was only a slight flow rate dependency of lung deposition without clinical relevance, it may additionally be concluded that the Aerolizer is a robust, easy to handle inhalation device with stable and reproducible drug delivery characteristics.

Peripheral deposition of alpha1-protease inhibitor using commercial inhalation devices.

Patients with hereditary alpha1-proteinase inhibitor (alpha1-PI) deficiency are at risk of developing lung emphysema. To prevent the development of this disease, alpha1-PI replacement therapy via inhalation may be a more convenient and effective therapy than the intravenous administration of the drug. In order to optimise this treatment approach, lung deposition of inhaled radiolabelled alpha1-PI (Prolastin) was studied using four different commercial inhalation devices (PARI-LC Star, HaloLite, and AKITA system in combination with LC Star and Sidestream) in six patients with alpha1-PI deficiency and mild-to-severe chronic obstructive pulmonary disease. The time required to deposit 50 mg of the Prolastin (5% solution) in the lung periphery was used as a measure for the efficiency of delivery. The time was calculated from measurements of total and peripheral lung deposition of the radiolabelled alpha1-PI. This time was shortest for the AKITA system (18-24 min) and significantly higher for the PARI-LC Star (44 min) and the HaloLite (100 min). The higher efficiency of drug delivery using the AKITA system is due to the fact that this device controls breathing patterns, which are optimised for each patient individually.

Pulmonary deposition of monodisperse aerosols in patients with chronic obstructive pulmonary disease.

In order to improve patient convenience and drug availability for patients with alpha 1-protease inhibitor deficiency, the administration via the inhalation route has been considered. This study investigated if it is possible to obtain high values of peripheral aerosol deposition by using optimized and controlled inhalation conditions. Therefore, peripheral deposition was studied in 10 patients with alpha 1-protease inhibitor deficiency (phenotype PiZ) and moderate to severe chronic obstructive pulmonary disease by measuring the 24-hour Clearance of radiolabeled inert iron oxide particles with diameters of 2 microns, 3 microns, and 4 microns. Patients inhaled a large volume of aerosol (1000 to 2000 cm3), which was normalized to the individual lung function, with a flow rate of 200 cm3/S. Due to this breathing pattern, peripheral deposition was for all particle sizes above 50% of the inhaled aerosol. The highest peripheral deposition (68%) was found for 3-microns particles.

Alveolar deposition of monodisperse aerosol particles in the lung of patients with chronic obstructive pulmonary disease.

Knowledge about the regional deposition of aerosol particles is essential in order to perform efficient inhalation therapy or to minimize health risks due to environmental or occupational aerosol particles. In this study, 2 techniques were used to measure thoracic deposition and to differentiate between bronchial and alveolar deposition. The first technique was the clearance-derived regional deposition (CRD) technique and the second the single-breath regional deposition (SBRD) technique. Deposition was measured in 12 patients with alpha1-antitrypsin deficiency and symptoms of moderate to severe chronic obstructive pulmonary disease (COPD) using monodisperse test particles with aerodynamic diameters of 2, 3, and 4 microm. In CRD, the kinetic of particle clearance within the first 24 hours after inhalation was used to determine bronchial and alveolar deposition. In SBRD, the longitudinal distribution of deposited inert test particles was used to calculate the particle fraction deposited within and distal to the dead space. Both techniques delivered very similar mean values for total and alveolar deposition. Due to controlled slow and deep inhalations, alveolar deposition was as much as 50%. Therefore, SBRD can be considered as an easy tool to study alveolar deposition in patients.

Comparison of clearance of particles inhaled with bolus and extremely slow inhalation techniques.

Ten healthy nonsmokers inhaled 6-microm (aerodynamic diameter) Teflon particles labelled with 111In twice, once with the shallow bolus technique (volumetic lung depth 76+/-20 mL ([+/- SD]) and once with the extremely slow inhalation technique (0.05 L/s). The radioactivity in the lungs was measured at 1 and 24 hours as well as at 1, 2, and 3 weeks after both inhalations. The 24-hour lung retention a percentage of lung deposition was significantly lower for the bolus inhalation, 46%+/-9% (+/- SD) than for the extremely slow inhalation, 56%+/-11%. The retention after 21 days as a percentage of the 24-hour retention was 55%+/-9% for the shallow bolus inhalation and 56%+/-10% for the extremely slow inhalation. Also within the subjects, clearance was similar for the 2 modes of inhalation. Deposition of particles inhaled with the 2 modes of inhalation was calculated with 2 model, one being based on Monte (Carlo particle transport together with an asymmetric lung model. Deposition predicted with this model agreed well with the experimental data under the assumption that there are large retained fractions only in small ciliated airways (bronchioli) and not in large ones. For the bolus inhalation, the model predicted 43% to 50% deposition in the bronchial (BB) region of initial lung deposition, 33% to 38% in the bronchiolar (bb) region, and 16% to 22% in the alveolar region. For the extremely slow inhalation, the model predicted 31% to 34% deposition in the BB region, 45% to 47% in the bb region, and 21% to 22% in the alveolar region. In addition, it predicted about the same ratio between bb and alveolar depositions for the 2 modes of inhalation. Thus, both the experimental and theoretical data indicate that the shallow bolus particles to a considerable extent reach both the bb and the alveolar regions and that they do that at about the same extent as the particles inhaled extremely slow. This conclusion is concerning the experimental data based on the assumption that there are no large retained fractions in the BB region. Another interpretation of the similar clearance for the two modes of inhalation is that there are large retained fractions in both the BB and the bb regions and that individual charactristics of clearance of these fractions are of importance rather than the site of deposition.

In vivo characterization of the transitional bronchioles by aerosol-derived airway morphometry.

Effective airway dimensions (EADs) were determined in vivo by aerosol-derived airway morphometry as a function of volumetric lung depth (VLD) to identify and characterize, noninvasively, the caliber of the transitional bronchiole region of the human lung and to compare the EADs by age, gender, and disease. By logarithmically plotting EAD vs. VLD, two distinct regions of the lung emerged that were identified by characteristic line slopes. The intersection of proximal and distal segments was defined as VLD(trans) and associated EAD(trans). In our normal subjects (n = 20), VLD(trans) [345 +/- 83 (SD) ml] correlated significantly with anatomic dead space (224 +/- 34 ml) and end of phase II of single-breath nitrogen washout (360 +/- 53 ml). The corresponding EAD(trans) was 0.42 +/- 0. 07 mm, in agreement with other ex vivo measurements of the transitional bronchioles. VLD(trans) was smaller (216 +/- 64 ml) and EAD(trans) was larger (0.83 +/- 0.04 mm) in our patients with chronic obstructive pulmonary disease (n = 13). VLD(trans) increased with age for children (age 8-18 yr; P = 0.006, n = 26) and with total lung capacity for age 8-81 yr (P < 0.001, n = 61). This study extends the usefulness of aerosol-derived airway morphometry to in vivo measurements of the transitional bronchioles.

[Diagnostic pneumology using model aerosols]. / Pneumologische Diagnostik mit Modellaerosolen.

Clearance of Aerosol Particles from the Airways: Measurement of the efficiency and kinetics of particle clearance from the airways is dependent on the site of particle deposition within the lungs. Insoluble particles deposited in the alveolar region are mainly cleared by macrophages over a period of hundreds of days, whereas particles from the tracheobronchial airways are mainly cleared within hours or days by mucociliary clearance. We introduce a method for mucociliary clearance measurements called 'Radio-Bolus-Scintigraphy'. A small volume of radiolabelled aerosol particles sandwiched in clean air (aerosol bolus) is inhaled near the end of a tidal breath which leads to a preferential deposition of the particles in the airways. Particles were Fe3O4 labelled with 99mTc with an aerodynamic particle diameter of 3.5 microns (monodisperse). The retention of the particles within the lungs was detected by Gamma Camera and Human Scintillation Counter. 26 healthy subjects volunteered in this study (14 nonsmokers and 12 smokers). The half width of the mucociliary clearance was found to be 2.4 h in nonsmokers and 3.3 h in smokers (p < 0.05). Intersubject variability was small, 24 hours after inhalation 55% (+/- 6%) of the inhaled particles were still found in the airways of the subjects. No difference was found between nonsmokers and smokers. Good intersubject reproducibility makes this method useful in therapy control as well as in early diagnosis of changes in mucociliary clearance kinetics and efficiency.