Implementation of an enhanced recovery protocol for lung volume reduction surgery: an observational cohort study.

OBJECTIVES: Lung volume reduction surgery (LVRS) is an established therapeutic option for advanced emphysema. To improve patients' safety and reduce complications, an enhanced recovery protocol (ERP) was implemented. This study aims to describe and evaluate the short-term outcome of this ERP. METHODS: This retrospective single-centre study included all consecutive LVRS patients (1 January 2017 until 15 September 2020). An ERP for LVRS was implemented and stepwise optimised from 1 August 2019, it consisted of changes in pre-, peri- and postoperative care pathways. Patients were compared before and after implementation of ERP. Primary outcome was incidence of postoperative complications (Clavien-Dindo), and secondary outcomes included chest tube duration, incidence of prolonged air leak (PAL), length of stay (LOS) and 90-day mortality. Lung function and exercise capacity were evaluated at 3 and 6 months post-LVRS. RESULTS: Seventy-six LVRS patients were included (pre-ERP: n=41, ERP: n=35). The ERP cohort presented with lower incidence of postoperative complications (42% vs 83%, P=0.0002), shorter chest tube duration (4 vs 12 days, P<0.0001) with a lower incidence of PAL (21% vs 61%, P=0.0005) and shorter LOS (6 vs 14 days, P<0.0001). No in-hospital mortality occurred in the ERP cohort versus 4 pre-ERP. Postoperative forced expiratory volume in 1 s was higher in the ERP cohort compared to pre-ERP at 3 months (1.35 vs 1.02 l) and at 6 months (1.31 vs 1.01 l). CONCLUSIONS: Implementation of ERP as part of a comprehensive reconceptualisation towards LVRS, demonstrated fewer postoperative complications, including PAL, resulting in reduced LOS. Improved short-term functional outcomes were observed at 3 and 6 months.

Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R. METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events. CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).

Treatment of unresectable stage III NSCLC: Real world cohort study and literature review.

INTRODUCTION: Until recently, the treatment for patients with locally advanced unresectable stage III non-small cell lung cancer (NSCLC) was combined chemoradiotherapy (CRT), delivered either concurrently (cCRT) or sequentially (sCRT). There is limited data on the outcomes and safety of CRT in a real-world setting. We conducted a real-world cohort analysis of our Leuven Lung Cancer Group (LLCG) experience with CRT for unresectable stage III NSCLC, prior to the era of consolidation treatment with immunotherapy. PATIENTS AND METHODS: In this observational, real-world monocentric cohort study, a total of 163 consecutive patients were included. They were diagnosed with unresectable stage III primary NSCLC and treated with CRT between January 1st, 2011, and December 31st, 2018. Patient and tumor characteristics, treatment patterns, toxicity, and primary outcome parameters such as PFS, OS and pattern of relapse were captured. RESULTS: CRT was concurrent in 108 patients, sequential in 55. Overall tolerability was good, with two thirds of patients without severe adverse events such as severe febrile neutropenia, ≥ grade 2 pneumonitis, or ≥ grade 3 esophagitis. All registered adverse events were more frequent in the cCRT group compared to the sCRT group. Median PFS was 13.2 months (95% CI 10.3-16.2), median OS was 23.3 months (95% CI 18.3-28.0), with a 47.5% survival rate at 2 years, and 29.4% at five years. CONCLUSIONS: This study provides a clinically relevant benchmark on the outcomes and toxicity of concurrent and sequential chemoradiotherapy in unresectable stage III NSCLC in a real-world setting in the pre-PACIFIC era.

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.

Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study.

PURPOSE: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available. PATIENTS AND METHODS: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial.

BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. FUNDING: Amgen.

[68Ga]Ga-DOTATATE-avid tumor volume, uptake and inflammation-based index correlate with survival in neuroendocrine tumor patients treated with [177Lu]Lu-DOTATATE PRRT.

To meet the increasing demand for PRRT in the treatment of patients with inoperable/disseminated well-differentiated neuroendocrine tumors (NETs) and to guide optimization strategies, adequate and accessible predictive tools that allow to stratify patients who will benefit from treatment from those who will not are becoming indispensable. Previously, we have investigated the role of baseline [68Ga]Ga-DOTATOC PET tumor uptake and volumetric parameters and a blood-derived inflammatory biomarker, the inflammation-based index (IBI), for outcome prediction in NET patients treated with [90Y]Y-DOTATOC. In this retrospective study in 83 NET patients treated with [177Lu]Lu-DOTATATE in a routine clinical setting, we aimed to evaluate the generalizability of our previous findings to [177Lu]Lu-DOTATATE treatment combined with a pre-therapeutic [68Ga]Ga-DOTATATE PET. A semi-automatic customized SUV threshold-based approach was used for tumor delineation. The previously identified SUVmean cut-off of 13.7 for better survival could not be applied to this patient cohort. Instead, a more optimal cut-off could be identified: an SUVmean lower or equal than 11.2 was associated with worse overall survival (OS) (hazard ratio (HR) 2.28; P = 0.008). Also in line with our previous study, a [68Ga]Ga-DOTATATE-avid tumor volume (TV) higher than 672 mL and an elevated baseline IBI were correlated with worse OS (HR 3.13 (P = 0.0001) and HR 2.00 (P = 0.034), respectively). Multivariate analysis confirmed independent associations between OS and baseline IBI (P = 0.032), SUVmean (P = 0.027) and [68Ga]Ga-DOTATATE-avid TV (P = 0.001). Taking baseline IBI, [68Ga]Ga-DOTATATE-avid TV and [68Ga]Ga-DOTATATE uptake into account may help guide PRRT treatment decisions.

Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis.

BACKGROUND: Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely unknown, owing to limited and contradictory findings in existing literature pointing at either T-helper 1 or T-helper 17-mediated autoimmunity. In this study, we aimed to gain novel insights into the mechanisms of ICI-related pneumonitis, thereby identifying potential therapeutic targets. METHODS: In this prospective observational study, single-cell RNA and T-cell receptor sequencing was performed on bronchoalveolar lavage fluid of 11 patients with ICI-related pneumonitis and 6 demographically-matched patients with cancer without ICI-related pneumonitis. Single-cell transcriptomic immunophenotyping and cell fate mapping coupled to T-cell receptor repertoire analyses were performed. RESULTS: We observed enrichment of both CD4+ and CD8+ T cells in ICI-pneumonitis bronchoalveolar lavage fluid. The CD4+ T-cell compartment showed an increase of pathogenic T-helper 17.1 cells, characterized by high co-expression of TBX21 (encoding T-bet) and RORC (ROR-γ), IFN-G (IFN-γ), IL-17A, CSF2 (GM-CSF), and cytotoxicity genes. Type 1 regulatory T cells and naïve-like CD4+ T cells were also enriched. Within the CD8+ T-cell compartment, mainly effector memory T cells were increased. Correspondingly, myeloid cells in ICI-pneumonitis bronchoalveolar lavage fluid were relatively depleted of anti-inflammatory resident alveolar macrophages while pro-inflammatory 'M1-like' monocytes (expressing TNF, IL-1B, IL-6, IL-23A, and GM-CSF receptor CSF2RA, CSF2RB) were enriched compared with control samples. Importantly, a feedforward loop, in which GM-CSF production by pathogenic T-helper 17.1 cells promotes tissue inflammation and IL-23 production by pro-inflammatory monocytes and vice versa, has been well characterized in multiple autoimmune disorders but has never been identified in ICI-related pneumonitis. CONCLUSIONS: Using single-cell transcriptomics, we identified accumulation of pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid-a phenotype explaining previous divergent findings on T-helper 1 versus T-helper 17 involvement in ICI-pneumonitis-,putatively engaging in detrimental crosstalk with pro-inflammatory 'M1-like' monocytes. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.

Pan-Cancer Detection and Typing by Mining Patterns in Large Genome-Wide Cell-Free DNA Sequencing Datasets.

BACKGROUND: Cell-free DNA (cfDNA) analysis holds great promise for non-invasive cancer screening, diagnosis, and monitoring. We hypothesized that mining the patterns of cfDNA shallow whole-genome sequencing datasets from patients with cancer could improve cancer detection. METHODS: By applying unsupervised clustering and supervised machine learning on large cfDNA shallow whole-genome sequencing datasets from healthy individuals (n = 367) and patients with different hematological (n = 238) and solid malignancies (n = 320), we identified cfDNA signatures that enabled cancer detection and typing. RESULTS: Unsupervised clustering revealed cancer type-specific sub-grouping. Classification using a supervised machine learning model yielded accuracies of 96% and 65% in discriminating hematological and solid malignancies from healthy controls, respectively. The accuracy of disease type prediction was 85% and 70% for the hematological and solid cancers, respectively. The potential utility of managing a specific cancer was demonstrated by classifying benign from invasive and borderline adnexal masses with an area under the curve of 0.87 and 0.74, respectively. CONCLUSIONS: This approach provides a generic analytical strategy for non-invasive pan-cancer detection and cancer type prediction.

The impact of endoscopic lung volume reduction on physical activity coaching in patients with severe emphysema.

Introduction: Endoscopic lung volume reduction (ELVR) aims to improve pulmonary function in severe emphysema. Physical activity (PA) coaching is expected to improve daily life PA. When improving ventilatory constrains in severe COPD, a better response to PA coaching is expected. The present study investigated the impact of PA coaching in addition to ELVR in severe emphysema. Methods: Patients allocated, based on fissure integrity, in the ELVR or no-ELVR cohort, received the PA coaching intervention with a step counter and smartphone application from 3 to 6 months follow-up. The primary end-point of this research question was the change in daily step count from baseline to 6 months follow-up compared between the ELVR and no-ELVR cohort. The secondary end-points were time spent in moderate to vigorous PA, movement intensity and patient-reported experience with PA between ELVR and no-ELVR. Results: At 6 months, PA in both ELVR+coaching (1479±460 steps·day-1; p=0.001) and no-ELVR+coaching (1910±663 steps·day-1; p=0.004) improved within group, without significant between-group differences (-405±781 steps·day-1; p=0.60). Patients in the ELVR group tended to experience less difficulty with PA compared to no-ELVR+coaching (7±4 points, p=0.08). Conclusion: We found that PA coaching is feasible and can help to enhance PA in patients with severe emphysema. Improving the ventilatory capacity through ELVR is not a prerequisite for a successful coaching intervention to increase objectively measured PA, although it alleviates patients' experienced difficulty with PA in those with severe COPD.

Value of [68Ga]Ga-somatostatin receptor PET/CT in the grading of pulmonary neuroendocrine (carcinoid) tumours and the detection of disseminated disease: single-centre pathology-based analysis and review of the literature.

BACKGROUND: Although most guidelines suggest performing a positron emission tomography/computed tomography (PET/CT) with somatostatin receptor (SSTR) ligands for staging of pulmonary carcinoid tumours (PC), only a limited number of studies have evaluated the role of this imaging tool in this specific patient population. The preoperative differentiation between typical carcinoid (TC) and atypical carcinoid (AC) and the extent of dissemination (N/M status) are crucial factors for treatment allocation and prognosis of these patients. Therefore, we performed a pathology-based retrospective analysis of the value of SSTR PET/CT in tumour grading and detection of nodal and metastatic involvement of PC and compared this with the previous literature and with [18F]FDG PET/CT in a subgroup of patients. METHODS: SSTR PET/CT scans performed between January 2007 and May 2020 in the context of PC were included. If available, [18F]FDG PET/CT images were also evaluated. The maximum standardized uptake (SUVmax) values of the primary tumour, of the pathologically examined hilar and mediastinal lymph node stations, as well as of the distant metastases, were recorded. Tumoural SUVmax values were related to the tumour type (TC versus AC) for both SSTR and [18F]FDG PET/CT in diagnosing and differentiating both tumour types. Nodal SUVmax values were compared to the pathological status (N+ versus N-) to evaluate the diagnostic accuracy of SSTR PET/CT in detecting lymph node involvement. Finally, a mixed model analysis of all pathologically proven distant metastatic lesions was performed. RESULTS: A total of 86 SSTR PET/CT scans performed in 86 patients with PC were retrospectively analysed. [18F]FDG PET/CT was available in 46 patients. Analysis of the SUVmax values in the primary tumour showed significantly higher SSTR uptake in TC compared with AC (median SUVmax 18.4 vs 3.8; p = 0.003) and significantly higher [18F]FDG uptake in AC compared to TC (median SUVmax 5.4 vs 3.5; p = 0.038). Receiver operating characteristic (ROC) curve analysis resulted in an area under the curve (AUC) of 0.78 for the detection of TC on SSTR PET/CT and of 0.73 for the detection of AC on [18F]FDG PET/CT. A total of 267 pathologically evaluated hilar and mediastinal lymph node stations were analysed. ROC analysis of paired SSTR/[18F]FDG SUVmax values for the detection of metastasis of TC in 83 lymph node stations revealed an AUC of 0.91 for SSTR PET/CT and of 0.74 for [18F]FDG PET/CT (difference 0.17; 95% confidence interval - 0.03 to 0.38; p = 0.10). In a sub-cohort of 10 patients with 12 distant lesions that were pathologically examined due to a suspicious aspect on SSTR PET/CT, a positive predictive value (PPV) of 100% was observed. CONCLUSION: Our findings confirm the higher SSTR ligand uptake in TC compared to AC and vice versa for [18F]FDG uptake. More importantly, we found a good diagnostic performance of SSTR PET/CT for the detection of hilar and mediastinal lymph node metastases of TC. Finally, a PPV of 100% for SSTR PET/CT was found in a small sub-cohort of patients with pathologically investigated distant metastatic lesions. Taken together, SSTR PET/CT has a very high diagnostic value in the TNM assessment of pulmonary carcinoids, particularly in TC, which underscores its position in European guidelines.

Lung Aeration in COVID-19 Pneumonia by Ultrasonography and Computed Tomography.

We conducted a prospective single-center observational study to determine lung ultrasound reliability in assessing global lung aeration in 38 hospitalized patients with non-critical COVID-19. On admission, fixed chest CT scans using visual (CTv) and software-based (CTs) analyses along with lung ultrasound imaging protocols and scoring systems were applied. The primary endpoint was the correlation between global chest CTs score and global lung ultrasound score. The secondary endpoint was the association between radiographic features and clinical disease classification or laboratory indices of inflammation. Bland−Altman analysis between chest CT scores obtained visually (CTv) or using software (CTs) indicated that only 1 of the 38 paired measures was outside the 95% limits of agreement (−4 to +4 score). Global lung ultrasound score was highly and positively correlated with global software-based CTs score (r = 0.74, CI = 0.55−0.86; p < 0.0001). Significantly higher median CTs score (p = 0.01) and lung ultrasound score (p = 0.02) were found in severe compared to moderate COVID-19. Furthermore, we identified significantly lower (p < 0.05) lung ultrasound and CTs scores in those patients with a more severe clinical condition manifested by SpO2 < 92% and C-reactive protein > 58 mg/L. We concluded that lung ultrasound is a reliable bedside clinical tool to assess global lung aeration in hospitalized non-critical care patients with COVID-19 pneumonia.

Targeted RNA sequencing for upfront analysis of actionable driver alterations in non-small cell lung cancer.

OBJECTIVES: Targeted RNA-based Next-Generation Sequencing (tRNA-seq) is increasingly being used in molecular diagnostics for gene fusion detection in non-small cell lung cancer (NSCLC). However, few data support its clinical application for the detection of single nucleotide variants (SNVs) and small insertions/deletions. In this study, we evaluated the performance of tRNA-seq using Archer FusionPlex for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in formalin-fixed, paraffin-embedded NSCLC tissue. MATERIALS AND METHODS: A total of 126 NSCLC samples, including 20 validation samples and 106 diagnostic cases, were analyzed by targeted DNA-based Next-Generation Sequencing (tDNA-seq) followed by tRNA-seq. RESULTS: All 28 SNVs and indels in the validation set, and 34 out of 35 mutations in the diagnostic set were identified by tRNA-seq. The only mutation undetected by tRNA-seq, ERBB2 p.(Ser310Tyr), was not included in the current Archer panel design. tRNA-seq revealed one additional BRAF p.(Val600Glu) mutation not found by tDNA-seq. SNVs and indels were correctly called by the vendor supplied software, except for ERBB2 duplication p.(Tyr772_A775dup) which was only detected by an additional in-house developed bio-informatics pipeline. Variant allelic frequency (VAF) values were generally higher at the expression level compared to the genomic level (range 6-96% for tRNA-seq versus 6-61% for tDNA-seq) and low VAF mutations in DNA (6-8% VAF) were all confirmed by tRNA-seq. Finally, tRNA-seq additionally identified a driver fusion or splice variant in 10 diagnostic NSCLC samples including one MET exon 14 skipping variant not detected by tDNA-seq. CONCLUSION: Our results demonstrate that tRNA-seq can be implemented in a diagnostic setting as an efficient strategy for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in NSCLC provided that adequate RNA-seq analysis tools are available, especially for the detection of indels. This approach allows upfront identification of currently recommended targetable molecular alterations in NSCLC samples.

INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.

MET amplification (METamp), a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors, occurs in up to 30% of patients with non-small-cell lung cancer (NSCLC) progressing on first-line osimertinib. Combining osimertinib with a MET inhibitor, such as tepotinib, an oral, highly selective, potent MET tyrosine kinase inhibitor, may overcome METamp-driven resistance. INSIGHT 2 (NCT03940703), an international, open-label, multicenter phase II trial, assesses tepotinib plus osimertinib in patients with advanced/metastatic EGFR-mutant NSCLC and acquired resistance to first-line osimertinib and METamp, determined centrally by fluorescence in situ hybridization (gene copy number ≥5 and/or MET/CEP7 ≥2) at time of progression. Patients will receive tepotinib 500 mg (450 mg active moiety) plus osimertinib 80 mg once-a-day. The primary end point is objective response, and secondary end points include duration of response, progression-free survival, overall survival and safety. Trial registration number: NCT03940703 (clinicaltrials.gov).

Osimertinib is used to treat a type of lung cancer that has specific changes (mutations) in a gene called EGFR. Although tumors will usually shrink (respond) during treatment with osimertinib, they can stop responding, or become resistant, to osimertinib. A common cause of resistance is 'MET amplification', which describes when extra copies of a gene called MET are present. Lung cancer that is resistant to osimertinib due to MET amplification could be treated by combining osimertinib with a treatment that blocks MET, such as tepotinib. INSIGHT 2 is an ongoing study that is designed to learn about the effects and safety of tepotinib combined with osimertinib, in patients with lung cancer that has stopped responding to osimertinib because of MET amplification. A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2021-1406.

Clinical validation of Guardant360 CDx as a blood-based companion diagnostic for sotorasib.

OBJECTIVES: Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS: KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS: Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION: Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib.

Remote System for Daily Symptom Monitoring During Systemic Anticancer Treatment: Patient Acceptance, Usability, and Compliance.

BACKGROUND: Electronic systems for remotely monitoring symptoms during cancer treatment are increasingly being used. Most of them are intended for weekly or periodic symptom monitoring. OBJECTIVE: The aim of this study was to explore the feasibility and usability of a remote system for daily symptom monitoring during systemic anticancer treatment. METHODS: We offered a remote system for daily symptom monitoring to patients starting their first ever systemic therapy. Patient acceptance was observed as the proportion of patients showing interest in using the system. System users were invited to complete the "Health information Technology Usability Evaluation Scale," and the number of patients' self-reports was used to evaluate patient compliance. RESULTS: Of 465 patients, 239 (51.4%) showed interest in using the system; 111 system users reported a fairly good overall usability score (4 of 5), and perceived ease of use scored the highest (4.7 of 5) and perceived usefulness lowest (3.7 of 5). Their daily compliance was 68.8% (±31.1) at 3 weeks and 59.1% (±31.2) at 12 weeks after the start of treatment. Less than half of respondents (49.5%) and only one third (31.2%) perceived that their symptom reports were used by the nurses and doctors, respectively. CONCLUSION: Half of patients starting their first ever systemic treatment showed interest in using a remote system for daily symptom monitoring. For these patients, daily symptom monitoring seems acceptable, and the system is well complied within the first 12 weeks of treatment. IMPLICATION FOR PRACTICE: A remote system for daily symptom monitoring is feasible and enables quick response to deteriorating symptoms. Use by healthcare professionals is a point of improvement.

Clinical practices underlie COVID-19 patient respiratory microbiome composition and its interactions with the host.

Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the respiratory microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 respiratory microbiome studies by analyzing the upper (n = 58) and lower (n = 35) respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We find that time in the intensive care unit and type of oxygen support, as well as associated treatments such as antibiotic usage, explain the most variation within the upper respiratory tract microbiome, while SARS-CoV-2 viral load has a reduced impact. Specifically, mechanical ventilation is linked to altered community structure and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomics of the lower respiratory tract of COVID-19 patients identifies specific oral bacteria in physical association with proinflammatory immune cells, which show higher levels of inflammatory markers. Overall, our findings suggest confounders are driving contradictory results in current COVID-19 microbiome studies and careful attention needs to be paid to ICU stay and type of oxygen support, as bacteria favored in these conditions may contribute to the inflammatory phenotypes observed in severe COVID-19 patients.