High efficacy of brigatinib for brain metastases in ALK fusion gene-positive non-small cell lung cancer: A case series.

Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer often shows brain metastasis at initial diagnosis or during the course of treatment. However, molecular-targeted drugs are known to pass through the blood-brain barrier and present positive effects for central nervous system lesions. There are few reports suggesting how effective molecular-targeted drug therapy alone is for brain metastasis lesions of ALK fusion-positive lung cancer, especially after the first use of ALK-tyrosine kinase inhibitor (TKI) or for bulky brain metastases. A patient in his mid-fifties with stage IV pleural dissemination developed brain metastases after 10 years of crizotinib use, but showed a complete response after switching to brigatinib. Moreover, a patient in her early sixties with stage III recurrent large brain metastases 5 years after chemoradiation therapy experienced dramatic tumor shrinkage with brigatinib. In each case of ALK fusion gene-positive lung cancer with brain metastases, brigatinib showed a high efficacy and was well-tolerated after previous ALK-TKI and for bulky lesions.

Flexible bronchoscopy for lung cancer diagnosis in patients aged ≥85 years.

AIM: Flexible bronchoscopy (FB) is a common modality for the diagnosis of lung cancer. Recently, the number of older patients with lung cancer is increasing, and FB is being utilized more for these patients. METHODS: FB carried out in patients aged ≥85 years at St. Marianna University Hospital, Kawasaki, Japan, were reviewed. The indication of FB was decided on a case-by-case basis, taking into consideration the condition of the patient, which included mental status and accessibility of the lesion. Outcomes included complications, diagnostic yields, treatment options and survival after FB evaluation. RESULTS: From April 2015 to March 2019, 1604 diagnostic FBs were carried out. A total of 28 were carried out for the diagnosis of lung cancer (19 transbronchial lung biopsy, 9 transbronchial needle aspiration) in patients aged ≥85 years. Although there were three complications reported (pneumonia, fever, asthma exacerbation), they were successfully treated. A total of 19 cases were diagnosed with malignancy; five were treated with stereotactic body radiation therapy, five were prescribed targeted therapy, two underwent surgery and one was treated by cytotoxic monotherapy. Six patients were not included for active treatment. A total of 12 patients who received active treatment for lung cancer reported a 2-year survival rate of >60%. CONCLUSIONS: FB for lung cancer diagnosis in patients aged ≥85 years were carried out with acceptable safety and diagnostic yield. Considering the development of less invasive therapeutic measures for lung cancer, FB is safe and valuable in individuals aged ≥85 years suspected of lung cancer with therapeutic indications. Geriatr Gerontol Int 2022; 22: 32-35.

A case of advanced adenocarcinoma genetically confirmed with EGFR/BRAF co-mutation in both primary and metastatic lesions.

Driver mutations in lung cancer have been generally considered mutually exclusive; however, multiple gene screenings have recently become mainstream. Therefore, it is not uncommon to identify two or more mutations at first diagnosis, making it difficult to determine which tyrosine kinase inhibitor to administer. A 69-year-old woman complaining of back pain was diagnosed with adenocarcinoma T4N3M1c, stage IVB. Although PCR mutation test detected exon21 L858R point mutation by bronchoscopic sample, the therapeutic effect of afatinib was poor. Subsequently, next-generation sequencing (NGS) panel test of a metastasized bone specimen confirmed BRAF V600E. Furthermore, high sensitivity NGS panel system found the gene mutation allele frequency was higher for BRAF V600E than EGFR exon21 L858R for both primary lung tissue and the metastasized specimen. Subsequent BRAF/MEK inhibitor administration showed a remarkable treatment effect. When two or more driver mutations are detected in lung cancer, confirming the allelic frequency of the mutant gene might be useful in selecting more effective agents for front-line treatment.

Assessment of Extensive Airway Obstruction Using Point-by-Point Lateral Pressure Measurements during Bronchoscopy.

BACKGROUND: The positioning of the stent at the flow-limiting segment is crucial for patients with extensive airway obstruction to relieve dyspnea. However, CT and flow-volume curves cannot detect the area of maximal obstruction. OBJECTIVES: The aim of this study is to physiologically evaluate extensive airway obstruction during interventional bronchoscopy. METHODS: We prospectively measured point-by-point lateral airway pressure (Plat) at multiple points from the lower lobe bronchus to the upper trachea using a double-lumen catheter in 5 patients. The site of maximal obstruction was evaluated continuously to measure point-by-point Plat at multiple points when the airway catheter was withdrawn from the lower lobe bronchus to the upper trachea. RESULTS: Remarkable pressure differences occurred at the site of maximal obstruction assessed by point-by-point Plat measurements. After initial stenting in 1 case, migration of the maximal obstruction to a nonstented segment of the weakened airway was seen with extensive stenosis from the trachea to the bronchi. In the second case, in addition to radiological analysis, point-by-point Plat measurements could identify the location of the maximal obstruction which contributed to dyspnea. CONCLUSIONS: Point-by-point Plat measurement could be used to detect the site of maximal obstruction physiologically. Furthermore, Plat measurement could assess the need for additional procedures in real time in patients with extensive airway obstruction.

Untreated Squamous Cell Lung Carcinoma May Contribute to the Occurrence of Hemophagocytic Syndrome.

A 44-year-old man presented at our hospital to be evaluated for persistent fever and dyspnea. A chest computed tomography (CT) scan showed diffuse ground glass shadows and a left hilar tumor shadow. Upon further examination, he was found to have leukopenia, thrombocytopenia, and elevated lactate dehydrogenase and ferritin levels. He was diagnosed with both squamous cell lung carcinoma by a transbronchial lung biopsy and hemophagocytic syndrome by a bone marrow biopsy. After receiving treatment with dexamethasone and etoposide, the blood test abnormalities and performance status improved. Chemotherapy for lung cancer was initiated. He had a partial response after first-line chemotherapy and thereafter underwent left upper sleeve lobectomy.

Pulmonary Perfusion Using Intrabronchial Capnography in Pulmonary Artery Stenosis.

Stenting at the flow-limiting segment can improve the ventilation-perfusion ratio in patients with central airway stenosis. However, there is no quantitative examination for assessing the perfusion status during interventional bronchoscopy. Intrabronchial capnography can estimate regional gas exchange by measuring carbon dioxide concentration. We herein report a case of bilateral bronchial stenosis where stenting was able to improve ventilation-perfusion ratio using intrabronchial capnography. A 44-year-old man was admitted to our institution with orthopnea. Chest computed tomography showed an extrinsic compression at the bilateral main bronchus and right pulmonary artery due to a mediastinal mass. After introduction of general anesthesia, arterial oxygen tension suddenly decreased in the supine position. After initial stenting, an increase was seen in ventilation at the right lung; however, a ventilation-perfusion mismatch occurred due to an increase in dead-space ventilation at the right pulmonary artery stenosis. Intrabronchial capnography was an effective modality to confirm the regional perfusion status during interventional bronchoscopy in real time.

Assessment of Bronchial Obstruction Using Lateral Pressure Measurement during Bronchoscopy.

BACKGROUND: In patients with bronchial obstruction estimating the location of the maximal obstruction is crucial for guiding interventional bronchoscopy. However, flow-volume curves cannot discriminate between the right and left lungs. OBJECTIVES: The aim of this study was to physiologically evaluate bronchial obstruction during interventional bronchoscopy. METHODS: We prospectively measured lateral airway pressure (Plat) at either side of the obstruction using a double-lumen catheter (pressure-pressure [P-P] curve) simultaneously to assess the degree of bronchial obstruction in 22 patients. The shape of the P-P curve was assessed to confirm the site of maximal obstruction. RESULTS: In the experimental study, Plat was uniform between both bronchi in the normal model. For the unilateral and bilateral obstruction models, a phase shift was only seen for the more obstructed side. In healthy subjects, the angle of the P-P curve was close to 45° and linear in shape. In patients with bronchial obstruction, the angle was much smaller but approached 45° after the bronchoscopic procedure. The degree of bronchial obstruction was significantly correlated with the angle of the P-P curve (r = -0.51, p < 0.01). Dyspnea significantly increased when the airway lumen was obstructed by more than 60% (p < 0.0001), and when the P-P curve appeared loop-shaped (p < 0.01). CONCLUSIONS: The shape of the P-P curve could be used to detect the site of maximal obstruction for the optimal positioning of the stent and assess the need for additional procedures in real time in patients with bronchial obstruction.

Comparison of Airway Measurements for Tracheobronchial Stenosis Between Stereoscopic Bronchoscope and MD-CT.

BACKGROUND: Stereoscopic bronchoscopy is a new diagnostic tool to measure the diameter and cross-sectional area of the airway. The stereoscopic bronchoscope, which operates the same as a standard bronchoscope, utilizes 2 lenses to measure the airway using the principles of triangulation. Furthermore, the stereoscopic bronchoscope has the capability to measure the size of the airway during intervention in real-time, including variable stenosis. MATERIALS AND METHODS: To prospectively compare preoperative stereoscopic and multidetector computed tomography (MD-CT) images to select the appropriate stent size for airway stenosis. Stereoscopic and MD-CT images were then measured to confirm the correct placement of the stent. RESULTS: Airway stenting was performed on 21 consecutive patients of whom, 15 were diagnosed with malignant and 6 with benign diseases. In total, 165 measurements were taken (134 healthy; 31 affected). For the diameter, Bland-Altman plots were used to measure data from 165 matched stereoscopic and MD-CT measurement sites (bias, 0.40±2.86 mm SD; percentage error, 33%), 134 healthy sites (bias, 0.554±2.83 mm SD; percentage error, 34%), and 31 affected sites (bias, 1.20±2.67 mm SD; percentage error, 52%). For the cross-sectional area, matched stereoscopic and MD-CT measurements were analyzed for 65 sites (bias, -10.53±92.85 mm SD; percentage error, 89%), 49 healthy sites (bias, -9.88±39.00 mm SD; percentage error, 32%), and 16 affected sites (bias, -13.12±48.81 mm SD; percentage error, 92%). CONCLUSION: Stereoscopic bronchoscopy was able to accurately measure the size of the airway during intervention, to assist in selecting the appropriate size of the stent.

Broncholithiasis Assessed by Bronchoscopic Saline Solution Injection.

A 68-year-old man was admitted with hemoptysis. Bronchoscopy showed bronchial obstruction at the right B(3)bii proximal to the broncholith. The distal end of the bronchoscope was placed in a wedge position at the right B(3)bii. After repeated injection of saline solution through the working channel of the bronchoscope, we observed that the broncholith was freed from the bronchial wall. The broncholith was easily removed with forceps through the working channel of the bronchoscope. Bronchoscopic saline solution injection was safe and effective in confirming the mobility of the broncholith as bronchoscopy alone could not detect the broncholiths due to bronchial occlusion.

Intractable pneumothorax managed by talc pleurodesis and bronchial occlusion with spigots.

Three cases of inoperable secondary spontaneous pneumothorax were diagnosed in patients with chronic obstructive pulmonary disease. Two cases initially underwent bronchial occlusion with endobronchial Watanabe spigot (EWS), while one underwent talc poudrage with pleuroscopy. As air leaks were not stopped completely in all cases with the initial procedures, we performed additional interventional treatments: pleuroscopic talc poudrage in cases when bronchial occlusion was performed first; and bronchial occlusion with EWS for a case that initially underwent talc pleurodesis. The air leaks ceased in all cases without complication. We successfully removed chest tubes 2-10 days after secondary procedure, which was 10-23 days after the first procedure. The combination of talc pleurodesis and bronchial occlusion with EWS, when a single, initial interventional treatment fails, can be considered in cases of intractable, inoperable secondary pneumothorax.

Left and right lung asynchrony as a physiological indicator for unilateral bronchial obstruction in interventional bronchoscopy.

BACKGROUND: In patients with bronchial obstruction, pulmonary function tests may not change significantly after intervention. The airflow asynchrony in both lungs due to unilateral bronchial obstruction may be applicable as a physiological indicator. The airflow asynchrony is reflected by the difference in the left and right lung sound development at tidal breathing. OBJECTIVES: To investigate the usefulness of left and right lung asynchrony due to unilateral bronchial obstruction as a physiological indicator for interventional bronchoscopy. METHODS: Fifty cases with central airway obstruction were classified into three groups: tracheal, bronchial and extensive obstruction. The gap index was defined as the absolute value of the average of gaps between the left and right lung sound intensity peaks for a 12-second duration. RESULTS: Before interventional bronchoscopy, the gap index was significantly higher in the bronchial (p<0.05) and extensive obstruction groups (p<0.05) than in the tracheal group. The gap index in cases with unilateral bronchial obstruction of at least 80% (0.18±0.04 seconds) was significantly higher than in cases with less than 80% obstruction (0.02±0.01 seconds, p<0.05). After intervention for bronchial obstruction, the dyspnea scale (p<0.001) and gap index significantly improved (p<0.05), although no significant improvements were found in spirometric assessments. The responder rates for dyspnea were 79.3% for gap indexes over 0.06 seconds and 55.6% for gap indexes of 0.06 seconds or under. CONCLUSIONS: Assessment of left and right lung asynchrony in central airway obstruction with bronchial involvement may provide useful physiological information for interventional bronchoscopy.

Talc pleurodesis for the management of malignant pleural effusions in Japan.

OBJECTIVE: Malignant pleural effusions are commonly treated with tube drainage followed by chemical pleurodesis to maintain the patient's quality of life. While talc is now accepted to be a worldwide gold-standard sclerosing agent for treating malignant pleural effusion, it is not yet approved in Japan. Instead, many patients are administered OK-432 for pleurodesis, which carries the risk of complications such as high-grade fever, chest pain, anaphylactic shock, interstitial pneumonia and acute renal failure. To assess the efficacy and safety of talc as a sclerosing agent in the management of malignant pleural effusions in Japanese patients. METHODS: Pleurodesis was performed using 4 g of sterile talc with thoracoscopic talc poudrage or the administration of talc slurry via a chest tube in patients with malignant pleural effusions. RESULTS: A total of 57 patients were included. The success rate of pleurodesis assessed on chest radiography at 30, 90 and 180 days was 90.6%, 80.9% and 76.1%, respectively. Complications occurring after talc pleurodesis included fever in 10.5% of the patients and chest pain in 14.0% of the patients. No major complications were reported. CONCLUSION: Talc pleurodesis is an effective and safe treatment for the management of malignant pleural effusion in Japanese patients.

New technique for endobronchial ultrasound-guided transbronchial needle aspiration to improve diagnostic yield.

BACKGROUND: Although the pooled sensitivity of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) using a convex scanning ultrasound bronchoscope is equivalent to the gold standard of mediastinoscopy, diagnosis cannot be obtained in a small number of patients with poor cellularity. The method described was investigated with the aim of avoiding puncturing the cartilage and enabling reliable tissue harvesting, as this can be expected to improve diagnostic yield. METHODS: Outer sheath method (OSM): While pressing the outer sheath (OS) of the puncture needle gently against the bronchial wall, the hyperechoic line appeared on surface of the bronchial wall on EBUS image. Then pulling and pushing the entire bronchoscope, the tip of OS moved to the epithelium above the bronchial cartilage while detecting the best position for puncturing on the EBUS images simultaneously. The bronchoscopist could visualize the cartilage moving longitudinally on EBUS image. The movement of the cartilage was stopped when the tip of the OS was caught in a concavity between 2 rings of cartilage. Group A consisted of 169 patients who underwent EBUS-TBNA before the introduction of OSM, and group B consisted of 169 patients who underwent EBUS-TBNA after the introduction of OSM. These 2 groups were compared with to investigate the usefulness of OSM. RESULTS: Adding this operation enabled a suitable puncture site to be identified, significantly improving diagnostic yield from 92.7% (group A) to 98.2% (group B). CONCLUSIONS: This method was regarded as useful for improving diagnostic yield by enabling the selection of a puncture site between rings of cartilage during EBUS-TBNA.

Cell therapy with adipose tissue-derived stem/stromal cells for elastase-induced pulmonary emphysema in rats.

AIMS: The purpose of this study was to elucidate the mechanism underlying the effects of adipose tissue-derived stem/stromal cell (ASC) transplantation on porcine pancreatic elastase-induced emphysema. MATERIALS & METHODS: ASCs (2.5 × 10(6)) were transplanted into pancreatic elastase (250 U/kg)-treated rats, after which gas exchange and growth factor/cytokine levels in lung tissue were determined. RESULTS: ASC transplantation restored pulmonary function (arterial oxygen tension and alveolar-arterial oxygen tension difference) almost to that of normal animals. Enlargement of the alveolar airspaces was inhibited. HGF and CINC-1 levels were significantly higher in the ASC group even at 2 weeks after transplantation. Sponge implantation with CINC-1 induced neovascular formation with increased HGF. In vitro secretion of HGF and CINC-1 from ASCs was promoted in the presence of IL-1ß. CONCLUSION: Not only HGF, but also CINC-1, secreted from transplanted and viable ASCs presumably contributed to lung repair through angiogenesis.

Novel multimodality imaging and physiologic assessments clarify choke-point physiology and airway wall structure in expiratory central airway collapse.

Choke points and airway wall structure in expiratory central airway collapse are poorly defined. Computed tomography, white light bronchoscopy, endobronchial ultrasound, vibration response imaging, spirometry, impulse oscillometry, negative expiratory pressure, and intraluminal catheter airway pressure measurements were used in a patient with cough, dyspnea, and recurrent pulmonary infections. Computed tomography and white light bronchoscopy identified dynamic collapse of the trachea and mainstem bronchi, consistent with severe crescent tracheobronchomalacia. Spirometry showed severe obstruction. Endobronchial ultrasound revealed collapse of the airway cartilage, and vibration response imaging revealed fluttering at both lung zones. Impulse oscillometry and negative expiratory pressure suggested tidal expiratory flow limitation in the intrathoracic airways. Intraluminal catheter airway pressure measurements identified the choke point in the lower trachea. After Y-stent insertion, the choke point migrated distally. Imaging studies revealed improved airway dynamics, airway patency, and ventilatory function. Novel imaging and physiologic assessments could be used to localize choke points and airway wall structure in tracheobronchomalacia.

Assessing the site of maximal obstruction in the trachea using lateral pressure measurement during bronchoscopy.

RATIONALE: Lateral airway pressure can provide valuable physiological information during bronchoscopy. OBJECTIVES: To evaluate tracheal obstruction during intervention. METHODS: To prospectively measure lateral airway pressure during bronchoscopy using a double-lumen catheter in 15 healthy subjects and 30 patients with tracheal obstruction. Pressure difference was used to evaluate the site of maximal obstruction. The angle between pressure recordings on either side of the stenosis was measured simultaneously (pressure-pressure curves) to assess the degree of tracheal obstruction. MEASUREMENTS AND MAIN RESULTS: In the experimental study, the angle of the pressure-pressure curve was unaffected by breathing maneuvers whereas the pressure difference was affected. In healthy subjects, no pressure difference between the carina and trachea was observed during tidal breathing, and the angle was close to 45°. In patients with tracheal obstruction, the dyspnea scale, pressure difference, and angle changed significantly beyond 50% obstruction (P<0.0001). After stenting, the pressure difference disappeared and the angle was close to 45°. The degree of tracheal obstruction was significantly correlated with the pressure difference (r=0.83, P<0.0001) and angle (r=-0.84, P<0.0001). The cross-sectional area, dyspnea scale, pulmonary function tests, pressure difference, and the angle significantly improved after procedures (P<0.0001). Responder rates on the modified Medical Research Council Scale were 84.6% for obstructions above 80%, and 58.8% for obstructions between 50 and 80%. CONCLUSIONS: The direct measurement of pressure difference and the angle of the pressure-pressure curve represent a new assessment modality for the success of interventional bronchoscopy. Measuring lateral airway pressure could estimate the need for additional procedures better than bronchoscopy alone.

[A case of recurrent Helicobacter cinaedi-associated bacteremia in a small cell lung cancer patient during chemotherapy].

A 46-year-old man was admitted to our hospital, because of cough and exertional dyspnea. We diagnosed small cell lung cancer, clinically staged as T2N3M0, limited disease. Radiation therapy was performed at first to relieve the severe stenosis of the proximal airway, followed by anti-cancer chemotherapy. Fever developed on the fifth day of chemotherapy, and he was successfully treated with intravenous antibiotics. A blood culture yielded Helicobacter cinaedi on the seventh day of incubation. H. cinaedi bacteremia occurred again during the second course of chemotherapy. The same bacteria were also found in his intestinal contents, with no gastrointestinal symptoms. We assume that the bacteria found in the blood was derived from his own intestinal contents. When bacteremia occurs in lung cancer patients during chemotherapy, an uncommon strain such as H. cinaedi is a possible causative agent.

[A case of salazosulfapyridine-induced pneumonitis presenting with multiple pulmonary nodules and lymphadenopathy].

We report a rare case of drug-induced pneumonitis, probably caused by salazosulfapyridine, showing a radiographic pattern of multiple pulmonary nodules and lymphadenopathy. An 18-year-old woman was admitted to our hospital because of fever, skin rash, dry cough and dyspnea on exertion. She had been given salazosulfapyridine for two weeks to treat Crohn's disease. A chest radiograph and computed tomographic scan showed multiple nodular shadows in both lung fields, mediastinal lymphadenopathy, and bilateral pleural effusions. Cessation of salazosulfapyridine followed by corticosteroid therapy led to an immediate symptomatic improvement. The drug-induced lymphocyte stimulation test for salazosulfapyridine was negative. The same symptoms reappeared with rechallenge of SASP, however, which led to diagnosis as salazosulfapyridine-induced pneumonitis. This is apparently the first case report of salazosulfapyridine-induced pneumonitis with a radiographic pattern of multiple pulmonary nodules; accumulation of similar case reports are needed to confirm the association.