Real-Time Particle Emission Monitoring for the Non-Invasive Prediction of Lung Deposition via a Dry Powder Inhaler.

Although inhalation therapy represents a promising drug delivery route for the treatment of respiratory diseases, the real-time evaluation of lung drug deposition remains an area yet to be fully explored. To evaluate the utility of the photo reflection method (PRM) as a real-time non-invasive monitoring of pulmonary drug delivery, the relationship between particle emission signals measured by the PRM and in vitro inhalation performance was evaluated in this study. Symbicort® Turbuhaler® was used as a model dry powder inhaler. In vitro aerodynamic particle deposition was evaluated using a twin-stage liquid impinger (TSLI). Four different inhalation patterns were defined based on the slope of increased flow rate (4.9-9.8 L/s2) and peak flow rate (30 L/min and 60 L/min). The inhalation flow rate and particle emission profile were measured using an inhalation flow meter and a PRM drug release detector, respectively. The inhalation performance was characterized by output efficiency (OE, %) and stage 2 deposition of TSLI (an index of the deagglomerating efficiency, St2, %). The OE × St2 is defined as the amount delivered to the lungs. The particle emissions generated by four different inhalation patterns were completed within 0.4 s after the start of inhalation, and were observed as a sharper and larger peak under conditions of a higher flow increase rate. These were significantly correlated between the OE or OE × St2 and the photo reflection signal (p < 0.001). The particle emission signal by PRM could be a useful non-invasive real-time monitoring tool for dry powder inhalers.

Optimal Inhalation Profile of Pressurized Metered Dry Powder Inhaler Using a Valved Holding Chamber: A Dynamic Analysis.

Background: The combined use of a pressurized metered-dose inhaler and valved holding chamber (pMDI+VHC) is recommended to improve efficiency and safety; however, aerosol release is likely to vary with the inhalation maneuver. This in vitro study investigated the aerodynamic characteristics and aerosol release features of pMDI+VHC (Aerochamber, Trudell Medical International). Methods: The static and dynamic changes in the airway resistance (Raw) during inhalation (withdrawal) through pMDI+VHC were measured. Subsequently, the aerosol released from pMDI+VHC was measured using simplified laser photometry during withdrawal with either fast ramp-up then steady or slow ramp-up followed by gradual decrement at different intensities and times to peak flow (TPWF). Results: Raw increased linearly with changes in the withdrawal flow (WF) rate between 10 and 50 L/min. The slope was steep in the low WF range (<50 L/min) and became milder in the higher range. The aerosol mass tended to increase with an increase in the peak WF (PWF) of slow ramp-up profile. When three different WF increment slopes (TPWF: 0.4, 1.4, and 2.4 seconds) were compared, the released aerosol mass tended to decrease, and the aerosol release time was prolonged at longer TPWF. When the PWF was increased, the aerosol release time became shorter, and the withdrawn volume required for 95% aerosol release became larger; however, it did not exceed 0.4 L at suitable TPWF (0.4 seconds). Conclusion: Raw analysis suggests that inhalation at 30-50 L/min is suitable for pMDI+VHC in this setting. Rapid (TPWF, 0.4 seconds) inhalation, but not necessarily long (maximum 2.0 seconds) and deep (but larger than 0.55 L), is also recommended. Practically, direct inhalation to be weaker than usual breathing, as fast as possible, and far less than 2.0 seconds.

Perioperative Evaluation of the Physical Quality of Life of Patients with Non-Small Cell Lung Cancer: A Prospective Study.

Surgery is the most effective treatment for early-stage lung cancer; however, it poses a higher physical burden than other treatment options. Therefore, understanding the perioperative course of patients is important. Using the Short Form Health Survey 36, we prospectively measured the physical quality of life of patients who underwent anatomical pulmonary resection for non-small cell lung cancer at Shonan Kamakura General Hospital, Kanagawa, Japan (n = 87). In the preoperative setting, patients who had lower performance status and lived alone had significantly worse physical quality of life scores on multivariate analysis (regression coefficient (95% confidence interval), -9.37 (-13.43--5.32) and -10.22 (-13.74--7.40), respectively, p < 0.0001 for both). At 6 months postoperatively, patients who stopped smoking within 1 year preoperatively (stopped smoking within 1 year vs. remote or never smokers, 41.0 ± 10.5 vs. 48.6 ± 7.2, p = 0.002), had lower performance status (0 vs. 1-2, 49.3 ± 6.6 vs. 38.6 ± 9.6, p < 0.0001), lived alone (living alone vs. living with somebody, 41.6 ± 9.7 vs. 48.1 ± 7.9, p = 0.021), and had higher comorbid burden (Charlson comorbidity index <3 vs. ≥3, 48.2 ± 6.9 vs. 39.1 ± 14.7, p = 0.003) had significantly worse physical quality of life scores on univariate analysis. More recent smoking (regression coefficient (95% confidence interval), -4.90 (-8.78-1.0), p = 0.014), lower performance status (8.90 (5.10-12.70), p < 0.0001), living alone (5.76 (1.39-10.13), p = 0.01), and higher comorbid burden (-6.94 (-11.78--2.10), p = 0.006) were significant independent predictors of worse postoperative physical quality of life on multivariate analysis. Therefore, patients with these conditions might need additional support to maintain their physical condition after anatomical lung cancer surgery.

Sniff and reverse-sniff nasal respiratory pressures after exacerbation of chronic obstructive pulmonary disease: A single-center prospective study.

BACKGROUND: and objective: This study examined the validity of sniff nasal inspiratory (SNIP) and reverse-sniff nasal expiratory pressures (RSNEP) for estimating respiratory muscle strength and for predicting poor life expectancy following exacerbation in patients with chronic obstructive pulmonary disease (COPD). METHODS: This prospective study included patients who were admitted for COPD exacerbation and underwent rehabilitation. At hospital discharge, SNIP, RSNEP, and maximum mouth inspiratory (MIP) and expiratory pressures (MEP) were measured, and the body mass index, degree of airflow obstruction, dyspnea, and exercise capacity (BODE) index was calculated by evaluating body mass index, forced expiratory volume in 1 s (FEV1), the Modified Medical Research Council Dyspnea Scale, and 6-min walk distance. RESULTS: Data from 43 patients (mean age 76.8 years, FEV1 42.8 % predicted) were analyzed. SNIP and RSNEP were moderately correlated with MIP and MEP, respectively. Bland-Altman plot means of SNIP (48.3 ± 17.5) and RSNEP (44.7 ± 23.8 cmH2O) were lower than those of MIP (54.8 ± 19.9) and MEP (76.4 ± 31.2 cmH2O), respectively, and the SNIP-MIP and RSNEP-MEP 95 % limits of agreement were wide. Logistic regression showed that SNIP and RSNEP were significantly associated with BODE score ≥7 (poor life expectancy), and predictive accuracy was 81.4 % when combining SNIP ≤49 and RSNEP ≤42 cmH2O. CONCLUSION: After exacerbation in patients with COPD, SNIP and RSNEP are useful indicators that complement MIP and MEP. Furthermore, a combined SNIP and RSNEP test may be beneficial in predicting poor life expectancy.

Dynamic Analysis of Aerosol Release from a Pressurized Metered Dose Inhaler Combined with a Valved Holding Chamber Using Simplified Laser Photometry.

Background: A pressurized metered dose inhaler combined with a valved holding chamber (pMDI+VHC) is used to prevent upper airway complications and improve the efficiency of inhaled drug delivery; however, the aerodynamic behavior of the released particles has not been well investigated. This study aimed at clarifying the particle release profiles of a VHC using simplified laser photometry. Methods: An inhalation simulator comprised a computer-controlled pump and a valve system that withdrew aerosol from a pMDI+VHC using a jump-up flow profile. A red laser illuminated the particles leaving VHC and evaluated the intensity of the light reflected by the released particles. Results: The data suggested that the output (OPT) from the laser reflection system represented particle concentration rather than particle mass, and the latter was calculated as OPT × instantaneous withdrawn flow (WF). Summation of OPT hyperbolically decreased with flow increment, whereas summation of OPT × instantaneous flow was not influenced by WF strength. Particle release trajectories consisted of three phases, namely increment with a parabolic curve, flat, and decrement with exponential decay phases. The flat phase appeared exclusively at low-flow withdrawal. These particle release profiles suggest the importance of early phase inhalation. The hyperbolic relationship between WF and particle release time revealed the minimal required withdrawal time at an individual withdrawal strength. Conclusions: The particle release mass was calculated as laser photometric output × instantaneous flow. Simulation of the released particles suggested the importance of early phase inhalation and predicted the minimally required withdrawal time from a pMDI+VHC.

In Vitro Comparison of Two Blister-Type Inhalers.

BACKGROUND: Ellipta is a respiratory device that is a successor of the Diskus. A major difference between the devices is that Ellipta, especially the 2-strip type, includes a pair of blisters rather than a single blister as contained in Diskus. This study aimed to compare the particle-release properties and mechanical features of both devices. METHODS: A pump was used to evacuate air from each dry powder inhaler (DPI) with either a ramp-up or triangular pattern. The particle release volume and peak inspiratory flow of the DPIs were compared. Then the resistance of each component was measured. RESULTS: Both DPIs required specific threshold flows for particle release. Inspiratory flows exceeding the threshold values (Ellipta 11.3 ± 4.0 L/min and Diskus 29.7 ± 4.7 L/min using ramp-up inhalations; Ellipta 10.6 ± 2.1 L/min and Diskus 28.4 ± 5.2 L/min using triangular ones) did not further increase particle release volumes. The inspiratory flows required for Ellipta were significantly less than those for Diskus. The particle release volume exceeding threshold flow for Ellipta was approximately 2.62 (ramp-up) and 2.01 (triangular) times those of Diskus. The resistance of one blister was similar (0.44 cm H2O/L/min vs 0.42 cm H2O/L/min for Ellipta and Diskus, respectively). As Ellipta includes 2 parallel blisters, similar resistances suggest that Ellipta requires twice the flow of Diskus. The flow distributions for particle release in Ellipta and Diskus were 35.3 and 5.2% of the total inspiratory flow, respectively. CONCLUSIONS: The Ellipta required lower inspiratory flow than Diskus, which arises from a higher distribution to blister flow. Ellipta may be preferable to Diskus for patients with impaired pulmonary function.

Daily inhaled flow profiles and drug release from dry powder inhalers in patients with bronchial asthma.

BACKGROUND: Inhalation flow profiles may affect particle release from dry powder inhalers (DPIs). Currently available measures include a limited number of laboratory-measured parameters such as peak inhalation flow (PIF) and inhaled volume (inhV). We aimed to investigate whether parameters obtained under such conditions are valid in real-world settings and determine the effective inhalation profile. METHOD: We included seven asthmatics without recent deterioration and regularly inhaling Turbuhaler® or Diskus®. Daily inhalation profiles and particle release from either DPI were measured at home using a newly designed handy analyzer (real-life inhalation events recorder [RLEFR]), for ≥2 weeks. Inhalation pressure drop and signals of particle release during each inhalation were recorded. RESULTS: All patients inhaled daily with similar patient-specific profiles. The mean PIF and inhV were 91.9-31.6 L/min and 0.84-2.05 L, respectively. PIFs were smaller than those obtained in previous laboratory studies, and only one patient exceeded inhV of 2.0 L. The mean flow acceleration and particle emission were 39-571 L/min/s and 0.37-1.54 s, respectively. Particle release was sporadic in one Turbuhaler® user whose PIF was 31.6 L/min, appearing at 1.55 s of inhalation. Particle release from Turbuhaler® appeared to be PIF-dependent, but that from Diskus® was not. CONCLUSION: Inhalation flow profile measured at home is highly reproducible, but tends to be weaker and shorter than that measured in the laboratory. The results confirm that rapid inhalations from the start are required when using a DPI. RLEFR is a promising device for patient education and clinical studies. TRIAL REGISTRATION NUMBER: UMIN000045193.

Safety and Immunogenicity of mRNA Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Lung Cancer Receiving Immune Checkpoint Inhibitors: A Multicenter Observational Study in Japan.

INTRODUCTION: Patients with cancer have been prioritized for vaccination against severe acute respiratory syndrome coronavirus 2. Nevertheless, there are limited data regarding the safety, efficacy, and risk of developing immune-related adverse events (irAEs) associated with mRNA vaccines in patients with lung cancer, especially those being actively treated with immune checkpoint inhibitors. METHODS: This multicenter observational study was conducted at nine hospitals in Japan. Patients with lung cancer (≥20 y) actively treated with immune checkpoint inhibitors between 4 weeks prefirst vaccination and 4 weeks postsecond vaccination were enrolled. The primary end point was the incidence of irAEs of any grade on the basis of an assumed incidence without vaccination rate of 35%. Immunogenicity was assessed by measuring anti-spike (S)-IgG antibody levels against severe acute respiratory syndrome coronavirus 2. RESULTS: A total of 126 patients with lung cancer (median age, 71 y; interquartile range, 65-74) were enrolled from May to November 2021 and followed up until December 2021. There were 26 patients (20.6%, 95% confidence interval: 13.9%-28.8%) and seven patients (5.6%, 95% confidence interval: 2.3%-11.1%) who developed irAEs of any grade pre- and postvaccination, respectively, which was lower than the predicted incidence without vaccination. None of the patients experienced exacerbation of preexisting irAE postvaccination. S-IgG antibodies were seroconverted in 96.7% and 100% of the patients with lung cancer and controls, respectively, but antibody levels were significantly lower in patients with lung cancer (p < 0.001). CONCLUSIONS: Patients with lung cancer who were actively treated with ICIs were safely vaccinated without an increased incidence of irAEs; however, their vaccine immunogenicity was lower. This requires further evaluation.

[CHARACTERISTICS OF BUDEFORU® FOR BUDESONIDE AND FORMOTEROL MIXTURE].

BACKGROUND: Recently, BudeForu® (BF), a generic of Symbicort Turbuhaler® (SMB), is widely used in Japan. Although appearance of BF resembles to SMB, several differences in length, weight, and side-hole sizes are seen with precise inspection. As particle releases from the inhalation device is strongly influenced by its mechanical characteristics, we compared their particle release patterns. METHODS: An inhalation simulator generated either ramp-up or triangular (time to reach peak inhaling flow (PIF) = 0.42 s) inhalation pattern. Time trajectories of inhaled flow and released particles from either device were depicted with a photo-reflection method. Internal resistances of them were also measured. RESULTS: Particle release patterns of both dry powder inhalers resembled each other. Immediately after release from the inhaler, they reached the peak value and then completed in 0.5 s. In either ramp-up or triangular inspiration pattern, a single burst developed at early inhalation. There were linear relationships between PIFs and emitted doses. The regression lines using ramp-up patters were: Y = 0.00241 X - 0.039, r2 = 0.700, p ＜ 0.0001 (BF), Y = 0.00210 X - 0.038, r2 = 0.654, p ＜ 0.0001 (SMB), and those using triangular patterns were: Y = 0.00223X － 0.0015, r2 = 0.445, p ＜ 0.0001 (BF), and Y = 0.00229X － 0.0023, r2 = 0.687, p ＜ 0.0001 (SMB). Internal resistances of the BF and SMB were 0.105±0.004 and 0.119±0.105 cmH2O0.5/L/min respectively. CONCLUSIONS: Present experimental study suggested that aerodynamic characteristics of BF were quite similar to those of SMB.

Antibody Responses to the BNT162b2 mRNA Vaccine in Healthcare Workers in a General Hospital in Japan: A Comparison of Two Assays for Anti-spike Protein Immunoglobulin G.

Objective This study assessed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody responses to the BNT162b2 mRNA vaccine in Japanese healthcare workers. Methods In this prospective cohort study, participants received two doses of the BNT162b2 mRNA vaccine on days 0 and 21 and provided blood for anti-SARS-CoV-2 antibody testing before the first vaccine and on days 21 and 35 after vaccination. Anti-spike protein immunoglobulin G (S-IgG) was measured using Abbott and Fujirebio chemiluminescent immunoassays. Patients One hundred healthcare workers (median age: 39 years old, interquartile range: 30-48 years old), including 6 who had been previously infected with SARS-CoV-2 and 3 individuals taking immunosuppressive drugs, participated in the study. Results The S-IgG antibody titers (AU/mL) measured using both the Abbott and Fujirebio assays increased significantly (p<0.001) over time, both with a prevalence of 100% at 35 days after the first vaccination. The multivariate log-normal linear regression analysis indicated the effect of immunosuppressant medication using both the Abbott (p=0.013) and Fujirebio (p=0.039) assays on S-IgG levels after complete vaccination. Pearson's correlation coefficient between the Abbott and Fujirebio S-IgG results in all 300 samples collected before and after vaccination and 50 positive controls from patients with coronavirus disease 2019 were 0.963 [95% confidence interval (CI): 0.954-0.970, p<0.001] and 0.909 (95% CI: 0.845-0.948, p<0.001), respectively. Conclusion The BNT162b2 mRNA vaccine was effective at increasing S-IgG levels in Japanese immunocompetent healthcare workers. The Fujirebio S-IgG assay showed high diagnostic accuracy, using the Abbott S-IgG assay as the reference test.

Optimal Inhalation Flow Pattern from Turbuhaler Predicted by Laser Photometry.

Background: The emitted dose (ED) from most dry powder inhalers (DPIs) is almost independent of peak inspiratory flow (PIF) above a certain value, which is specific to the individual DPI. However, the ED of the Turbuhaler® (TBH) increases linearly with PIF increments. This study investigated the powder clearance and clinical utility of TBH performance features by using the photo-reflection method (PRM), a type of laser photometry. Methods: Pulmicort® (PLM) (containing budesonide only) and Symbicort® (SMB) (drugs with lactose particles) were inspired with a ramp-up pattern of several PIF intensities using a vacuum pump. Time trajectories of particle release and PIF were then compared. Results: The particle-release trajectories from both types of DPIs were similar, consisting of a sharp increment phase (∼0.15 seconds) followed by exponential decay. Both onset to the peak of particle-release time and particle-release times were not affected by PIF changes when the PIF was >40 L/min. EDs from both TBHs were linearly related to PIFs, and the slope of the regression equation for SMB was 2.4-fold larger than that of PLM. The peak of the released particles (PKIED) was also linearly related to PIF. A linear relationship was also observed between ED and PKIED in both TBHs, and these regression lines overlapped. Conclusion: EDs from the TBH were dependent on PKIED. Therefore, rapid, initially strong, and deep inhalation should be advised while using the TBH. PRM could measure the fine and small amount of particles released from the TBH.

Antibody responses to SARS-CoV-2 nucleocapsid and spike proteins in hospitalized patients with COVID-19: A multicenter, retrospective, cross-sectional study in Japan.

BACKGROUND: There are many commercially available automated assays for assessing coronavirus disease 2019 (COVID-19) immune responses; however, owing to insufficient data, their validities remain unknown. Here, we examined antibody responses during acute-phase COVID-19 using four assays that detect anti-spike protein IgM (S-IgM), anti-nucleocapsid protein IgG (N-IgG), anti-spike protein total Ig (S-total Ig), and anti-spike protein IgG (S-IgG). METHODS: We measured antibody levels in 1154 serum samples collected from 286 hospitalized patients with confirmed COVID-19 by a gene amplification method between February and December 2020 in Japan. Sera from 860 healthcare workers were used as negative controls. RESULTS: The antibody positivity rates increased on week 2, peaked, and then started to plateau by the beginning of week 3 after symptom onset. On week 1, there were some significant differences in seropositivity rates between assays (p = 0.032): 14.9% (11.0%-19.4%) for S-IgM and 8.9% (6.0%-12.7%) for N-IgG. The seropositivity for the S-total Ig (10.6% [7.3%-14.6%]) assay was considerably better than that for the S-IgG (6.9% [4.3%-10.4%]) assay, although the difference was not statistically significant (p = 0.150). The levels of S-IgM antibodies and the three others peaked on weeks 3 and 5, respectively. All four assays showed high specificities (>99%). CONCLUSIONS: All four assays had good specificities and were suitable for seropositivity detection after week 3 of symptom onset. Assays of IgM alone or total Ig (containing IgM) were better than those of IgG alone as an adjunct serological test for early-stage COVID-19 diagnosis, albeit the use of a serological assay alone is insufficient.

Correcting Photo Reflection Method Output and Its Application in the Dynamic Analysis of Particle Release from Dry Powder Inhalers.

Background: The photo reflection method (PRM) is used to measure light reflected from particles released from dry powder inhalers (DPIs). This simple method depicts time trajectories of released drugs; however, it underestimates the number of particles at high peak inhalation flow rates (PIFs). In this study, we aimed to correct this underestimation and clarify whether long inhalation is necessary for capsule-type DPIs, using this unique method. Methods: To establish quantitative measurements using the PRM, several types of DPIs were inhaled with square-wave inhalations at different PIFs using an inhalation simulator, and the total emitted dose (TED) and the release time of the TED (TTED) were measured. Next, capsule-type DPIs were inhaled using inhalation patterns of patients with chronic obstructive pulmonary disease (COPD), and particle release time trajectories were recorded. Results: For all DPIs, except for Turbuhaler® (TBH), both TED and TTED were hyperbolically decreased with an increase in the PIF of square-wave inhalations. TED correction using the TTED showed flat TED changes at high PIF ranges. The patient inhalation analysis showed that the corrected TEDs of seven COPD inhalation patterns were not significantly different. The PRM further revealed that the inhaled flow rate and release time of all seven patterns were sufficient to release particles in the capsule. Conclusions: The inhaled flow rate and TTED that exceeded specific conditions enabled complete particle release from the DPIs except for TBH. Therefore, an extremely long inhalation is not required for capsule-type DPIs. Our corrected time trajectory analysis using the PRM provides a new strategy for the particle release analysis of DPIs.

Analysis of Drug Release Dynamics of the Reservoir-type Dry Powder Inhalers.

OBJECTIVE: Dry powder inhalers (DPIs) are classified as capsule, blister, and reservoir types. Currently, two reservoir-type DPIs, i.e., TurbuhalerTM (TBH) and GenuairTM (GNA), are available, but their physical characteristics differ. Therefore, we compared their drug release patterns. METHODS: An inhalation f low simulator was set to reach peak inhalation f low (PIF) at two time points, 0.4 s (rapid) or 1.5 s (moderate), and then the drug release from both the DPIs were compared. RESULTS: The amount of drug release from the TBH increased linearly with increase in PIF, and the amounts were higher during rapid inhalation than during moderate inhalation. The GNA had a threshold flow for drug release, above which the flow was PIF-dependent (rapid) or independent (moderate). With rapid inhalation, drug release was dependent on the peak value and releasing time in both the DPIs. With moderate inhalation, the peak flow dependency of the TBH was attenuated, whereas that of the GNA remained time-dependent. CONCLUSION: Rapid and strong inhalation are best for drug release in both the DPIs, but a longer inhalation was required for the GNA. Therefore, if a patient cannot inhale rapidly, then a moderately rapid and long inhalation could be considered, but strong inhalation is still mandatory for TBH.

[IS IT NECESSARY TO PROHIBIT SIDE-HOLE CLOSURE IN USE OF THE DRY POWDER INHALERS?]

BACKGROUND: In use of Ellipta (EPT), Diskus (DKS) or Turbuhaler (TBH), an instruction not to close side holes is sometimes given, but validity of such instruction has not been proved. METHOD: Using an inhalation simulator we measured peak inhaled flow (PIF), peak inhaled pressure (PIP) and amount of the drug release from these DPIs before and after closure of side holes (SHC). In the case of EPT, incomplete obstruction was also assessed. RESULTS: SHC increased internal resistance by 2.8 times in TBH, 1.0 in DKS, and 1.28 (incomplete obstruction) and 1.86 (complete) in EPT. Inhaled flows at pressure of -15cmH2O were 14L/min in TBH, 47 in DKS and 34 in EPT (incomplete obstruction). SHC suppressed drug release from TBH but statistical significance was not obtained. Drug release was not suppressed by SHC in DKS, while it was almost half during SHC in EPT. The level of PIF decreased by SHC was serious since fine particles generation is not expected. Such severe decreases were not found in DKS and EPT. CONCLUSION: SHC severely inhibited drug release from TBH, but almost no effects on DKS. Such negative effect was limited in usual use of EPT.

Pembrolizumab-induced myasthenia gravis with myositis in a patient with lung cancer.

In the new era of cancer immunotherapy, clinical research has uncovered diverse and unpredictable immune-related adverse events. Here, we report the first case of pembrolizumab-induced myasthenia gravis (MG) and myositis in a patient with lung cancer. The patient developed symptoms after the second infusion of pembrolizumab and was successfully treated with systemic corticosteroid therapy. With the accelerated development of immune checkpoint inhibitors as mono- or combination therapies for various malignancies, clinicians should closely monitor patients for important immune-related adverse events, such as MG, especially during the early phase of the treatment.

Diffusion-weighted magnetic resonance imaging-directed biopsy of a metastatic bone tumor: Lung adenocarcinoma with ALK rearrangement.

A previously healthy 44-year-old Japanese man with a 5-month history of lumbago presented to the emergency department with acute respiratory failure caused by pneumonia, and was immediately intubated. Computed tomography revealed a lung mass, pleural effusion, and multiple osteolytic lesions; however, the results of thoracentesis and bronchial brushing were not definitive. We performed a bone tumor biopsy guided by diffusion-weighted magnetic resonance imaging (DW-MRI) with mechanical ventilation, which enabled the diagnosis of ALK rearrangement-positive lung adenocarcinoma. In the era of precision medicine requiring proper biological tissue collection, DW-MRI was critical for identifying the biopsy site safely and with high precision.

Pulmonary lymphangitic carcinomatosis with ground-glass opacities as presentation of prostate cancer.

There is a broad differential diagnosis for interstitial shadows on chest computed tomography in rheumatoid arthritis patients, especially those previously treated with immunosuppressant drugs. We report an immunocompromised rheumatoid arthritis patient in respiratory failure with diffuse ground-glass opacities (GGOs), who was diagnosed with pulmonary lymphangitic carcinomatosis as the initial presentation of prostate cancer. He was successfully treated with chemohormonal androgen deprivation therapy, including bicalutamide, leuprorelin acetate, denosumab, and docetaxel. Metastatic pulmonary lymphangitis, rarely from the prostate, should always be considered in the differential diagnosis of GGOs, even when the patient has no known prior malignancies.