Pre-Existing Interstitial Lung Abnormalities Are Independent Risk Factors for Interstitial Lung Disease during Durvalumab Treatment after Chemoradiotherapy in Patients with Locally Advanced Non-Small-Cell Lung Cancer.

Introduction/Background: Chemoradiotherapy (CRT) followed by durvalumab, an immune checkpoint inhibitor, is the standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a life-threatening toxicity caused by these treatments; however, risk factors for the ILD have not yet been established. Interstitial lung abnormalities (ILAs) are computed tomography (CT) findings which manifest as minor interstitial shadows. We aimed to investigate whether ILAs could be risk factors for grade-two or higher ILD during durvalumab therapy. Patients and Methods: Patients with NSCLC who received durvalumab after CRT from July 2018 to June 2021 were retrospectively enrolled. We obtained patient characteristics, laboratory data, radiotherapeutic parameters, and chest CT findings before durvalumab therapy. Results: A total of 148 patients were enrolled. The prevalence of ILAs before durvalumab treatment was 37.8%. Among 148 patients, 63.5% developed ILD during durvalumab therapy. The proportion of patients with grade-two or higher ILD was 33.8%. The univariate logistic regression analysis revealed that older age, high dose-volume histogram parameters, and the presence of ILAs were significant risk factors for grade-two or higher ILD. The multivariate analysis showed that ILAs were independent risk factors for grade-two or higher ILD (odds ratio, 3.70; 95% confidence interval, 1.69−7.72; p < 0.001). Conclusions: We showed that pre-existing ILAs are risk factors for ILD during durvalumab treatment after CRT. We should pay attention to the development of grade-two or higher ILD during durvalumab treatment in patients with ILAs.

Hochuekkito Combined with Pulmonary Rehabilitation in Apathetic Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Pilot Trial.

The main treatment goals for chronic obstructive pulmonary disease (COPD) are the reduction of its symptoms and future risks. The addition of the traditional herbal medicine Hochuekkito (TJ-41) treatment to pulmonary rehabilitation (PR) has been reported to improve dyspnea and health-related quality of life (HRQOL) in patients with COPD. However, the reason for this improvement is not sufficiently understood. The purpose of the present study was to investigate whether the addition of TJ-41 treatment to PR improves symptoms of apathy, dyspnea, and HRQOL and increases physical activity among apathetic patients with COPD. Apathetic patients with COPD were randomly assigned to receive low-intensity exercise with (TJ-41 group) or without (control group) TJ-41 treatment for 12 weeks. A total of 29.9% of COPD patients had apathetic symptoms without severe depression. After the 12-week treatment, Apathy Scale, Patient Health Questionnaire-9, visual analog scale for dyspnea, and COPD assessment test energy scores decreased significantly in the TJ-41 group (p < 0.05), but not in the control group. Additionally, the total number of steps taken was significantly higher in the TJ-41 group than in the control group. TJ-41 combined with PR may benefit apathetic patients with COPD with respect to apathy, dyspnea, HRQOL, and physical activity, but larger randomized placebo-controlled trials are required to validate the findings because of the small sample size and lack of placebo controls in this study.

Gemcitabine maintenance therapy after gemcitabine and platinum drug chemotherapy for naive stage IIIB/IV squamous cell lung cancer: a phase II study.

Platinum doublet is the standard chemotherapy regimen for unresectable nonsmall-cell lung cancer (NSCLC) without a driver mutation. However, for squamous cell lung cancer, the most effective cytotoxic regimen is not yet established. Combination therapy of gemcitabine with a platinum agent is a highly effective treatment among the platinum doublet regimens and is promising as a treatment for advanced squamous cell lung carcinoma. In this study, we prospectively evaluated the efficacy of gemcitabine + platinum combination therapy followed by maintenance gemcitabine monotherapy in untreated advanced squamous cell lung cancer. Patients with squamous cell lung cancer received four cycles of gemcitabine + platinum combination therapy every 3 or 4 weeks. After the induction therapy, gemcitabine maintenance therapy was administered every 3 or 4 weeks until disease progression or unacceptable toxicity. Of 18 patients enrolled, the median progression-free survival was 3.9 months. Only six patients received maintenance chemotherapy with gemcitabine. The median survival time of all enrolled patients was 18.1 months. Cytopenia of any grade occurred in at least 70% of the enrolled patients. However, severe adverse events were observed in only a few cases. Gemcitabine maintenance therapy after gemcitabine plus platinum agents is a suggested treatment for unresectable squamous cell lung cancer. While the overall toxicity profile of this therapy is acceptable, attention should be paid to bone marrow suppression.

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol.

INTRODUCTION: Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. METHODS: We constructed an umbrella-type lung cancer patient registry (CS-Lung-003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS-Lung-003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. DISCUSSION: We successfully launched the umbrella-type CS-Lung-003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. KEY POINTS: CS-Lung-003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment.

Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis.

OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations. MATERIALS AND METHODS: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups. RESULTS: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076-2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510-20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899-2.298) (pinteraction = 0.015). CONCLUSION: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.

Treatment rationale and design of the PROLONG study: safety and efficacy of pembrolizumab as first-line therapy for elderly patients with non-small cell lung cancer.

BACKGROUND: Pembrolizumab is recommended as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a Programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, the safety and efficacy were not investigated among patients who were ≥75 years old. METHODS: This open-label single-arm phase II study is designed to evaluate pembrolizumab as first-line therapy for patients who are ≥75 years old with advanced NSCLC and a PD-L1 TPS of ≥50% without driver mutations. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, objective response rate, safety, and quality of life. Recruitment started in October 2017 and is expected to continue for approximately 3 years. CONCLUSIONS: Given the currently poor prognosis of elderly patients with advanced NSCLC, we hope that the findings of this study will facilitate more effective treatment in this setting.

Multicenter phase II study on cisplatin, pemetrexed, and bevacizumab followed by maintenance with pemetrexed and bevacizumab for patients with advanced or recurrent nonsquamous non-small cell lung cancer: MAP study.

BACKGROUND: We evaluated the safety and efficacy of induction chemotherapy with bevacizumab followed by maintenance chemotherapy with bevacizumab for advanced non-small cell lung cancer (NSCLC) in this multicenter phase II study. METHODS: Chemotherapy-naïve patient with stage IIIB-IV or recurrent nonsquamous NSCLC were eligible. We planned approximately four cycles of induction cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) followed by maintenance with pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) until disease progression. Progression-free survival (PFS) was the primary endpoint. RESULTS: Forty patients received a median of four induction chemotherapy cycles. Of them, 35 (87.5%) patients received a median of nine maintenance chemotherapy cycles. The objective response was 70.6%, and the disease control rate was 97.1%. The median PFS was 10.8 (95% CI, 9.0-12.6), and overall survival was 48.0 (95% CI, 32.9-63.1) months. Median PFS of 23 patients with epidermal growth factor receptor (EGFR) mutations and of 16 patients without EGFR mutations were 12.9 (95% CI, 9.4-16.3) and 7.9 (95% CI, 1.1-14.7) months, respectively. Toxicities graded ≥3 included neutropenia (15%), anemia (15%), hypertension (7.5%), anorexia (7.5%), fatigue (7.5%), thromboembolic events (5%), jaw osteonecrosis (5%), nausea (2.5%), oral mucositis (2.5%), tumor pain (2.5%), hyponatremia (2.5%), and gastrointestinal perforation (2.5%). Treatment-related deaths were not found. CONCLUSIONS: In patients with advanced or recurrent nonsquamous NSCLC, induction chemotherapy with cisplatin, pemetrexed, and bevacizumab followed by maintenance chemotherapy with pemetrexed and bevacizumab is safe and effective regardless of their EGFR mutation status. TRIAL REGISTRATION: UMIN Clinical Trial Registry: UMIN000005569 . Registered date: May 8, 2011.

Effects of Hochuekkito combined with pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) has significant systemic effects, such as weight loss, which affects exercise capacity, health-related quality of life (HRQOL) and survival. The traditional herbal medicine, Hochuekkito (TJ-41), improves the nutritional status and decreases systemic inflammation in patients with COPD. However, to date, the additive effect of TJ-41 on pulmonary rehabilitation (PR) in patients with COPD has not been researched comprehensively. The purpose of the present study was to investigate the efficacy and safety of adding TJ-41 to PR for patients with COPD. Thirty-three malnourished patients with COPD were randomly assigned to receive low-intensity exercise with (TJ-41 group) or without (control group) TJ-41 treatment for 12 weeks. The primary outcome was the change in the 6-min walk distance (6MWD). Secondary outcomes included changes in the body composition, peripheral muscle strength, modified Medical Research Council dyspnea score, visual analog scale (VAS) score for dyspnea, VAS score for fatigue and COPD assessment test (CAT) score. After the 12-week treatment, body weight and percent ideal body weight were significantly increased in the TJ-41 group (P<0.05), but not in the control group. After the 12-week treatment, the modified Medical Research Council dyspnea score, VAS score for dyspnea, VAS score for fatigue and total CAT score decreased significantly in the TJ-41 group (all P<0.05), but not in the control group. There were no significant differences in the 6MWD and peripheral muscle strength between baseline and after 12 weeks of treatment in either group. No adverse effects were noted with the use of TJ-41. It was concluded that the addition of TJ-41 to PR may benefit malnourished patients with COPD with respect to dyspnea and HRQOL.

Lung cancer screening with ultra-low dose CT using full iterative reconstruction.

PURPOSE: To investigate the diagnostic capability of ultra-low-dose CT (ULDCT) with full iterative reconstruction (f-IR) for lung cancer screening. MATERIALS AND METHODS: All underwent ULDCT and/or low-dose CT (LD-CT) on a 320-detector scanner. ULDCT images were reconstructed with f-IR. We qualitatively and quantitatively studied 95 nodules in 69 subjects. Two radiologists classified the nodules on ULDCT images as solid-, part-solid-, and pure ground-glass (PGG) and recorded their mean size. Their findings were compared with the reference standard. The observer performance study included 7 other radiologists and 35 subjects with- and 15 without nodules. The results were analyzed by AFROC analysis. RESULTS: In the qualitative study, the kappa values between observers 1 and 2, respectively, and the reference standard were 0.70 and 0.83; the intra-class correlation coefficients for the nodule diameter between the reference standard and their measurements were 0.84 and 0.90. The 95% confidence interval (CI) for the area under the curve (AUC) difference for nodule detection on LDCT and ULDCT was -0.03 to 0.07. The 95% CI crossed the 0 difference in the AUC but not the pre-defined non-inferiority margin of -0.08. CONCLUSION: The diagnostic ability of ULDCT using f-IR is comparable to LDCT.

Effects of Iterative Reconstruction Algorithms on Computer-assisted Detection (CAD) Software for Lung Nodules in Ultra-low-dose CT for Lung Cancer Screening.

RATIONALE AND OBJECTIVES: This study aimed to evaluate the effects of iterative reconstruction (IR) algorithms on computer-assisted detection (CAD) software for lung nodules in ultra-low-dose computed tomography (ULD-CT) for lung cancer screening. MATERIALS AND METHODS: We selected 85 subjects who underwent both a low-dose CT (LD-CT) scan and an additional ULD-CT scan in our lung cancer screening program for high-risk populations. The LD-CT scans were reconstructed with filtered back projection (FBP; LD-FBP). The ULD-CT scans were reconstructed with FBP (ULD-FBP), adaptive iterative dose reduction 3D (AIDR 3D; ULD-AIDR 3D), and forward projected model-based IR solution (FIRST; ULD-FIRST). CAD software for lung nodules was applied to each image dataset, and the performance of the CAD software was compared among the different IR algorithms. RESULTS: The mean volume CT dose indexes were 3.02 mGy (LD-CT) and 0.30 mGy (ULD-CT). For overall nodules, the sensitivities of CAD software at 3.0 false positives per case were 78.7% (LD-FBP), 9.3% (ULD-FBP), 69.4% (ULD-AIDR 3D), and 77.8% (ULD-FIRST). Statistical analysis showed that the sensitivities of ULD-AIDR 3D and ULD-FIRST were significantly higher than that of ULD-FBP (P < .001). CONCLUSIONS: The performance of CAD software in ULD-CT was improved by using IR algorithms. In particular, the performance of CAD in ULD-FIRST was almost equivalent to that in LD-FBP.

[Case of pulmonary pseudallescheriasis responding successfully to treatment with voriconazole].

A 27-year-old man was admitted with hemoptysis in October 2005. Chest radiograph and CT showed multiple nodules forming a large mass in the left upper lobe. We suspected pulmonary aspergillosis because we detected filamentous fungi made of chains of cells in the bronchial washing fluid. On October 6, therapy with micafungin was initiated. Despite this intervention, the patient's clinical status worsened. On Octorber 11, we suspected pulmonary pseudallescheriasis because we detected colonis resembling white down in Sabouraud agar, thus mica-fungin was discontinued due to the lack of response and we began treatment with voriconazole. The patient's clinical status subsequently improved. We performed a left upper lobectomy, because residual the shadows were recognized on chest CT. Here we report a rare case of pulmonary pseudallescheriasis successfully treated with voriconazole and left upper lobectomy.

Endobronchial ultrasonography with a guide-sheath and virtual bronchoscopy navigation aids management of peripheral pulmonary nodules.

Occasionally, we have difficulty in diagnosing small peripheral pulmonary nodules. However, efforts have been made to resolve this problem. For instance, computed-tomography (CT), positron emission tomography (PET), flexible bronchoscopy examination (BF), and video-assisted thoracic surgery (VATS) have been performed to investigate such nodules. We have used endobronchial ultrasonography with a guide-sheath (EBUS-GS) for BF examination, and recently applied the virtual reality technique "virtual bronchoscopy (VB)". Here, we present a case in which a combined technique with VB and EBUS-GS was useful. The patient was a 54-year-old man with a persistent cough and chest pain. Small nodules were seen in the bilateral lungs on the chest CT taken at the local hospital. A slight increase in the CEA level (6.1 ng/ml; normal level < 5.0 ng/ml) was shown as well as an uptake in the latter term on PET. As a result, he was referred to our hospital for a detailed work-up. We applied VB to confirm the location of the tumor, which allowed us to approach the lesion easily. Furthermore, we precisely localized the lesion using EBUS-GS. Then a biopsy was performed, which demonstrated bronchiolitis obliterans organizing pneumonia (BOOP). As seen in this case, combining VB and EBUS-GS seems beneficial for diagnosing peripheral pulmonary nodules.

Virtual bronchoscopy aids management of lung cancer.

The development of CT scanning has been beneficial for clinical medicine. In this case, virtual bronchoscopy (VB) was of clinical benefit. A 71-year-old woman with suspected lung cancer in the upper left lobe remained undiagnosed after investigation at another hospital. VB was used to confirm the location of the tumour, which facilitated an appropriate trans-bronchial lung biopsy being performed. The volume-rendering technique yielded information regarding an arterial anomaly, allowing high-quality and safe medical treatment to be provided. VB assists navigation in bronchoscopy, and the volume-rendering technique is effective in finding congenital anomalies of the vessels during preoperative assessment.