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Cryospray Ablation up to 4 -5 second cycles for up to 4 treatments in the first 30 days

CryoSpray Ablation

Michael Machuzak, M.D.

The purpose of this study is to evaluate the safety, effectiveness, and side effects of the CryoSpray AblationTM System (CryoSpray AblationTM, "CSA" or "cryospray therapy") to treat benign airway disease in the lung using liquid nitrogen sprayed through a catheter via flexible fiber optic bronchoscopy (FFB)

The proposed study is a single center pilot study consisting of up to 10 subjects with benign airway disease. Treatment dosimetry will be up to 4, 5-second spray cycles. Subjects will have initial cryospray treatment at Day 0. Subjects will undergo repeat bronchoscopy in the first three to seven days after the initial treatment, to check for mucosal sloughing and to reassess luminal patency of the airway. Subjects may undergo up to one bronchoscopy per week with CSA therapy for a total of four (4) treatments in the first month. If they present with symptoms thereafter, then a repeat bronchoscopy will be performed; if luminal obstruction is noted, then the subject will begin the treatment protocol again. If disease exists bilaterally, only one side will be sprayed initially.

Interventional Cryotherapy for the Eradication of Benign Airway Disease ("ICE the BAD")

Assessment of the Safety, Side Effects and Efficacy of Interventional Cryotherapy for the Eradication of Benign Airway Disease("ICE THE BAD")

need for additional treatments within specified period

CSA Medical, Inc.

All subjects enrolled will received CSA cryospray.

CryoSpray Ablation (tm): The CryoSpray Ablation(TM) System is a cryosurgical device utilizing a low-pressure liquid nitrogen spray tip CSATM Catheter. Medical grade liquid nitrogen is the cryogen used in the device. The device is used to destroy unwanted tissue by the application of extreme cold with the focused application to select tissue. The cryogen is stored in a liquid nitrogen holding tank integrated into the system.

All Subjects Receiving CSA Cryospray

subjects will receive up to 4 -5 second cycles of cryospray ablation

Cryo Spray Ablation

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Ann Murphy Legg, Director of Clinical Research

study terminated by Sponsor-data not analyzed

Improvement in Luminal Patency Following Cryospray Treatment

Treatment Durability

subjects receiving up to 4 -5 second spray cycles

Overall Study

Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Small Cell

Lung Neoplasms

Pulmonary Emphysema

Emphysema

Thoracic Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pulmonary Disease, Chronic Obstructive

Chronic Disease

Chronic Graft Versus Host Disease

Biopsy samples will be taken as a 2mm x 2cm excision of a wedge of skin at the edge of the incision during your surgery at the Mayo Clinic Rochester. Such excisions are frequently done as part of routine skin closure for optimal skin cosmesis following the surgical procedure.

Skin Biopsy

Dennis A Wigle, MD, PhD

As part of the long-term goal of successfully implementing tissue regeneration strategies in an individualized manner for patients with thoracic diseases including, but not limited to: cystic fibrosis, pulmonary fibrosis and pulmonary hypertension, the investigators will assess the feasibility of collecting skin biopsies from patients undergoing surgery for thoracic disease, culturing skin fibroblasts from the biopsy, and reprogramming these skin fibroblasts into induced pluripotent cells.

A Phase I Study of iPS Cell Generation From Patients With COPD

As part of the long-term goal of successfully implementing tissue regeneration strategies in an individualized manner for patients with thoracic diseases including, but not limited to: cystic fibrosis, pulmonary fibrosis and pulmonary hypertension, we will assess the feasibility of collecting skin biopsies from patients undergoing surgery for thoracic disease, culturing skin fibroblasts from the biopsy, and reprogramming these skin fibroblasts into induced pluripotent cells. Markers of induced pluripotent phenotype will be utilized to assess successful reprogramming.

Mayo Clinic

M.D., P.h.D.

Inflammation

Pneumonia

Cough

Bronchoscopy subjects \>=21 yo, current or former smokers

Bronchoscopy subjects \>=21 yo, never smokers

Observational only, all subjects; measure DNA mutation and proteomic survey.

Ahamefule Okorozo, MBBS

Karen Milian

Simon D Spivack, MD

Ahamefue Okorozo, MBBS

Background: The lung is a privileged organ; blood does not reflect most lung processes well, if at all. Therefore, for population scale diagnostics, the investigator team is developing non-invasive portals to the lung, for eventual early detection/risk assessment and diagnostic purposes. However, large macromolecules are not likely suspended nor readily detected in the breath. In particular, genomic DNA in the breath condensate (EBC) is very sparse, and where present, generally highly fragmented, not readily amenable to sequencing based assessments of DNA somatic mutation burden or distribution. Because gDNA (and protein) is challenging to obtain non-invasively from EBC, the study team considered alternative surrogate lower airway specimens. Cough capture is rarely done, and the investigator team is in the process of optimizing its collection. Importantly, the team will be evaluating how much of coughed material is from saliva contamination. Additionally, analyzing material that is target captured by capturing deep lung extracellular vesicles (EVs) using immobilized CCSP/SFTPC antibodies targeting EVs from distal bronchiole Club and alveolar type 2 cells could circumvent the mouth contamination problem, leaving a non-invasive portal to the deep lung suitable for large molecules, and in turn suitable for myriad epidemiologic and clinical applications. Proposal: The investigator team proposes (Aim 1) to pursue optimizing cough collection, and testing the efficacy and practicality of partitioning cough specimen for deep-lung specific extra-cellular vesicles (EVs). This cough specimen will be compared to that from invasively collected deep lung samples BAL/bronchial brushings, and to the potential contaminating mouthrinse, all from the same individuals. (Aim 2) The study team initially proposes to examine these cough specimens for somatic mutations by SMM bulk sequencing for single nucleotide variation, developed in the Vijg/Maslov labs. Finally, the investigator team will (Aim 3) test all airway specimens (cough, mouthwash and BAL) for lung surrogacy of cough, using proteins known to be specific for lung, as opposed to oral cavity/saliva, in the Sidoli/proteomics core. Impact: The investigator team envisions that the translational impact of non-invasively obtained DNA or protein markers could allow for more rapid acute clinical diagnoses, and facilitate precision prevention and/or early detection of many acute and chronic respiratory disorders, including lung cancer, asthma and COPD, acute and chronic infectious diseases, and indeed systemic disorders of inflammation and metabolism.

Hypothesis: Cough can serve as a valid non-invasive surrogate for the lung for large molecules such as DNA and proteins, potentially for a variety of clinical and public health purposes.

Proposal in Brief: For development of an epidemiological and clinically-applicable platform for large molecules captured uniquely from deep lung, the investigator team will pursue a new approach that includes cough collection, and testing the efficacy and practicality of partitioning cough specimen for deep-lung specific extra-cellular vesicles (EVs). This cough specimen will be compared to that from invasively collected deep lung samples BAL/bronchial brushings, and to the potential contaminating mouthrinse, all from the same individuals. The study team initially proposes to examine these crude cough specimens, and then EV partitioned airway samples, for somatic mutations by SMM bulk sequencing for somatic mutations, state-of-art techniques developed in the Vijg/Maslov labs and for proteins known to be specific for lung, as opposed to oral cavity/saliva, in the Sidoli/proteomics core.

Specific Aims:

1. Cough will be captured by aerochamber or equivalent/optimized device in 5 healthy volunteers, and in 5 current smokers, in parallel with mouthrinse and with BAL. Lung-specific EVs from these same samples via deep lung capture (Loudig lab) will be performed in parallel.
2. Cough will undergo DNA mutation analyses using single molecule mutation sequencing (SMM-seq).
3. Cough, mouthwash and BAL will undergo proteomic analysis using LC-MS in our Core facility.

Approach:

Human Lung Studies protocol practices, in general: Ongoing subject enrollment is part of a longstanding IRB-approved Einstein-Montefiore clinical case-control protocol (2007-407). Individuals from pulmonary practices eligible to enroll are: Age \> 21 years old, any smoking status, myriad comorbid status except contraindications to BAL, planned for clinically-indicated lung collection procedure (bronchoscopy) as part of routine care. This amounts to \>100-150 bronchoscopy and related former smoker donors recruits per year. Over 150-200 such pre-existing bronchoscopic sample sets, and attendant non-invasive EBC, along with MW, buccal brush, others\] are banked and potentially available for the current study. All data/specimens are collected pre-diagnosis and pre-procedure; each subject provides EBC (and other non-invasives such as Cough) samples pre- bronchoscopy. As such, this active protocol minimizes (i) recall bias; and (ii) contamination of non-invasive specimens from the disruptions and spillage of the lung tissue inherent to these lung procedures. Each subject will be followed for 3 months in the medical record to gather updated diagnostics/testing, and minimize case-control misclassification. Extensive demographic, exposure and clinical data are available: (1) demographic information; (2) smoking details: (3) markers of underlying lung disease: (4) existing imaging (5) clinical information/pathological findings. For this ICTR pilot:

1. Aim 1: Cough will be captured in 5 healthy volunteers, and in 5 current smokers prior to undergoing bronchoscopy. Research BAL and mouthrinse specimens will also be collected. Lung-specific EVs from these samples via deep lung capture (Loudig lab) will be performed in parallel.

Cough will be captured in aerochamber (common, disposable hand held spacer device for asthma meter dose inhalers/pumps). The investigator team has found that it is an adequate cough (forced exhalation) capture device, pending further optimization. Under a planned amendment, the patient is instructed to cough every 30 seconds into the handheld plastic chamber, during an overall period of 10 minutes. All inside surfaces of the entire chamber is then rinsed with 2-4 ml of PBS, and the rinse/wash is snap frozen. The rinse is subsequently processed according to the analyte to be studied. For DNA, there is an Isopropanol/EtOH precipitation step, followed by resuspension in smaller volume, and extraction by Qiagen/Zymo DNA isolation kit. For protein, the crude extract in PBS is handled directly in the core by precipitation, drying, resuspension in buffer, and injection in the LC-MS platform for shotgun analyses.

The EV partitioning procedure is published. EV-CATCHER™ can be customized to target unique surface membrane proteins particular to the desired cell type and thus to direct capture of cell-specific EVs. The Loudig lab has compiled extensive data demonstrating, for example, that using antibodies targeting deep lung cell unique and specific proteins (e.g., Clara Cell Specific protein (CCSP), Alveolar type 2 cell Surfactant Protein-C (SFTPC)) can specifically purify EVs from Bronchoalveolar lavages (BAL) and exhaled breath condensates (EBC) and obtain similar miRNA expression profiles. Finally, by adding an enzymatically degradable uracylated double-stranded biotin-labeled DNA linker between immobilizing platform (polystyrene 96-well plate) and the activated antibody, the intact release of immunopurified EVs by incubation with uracil glycosylase (UNG) can be facilitated.

Approach: Aliquots from the 10 initial donors providing cough, mouthrinse, and BAL samples (5 current smokers, 5 never smokers) totaling 30 initial samples among all sample types for EV partitioning. Then, both whole-unpartitioned and EV-partitioned samples will be generated (totaling 60 samples) to be triaged to the two main assays, SMM for somatic mutation, and shotgun proteomics, below, both for feasibility demonstration, and pilot evaluation of surrogacy of cough for lung.

Aim 2: Cough will undergo DNA mutation analyses using SMM. Direct analysis of genome sequence integrity in normal cells. A key problem in studying genome sequence integrity in normal human tissues is the random nature of DNA mutations in the genome. While some mutations are clonally amplified, the vast majority are unique to each cell, and therefore rare and variant, which necessitates either single-cell whole genome amplification or in vitro clonal amplification assays. Both approaches have been associated with artifacts. Recently, the Maslov/Vijg lab developed reliable methods to quantitatively assess somatic mutations in single cells or in clonally amplified single cells. Using these methods it was demonstrated that base substitution mutations increase with smoking (and age) in proximal bronchial epithelial basal cells. A newer method for the quantitative analysis of somatic mutations, Single Molecule Mutation-seq (SMM-seq), is much more cost effective and can be applied to small amounts of bulk DNA. This latest SMM-seq method is significant because it allows, among other considerations, a practical means to accurately detect mutations in cytologically normal cells.

Approach: The 20 cough samples (10 unfractionated, 10 fractionated) will undergo DNA extraction, and library preparation and sequencing as described in the protocol. Somatic mutations among all the detected variants occurs by subtraction of germline polymorphisms found by analysis of regular sequencing library from DNA of the same individual. The number of somatic variants is normalized to the number of callable bases, i.e., bases with coverage more than 7X in SMM-seq libraries and with coverage more than 20X in regular libraries. Somatic mutation frequency will be expressed as a number of mutations per genome. The remaining 40 samples (20 from mouthwash and 20 from BAL) will be processed under other ongoing funding mechanisms, given budgetary constraints.

Aim 3: Cough, mouthwash, and BAL will undergo proteomic analysis using LC-MS in Einstein's Core facility. Prior proteomics attempts in cough do not exist to the investigator team's knowledge, perhaps due to technical limitations of low abundance material. The proteomics core (Sidoli, et al) will optimize a strategy to enhance sensitivity and speed for quantifying low abundance proteins/peptides. The sample preparation protocol will be modified to minimize sample loss and miniaturize nano-liquid chromatography coupled with state-of-the-art MS to quantify proteins/peptides in BAL, MW, and EBC specimens.

Approach: Sample preparation for proteomics: Cough specimen is dried to completion and then resuspended in 5 µL of 50 mM ammonium bicarbonate (pH = 8) for canonical proteomics sample preparation (20 ng of trypsin). The entire sample is then analyzed using a Dionex RSLC Ultimate 300 (Thermo Scientific) nano-liquid chromatographer coupled online with an Orbitrap Fusion Lumos (Thermo Scientific) mass spectrometer. For separation, the lab will utilize an in-house packed analytical column with minimal internal diameter (50 µm ID, 25 cm length) so that molecules with a \~100 nL/min flow-rate can be separated. The low flow-rate provides enhanced pre-concentration of the sample eluting from the column, leading to sub-attomole sensitivity.

Data analysis, including data transformation, is then performed using a pipeline in the Sidoli lab. Briefly, proteomics MS spectra are identified and quantified using Proteome Discoverer (v2.5, Thermo Scientific) with thresholds more stringent than currently recommended by the community for false discovery rate (\<1% FDR for spectrum matches, peptides and proteins). Quantitative values are then transformed and normalized as described by the Sidoli lab. Statistical regulation is assessed using parametric statistics (p\< 0.05). Chromatograms are manually inspected, given the relatively short list of candidates.

All cough samples (10 unfractionated, 10 fractionated x 3 specimen types=60 samples) will undergo proteomic analysis as described.

Cross-compartment comparisons: Determining cough surrogacy for lung can be performed in analogous fashion to that performed for EBC surrogacy for the lung. Within a given platform, the levels (and signature) of SMM mutation will be compared. In the recent past in the exhaled microRNA environment (not proposed here), this has been performed by Spearman correlations of microRNA-seq data clustering in principal components, PCA (not shown) and Spearman correlations (not shown). For the proteomics environment, this surrogacy of cough for lung can be shown for cough similarly by clustering heatmaps, PCA, and methods such as Spearman correlation.

Outcome: This initial pilot testing of cough as a new platform biospecimen is high risk, high reward pragmatic translational work. If this pilot project shows cough to be a valid surrogate for lung, on the two platforms examined, then that will provide strong preliminary evidence for supporting further federal funding. This potential for an airway based portal to the lung could be envisioned for a wide variety of acute and chronic clinical and public health purposes.

Cough is captured by voluntary cough singlets, with a subject handheld mouthpiece in place, currently Aerochamber or equivalent. Sample is collected by rinse, solvated in PBS or other buffer appropriate to the analyte.

Cough Capture as a Portal Into the Lung

Cough Capture as a Portal Into the Lung-ICTR Pilot

Yes, after publication, all IPD can be made available.

Somatic DNA analysis will be conducted using Single Molecule Mutation sequencing (SMM-seq) to identify mutations in EV-partitioned cough samples. The number will be determined by statistical testing using Fishers Exact Test to determine if there is a nonrandom association between the two variables

Somatic DNA analysis will be conducted using Single Molecule Mutation sequencing (SMM-seq) to identify mutations in EV-partitioned cough samples. The aggregate median mutation rate (somatic mutation burden) in the cough from the group of smokers, as compared to that of non-smoking individuals, will be determined by statistical T-test.

Proteomic analysis will be conducted via LC-MS on the collected and EV-partitioned cough samples, MW samples, and BAL samples, respectively. To evaluate cough surrogacy for the deep lung (BAL) specimen, Spearman correlations of the most highly expressed 80 proteins among the three specimen types will be compared. The number of participant specimens demonstrating Spearman inter-tissue correlation values in excess of their corresponding threshold (0.3) will be tabulated.

Proteomic analysis will be conducted via LC-MS on the collected and EV-partitioned cough samples, MW samples, and BAL samples, respectively. The proteomic signature of the most highly expressed 80 proteins in each of three specimen types will be compared between the current smoker and the non-smoker participants using PCA.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Interventional Cryotherapy for the Eradication of Benign Airway Disease ("ICE the BAD")	NCT00747461	Lung Diseases, ... Sarcoidosis Wegener's Granu... Rhinoscleroma Recurrent Respi...	CryoSpray Ablat...	18 Years -	CSA Medical, Inc.
A Phase I Study of iPS Cell Generation From Patients With COPD	NCT01860898	Thoracic Diseas... Respiratory Tra... Cancer of Lung Cancer of the L... Lung Cancer Lung Diseases, ... COPD Pulmonary Emphy... Neoplasms, Lung Neoplasms, Pulm... Pulmonary Cance... Pulmonary Neopl... Carcinoma, Non-... Carcinoma, Smal...	Skin Biopsy	18 Years -	Mayo Clinic
A Phase I Study of iPS Cell Generation From Patients With COPD	NCT01860898	Thoracic Diseas... Respiratory Tra... Cancer of Lung Cancer of the L... Lung Cancer Lung Diseases, ... COPD Pulmonary Emphy... Neoplasms, Lung Neoplasms, Pulm... Pulmonary Cance... Pulmonary Neopl... Carcinoma, Non-... Carcinoma, Smal...	Skin Biopsy	18 Years -	Mayo Clinic
Cough Capture as a Portal Into the Lung	NCT05854563	Lung Diseases Lung Cancer Lung Diseases, ... Lung Diseases, ... Lung Inflammati...	Observational o...	21 Years - 95 Years	Albert Einstein College of Medicine
Cough Capture as a Portal Into the Lung	NCT05854563	Lung Diseases Lung Cancer Lung Diseases, ... Lung Diseases, ... Lung Inflammati...	Observational o...	21 Years - 95 Years	Albert Einstein College of Medicine
Cough Capture as a Portal Into the Lung	NCT05854563	Lung Diseases Lung Cancer Lung Diseases, ... Lung Diseases, ... Lung Inflammati...	Observational o...	21 Years - 95 Years	Albert Einstein College of Medicine

Spots Global Cancer Trial Database for lung diseases, obstructive