Reisenauer, Janani

Abstract RATIONALE: Research since 2017 has highlighted artificial intelligence (AI)-based technologies to assist in detecting and/or classifying lung nodules on Computed Tomography (CT) scans. However, few have combined detection and classification tasks, and most have required extensive hands-on image manipulation to process the cases, which is both costly and time-consuming. Here, we present a closed loop, fully automated software package, Bronchosolve, which handles cases from scan to result without manual intervention. METHODS: The software package combined pre-processing, analysis, and result generation system including a deep learning convolutional neural network (CNN) for assessment of suspicious pulmonary nodules. Model inputs were full CT cases formatted in Digital Imaging and Communications in Medicine (DICOM), without demographics or clinical variables. Automated steps included 1) automatic selection of the optimal CT series for analysis; 2) normalization and pre-processing of the series; 3) AI-based analysis of the images to both detect and classify suspicious lung lesions; and 4) generation of analysis report. The system was trained using a multi-center dataset of over 2,358 cases of suspicious lung nodules, including cancers and non-cancers. A United States-based, multi-site cohort (n=184) was used for initial algorithm validation where positive cases were defined as biopsy-proven cancer within 1 year, and negatives as negative biopsy or 2+ year negative follow-up. RESULTS: In the validation set, the system achieved a technical completion rate of 100%, automatically for all cases. Median patient age was 62.5 years (interquartile range 58.5 to 66.5 years), 45% were former smokers, 55% were current smokers, and 40% were female. The AI cancer risk (CA-risk) model achieved an area under the receiver-operating-characteristic curve (AUC) of 0.828 [CI: 0.773 – 0.883] in differentiating cancer from non-cancer in cases with known suspicious pulmonary nodules, as confirmed by biopsy, surgery, and/or follow-up. These results were statistically superior to Lung-RADS pAUC of 0.669 [CI: 0.601 – 0.737] and trended better than Brock model AUC of 0.783 [CI: 0.723 – 0.842], Figure 1. At the Youden operating point, model sensitivity was 73.1% [CI: 66.7 – 79.5%], and specificity was 82.5% [CI: 77.0 – 88.0%]. The model's performance was consistent across various CT scanner manufacturers and tested slice thickness. CONCLUSIONS: The closed loop, automated software system, Bronchosolve, consistently processed and analyzed a wide range of CT scans, providing accurate assessment in risk-classifying suspicious lung nodules. This approach has the potential to improve non-invasive assessment of lung nodules eliminating the need for additional user training and time.

Abstract RATIONALE: As technology for biopsy of peripheral pulmonary nodules advances, the size of suspicious nodules referred for biopsy has decreased. This can be partly attributed to tools such as shape-sensing robotic-assisted bronchoscopy (ssRAB), which can increase the likelihood of a diagnostic result. Literature describing the biopsy of sub-centimeter nodules is primarily single center with a reported diagnostic yield for robotic bronchoscopy of 67%1, and 71%2 for CT-guided percutaneous biopsy; robust prospective multi-center data is needed to further understand the feasibility and clinical value of <1cm nodule biopsies. Herein, we report data from the prospective Ion Registry describing outcomes for patients with sub-centimeter nodules biopsied using ssRAB. METHODS: Patients with at least one (1) nodule <1cm that underwent ssRAB biopsy were identified from those enrolled in the Ion Registry. Subjects with multiple lesions were included if all nodules were <1cm in largest diameter. Nodule and procedure characteristics are reported with descriptive statistics; diagnostic yield was assessed using the ATS/ACCP recommended guidelines of index biopsy results only. Safety was assessed as the rate of pneumothorax requiring intervention and Nashville Grade ≥3 bleeding. RESULTS: Fifty-four (54) subjects and 57 sub-centimeter nodules were identified across 9 centers and 15 investigators; procedures were completed October 2023 through September 2024. The majority of nodules (47.4%) were incidental findings. Median nodule diameter was 8 mm (IQR: 7,9; range: 4.0-9.7 mm) with 66.7% of nodules located in the outer-third of the lung, and predominantly (57.9%) in the upper lobes. CT bronchus sign was present in 24.6% of nodules, and most (89.5%) nodule were solid. Median procedure time was 34.5 mins (IQR: 26,47; range: 9-89 mins); fixed or mobile CBCT was utilized for 80.7% (46/57) of nodules. The flexision biopsy needle and cryoprobe were used in 91% and 49% of biopsies, respectively. Diagnostic yield was 83% (45/54) using index biopsy results, 59% of which were malignant. No (0%) pneumothorax requiring intervention, Nashville Grade ≥3 bleeding events. CONCLUSION: Preliminary results from this prospective, multi-center registry cohort demonstrate peripheral nodules <1cm can be safely and effectively diagnosed through ssRAB biopsy and highlight the impact of ssRAB in enhancing lung nodule diagnosis, particularly when combined with CBCT. These findings suggest ssRAB may be considered a viable option for the biopsy of suspicious sub-centimeter nodules, further optimizing the management of patients with suspected lung cancer. REFERENCES:1. 10.1016/j.chest.2021.07.2169 2. https://doi.org/10.1016/j.clinimag.2020.04.040

Abstract Rationale: Airway-stenosing disease is a significant clinical problem in multiple populations. While the immediate endoscopic and clinical response to bronchoscopic interventions are high, rates of clinically significant recurrence are elevated, and often require multiple and frequent reinterventions. Newer strategies to prevent recurrence of central and proximal airway stenosis are needed. Methods: Retrospective review of bronchoscopic balloon bronchoplasties performed at the Mayo Clinic utilizing paclitaxel coated balloons (PCB) in 2023-2024 for recurrent airway stenosis. IN.PACT Admiral and AV balloons (sizes 5-12 mm, 3.5 mcg/mm2 paclitaxel dose) were used with an inflation time of 2-3 minutes. Procedural success was defined as <50% airway stenosis or resolution of the procedural indication. Reintervention was considered only if a therapeutic bronchoscopy was subsequently required to address the same lesion treated with PCB. Only patients with follow-ups >90 days were included in the reintervention inter-procedural time analysis. Results: Thirty-three procedures were performed in 18 patients. Seventeen (51%) for lung transplantation-associated stenosis (29% anastomotic/perianastomotic, 76% lobar and segmental stenoses), 8 (24%) for granulomatous polyangiitis-associated stenosis, 3 for postintubation tracheal stenosis and 2 for chemical/pill injury. Eighteen cases (54%) utilized an additional dilation modality (12 non-coated balloon dilation, 4 rigid dilation), 5 spray cryotherapy, 6 other ablative therapies (4 CO2-laser, 2 electrocautery cuts), and 6 received an airway stent during the same procedure. 57% percent of interventions occurred in the lobar, 27% mainstem/bronchus intermedius, 9% tracheal, 7% segmental airways. Thirty-one (93%) cases had a satisfactory initial endoscopic result. The median number of bronchoscopic therapeutic interventions required before the use pf PCB was 5 (IQR 2.5-11.5), which significantly decreased to 0.1 (IQR 0-1, range 0-9) after PCB (p <0.001). The reintervention-free survival significantly increased after PCB dilation from a median 35 days (IQR 28.7-80.5) to 132 days (IQR 64-197; p=0.004). Twenty-one cases required subsequent bronchoscopies, sixteen (76%) of which demonstrated improvement in lesion severity when compared to the results of prior interventions. Only 16 (48%) required therapeutically addressing the same lesion. Only 2 minor complications occurred (6%, self-limited bleeding and unplanned admission), none related to paclitaxel use. Six-month mortality was 3% from an unrelated cause. Conclusions: The locoregional antiproliferative effects of paclitaxel show promise in preventing recurrence, minimizing the need for repeat procedures, and extending intervals between interventions in patients with recurrent, predominantly benign airway stenosis. Its use is feasible, safe, and future research is warranted, particularly comparing PCB with the currently available strategies.

Purpose of review Persistent air leaks, defined as an air leak extending beyond 5 days, pose a significant challenge for cardiothoracic surgeons and pulmonologists. Although current guidelines advocate for surgical intervention as the primary treatment, many patients may not suitable candidates for immediate return to the operating room. Alternatively, conservative management, which involves watchful waiting for pleural healing, often results in prolonged hospital stays and increased morbidity. Recent findings Although current guidelines advocate for surgical intervention as the primary treatment, many patients may not suitable candidates for immediate return to the operating room. Alternatively, conservative management, which involves watchful waiting for pleural healing, often results in prolonged hospital stays and increased morbidity. For patients who are not surgical candidates, use of autologous blood patch, pleurodesis or endobronchial valves may offer a viable alternative to conservatively manage air leak. Summary This review evaluates the various noninvasive therapies that have been explored, including sealants, Heimlich valves, chemical and autologous blood patch pleurodesis, and endo and intrabronchial valves. Although these alternatives show promise, further research is needed to compare these treatments before they can be recommended in new guidelines.

8634 Background: Patients with unresectable non-small cell lung cancer (NSCLC) with an inadequate response to immune checkpoint inhibitors (ICI) have limited therapeutic options and expected median overall survival (mOS) of 11.6 to 14.5m (PMID: 35658002 ). The immunosuppressive tumor microenvironment and the lack of a specific T cell response underpin inadequate clinical response. CAN-2409 is a replication-defective adenovirus encoding the HSV-tk gene. Transduced cells activate orally delivered valacyclovir, resulting in immunogenic cell death, and in situ immunization against the patient’s tumor antigens, eliciting a specific immune response against the injected tumor and uninjected metastases. Methods: NCT04495153 is an open-label, phase 2 clinical trial of CAN-2409 + valacyclovir in combination with continued ICI in patients with non-resectable, stage III/IV NSCLC, refractory or resistant to anti-PD-(L)1. Patients were enrolled in 2 cohorts (C) depending on disease status at enrolment: C1, stable disease or C2, progressive disease. Two doses of CAN-2409 (5x1011vp) were given 5-7w apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, each followed by oral prodrug. Patients were assessed for safety, immunologic biomarkers, and OS. Results: As of 16Jan2024, 73 patients were treated (safety population: ≥1 dose of CAN-2409) and 44 were evaluable per protocol (received 2 doses of CAN-2409+ valacyclovir and 12-week CT scan). Baseline treated pt median age was 67 [43-88] yrs, 44% female, 68% on aPD(L)1 alone and 32% aPD(L)1 + pemetrexed regimen. We observed no dose-limiting toxicities or ≥grade 4 treatment-related AEs. mOS of the evaluable population was estimated as 22.0m (95% CI: 14.3m, NA; median follow up (mFU) time of 18.2m). In C2 (n = 38) mOS was 20.6 (mFU 19.2.m) and in C1 (n = 6) was N.A. (mFU 15.2m). mOS in the safety population (n = 73) was 14.3.m (mFU16.8m). 64% of evaluable patients had systemic clinical response with shrinkage of both injected and uninjected lesions. We found a significant correlation between increases in T cell populations after the second injection of CAN-2409 (circulating memory and effector memory CD4+ and CD8+T cells, CD4+ Ki67+IFNg+ and CD4+granzymeB+ T cells, CD8+granzymeB+Ki67+ T cells, T regulatory cells) and subsequent OS (R2 between 0.181 and 0.354 and p = 0.043 and 0.004). Conclusions: Experimental treatment with CAN-2409+valacyclovir in NSCLC pts following an inadequate response to ICI is well tolerated and results in the induction of a cytotoxic and memory circulating T cell response associated with shrinkage of injected and uninjected lesions and a raised tail of the survival curve. mOS of the evaluable population was estimated as 22.0m, markedly longer than the expected mOS of 11.6-14.5m. Clinical trial information: NCT04495153 .

Background: CO2 Laser (CO2L) technology deployable through flexible endoscopes now allows for their use throughout the airway, although published data are limited. Methods: Retrospective analysis of CO2L bronchoscopic procedures, excluding glottic and subglottic interventions. Procedural success was defined as >50% visual reduction in airway obstruction in the area treated or resolution of the procedural indication. Results: Seventy-two procedures were performed on 36 patients. Nonmalignant indications comprised 66%: stent-associated granulation tissue (28%), granulomatosis with polyangiitis lesions (23%), and lung transplant-related granulation tissue (16%) were the most common. Bronchoscopic access was flexible only in 81% and primarily rigid (combined with flexible) in 18%. The site of intervention was the trachea at 19%, the mainstem at 56%, and lobar/segmental airways at 45%. Procedural success was 89%. CO2L was used exclusively in 19%; in 81%, additional techniques were required, most commonly balloon dilation (59%), cryo-debulking (23%), and rigid dilation (16%). Malignant indications had a nonsignificant trend toward requiring adjuvant techniques (P=0.05). Seventy-six percent of the patients required more than 1 procedure. CO2L exclusive cases had no statistically different needs for subsequent therapeutic bronchoscopies (P=0.10) or time to reintervention (109 vs. 41 days, P=0.07), and reintervention-free survival was similar (P=0.10) and difficult to predict. The complication rate attributable to CO2L was 2.7%. Conclusion: CO2L is a safe and useful tool when precise cutting and vaporization are desired. Its use in multi-modality approaches has high levels of success in adequately selected lesions, adding an ablative potential to dilation techniques. Vasculitis-associated scars/webs and granulation tissue (including stent-associated) appear to be ideal targets.

Abstract Background: Non-small cell lung cancer (NSCLC) tissue is a valuable resource for diagnosis, treatment planning, and drug development. Current 2D histopathological techniques introduce under-sampling error (i.e., a single 5 um section represents 0.5% of a 1 mm thick biopsy), interobserver variability, and fail to capture the biology contained within the entire tissue sample. We have developed a suite of technologies to stain, chemically clarify, image, visualize, and analyze entire intact NSCLC tissue samples. Methods: Human NSCLC tissue, stored frozen in OCT, was fixed in 4% paraformaldehyde, stained with nuclear (TOPRO-3) and general protein (Eosin) fluorescent dyes, and optically cleared using a modified iDISCO protocol with ethyl cinnamate as the refractive index matching solution. Whole, intact tissue samples, roughly 1-5mm3 in volume, were imaged at 2 microns/pixel resolution with an open-top light-sheet microscope (3Di, Alpenglow Biosciences). Smaller regions of interest (ROIs) with key pathologic features were reimaged at higher resolution, 0.17 microns/pixel, to reveal subnuclear features and for cell typing. Visualization was performed using Aivia software. Results: NSCLC tissue samples were successfully imaged in 3D. Low resolution images (2 microns/pixel) were obtained within 4-31 minutes, depending on the tissue volume. The 3D distribution of cancer cells, immune cells, vessels, and fibrosis varied substantially throughout the volume of the tissue. Recognizable histologic features, including nests of tumor cells surrounded by vasculature and immune cells, were readily visualized. Squamous and adenocarcinoma with its subtypes (solid, acinar, lepidic, and micropapillary) morphologies were recognizable in 2D optical sections of the 3D datasets. Imaging quality degraded in tissue deeper than 1 mm due to light scattering. Conclusion: We assessed intact NSCLC tissue samples measuring up to 5 mm3 using our custom light-sheet microscope and tissue clearing techniques. This novel method enables us to visualize key features of NSCLC such as the tumor interfaces, tertiary lymphoid structures, vessels and fibrosis in the entire tissue sample, preventing under sampling error, and potentially enabling new biologic insights. Next steps include segmentation and quantification of key tissue structures such as tumor volume, immune cell distribution, and fibrosis/immune cell exclusion. This proof-of-concept study provides motivation for further investigation into the significance of 3D tissue features in NSCLC tissue samples. Citation Format: Alexandra Alvarsson, Carl Storey, Brandy Olin Pope, Caleb Stoltzfus, Robert Vierkant, Jessica Tufariello, Aaron Bungum, Julia Naso, Cheuk Ki Chan, Eric Edell, Christopher Hartley, Janani Reisenauer, Nicholas Reder. 3D assessment of the lung cancer microenvironment using multi-resolution open-top light-sheet microscopy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6624.

AbstractLung cancer is the deadliest cancer worldwide, therefore, early and prompt diagnosis is essential for better patient outcomes. It is known to have a high predilection for metastasis to the adrenal glands; however, two‐thirds of adrenal masses in patients with lung cancer will turn out to be benign, so timely detection is crucial. We present a case of a lung squamous cell carcinoma diagnosed by shape‐sensing robotic‐assisted bronchoscopy (ssRAB), negative mediastinal and hilar staging with endobronchial ultrasound (EBUS) and transbronchial needle aspiration (TBNA), and a pheochromocytoma diagnosed through endoscopic ultrasound with bronchoscope (EUS‐B) fine needle aspiration (FNA) all in the same endoscopic procedure.

AbstractBackgroundObtaining a diagnosis and treating pulmonary malignancies during the same anesthesia requires either an on‐site pathologist or a system for remotely evaluating microscopic images. Cytology specimens are challenging to remotely assess given the need to navigate through dispersed and three‐dimensional cell clusters. Remote navigation is possible using robotic telepathology, but data are limited on the ease of use of current systems, particularly for pulmonary cytology.MethodsAir dried modified Wright‐Giemsa stained slides from 26 touch preparations of transbronchial biopsies and 27 smears of endobronchial ultrasound guided fine needle aspirations were scored for ease of adequacy assessment and ease of diagnosis on robotic (rmtConnect Microscope) and non‐robotic telecytology platforms. Diagnostic classifications were compared between glass slides and the robotic and non‐robotic telecytology assessments.ResultsCompared to non‐robotic telecytology, robotic telecytology had a greater ease of adequacy assessment and non‐inferior ease of diagnosis. The median time to diagnosis using robotic telecytology was 85 s (range 28–190 s). Diagnostic categories were concordant for 76% of cases in robotic versus non‐robotic telecytology and 78% of cases in robotic telecytology versus glass slide diagnosis. Weighted Cohen's kappa scores for agreement in these comparisons were 0.84 and 0.72, respectively.ConclusionsUse of a remote‐controlled robotic microscope improved the ease of adequacy assessment compared to non‐robotic telecytology and enabled strongly concordant diagnoses to be expediently rendered. This study provides evidence that modern robotic telecytology is a feasible and user‐friendly method of remotely and potentially intraoperatively rendering adequacy assessments and diagnoses on bronchoscopic cytology specimens.