Role of G-protein-coupled estrogen receptor in the pathogenesis of chronic asthma.

BACKGROUND AND AIM: G protein-coupled estrogen receptor (GPER) is an estrogen receptor located on the plasma membrane. We previously reported that the administration of G-1, a GPER-specific agonist, suppressed development of acute ovalbumin (OVA)-induced asthma in a mouse model. Herein, we evaluate the involvement of GPER in a mouse model of chronic OVA asthma. METHODS: G-1 or saline was administered subcutaneously to BALB/c mice with chronic OVA asthma, and pathological and immunological evaluation was performed. In addition, Foxp3-expressing CD4-positive T-cells in the spleen and ILC2 in the lungs were measured using flow cytometry. RESULTS: We observed a significant decrease in the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) in the G-1 treated group. In the airways, inflammatory cell accumulation, Th2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and epithelial cytokine TSLP were suppressed, while in the BALF, anti-inflammatory cytokines (IL-10 and TGF-ß) were increased. Furthermore, in splenic mononuclear cells, Foxp3-expressing CD4-positive T-cells were increased in the G-1 group, whereas treatment with G-1 did not change the percentage of ILC2 in the lungs. CONCLUSION: G-1 administration suppressed allergic airway inflammation in mice with chronic OVA asthma. GPER may be a potential therapeutic target for chronic allergic asthma.

Acute Exacerbation of Interstitial Lung Disease After SARS-CoV-2 Vaccination: A Case Series.

CASE PRESENTATION: An acute exacerbation of interstitial lung disease (ILD) is an acute deterioration that can occur at any time and is associated with significant morbidity and mortality rates. We herein report three patients with ILD who experienced acute respiratory failure after SARS-CoV-2 messenger RNA vaccination. All the patients were male; the mean age was 77 years. They had a smoking history that ranged from 10 to 30 pack-years. Duration from the vaccination to the onset of respiratory failure was 1 day in two patients and 9 days in one patient. In an autopsied case, lung pathologic evidence indicated diffuse alveolar damage superimposed on usual interstitial pneumonia. In the other two cases, CT scans showed diffuse ground-glass opacities and subpleural reticulation, which suggests acute exacerbation of ILD. Two patients were treated successfully with high-dose methylprednisolone. Although benefits of vaccination outweigh the risks associated with uncommon adverse events, patients with chronic lung diseases should be observed carefully after SARS-CoV-2 vaccination.

Morphological features of bronchiectasis in patients with non-tuberculous mycobacteriosis and interstitial pneumonia.

OBJECTIVE: To compare the morphological features of bronchiectasis between patients with different underlying diseases, we performed quantitative analysis of high-resolution computed tomography (HRCT) images of 14 patients with non-tuberculous mycobacteriosis (NTM) and 13 with idiopathic pulmonary fibrosis (IPF). A 3D image of the bronchial structure was made from HRCT data. Bronchiectasis was defined as abnormal dilatation of the bronchi with the diameter greater than that of the accompanying pulmonary artery. We measured the inner and outer diameters, wall area as %total airway cross sectional area (WA%), and wall thickness to airway diameter ratio (T/D) of the 4-8th generations of bronchi. RESULTS: In patients with IPF, the inner and outer diameters linearly decreased toward the distal bronchi. In contrast, the inner and outer diameters of NTM fluctuated. The coefficient of variation of the outer diameters of the 6-7th generations of bronchi was larger in the NTM patients than in those with IPF, whereas no significant difference was observed in the coefficient of variation of the inner diameters between the groups. In IPF patients, WA% and T/D varied between the generation of bronchi, but the coefficient of variation of WA% and T/D was relatively small in those with NTM.

Procalcitonin expression in patients with large cell neuroendocrine carcinoma of the lung.

OBJECTIVE: Procalcitonin (PCT) has received much attention as a serum marker for bacterial infection. Elevated serum PCT is occasionally seen in severe trauma, heatstroke, and neoplastic diseases, including lung cancer with neuroendocrine component. RESULTS: In the present study, we evaluated PCT expression in the specimen of pulmonary neuroendocrine tumors, comparing large cell neuroendocrine carcinoma (LCNEC), carcinoid, and small cell lung carcinoma (SCLC). Pathological specimens of 10 LCNEC, 4 carcinoid, and 7 SCLC cases were evaluated with immunochemical staining of PCT. Clinical characteristics and serum levels of PCT and C-reactive protein were also evaluated. We observed positive PCT expression in 5 (50%) LCNEC and 2 (50%) carcinoid specimens that were surgically resected. Whereas serum PCT levels were not elevated in patients with PCT-positive carcinoid, two out of three LCNEC patients with high PCT expression in the tumor had elevated serum PCT levels that reflected disease progression. In patients with SCLC, PCT was not detected in the tumor or serum. This is the first immunohistochemical study of the PCT expression in the lung tumor specimens. We concluded that, in patients with LCNEC, high serum PCT levels may be indicative of disease activity and serve as a biomarker.

A Phase I/II Study of Biweekly Carboplatin and Nab-paclitaxel With Concurrent Radiotherapy for Patients With Locally Advanced Unresectable Stage III Non-small-cell Lung Cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced non-small-cell lung cell cancer (LA-NSCLC). We conducted a phase I/II study of biweekly carboplatin and nab-paclitaxel (nab-PTX) with radiotherapy (RT). MATERIALS AND METHODS: In the phase I part, patients with inoperable stage IIIA/IIIB NSCLC were treated with carboplatin (area under the time-concentration curve, 4) and nab-PTX (60-100 mg/m2) on days 1, 15, and 29. Thoracic RT was administered from day 1 to a total dose of 60 Gy in 30 fractions. In the phase II part, patients were administered carboplatin and nab-PTX on days 1, 15, and 29 at the recommended dose (RD). The primary endpoint of the phase I part was to determine the maximum tolerated dose and the RD. In the phase II part, the primary endpoint was 2-year overall survival (OS) rate, and secondary endpoints were the objective response rate, progression-free survival, OS, and safety profile. RESULTS: In the phase I part, although maximum tolerated dose was not obtained, the RD was carboplatin (area under the time-concentration curve, 4) and nab-PTX (100 mg/m2). Of the evaluable 28 patients, the rate of 2-year OS was 67.8% (95% confidence interval, 49.3%-82.1%). The objective response rate was 96.4%, and the median follow-up time was 33.2 months. The median progression-free survival was 18.2 months (95% confidence interval, 13.1 months to not reached). The most common toxicities of grade 3 or higher were neutropenia (60.5%), anemia (14.2%), thrombocytopenia (7.2%), and pneumonitis (3.6%). CONCLUSIONS: This study achieved the primary endpoint. Biweekly carboplatin and nab-PTX with concurrent RT was well-tolerated and exerted promising antitumor activity.

Destroyed lung due to sustained inflammation after chemoradiotherapy followed by durvalumab.

A 68-year-old male patient with squamous cell carcinoma (cT4N2M0) of the left upper lobe received chemoradiotherapy followed by durvalumab, an immune checkpoint inhibitor. The tumour responded well to the therapy, but an infiltrative shadow appeared in the left upper lobe, which was outside the radiation field. Despite treatment with corticosteroid and antibiotics, the development of a cavitary lesion was noted. As Aspergillus fumigatus was isolated from the bronchoscopy specimen, antifungal agents were also administered, but the cavitary lesion further developed. Because his general condition worsened and the entire left lung was destroyed, the patient underwent a left pneumonectomy and recovered without recurrence. The pathology of the removed lung revealed a scarred nodule with granulation tissue around and a cavernous lesion having a necrotic substance inside. We considered that durvalumab might further accelerate the inflammatory response, which had been introduced by fungal infection, leading to uncontrollable inflammation of the lung.

A pilot study of adjuvant chemotherapy with carboplatin and oral S-1 for patients with completely resected stage II to IIIA non-small cell lung cancer.

BACKGROUND: Adjuvant chemotherapy with platinum-based regimens for completely resected early-stage non-small cell lung cancer (NSCLC) provides overall survival benefit in several clinical trials. OBJECTIVES: We conducted this prospective study to evaluate the efficacy and safety of adjuvant chemotherapy with carboplatin and S-1 for patients with completely resected stage II to IIIA NSCLC. METHODS: Patients with completely resected stage IIA to IIIA NSCLC were treated with four cycles of carboplatin with area under the concentration time curve of 5 mg/mL/min on day 1 plus S-1 at 80-120 mg/bodyweight per day for two weeks, followed by one-week rest as adjuvant chemotherapy. The primary endpoint was the completion rate of three cycles of the treatment. The secondary endpoints were safety and two-year survival rate. RESULTS: A total of 19 patients were enrolled, until the study was terminated prematurely because of fatal pulmonary embolism in two patients. The median number of treatment cycles was three (range: 1-4). The completion rate of three cycles was 78.9% (95% confidence interval [CI]: 56.6-91.4%). Two-year disease-free survival rate was 57.8%. Grade 3 or 4 hematological toxicities included neutropenia (26.2%), anemia (5.2%), and thrombocytopenia (15.7%). Grade 3 or 4 nonhematological toxicities were anorexia (10.5%) and nausea (10.5%). Febrile neutropenia developed in 5.2%. In two patients (10.5%), grade five pulmonary embolism was observed, and the causal relationship with treatment could not be denied. CONCLUSIONS: Carboplatin and oral S-1 had modest survival benefit, but this regimen was not tolerable in an adjuvant setting because fatal pulmonary embolism occurred in two patients. KEY POINTS: Carboplatin and oral S-1 had modest survival benefit but this regimen was not tolerable. Fatal pulmonary embolism occurred in this regimen.

Effect of nintedanib on non-small cell lung cancer in a patient with idiopathic pulmonary fibrosis: A case report and literature review.

Nintedanib has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In addition, in EU countries, nintedanib plus docetaxel is used for patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. Here, we report a case of advanced NSCLC in a patient with IPF successfully treated with nintedanib monotherapy. A 69-year-old man was diagnosed with NSCLC complicated by IPF. After three lines of chemotherapy, he still had progressive disease. Because his IPF had also progressed, requiring supplemental oxygen, we decided to start best supportive care and introduced nintedanib to treat his IPF. One month later, we observed a partial remission of the primary tumor and pleural disseminations without severe adverse events. Nintedanib monotherapy might therefore be an effective therapeutic choice for NSCLC in patients with IPF who are unable to tolerate cytotoxic chemotherapy. KEY POINTS: Efficacy of nintedanib administered in a NSCLC patient with IPF. Nintedanib monotherapy might be a therapeutic option for NSCLC patients with IPF who are unable to tolerate chemotherapy.

Real-world study of afatinib in first-line or re-challenge settings for patients with EGFR mutant non-small cell lung cancer.

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), was approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real-world practice. Medical records of patients who received afatinib for advanced EGFR-mutant NSCLC were retrospectively reviewed. In total, 128 patients were analyzed. Seventy-six patients received afatinib as the first-line setting and 52 as the re-challenge setting (i.e., after failure of prior first-generation TKI). There was no difference in patient characteristics, such as age, sex, and PS, between the first-line and the re-challenge settings. In the first-line setting, the median progression-free survival (PFS) was 17.8 months (95% confidence interval [CI] 13.7-21.5 months). The overall survival (OS) was 39.5 months (95% CI 34.4- not reached). The response rate (RR) was 64.4%. Subset analysis indicated that patients with dose reduction showed longer PFS than those without dose reduction (18.5 months versus 7.9 months) (P = 0.016). In the re-challenge setting, the median PFS was 8.0 months (95% CI 4.9-9.5 months). The RR was 25%. Most common adverse events leading to dose modification or treatment discontinuation included diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). In the real-world practice in Japan, afatinib showed comparable or better efficacy compared with that shown in previous clinical trials in both the first-line and the re-challenge settings.

The efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring driver mutations.

The present retrospective study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Patients with NSCLC harboring driver mutations who received ICIs (nivolumab or pembrolizumab) were reviewed in Hirosaki University and Aomori Prefectural Central Hospital. There were 139 patients who received molecular targeted drugs, including 24 patients treated with ICIs. Patient characteristics were as follows: Male/female, 5/19; median age 68 (range 39-82); smoking/non-smoking, 6/18; PS 0-1/2, 20/4; driver mutation status, EGFR/ALK/RET/ROS1: 21/1/1/1. The overall response rate was 16.7% [95% confidence interval (CI), 7.0-37.1%] and the disease control rate was 33.4% (95% CI, 18.9-55.1%). The median progression-free survival (PFS) time was 62 days (95% CI 52-81 days). In the patients who had been treated by the preceding tyrosine kinase inhibitor (TKI) for >1 year, the PFS time was 110 days. On the other hand, in the patients who had received a TKI for less than a year, the PFS time was 56 days, which was significantly shorter (P=0.012). To conclude, some of the patients with NSCLC harboring driver mutation could benefit from ICIs, and the duration of previous TKI treatment may be associated with the efficacy.

Efficacy of pembrolizumab for patients with both high PD-L1 expression and an MET exon 14 skipping mutation: A case report.

Pembrolizumab has become the standard first-line treatment for non-small cell lung cancer (NSCLC) patients with high PD-L1expression. MET exon 14 skipping is a rare mutation typically found in older, female, and non-smoking patients with NSCLC. Herein, we report the case of a 71-year-old non-smoking woman who was diagnosed with NSCLC in the left lung. EGFR mutation and ALK fusion were not detected. Because the biopsy specimen showed high PD-L1 expression with a tumor proportion score of 95%, pembrolizumab was introduced as first-line therapy, but resulted in no clinical benefit. The patient was subsequently administered chemotherapy with carboplatin and pemetrexed, leading to remarkable tumor shrinkage. A next-generation sequencing panel analysis revealed a MET exon 14 skipping mutation. Thus, pembrolizumab might not be effective for NSCLC patients with MET exon 14 skipping mutations, even if PD-L1 expression is high.

A phase I study of afatinib for patients aged 75 or older with advanced non-small cell lung cancer harboring EGFR mutations.

This phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose of afatinib for phase II trial in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or older with advanced NSCLC harboring EGFR mutations were enrolled. The doses of afatinib, which were given once daily, were planned as follows: level 1, 20 mg/day; level 2, 30 mg/day; level 3, 40 mg/day. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic, persistent grade > 2 diarrhea for > 2 days despite concomitant medications or grade 3 non-hematologic toxicity. DLT was evaluated during day 1-28. Fifteen patients were enrolled. Patient characteristics were: male/female 3/12; median age 79 (range 75-87); PS 0/1, 2/13. Six patients have been treated at levels 1 and 3, and three patients at level 2. At level 1, one of six patients experienced grade 3 rush, grade 3 anorexia, and grade 3 infection as DLTs. At level 2, none of three patients experienced a DLT. At level 3, two patients developed grade 3 diarrhea, one of whom also experienced grade 3 anorexia. Most frequent adverse events of any grade were diarrhea, paronychia, rush, and nausea. Most patients at level 2 and 3 required dose reduction in 3 months. MTD was defined as 40 mg/day, and recommended dose for phase II study in elderly patients was 30 mg/day.

Emergency Radiotherapy for Spinal Cord Compression due to Bone Sarcoidosis.

Sarcoidosis is an inflammatory granulomatous disease that is systemic, but bone involvement is uncommon. A 68-year-old man was referred to our hospital complaining of right shoulder pain with numbness. Computed tomography revealed systemic lymphadenopathy and multiple bone lesions. Because malignant lymphoma with a mass lesion protruding into the vertebral canal was considered, he underwent urgent radiotherapy. Thereafter, a needle biopsy of the left parasternal node was performed and showed epithelioid granulomas, confirming a diagnosis of sarcoidosis. Since his neurologic symptoms improved, the patient was not given systemic corticosteroids. Radiotherapy may be useful for local control of bone sarcoidosis.

A single-arm phase II study of nab-paclitaxel for patients with chemorefractory non-small cell lung cancer.

BACKGROUND: We aimed to evaluate the efficacy and safety of nab-paclitaxel in patients with refractory advanced non-small cell lung cancer who failed previous chemotherapy. METHODS: Patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function. Patients received nab-paclitaxel, 100 mg/m2 i.v. on days 1, 8, and 15 every 4 weeks. The primary endpoint was the overall response rate. Secondary endpoints were the progression-free survival time, overall survival, and the toxicity profile. RESULTS: From July 2013 to July 2015, a total of 31 patients were enrolled. Fourteen patients received nab-paclitaxel as a second-line and 17 received it as an over third-line therapy. Each patient received a median of 5 treatment cycles (range, 1-11). The overall response rate was 19.3% (95% confidence interval, 9.1-36.2%) (complete response (n = 0), partial response (n = 6), stable disease (n = 17), and progressive disease (n = 8)). The median progression-free survival time was 4.5 months (95% confidence interval 3.5-6.3 months), median overall survival time was 15.7 months, and 1-year survival rate was 54.8%. Most common grade 3 or 4 non-hematological toxicities were elevated aspartate transaminase level (3.2%) and sensory neuropathy (9.6%). Neutropenia was the most common grade 3 or 4 adverse events (38.6%), and febrile neutropenia developed in 12.9% patients. No treatment-related deaths were observed in this study. CONCLUSION: Primary endpoint was met. Single agent nab-paclitaxel showed significant clinical efficacy and manageable toxicities for patients with chemorefractory advanced non-small cell lung cancer even if late line setting. TRIAL REGISTRATION: UMIN000011696 . The date of registration was July 11th, 2013.

Regression of Crizotinib-Associated Complex Cystic Lesions after Switching to Alectinib.

Crizotinib, which is effective in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, is sometimes associated with the generation of complex renal cysts. A 56-year-old man with ALK positive adenocarcinoma received crizotinib. Ten months after the introduction of crizotinib, a cystic lesion developed from his right kidney to the iliopsoas muscle, accompanied by fever, anemia, and hypoproteinemia. After 17 months of treatment, crizotinib was switched to alectinib, followed by the recovery of hypoproteinemia and systemic inflammation. Switching to alectinib may be beneficial in patients demonstrating crizotinib-associated complex renal cysts with systemic inflammation and exhaustion.

Dramatic response to alectinib in a patient of ALK-rearranged lung cancer with poor performance status.

BACKGROUND: Lung cancers with anaplastic lymphoma kinase rearrangements are highly sensitive to anaplastic lymphoma kinase tyrosine kinase inhibition, underscoring the notion that such cancers are addicted to anaplastic lymphoma kinase activity. Several anaplastic lymphoma kinase inhibitors have been identified and are being evaluated in clinical trials. However patients with poor performance status (3 or 4) were not involved in these clinical trials, it has been unclear to use anaplastic lymphoma kinase-tyrosine kinase inhibitors for these patients. Here, we report an anaplastic lymphoma kinase-positive non small cell lung cancer patient with performance status 4, who was successfully treated with alectinib. CASE PRESENTATION: We report on a 52-year-old patient diagnosed as non small cell lung cancer harboring echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. His performance status was 4 because of severe respiratory failure. We treated this patient with alectinib as the first line therapy. Dramatic response was obtained and his performance status improved from 4 to 1 without severe adverse events. CONCLUSION: Alectinib is a therapeutic option for the anaplastic lymphoma kinase positive patients with poor performance status.

Spurious Thrombocytosis Caused by Tumor Cell Lysis in a Patient with Acute Monocytic Leukemia.

BACKGROUND: Tumor lysis syndrome can occur after treatment of fast-growing cancers. Early detection of tumor lysis is crucial to minimize the toxic effects on organs and potentially life-threatening complications. METHODS: A patient with acute monocytic leukemia presented with spurious thrombocytosis. A peripheral blood smear was stained with alpha-naphthyl butyrate esterase to discriminate tumor cell fragments from platelets. RESULTS: Peripheral blood smears showed widespread leukemic cell fragmentation. Tumor lysis syndrome (TLS) after treatment for acute monocytic leukemia was diagnosed. The patient underwent chemo- and radiotherapy followed by umbilical cord blood transplantation and remains symptom-free two years after transplantation. CONCLUSIONS: For patients with thrombocytosis accompanied by bizarre scatter-grams on automatic hematologic analyzers, further diagnostic procedures should be performed to determine the exact cause of thrombocytosis.

Sepsis caused by Listeria monocytogenes during chemotherapy for small cell carcinoma of the thymus.

BACKGROUND: Listeria monocytogenes is a facultative intracellular parasitic bacterium that is Gram positive, catalase positive, oxidase negative, and a facultative anaerobe. It is known to infect humans through food. It is a bacillus with low virulence, but can cause meningitis and sepsis in infants and immunocompromised patients. CASE PRESENTATION: A case of 75-year-old Japanese female with small cell carcinoma of the thymus and pleural dissemination is described. She was treated with carboplatin and etoposide and showed a partial response. However, the tumor recurred 6 months later. Therefore, we again administered carboplatin and etoposide. Though peritoneal dissemination was suspected based on abdominal computed tomography findings after two courses, the assessment was stable disease. She was occasionally treated for constipation. She developed chills, rigor, and diarrhea, necessitating admission on the 7th day of the third course of chemotherapy. We suspected intestinal infection, and cefepime was thus administered. However, her blood pressure dropped and neutropenia manifested on the 4th day of admission. We therefore switched the antibiotic from cefepime to meropenem and also administered granulocyte-colony stimulating factor. Listeria monocytogenes was detected by two blood cultures, and the antimicrobial medication was thus switched to ampicillin, in consideration of sensitivity. Her general condition improved and she was able to leave the hospital on the 19th day after admission. CONCLUSIONS: During chemotherapy, factors such as impaired bowel movements, malnutrition, and myeloablation can contribute to the development of severe infections. It is necessary to comprehensively assess a patient's state and treat all aspects of illness.