Immune checkpoint inhibitor (ICI) pneumonitis is the most common fatal immune-related adverse event (irAE) from PD-1/ PD-L1 blockade, and a diagnosis of exclusion. Based on single-cell transcriptomics, we identified pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid (BALF), putatively engaging with pro-inflammatory "M1-like" monocytes, as a key pathophysiologic mechanism. Herein, we present the cytokine profile of ICI-pneumonitis BALF, aiming to identify further mechanistic insights and diagnostic biomarkers.

The CLIO trial (NCT02822157) randomized patients with relapsed ovarian cancer to Olaparib monotherapy (OLA) versus chemotherapy (CT) (ASCO 2019; SGO 2020). Here, we report the results of Olaparib monotherapy in relation to homologous recombination deficiency (HRD). Patients with recurrent measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to OLA (300 mg tablets, BID) or CT. Patients with platin-sensitive ovarian cancer (PSOC) and a BRCA mutation known at randomization were excluded. Patients randomized to CT crossed over to OLA upon progression. FFPE samples of the primary tumor were used for somatic homologous recombination repair (HRR) mutational (MUT) analysis using the SureMASTR HRR assay and for HRD scarring analysis using an amplicon-based sequencing assay targeting ∼ 5000 SNPs genome-wide. HRR and HRD assays were developed by Agilent Technologies (Niel, Belgium) in close collaboration with the Leuven University. Both assays are for Research Use Only and not for use in diagnostic procedures. 160 patients were randomized to OLA (n=107) or CT (n=53). Of the CT group, 44 patients crossed over to OLA at progression. Ultimately, 151 patients were treated with OLA (median follow-up 28.2 months). Median prior lines was 3 (range 1–9). ORR according to platin-sensitivity and detected HRR-MUT are presented in the table. Median progression-free survival (PFS) was 4.8 months; 7.6 and 2.8 months for PSOC and PROC (platin-resistant) respectively (HR 0.53, 95%CI: 0.36-0.78); 7.4 and 2.9 months for HRR-MUT and HRR-nonMUT respectively (HR 0.68, 95%CI; 0.43-1.09).Table:Response rates according to platin sensitivity and HRR-MUTAll patientsPlatin-resistantPlatin-sensitiveAll patients32/151 (21%)14/105 (13%)18/46 (39%)BRCA mutated9/21 (43%)5/16 (31%)4/5 (80%)BRCA wild type23/130 (18%)9/89 (10%)14/41 (34%)HRR mutated9/27 (33%)5/21 (24%)4/6 (67%)HRR wild type23/124 (19%)9/84 (11%)14/40 (35%)BRCA18/18 (44%)4/13 (31%)4/5 (80%)BRCA21/3 (33%)1/3 (33%)-BRIP10/3 (0%)0/2 (0%)0/1 (0%)RAD51C0/2 (0%)0/2 (0%)-RAD51D0/1 (0%)0/1 (0%)- Open table in a new tab . OLA monotherapy showed an interesting efficacy in PSOC and PROC patients, also without the presence of HRR gene mutations. HRD scarring analysis performed by our group will be presented at the meeting.

OBJECTIVE:Study of the links between breathing pattern, negative affectivity, and psychosomatic complaints at rest and following hyperventilation.METHODS:In 819 patients with anxiety and somatoform disorders and 159 healthy subjects, self-reported symptoms, breathing pattern, and end-tidal CO(2) concentration (FetCO(2)) were recorded during rest and following a hyperventilation provocation test (HVPT). The relationship between disorder category, symptoms, age, and score of STAI-trait (as a measure of negative affectivity) on the one hand, and breathing pattern on the other was investigated, separately in men and women.RESULTS:Anxiety disorders, and to a lesser extent, somatoform disorders, were characterized by breathing instability (progressive decrease of FetCO(2) at rest during mouthpiece breathing, delayed recovery of FetCO(2) following HVPT), the mean values of respiratory frequency, and FetCO(2) being modulated by STAI-trait. After grouping the symptoms into independent factors, links were observed between symptoms and breathing pattern, independently from the presence of an anxiety or somatoform disorder.CONCLUSION:Some symptom factors appeared to be related to a lower FetCO(2) during hyperventilation, others likely directly influenced the breathing pattern. Among those, mainly respiratory symptoms were accompanied by a reduction of FetCO(2) at rest, with slower recovery of FetCO(2) following HVPT. The latter was observed also in the presence of marked anxiety. In contrast, subjects complaining of dizziness, fainting, and paresthesias in daily life presented higher values of FetCO(2) following HVPT, probably due to a voluntary braking of ventilation during HVPT.

In some patients exercise induces numerous complaints which cannot be attributed to an organic disorder, and which are suggestive of hyperventilation. The study was designed to investigate in this type of patient: 1) exercise capacity and muscle force; 2) breathing pattern and symptoms during maximal exercise and recovery; 3) relationships between symptoms and breathing pattern. Twenty-four patients were compared with 20 healthy subjects. They performed a maximal incremental cycle ergometer test and peripheral and respiratory muscle strength were measured. Patients tended to have a decreased exercise capacity and presented with moderately reduced muscle strength. At comparable minute ventilation, breathing frequency was higher (mean: 24 versus 21 per minute) and tidal volume smaller (mean: 1.42 versus 1.67 L). End-tidal partial pressure of carbon dioxide (PET,CO2) was not significantly different. A significant relation was observed between PET,CO2 and respiratory frequency during recovery in patients, suggesting a reduced flexibility of the ventilatory response to exercise. In patients respiratory complaints and paresthesias were weakly correlated to PET,CO2 at moderate exercise. It is suggested that the physical deconditioning observed in those patients is rather a consequence than a cause of the response to exercise. The link between symptoms and breathing pattern might be explained by a psychological conditioning process.

The purpose of the present study was to investigate the diagnostic specificity of bodily symptoms and respiratory behavior at rest and after a hyperventilation provocation test (HVPT) in patients that were either grouped according to the DSM classification or diagnosed as suffering from hyperventilation syndrome. Nine hundred three anxiety and somatoform patients, showing symptoms supposedly caused by psychogenic hyperventilation, and 170 healthy subjects, were studied. Breathing pattern and end-tidal CO2 concentration were recorded during breathing at rest and following a HVPT. Subjective symptoms in daily life and after HVPT were measured. A principal-components analysis was performed on both the symptoms and breathing variables and their specificity levels were compared in the two classifications of patients. Some symptoms in daily life were grouped together with the same symptoms after the HVPT, other symptoms were not. This suggests that the HVPT elicited partly specific symptoms, and partly reproduced the symptoms experienced in daily life. Similar findings were observed with respect to the breathing variables. Patients with panic differed from other patients with anxiety disorders by an increased level of symptoms and a FETCO2 decline at rest. The HVPT may be informative for diagnosis because it provokes some of the typical somatic and psychological symptoms, and it identifies the breathing instability that is characteristic of both patients with HVS and with anxiety. The same symptoms and breathing variables characterized the patients, whatever their classification. Overall, the specificity of breathing variables is rather low.

The breathing pattern of 399 patients with hyperventilation syndrome (HVS) and/or with anxiety disorders and that of 347 normal controls was investigated during a 5 min period of quiet breathing and after a 3 min period of voluntary hyperventilation. The diagnosis of HVS was based on the presence of several suggestive complaints occurring in the context of stress, and reproduced by voluntary hyperventilation. Organic diseases as a cause of the symptoms were excluded. The anxiety disorders were diagnosed by means of an abbreviated version of the Anxiety Disorders Interview Schedule (ADIS). There was a large overlap between the two diagnoses. Simply breathing via a mouthpiece and pneumotachograph made end-tidal CO2 fractional concentration (FET,CO2) decrease progressively both in hyperventilators and in patients with anxiety disorders, but not in normals. At the start of the measurement the FET,CO2 was not different between patients and healthy subjects. In patients < or = 28 yrs, the decrease of FET,CO2 resulted from a higher tidal volume, and in patients > or = 29 years from an increase in frequency. After voluntary hyperventilation, the recovery of FET,CO2, was delayed in patients, due to a slower normalization of respiratory frequency in females and in older males, and of tidal volume in younger males, and also due to less frequent end-expiratory pauses. When breathing was recorded first by means of inductive plethysmography (Respitrace), the progressive decline of FET,CO2 seen in patients was not observed: from the onset of the recording, FET,CO2 was reduced in patients. It did not change further when, immediately afterwards, the subject switched to mouthpiece breathing. The finding that breathing through a mouthpiece induces hyperventilation in patients and that recovery of FET,CO2 is delayed after voluntary hyperventilation, suggests that the respiratory control system is less resistant to challenges (mouthpiece or voluntary hyperventilation) in those patients. On the other hand, the lower values of FET,CO2 measured during recording by means of a Respitrace probably result from a challenge, prior to the recordings, induced by the fitting of the measuring device to the patient. This unsteadiness of breathing characterizes patients with hyperventilation syndrome and those with anxiety disorders, but is not sufficiently sensitive to be used for individual diagnosis.

The purpose of this study was to determine whether the forced oscillation technique is more sensitive than spirometry to detect lung function alterations in subjects with respiratory complaints. The input impedance of the respiratory system (between 2 and 24 Hz) and maximal expiratory flows and volumes were measured in 1,255 subjects referred for routine spirometry. A questionnaire concerning respiratory complaints was administered. A discriminant analysis was performed between subgroups of subjects without (137 males and 140 females), with moderate (115 males and 109 females) and with marked respiratory complaints (149 males and 132 females). A clear-cut separation was achieved by this analysis only between those subjects without and with marked complaints. Both lung volumes and flows as well as impedance parameters (mean value and frequency dependence of resistance in females, mean resistance in males) contributed to the discrimination of subjects without and with marked respiratory complaints, although there was only a moderate decrease of discriminative power when the impedance parameters were excluded. The contribution of the forced oscillation parameters to discriminative power was larger in females than in males (40 vs 19%), which may be related to the higher prevalence of asthma in our population of females. Excluding the subjects with marked functional impairment improved the share of forced oscillation parameters only slightly with respect to lung volumes and flows (females 54 vs males 23%). Considered separately, however, the sensitivity of spirometry and forced oscillation technique to detect symptomatic people appeared to be similar. We conclude that impedance measurements by forced oscillation technique and routine spirometry are both associated with respiratory complaints. Our results indicate that the information provided by impedance measurements can be complimentary to that obtained by spirometric indices.

A technique is described on how to calculate the pulmonary resistance and compliance from the higher order harmonics present in mouth flow and transpulmonary pressure signals during spontaneous breathing. The estimates of resistance and compliance (or rather reactance) obtained from these harmonics following a conventional Fourier transform are not reliable because of a lack of reproducibility. This is obviated by a preliminary smoothing of the signals by means of auto- and cross-correlation functions. Both the conventional and the modified technique yield identical results for the fundamental component of breathing.

In 59 patients with respiratory insufficiency due to chronic obstructive pulmonary disease (COPD) the relationship between the state of consciousness, the blood gases and blood ammonia were studied. Interindividually, a significant correlation was found between the encephalopathy and SaO2, PaCO2 or ammonia, and also between the blood gases and ammonia. On the other hand, an intraindividual study, performed on patients with minor cerebral dysfunction, showed that only PaCO2 was significantly correlated with the stage of consciousness. Ammonia did not appear to have a neurotoxic influence. The ammonia level seemed to be influenced primarily by other factors than the blood gases, although there was a borderline influence of SaO2 on aterial ammonia and a significant influence of PaCO2-HCO3 and pH on venous ammonia.