Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-naïve advanced non-squamous non-small cell lung cancer with EGFR mutations.

Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I 'Quartet Trial' to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles. We examined the dose-limiting toxicity (DLT) to determine the maximum tolerated dose (MTD) and recommended dose (RD). Results Ten patients (3 men and 7 women) with a median age of 69 years were enrolled. Four and 6 patients had exon 19 and 21 mutations, respectively; 8 received maintenance therapy without unexpected or cumulative toxicities. One of 6 patients experienced grade 3 vagal reflex at 60 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab, which was designated the RD. Four patients experienced no DLT with 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab (designated the MTD); however, 3 underwent dose reduction due to severe toxicities (grade 3 gastrointestinal hemorrhage, skin rash, nausea, and febrile neutropenia) during induction chemotherapy. The most frequent DLT-phase adverse events were nausea, anorexia, and fatigue. The overall response rate was 100%. Furthermore, the progression-free and overall survival rates were 17.9 and 32.0 months, respectively. Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536).

Vascular responses to abrupt blood flow change after bypass surgery for complex intracranial aneurysms.

BACKGROUND: Bypass surgery for complex intracranial aneurysms (IAs) results in drastic blood flow changes in intracranial arteries. The aim of the study was to elucidate how vessels adapt to blood flow changes after bypass surgery with phase-contrast magnetic resonance imaging (PC-MRI). METHODS: This is a prospective observational study to assess changes of the blood flow in intracranial arteries after bypass surgery for IAs. Flow rates and vessel diameters were measured with PC-MRI in 52 intracranial arteries of 7 healthy volunteers and 31 arteries of 8 IA patients who underwent bypass surgery. Wall shear stress (WSS) was calculated with the Hagen-Poiseuille formula. In 18 arteries of 5 patients, the same measurement was performed 1, 3, and 12 months after surgery. RESULTS: PC-MRI showed a strong positive correlation between the flow rate and the third power of vessel diameter in both healthy volunteers (r = 0.82, P < 0.0001) and IA patients (r = 0.90, P < 0.0001), indicating the constant WSS. Of the 18 arteries in 5 patients, WSS increased in 7 arteries and decreased in 11 arteries immediately after surgery. In the WSS-increased group, WSS returned to the preoperative value in the third postoperative month. In the WSS-decreased group, WSS increased in the 12th month, but did not return to the preoperative level. CONCLUSIONS: In a physiological state, WSS was constant in intracranial arteries. Changed WSS after bypass surgery tended to return to the preoperative value, suggesting that vessel diameter and flow rate might be controlled so that WSS remains constant.

[CLINICAL STUDY OF 29 CASES OF ENDOBRONCHIAL TUBERCULOSIS].

[Background] Endobronchial tuberculosis (EBTB) is defined as a tuberculosis infection of the tracheobronchial tree and is often misdiagnosed as bronchial asthma or bron- chitis owing to a lack of typical imaging findings. [Aim] The aim of this study was to elucidate the clinical characteristics of EBTB. [Method] We retrospectively studied EBTB patients hos- pitalized at the National Hospital Organization Kinki-chuo Chest Medical Center (Sakai City, Japan) between January 2005 and April 2014. [Result] A total of 29 patients (8 men and 21 women) were enrolled in this study. The patients' ages ranged from 17 to 86 years. Cough was the most frequently reported symptom. The interval between the appearance of symptoms and an EBTB diagnosis was significantly longer than usual when there was an initial misdiagnosis of bronchial asthma. The most frequent finding of fiber-optic bronchoscopy performed after more than 1 month of treatment was a V-type scar based on Arai's classification system. [Conclusion] A misdiagnosis of EBTB as bronchial asthma leads to a significant delay in correct diagnosis and treat- ment. EBTB must be included in the differential diagnoses of chronic cough and airway constriction sound.

A case of eosinophilic pneumonia induced by lettuce.

A 56-year-old female lettuce farmer was admitted to the hospital with a low-grade fever, worsening cough, and dyspnoea. A blood test revealed eosinophilia and a high serum IgE concentration. The 3-year follow-up showed that her total IgE level increased in December, peaked in May, and suddenly decreased in August. This result was consistent with the lettuce harvest season. A chest x-ray taken on admission showed an infiltrative shadow in the upper lung field. Chest CT revealed patchy ground glass opacity on the upper lung field and thickening of the bronchial wall. The bronchoalveolar lavage fluid contained 8% eosinophils. She was treated with prednisolone, and her symptoms and radiological findings improved. The 37 kDa protein that reacted with the patient's sera was identified by immunoblot analysis.

Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment.

Vitamin B12 deficiency is associated with cognitive impairment, hyperhomocysteinemia, and hippocampal atrophy. However, the recovery of cognition with vitamin B12 supplementation remains controversial. Of the 1716 patients who visited our outpatient clinic for dementia, 83 had vitamin B12 deficiency. Among these, 39 patients (mean age, 80.1 ± 8.2 years) had undergone Mini-Mental State Examination (MMSE) and laboratory tests for vitamin B12, homocysteine (Hcy), and folic acid levels. The hippocampal volume was estimated using the z-score of the MRI-voxel-based specific regional analysis system for Alzheimer's disease. This is multi-center, open-label, single-arm study. All the 39 patients were administered vitamin B12 and underwent reassessment to measure the retested for MMSE and Hcy after 21−133 days (median = 56 days, interquartile range (IQR) = 43−79 days). After vitamin B12 supplementation, the mean MMSE score improved significantly from 20.5 ± 6.4 to 22.9 ± 5.5 (p < 0.001). Hcy level decreased significantly from 22.9 ± 16.9 nmol/mL to 11.5 ± 3.9 nmol/mL (p < 0.001). Significant correlation was detected between the extent of change in MMSE scores and baseline Hcy values. The degree of MMSE score was not correlated with hippocampal atrophy assessed by the z-score. While several other factors should be considered, vitamin B12 supplementation resulted in improved cognitive function, at least in the short term, in patients with vitamin B12 deficiency.

Resumption/efficacy and safety of an azithromycin-containing regimen against Mycobacterium avium complex lung disease in patients who experienced adverse effects with a clarithromycin-containing regimen.

BACKGROUND: Antibiotic therapy, including clarithromycin (CLR), has been widely used for the management of Mycobacterium avium complex (MAC) lung disease in clinical settings. When patients develop adverse events (AEs) during CLR-based treatment, the treatment regimen is modified or chemotherapy itself is discontinued. The need for alternative macrolide treatment strategies is emphasized due to the high rate of AEs possibly caused by CLR. Thus, the current study aimed to examine the efficacy and safety of azithromycin (AZM) in patients with MAC lung disease whose treatment was switched from CLR to AZM. METHODS: We performed a retrospective study of patients with MAC lung disease. The inclusion criteria were as follows: (1) patients who experienced AEs during treatment with antibiotics, including CLR, between December 2012 and November 2017, and (2) those who had antimicrobial therapy that was switched from CLR to AZM. The efficacy and safety of AZM during the clinical course of the disease after switching the regimen from CLR to AZM were investigated. RESULTS: Antibiotic therapy was switched in 31 patients who presented with AEs including drug-induced fever, rash, dysgeusia, liver dysfunction, and neutropenia during treatment with CLR-containing regimens. After switching to AZM, the median duration of treatment was 1286 (364-4615) days. During follow-up, 13 patients had a negative conversion of sputum culture. CONCLUSIONS: AZM may be safe and effective for patients with MAC lung disease who have difficulty tolerating CLR. In patients who experienced AEs possibly caused by CLR, switching from CLR to AZM might be an appropriate strategy.

Influences of Folate Supplementation on Homocysteine and Cognition in Patients with Folate Deficiency and Cognitive Impairment.

Although folate deficiency was reported to be associated with hyperhomocysteinemia, influence of folate supplementation on cognition remains controversial. Therefore, we explored the effects of folate supplementation on the cognition and Homocysteine (Hcy) level in relatively short periods in patients with folate deficiency and cognitive impairment. Enrolled 45 patients (mean age of 79.7 ± 7.9 years old) with folate deficiency (<3.6 ng/mL) with cognitive impairment underwent Mini-Mental State Examination (MMSE), and laboratory examinations, including folate, vitamin B12, and Hcy. The degree of hippocampal atrophy in MRI was estimated using a voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). Patients were administrated folate (5 mg/day), then Hcy, and MMSE score were re-examined after 28 to 63 days. Mean Hcy significantly decreased from 25.0 ± 18.0 to 11.0 ± 4.3 nmol/mL (p < 0.001). Average MMSE scores also significantly changed from 20.1 ± 4.7 to 22.2 ± 4.3 (p < 0.001). The degree of change in the MMSE score and basic Hcy or Hcy change was significantly positively correlated, while degree of hippocampal atrophy in MRI did not. Although several factors should be taken into account, folate supplementation ameliorated cognitive impairment, at least for a short period, in patients with folate deficiency.

Clinical Features of Nontuberculous Mycobacterial Pleurisy: A Review of 12 Cases.

Objective The incidence of pulmonary nontuberculous mycobacterial (NTM) infections has increased in recent decades. Nevertheless, NTM pleurisy is still a rare disease. The objective of the present study was to elucidate the clinical features and outcomes of NTM pleurisy. Methods A retrospective study was undertaken of consecutive patients whose pleural effusion culture yielded NTM, from 2002 to 2016 at a respiratory hospital in Japan. The clinical features, treatment, and outcomes of these patients were analyzed. Result The 12 patients with NTM pleurisy were predominantly male, with a median age of 69 years (range, 48-93 years). They included eight patients with a history of smoking and six patients with immunosuppressive comorbidities such as malignancy, diabetes mellitus, and conditions requiring steroid administration. Fibrocavitary disease was the most common radiographic feature of these patients, and Mycobacterium avium complex was the most common pathogen. Pneumothorax was complicated in 11 patients. Surgery was performed on seven patients, in addition to thoracic drainage for the treatment of pleurisy and pneumothorax. Three patients died of respiratory failure. Conclusion Pneumothorax is a frequent complication of NTM pleurisy, often making the condition difficult to treat. Surgery at an appropriate time should therefore considered for refractory cases.

Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer.

BACKGROUND/AIM: Although immune checkpoint inhibitors play an important role in the therapy of lung cancer, they are associated with various immune-related adverse events and predictive factors of them are unclear. In this study, we investigated predictive factors of nivolumab-induced hypothyroidism which is one of the adverse events in patients with lung cancer. PATIENTS AND METHODS: Patients with non-small-cell lung cancer who were administered nivolumab at our hospital between December 2015 and May 2016 were retrospectively enrolled. The thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were analyzed. RESULTS: Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The TPO and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism. CONCLUSION: TPO and thyroglobulin antibody levels at baseline may be predictive of hypothyroidism.

Analysis of the impact of lung cancer treatment on nontuberculous mycobacterial lung diseases.

BACKGROUND: Although nontuberculous mycobacteria (NTM) lung diseases can occur in association with lung cancer, no study has evaluated the effect of lung cancer treatment on NTM lung diseases. Therefore, the present study aimed to retrospectively examine the effect of lung cancer treatment on NTM lung diseases. METHODS: Patients diagnosed with NTM lung diseases in combination with cytologically or histologically proven lung cancer between January 1, 2010 and October 31, 2014 were enroled. The clinical history of eligible patients was retrospectively reviewed. RESULTS: Seven hundred twenty-eight patients were diagnosed with NTM lung diseases. Among these patients, 29 (3.9%) also had lung cancer. Of the 29 patients with NTM and lung cancer, 62% had Mycobacterium avium complex as the pathogenic organism. The most common lung cancer histology was adenocarcinoma (62.1%). Anti-cancer cytotoxic chemotherapy was administered to seven patients, and the two patients who did not receive NTM treatment showed worsening of their NTM lung disease. CONCLUSION: Whether NTM lung disease should be treated during anti-cancer chemotherapy has not been not clarified by this study. Induction of anti-NTM therapy should be made after careful consideration, because the duration of anti-NTM treatment is long and anti-mycobacterial drugs have extensive effects on anti-cancer drugs. However, we think that anti-NTM therapy should be introduced after consideration of the worsening of symptoms and radiological findings associated with NTM lung disease.

Efficacy of nanoparticle albumin-bound paclitaxel regimens for relapsed small cell lung cancer: A retrospective analysis.

Although small cell lung cancer (SCLC) is initially sensitive to chemotherapy, it recurs in most cases. Standard regimens for salvage chemotherapy have not been established, and the prognosis of relapsed SCLC remains poor. In the present study, we investigated the clinical efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimens for the treatment of relapsed SCLC.In this retrospective multicenter analysis, 14 patients (3 women and 11 men; median age 71 years) with relapsed SCLC received nab-paclitaxel alone or in combination with carboplatin between February 2013 and July 2014. The safety and efficacy of the regimens were evaluated.The response rates, disease control rates, and median overall survival for the total patient population were 36%, 64%, and 7.8 months, respectively. Response rates, disease control rates, and the median overall survival were 11%, 44%, and 4 months, respectively, in the monotherapy group; and 80%, 100%, and 10.6 months, respectively, in the combination therapy group. The most common adverse events were hematological toxicities such as neutropenia and anemia. Severe neutropenia appeared in some patients, although it was resolved by treatment in all. The most common nonhematological toxicity was anorexia (64%), followed by neurotoxicity and constipation. All nonhematological toxicities were mild and manageable.Our results suggest that chemotherapy with nab-paclitaxel regimens for relapsed SCLC exhibits moderate clinical efficacy and is well-tolerated. Further clinical trials in relapsed SCLC patients are warranted.

Combination of virtual bronchoscopic navigation, endobronchial ultrasound, and rapid on-site evaluation for diagnosing small peripheral pulmonary lesions: a prospective phase II study.

BACKGROUND: The diagnostic yield of peripheral pulmonary lesions (PPLs) by flexible bronchoscopy (FB) is still insufficient. To improve the diagnostic yield of bronchoscopy, several techniques such as endobronchial ultrasound (EBUS), virtual bronchoscopic navigation (VBN), and rapid on-site evaluation (ROSE) have been examined. The primary purpose of the present study was to evaluate the usefulness of combining EBUS, VBN, and ROSE for diagnosing small PPLs. METHODS: Patients with PPLs 30 mm or less on chest computed tomography (CT) were prospectively enrolled. We determined the responsible bronchus for the target lesions using VBN before bronchoscopy was performed. EBUS and ROSE were performed during the examination to determine whether the bronchus and specimen were adequate. On the basis of previous studies, we assumed that the diagnostic yield of 85% among eligible patients would indicate potential usefulness, whereas, the diagnostic yield of 75% would indicate the lower limit of interest. The required number of patients was estimated as 45 for a one-sided α value of 0.2 and a ß value of 0.8. The primary study endpoint was the diagnostic yield. RESULTS: Between June 2014 and July 2015, we enrolled 50 patients in the present study, and we excluded 5 patients. The total diagnostic yield of 45 PPLs was 77.7%. In cases of lung cancer, the diagnostic yield was 84.2%. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were 90.6%, 92.3%, 96.7%, and 80.0%, respectively. The diagnostic yield of PPLs from 20 to 30 mm was 87.5%, and the diagnostic yield of PPLs less than 20 mm was 66.7%. PPLs for which the probe was located within the lesion had the highest diagnostic yield. CONCLUSIONS: We could not demonstrate usefulness for diagnosing small PPLs by combining EBUS, VBN, and ROSE. However, combining these techniques may be useful for diagnosing lung cancer.