Clinical and pathological predictors of engraftment for patient-derived xenografts in lung adenocarcinoma.

Patient-derived xenografts (PDXs) are increasingly utilized in preclinical drug efficacy studies due to their ability to retain the molecular, histological, and drug response characteristics of patient tumors. This study aimed to investigate the factors influencing the successful engraftment of PDXs. Lung adenocarcinoma PDXs were established using freshly resected tumor tissues obtained through surgery. Radiological data of pulmonary nodules from this PDX cohort were analyzed, categorizing them into solid tumors and tumors with ground-glass opacity (GGO) based on preoperative CT images. Gene mutation status was obtained from next generation sequencing data and MassARRAY panel. A total of 254 resected primary lung adenocarcinomas were utilized for PDX establishment, with successful initial engraftment in 58 cases (22.8 %); stable engraftment defined as at least three serial passages was observed in 43 cases (16.9 %). The stable engraftment rates of PDXs from solid tumors and tumors with GGO were 22.1 % (42 of 190 cases) and 1.6 % (1 of 64 cases), respectively (P < 0.001). Adenocarcinomas with advanced stage, poor differentiation, solid histologic subtype, and KRAS or TP53 gene mutations were associated with stable PDX engraftment. Avoiding tumors with GGO features could enhance the cost-effectiveness of establishing PDX models from early-stage resected lung adenocarcinomas.

Impact of pulmonary vein-first ligation during lobectomy on the postoperative survival and recurrence rates in patients with non-small cell lung cancer: a multicenter propensity score-matched study.

PURPOSE: Surgical manipulation of the lungs increases the number of circulating tumor cells and the subsequent risk of metastasis in patients with lung cancer. This study investigated whether or not ligating the tumor-draining pulmonary vein first during lobectomy could improve the prognosis of these patients. METHODS: We retrospectively evaluated patients who underwent curative lobectomy for solitary nonsmall-cell lung carcinoma between January 2012 and December 2016. We divided the patients into the vein-first group, in which all associated pulmonary veins were dissected and severed before cutting the pulmonary artery, bronchus, or pulmonary fissure, and the other procedure group. RESULTS: Overall, we included 177 and 413 patients in the vein-first and other procedure groups, respectively. Propensity score matching yielded 67 pairs of patients. The 5-year overall survival (85.6% [95% confidence interval, 77.3-94.8%] vs. 69.4% [58.7-81.9%], P = 0.03%) and recurrence-free survival (73.4% [63.3-85.1%] vs. 53.5% [42.5-67.3%], P = 0.02) were significantly better in the vein-first group than in the other procedure group. The cumulative recurrence rate at 5 years post-surgery was significantly lower in the vein-first group than in the other procedure group (21.7% vs. 38.3%, P = 0.04). CONCLUSION: Our study suggests that ligating the pulmonary vein first during lobectomy for lung cancer can improve the overall survival, recurrence-free survival, and cumulative recurrence rate.

Dose Optimization of Intravenous Indocyanine Green for Malignant Lung Tumor Localization.

Background: Intravenously administered indocyanine green (ICG) accumulates in lung tumors, facilitating their detection via a fluorescence spectrum measurement. This method aids in identifying tumor locations that are invisible to the naked eye. We aim to determine the optimal ICG dose and administration method for accurate tumor identification during lung resection surgeries, utilizing a novel ICG fluorescence spectroscopy system for precise tumor localization. Materials and Methods: ICG should be dissolved in the provided solution or distilled water and administered intravenously approximately 24 h before surgery, beginning with an initial dose of 0.5 mg/kg. If the tumor detection rate is insufficient, the dose may be gradually increased to a maximum of 5.0 mg/kg to determine the optimal dosage for effective tumor detection. This fluorescence spectroscopy during surgery may reveal additional lesions that remain undetected in preoperative assessments. The primary endpoint includes the correct diagnostic rate of tumor localization. The secondary endpoints include the measurement of the intraoperative ICG fluorescence spectral intensity in lung tumors, the assessment of the operability and safety of intraperitoneal ICG administrations, the measurement of the ICG fluorescence spectral intensity in surgical specimens, the comparison of the spectral intensity in lung tissues during collapse and expansion, the correlation between ICG camera images and fluorescence spectral intensity, and the comparison of fluorescence analysis results with histopathological findings. The trial has been registered in the jRCT Clinical Trials Registry under the code jRCTs011230037. Results and Conclusions: This trial aims to establish an effective methodology for localizing and diagnosing malignant lung tumors, thereby potentially improving surgical outcomes and refining treatment protocols.

A simple and safe surgical technique for nonpalpable lung tumors: One-stop Solution for a nonpalpable lung tumor, Marking, Resection, and Confirmation of the surgical margin in a Hybrid operating room (OS-MRCH).

When performing thoracoscopic partial resections of nonpalpable lung tumors such as ground-glass opacities (GGOs) and small tumors, detecting the location of the lesion and assessing the resection margins can be challenging. We have developed a novel method to ease this difficulty, the One-stop Solution for a nonpalpable lung tumor, Marking, Resection, and Confirmation of the surgical margin in a Hybrid operating room (OS-MRCH), which uses a hybrid operating room wherein the operating table is seamlessly integrated with cone-beam computed tomography (CBCT). We performed the OS-MRCH method on 62 nodules including primary lung cancer presenting with GGO. Identification of the lesion and confirmation of the margin were performed in 58 of the cases, while nodules were detected in all. The frequency of computed tomography (CT) scans performed prior to resection was one time in 51 cases, two times in eight cases, and ≥3 times in three cases. Additional resection was performed in two cases. The median operative time was 85.0 minutes, and the median pathological margin was 11.0 mm. The key advantages of this method are that all surgical processes can be completed in a single session, specialized skill sets are not required, and it is feasible to perform in any facility equipped with a hybrid operating room. To overcome its disadvantages, such as longer operating time and limited patient positioning, we devised various methods for positioning patients and for CT imaging of the resected specimens. OS-MRCH is a simple, useful, and practical method for performing thoracoscopic partial resection of nonpalpable lung tumors.

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.

BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

Assessment of effectiveness and safety of thrombolytic therapy to pulmonary emboli by endobronchial ultrasound-guided transbronchial needle injection.

Objective: Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) may effectively treat acute pulmonary embolisms (PEs). Here, we assessed the effectiveness of clot dissolution and safety of tissue plasminogen activator (t-PA) injection using EBUS-TBNI in a 1-week survival study of a porcine PE model. Methods: Six pigs with bilateral PEs were used: 3 for t-PA injection using EBUS-TBNI (TBNI group) and 3 for systemic administration of t-PA (systemic group). Once bilateral PEs were created, each 25 mg of t-PA injection using EBUS-TBNI for bilateral PEs (a total of 50 mg t-PA) and 100 mg of t-PA systemic administration was performed on day 1. Hemodynamic parameters, blood tests, and contrast-enhanced computed tomography scans were carried out at several time points. On day 7, pigs were humanely killed to evaluate the residual clot volume in the pulmonary arteries. Results: The average of percent change of residual clot volumes was significantly lower in the TBNI group than in the systemic group (%: systemic group 36.6 ± 22.6 vs TBNI group 9.6 ± 6.1, P < .01) on day 3. Considering the elapsed time, the average decrease of clot volume per hour at pre-t-PA to post t-PA was significantly greater in the TBNI group than in the systemic group (mm3/hour: systemic 68.1 ± 68.1 vs TBNI 256.8 ± 148.1, P < .05). No hemorrhage was observed intracranially, intrathoracically, or intraperitoneally on any contrast-enhanced computed tomography images. Conclusions: This study revealed that t-PA injection using EBUS-TBNI is an effective and safe way to dissolve clots.

Transbronchial real-time lung tumor localization with folate receptor-targeted near-infrared molecular imaging: A proof of concept study in animal models.

OBJECTIVE: The diagnostic yield of bronchoscopy is not satisfactory, even with recent navigation technologies, especially for tumors located outside of the bronchial lumen. Our objective was to perform a preclinical assessment of folate receptor-targeted near-infrared imaging-guided bronchoscopy to detect peribronchial tumors. METHODS: Pafolacianine, a folate receptor-targeted molecular imaging agent, was used as a near-infrared fluorescent imaging agent. An ultra-thin composite optical fiberscope was used for laser irradiation and fluorescence imaging. Subcutaneous xenografts of KB cells in mice were used as folate receptor-positive tumors. Tumor-to-background ratio was calculated by the fluorescence intensity value of muscle tissues acquired by the ultra-thin composite optical fiberscope system and validated using a separate spectral imaging system. Ex vivo swine lungs into which pafolacianine-laden KB tumors were transplanted at various sites were used as a peribronchial tumor model. RESULTS: With the in vivo murine model, tumor-to-background ratio observed by ultra-thin composite optical fiberscope peaked at 24 hours after pafolacianine injection (tumor-to-background ratio: 2.56 at 0.05 mg/kg, 2.03 at 0.025 mg/kg). The fluorescence intensity ratios between KB tumors and normal mouse lung parenchyma postmortem were 6.09 at 0.05 mg/kg and 5.08 at 0.025 mg/kg. In the peribronchial tumor model, the ultra-thin composite optical fiberscope system could successfully detect fluorescence from pafolacianine-laden folate receptor-positive tumors with 0.05 mg/kg at the carina and those with 0.025 mg/kg and 0.05 mg/kg in the peripheral airway. CONCLUSIONS: Transbronchial detection of pafolacianine-laden folate receptor-positive tumors by near-infrared imaging was feasible in ex vivo swine lungs. Further in vivo preclinical assessment is needed to confirm the feasibility of this technology.

Repeated photodynamic therapy mediates the abscopal effect through multiple innate and adaptive immune responses with and without immune checkpoint therapy.

In combination with immune checkpoint inhibitors, photodynamic therapy can induce robust immune responses capable of preventing local tumor recurrence and delaying the growth of distant, untreated disease (ie. the abscopal effect). Previously, we found that repeated photodynamic therapy (R-PDT) using porphyrin lipoprotein (PLP) as a photosensitizer, without the addition of an immune checkpoint inhibitor, can induce the abscopal effect. To understand why PLP mediated R-PDT alone can induce the abscopal effect, and how the addition of an immune checkpoint inhibitor can further strengthen the abscopal effect, we investigated the broader immune mechanisms facilitated by R-PDT and combination R-PDT + anti-PD-1 monoclonal antibody (αPD-1) in a highly aggressive, subcutaneous AE17-OVA mesothelioma dual tumor-bearing C57BL/6 mice. We found a 46.64-fold and 61.33-fold increase in interleukin-6 (IL-6) after R-PDT and combination R-PDT + αPD-1 relative to PBS respectively, suggesting broad innate immune activation. There was a greater propensity for antigen presentation in the spleen and distal, non-irradiated tumor draining lymph nodes, as dendritic cells and macrophages had increased expression of MHC class II, CD80, and CD86, after R-PDT and combination R-PDT + αPD-1. Concurrently, there was a shift in the proportions of CD4+ T cell subsets in the spleen, and an increase in the frequency of CD8+ T cells in the distal, non-irradiated tumor draining lymph nodes. While R-PDT had an acceptable safety profile, combination R-PDT + αPD-1 induced 1.26-fold higher serum potassium and 1.33-fold phosphorus, suggestive of mild laboratory tumor lysis syndrome. Histology revealed an absence of gross inflammation in critical organs after R-PDT and combination R-PDT + αPD-1 relative to PBS-treated mice. Taken together, our findings shed light on how the abscopal effect can be induced by PDT and strengthened by combination R-PDT + αPD-1, and suggests minimal toxicities after R-PDT.

Optimization of thrombolytic dose for treatment of pulmonary emboli using endobronchial ultrasound-guided transbronchial needle injection.

OBJECTIVE: Severe pulmonary embolism is often managed with thrombolysis. We sought to determine whether endobronchial ultrasound (EBUS)-guided transbronchial thrombolysis remained effective at lower alteplase doses, with the goal of minimizing potential bleeding risk. METHODS: Yorkshire pigs were anesthetized and ventilated. Preformed autologous blood clots were administered into bilateral pulmonary arteries via EBUS-guided transbronchial injection. After documenting baseline clot sizes, alteplase was injected into the clots using a 25-gauge transbronchial needle and clot dissolution was monitored over 30 minutes. The study was performed in 2 phases. First, alteplase doses of 5 and 12.5 mg were evaluated. These results informed dose selection for the second phase. Results were compared with 25-mg dose data using EBUS from a previous study. RESULTS: In the first phase, 3 clots were evaluated. Distilled water, 5 mg, and 12.5 mg alteplase were administered. The dissolved clot volume (Vdis) and percentage clot volume loss (Rdis) were -10.9, 111.6, and 160.3 mm3, and -1.6%, 11.0%, and 59.3%, respectively. In the second phase, alteplase doses of 5, 10, and 15 mg were evaluated in 12 clots across 6 pigs. The Vdis were 247.5 mm3 (Rdis, 20.1%), 910.8 mm3 (Rdis, 80.9%), and 798.3 mm3 (Rdis, 76.0%) for 5, 10, and 15 mg alteplase, respectively. Remakably reduced performance was observed with 5 mg alteplase versus 10 mg (Vdis: P < .001, Rdis: P < .001), and 15 mg (Vdis: P = .004; Rdis: P < .001). No complications were observed. CONCLUSIONS: Alteplase doses ≥10 mg were optimal for EBUS-guided transbronchial thrombolysis. This technique might represent an effective alternative therapy for central pulmonary embolism.

Preclinical feasibility of bronchoscopic fluorescence-guided lung sentinel lymph node mapping.

OBJECTIVE: Lung sentinel lymph node mapping, where peritumorally injected material is tracked through the lymphatics, aims to find the first potential sites of nodal metastasis. We sought to evaluate the preclinical feasibility of bronchoscopic fluorescence-guided sentinel lymph node mapping. METHODS: Healthy Yorkshire pigs were used; sentinel lymph node mapping was performed with indocyanine green. The primary fluorescence imaging method was an ultrathin composite fiberscope placed in the bronchoscope working channel. Secondary methods used a fluorescence thoracoscope placed in the trachea (rigid bronchoscopy) and pretracheal fascial plane (mediastinoscopy) to validate ultrathin composite fiberscope settings for sentinel lymph node detection. A tracheostomy was created, and the pig was placed in a lateral decubitus position. Transbronchial intraparenchymal indocyanine green injection was performed primarily in the right lower lobe. Ultrathin composite fiberscope and rigid bronchoscopy were performed with (n = 6) or without (n = 2) mediastinoscopy, with the former group guiding dose and ultrathin composite fiberscope optimization. Fluorescent targets were interrogated by endobronchial ultrasound before ultrathin composite fiberscope-guided transbronchial needle aspiration. Specimen fluorescence was documented before creating cytological smears. Pigs were killed postprocedure for nodal dissection. RESULTS: A total of 100 µL of 10 mg/mL indocyanine green generated strong transbronchial fluorescence with low risk of indocyanine green contamination. Fluorescence was detectable by 10 minutes postinjection. There was concordance among ultrathin composite fiberscope, rigid bronchoscopy, and mediastinoscopy. Except for 1 pig with airway contamination, ultrathin composite fiberscope-guided endobronchial ultrasound transbronchial needle aspiration obtained fluorescent material in all pigs. Specimen fluorescence was associated with specimen adequacy. CONCLUSIONS: Bronchoscopic fluorescence-guided sentinel lymph node mapping was feasible, with specimen fluorescence providing real-time feedback on sentinel lymph node biopsy success. If translated to clinical practice, attention must be paid to minimizing indocyanine green leakage.

Preclinical evaluation of thin convex probe endobronchial ultrasound-guided transbronchial needle aspiration for intrapulmonary lesions.

Background: Conventional flexible bronchoscopy has not achieved the high diagnostic yield for intrapulmonary lesions as seen with image-guided transthoracic biopsy. A thin convex probe endobronchial ultrasound bronchoscope (TCP-EBUS) with a 5.9-mm tip was designed to improve peripheral access over conventional EBUS bronchoscopes to facilitate real-time sampling of intrapulmonary lesions under ultrasound guidance. Methods: TCP-EBUS was inserted into the distal airways of ex-vivo human lungs to assess bronchial accessibility relative to clinically available bronchoscopes. The short- (≤1 h) and medium-term (≤10 d) safety of TCP-EBUS insertion and EBUS-guided transbronchial needle aspiration (TBNA) using a 25-gauge needle were evaluated physiologically and radiologically in live pigs. TCP-EBUS-guided TBNA feasibility was assessed in-vivo with pig intrapulmonary pseudo-tumors and ex-vivo with resected human lung cancer specimens. Results: For bronchial accessibility, TCP-EBUS demonstrated greater reach than the 6.6-mm convex probe endobronchial ultrasound (CP-EBUS) in all bronchi, as well as surpassed a 5.5-mm conventional bronchoscope in 63% (131/209) and a 4.8-mm conventional bronchoscope in 27% (57/209) of assessed bronchi. The median bronchial generation and the mean diameter of bronchi TCP-EBUS reached was 4 (range, 3-7) and 3.3±0.7 mm, respectively. No major complications related to TCP-EBUS-guided TBNA in distal airways were observed in the live pigs. Scattered mucosal erythema of the bronchial walls was observed immediately after TCP-EBUS insertion; this self-resolved by day 10. TCP-EBUS could successfully reach and visualize intrapulmonary targets via ultrasound, with no difficulty in needle deployment or sampling. Conclusions: TCP-EBUS has the potential to facilitate safe real-time transbronchial sampling of intrapulmonary lesions in the central and middle lung fields.

Endobronchial ultrasound-guided bipolar radiofrequency ablation for lung cancer: A first-in-human clinical trial.

OBJECTIVE: Percutaneous radiofrequency ablation (RFA) is a therapeutic option for lung tumors. However, percutaneous approaches have limited access to central lung regions and a relatively high complication rate. To overcome these limitations, a needle-type bipolar RFA device compatible with an endobronchial ultrasound (EBUS) bronchoscope was developed. The aim of this pilot study was to evaluate the immediate-term safety and ablation zone of lung tumor EBUS-guided RFA. METHODS: This was an ablate-and-resect study in patients scheduled for surgical resection of clinical stage I or II lung cancer or metastatic lung lesions ≥1 cm that were accessible using an EBUS bronchoscope. The RFA electrodes were placed within the lung nodule using EBUS guidance followed by ablation. Bronchoscopy and contrast-enhanced computed tomography were performed to evaluate for post-RFA complications. The resected lung underwent pathological assessment to characterize the ablation zone. RESULTS: A total of 5 primary lung cancers were ablated in 5 separate patients; no patients with metastatic lesions were recruited. For a total energy of 4 kJ (n = 3), 6 kJ (n = 1), and 8 kJ (n = 1) delivered, the ablation time was a mean of 13.8 (range, 10.3-16.0) minutes, 8.4 minutes, and 15.6 minutes, respectively, and the maximum ablation diameter was a mean of 1.8 (range, 1.3-2.1) cm, 2.7 cm, and 2.6 cm, respectively. No immediate post-RFA complications were observed. CONCLUSIONS: EBUS-guided bipolar RFA can ablate lung tumors using real-time ultrasound guidance. EBUS-guided RFA might ultimately represent a minimally invasive therapy for lung cancer in patients unable to tolerate surgery. Longer-term safety will need to be evaluated.

Development of a minimally invasive pulmonary porcine embolism model via endobronchial ultrasound.

Background: Current massive pulmonary embolism (PE) animal models use central venous access to deliver blood clots, which have features of random clot distribution and potentially fatal hemodynamic compromise. A clinically relevant preclinical model for generating pulmonary emboli in a more controlled fashion would be of value for a variety of research studies, including initial evaluation of novel therapeutic approaches. Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) is a newly established approach for peri-tracheal/bronchial targets. The purpose of the present work was to establish a minimally invasive PE model in swine via a transbronchial approach. Methods: In anesthetized Yorkshire pigs, a 21-G EBUS-guided transbronchial needle aspiration (EBUS-TBNA) needle was introduced into the pulmonary artery under EBUS guidance. Autologous blood clots were administered into the right and left lower pulmonary arteries sequentially (PE1 and PE2, respectively). Hemodynamic and biochemical responses were evaluated. Results: Ten pigs were evaluated; all 20 blood clots (6.3±1.9 mL) were successfully injected. After injection, mean pulmonary artery pressure (mPAP; mmHg) increased (baseline: 16.6±5.6 vs. PE1: 24.5±7.6, P<0.0001 vs. PE2: 26.9±6.7, P<0.0001), and a positive correlation was observed between clot volume and change in mPAP (PE1: r=0.69, P=0.025; PE1 + PE2: r=0.60, P=0.063). Mean arterial pressure (MAP; mmHg) (baseline: 57.5±5.1 vs. PE1: 59.0±9.1, P=0.918 vs. PE2: 60.9±9.6, P=0.664) remained stable. No complications were observed. Conclusions: EBUS allows minimally invasive, precise, and reliable generation of pulmonary emboli in pigs. This model may serve as an important tool for new PE-related diagnostic and therapeutic research.

Intralobar pulmonary sequestration associated with left main coronary artery obstruction and mitral regurgitation.

A 4-year-old boy with left intralobar pulmonary sequestration associated with left main coronary artery obstruction (LMCAO) and severe mitral regurgitation (MR) was admitted to our hospital. Since the patient presented with dyskinesia of the cardiac apex and increased left ventricular end-diastolic volume (LVEDV), left main coronary artery reconstruction and mitral annuloplasty were performed. The enlargement of the left ventricle was improved after sequential surgeries. There was a risk of deterioration of MR and regrowth of LVEDV due to shunt blood flow; therefore, left lower lobectomy and aberrant artery division were performed. This is a very rare case of a patient with pulmonary sequestration associated with LMCAO and severe MR.

Pilot study using virtual 4-D tracking electromagnetic navigation bronchoscopy in the diagnosis of pulmonary nodules: a single center prospective study.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is a navigation technology intended to improve the diagnostic yield of pulmonary nodules. However, nodule displacement due to respiratory motion may compromise the accuracy of the navigation guidance. The Veran SPiNDrive ENB system employs respiratory-gating (4D-tracking) to compensate for this motion. The aim of the present study was to evaluate the diagnostic performance and safety of the Veran SPiNDrive system for biopsy of pulmonary nodules. METHODS: Adult patients with pulmonary nodules of ≥1 cm were enrolled at a single center. Both conventional bronchoscopy and 4D-tracking ENB were performed in one procedure session under general anesthesia, with the procedure order being randomly assigned. Radial probe endobronchial ultrasound and fluoroscopy were used in both groups. The diagnostic performance, safety, total procedure time, and total fluoroscopy time of the ENB phase were compared to the corresponding conventional bronchoscopy phase. RESULTS: The study was terminated due to poor accrual; a total of eleven patients were enrolled. The mean size of pulmonary nodules was 2.1 cm. The sensitivity for malignancy was 67% (6/9) and 56% (5/9) with conventional bronchoscopy and with 4D-tracking ENB, respectively. Two cases developed minor bleeding after conventional bronchoscopy, while no complications were observed after 4D-tracking ENB. The mean procedure time was 16.1 and 21.7 min (P=0.090), and the mean duration time for fluoroscopy use was 77 and 44 sec (P=0.056) for the conventional bronchoscopy and the 4D-tracking ENB phases, respectively. CONCLUSIONS: The diagnostic performance of the Veran SPiNDrive 4D-tracking ENB did not exceed that of conventional bronchoscopy for pulmonary nodules. No complications were seen during 4D-tracking ENB. A study with a larger number of participants is required for further assessment.

Thrombolysis of Pulmonary Emboli via Endobronchial Ultrasound-Guided Transbronchial Needle Injection.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) is a novel technique for treating peribronchial targets. The aim of this study was to evaluate preliminary feasibility of thrombolysis of pulmonary emboli via EBUS-TBNI. METHODS: Yorkshire pigs (30-48 kg) were anesthetized and mechanically ventilated. Pre-formed autologous clots were injected sequentially into bilateral lower pulmonary arteries in bilateral models (PE1 and PE2, respectively) or into 1 side in unilateral models using a 21-gauge EBUS-TBNA needle under EBUS guidance. In the bilateral model, 2 hours after clot injection either 25 mL of tissue-plasminogen activator (t-PA; 1mg/mL) or distilled water were administered into each embolus via 25-gauge EBUS-TBNA needle. In the unilateral model, 25 mg t-PA was administered intravenously. Hemodynamic parameters were monitored continuously, and clot dissolved volume was evaluated by EBUS 30 minutes post-treatment administration. RESULTS: All clots (6.1 ± 1.7 mL) were successfully injected as documented by EBUS Doppler imaging. Clot injection in the bilateral model (n = 6) increased pulmonary arterial pressure (mm Hg: Baseline 19.2 ± 5.9 vs PE1: 26.7 ± 9.1, P = .005 vs PE2 29.9 ± 7.1, P = .0007). After t-PA TBNI in the bilateral model (n = 6), pulmonary arterial pressure at 30 minutes post-injection showed improvement (mm Hg: PE2 29.9 ± 7.1 vs post-t-PA 24.4 ± 3.9, P = .0283). Treatment with t-PA TBNI demonstrated superior clot dissolution at 30 minutes post-treatment (dissolved mm3: t-PA TBNI 625.4 ± 156.6 vs t-PA intravenously: 181.6 ± 94.3, P = .0003 vs distilled water TBNI 42.5 ± 33.0, P < .0001). There were no complications. CONCLUSIONS: EBUS-guided transbronchial thrombolysis may be a feasible approach for treating central pulmonary emboli.

A preclinical research platform to evaluate photosensitizers for transbronchial localization and phototherapy of lung cancer using an orthotopic mouse model.

BACKGROUND: Establishing the efficacy of novel photosensitizers (PSs) for phototherapy of lung cancer requires in vivo study prior to clinical evaluation. However, previously described animal models are not ideal for assessing transbronchial approaches with such PSs. METHODS: An ultra-small parallel-type composite optical fiberscope (COF) with a 0.97 mm outer diameter tip. The integration of illumination and laser irradiation fibers inside the COF allows simultaneous white-light and fluorescence imaging, as well as real-time monitoring of tip position during laser phototherapy. An orthotopic lung cancer mouse model was created with three human lung cancer cell lines transbronchially inoculated into athymic nude mice. The COF was inserted transbronchially into a total of 15 mice for tumor observation. For in vivo fluorescence imaging, an organic nanoparticle, porphysome, was used as a PS. Laser excitation through the COF was performed at 50 mW using a 671 nm source. RESULTS: The overall success rate for creating orthotopic lung tumors was 71%. Transbronchial white light images were successfully captured by COF. Access to the left main bronchus was successful in 87% of mice (13/15), the right main bronchus to the cranial lobe bronchus level in 100% (15/15), and to the right basal trifurcation of the middle lobe, caudal lobe and accessory lobe in 93% (14/15). For transbronchial tumor localization of orthotopic lung cancer tumors, PS-laden tumor with the strong signal was clearly contrasted from the normal bronchial wall. CONCLUSIONS: The ultra-small COF enabled reliable transbronchial access to orthotopic human lung cancer xenografts in vivo. This method could serve as a versatile preclinical research platform for PS evaluation in lung cancer, enabling transbronchial approaches in in vivo survival models inoculated with human lung cancer cells.

A novel approach for the complete extraction of large tumours in video-assisted thoracoscopic surgery.

BACKGROUND: Video-assisted thoracoscopic (VATS) lobectomy has recently become the standard for treating lung cancer. However, the complete removal of large tumours from the chest cavity is often difficult. Therefore, we developed a novel approach to extract large tumours from the wound without rib resection or fracture (the eXtraction of resected specimens through the Lower INterCostal route [XLINC] method). SUBJECTS AND METHODS: In XLINC, a skin incision is made on the tenth intercostal space, and the resected lung tissue is extracted. This retrospective study included patients who underwent VATS lobectomy using XLINC in our institution from 2016 to 2018. As a control group, six patients who had undergone thoracotomy during VATS surgery due to a large tumour diameter were included in the conversion group. RESULTS: Four men and six women (median age = 66 years, maximum median tumour diameter = 59 mm) were included in the study. The median length of the wound incision for XLINC was 4.5 (range: 4-8) cm. The median operative time was 183 min, and the estimated blood loss was 50 ml. Rib resection was not required, and no fractures were noted. The median length of hospital stay was 8 days. No patients developed major complications caused by XLINC. There were no significant differences, except in operation time and amount of blood loss, between the two groups. However, the XLINC group used fewer post-operative analgesics. CONCLUSION: Our report suggests that XLINC might be a simpler, less invasive procedure that could be used in patients with large tumours.

Repeated porphyrin lipoprotein-based photodynamic therapy controls distant disease in mouse mesothelioma via the abscopal effect.

While photodynamic therapy (PDT) can induce acute inflammation in the irradiated tumor site, a sustained systemic, adaptive immune response is desirable, as it may control the growth of nonirradiated distant disease. Previously, we developed porphyrin lipoprotein (PLP), a ∼20 nm nanoparticle photosensitizer, and observed that it not only efficiently eradicated irradiated primary VX2 buccal carcinomas in rabbits, but also induced regression of nonirradiated metastases in a draining lymph node. We hypothesized that PLP-mediated PDT can induce an abscopal effect and we sought to investigate the immune mechanism underlying such a response in a highly aggressive, dual subcutaneous AE17-OVA+ mesothelioma model in C57BL/6 mice. Four cycles of PLP-mediated PDT was sufficient to delay the growth of a distal, nonirradiated tumor four-fold relative to controls. Serum cytokine analysis revealed high interleukin-6 levels, showing a 30-fold increase relative to phosphate-buffered solution (PBS) treated mice. Flow cytometry revealed an increase in CD4+ T cells and effector memory CD8+ T cells in non-irradiated tumors. Notably, PDT in combination with PD-1 antibody therapy prolonged survival compared to monotherapy and PBS. PLP-mediated PDT shows promise in generating a systemic immune response that can complement other treatments, improving prognoses for patients with metastatic cancers.

Feasibility of limited resection for peripheral small-sized non-small cell lung cancer: a retrospective single-center-based study.

PURPOSE: This study aimed to establish new criteria for limited resection of non-small cell lung cancer (NSCLC) based on computed tomography findings and maximum standardized uptake value (SUVmax). METHODS: Between December 2007 and December 2015, 611 patients underwent lung cancer surgery; of these, 70 with cT1aN0M0 who underwent limited resection were enrolled. Criteria for undergoing intentional limited resection (ILR) were (1) tumor ground-glass opacity (GGO) ratio of ≥ 0.75 and (2) tumor SUVmax ≤ 1.5. Patients who met criteria (1) and (2) underwent partial resection, and those who only met criteria (2) underwent segmentectomy as ILR. The control group was subjected to limited surgery without meeting the criteria. RESULTS: Overall, 45 and 25 patients who met the criteria were included in the ILR and control groups, respectively. In the ILR group, 13 patients underwent partial resection, and 32 underwent segmentectomy; in the control group, 18 patients underwent partial resection and 7 underwent segmentectomy. According to our criteria, no relapsed cases occurred in the ILR group, although six patients showed recurrence of lung cancer in the control group. The 5-year overall survival (OS) rates in the ILR and control groups were 100% and 67.7%, respectively, and the relapse-free survival (RFS) rates were 100% and 61.6%, respectively. The log-rank test showed that this difference was statistically significant (OS: P < 0.0001, RFS: P < 0.0001). CONCLUSIONS: SUVmax may serve as a predictive marker of recurrence to determine the treatment strategy for patients with NSCLC. Patients with low GGO ratio and low SUVmax may be cured by limited resection.