Association between preexisting lung involvements and the risk of diffuse alveolar hemorrhage in patients with microscopic polyangiitis: A multi-center retrospective cohort study.

Objectives: To identify the factors associated with the risk of diffuse alveolar hemorrhage (DAH) in patients with microscopic polyangiitis (MPA), focusing on other preexisting lung involvements such as interstitial lung disease (ILD) and airway disease.Methods: In this retrospective cohort study, we analyzed consecutive patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive MPA who had undergone chest computed tomography (CT) before starting treatment between 2006 and 2016. Patients who already had DAH at initial CT imaging were excluded. CT images were evaluated for the presence of ILD and airway disease. The association between preexisting lung involvements and the development of DAH was assessed using logistic regression models adjusted for various clinical characteristics.Results: We identified 113 patients (median age 72 years; median follow-up duration 39 months), and 27 (24%) of them developed DAH during the follow-up. Airway disease was identified in 41 (36%) patients and was independently associated with the development of DAH (adjusted odds ratio 6.86, 95% confidence interval 1.85-25.4). However, ILD identified in 45 (40%) patients was not associated with DAH.Conclusion: Our findings suggest that DAH in MPA occurs frequently in patients with airway disease. Attention to preexisting airway disease may help predict the development of DAH.

Osimertinib in Elderly Patients with Epidermal Growth Factor Receptor T790M-Positive Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment: A Phase II Trial.

LESSONS LEARNED: Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. BACKGROUND: Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. RESULTS: A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. CONCLUSION: Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

Two Cases of Lung Abscess and Pleuritis in Severe COVID-19 Patients.

We report two patients who were treated with remdesivir, steroids, and tocilizumab for severe coronavirus disease 2019 (COVID-19) and developed lung abscesses and pleuritis. Although complications due to bacterial infections are often reported in COVID-19 patients, these severe infections are rare. Patients receiving tocilizumab are at a high risk of developing serious bacterial infections, and the diagnosis is often delayed because symptoms such as fever and elevated C-reactive protein levels are often minimal. The possibility of complications owing to severe bacterial infections should be considered when treating patients with severe COVID-19.

Cytokine Release Syndrome with Relative Adrenal Insufficiency Induced by Ipilimumab and Nivolumab Combination Therapy for Clear Cell Renal Cell Carcinoma.

Combination therapy with ipilimumab and nivolumab is indicated for many types of cancers; however, several patients experience immune-related adverse events (irAEs). We herein report a case of cytokine release syndrome (CRS) in a 63-year-old woman with stage IV left clear cell renal cell carcinoma. Our patient developed CRS while taking prednisolone, 43 days after the start of ipilimumab and nivolumab administration. The patient was treated with steroid pulse therapy, which improved the symptoms of shock and respiratory failure. Increased vascular permeability and relative adrenal insufficiency are considered to be the main pathogeneses. The early administration of high-dose steroids is crucial as a replacement for corticosteroids.

Non-small Cell Lung Cancer With Proto-Oncogene B-Raf V600E Presenting a Distinctive Clinical Course: A Case Report.

Cases of proto-oncogene B-Raf (BRAF) V600E mutation are rare, accounting for 1%-4% of non-small cell lung cancers (NSCLCs), and its clinical features remain unclear. Here, we report a case of BRAF mutation-positive lung adenocarcinoma with an atypical clinical course and long-term survival. The patient was a 63-year-old female nonsmoker who was diagnosed with stage IA adenocarcinoma after surgical resection. Five years after the surgery, cancer recurred and was treated with various cytotoxic anticancer agents. During the course of treatment, the patient was found to be BRAF V600E mutation-positive and was treated with molecular-targeted drugs. Although multiple brain, subcutaneous, and tonsillar metastases appeared, the progression was significantly slower, and the patient survived for 14 years and three months after the diagnosis. There have been few case reports of long-term survival in BRAF-positive lung cancer, and more cases need to be accumulated in the future to gather more information. Based on this case, we speculate that sensitivity to cytotoxic anticancer agents such as pemetrexed (PEM) and maintenance of performance status (PS), in addition to molecular-targeted agents, are important for long-term survival.

Exacerbation of Eosinophilic Granulomatosis With Polyangiitis After Administering Dupilumab for Severe Asthma and Eosinophilic Rhinosinusitis With Nasal Polyposis.

Eosinophilic granulomatosis with polyangiitis (EGPA) refers to systemic vasculitis in patients with bronchial asthma and eosinophilic rhinosinusitis. Dupilumab has been approved for the treatment of asthma, eosinophilic rhinosinusitis, and atopic dermatitis. A man in his 50s with a history of asthma and eosinophilic rhinosinusitis with nasal polyposis developed high fever and dyspnea while undergoing dupilumab treatment. Laboratory examinations identified hypereosinophilia. Chest radiography and computed tomography revealed right-sided tracheal dislocation, extensive consolidation, and ground-glass opacities with traction bronchiectasis. Evidence of interstitial pneumonia, eosinophilia, and increased eosinophil counts in the bronchoalveolar lavage fluid was observed. We diagnosed the patient with EGPA and administered corticosteroids, which improved his symptoms and radiographic signs. Although the relationship between EGPA and dupilumab treatment is unclear, EGPA may have been exacerbated by dupilumab in this case. Therefore, when administering dupilumab to patients with partial symptoms of EGPA, care should be taken to monitor for adverse symptom development and exacerbation.

Pembrolizumab monotherapy for untreated PD-L1-Positive non-small cell lung cancer in the elderly or those with poor performance status: A prospective observational study.

Objectives: We investigated the efficacy and safety of pembrolizumab monotherapy as first-line treatment for poor Eastern Cooperative Oncology Group performance status (PS) and elderly patients with programmed cell death-ligand 1 (PD-L1)-positive advanced non-small cell lung cancer (NSCLC). We also investigated clinical prognostic factors for the efficacy of pembrolizumab monotherapy, based on patient characteristics. Materials and methods: In this prospective observational study, PS-2 and elderly NSCLC patients with PD-L1 tumor proportion score (TPS) ≥1% who received first-line pembrolizumab monotherapy, from October 2019 to March 2021, at 10 institutions in Japan were enrolled. Patients judged eligible by their physicians for combined chemotherapy and PD-1/PD-L1 inhibitors as first-line treatment were excluded. Clinicopathological characteristics and adverse events were investigated for correlation with clinical outcomes. Results: Forty patients were enrolled in the study. The median progression-free survival (PFS) of patients with PS 2 and those aged ≥ 75 years were 4.4 (95% confidence interval [CI]: 0.9-14.4) months and 5.3 (95% CI 2.9-9.4) months, respectively. The median overall survival (OS) of patients with PS 2 and those aged ≥ 75 years were 11.6 (95% CI: 1.4-not evaluable [NE]) months and 11.6 (95% CI 7.4-18.1) months, respectively. Immune-related adverse events (irAEs) were observed in 19 patients; 6 patients had severe irAEs of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher. Patients who achieved stable disease or better, had a statistically significant increase in PFS (p < 0.001) and OS (p < 0.001). In the multivariate analysis, the acquisition of disease control with pembrolizumab monotherapy was an independent prognostic factor for PFS and OS. Conclusion: Pembrolizumab monotherapy was relatively effective and tolerable as a first-line treatment for patients with PD-L1-positive advanced NSCLC who had poor PS or were elderly. Our results suggest that disease control might be an independent prognostic factor for PFS and OS in this population. (UMIN000044052 https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050176).

Prognostic Nutritional Index and Lung Immune Prognostic Index as Prognostic Predictors for Combination Therapies of Immune Checkpoint Inhibitors and Cytotoxic Anticancer Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer.

Combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapies (chemoimmunotherapy) is associated with significantly better survival outcomes than cytotoxic chemotherapies alone in patients with advanced non-small cell lung cancer (NSCLC). However, there are no prognostic markers for chemoimmunotherapy. The prognostic nutritional index (PNI) and lung immune prognostic index (LIPI) are prognostic biomarkers for immune checkpoint inhibitor (ICI) monotherapy or cytotoxic chemotherapies. Thus, we aimed to examine whether these factors could also be prognostic markers for chemoimmunotherapy. We retrospectively examined 237 patients with advanced NSCLC treated with chemoimmunotherapy. In the total group, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 8.6 months. Multivariate analysis of OS and PFS revealed significant differences based on PNI and LIPI. Programmed cell death ligand 1 (PD-L1) was also significantly associated with OS and PFS. PNI and a PD-L1 tumor proportion score (TPS) of <50% and poor LIPI (regardless of PD-L1 TPS) were associated with poor prognosis. PNI and LIPI predicted survival outcomes in patients with advanced NSCLC treated with chemoimmunotherapy, especially in patients with PD-L1 TPS <50%. For patients in this poor category, chemoimmunotherapy may result in a worse prognosis than expected.

Prolonged persistence of SARS-CoV-2 infection during A+AVD therapy for classical Hodgkin's lymphoma: A case report.

We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.

A case of non-small cell lung cancer with danazol-dependent aplastic anemia induced by pembrolizumab.

Programmed cell death protein 1 immune checkpoint inhibitor is an effective treatment for non-small cell lung cancer. Although hematological immune-related adverse events induced by antiprogrammed-cell-death-protein-1 immunotherapy have been reported, they are rare, and there remain many unknowns. We report the case of a 77-year-old woman with non-small cell lung cancer and pembrolizumab-induced danazol-dependent aplastic anemia. Sixteen days after she received pembrolizumab with carboplatin and pemetrexed as first-line treatments, she developed pancytopenia, including severe thrombocytopenia (1 × 109/L) with oral bleeding, epistaxis, and systemic purpura. We initially diagnosed immune-related thrombocytopenia based on an elevated level of platelet-associated immunoglobulin G (922ng/107 cells), but her thrombocytopenia was refractory to prednisolone (1mg/kg) and thrombopoietin receptor agonists. We eventually diagnosed aplastic anemia based on the findings of bone marrow hypoplasia. Treatment with cyclosporine and danazol 300mg (7.5mg/kg) was initiated. Eighteen days later, her blood cell count increased, and we reduced danazol to 100mg. Twenty-four days after the reduction of danazol, her platelet count dropped again to 14 × 109/L; subsequently, increasing danazol improved her platelet count in a few days. Although aplastic anemia was recovered, she died owing to lung cancer progression. In this case, the thrombocytopenia was noticeable initially; however, pancytopenia appeared a month later, and we diagnosed her with aplastic anemia. Platelet counts improved rapidly with the use of danazol. No effective treatment has yet been established for aplastic anemia induced by antiprogrammed-cell-death-protein-1 immunotherapy, but our case suggests that danazol is an effective therapy.

[A case of Goodpasture's syndrome complicated with cytomegalovirus pneumonia during treatment with plasma exchange and immunosuppressive therapy].

A 63-year-old man presented to another hospital with hematuria and an elevated serum creatinine level. He was admitted, and hemodialysis was initiated. One month after admission, hemoptysis developed and the patient was referred to our hospital for further evaluation. Goodpasture's syndrome was diagnosed on the basis of elevated anti-glomerular basement membrane (anti-GBM) antibody levels. Due to massive alveolar hemorrhage, the patient was treated with plasma exchanges, pulse methylprednisolone and pulse cyclophosphamide followed by oral prednisolone, which lowered his anti-GBM antibody level. However, a chest radiograph obtained on the 56th hospital day showed bilateral ground glass opacities, and his condition deteriorated. Since his blood was positive for the cytomegalovirus pp65 antigen, ganciclovir was started. This improved his condition, with improvement in his chest radiograph and a decrease in the number of antigen-positive cells. It is important to consider the development of cytomegalovirus infection during the treatment of Goodpasture's syndrome with immunosuppressive therapy.

High levels of anti-SSA/Ro antibodies in COVID-19 patients with severe respiratory failure: a case-based review : High levels of anti-SSA/Ro antibodies in COVID-19.

We treated two patients with severe respiratory failure due to coronavirus disease 2019 (COVID-19). Case 1 was a 73-year-old woman, and Case 2 was a 65-year-old-man. Neither of them had a history of autoimmune disease. Chest computed tomography scans before the antiviral therapy showed bilateral multiple patchy ground-glass opacities (GGO) consistent with COVID-19 pneumonia. The GGO regressed over the course of the antiviral treatment; however, new non-segmental patchy consolidations emerged, which resembled those of interstitial lung disease (ILD), specifically collagen vascular disease-associated ILD. We tested the patients' sera for autoantibodies and discovered that both patients had high anti-SSA/Ro antibody titers. In Case 1, the patient recovered with antiviral therapy alone. However, in Case 2, the patient did not improve with antiviral therapy alone but responded well to corticosteroid therapy (methylprednisolone) and made a full recovery. The relationship between some immunological responses and COVID-19 pneumonia exacerbation has been discussed previously; our discovery of the elevation of anti-SSA/Ro antibodies suggests a contribution from autoimmunity functions of the immune system. Although it is unclear whether the elevation of anti-SSA/Ro antibodies was a cause or an outcome of aggravated COVID-19 pneumonia, we hypothesize that both patients developed aggravated the COVID-19 pneumonia due to an autoimmune response. In COVID-19 lung injury, there may be a presence of autoimmunity factors in addition to the known effects of cytokine storms. In patients with COVID-19, a high level of anti-SSA/Ro52 antibodies may be a surrogate marker of pneumonia severity and poor prognosis.

Impact of preexisting antinuclear antibodies on combined immunotherapy and chemotherapy in advanced non-small cell lung cancer patients.

Combined immunotherapy and chemotherapy is a promising standard treatment in patients with advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the relationship between the combined therapy and pretreatment serum antinuclear antibody (ANA) levels as a prognostic indicator in patients with NSCLC. We retrospectively analyzed patients with advanced NSCLC who were treated with combinatorial immunotherapy and chemotherapy between January and December 2019 at six institutions in Japan. Relationship between ANA status and patients' characteristics were reviewed. A total of 77 patients with advanced NSCLC were enrolled in the study. Patients were divided into ANA-positive (ANA ≥ 1:160) and ANA-negative (ANA < 1:160) groups. The ANA-positive group tended to have a shorter progression-free survival and significantly shorter overall survival in univariate (hazard ratio [HR], 2.11, 95% confidence interval [CI] 0.88-5.07, p = 0.093; and HR 3.11, 95% CI 1.14-8.49, p = 0.027, respectively) and multivariate (HR 1.90, 95% CI 0.77-4.68, p = 0.16; and HR 3.37, 95% CI 1.15-9.86, p = 0.027, respectively) analyses than ANA-negative group. The incidence of discontinuation of all treatment components due to severe adverse events was significantly higher in the ANA-positive than in ANA-negative group (50% vs. 15.9%, p = 0.042). The study showed that the presence of antinuclear antibodies may result in a poor prognosis in patients treated with combinatorial immunotherapy and chemotherapy, although further prospective investigations are needed.

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9-17.5), and the median OS was 22.0 months (95% CI: 16.0 months-not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3-4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old.

Carcinoembryonic antigen and CYFRA 21-1 responses as prognostic factors in advanced non-small cell lung cancer.

BACKGROUND: It is unclear whether changes in serum tumor marker expression post-treatment are of prognostic value. We investigated the associations between changes in serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) after first-line treatment and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: Advanced NSCLC patients (April 2010 to December 2015) with elevated serum CEA or CYFRA 21-1 were included. The associations between tumor marker changes after treatment initiation and OS were analyzed. RESULTS: Ninety-six and 55 patients were CEA- and CYFRA 21-1-positive, respectively. The serum CEA response at 4 months and CYFRA 21-1 responses at 1 and 4 months were significantly associated with OS in the univariate analyses (P=0.025, P=0.016 and P<0.001, respectively). Moreover, in the multivariate analyses, serum CYFRA 21-1 response at 4 months was significantly associated with improved OS (P=0.038). CONCLUSIONS: In NSCLC patients, serum CEA and CYFRA 21-1 responses after treatment initiation may predict longer OS.

Prognostic impact of pleural effusion in EGFR-mutant non-small cell lung cancer patients without brain metastasis.

BACKGROUND: In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), brain metastasis is known as a poor prognosis factor. However, prognostic factors in the patients without brain metastasis remain unclear. In this study, we aimed to clarify the differences between metastatic site and prognosis in common EGFR-mutant NSCLC patients without brain metastasis. METHODS: Chemotherapy-naïve, advanced EGFR-mutant NSCLC patients without brain metastasis diagnosed between January 2010 and March 2016 were enrolled. We evaluated prognosis according to the presence or absence of bone metastases, liver metastasis, and pleural effusion. RESULTS: A total of 50 EGFR-mutant NSCLC patients without brain metastasis were enrolled. The median progression-free survival and overall survival were significantly shorter in patients with pleural effusion than in those patients without (progression-free survival 7.0 months, 95% confidence interval [CI] 3.7-13.0 vs. 13.0 months, 95% CI 9.1-21.7, hazard ratio [HR] 2.29, 95% CI 1.11-4.73, P = 0.020; overall survival 19.5 months, 95% CI 5.7-28.8 vs. 55.3 months, 95% CI 24.0-not evaluable, HR 3.00, 95% CI 1.35-6.68, P = 0.005). Pleural effusion was an independent factor of poor prognosis for progression-free survival (HR 3.44, 95% CI 1.50-7.88, P = 0.003) and overall survival (HR 2.34, 95% CI 1.00-5.44, P = 0.049). CONCLUSION: Pleural effusion might be a poor prognosis factor for advanced EGFR-mutant NSCLC patients without brain metastasis treated with first-generation EGFR-tyrosine kinase inhibitors. Further precision medicine according to the metastatic site is required.

BK virus pneumonia following stem cell transplantation against diffuse large B-cell lymphoma.

The patient, a 70-year-old woman with diffuse large B-cell lymphoma (DLBCL), developed haemorrhagic cystitis associated with the BK virus (BKV) and adenovirus type 11. Moreover, chest computed tomography showed ground-glass opacity (GGO) in the bilateral upper lobe, and we performed bronchoalveolar lavage (BAL). The BKV DNA load was elevated not only in blood but also in BAL fluid (BALF), leading to the diagnosis of BKV pneumonia. After administering cidofovir, the respiratory symptoms and GGO abated. Therefore, detection of BKV DNA in BALF is useful for diagnosing BKV pneumonia. The patient with DLBCL developed BKV pneumonia. We performed BAL, and BKV DNA load was elevated on BALF. The detection of BKV DNA in BALF is useful for diagnosing BKV pneumonia.

Pulmonary pleomorphic carcinoma with pseudoprogression during nivolumab therapy and the usefulness of tumor markers: A case report.

Pseudoprogression was reported as one of the unconventional responses during immune checkpoint inhibitor therapy. A 70-year-old man with pulmonary pleomorphic carcinoma received nivolumab therapy. Pleural effusion and pulmonary metastasis increased, however then shrank and serum cytokeratin 19 fragment levels decreased. Serum tumor marker might help to distinguish pseudoprogression.

An observational study of the epidermal growth factor receptor-tyrosine kinase inhibitor resistance mechanism in epidermal growth factor receptor gene mutation-positive non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation show a high response to EGFR-tyrosine kinase inhibitor (EGFR-TKI). Clinically, EGFR-positive NSCLC acquires several resistance mechanisms during EGFR-TKI treatment, such as the emergence of a secondary mutation (T790M), MET gene amplification, and transformation to small cell lung cancer. However, the mechanism of resistance to afatinib, a second-generation EGFR-TKI, remains unclear. In this study, we prospectively investigate the mechanism of resistance to afatinib using proteomic analyses.In total, 35 EGFR-positive NSCLC patients of both sexes and ≥20 years old will be included. NSCLC patients with major obstacles in major organs, such as bone marrow, heart, lung, liver, and kidney, will be excluded. Eligible patients will be administered afatinib or gefitinib until disease progression and proteomic analysis will be performed with biopsy samples before treatment and at disease progression.The primary outcome is to detect the potential predictive anomalies in proteins that can be candidates for the resistance factor of afatinib. The secondary outcome is to detect gene and protein abnormalities affecting progression-free survival, response rate, and rate of disease control in afatinib therapy.The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. The results of the study will be disseminated via publications in peer-reviewed journals.Trial registration number is UMIN000031013.

[Surgical management of eight cases of bronchiectasis].

Few reports are currently available on the surgical management of bronchiectasis. We report our experience with 8 cases of bronchiectasis. The indications of pulmonary resection were recurrent pneumonia and/or hemoptysis in spite of medical treatment and the extent mainly limited to the unilateral lung. With the exception of one patient, who died from postoperative pneumonia, all patients showed improvement in symptoms. However, in two cases, hemoptysis recurred; these patients had cystic bronchiectasis, Pseudomonas aeruginosa infections and minimal disease in the contralateral lung, which accounted for the recurrence of hemoptysis. A few reports indicated that cystic bronchiectasis and incomplete resection were adverse prognostic factors and that Pseudomonas aeruginosa infections were related to the development of new bronchiectasis. However, according to some other reports, these factors were not adverse prognostic factors. It is thought that the analysis of many cases is required to determine the indication of lung resection and the appropriate type of resection for bronchiectasis; however, it is difficult to conduct randomized control studies. Since the accumulation of case reports is also considered to be important, we report our series of cases.