Clinical Characteristics of Severe Refractory Asthma Associated with the Effectiveness of Bronchial Thermoplasty.

We investigated the clinical characteristics of refractory asthma associated with the effectiveness of bronchial thermoplasty (BT). We retrospectively evaluated data from 10 patients who underwent BT between June 2016 and December 2017 at Okayama Medical Center. The following were measured before and 6 months post-BT: forced expiratory volume in 1.0 s (FEV1), fractional exhaled nitric oxide (FeNO), immunoglobulin E (IgE) level, blood eosinophil counts (Eosi), Asthma Quality of Life Questionnaire (AQLQ) score, and preventive medication use. At baseline, the mean post-bronchodilator FEV1 was 80.9% of the predicted value (range 45.6-115.7%). All patients were being treated with moderate- or high-dose inhaled corticosteroids and long-acting ß2 agonists. The AQLQ improved from 4.26±1.67 at baseline to 5.59±0.94 at 6 months post-BT (p<0.05). The %FEV1, FeNO, IgE, and Eosi did not change significantly between baseline and 6 months post-BT. No severe complications were reported. BT was effective for non-allergic and non-eosinophilic in 3 patients, and allergic or eosinophilic in 4 patients. Their AQLQ improved by > 0.5 points post-BT. For both allergic and eosinophilic asthmatics following mepolizumab, BT was not useful. BT was effective for non-allergic and non-eosinophilic or allergic asthmatics, but insufficient for both allergic and eosinophilic following mepolizumab.

A case of colorectal cancer with double-activating epidermal growth factor receptor mutations.

We describe the case of a 72-year-old woman with locally advanced lung tumor mimicking primary lung cancer. She was diagnosed with rectal cancer at the age of 65 years and was initially treated with platinum-based chemotherapy and thoracic irradiation as a treatment for primary lung cancer. One year later, a thyroid tumor was detected in her right thyroid lobe and was confirmed to have metastasized from rectal cancer based on pathological findings. Therefore, we suspected that she had metachronous double cancers and treated her with conventional chemotherapy for colorectal cancer. However, new life-threatening multiple lung metastases appeared. We treated her with the drug erlotinib because additional genetic analysis against primary lung tumor revealed typical double-activating epidermal growth factor receptor mutations. Histological review by immunostaining concluded that the primary lung tumor was composed of metastatic tumors from rectal cancer. In addition, genetic analysis revealed that the primary rectal cancer contained nearly the same types of double-activating epidermal growth factor receptor mutations as were present in the lung tumor. This is the first report of a case of rectal adenocarcinoma with double-activating epidermal growth factor receptor mutations.

[A case of small cell lung cancer that presented with paraneoplastic syndrome].

A 65-year-old man had suffered from systemic erythema from November 2008 and had noticed gradually progressing weakness in the upper and lower limbs. He received medical treatment in another hospital but his symptoms did not improve. He was admitted to our hospital for treatment of diabetes in June 2009, and his chest X-ray images and CT scans showed a mass shadow in the right upper lobe with hilar and mediastinal lymphadenopathy. We performed bronchoscopy, and diagnosed small cell lung cancer (T2N2M1, stage IV). However, he had hand grip weakness and continuing upper and lower limb muscle weakness, and therefore electromyography was performed, which showed the presence of waxing in the right leg. Subsequently, a diagnosis of Lambert-Eaton myasthenic syndrome was made. As he also showed ataxia of the left lower extremity, we also diagnosed paraneoplastic cerebellar degeneration. We gave the patient chemotherapy consisting of carboplatin and etoposide which resulted in the disappearance of his waxing, and his grip strength and erythema immediately improved with regression of the tumor after 1 course of chemotherapy. We report a case of small cell lung cancer associated with Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration and erythema which presented as paraneoplastic syndrome, which improved with chemotherapy.

Sex difference in the influence of smoking status on the responsiveness to gefitinib monotherapy in adenocarcinoma of the lung: Okayama Lung Cancer Study Group experience.

BACKGROUND: Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma. METHODS: We reviewed the clinical records of 260 Japanese patients with lung adenocarcinoma who received gefitinib therapy (250 mg/day), and whose smoking status was known. Tumour response and survival were evaluated and stratified by smoking status and gender. RESULTS: Among the 260 patients, 157 were male (60%). Median pack-years was 40 (range 8-160) and 23 (range 1-74) in male and female smokers, respectively. Objective response was observed in 62 (23.8%) of the 260 patients, and 1-year overall survival and progression-free survival were 45.1 and 24.3%, respectively. Multivariate analysis revealed that smoking status (pack-years) was an independent predictive factor for response to gefitinib [odds ratio (OR) = 0.971, 95% confidence interval (CI) = 0.947-0.995; P = 0.0159] in male patients, but not in female patients (OR = 0.999, 95%CI = 0.957-1.042). Additionally, pack-years significantly influenced the overall survival in males (hazard ratio = 1.010; 95%CI = 1.002-1018, P = 0.0169), while differential survival of females was not significantly predicted by this factor (P = 0.7639). CONCLUSIONS: In male patients with lung adenocarcinoma, cumulative smoking significantly affected response and survival following gefitinib treatment, while in female patients, responsiveness to gefitinib was independent of smoking status. These results suggest that the influence of smoking habit on responsiveness to gefitinib is gender specific.

[Patient with autoimmune alveolar proteinosis who did not respond to GM-CSF inhalation therapy and underwent repeated whole-lung lavage].

A 63-year-old man visited our department due to dry cough in September 2005. Chest radiography showed an infiltrative shadow extending from the bilateral hila to the peripheral areas. Chest CT scanning revealed a crazy-paving appearance. Bronchoalveolar lavage and transbronchial lung biopsy confirmed alveolar proteinosis. In addition, based on the absence of an underlying disease and a high titer of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody, a diagnosis of autoimmune alveolar proteinosis was made. His course was observed on an outpatient basis because of mild symptoms, but dyspnea on exertion gradually increased. In July 2007, GM-CSF inhalation therapy was initiated in another hospital, but no improvement was observed. In November of the same year, he underwent whole-lung lavage for one lung followed by that for the other at our department. The symptoms rapidly improved after the lavage but were aggravated again after 6 months. In May 2008, whole-lung lavage was performed again. There have been no reports of adults with autoimmune alveolar proteinosis who did not respond to GM-CSF inhalation therapy and who underwent whole-lung lavage twice. GM-CSF inhalation therapy for autoimmune alveolar proteinosis is a pathogenesis-based epoch-making therapy, but the response rate is about 60%. In patients with treatment-resistant autoimmune alveolar proteinosis showing repeated aggravation of symptoms, whole-lung lavage under general anesthesia is a reliable therapeutic method.

[Pleomorphic carcinoma of the lung with uncommon initial manifestation of intestinal perforation].

A 47-year-old woman suddenly developed abdominal pain and visited the emergency room of our hospital. Chest and abdominal CT scan revealed free air in the abdominal cavity and a bulky pulmonary tumor in the right middle lobe. The perforated sigmoid colon was removed in an emergency operation. Histological examination of the resected tissue revealed undifferentiated carcinoma, but the histological differentiation could not be determined. We used immunohistochemical staining to distinguish primary non-small cell lung cancer from colon cancer; the resected tumor was positive for TTF-1 and CK7, but negative for CK20. Therefore, by using immunohistochemical staining we could diagnose the tumor of the large intestine as metastasis from non-small cell lung cancer. After the operation, systemic chemotherapy with carboplatin and docetaxel was repeated, but the lung tumor did not regress and the patient died. Autopsy examination confirmed the histology of the lung tumor as pleomorphic carcinoma. Morphological characteristics and the immunohistochemical staining pattern of the pulmonary tumor were consistent with that of the colon tumor. In Japan, this is the first report in which the initial manifestation of lung cancer was perforation of the large intestine due to metastasis.

[Pulmonary carcinomatous lymphangiosis from recurrent breast cancer 10 years after resection of the primary tumor].

A 55-year-old woman had a history of left mastectomy due to early breast cancer in 1998. She had been suffering from dyspnea on effort and dry cough since August in 2007, and visited our hospital 6 months later because the symptoms had been becoming worse. She was hypoxic and her chest radiograph showed bilateral diffuse shadows, so she was hospitalized. The specimen of transbronchial lung biopsy showed undifferentiated adenocarcinoma cells in lymphatics identified by lymphatic endothelium antibody D2-40 stain, so we diagnosed carcinomatous lymphangiosis. It also revealed the cells staining positive for Cytokeratin 7, negative for Cytokeratin 20, and positive for both estrogen receptor and progesterone receptor. These features were identical to the immunohistological findings of the specimen from the previously resected breast cancer. Chemotherapy with docetaxel was effective and improved her respiratory condition and the chest radiograph. The immunohistological findings are useful for diagnosis and selection of cancer therapy. We cannot find any case reports of recurrence with carcinomatous lymphangiosis over 10 years after resection of breast cancer in Japan. We must keep in mind that some cancers relapse after a long disease-free interval.

[Treatment-refractory-dental-extraction-associated pyothorax involving infection by 2 species of oral originated bacteria requires surgical debridement by video assisted thoracoscopic surgery (VATS)].

Cases of septic pulmonary embolism (SPE) diagnosed clinically by CT after dental extraction rarely include verification of bacteria from the local infection site. We report the case of a 70-year-old man without background disease suffering severe pyothrax after dental extraction. We detected two species of oral bacteria from his pleural effusion. Treatment was so difficult that it required surgical debridement by video assisted thoracoscopic surgery (VATS), even after the appropriate administration of antibiotics. According to the American Heart Association (AHA) prophylaxis guidelines for preventing infective endocarditis indicate that it is uncommon to prescribe antibiotics to patients without background disease after dental extraction. No appropriate Japanese guidelines exist considering the prevention of SPE causing severe pyothorax as in our case. The hematogenous spread of bacteria such as SPE caused by sepsis after tooth extraction thus requires more attended careful consideration in clinical practice if patients are to be properly protected against potentially serious complications.

Usefulness of Bronchial Thermoplasty for Patients with a Deteriorating Lung Function.

Bronchial thermoplasty is a novel procedure for patients with severe asthma showing a stable lung function. We herein report two cases with a deteriorating lung function. The lung function tended to improve in one case, while the other case discontinued mepolizumab medication after the procedure. Treatment was performed safely under general anesthesia in both cases. The use of bronchial thermoplasty may therefore be useful for the treatment of patients with a deteriorating lung function.

Success of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer.

Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case.

A phase II trial of cisplatin and irinotecan alternating with doxorubicin, cyclophosphamide and etoposide in previously untreated patients with extensive-disease small-cell lung cancer.

PURPOSE: The aim of this trial was to investigate the efficacy and safety of cisplatin (P) and irinotecan (I) (PI) alternating with doxorubicin (A), cyclophosphamide (C) and etoposide (E) (ACE) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Patients with previously untreated ED-SCLC were enrolled in this trial. In the first, third and fifth cycles, PI (P: 60 mg/m(2) on day 1; I: 60 mg/m(2)/day on days 1, 8 and 15) was administered, whereas ACE (A: 50 mg/m(2) on day 1; C: 750 mg/m(2) on day 1; E 80 mg/m(2)/day on days 1-3) was given in the second, fourth and sixth cycles. Each cycle was repeated every 4 weeks. At the end of six cycles, patients who had obtained a complete response were given prophylactic cranial irradiation. RESULTS: In total, 28 patients were enrolled, of whom 27 were assessable for efficacy and safety. Objective responses, including 4 (15%) complete responses, were observed in 25 patients (93%). Median survival time was 12.9 months. The principal toxicity was myelosuppression; grade 4 neutropenia and thrombocytopenia were observed in 89 and 4%, respectively. Febrile neutropenia occurred in 30% of patients. Diarrhea was mild (grade 3-4; 4%). All toxicities were reversible and there were no treatment-related deaths. The mean percentage of the delivered doses, relative to the projected doses, of PI and ACE were 84.6 and 91.1%, respectively. CONCLUSIONS: These results indicate the PI-ACE regimen to have promising activity against ED-SCLC with moderate toxicities.

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study.

PURPOSE: We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m(2) and 30 mg/m(2), respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m(2) was conducted and primary objective in the phase II portion was response rate. RESULTS: The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m(2) because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C (max) and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. CONCLUSION: These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.

Multiple Mucosa-associated Lymphoid Tissue Lymphoma of the Trachea.

Mucosa-associated lymphoid tissue lymphoma is a common type of primary pulmonary carcinoma, but the presence of polypoid nodules is extremely rare. We herein report two cases with multiple nodules in the trachea. One case involved polypoid nodules and airway stenosis mimicking asthma; the other case had concurrent nontuberculous mycobacterial infection. The diagnosis of both cases was confirmed by bronchoscopy. The two cases were sensitive to radiotherapy and chemotherapy, respectively.

Phase I study of docetaxel and irinotecan in patients with advanced non-small-cell lung cancer.

The role of non-platinum combination chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan (CPT) in patients with advanced NSCLC were evaluated. Previously untreated patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV were eligible. Both drugs were administered by 1-h intravenous infusion on day 1, and repeated every 3 weeks. DCT was given before CPT administration. Five escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165 mg/m2) were studied. Eighteen patients received 44 courses. The DLT was considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or more was observed in three patients, which was accompanied with three episodes of febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred in three patients. Since all the three patients treated at the fifth dose level (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in two patients and grade 3 hepatic toxicity in one), this dose level was determined to be the MTD. The objective response rate was 33.3%, and the median survival time was 13.6 months. To confirm the effectiveness of this combination for advanced NSCLC which was suggested in the present study, a phase II study with the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.

Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer.

To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage small-cell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily x 30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m(2), respectively. In the phase II study, the overall response rate was 100% (complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (>/=grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens.

Three cases of non-specific interstitial pneumonia associated with primary lung cancer.

NSIP associated with primary lung cancer has been rarely reported. In the present report, three cases of histologically proven non-specific interstitial pneumonia (NSIP) associated with primary lung cancer are described. Importantly, in our 3 cases, interstitial pneumonia which is histologically proven to be NSIP was observed diffusely in both lungs. NSIP in these 3 cases responded to steroid therapy. However, 2 patients died from primary lung cancer and 1 patient died from progression of the interstitial pneumonia. Although the association between lung cancer and NSIP has been rarely documented, this combination was considered to be one of the paraneoplastic phenomena. The possible association between primary lung cancer and NSIP is discussed.

Comparison of chemosensitivity tests: clonogenic assay versus MTT assay.

When the development of chemotherapeutic agents reaches the clinical trial stage, it is necessary to perform drug sensitivity tests quickly in order to select the most promising agents for the treatment of cancer. In order to assess the possibility of using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as a substitute for the human tumor clonogenic assay (HTCA), we evaluated the correlation between the results obtained by these 2 assays in 5 human lung cancer cell lines. The correlation coefficient between the results of the HTCA and the MTT assay was 0.673, indicating a relatively good correlation. The correlation was most prominent in platinum analogues (r = 0.939) and good in anthracyclines/anthracenedione (r = 0.611). However, no significant correlation was observed in vinca alkaloids, etoposide, irinotecan, SN-38 (an active metabolite of irinotecan), and rhizoxin. The results of the MTT assay showed a high degree of correlation with those of the HTCA in predicting the sensitivity of cancer cell lines to platinum analogues, and anthracyclines/anthracenedione. These results suggest that the MTT assay may be more convenient and quickly performed than the HTCA and can replace HTCA in evaluating the effects of anticancer agents, especially the platinum analogues and anthracyclines/anthracenedione.

nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma.

We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma.

Carboplatin plus either docetaxel or paclitaxel for Japanese patients with advanced non-small cell lung cancer.

AIM: Assessment of the efficacy of docetaxel plus carboplatin vs. paclitaxel plus carboplatin in Japanese patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients were randomly assigned at a ratio of 2 to 1 to receive six cycles of either docetaxel (60 mg/m(2)) plus carboplatin [area under the curve (AUC)=6 mg/ml min] or paclitaxel (200 mg/m(2)) plus carboplatin (same dose), on day 1 every 21 days. The primary end-point was progression-free survival (PFS). RESULTS: A total of 90 patients were enrolled. Overall response rate, median PFS and median survival time in the docetaxel-plus-carboplatin group and the paclitaxel-plus-carboplatin group were 23% vs. 33%, 4.8 months vs. 5.1 months, and 17.6 months vs. 15.6 months, respectively. The docetaxel-plus-carboplatin group had a higher incidence of grade 3 or 4 neutropenia (88% vs. 60%). CONCLUSION: Both regimens were similarly effective in Japanese patients with advanced NSCLC.