An increased relative eosinophil count as a predictive dynamic biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: An increased relative eosinophil count (REC) has potential as a predictive biomarker for a beneficial clinical response and outcome to cancer immunotherapies. Therefore, the present study investigated the impact of an increased posttreatment REC on the prognosis of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). METHODS: We retrospectively reviewed all 151 patients diagnosed with NSCLC and treated with ICI monotherapy and blood test data between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. RESULTS: A total of 151 patients with a mean age of 69 years were included. REC after 4 weeks of initial ICI monotherapy was higher than pretreatment REC in 87 patients but not in 64. REC after 4 weeks of the ICI treatment with and without an increased REC were 4.4 and 1.8%, respectively (p < 0.001). Disease control rates (DCR) were significantly higher in patients with than in those without an increased REC (84% vs. 47%, p < 0.001). The median overall survival (OS) of lung cancer patients with or without an increased REC were 674 and 234 days, respectively. A Kaplan-Meier univariate analysis revealed a significant difference in OS between the two groups (p < 0.001). A Cox proportional regression analysis identified an increased REC as an independent predictor of OS (p = 0.003). CONCLUSION: ICI-treated NSCLC patients with an increased REC after 4 weeks of treatment had a better DCR and prognosis than the other patients examined.

Pretreatment eosinophil counts as a predictive biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: The peripheral blood eosinophil count prior to treatment has potential as a predictive biomarker for a beneficial clinical response to cancer immunotherapies. Therefore, the present study investigated the impact of the eosinophil count on overall survival (OS) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). METHODS: We retrospectively reviewed all patients diagnosed with NSCLC and treated with ICI monotherapy between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. RESULTS: A total of 166 patients were included. Fifty-five patients had an eosinophil count of less than 100 cells/µL (Eo < 100). Nighty-eight patients had an eosinophil count of 100 cells/µL or more, but less than 500 cells/µL (100 ≤ Eo < 500). Thirteen patients had an eosinophil count of 500 cells/µL or more (Eo ≥500). The median OS of all lung cancer patients was 476 days. The median OS of lung cancer patients with Eo <100, 100 ≤ Eo <500, and Eo ≥500 was 339, 667, and 143 days, respectively. A Kaplan-Meier univariate analysis showed a significant difference in OS between these three groups (p < 0.001). A Cox proportional regression analysis identified 100 ≤ Eo <500 (p = 0.04), ECOG PS score ≥ 2 (p = 0.02), tumor size ≥5 cm (p = 0.02), and PD-L1 ≥ 1% (p = 0.01) as independent predictors of OS. CONCLUSION: OS was significantly longer in ICI-treated NSCLC patients with a pretreatment eosinophil count of 100 ≤ Eo <500 than in the other patients and, thus, has potential as a new predictive biomarker.

Non-small cell lung cancer with EGFR (L858R and E709X) and CNNB1 mutations responded to afatinib.

Lung cancer with complex epidermal growth factor receptor (EGFR) and CTNNB1 comutations is rare, and the efficacy of tyrosine kinase inhibitors (TKIs) is generally poor. Here, we encountered a lung cancer patient with complex EGFR (L858R and E709X) and CTNNB1 comutations who successfully responded to afatinib. A 78-year-old woman visited our hospital with a cough and bloody sputum that had worsened over the past year. She had multiple mass shadows in both lungs and nodular shadows in the bronchi. The patient was diagnosed with lung adenocarcinoma cT4N3M1c stage IVB. A genetic analysis of the primary tumor using the Oncomine Dx target test multi-CDx system revealed positivity for EGFR (L858R and E709X) and CTNNB1 mutations. The expression of programmed death ligand 1 (22C3 clones) in tumor cells was negative by immunostaining. The patient was treated with afatinib as first-line therapy and achieved clinical improvement and a partial response and is continuing treatment 1 year later. Case reports of lung cancer patients with EGFR/CTNNB1 comutations are rare, and TKIs are not considered to be effective. We herein present the first case report of lung cancer with the co-occurrence of uncommon and complex EGFR (L858R and E709X) and CTNNB1 mutations that was successfully treated with afatinib.

Late-onset acute type 1 diabetes mellitus 7 months after discontinuation of pembrolizumab against lung cancer.

Immune-related adverse events (irAEs) occur in rare cases, even after the completion of immune checkpoint inhibitor (ICI) therapy. We encountered a lung cancer patient diagnosed with acute-onset type 1 diabetes mellitus (DM) 7 months after the cessation of ICI. A 68-year-old woman was referred to our hospital for chest abnormalities. She was diagnosed with lung adenocarcinoma cT4N2M1c, stage IVB. Immunostaining showed that the expression of programmed death ligand 1 in tumor cells was negative. A genetic analysis using the Oncomine Dx Target Test Multi-CDx System revealed that the primary tumor was positive for ERBB2. Combined immunotherapy with carboplatin, pemetrexed, and pembrolizumab was performed as first-line therapy, followed by maintenance therapy with pemetrexed plus pembrolizumab, which was successful. After the seventh course, maintenance therapy was stopped because only the primary tumor showed local enlargement. Local chest radiotherapy (66 Gy/33 Fr) was performed, and the patient was followed up. HbA1c was 4.9% 3 months after the completion of pembrolizumab, and dry mouth and polyuria occurred after 5 months. Seven months later, the patient developed diabetic ketoacidosis with a blood glucose of 348 mg/dL and an HbA1c of 11.3%. Antiglutamic acid decarboxylase antibodies were negative and urinary C-peptide was 9.3 µg/day. The patient was diagnosed with acute-onset type 1 diabetes and received insulin therapy. There has been no case report of type 1 diabetes diagnosed 7 months after the last administration of an ICI. These results indicate that irAE needs to be considered even after the cessation of ICI.

Early mortality factors in immune checkpoint inhibitor monotherapy for advanced or metastatic non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) are a promising treatment, but may cause hyperprogressive disease and early death. The present study investigated early mortality factors in ICI monotherapy for lung cancer. PATIENTS AND METHODS: We retrospectively reviewed all patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC) and treated with ICI monotherapy (nivolumab, pembrolizumab, and atezolizumab) between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University. Early death was defined as patients who died within 60 days of ICI treatment. RESULTS: A total of 166 patients were included. The majority of patients (87%) had an Eastern cooperative oncology group (ECOG) Performance status (PS) of 0/1. There were 21 early deaths. Significant differences were observed in ECOG PS, the histological type, liver metastasis, tumor size, the white blood cell count, neutrophils (%), lymphocytes (%), the neutrophil-to-lymphocyte ratio in serum (sNLR), C-reactive protein (CRP), and albumin between the groups with or without early death. Univariate logistic regression analyses identified ECOG PS score ≥ 2, liver metastasis, tumor size ≥ 5 cm, neutrophils ≥ 69%, lymphocytes < 22%, sNLR ≥ 4, CRP ≥ 1 mg/dl, and albumin < 3.58 g/dl as significant risk factors for early death. A multivariate logistic regression analysis revealed that liver metastasis (Odds ratio [OR], 10.3; p = 0.008), ECOG PS score ≥ 2 (OR, 8.0; p = 0.007), and a smoking history (OR, 0.1; p = 0.03) were significant risk factors for early death. CONCLUSION: Liver metastases, ECOG PS score ≥ 2, and a non-smoking history are early mortality factors in ICI monotherapy for advanced or metastatic NSCLC.

A single dose of pembrolizumab treatment causing a profound and durable response in lung cancer.

Profound and durable responses to a single dose of pembrolizumab in lung cancer are rare. We encountered a non-small cell lung cancer patient showing a deep and durable response with a single dose of pembrolizumab. A 79-year-old man reported bloody sputum for several weeks and visited a general physician. A chest x-ray revealed a tumor shadow in the right middle lung field at that time, and the patient was referred to our hospital. He was diagnosed with adenocarcinoma of the lung by transbronchial biopsy. The expression of programmed death ligand 1 in tumor cells was 100% by immunostaining. Based on the above, immunotherapy with pembrolizumab was performed as first-line therapy. Cancer cells had significantly shrunk at the end of the first cycle. The patient had grade-3 immune-related hepatitis at the end of the first cycle. Pembrolizumab treatment was stopped and prednisolone (80 mg/body) was initiated. Subsequently, liver function normalized, and prednisolone was tapered and discontinued. Since then, no tumor recurrence has been detected for 1.5 years without treatment. There have been few reports of profound and durable responses to a single dose of pembrolizumab in lung cancer. The results indicate that a single dose of pembrolizumab alone may be sufficient to cause durable response and serious immune-related adverse events in some cases.

Eosinophilic pleural effusion due to lung cancer has a better prognosis than non-eosinophilic malignant pleural effusion.

OBJECTIVE: Tumor-related eosinophilia may have extended survival benefits for some cancer patients. However, there has been no report on the prognosis difference between eosinophilic pleural effusion (EPE) and non-EPE in lung cancer patients. Our study aimed to investigate the prognosis difference between EPE and non-EPE due to lung cancer. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed with lung cancer who presented with malignant pleural effusion (MPE) between May 2007 and September 2020 at the National Hospital Organization Kochi Hospital. EPE is defined as pleural fluid with a nucleated cell count containing 10% or more eosinophils. RESULTS: A total of 152 patients were included: 89 were male (59%). The median age was 74.4 years (range 37-101), and all patients were pathologically shown to have MPE. Most patients (140; 92%) had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0/1. Twenty patients had EPE. The median overall survival (OS) of all 152 lung cancer patients with MPE was 298 days. The median OS of the patients with EPE was 766 days, and the median OS of the patients with non-EPE was 252 days. Kaplan-Meier univariate analysis showed that lung cancer patients with EPE had a significantly better prognosis than patients with non-EPE (P < 0.05). Cox proportional regression analysis showed that EPE, ECOG PS, sex, and the neutrophil-to-lymphocyte ratio in the serum (sNLR) may be independent prognostic factors affecting survival in patients with MPE. CONCLUSION: Lung cancer patients with EPE have a better prognosis than those with non-EPE.

Dramatic response to immunochemotherapy followed by salvage surgery in an elderly lung cancer patient.

Immune checkpoint inhibitors (ICIs) have caused a paradigm shift in the treatment of lung cancer. Here, we encountered a case of inoperable locally advanced squamous cell carcinoma of the lung that became operable with pembrolizumab-based immunochemotherapy and achieved a pathological complete response. An 82-year-old man suspected of having lung cancer was referred to our hospital. The patient was clinically diagnosed with left upper lobe squamous cell carcinoma cT2aN3M0 c-stage IIIC. Immunostaining revealed the expression of programmed death-ligand 1 in 60% of tumor cells. The cancer cells disappeared after two cycles of chemotherapy with carboplatin and nanoparticle albumin-bound paclitaxel plus pembrolizumab. As the abnormal accumulation of 18 F-fluorodeoxyglucose (FDG) on FDG-positron emission tomography/computed tomography before chemotherapy almost disappeared after pembrolizumab-based immunochemotherapy, left upper lobectomy and lymph node dissection were performed. No cancer cells were pathologically detected from the resected tissue. Therefore, ICIs combined with chemotherapy may enable inoperable advanced lung cancer patients to undergo surgery and achieve a complete response.

Complete and durable response of pulmonary large-cell neuroendocrine carcinoma to pembrolizumab.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive tumor with a poor prognosis and standard therapy has not yet been established. CASE: A 65-year-old male with a cough for 2 months presented to our hospital. He was clinically diagnosed with non small cell lung cancer cT3N1M0 stage IIIA and underwent right pneumonectomy. The final diagnosis was pulmonary LCNEC pT3N1M0 stage IIIA. Multiple subcutaneous masses were detected 4 months after surgery, and biopsy revealed postoperative recurrence and metastasis. Chemotherapy with carboplatin plus etoposide was initiated. Subcutaneous masses increased and multiple new brain metastases developed after two cycles. Additional tests revealed that epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 (PD-L1) expression rate in tumor cells was 40% (22C3 clones). The primary cells infiltrating the tumor were CD3-positive T cells and CD138-positive plasma cells. Second-line treatment with pembrolizumab was started. The shrinkage of subcutaneous masses was observed after one cycle, and the tumor had completely disappeared after six cycles. Treatment was continued for approximately 2 years. This response has been maintained for 4 years and is still ongoing. CONCLUSION: Pembrolizumab may be used as a treatment option for pulmonary LCNEC.

Elevated Levels of Intelectin-1, a Pathogen-binding Lectin, in the BAL Fluid of Patients with Chronic Eosinophilic Pneumonia and Hypersensitivity Pneumonitis.

Objective Human intelectin-1 (hITLN-1) binds to galactofuranosyl residues, which are present in the microbial cell wall, but which are absent in mammalian tissues, and has been suggested to play an immunological role against microorganisms. However, the involvement of hITLN-1 in the pathogenesis of diffuse pulmonary diseases remains unknown. The aim of this study was to compare the hITLN-1 concentrations in the bronchoalveolar lavage (BAL) fluid of patients with diffuse pulmonary diseases. Methods The cell components and concentrations of hITLN-1 were analyzed in the BAL fluid of 8 patients with idiopathic chronic eosinophilic pneumonia (ICEP), 3 patients with drug-induced eosinophilic pneumonia, 4 patients with hypersensitivity pneumonitis (HP), 11 patients with sarcoidosis, 9 patients with cryptogenic organizing pneumonia, and 5 patients with idiopathic fibrosing interstitial pneumonia (fibrosing nonspecific interstitial pneumonia or usual interstitial pneumonia). Results The hITLN-1 concentrations in the BAL fluid of patients with ICEP and HP were higher than in those with other diseases. In the ICEP group, no significant difference was observed in the hITLN-1 concentrations of patients with or without a history of bronchial asthma. Conclusion The results of the present study suggest that hITLN-1 may be involved in the pathogenesis of ICEP and HP, and that an increase in the hITLN-1 concentration in the BAL fluid may represent a new biomarker for these diseases.

Phase II study of tailored S-1 monotherapy with a 1-week interval after a 2-week dosing period in elderly patients with advanced non-small cell lung cancer.

BACKGROUND: S-1 is an oral fluoropyrimidine that is active in the treatment of non-small cell lung cancer (NSCLC); however, an optimal treatment schedule and appropriate dose adjustments of S-1 in elderly patients have not yet been established. METHODS: We conducted a phase II trial to evaluate the efficacy and safety of a 2-week S-1 monotherapy treatment followed by a 1-week interval as a first-line treatment of elderly NSCLC patients, by adjusting the dose based on the individual creatinine clearance (Ccr) and body surface area (BSA). The primary endpoint was the disease control rate. RESULTS: Forty patients were enrolled. The disease control and response rates were 89.5% (95% confidence interval [CI] = 79.8-99.2) and 7.9% (95% CI = 0.0-16.4), respectively. The median progression-free survival and overall survival times were 4.4 months (95% CI = 4.2-8.5) and 17.0 months (95% CI = 11.2-18.7), respectively. Neutropenia, anorexia, hyponatremia, hypokalemia, and pneumonia of grade ≥ 3 occurred in 5.0%, 7.5%, 5.0%, 2.5%, and 2.5% of patients, respectively. Among the patient-reported outcomes, most of the individual factors in the patients' quality of life, including upper intestine-related symptoms improved with the treatment, except for dyspnea, which slightly albeit continuously worsened throughout the study. CONCLUSIONS: In elderly patients with previously untreated advanced NSCLC, a 2-week S-1 monotherapy treatment, tailored to both the Ccr and BSA, with a 1-week interval was well tolerated and demonstrated promising efficacy. This study was registered at the University Hospital Medical Information Network (UMIN) Center (ID: UMIN000002035), Japan.

Carboplatin plus Weekly Paclitaxel with Bevacizumab for First-line Treatment of Non-small Cell Lung Cancer.

AIM: The present study aimed to evaluate the effectiveness and safety of weekly paclitaxel (PTX) combined with carboplatin (CBDCA) plus bevacizumab (BEV), followed by maintenance BEV in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with unresectable stage IIIB and IV NSCLC (n=43) were treated with CBDCA (AUC 6, day 1), BEV (15 mg/kg, day 1), and PTX (70 mg/m(2), days 1, 8, 15) intravenously every 4 weeks, for 3 to 6 cycles, followed by maintenance BEV (15 mg/kg) every 3 weeks. RESULTS: The objective response rate and disease control rate were 67.4% and 90.7%, respectively. The median progression-free survival was 7.6 months. The median overall survival was 17.7 months. Common adverse events were tolerable bone marrow suppression, fatigue, hypertension, and nasal bleeding. CONCLUSION: Weekly administration of PTX combined with CBDCA plus BEV therapy was effective, and well-tolerated by advanced NSCLC patients.

Kikuchi-Fujimoto disease associated with community acquired pneumonia showing intrathoratic lymphadenopathy without cervical lesions.

INTRODUCTION: Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare entity of unknown etiology in young adults that is typically characterized by cervical lymphadenopathy and persistent fever. The pathogenesis of KFD has been suggested to be an abnormal immune response, and infections or autoimmune diseases are considered to be involved in KFD. However, KFD associated with community acquired pneumonia (CAP) has not been reported. CASE DESCRIPTION: A 35-year-old male was admitted due to high fever, diffuse air-space consolidation in the right lung with ipsilateral pleural effusion and massive mediastinal and hilar lymphadenopathy without cervical lesions. On clinical suspicion of malignant lymphoma complicated with pneumonia, we performed a video-assisted thoracoscopic lymph node biopsy, and the diagnosis of KFD was established. Complete cure of the intrathoratic lesions was observed by administration of ß-lactam antibiotics alone without steroid therapy. DISCUSSION AND EVALUATION: Previous large case series have identified no pathogenic relationship between KFD and pneumonia. The hilar adenopathy could have caused airway compression leading to pneumonia. CONCLUSIONS: KFD should be considered in the differential diagnosis of massive mediastinal and hilar lymphadenopathy, even when there are no superficial lesions. In addition, we need to bear in mind that unexpected disorders occasionally coexist with common diseases.

Primary Gingival Tuberculosis Diagnosed Based on Genetic Identification.

A case of primary gingival tuberculosis in a 71-year-old Japanese woman is herein presented. A serous saliva culture was positive for tuberculosis, and we recognized that the origin of the tuberculosis infection was the gingiva based on the genetic identification in gingival biopsy tissue. The definitive diagnosis was facilitated by the genetic identification, a useful modern tool for diagnosing infectious diseases. The location and clinical presentation of this lesion were unusual, which underlines the importance of considering tuberculosis in the differential diagnosis of oral lesions that affect the gingiva.

Asymptomatic tracheal MALT lymphoma discovered on spirometric findings presenting with elevated respiratory resistance.

BACKGROUND: Central airway obstruction (CAO) may be caused by various etiologies. However, conventional chest X-rays are rarely diagnostic for patients with CAO. CASE PRESENTATION: We here described a 64-year-old asymptomatic female with tracheal mucosa-associated lymphoid tissue lymphoma discovered on spirometric findings during a complete physical examination. The plateau of forced expiratory flow was consistent with CAO. A decreased peak expiratory flow rate was noted at least 3 years before the diagnosis, and was attributed to an insufficient effort by the patient. Impulse oscillometric measurements, which were taken during quiet breathing and were effort-independent, suggested elevated respiratory resistance. These abnormalities completely disappeared after radiation therapy. CONCLUSION: The addition of impulse oscillometry to spirometry may be useful for screening CAO in routine health examinations.

Epstein-Barr Virus-Positive Pyothorax-Associated Lymphoma Arising from a Posttraumatic Empyema.

Pyothorax-associated lymphoma (PAL) develops from a pyothorax caused by an artificial pneumothorax created during the treatment of pulmonary tuberculosis or tuberculous pleuritis. We report the first case of Epstein-Barr virus (EBV)-positive PAL arising from a posttraumatic empyema. A 75-year-old woman with chronic posttraumatic empyema presented with a tumor, which was connected to the wall of a pyothorax in the right thoracic cavity. She had a history of trauma to the right chest, which had occurred at the age of 45 years and had caused the chronic posttraumatic empyema. Pathological features of the resected tumor were conclusive for a diagnosis of EBV-positive PAL. Although neither postoperative chemotherapy nor radiotherapy was performed, remission was maintained for 3 years until recurrence in the liver. Combination chemotherapy led to complete remission, and 9 years after the initial diagnosis of PAL, the patient is still alive. An intriguing finding is the phenotypic alteration during the disease course. Although the primary tumor was negative for CD20 and CD3, the recurrent tumor expressed both of these molecules. We discuss this case of PAL, which was not a complication of lung tuberculosis, and the aberrant chronological phenotypic change observed in the lymphoma cells, and compare it with a usual case of PAL.