Safety and Feasibility of a Novel Externally Cooled Bronchoscopic Radiofrequency Ablation Catheter for Ablation of Peripheral Lung Tumours: A First-In-Human Dose Escalation Study.

BACKGROUND: Radiofrequency ablation (RFA) is an established modality for percutaneous ablation of non-small cell lung cancer (NSCLC) in medically inoperable patients but is underutilized clinically due to side effects. We have developed a novel, completely endobronchial RFA catheter with an externally cooled electrode. OBJECTIVES: The objective of this study was to establish the safety and feasibility of bronchoscopic RFA using a novel, externally cooled catheter for ablation of peripheral NSCLC. METHODS: Patients with stage I biopsy-confirmed NSCLC underwent bronchoscopic RFA of tumour 7 days prior to lobectomy. The RFA catheter was delivered bronchoscopically to peripheral NSCLC lesions, guided by radial endobronchial ultrasound, with positioning confirmed using intra-procedural cone beam CT. Pre-operative CT chest and histologic examination of resected specimens were used to establish distribution/uniformity of ablation and efficacy of tumour ablation. RESULTS: RFA in the first patient was complicated by dispersal of heated saline due to cough, resulting in ICU admission. The patient recovered fully and underwent uncomplicated lobectomy. Subsequently, the protocol was altered to mandate neuromuscular blockade with a pre-determined dose escalation, with algorithm-restricted energy (kJ) and irrigated saline volume (mL) constraints. A further 10 patients consented and seven underwent successful bronchoscopic RFA of peripheral NSCLC. No significant adverse events were noted. Ablation zone included tumour in all cases (proportion of tumour ablated ranged 8-72%), with uniform necrosis of tissue within ablation zones observed at higher energy levels. Ablation zone diameter correlated with RFA energy delivered (R2 = 0.553), with maximum long axis diameter of ablation zone 3.1 cm (22.9 kJ). CONCLUSION: Bronchoscopic RFA using an externally cooled catheter is feasible, appears safe, and achieves uniform ablation within the treatment zone. Uncontrolled escape of heated saline poses a major safety risk but can be prevented procedurally through neuromuscular blockade and by limiting irrigation.

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.

Endobronchial Phenylephrine in Airway Bleeding During Bronchoscopy Does not Cause Hypertension: A Retrospective Observational Study.

BACKGROUND: Bleeding is a known complication during bronchoscopy, with increased incidence in patients undergoing a more invasive procedure. Phenylephrine is a potent vasoconstrictor that can control airway bleeding when applied topically and has been used as an alternative to epinephrine. The clinical effects of endobronchial phenylephrine on systemic vasoconstriction have not been clearly evaluated. Here, we compared the effects of endobronchial phenylephrine versus cold saline on systemic blood pressure. METHODS: In all, 160 patients who underwent bronchoscopy and received either endobronchial phenylephrine or cold saline from July 1, 2017 to June 30, 2022 were included in this retrospective observational study. Intra-procedural blood pressure absolute and percent changes were measured and compared between the 2 groups. RESULTS: There were no observed statistical differences in blood pressure changes between groups. The median absolute change between the median and the maximum intra-procedural systolic blood pressure in the cold saline group was 29 mm Hg (IQR 19 to 41) compared with 31.8 mm Hg (IQR 18 to 45.5) in the phenylephrine group. The corresponding median percent changes in SBP were 33.6 % (IQR 18.8 to 39.4) and 28% (IQR 16.8 to 43.5) for the cold saline and phenylephrine groups, respectively. Similarly, there were no statistically significant differences in diastolic and mean arterial blood pressure changes between both groups. CONCLUSIONS: We found no significant differences in median intra-procedural systemic blood pressure changes comparing patients who received endobronchial cold saline to those receiving phenylephrine. Overall, this argues for the vascular and systemic safety of phenylephrine for airway bleeding as a reasonable alternative to epinephrine.

Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models.

There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3ß1, αvß3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.

Cerebral gas embolism from bronchoscopic argon plasma coagulation: a case report.

Argon plasma coagulation (APC) is a common and safe bronchoscopic technique used in the management of obstructing lesions and hemorrhage in the central airways. Complications of bronchoscopic APC are uncommon and include hemorrhage, perforation and fire in the airways. While bronchoscopic APC has been reported to cause systemic gas embolization and associated cardiovascular collapse, we report a case of cerebral gas embolization that occurred during bronchoscopic APC and highlight underappreciated potential risk factors for its occurrence.

Interventional pulmonology use of cell-free DNA assay for metastatic non-small cell lung cancer: the UC Davis experience.

BACKGROUND: Interventional pulmonologists (IPs) are often the first specialist to see patients with suspected metastatic non-small cell lung cancer (mNSCLC). Consequently, they are potentially ideally positioned to expedite the identification of actionable molecular mutations by ordering blood-based cell-free DNA (cfDNA), prior to or upon tissue diagnosis of mNSCLC. METHODS: Retrospective review of cfDNA ordered by IP as part of a routine clinical practice. Patients were categorized into two groups based on when cfDNA was ordered by IP: (1) IP suspected mNSCLC prior to histologic confirmation or (2) IP diagnosed mNSCLC based on histologic confirmation of NSCLC. RESULTS: Twenty patients were identified. Twelve of 13 in group 1 were confirmed to have mNSCLC by oncology and 1 had stage IIIA. Seven of 7 in group 2 were confirmed to have mNSCLC by oncology. Fifteen of 20 also had next-generation tissue molecular testing. Thirteen of 20 (65%) had targetable alterations. Seven of 13 (54%) were identified on cfDNA and tissue, 5/13 (38%) on cfDNA only, and 1/13 (8%) on tissue alone. Tissue results were available a medium of 24 days after, and cfDNA results a medium of 4 days prior to, the patients' first oncology visit. CONCLUSIONS: IP appears to be able identify patients who have mNSCLC and for whom testing for molecular mutations is appropriate even prior to tissue confirmation of NSCLC. A strategy whereby IP employ blood-based cfDNA testing in suspected and tissue confirmed mNSCLC could potentially provide medical oncologists with more timely information on actionable mutations than tissue-based testing first, potentially expediting patient treatment.

Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC.

BACKGROUND: Lack of biomarkers and in vitro models has contributed to inadequate understanding of the mechanisms underlying the inferior clinical response to immune checkpoint inhibitors (ICIs) in patients with oncogene-driven non-small cell lung cancer (NSCLC). METHODS: The effect of small molecule tyrosine kinase inhibitors (TKIs) on peripheral blood mononuclear cells (PBMCs) in 34 patients with oncogene-driven NSCLC (cohort A) was compared with those from 35 NSCLC patients without oncogene-driven mutations received ICI (cohort B) or from 22 treatment-naïve NSCLC patients (cohort C). Data for each blood biomarker were summarized by mean and standard deviation and compared by Wilcoxon rank sum tests or Kruskal-Wallis tests with significance at 2-sided p value < 0.05. Co-culture of PBMCs and pleural effusion-derived tumor cells from individual patients with oncogene-driven NSCLC was used to determine the in vitro cytotoxicity of TKI and ICI. RESULTS: Except for low CD3% in cohort A, there were no significant differences in other 12 blood biomarkers among the 3 cohorts at baseline. TKI treatment in cohort A was associated with significant increase in CD3% and decrease in total and absolute neutrophils (p < 0.05). In cohort B, patients with good clinical response to ICI treatment (N = 18) had significant increases in absolute lymphocyte counts (ALCs), CD4 and/or CD8 cell counts. Conversely, those patients with poor clinical response to ICI (N = 17) had significant decreases in these cell counts. Of the 27 patients with pre- and post-treatment blood samples in cohort A, 11 had poor clinical response to TKIs and decreased lymphocyte counts. Of the remaining 16 patients who had good clinical response to TKI therapy, 10 (62.5%) patients had decreased, and 6 (37.5%) patients had increased lymphocyte counts. Multicolor immunophenotyping of PBMCs revealed ICI treatment activated additional immune cell types that need further validation. We confirmed that TKI treatment could either antagonize or enhance the effect of ICIs in the co-culture assay using patient's tumor cells and PBMCs. CONCLUSIONS: To the best of our knowledge, this is the first study showing that TKIs can have various effects on blood immune cells, which may affect their response to ICIs. Further validation of the blood biomarker and in vitro assay is warranted.

Molecular testing strategies in non-small cell lung cancer: optimizing the diagnostic journey.

Molecular testing identifies patients with advanced non-small cell lung cancer (NSCLC) who may benefit from targeted therapy or immunotherapy (i.e., immune checkpoint inhibitor treatment for patients with high tumor mutational burden (TMB), microsatellite instability-high or mismatch repair-deficient tumors). Current guidelines state that molecular testing should be conducted at the time of initial diagnosis and tumor progression on targeted therapy. In real-world clinical practice in the United States (US), molecular testing is often not conducted or happens late in the diagnostic journey, resulting in delayed or inappropriate treatment. Herein, we review the rationale for molecular testing in advanced NSCLC, along with best-practice guidelines based on published recommendations and our own clinical experience, including a case study. We propose three strategies to optimize molecular testing in newly diagnosed patients with advanced NSCLC: (I) pulmonologists, interventional radiologists, or thoracic surgeons order molecular tests as soon as advanced NSCLC with an adenocarcinoma component is suspected; (II) liquid biopsies conducted early in the diagnostic pathway; and (III) pathologist-directed reflex testing, as conducted in other areas of oncology. To help facilitate these strategies, we outline our recommendations for optimal sample collection techniques and stewardship. In summary, we believe that implementation of these individual strategies will allow clinicians to effectively leverage available treatment options for advanced NSCLC, reducing the time to optimal treatment and improving patient outcomes.

Bronchial Thermoplasty: A Decade of Experience: State of the Art.

Bronchial thermoplasty (BT) delivers targeted radiofrequency energy to bronchial airway walls and results in the partial ablation of the airway smooth muscle that is responsible for bronchoconstriction. It is approved for the treatment of severe persistent asthma. Multiple, large clinical trials including a recent "real-world" study demonstrate significant improvements in asthma-related quality of life, reduction in asthma exacerbations, emergency department visits, and hospitalizations after BT that is sustained out to 5 years. In this article, we review the state of the art of BT treatment in severe persistent asthma and share a decade of BT research and clinical experience. We share our personal experience and introduce the three "I"s (identification, implementation, and intense follow-up) that we believe promote successful patient outcomes and help build a successful BT program.

Airway transcriptomic profiling after bronchial thermoplasty.

BACKGROUND: Bronchial thermoplasty is a nonpharmacological, device-based treatment option for a specific population of severe asthmatic subjects, but the underlying mechanisms are largely unknown. The purpose of this study is to identify potential altered pathways by bronchial thermoplasty using a transcriptomic approach. METHODS: Patients undergoing bronchial thermoplasty were recruited to the study, and a bronchial brushing sample was obtained before each bronchial thermoplasty session and sent for RNA sequencing. A variance component score test was performed to identify those genes whose expression varied after bronchial thermoplasty sessions. Differential gene expression meta-analysis of severe asthmatic subjects versus controls was performed using public repositories. Overlapping genes were included for downstream pathway and network analyses. RESULTS: 12 patients were enrolled in our study. A total of 133 severe asthma cases and 107 healthy controls from the public repositories were included in the meta-analysis. Comparison of differentially expressed genes from our study patients with the public repositories identified eight overlapping genes: AMIGO2, CBX7, NR3C2, SETBP1, SHANK2, SNTB1, STXBP1 and ZNF853. Network analysis of these overlapping genes identified pathways associated with neurophysiological processes. CONCLUSION: We have shown that bronchial thermoplasty treatment alters several gene networks that are important in asthma pathogenesis. These results potentially elucidate the disease-modifying mechanisms of bronchial thermoplasty and provide several targets for further investigation.

Correction to: High-affinity peptide ligand LXY30 for targeting α3ß1 integrin in non-small cell lung cancer.

The original article [1] contains an error in Fig. 2 whereby Fig. 2D has mistakenly been omitted. Fig. 2 can be viewed in its entirety - including Fig. 2D - in this Correction article.

High-affinity peptide ligand LXY30 for targeting α3ß1 integrin in non-small cell lung cancer.

BACKGROUND: α3ß1 integrin is a promising cancer biomarker and drug target. We previously identified a 9-amino-acid cyclic peptide LXY30 for detecting α3ß1 integrin on the surface of live tumor cells. This study was undertaken to characterize LXY30 in the detection, cellular function, imaging, and targeted delivery of in vitro and in vivo non-small cell lung cancer (NSCLC) models. METHODS: The whole-cell binding assay was performed by incubating NSCLC cells, extracellular vesicles (EVs), and peripheral blood mononuclear cells (PBMCs) with TentaGel resin beads coated with LXY30. In this study, we defined the nanosize EVs as exosomes, which were characterized by flow cytometry, transmission electron microscopy, dynamic light scattering, and Western blots. The function of LXY30 was determined by modulating the epidermal growth factor receptor (EGFR) signaling pathway by growth inhibition and Western blots. For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were administrated intraveneously with LXY30-biotin/streptavidin-Cy5.5 complex and then analyzed for in vivo and ex vivo optical imaging and histopathology. RESULTS: We showed that LXY30 specifically and sensitively detected α3ß1 integrin-expressing NSCLC cells and tumor-derived exosomes. Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC. LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing. LXY30 detected increased α3ß1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells. We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting αvß3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells. Analysis of The Cancer Genome Atlas (TCGA) revealed high α3 integrin expression was associated with poor prognosis in lung squamous cell carcinoma. LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various α3ß1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues. CONCLUSION: LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.

The evolving role of interventional pulmonary in the interdisciplinary approach to the staging and management of lung cancer. Part III: diagnosis and management of malignant pleural effusions.

The diagnosis and management of a malignant pleural effusion can be one of the most vexing problems faced by physicians and their patients. Lung cancer is the most common primary tumor of origin with a prognosis that is limited, but variable and correlated with performance status (PS). Therefore, with a poor PS and known advanced lung cancer, establishing whether or not an effusion is malignant might not be necessary. Conversely, identifiable subsets of patients will have a much better survival, and establishing a definitive diagnosis could be of critical importance. In the great majority of cases, a diagnosis can be determined by serial thoracenteses with or without closed pleural biopsy. However, thoracoscopy is increasingly being utilized and can expedite the workup by obviating the need for repeated thoracenteses and/or closed pleural biopsy, while in the same setting providing definitive palliative treatment. Although studies comparing diagnostic and treatment strategies are limited, we will present the available data with the intention of providing the practicing oncologist with a practical strategy for the diagnosis and management of malignant pleural effusions due to lung cancer. The interventional pulmonologist can play an important role from diagnosis to palliation, greatly facilitating the care of patients with malignant pleural effusions.

Bronchial thermoplasty: implementing best practice in the era of cost containment.

Increasing dependence on advanced technologies in the 21st century has created a dilemma between the practice and business of medicine. From information technology to robotic surgery, new technologies have expanded treatment possibilities and have potentially improved patient outcomes and safety. Simultaneously, their escalating costs limit access for certain patients and health care facilities. Nevertheless, medical decisions should not simply be based on cost. Input from physicians and other health care specialists as well as adherence to best practice position statements, are vital to implementing truly cost-effective strategies in medicine. Bronchial thermoplasty (BT), a US Food and Drug Administration approved bronchoscopy procedure in difficult-to-control persistent asthma, is a prime example of a new technology facing cost and implementation challenges. We discuss the specific indications and contraindications for BT and review recent real-world experiences that can provide the foundation for building a comprehensive asthma program that provides BT for difficult-to-control asthma patients who fail national guideline treatment recommendations after an adequate clinical trial of one. We also offer insight into the barriers to implementing a successful BT program and strategies for overcoming them.

Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report.

BACKGROUND: Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) inhibitors have quickly become standard of care for patients with advanced non-small cell lung cancer and increasing numbers of other cancer types. In this report, we discuss the clinical history, pathological evaluation, and genomic findings in a patient with metastatic lung squamous cell cancer (SCC) who developed severe nivolumab-induced pneumonitis preceding durable clinical remission after three doses of nivolumab. CASE PRESENTATION: A patient with chemotherapy-refractory, metastatic lung SCC developed symptomatic pneumonitis by week 4 after nivolumab treatment, concurrently with onset of a potent antitumor response. Despite discontinuation of nivolumab after three doses and the use of high dose oral corticosteroids for grade 3 pneumonitis, continued tumor response to a complete remission by 3 months was evident by radiographic assessment. At the time of this submission, the patient has remained in clinical remission for 14 months. High PD-L1 expression by immunohistochemistry staining was seen in intra-alveolar macrophages and viable tumor cells in the pneumonitis and recurrent tumor specimens, respectively. Tumor genomic profiling by FoundationOne targeted exome sequencing revealed a very high tumor mutation burden (TMB) corresponding to 95-96 percentile in lung SCC, i.e., 87.4-91.0 and 82.9 mut/Mb, respectively, in pre- and post-nivolumab tumor specimens. Except for one, the 13 functional genomic alterations remained the same in the diagnostic, recurrent, and post-treatment, relapsed tumor specimens, suggesting that nivolumab reset the patient's immune system against one or more preexisting tumor-associated antigens (TAAs). One potential TAA candidate is telomerase reverse transcriptase (TERT) in which an oncogenic promoter -146C>T mutation was detected. Human leukocyte antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA class I allele that has been used to develop universal cancer vaccine targeting TERT-derived peptides. CONCLUSIONS: Nivolumab could quickly reset and sustain host immunity against preexisting TAA(s) in this chemotherapy-refractory lung SCC patient. Further mechanistic studies are needed to characterize the effective immune cells and define the HLA-restricted TAA(s) and the specific T cell receptor clones responsible for the potent antitumor effect, with the aim of developing precision immunotherapy with improved effectiveness and safety.

Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials.

INTRODUCTION: Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials (ClinicalTrials.gov identifiers, NCT00585195, NCT00932451, NCT00932893, and NCT01154140). MATERIALS AND METHODS: Grade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive. RESULTS: The independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients). CONCLUSION: ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.

The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema.

Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1)x10(4) cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2)x10(4) cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.

Interstitial lung disease associated with epidermal growth factor receptor tyrosine kinase inhibitor therapy in non-small-cell lung carcinoma.

Interstitial lung disease is a rare but serious complication of epidermal growth factor receptor tyrosine kinase inhibitor therapy. Although our understanding of this phenomenon remains incomplete, recently there have been significant insights made into the mechanisms of injury, incidence, risk factors, and its clinical manifestations. Japanese patients appear to be at a higher risk (1.6%-3.5%) than patients in the rest of the world (0.3%), and other risk factors, such as coincident interstitial lung disease, concurrent chemotherapy, previous radiation, preexisting pulmonary fibrosis, and male sex, have been identified. In the majority of cases, the histopathology, the acute and often dramatic clinical presentation, and the radiographic findings resemble acute respiratory distress syndrome. Aside from immediate cessation of the offending agent, the treatment is largely supportive, although corticosteroids appear to be of benefit. The mortality remains high at approximately 30%-50%. We present a review of the incidence, risk factors, clinical manifestations, diagnosis, management, and outcome of this disorder.

Temporary Endobronchial Stent as a Bridge to Corrective Surgery For Severe Kyphoscoliosis-associated Central-Airway Extrinsic Compression.

Kyphoscoliosis is known to compromise lung function, with the primary mechanism being reduced chest wall compliance with a resultant restrictive pulmonary physiology. Severe scoliosis can also cause extrinsic compression of the central airways, leading to recurrent respiratory infections, lobar atelectasis, and potentially acute respiratory failure. Definitive therapy is corrective surgery of the spine. However, patients with severe scoliosis are at a potentially high risk of perioperative pulmonary complications. To our knowledge, we report the first successful use of retrievable endobronchial stents as a bridge to corrective surgery for kyphoscoliosis-associated complete central-airway extrinsic compression in a patient who was considered as too high risk for surgical correction due to her respiratory status. After surgery, the stents were removed and our patient experienced sustained improvement in pulmonary function and the clinical respiratory status.