High red blood cell distribution width attenuates the effectiveness of Immune checkpoint inhibitor therapy: An exploratory study using a clinical data warehouse.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes in cancer treatment but are also associated with adverse events and financial burdens. Identifying accurate biomarkers is crucial for determining which patients are likely to benefit from ICIs. Current markers, such as PD-L1 expression and tumor mutation burden, exhibit limited predictive accuracy. This study utilizes a Clinical Data Warehouse (CDW) to explore the prognostic significance of novel blood-based factors, such as the neutrophil-to-lymphocyte ratio and red cell distribution width (RDW), to enhance the prediction of ICI therapy benefit. METHODS: This retrospective study utilized an exploratory cohort from the CDW that included a variety of cancers to explore factors associated with pembrolizumab treatment duration, validated in a non-small cell lung cancer (NSCLC) patient cohort from electronic medical records (EMR) and CDW. The CDW contained anonymized data on demographics, diagnoses, medications, and tests for cancer patients treated with ICIs between 2017-2022. Logistic regression identified factors predicting ≤2 or ≥5 pembrolizumab doses as proxies for progression-free survival (PFS), and Receiver Operating Characteristic analysis was used to examine their predictive ability. These factors were validated by correlating doses with PFS in the EMR cohort and re-testing their significance in the CDW cohort with other ICIs. This dual approach utilized the CDW for discovery and EMR/CDW cohorts for validating prognostic biomarkers before ICI treatment. RESULTS: A total of 609 cases (428 in the exploratory cohort and 181 in the validation cohort) from CDW and 44 cases from EMR were selected for study. CDW analysis revealed that elevated red cell distribution width (RDW) correlated with receiving ≤2 pembrolizumab doses (p = 0.0008), with an AUC of 0.60 for predicting treatment duration. RDW's correlation with PFS (r = 0.80, p<0.0001) and its weak association with RDW (r = -0.30, p = 0.049) were confirmed in the EMR cohort. RDW also remained significant in predicting short treatment duration across various ICIs (p = 0.0081). This dual methodology verified pretreatment RDW elevation as a prognostic biomarker for shortened ICI therapy. CONCLUSION: This study suggests the utility of CDWs in identifying prognostic biomarkers for ICI therapy in cancer treatment. Elevated RDW before treatment initiation emerged as a potential biomarker of shorter therapy duration.

Improved diagnostic accuracy with three lung tumor markers compared to six-marker panel.

Background: Combining multiple tumor markers increases sensitivity for lung cancer diagnosis in the cost of false positive. However, some would like to check as many as tumor markers in the fear of missing cancer. We though to propose a panel of fewer tumor markers for lung cancer diagnosis. Methods: Patients with suspected lung cancer who simultaneously underwent all six tests [carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA), squamous cell carcinoma-associated antigen (SCC), neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), and sialyl Lewis-X antigen (SLX)] were included. Tumor markers with significant impact on the lung cancer in a logistic regression model were included in our panel. Area under the curve (AUC) was compared between our panel and the panel of all six. Results: We included 1,733 [median 72 years, 1,128 men, 605 women, 779 (45%) confirmed lung cancer]. Logistic regression analysis suggested CEA, CYFRA, and NSE were independently associated with the lung cancer diagnosis. The panel of these three tumor markers [AUC =0.656, 95% confidence interval (CI): 0.630-0.682, sensitivity 0.650, specificity 0.662] had better (P<0.001) diagnostic performance than six tumor markers (AUC =0.575, 95% CI: 0.548-0.602, sensitivity 0.829, specificity 0.321). Conclusions: Compared to applying all six markers (at least one marker above the upper limit of normal), the panel with three markers (at least one marker above the upper limit of normal) led to a better predictive value by lowering the risk of false positives.

Real-world evidence of efficacy of pembrolizumab plus chemotherapy and nivolumab plus ipilimumab plus chemotherapy as initial treatment for advanced non-small cell lung cancer.

BACKGROUND: For advanced non-small cell lung cancer (NSCLC), combination therapies including a PD-1 inhibitor plus chemotherapy or a PD-1 inhibitor, CTLA-4 inhibitor, and chemotherapy are standard first-line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real-world setting. METHODS: In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first-line therapies in 182 patients with stage IIIB-IV NSCLC. Primary outcomes were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan-Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD-L1 expression. RESULTS: In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3-4 adverse events occurred comparably, but immune-related adverse events were numerically more frequent in the CNI group. CONCLUSIONS: In real-world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC.

Nintedanib plus Chemotherapy for Small Cell Lung Cancer with Comorbid Idiopathic Pulmonary Fibrosis.

Rationale: A fatal acute exacerbation (AE) occasionally develops during chemotherapy for small cell lung cancer (SCLC) with comorbid idiopathic pulmonary fibrosis (IPF).Objectives: This study aimed to assess the safety and efficacy of carboplatin, etoposide, and nintedanib combination therapy for unresectable SCLC with comorbid IPF.Methods: The NEXT-SHIP study is a multicenter, single-arm, phase 2 trial for unresectable SCLC with IPF (Japan Registry of Clinical Trials registry number jRCTs031190119). The patients received carboplatin, etoposide, and nintedanib (150 mg twice daily). The primary endpoint was the incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy, and the sample size was set at 33 (5.0% expected, 20.0% threshold).Results: A total of 33 patients were registered; 87.9% were male, the median age was 73 years, the median percentage forced vital capacity was 85.2%, and 51.5% had honeycomb lungs. The median observation period was 10.5 months. The incidence of IPF-AE at 28 days after the last administration of cytotoxic chemotherapy was 3.0% (90% confidence interval [CI], 0.2-13.6). The objective response rate was 68.8% (95% CI, 50.0-83.9). The median progression-free survival and overall survival times were 4.2 months (95% CI, 4.2-5.5) and 13.4 months (95% CI, 8.1-21.6), respectively. The most common adverse event of grade 3 or higher was neutropenia (81.8%), followed by leukopenia (39.4%) and thrombocytopenia (30.3%).Conclusions: This study met its primary endpoint regarding the incidence of IPF-AEs with promising results for efficacy. Carboplatin, etoposide, and nintedanib combination therapy may be one of the standard treatment options for SCLC with comorbid IPF.Clinical trial registered with the Japan Registry of Clinical Trials (jRCTs031190119).

Favourable surgical outcomes for either second primary lung cancer or intrapulmonary metastasis after resection of non-small-cell lung cancer.

OBJECTIVES: Metachronous lung cancer arising after resection of non-small-cell lung cancer is either a second primary lung cancer (SPLC) or intrapulmonary metastasis (IPM) of the initial lung cancer; however, differential diagnosis is difficult. We evaluated the surgical outcomes of metachronous lung cancer in a combined population of patients with SPLC and IPM. METHODS: A retrospective study of 3534 consecutive patients with resected non-small-cell lung cancer between 1992 and 2016 was conducted at 4 institutions. RESULTS: A total of 105 patients (66 males; median age, 70 years) who underwent a second pulmonary resection for metachronous lung cancer were included. Most patients (81%) underwent sublobar resection, and there was no 30-day mortality. All metachronous lung cancers were cN0, 5 were pN1-2. The postoperative comprehensive histologic assessment revealed SPLC (n = 77) and IPM (n = 28). The 5-year overall survival rate after the second resection was 70.6% (median follow-up: 69.7 months). A multivariable analysis showed that age >70 years at the second resection (P = 0.013), male sex (P = 0.003), lymph node involvement in metachronous cancer (P < 0.001), pathological invasive size of metachronous cancer >15 mm (P < 0.001) and overlapping squamous cell carcinoma histology of the initial and metachronous cancers (P = 0.003) were significant prognostic factors for poor survival after the second resection, whereas histological IPM was not (P = 0.065). CONCLUSIONS: Surgery for cN0 metachronous lung cancer is safe and shows good outcomes. There were no statistically significant differences in the SPLC and IPM results. Caution should be exercised when operating on patients with overlapping squamous cell carcinoma.

ILD-GAP combined with the monocyte ratio could be a better prognostic prediction model than ILD-GAP in patients with interstitial lung diseases.

BACKGROUND: The ILD-GAP scoring system is known to be useful in predicting prognosis in patients with interstitial lung disease (ILD). An elevated monocyte count was associated with increased risks of IPF poor prognosis. We examined whether the ILD-GAP scoring system combined with the monocyte ratio (ILD-GAPM) is superior to the conventional ILD-GAP model in predicting ILD prognosis. METHODS: In patients with ILD treated between April 2013 and April 2017, we were retrospectively assessed the relationships between baseline clinical parameters, including age, sex, Charlson Comorbidity Index score (CCIS), ILD diagnosis, blood biomarkers, pulmonary function test results, and disease outcomes. In ILD patients were included idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD). We also assessed the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPM models. RESULTS: A total of 179 patients (mean age, 73 years) were assessed. All of them were taken pulmonary function test, including percentage predicted diffusion capacity for carbon monoxide. ILD patients included 56 IPF cases, 112 iNSIP and CVD-IP cases, 6 CHP cases and 5 UC-ILD cases. ILD-GAPM provided a greater area under the receiver-operating characteristic curve (0.747) than ILD-GAP (0.710) for predicting 3-year ILD-related events. Furthermore, the log-rank test showed that the Kaplan-Meier curves in ILD-GAPM were significantly different by stage (P = 0.015), but not by stage in ILD-GAP (P = 0.074). CONCLUSIONS: The ILD-GAPM model may be a more accurate predictor of prognosis for ILD patients than the ILD-GAP model.

A Phase â ¡ Study of Ubenimex Combined With Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small-Cell Lung Cancer: TORG2241 (UBE-Q).

BACKGROUND: According to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non-small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. PATIENTS AND METHODS: This prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee. CONCLUSIONS: This is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies.

Tailoring Therapeutic Strategies in Non-Small-Cell Lung Cancer: The Role of Genetic Mutations and Programmed Death Ligand-1 Expression in Survival Outcomes.

BACKGROUND: This study aims to assess the real-world impact of advancements in first-line systemic therapies for non-small-cell lung cancer (NSCLC), focusing on the role of driver gene mutations and programmed death-ligand 1 (PD-L1) expression levels. METHODS: Conducted across eight medical facilities in Japan, this multicenter, retrospective observational research included 863 patients diagnosed with NSCLC and treated between January 2015 and December 2022. The patients were categorized based on the type of systemic therapy received: cytotoxic agents, molecular targeting agents, immune checkpoint inhibitors, and combination therapies. Comprehensive molecular and immunohistochemical analyses were conducted, and statistical evaluations were performed. RESULTS: The median overall survival (OS) shows significant variations among treatment groups, with targeted therapies demonstrating the longest OS. This study also revealed that high PD-L1 expression was common in the group treated with immune checkpoint inhibitors. Multivariate analysis was used to identify the type of anticancer drug and the expression of PD-L1 at diagnosis as the impactful variables affecting 5-year OS. CONCLUSIONS: This study underscores the efficacy of targeted therapies and the critical role of comprehensive molecular diagnostics and PD-L1 expression in affecting OS in NSCLC patients, advocating for their integration into routine clinical practice.

Atezolizumab addition to platinum doublet: evaluating survival outcomes for patients with extensive disease small cell lung cancer.

BACKGROUND: The efficacy of adding atezolizumab to the platinum doublet regimen for extensive disease small cell lung cancer (ED-SCLC) remains marginally limited. METHODS: We retrospectively assessed the real-world efficacy and safety of atezolizumab in addition to carboplatin and etoposide (EP + A), versus carboplatin and etoposide (EP) alone in previously untreated ED-SCLC patients. RESULTS: From a total of 99 patients, 46 were assigned to the EP + A group, and 53 to the EP group. No significant difference was observed in progression-free survival between the groups. However, the overall survival (OS) was significantly longer in the EP + A group (20.8 vs 12.1 months; HR: 0.52; p = 0.0127). Patients older than 70 years, male, with performance status 0-1, without liver metastasis, and low levels of C-reactive protein and neutrophil-lymphocyte ratio, experienced longer OS in the EP + A group compared to the EP group. CONCLUSION: The addition of atezolizumab to the platinum doublet regimen significantly extended OS in ED-SCLC patients, particularly among certain subgroups, suggesting its potential value in personalized treatment strategies. Further investigation is warranted to validate these findings.

Adverse events induced by durvalumab and tremelimumab combination regimens: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have shown remarkable therapeutic outcomes among cancer patients. Durvalumab plus tremelimumab (DT) is under investigation as a new ICI combination therapy, and its efficacy has been reported in various types of cancer. However, the safety profile of DT remains unclear, especially considering rare adverse events (AEs). Objective: We aimed to assess the frequency of AEs associated with DT. Design: This study type is a systematic review and meta-analysis. Data Sources and Methods: Four databases were searched for articles. Randomized trials, single-arm trials, and prospective and retrospective observational studies were included. The type of cancer, previous treatment, and performance status were not questioned. Major AE indicators such as any AE and the pooled frequency of each specific AE were used as outcomes. As a subgroup analysis, we also compared cases in which DT was performed as first-line treatment with those in which it was performed as second-line or later treatment. The protocol for this systematic review was registered on the University Hospital Medical Information Network (UMIN) Center website (ID: UMIN000046751). Results: Forty-one populations including 3099 patients were selected from 30 articles. Pooled frequencies of key AE indicators are shown below: any AEs, 77.8% [95% confidence interval (CI): 67.9-87.6]; grade ⩾ 3 AEs, 29.3% (95% CI: 24.2-34.4); serious AEs, 34.9% (95% CI: 28.1-41.7); AE leading to discontinuation, 13.3% (95% CI: 9.3-17.4); treatment-related deaths, 0.98% (95% CI: 0.5-1.5). AEs with a frequency exceeding 15% are shown below: fatigue, 30.1% (95% CI: 23.8-36.3); diarrhea, 21.7% (95% CI: 17.8-25.6); pruritus 17.9% (95% CI: 14.4-21.3); decreased appetite, 17.7% (95% CI: 13.7-22.0); nausea, 15.6% (95% CI: 12.1-19.6). There were no significant differences in these pooled frequencies between subgroups. Conclusions: The incidence of any AE in DT therapy was approximately 78%, and the incidence of grade 3 or higher AEs was approximately 30%, which was independent of prior therapy.

Comparison of the slow-pull and aspiration methods of endobronchial ultrasound-guided transbronchial needle aspiration for next-generation sequencing-compatible tissue collection in non-small cell lung cancer.

BACKGROUND: Personalized treatment for non-small cell lung cancer (NSCLC) has advanced rapidly, and elucidating the genetic changes that trigger this disease is crucial for appropriate treatment selection. Both slow-pull and aspiration methods of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are accepted methods for collecting samples suitable for next-generation sequencing (NGS) to examine driver gene mutations and translocations in NSCLC. Here, we aimed to determine which of these two methods is superior for obtaining higher-quality samples from patients with NSCLC. METHODS: Seventy-one patients diagnosed with NSCLC via EBUS-TBNA using the slow-pull or aspiration (20-mL negative pressure) methods between July 2019 and September 2022 were included. A total of 203 tissue samples from the 71 patients were fixed in formalin, embedded in paraffin, and mounted on slides. The presence of tissue cores, degree of blood contamination, and number of tumor cells were compared between the groups. The success rate of NGS, using Oncomine Dx Target Test Multi-CDx, was also compared between the groups. RESULTS: The slow-pull method was associated with a higher yield of tissue cores, lower degree of blood contamination, and higher number of tumor cells than the aspiration method. The success rate of the NGS was also significantly higher for the slow-pull group (95%) than for the aspiration group (68%). CONCLUSION: Overall, these findings suggest that the slow-pull method is a superior technique for EBUS-TBNA to obtain high-quality tissue samples for NGS. The slow-pull method may contribute to the identification of driver gene mutations and translocations and facilitate personalized treatment of NSCLC.

The clinical impact of comorbidities among patients with idiopathic pulmonary fibrosis undergoing anti-fibrotic treatment: A multicenter retrospective observational study.

BACKGROUND: Among patients with idiopathic pulmonary fibrosis (IPF), few studies have investigated the clinical impact of anti-fibrotic treatment (AFT) with and without comorbidities. The aim of the study was to determine whether Charlson Comorbidity Index score (CCIS) can predict the efficacy of AFT in patients with IPF. METHODS: We retrospectively assessed data extracted from the medical records of IPF patients who received anti-fibrotic agents between 2009 and 2019. The collected data included age, sex, CCIS, pulmonary function test, high-resolution computed tomography (HRCT) pattern, gender/age/physiology (GAP) score, and 3-year IPF-related events defined as the first acute exacerbation or death within 3 years after starting AFT. RESULTS: We assessed 130 patients (median age, 74 years) who received nintedanib (n = 70) or pirfenidone (n = 60). Median duration of AFT was 425 days. Patients were categorized into high (≥ 3 points) and low (≤ 2 points) CCIS groups. There was no significant difference between the groups in terms of age, sex, duration of AFT, GAP score, or incidence of usual interstitial pneumonia pattern on HRCT except percentage predicted diffusion capacity of lung for carbon monoxide. Also, significant difference was not seen between the groups for 3-year IPF-related events (P = 0.75). Especially, in the low CCIS group but not the high CCIS group, the longer duration of AFT had better disease outcome. CONCLUSION: In the present study, we could not show any relation between CCIS and IPF disease outcomes in patients undergoing AFT, though the longer duration of AFT might be beneficial for IPF outcomes among patients with low CCIS.

Predictors of lung injury during durvalumab maintenance therapy following concurrent chemoradiotherapy in unresectable locally advanced non-small cell lung carcinoma.

BACKGROUND: Based on the results of the PACIFIC trial, maintenance with durvalumab has emerged as the standard treatment following concurrent chemoradiotherapy in patients with unresectable locally advanced non-small cell lung carcinoma (NSCLC). However, adverse events attributed to durvalumab, especially lung injuries, including immune-related adverse events, and radiation pneumonitis, are concerning. This study retrospectively investigated the factors related to lung injury in patients receiving the PACIFIC regimen. METHODS: Patients with unresectable locally advanced NSCLC who received durvalumab maintenance therapy following concurrent chemoradiotherapy at Yokohama City University Medical Centre between July 2018 and March 2022 were included. Clinical data, volume of normal lung receiving 20 or 5 Gy or more (V20 or V5), planning target volume (PTV), and relative lung parenchyma volume in emphysematous lung receiving 20 or 5 Gy or more (RLPV20 or 5; V20 or V5/100-percentage of low-attenuation volume) were evaluated. RESULTS: Performance status (PS), V20, V5, PTV, RLPV20, and RLPV5 were significantly higher in the lung injury group in the univariate analysis. Furthermore, RLPV20 was the most significant factor in the lung injury group in the multivariate analysis comprising PS, PTV, V20, and RLPV20. CONCLUSION: RLPV20 and RLPV5 are useful in estimating lung inflammation. RLPV20 could be considered the most reliable risk factor for maintenance therapy with durvalumab following concurrent chemoradiotherapy in patients with unresectable locally advanced NSCLC.

Association of PD-L1 tumor proportion score ≥20% with early resistance to osimertinib in patients with EGFR-mutated NSCLC.

BACKGROUND: The relationship between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance, including osimertinib, and programmed cell death-ligand 1 (PD-L1) expression status in EGFR-mutated non-small cell lung carcinoma (NSCLC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 64 patients with unresectable advanced or metastatic NSCLC carrying EGFR exon 19 deletions (ex19del) or EGFR exon 21 L858R substitutions (L858R) who received osimertinib as the first-line treatment. We compared progression-free survival (PFS) between eligible patients with PD-L1 tumor proportion scores (TPS) ≥20% and PD-L1 TPS <20% using the Kaplan-Meier survival plots with a log-rank test. Multivariate analysis was performed to examine the poor prognostic factors of PFS. RESULTS: The PD-L1 TPS ≥20% group included 22 cases (median [range] age: 70.5 [33-86] years; 10 women [45.5%]; 11 current or ex-smokers [50%]); ECOG performance status (PS) of 0-1/2/3/4 was noted in 16/4/1/1 patients, respectively. The PD-L1 TPS <20% group included 42 patients (median [range] age 73 [43-88] years; 29 women [69%]; 12 current or ex-smokers [28.6%]); ECOG PS of 0-1/2/3/4 was noted in 33/6/3/0 cases, respectively. The median PFS was 9.1 and 28.1 months in the PD-L1 TPS ≥20% and PD-L1 TPS <20% groups, respectively (log-rank p = 0.013). Multivariate analysis revealed that PD-L1 TPS ≥20% was associated with PFS (hazard ratio: 2.35, 95% confidence interval: 1.09-5.08, p = 0.030). CONCLUSION: PD-L1 TPS ≥20% in patients with EGFR-mutated NSCLC may be associated with early resistance to osimertinib.

Recurrent Transient Asymptomatic Pulmonary Opacity with Long-Term Afatinib: A Case Report.

Afatinib is the second generation EGFR-TKI. Recently, transient asymptomatic pulmonary opacity (TAPO) was reported in EGFR-mutation harboring NSCLC receiving osimertinib. However, TAPO related to other EGFR-TKI has not been reported. Here, we reported a case of TAPO related to afatinib in lung adenocarcinoma harboring EGFR mutation. A 64-year-old male had the diagnosis of stage IV (The 7th edition of the staging system by the Union for International Cancer Control) lung adenocarcinoma harboring EGFR del 19 mutation. He received afatinib 40 mg per day from May 2015. Partial response was achieved, though the dose was reduced to 30 mg per day due to grade 3 rash. In January 2016, CT showed ground glass opacity in the right middle lobe, which resolved spontaneously 2 weeks later. He had no symptom and laboratory findings were not remarkable. Thereafter, recurrent GGO was revealed with chest CT, but all opacity improved without any medication (i.e., corticosteroids) or stopping afatinib. Therefore, we diagnosed a series of opacity as recurrent TAPO with afatinib. TAPO could occur with EGFR-TKI other than osimertinib. Further study is needed to establish the management of new opacity suggesting TAPO under EGFR-TKI treatment.

Thymic atypical carcinoid tumors with elevated mitotic counts in a patient with multiple endocrine neoplasia: A case report.

Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large-cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC-h), an intermediate condition between carcinoid and LCNEC. A 27-year-old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti-programmed death-ligand 1 antibody and platinum-containing chemotherapy. The needle biopsy specimen was submitted for next-generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re-examination of the surgical specimen from 15 years prior showed that it corresponded to AC-h. Although thymic AC-h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.

Primary tracheal small-cell carcinoma detected 11 months after surgery for pulmonary large-cell neuroendocrine carcinoma: A case report.

Primary tracheal small-cell carcinoma is rare, and is often treated using small-cell lung cancer guidelines given that no standard treatment has been established for it. We report a patient in whom nodules appeared in the trachea and left main bronchus 11 months after surgery for pulmonary large-cell neuroendocrine carcinoma; a biopsy revealed small-cell carcinoma. Given the absence of malignant lesions elsewhere in the body, the lesions were diagnosed as primary tracheal small-cell carcinoma. Respiratory failure progressed rapidly owing to airway stenosis caused by the growing lesion, and the patient required nasal high-flow therapy. However, the lesions shrank a few days after commencing first-line chemotherapy, and his respiratory failure resolved. Accelerated hyperfractionated radiotherapy was administered in conjunction with the third course of chemotherapy, and the patient ultimately achieved a complete response. Although the lesions were initially suspected of being postoperative recurrence of pulmonary large-cell neuroendocrine carcinoma, the fact that the biopsy revealed them to be primary tracheal small-cell carcinoma indicates that intra-airway nodules that appear after lung cancer surgery may possibly be primary tracheal tumors.

Regional differences in epidermal growth factor receptor-tyrosine kinase inhibitor therapy in lung cancer treatment using a national database in Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are extensively used in the treatment of non-small cell lung cancer (NSCLC); hence, equal access to them is important. Therefore, this study aimed to identify regional differences in the prescription of EGFR-TKIs and the factors contributing to these differences. In this ecological study, we collected data using the National Database Open Data and the National Cancer Registry. The standardized claim ratio (SCR) was used as an indicator of the number of EGFR-TKI prescriptions. Additionally, we examined the association between SCR and various factors to identify the factors associated with this difference. The average SCR for the top three provinces was 153.4, while the average for the bottom three provinces was 61.6. Multivariate analysis used for evaluating the association of SCR with variables revealed that the number of designated cancer hospitals and radiation therapies were independent factors associated with the SCR of EGFR-TKIs. There were significant regional differences in the prescriptions of EGFR-TKIs in Japan based on the number of coordinated designated cancer hospitals and the number of patients receiving radiotherapy alone. These findings emphasize the need to implement policies to increase the number of hospitals to reduce regional differences.

ILD-GAP Combined with the Charlson Comorbidity Index Score (ILD-GAPC) as a Prognostic Prediction Model in Patients with Interstitial Lung Disease.

Background: The ILD-GAP scoring system has been widely used to predict the prognosis of patients with interstitial lung disease (ILD). The ability of the ILD-GAP scoring system combined with the Charlson Comorbidity Index score (CCIS) (ILD-GAPC) to predict ILD prognosis was investigated. Methods: In ILD patients, including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD), treated between April 2013 and April 2017, the relationships between baseline clinical parameters, including age, sex, CCIS, ILD diagnosis, pulmonary function test results, and disease outcomes, were retrospectively assessed, and the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPC models, respectively. Results: A total of 185 patients (mean age, 71.9 years), all of whom underwent pulmonary function testing, including percentage predicted diffusion capacity for carbon monoxide, were assessed. ILD diagnosis consisted of IPF in 57 cases, iNSIP and CVD-IP in 117 cases, CHP in 6 cases, and UC-ILD in 5 cases. The ILD-GAPC provided a greater area under the receiver operating characteristic curve (0.758) for predicting 3-year ILD-related events than the ILD-GAP (0.721). In addition, log-rank tests showed that the Kaplan-Meier curves differed significantly among low, middle, and high ILD-GAPC scores (P < 0.001), unlike ILD-GAP scores (P = 0.083). Conclusions: The ILD-GAPC model could provide more accurate information for predicting prognosis in patients with ILD than the ILD-GAP model.

Elderly sarcoidosis in Japan.

OBJECTIVE: The manifestations of sarcoidosis differ by ethnicity and region. However, the few studies that have focused on elderly sarcoidosis are only from Western countries. Therefore, we investigated elderly sarcoidosis in Japan. METHODS: We retrospectively reviewed the records of adult patients (≥18 years old) who were diagnosed with sarcoidosis from 1 April 2006 to 31 March 2020. The diagnosis was pathologically confirmed in all patients. We compared the clinical features of elderly (diagnosed at ≥65 years old) and non-elderly (diagnosed at <65 years old) patients. RESULTS: Thirty-five (33%) of 106 patients were elderly. The elderly group had significantly more comorbidities than the non-elderly group (median [range], 1 [0-4] vs. 0 [0-5]). The biopsy site at diagnosis included significantly more extrathoracic sites in the elderly than non-elderly group (57.1% vs. 33.8%). The elderly group had significantly more muscle lesions than the non-elderly group at the time of diagnosis (11.4% vs. 1.4%) and at any time during follow-up (17.1% vs. 1.4%). CONCLUSION: In Japan, elderly patients with sarcoidosis might have more muscle involvement and comorbidities than younger patients. Because comorbidities might affect the prognosis of elderly sarcoidosis, further study is needed to clarify the effect of comorbidities on elderly sarcoidosis.