Next-generation sequencing of tyrosine kinase inhibitor-resistant non-small-cell lung cancers in patients harboring epidermal growth factor-activating mutations.

BACKGROUND: The aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer. METHODS: Fifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2. RESULTS: All 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0%) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7%) exhibiting TP53 P72R mutations, 5 cases (33.3%) of KDR Q472H, and 2 cases (13.3%) of KIT M541L. CONCLUSIONS: Here, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR-activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis.

Role of sedation for agitated patients undergoing noninvasive ventilation: clinical practice in a tertiary referral hospital.

BACKGROUND: Although sedation is often required for agitated patients undergoing noninvasive ventilation (NIV), reports on its practical use have been few. This study aimed to evaluate the efficacy and safety of sedation for agitated patients undergoing NIV in clinical practice in a single hospital. METHODS: We retrospectively reviewed sedated patients who received NIV due to acute respiratory failure from May 2007 to May 2012. Sedation level was controlled according to the Richmond Agitation Sedation Scale (RASS). Clinical background, sedatives, failure rate of sedation, and complications were evaluated by 1) sedative methods (intermittent only, switched to continuous, or initially continuous) and 2) code status (do-not-intubate [DNI] or non-DNI). RESULTS: Of 3506 patients who received NIV, 120 (3.4 %) consecutive patients were analyzed. Sedation was performed only intermittently in 72 (60 %) patients, was switched to continuously in 37 (31 %) and was applied only continuously in 11 (9 %). Underlying diseases in 48 % were acute respiratory distress syndrome/acute lung injury/severe pneumonia or acute exacerbation of interstitial pneumonia. In non-DNI patients (n = 39), no patient required intubation due to agitation with continuous sedation, and in DNI patients (n = 81), 96 % of patients could continue NIV treatment. PaCO2 level changes (6.7 ± 15.1 mmHg vs. -2.0 ± 7.7 mmHg, P = 0.028) and mortality in DNI patients (81 % vs. 57 %, P = 0.020) were significantly greater in the continuous use group than in the intermittent use group. CONCLUSIONS: According to RASS scores, sedation during NIV in proficient hospitals may be favorably used to potentially avoid NIV failure in agitated patients, even in those having diseases with poor evidence of the usefulness of NIV. However, with continuous use, we must be aware of an increased hypercapnic state and the possibility of increased mortality. Larger controlled studies are needed to better clarify the role of sedation in improving NIV outcomes in intolerant patients.

Detection of herpes viruses by multiplex and real-time polymerase chain reaction in bronchoalveolar lavage fluid of patients with acute lung injury or acute respiratory distress syndrome.

BACKGROUND: Human herpes viruses (HHVs) are important pathogens in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Rapid and efficient diagnostic tools are needed to detect HHVs in the lung in ALI/ARDS patients. OBJECTIVES: This study aimed to evaluate the usefulness of multiplex and real-time polymerase chain reaction (PCR) analysis of bronchoalveolar lavage fluid (BALF) for detecting HHV reactivation in ALI/ARDS patients. METHODS: Between August 2008 and July 2012, eighty-seven BALF samples were obtained from ALI/ARDS patients with unknown etiology and analyzed for HHVs. The types of HHVs in the BALF samples were determined using qualitative multiplex PCR followed by quantitative real-time PCR. RESULTS: Multiplex PCR identified herpes simplex virus type 1 (HSV-1) (n = 11), Epstein-Barr virus (EBV) (n = 16), cytomegalovirus (CMV) (n = 21), HHV type 6 (HHV-6) (n = 2), and HHV-7 (n = 1) genomic DNA in 35 (40%) of the BALF samples, including 14 (16%) samples containing 2 or 3 HHV types. CMV and EBV reactivation was rare in immunocompetent patients, whereas reactivation of HSV-1 was predominantly observed in intubated patients regardless of their immune status. Overall, HHVs were almost exclusively found in patients with immunosuppression or endotracheal intubation. Real-time PCR detected 0.95-1.59 × 10(6) copies of viral DNA/µg human genome DNA, and HSV-1 (n = 4), CMV (n = 9), and HHV-6 (n = 1) were identified as potentially pathogenic agents. CONCLUSIONS: The implementation of multiplex and real-time PCR of BALF was feasible in ALI/ARDS patients, which allowed efficient detection and quantification of HHV DNA.

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

BACKGROUND: The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation. METHODS: The study investigated 78 EGFR-mutant patients who had undergone rebiopsy after TKI failure. The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method was used in EGFR mutational analyses. Various patient characteristics and postprogression survivals (PPSs) after initial TKI failure were retrospectively compared in patients with and without T790M. RESULTS: The T790M mutation was identified in 4 (17%) of 24 central nervous system lesions, and in 22 (41%) of 54 other lesions (P = .0417). No other characteristics had a statistical association with T790M prevalence. Median PPS was 31.4 months in 26 patients with T790M, and 11.4 months in 52 patients without T790M (P = .0017). In the multivariate analysis, statistically significant factors for longer PPS included T790M-positive, good performance status, and no carcinomatous meningitis. CONCLUSIONS: The emergence of T790M in central nervous system lesions was rare, compared with other lesions. Patients with T790M after TKI failure appear to have better prognoses than those without T790M. TKI rechallenge or continuous administration beyond progression may be effective after initial TKI failure.

Serum procalcitonin is a valuable diagnostic marker in acute exacerbation of interstitial pneumonia.

BACKGROUND AND OBJECTIVE: Acute exacerbation (AE) of interstitial pneumonia (IP) is defined as a life-threatening deterioration of IP without identifiable cause. We evaluated the diagnostic and prognostic role of serum procalcitonin (PCT) in AE-IP. METHODS: Twenty consecutive patients admitted for AE-IP between May 2010 and April 2012 were evaluated. Controls consisted of 13 consecutively admitted patients with acute respiratory distress syndrome (ARDS) due to bacterial pneumonia (BP) and 24 with bacterial pneumonia with stable IP ('BP with IP'). Serum PCT was measured at baseline, at days 2, 4 and 8 in patients with AE-IP, and at baseline in controls. RESULTS: Serum PCT levels in AE-IP were significantly lower than in BP-ARDS (mean ± standard deviation, 0.62 ± 1.30 vs 30.14 ± 22.76 ng/mL; P < 0.0001) or 'BP with IP' (mean ± standard deviation, 0.62 ± 1.30 vs 8.31 ± 14.83 ng/mL; P < 0.05). Thus, serum PCT discriminated well between AE-IP and BP-ARDS, or 'BP with IP' (area under the curve 0.99 and 0.85, respectively). However, there were no significant differences in serum PCT between 30-day survivors or non-survivors. Serum PCT tended to be reduced in both patient groups. CONCLUSIONS: Serum PCT is a useful marker for discriminating between AE-IP and BP. However, serum PCT is not useful as a prognostic marker for survival.

Evaluation of the chronic obstructive pulmonary disease assessment test for measurement of health-related quality of life in patients with interstitial lung disease.

BACKGROUND AND OBJECTIVE: A well-validated instrument that is simple to use is needed to assess health-related quality of life in patients with interstitial lung disease (ILD). The COPD assessment test (CAT) is a recently introduced, short and simple questionnaire for COPD patients, which shows good and valid measurement properties. This study was conducted to evaluate the validity of the CAT in patients with ILD. METHODS: Patients with ILD (n = 55) completed the CAT and the St. George's Respiratory Questionnaire (SGRQ). These patients also completed the Medical Research Council (MRC) dyspnoea scale, the Leicester Cough Questionnaire (LCQ), and the hospital anxiety and depression scale; performed 6-min walk tests and pulmonary function tests; and provided samples for arterial blood gas analysis. RESULTS: There was a very strong correlation between the CAT score and the SGRQ total score (r = 0.93, P < 0.0001). The CAT score was also significantly correlated with the SGRQ symptoms score (r = 0.74, P < 0.0001), the SGRQ activity score (r = 0.87, P < 0.0001) and the SGRQ impact score (r = 0.89, P < 0.0001). Stepwise multiple regression analysis demonstrated that the MRC and LCQ scores contributed most to both the CAT score and the SGRQ total score. CONCLUSIONS: The CAT is a short and simple questionnaire that shows good and valid measurement properties for assessing the health status of patients with ILD.

Clinical features and outcome of acute exacerbation of interstitial pneumonia: collagen vascular diseases-related versus idiopathic.

BACKGROUND: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). OBJECTIVES: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). METHODS: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003-2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. RESULTS: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO(2)/FiO(2) at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). CONCLUSION: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.

[Direct low-dose fentanyl patch (2.1mg) introduction for opioid naïve outpatients with cancer pain].

BACKGROUND: The administration of opioids to outpatients with cancer pain can be difficult because the constant dose modification and treatments of side effects involved are occasionally impossible. Therefore, more effective and safer drugs with better patients compliance are needed to complete a successful opioid introduction. Compared with other opioids, low-dose fentanyl has been suggested to produce milder side effects such as nausea, constipation, and somnolence. Further more, compliance can be improved because the drug is a patch,administered transdermally. METHODS: Between July 2008 and December 2009, we investigated the safety and analgesic effect of a fentanyl patch (2.1 mg) as a direct opioid introduction for 36 outpatients with cancer pain without titrations of other opioids. RESULTS: Side effects of constipation, nausea, somnolence, and dizziness were observed in 17 (47%), 6 (17%), 4 (11%), and 3 (8%) patients, respectively, and no respiratory suppression was observed. Regarding the analgesic effect, 23 (64%) patients reported improvement on pain scales one week after the initiation of the fentanyl patch. CONCLUSIONS: Opioid introduction to opioid-naÏve outpatients with cancer pain using the low-dose fentanyl patch (2.1 mg) may be effective.

[Two cases of effective S-1 monotherapy for patients with metastatic adenocarcinoma of the lung after multiple previous chemotherapies].

Case one was a 76-year-old woman. She was diagnosed as having lung adenocarcinoma with multiple metastases (cT4N0M1, stage IV, mucinous BAC)in June, 2004. Starting in July, 2004, she received various modalities of chemotherapy( cisplatin+vinorelbine, gefitinib, pemetrexed, gemcitabine, docetaxel, paclitaxel). S-1 monotherapy given to her starting April, 2006 achieved a partial response(PR)as a seventh-line treatment. Case two was a 60-year-old woman. She was diagnosed as having lung adenocarcinoma with multiple metastases(cT4N3M1, stage IV)in October, 2004. That month, her chemotherapy began. After various treatments(cisplatin+vinorelbine, docetaxel, gefitinib), S-1 monotherapy was initiated in February, 2007 as the fourth-line treatment; as a result, PR was achieved. Even though chemotherapies were performed in succession, in the condition of good general status, salvage chemotherapy can be affected by the rotation of drugs. In such cases, S-1 monotherapy can be a reasonable choice from the standpoint of feasibility and effectiveness.

EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small cell lung cancer.

BACKGROUND: Efficacies of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) rechallenge have been demonstrated in EGFR-mutant non-small cell lung cancer (NSCLC). However, their efficacies were only moderate. Some preclinical studies suggested synergistic effects of bevacizumab to EGFR-TKI in TKI-resistant models. METHODS: We retrospectively evaluated clinical efficacy and safety of EGFR-TKI rechallenge with bevacizumab. Rebiopsy was performed on all studied cases to examine T790M-resistant mutation status. RESULTS: Between January 2010 and June 2014, a total of 24 EGFR-mutant NSCLC patients who had been previously treated with EGFR-TKIs (gefitinib, erlotinib, and/or afatinib) received EGFR-TKI rechallenge with bevacizumab. Twenty-two (92 %) patients underwent erlotinib and two (8 %) gefitinib as rechallenge EGFR-TKIs in combination with bevacizumab. Three patients achieved partial response, and 18 had stable disease, resulting in the response rate (RR) of 13 % and disease control rate (DCR) of 88 %, respectively. The median progression-free survival (PFS) was 4.1 [95 % confidence interval (CI) 2.3-4.9] months, and the median overall survival (OS) was 13.5 (95 % CI 9.7-27.4) months. The RR, DCR, median PFS, and median OS for T790M-positive versus T790M-negative were 0 versus 18 % (p = 0.530), 86 versus 88 % (p = 1.00), 3.3 versus 4.1 months (p = 0.048), and 15.1 versus 13.5 months (p = 0.996), respectively. Severe adverse events (≥grade 3): grade 3 of 1 (4 %) rash; grade 3 of 1 (4 %) paronychia; grade 3 of 1 (4 %) hypertension; and grade 3 of 1 (4 %) anemia, were observed. CONCLUSIONS: EGFR-TKI rechallenge with bevacizumab demonstrated higher DCR and modestly longer PFS than historical data on EGFR-TKI rechallenge alone. Its activity was notably higher in T790M-negative population.

Evaluation of discomfort and tolerability to bronchoscopy according to different sedation procedures with midazolam.

Patients frequently experience great discomfort during a bronchoscopy for the diagnosis of lung neoplasms. Sedation is generally recommended during bronchoscopy; however, few studies have evaluated the discomfort and tolerability of patients to a bronchoscopy with regard to the administration procedures. The aim of the present study was to evaluate the discomfort and tolerability of patients undergoing a bronchoscopy using different sedation procedures with midazolam. The retrospective survey of sedation during bronchoscopy involved the comparison of two periods: January-March 2012 (first period) and July-September 2012 (second period). A numerical rating score, which ranged between 1 (best) and 5 (worst) according to the subjective view of the patients, was used to rate patient discomfort, pain, sensation, time and tolerability to the bronchoscopy. In the first period, 2.5 mg midazolam was administered prior to the initiation of surgery, and additional doses of midazolam was added in 2.5-mg increments whenever the patient deviated from the target sedation level. In the second period, 2.0 or 3.0 mg midazolam was administered prior to the initiation of surgery, and additional midazolam doses were administered in 1.0-mg increments until the patients were sedated to the target sedation level. In total, 60 and 68 valid responses were obtained in the first and second periods, respectively. The patients in the second period exhibited significantly improved discomfort and pain scores during the bronchoscopy and higher rates of consent to re-examination, as compared with the patients in the first period (1.89±1.40 vs. 2.78±1.52, P<0.001; 1.48±1.13 vs. 2.00±1.37, P=0.005; 2.45±1.62 vs. 3.13±1.47, P=0.013, respectively). The amount of midazolam administered was significantly higher in the second period. There were no fatal complications during the bronchoscopy in either period. In conclusion, the present study observed that the administration of additional midazolam in small doses, until the target sedation level is achieved, is a safe procedure that is associated with significantly less discomfort and pain during bronchoscopy and a greater consent to re-examination when compared with the administration of a fixed dose of midazolam.

A new strategy for metachronous primary lung cancer: stereotactic body radiation therapy with concurrent chemotherapy.

BACKGROUND/AIM: Patients with malignant lung cancer often develop a solitary pulmonary nodule after treatment of the initial cancer. In those cases, it is difficult to distinguish primary lung cancer (PLC) from lung metastasis. Therefore, both local therapy for a single lung lesions and systemic therapy for micrometastases are needed. This retrospective study aimed to evaluate the safety and tolerability of concurrent stereotactic body radiation therapy (SBRT) and chemotherapy in patients with metachronous PLC. PATIENTS AND METHODS: We reviewed the records of 10 patients with metachronous PLC treated with SBRT and concurrent chemotherapy with curative intent from 2007 to 2013. The delivered radiation dose was 48 Gy in four fractions. RESULTS: All patients received SBRT with concurrent chemotherapy on schedule. Complete response rate was 90%. Safety profile of this treatment was compatible with that of traditional chemoradiotherapy. CONCLUSION: Our study showed good feasibility and safety for SBRT with concurrent chemoradiotherapy.

Validation of an Ion Torrent Sequencing Platform for the Detection of Gene Mutations in Biopsy Specimens from Patients with Non-Small-Cell Lung Cancer.

BACKGROUND: Treatment for patients with advanced non-small cell lung cancer (NSCLC) is often determined by the presence of biomarkers that predict the response to agents targeting specific molecular pathways. Demands for multiplex analysis of the genes involved in the pathogenesis of NSCLC are increasing. METHODS: We validated the Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel and compared the results with those obtained using the gold standard methods, conventional PCR and Sanger sequencing. The cycleave PCR method was used to verify the results. RESULTS AND CONCLUSION: The Ion Torrent PGM resulted in a similar level of accuracy in identifying multiple genetic mutations in parallel, compared with conventional PCR and Sanger sequencing; however, the Ion Torrent PGM was superior to the other sequencing methods in terms of increased ease of use, even when taking into account the small amount of DNA that was obtained from formalin-fixed paraffin embedded (FFPE) biopsy specimens.

Prognostic impact of central nervous system metastases after acquired resistance to EGFR-TKI: poorer prognosis associated with T790M-negative status and leptomeningeal metastases.

AIM: The aim of the present study was to investigate the prognostic impact of central nervous system metastases (CNS) after acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in EGFR-mutant non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We defined CNS-collapse as death due to uncontrolled and progressive CNS metastases. Post-progression survival (PPS) after initial TKI failure and T790M status were retrospectively compared in 92 patients with or without CNS collapse. RESULTS: The median PPS in 32 patients with CNS-collapse (16.7 months) was significantly shorter than that of 60 without (26.8 months) (p=0.0002). T790M was detected in four (12%) out of the 32 CNS-collapse patients and in 26 (43%) out of 60 without (p=0.0026). Median PPS in 39 patients with leptomeningeal metastases (LM) (11.4 months) was significantly shorter versus 53 without (26.8 months) (p=0.0006). The median PPS was 25.1 months in 40 patients with brain metastases and 11.2 months in 52 without (p=0.0387). T790M was detected in 4/5 resected brain tumors (80%) and in 1/26 cerebrospinal fluid (CSF) samples (4%) (p=0.0008). CONCLUSION: CNS-collapse represented poorer prognosis, which was associated with T790M-negative status and LM. Controlling CNS metastases, especially LM, is important to achieve longer survival.

Early pulmonary involvement of anti-CADM-140 autoantibody-positive rapidly progressive interstitial lung disease preceding typical cutaneous symptoms.

We herein report a patient with clinically amyopathic dermatomyositis (CADM) who developed anti-CADM-140 autoantibody in association with rapidly progressive interstitial lung disease (RP-ILD). Chest high-resolution computed tomography (HRCT) revealed early pulmonary involvement preceding typical cutaneous lesions. Primary lesions of patchy peribronchial opacity developed ground-glass opacity and consolidation with architectural distortion and traction bronchiectasis. The possibility of anti-CADM-140 autoantibody-associated RP-ILD should be considered when patchy peribronchial opacity of an unknown cause is visible on chest HRCT.

The safety and efficacy of paclitaxel and carboplatin with or without bevacizumab for treating patients with advanced nonsquamous non-small cell lung cancer with interstitial lung disease.

PURPOSE: Optimal chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is established for paclitaxel and carboplatin, but is otherwise controversial. Therefore, we assessed the efficacy and safety of paclitaxel and carboplatin with or without bevacizumab for treating these patients. METHODS: We analyzed the outcomes of 21 patients with advanced nonsquamous NSCLC with ILD who received paclitaxel and carboplatin without (paclitaxel-carboplatin group; n = 11) or with bevacizumab (paclitaxel-carboplatin-bevacizumab group; n = 10) between April 2008 and October 2013. RESULTS: The median progression-free survival time of the paclitaxel-carboplatin-bevacizumab group was 5.3 months (95 % CI 0.4-11.6 months) compared with 4.4 months (95 % CI 0.9-6.3 months) for the paclitaxel-carboplatin group (p = 0.060). Their respective median overall survival times were 16.1 months (range 0.4-34.8 months) and 9.7 months (range 2.6-37.0 months) (p = 0.772) with corresponding overall response rates of 40 and 27 % (p = 0.659), respectively. One patient in the paclitaxel-carboplatin-bevacizumab group experienced chemotherapy-related exacerbation of ILD (0/11 vs. 1/10; p = 0.476). CONCLUSIONS: The addition of bevacizumab to paclitaxel and carboplatin may provide an effective and safe treatment option for patients with advanced nonsquamous NSCLC with ILD.

Bevacizumab plus weekly paclitaxel with or without carboplatin for previously-treated non-squamous non-small cell lung cancer.

AIM: The aim of this retrospective study was to evaluate bevacizumab combined with weekly paclitaxel with and without carboplatin in pre-treated patients with non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Between November 2009 and October 2011, 43 pre-treated patients with non-squamous NSCLC received bevacizumab (15 mg/kg, day 1) plus weekly paclitaxel (60-80 mg/m(2), days 1, 8, 15) with carboplatin (area under the curve=4-5, day 1) (n=36), or bevacizumab plus weekly paclitaxel (n=7) alone every four weeks. RESULTS: The response rate and disease control rates were 48.8% (21/43) and 86.0% (37/43), respectively. Median progression-free survival was 5.7 months, and overall survival was 14.5 months. Grade 3/4 neutropenia was observed in 37.2% of patients and peripheral neurotoxicity in 0%. No bevacizumab-related death was observed. CONCLUSION: Even for heavily pre-treated patients, bevacizumab plus weekly paclitaxel with or without carboplatin was effective and tolerable in non-squamous NSCLC.

Prognostic value of bronchoalveolar lavage in patients with non-HIV pneumocystis pneumonia.

OBJECTIVE: Non-HIV patients with pneumocystis pneumonia (PCP) have a poor prognosis. We aimed to evaluate the prognostic factors for in-hospital mortality in terms of the clinical findings, including the results of bronchoalveolar lavage fluid (BALF)-analyses, in non-HIV PCP patients. METHODS: We retrospectively reviewed non-HIV PCP patients diagnosed using bronchoalveolar lavage between April 2006 and July 2012. For patients with a poor respiratory status, noninvasive positive pressure ventilation (NPPV) was used during the bronchoalveolar lavage (BAL) procedure. Data regarding demographics, laboratory findings and the prognosis were evaluated. RESULTS: A total of 29 non-HIV PCP patients were analyzed. NPPV was carried out safely and successfully in 12 patients during the BAL procedure. Twelve patients (41%) died. The multivariate logistic regression analysis identified only BALF neutrophilia to be a significant prognostic factor determining in-hospital mortality. The log-rank test showed that the patients with BALF neutrophilia (≥ 31%) had a significantly lower survival rate than the other patients (p=0.001). CONCLUSION: Only BALF neutrophilia was found to be a significant predictor of survival in patients with non-HIV PCP. Our data also emphasize the significance of performing BAL in such patients, as it provides both diagnostic and prognostic information.

Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis.

Mutated epidermal growth factor receptor (EGFR) and signaling pathways were associated with multiple brain and intra-pulmonary metastases, oncogenic progression and metastasis. However, features of metastasis to other organs and the independent prognostic influence of metastatic lesions were not elucidated in patients with lung cancer harboring EGFR mutations. Between January 2007 and April 2012, we treated 277 patients diagnosed with stage IV lung adenocarcinoma. Studied were 246 patients with available tumor EGFR mutation data who also underwent radiographic evaluation of lung, abdominal, brain, and bone metastases. The EGFR mutated group (N = 98) had significantly more metastatic lesions in the brain and bone than the wild-type group (N = 148): brain, 3 (1-93) versus 2 (1-32) median (range), P = 0.023; bone, 3 (1-43) versus 2 (1-27), P = 0.035, respectively. In addition, EGFR mutations were significantly more frequent in patients with multiple than non-multiple lung metastases (24/40 vs. 12/42, P = 0.004). Multivariate analysis showed that bone metastasis was a significant independent negative predictive factor of overall survival (OS) in patients with mutated [hazard ratio (HR) 2.04; 95 % confidence interval (CI) 1.17-3.64; P = 0.011] and wild-type EGFR (HR 2.09; 95 % CI 1.37-3.20; P < 0.001). In conclusion, patients with mutated EGFR had more lung, brain, and bone metastases, and bone metastasis was an independent negative predictor of OS.

Weekly administration of paclitaxel and carboplatin with concurrent thoracic radiation in previously untreated elderly patients with locally advanced non-small-cell lung cancer: A case series of 20 patients.

Elderly patients with stage III non-small-cell lung cancer (NSCLC) are frequently underrepresented in clinical trials that evaluate chemoradiotherapy, due to their poor functional status, coexisting illnesses and limited life expectancy. The Japan Clinical Oncology Group 0301 trial (JCOG0301) was the first study to demonstrate that thoracic radiation therapy (TRT) with daily low-dose carboplatin may improve the outcome of elderly patients with stage III NSCLC. However, the efficacy and safety profiles of chemoradiotherapy, including platinum doublets, have not been clearly determined in this patient population. We retrospectively assessed the efficacy and toxicity of weekly paclitaxel in combination with carboplatin and concurrent TRT in patients aged ≥75 years with previously untreated locally advanced NSCLC. Between February, 2004 and July, 2013, we collected the data of 20 patients treated with weekly paclitaxel and carboplatin for 6 weeks and concurrent TRT. The objective response rate was 90%, the disease control rate was 95%, the median progression-free survival was 8.63 months [95% confidence interval (CI): 5.7-16.7] and the median overall survival (OS) was 16.1 months (95% CI: 10.7-41.6). There were no grade 4 hematological or non-hematological toxicities and no reported treatment-related deaths. Therefore, platinum doublet therapy in combination with TRT did not provide a clinically significant survival benefit in our population of elderly patients with locally advanced NSCLC. However, the present study demonstrated the good feasibility and safety of this regimen. Further prospective clinical trials are required to evaluate the efficacy and safety of platinum doublet with TRT in elderly patients.