[Patient with Breast Cancer That Developed Severe Drug-Induced Pneumonia after Administration of Trastuzumab Emtansine following Off-Label Use of Nivolumab].

Nivolumab is known to cause immune-related interstitial lung diseases. A 44-year-old woman developed multiple lung metastases 5 years after breast cancer resection. She was treated with docetaxel/trastuzumab/pertuzumab and obtained a complete response. This was a case of off-label use of nivolumab as an immune checkpoint inhibitor evaluated in a private clinic. After standard therapy with T-DM1, she developed fever and hypoxemia. Drug-induced pneumonia was suspected based on a ground-glass shadow finding in chest computed tomography. Drug-induced pneumonia may develop following molecular-targeted therapy delivered after nivolumab administration, and fatal cases have been reported. The antitumor effects of nivolumab for breast cancer have not been proven, and its off-label use may have possible adverse effects on future treatments.

Lung squamous cell carcinoma responding to nivolumab retreatment six years after initial treatment: A case report.

A 61-year-old man presented to our hospital with a chief complaint of chronic cough. He was diagnosed with lung squamous cell carcinoma at clinical stage cT2aN3M1a. He received chemotherapy up to the fourth line, but both the primary tumor and lymph node metastases increased in size. Nivolumab, administered as the fifth line, resulted in a complete response (CR) that continued for 2 years and 8 months. Treatment was stopped due to the appearance of common terminology criteria for adverse events grade 1 pneumonitis. He was followed up without treatment for 3 years and 8 months, but a left supraclavicular fossa lymph node metastasis appeared. Retreatment with nivolumab was initiated, and the patient achieved CR again. One year and 6 months after retreatment, CR was maintained with nivolumab. This case represents a rare instance in which nivolumab yielded a significant response after a prolonged immune checkpoint inhibitor (ICI)-free interval. Our experience has shown that the long-term response to ICIs may deteriorate in the future. Therefore, retreatment with ICIs may be effective when the initial therapy is successful.

Primary lung cancer with pulmonary alveolar proteinosis treated with immune checkpoint inhibitor: A case report.

Primary lung cancer with pulmonary alveolar proteinosis (PAP) is a rare condition. We present a case of a patient with primary lung cancer with PAP treated with an immune checkpoint inhibitor (ICI). A 62-year-old man was diagnosed with autoimmune PAP 8 years prior to current admission. Lung adenocarcinoma was found in his right lung, and platinum-based chemotherapy was administered, followed by atezolizumab. He experienced disease progression after atezolizumab treatment, whereas ICI-induced pneumonia or exacerbation of PAP did not occur. This indicates that ICI may be safely used in patients with primary lung cancer with PAP.

Lipoid Pneumonia Caused by Esophageal Achalasia.

A 59-year-old man presented with esophageal achalasia complicated by lipoid pneumonia. Dysphagia and diffuse ground-glass shadows on computed tomography led to the diagnosis of esophageal achalasia. An analysis of bronchoalveolar lavage (BAL) revealed yellow BAL fluid, with two distinct layers. Oil droplets were observed in the upper layer. Macrophages that phagocytosed lipids were also observed. He was diagnosed with lipoid pneumonia secondary to esophageal achalasia. His lipoid pneumonia improved after peroral endoscopic myotomy because of the reduction in aspiration risk.

Whole lung lavage decreases physiological dead space in patients with pulmonary alveolar proteinosis: two case reports.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by progressive accumulation of the alveolar surfactant. Whole lung lavage (WLL) using a high volume of warmed saline remains the standard therapy. However, no established bedside monitoring tool can evaluate the physiological effect of WLL in the perioperative period. Indirect calorimetry, which is generally used to measure resting energy expenditure, can detect carbon dioxide (CO2) production and mixed-expired partial pressure of CO2 breath by breath. In this physiological study, we calculated CO2 elimination per breath (VTCO2,br) and Enghoff's dead space using indirect calorimetry and measured the extravascular lung water index to reveal the effect of WLL. CASE PRESENTATION: We measured VTCO2,br, Enghoff's dead space, and the extravascular lung water and cardiac indices before and after WLL to assess the reduction in shunt by washing out the surfactant. A total of four WLLs were performed in two PAP patients. The first case involved an Asian 62-year-old man who presented with a 3-month history of dyspnea on exertion. The second case involved an Asian 48-year-old woman with no symptoms. VTCO2,br increased, and the Enghoff's dead space decreased at 12 h following WLL. An increase in the extravascular lung water was detected immediately following WLL, leading to a transient increase in Enghoff's dead space. CONCLUSION: WLL can increase efficient alveolar ventilation by washing out the accumulated surfactant. However, the lavage fluid may be absorbed into the lung tissues immediately after WLL and result in an increase in the extravascular lung water.

Characterization of a spontaneous mouse model of mild, accelerated aging via ECM degradation in emphysematous lungs.

Emphysema limits airflow and causes irreversible progression of chronic obstructive pulmonary disease (COPD). Strain differences must be considered when selecting mouse models of COPD, owing to disease complexity. We previously reported that a novel C57BL/6JJcl substrain, the Mayumi-Emphysema (ME) mouse, exhibits spontaneous emphysema; however, the other characteristics remain unknown. We aimed to characterize the lungs of ME mice and determine their experimental availability as a model. ME mice had a lower body weight than the control C57BL/6JJcl mice, with a median survival time of ~80 weeks. ME mice developed diffused emphysema with respiratory dysfunction from 8 to 26 weeks of age, but did not develop bronchial wall thickening. Proteomic analyses revealed five extracellular matrix-related clusters in downregulated lung proteins in ME mice. Moreover, EFEMP2/fibulin-4, an essential extracellular matrix protein, was the most downregulated protein in the lungs of ME mice. Murine and human EFEMP2 were detected in the pulmonary artery. Furthermore, patients with mild COPD showed decreased EFEMP2 levels in the pulmonary artery when compared to those without COPD. The ME mouse is a model of mild, accelerated aging with low-inflammatory emphysema and respiratory dysfunction that progresses with age and pulmonary EFEMP2 decrease, similar to that observed in patients with mild COPD.

A Retrospective Study of Pneumococcal Pneumonia in Hospitalized Patients Aged ≥65 Years in Izumo, Japan: 2010 to 2014.

Purpose: In Japan, both a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a 13-valent pneumococcal conjugate vaccine (PCV13) are available. Although randomized controlled trials have examined the effects of pneumococcal vaccines, few epidemiological studies have investigated the onset of pneumococcal pneumonia in general practice. In Izumo, Shimane Prefecture, Japan, a public subsidy for PPSV23 inoculation began in November 2012. Patients and Methods: The subjects were pneumonia patients aged 65 and over who were admitted to a hospital in Izumo. This retrospective study analyzed the following data extracted from medical records: pneumococcal pneumonia prevalence, pneumonia severity, mortality rate, PPSV23 vaccination rate, and length of hospital stay. The 2 years before the start of the public subsidy were defined as the early phase, and the 2 years after the subsidy initiation were defined as the late phase. We compared the two phases in terms of PPSV23 vaccination rate, prevalence and severity of pneumococcal pneumonia, and mortality rate. Results: We investigated data from a total of 1188 and 1086 patients in the early and late phases, respectively. The prevalence of pneumococcal pneumonia was 21.0% and 21.3% in the early and late phases, respectively. The mortality rate from pneumococcal pneumonia was 10.4% and 5.4% in the early and late phases, respectively (p = 0.080), indicating a 50% reduction. The PPSV23 vaccination rate (p < 0.001) and the comorbidity rates of chronic respiratory disease (p = 0.022) and chronic renal disease (p < 0.001) were significantly different between the early and late phases. Conclusion: This study showed that the rate of in-hospital deaths due to pneumococcal pneumonia was halved after the PPSV23 vaccine was subsidized. The causal relationship between the pneumococcal vaccination rate and the mortality rate of pneumococcal disease was unclear. Further investigation is deemed necessary.

Cytokine Release Syndrome More than Two Years after Pembrolizumab Introduction: A Case Report.

A 71-year-old man with advanced lung adenocarcinoma was treated with carboplatin, pemetrexed, and pembrolizumab in June 2020. Pemetrexed and pembrolizumab maintenance therapy were continued until November 2022. A fever and severe fatigue occurred in December 2022; however, the cause of the infection was inconclusive based on the patient's symptoms, imaging findings, and culture tests. Although the patient was administered antibiotics, his general condition worsened. Considering the possible diagnosis of immune-related cytokine release syndrome (CRS), the patient was administered prednisolone (1 mg/kg/day) and showed improvement. In conclusion, CRS can occur even long after the initial administration of immune checkpoint inhibitor therapy.

Prospective Real-World Analysis of Asthma Patients With Preserved and Reduced Physical Activity.

BACKGROUND: Asthma is a highly heterogeneous airway disease, and the clinical characteristics of patients with asthma with preserved and reduced physical activity are poorly understood. OBJECTIVE: We aimed to investigate the risk factors and clinical phenotypes associated with reduced physical activity in a wide range of patients with asthma. METHODS: We conducted a prospective observational study of 138 patients with asthma, including patients with asthma without chronic obstructive pulmonary disease (COPD) (n = 104) and asthma-COPD overlap (n = 34), and 42 healthy controls. Physical activity levels were measured for 2 weeks using a triaxial accelerometer at baseline and 1 year later. RESULTS: Higher eosinophils and body mass index (BMI) were associated with reduced physical activity in patients with asthma without COPD. Cluster analysis of asthma without COPD revealed 4 asthma phenotypes. We identified a cluster with preserved physical activity (n = 43) that was characterized by good symptom control and lung function and included a high proportion of biologics users (34.9%). Multivariate regression analysis revealed that patients with late-onset eosinophilic (n = 21), high-BMI noneosinophilic (n = 14), and symptom-predominant asthma phenotypes (n = 26) had lower levels of physical activity than controls. Patients with asthma-COPD overlap also had significantly lower physical activity levels than controls. Similar trends in physical activity levels were observed in each asthma group at 1-year follow-up. CONCLUSION: This study showed the clinical features of patients with asthma with preserved and reduced physical activity. Reduced physical activity was observed in various asthma phenotypes and in asthma-COPD overlap.

Prognosis of frail older patients treated with intubation and artificial ventilation for respiratory failure.

BACKGROUND: Older patients with severe respiratory failure have higher mortality rates and are more likely to experience impairments in activities of daily living (ADL). METHODS: We retrospectively reviewed patients (??75 years) who received intubation and artificial ventilation for respiratory failure at Shimane University Hospital between November 2014 and December 2020. We compared the outcomes of frail patients with those of self-sufficient patients. RESULTS: Thirty-two patients were included. ADL ability before respiratory failure was rated self-sufficient in 18 patients (self-sufficient group) and not self-sufficient in 14 patients (frail group). None of the patients in either group underwent advanced care planning prior to the onset of respiratory failure. In the self-sufficient and frail groups, the in-hospital mortality rates were 33% and 50%, and the incidence of bedridden patients at discharge was 6% and 43%, respectively. Most patients in the frail group (93%) died or were bedridden. The median hospitalization cost was JPY 2,984,000 for the self-sufficient group and JPY 3,008,000 for the frail group. CONCLUSION: The overall prognosis of frail older patients who underwent intubation and artificial ventilation was poor. When providing intensive care to such patients, it is important to carefully consider their suitability for the treatment. J. Med. Invest. 70 : 494-498, August, 2023.

Picropodophyllin inhibits the growth of pemetrexed-resistant malignant pleural mesothelioma via microtubule inhibition and IGF-1R-, caspase-independent pathways.

Background: Acquired pemetrexed resistance leads to treatment interruption in patients with malignant pleural mesothelioma (MPM). Insulin-like growth factor-I receptor (IGF-1R) inhibitor is a candidate for treating pemetrexed-naïve MPM. However, the efficacy of cytotoxic and targeted drugs in acquired-pemetrexed resistant MPM is unclear. We explored anticancer drugs, including the IGF-1R inhibitor picropodophyllin, against acquired pemetrexed-resistant MPMs. Methods: Acquired pemetrexed-resistant human MPM cell lines, named as H2452/PEM and 211H/PEM after their parental lines H2452 and 211H, respectively, were established by exposure to pemetrexed in vitro. Picropodophyllin and siRNA for IGF-1R knockdown were used to evaluate the efficacy of IGF-1R inhibition. Immunofluorescence was used to evaluate microtubule localization. The efficacy of picropodophyllin was evaluated in 3-dimensional MPM models. Results: The acquired pemetrexed-resistant MPM lines retained their resistance after the removal of culture treatment. IGF-1R levels in H2452/PEM cells were higher than those in H2452 cells but not in 211H/PEM cells compared to the respective parental line. Picropodophyllin induced sub-G1 arrest in H2452/PEM cells but induced G2/M phase arrest in 211H/PEM cells, leading to caspase-independent cell death in the two acquired pemetrexed-resistant MPM lines. Although picropodophyllin inhibited phosphorylation of IGF-1R, specific inhibition of IGF-1R by RNA interference did not reduce the viability of pemetrexed-resistant MPM lines. Additionally, picropodophyllin reduced the viability of both IGF-1R knockdown pemetrexed-resistant MPM cells. Picropodophyllin was cytotoxic in acquired-pemetrexed-resistant MPM lines because of inhibition of microtubule formation and induction of aberrant mitosis. Moreover, combination treatment with picropodophyllin and vinorelbine synergistically affected the pemetrexed-resistant MPM lines but not the parental lines. Furthermore, we observed a similar efficacy of picropodophyllin in 3-dimensional pemetrexed-resistant MPM models. Conclusions: Picropodophyllin may offer novel therapeutic properties for treating acquired pemetrexed-resistant MPM. Targeting tubulin may be an important strategy in the treatment of MPM after the discontinuation of pemetrexed.

Deep learning-based diagnosis from endobronchial ultrasonography images of pulmonary lesions.

Endobronchial ultrasonography with a guide sheath (EBUS-GS) improves the accuracy of bronchoscopy. The possibility of differentiating benign from malignant lesions based on EBUS findings may be useful in making the correct diagnosis. The convolutional neural network (CNN) model investigated whether benign or malignant (lung cancer) lesions could be predicted based on EBUS findings. This was an observational, single-center cohort study. Using medical records, patients were divided into benign and malignant groups. We acquired EBUS data for 213 participants. A total of 2,421,360 images were extracted from the learning dataset. We trained and externally validated a CNN algorithm to predict benign or malignant lung lesions. Test was performed using 26,674 images. The dataset was interpreted by four bronchoscopists. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the CNN model for distinguishing benign and malignant lesions were 83.4%, 95.3%, 53.6%, 83.8%, and 82.0%, respectively. For the four bronchoscopists, the accuracy rate was 68.4%, sensitivity was 80%, specificity was 39.6%, PPV was 76.8%, and NPV was 44.2%. The developed EBUS-computer-aided diagnosis system is expected to read EBUS findings that are difficult for clinicians to judge with precision and help differentiate between benign lesions and lung cancers.

Acute Exacerbation of Tracheal Obstruction and Severe Respiratory Failure after a Single Dose of 2-Gy Irradiation for Squamous Cell Lung Carcinoma: A Case Report.

The patient, a 62-year-old woman, complained chiefly of cough. We planned chemoradiotherapy for squamous nonsmall cell lung cancer. A single dose of 2-Gy irradiation and no anticancer agent administration exacerbated the airway stenosis with severe respiratory failure. Urgent tracheal intubation was performed, and a tracheal stent was implanted under extracorporeal membrane oxygenation (ECMO). Because her performance status (PS) worsened from 1 to 2, we administered radiotherapy. The tumor size decreased. There was no recurrence for the next 3 months, and her PS improved to 1. Emergency tracheal intubation and tracheal stent placement under ECMO can be effective for exacerbated airway obstruction after radiotherapy.

Ultra-magnifying Imaging of Thoracoscopic Biopsy Specimens Using Ex vivo Endocytoscopy in Three Patients with Mesothelioma.

We performed endocytoscopy (ECS) for the ex vivo evaluation of mesothelioma in specimens biopsied during medical thoracoscopy in three patients. We evaluated 19 biopsy specimens based on the density of nuclei and irregularity in the nuclei shape using ECS and compared them with the histopathological findings. All 10 specimens considered malignant based on ECS were diagnosed as malignant based on histopathology. The nine specimens evaluated as non-malignant based on ECS consisted of six specimens diagnosed as malignant based on histopathology and three diagnosed as non-malignant based on histopathology. ECS was feasible and had some utility for ex vivo ultra-magnifying imaging of thoracoscopic biopsy specimens from patients with mesothelioma.

Results of 10-year mobile low-dose computed tomography screenings for lung cancer in Shimane, Japan.

BACKGROUND: Some randomized controlled trials have evaluated the effects of low-dose computed tomography (CT) screening on lung cancer mortality in heavy smokers. Based on the results of those trials, our CT screening program recommended screening for people aged ≥40 years with a history of smoking. This retrospective study aimed to verify the validity of our CT screening program and elucidate the current state of CT screening program. METHODS: We retrospectively examined lung cancer detection in 25,189 participants who underwent chest CT screening by a mobile low-dose CT screening unit in the 10-year period from April 2009 to March 2019. Participants were recruited at Japan Agricultural Cooperatives (JA) Shimane Kouseiren. Participants requested CT screening for lung cancer. CT images were read by two pulmonologists. RESULTS: Lung cancer was identified in 82 of the 25,189 participants over 10 years, an overall lung cancer detection rate (percentage of lung cancers detected among all participants) of 0.33%. Lung cancer among never smokers accounted for 54.9% of the detected cases. The lung cancer detection rate was similar for smokers versus never smokers. The stage IA detection rate (percentage of stage IA lung cancers among all lung cancers detected) was 62%, while the stage Ⅳ detection rate was 10%. CONCLUSIONS: Chest CT detected lung cancer in never smokers as well as current or former smokers. Our CT screening program was not effective for never smokers; thus, further study of the effectiveness of CT screening in never smokers is needed.

Reproducible abscopal effect in a patient with lung cancer who underwent whole-brain irradiation and atezolizumab administration.

Due to the emergence of immune checkpoint inhibitors, the abscopal effect has gained more attention. We report a case of extracranial abscopal effect after whole-brain irradiation therapy due to brain metastasis. After the initial abscopal effect was confirmed, a second abscopal effect was confirmed following radiation therapy for bone metastases. This case confirms the reproducibility of the abscopal effect. Moreover, the abscopal effect was not observed in metastatic lesions with low immunogenicity, even in the same patient.

Ability of the Glasgow Prognostic Score to predict the tolerability and efficacy of platinum-combination chemotherapy among elderly patients with advanced non-small cell lung cancer.

Background : Although platinum-combination chemotherapy is widely used to treat advanced non-small cell lung cancer (NSCLC), not all elderly patients benefit from this regimen. In this retrospective study, we aimed to evaluate whether the Glasgow Prognostic Score (GPS), an indicator of systemic inflammation and malnutrition, could predict the tolerability and efficacy of platinum-combination chemotherapy among elderly patients with NSCLC. Methods : The eligibility criteria included patients aged ≥ 70 years with NSCLC treated with first-line platinum-combination chemotherapy at Shimane University Hospital between January 2015 and December 2018. Results : Thirty-two patients with NSCLC (median age, 74 years) were included. The GPS scores were 0-1 for 19 patients and 2 for 13 patients. Four chemotherapy cycles were completed by 57.9% and 30.8% of patients in the GPS 0-1 and GPS 2 groups, respectively. The GPS 0-1 group experienced better outcomes than the GPS 2 group (response rate : 26% vs. 15%, P = 0.67 ; median progression-free survival : 4.1 vs. 2.1 months, P = 0.0026 ; median overall survival : 22.8 vs. 9.6 months, P = 0.0092). Conclusions : Platinum-combination chemotherapy demonstrated promising efficacy among elderly NSCLC patients with a GPS 0-1. Therefore, GPS may be crucial in determining whether treatments recommended for younger patients are suitable for older patients with NSCLC. J. Med. Invest. 68 : 260-264, August, 2021.

Comparative postoperative outcomes of GGN-dominant vs single lesion lung adenocarcinomas.

BACKGROUND: Multiple synchronous ground glass nodules (GGNs) are known to be malignant, however, they tend to progress slowly. Multiple synchronous lesions in the same patient which show different characteristics must be treated individually. METHODS: This was a retrospective review of 34 lung adenocarcinoma patients with multiple synchronous GGNs in an Asian population. One hundred twenty-seven single lung adenocarcinoma patients were included for comparison purposes. The follow-up period was 5 years for all patients. RESULTS: The 5-year overall survival (OS) patients with multiple lesions did not differ from that of the patients with single lesions to a statistically significant extent (Single: 81.8% vs. Multiple: 88.2%, P = 0.3602). Dominant tumors (DTs) with a ground glass component and consolidation were divided into three categories based on the consolidation-to-tumor ratio on radiological imaging. No significant differences were observed among the three DT categories. Twenty-four patients had unresected GGNs, while a progression of the unresected GGN occurred in 10 of these cases. The OS and disease-free survival (DFS) curves of patients with and without GGN progression did not differ to a statistically significant extent (OS: 80% vs. 92.9%, P = 0.3870; DFS: 80% vs. 100%, P = 0.0977). CONCLUSIONS: The outcomes were best predicted by the stage of the DT. After surgery patients require a careful follow-up because unresected GGNs may show progression. At the same time, the increase in residual lesions and the appearance of new GGNs were not related to OS. The management of such patients should be determined according to the DT with the worst prognosis.

Anticancer Activity of ZnO Nanoparticles against Human Small-Cell Lung Cancer in an Orthotopic Mouse Model.

Small-cell lung cancer, a highly malignant form of lung cancer, often responds to first-line treatments but relapses in most cases with resistance to further treatments. We tested zinc oxide (ZnO) nanoparticles against small-cell lung cancer and other cancer cell lines, in light of reported anticancer effects in vitro Because of a strong safety record, ZnO nanoparticles are frequently used in biomedical research, including in cellular imaging and drug delivery, and have been used for many years in several commercial products such as skin care agents. Strikingly, ZnO nanoparticles were genotoxic against small-cell lung cancer cells, resulting in low viability, even in cells orthotopically grafted onto mouse models. However, the nanoparticles were less cytotoxic against normal lung-derived cells and did not elicit observable adverse effects after intravenous administration. ZnO nanoparticles were also found to induce highly reactive oxygen species and DNA leakage from nuclei. This study is the first comprehensive evaluation of the anticancer effects of ZnO nanoparticles in vitro and in vivo and highlights new therapeutic opportunities against small-cell lung cancer.

Therapeutic bronchoscopy in a lung abscess secondary to broncholithiasis.

A 60-year-old woman developed a pulmonary abscess due to broncholithiasis. It was treated by bronchoscopic broncholithectomy after antibiotic administration. Broncholithiasis is a rare disease and various treatment options are available, which include bronchoscopic broncholithectomy and surgery. Bronchoscopic broncholithectomy has proved to be more useful because it can be used to easily extract the broncholith by using a balloon and haemostasis can be obtained at the same time.