The prognostic value of serum CA 19-9 for patients with advanced lung adenocarcinoma.

BACKGROUND: This study aimed to assess the prognostic accuracy of serum CA 19-9 in patients with advanced lung adenocarcinoma. METHODS: We retrospectively reviewed data of 246 patients who were diagnosed at our institute with advanced (stage IIIB or IV) lung adenocarcinoma between March 2006 and December 2012. We excluded patients who received no chemotherapy, or for whom we had no data on pre-treatment tumor markers. We also evaluated 116 consecutive resected specimens from patients with clinical stage I lung adenocarcinoma pathologically. RESULTS: The 76 (31 %) patients who were CA 19-9+ had shorter overall survival (OS) than CA 19-9- group (12.5 vs 26.2 months, P = 0.005). Cox's multivariate regression analysis identified Eastern Cooperative Oncology Group Performance Status 0 or 1 (P < 0.001), mutated epidermal growth factor receptor (EGFR) status (P < 0.001), stage IIIB (P < 0.001), CYFRA 21-1- (P < 0.001), CA 19-9- (P = 0.005) and use of platinum doublet therapy (P = 0.034) as independent predictors of longer OS. We stratified patients by CA 19-9 and CYFRA 21-1 as double positive (CA 19-9+/CYFRA 21-1+, n = 59), single positive (either CA19-9+ or CYFRA 21-1+, n = 113), or double negative (CA 19-9-/CYFRA 21-1-, n = 74). Their respective OS were 10.0, 23.3 and 31.8 months (P < 0.001). Pathological analysis also correlated CA 19-9 expression with malignant features such as vessel invasion, pleural invasion, cancer invasive factors and mucin production. CONCLUSIONS: CA 19-9 and CYFRA 21-1 are independent prognostic markers in patients with advanced lung adenocarcinoma. Combined use of CA 19-9 and CYFRA 21-1 provides further prognostic information in patients with advanced lung adenocarcinoma.

Analysis of advanced lung cancer patients diagnosed following emergency admission.

Data on prognosis and predictors of overall survival in advanced lung cancer patients diagnosed following emergency admission (DFEA) are currently lacking. We retrospectively analysed data from 771 patients with advanced nonsmall cell lung cancer between April 2004 and April 2012. Of the 771 patients, 103 (13%) were DFEA. DFEA was not an independent predictor of overall survival by multivariate Cox proportional hazard models, whereas good performance status (PS), epidermal growth factor receptor gene mutation, stage IIIB, adenocarcinoma and chemotherapy were independent predictors of overall survival (hazard ratio (95% CI) 0.36 (0.29-0.44), p<0.001; 0.49 (0.38-0.63), p<0.001; 0.64 (0.51-0.80), p<0.001; 0.81 (0.67-0.99), p=0.044; and 0.40 (0.31-0.52), p<0.001, respectively). Good PS just prior to opting for chemotherapy, but not at emergency admission, was a good independent predictor of overall survival in DFEA patients (hazard ratio (95% CI) 0.26 (0.12-0.55); p<0.001). DFEA is relatively common. DFEA and PS at emergency admission were not independent predictors of overall survival, but good PS just prior to opting for chemotherapy was an independent predictor of longer overall survival. Efforts to improve patient PS after admission should be considered vital in such circumstances.

Truncation of N- and C-terminal regions of Streptococcus mutans dextranase enhances catalytic activity.

Multiple forms of native and recombinant endo-dextranases (Dexs) of the glycoside hydrolase family (GH) 66 exist. The GH 66 Dex gene from Streptococcus mutans ATCC 25175 (SmDex) was expressed in Escherichia coli. The recombinant full-size (95.4 kDa) SmDex protein was digested to form an 89.8 kDa isoform (SmDex90). The purified SmDex90 was proteolytically degraded to more than seven polypeptides (23-70 kDa) during long storage. The protease-insensitive protein was desirable for the biochemical analysis and utilization of SmDex. GH 66 Dex was predicted to comprise four regions from the N- to C-termini: N-terminal variable region (N-VR), conserved region (CR), glucan-binding site (GBS), and C-terminal variable region (C-VR). Five truncated SmDexs were generated by deleting N-VR, GBS, and/or C-VR. Two truncation-mutant enzymes devoid of C-VR (TM-NCGΔ) or N-VR/C-VR (TM-ΔCGΔ) were catalytically active, thereby indicating that N-VR and C-VR were not essential for the catalytic activity. TM-ΔCGΔ did not accept any further protease-degradation during long storage. TM-NCGΔ and TM-ΔCGΔ enhanced substrate hydrolysis, suggesting that N-VR and C-VR induce hindered substrate binding to the active site.

Repair activity of base and nucleotide excision repair enzymes for guanine lesions induced by nitrosative stress.

Nitric oxide (NO) induces deamination of guanine, yielding xanthine and oxanine (Oxa). Furthermore, Oxa reacts with polyamines and DNA binding proteins to form cross-link adducts. Thus, it is of interest how these lesions are processed by DNA repair enzymes in view of the genotoxic mechanism of NO. In the present study, we have examined the repair capacity for Oxa and Oxa-spermine cross-link adducts (Oxa-Sp) of enzymes involved in base excision repair (BER) and nucleotide excision repair (NER) to delineate the repair mechanism of nitrosative damage to guanine. Oligonucleotide substrates containing Oxa and Oxa-Sp were incubated with purified BER and NER enzymes or cell-free extracts (CFEs), and the damage-excising or DNA-incising activity was compared with that for control (physiological) substrates. The Oxa-excising activities of Escherichia coli and human DNA glycosylases and HeLa CFEs were 0.2-9% relative to control substrates, implying poor processing of Oxa by BER. In contrast, DNA containing Oxa-Sp was incised efficiently by UvrABC nuclease and SOS-induced E.coli CFEs, suggesting a role of NER in ameliorating genotoxic effects associated with nitrosative stress. Analyses of the activity of CFEs from NER-proficient and NER-deficient human cells on Oxa-Sp DNA confirmed further the involvement of NER in the repair of nitrosative DNA damage.

Characteristics and Prognostic Impact of Pneumonitis during Systemic Anti-Cancer Therapy in Patients with Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Data on characteristics, outcomes, and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who develop pneumonitis during systemic anti-cancer therapy (pneumonitis) are currently lacking. METHODS: We conducted a retrospective cohort study of 910 consecutive patients diagnosed with advanced NSCLC between January 2004 and January 2014. Of these, 140 patients were excluded because they did not receive systemic anti-cancer therapy at this hospital. RESULTS: A total of 770 patients were included in the study, of whom 44 (6%) were diagnosed with pneumonitis. The mortality rate of pneumonitis was 36%. The incidence of pneumonitis was independently associated with pre-existing ILD (adjusted odds ratio, 2.99, P = 0.008), and survivors were significantly associated with younger age (P = 0.003) and radiographic non-acute interstitial pneumonia pattern (P = 0.004). In all patients, pneumonitis was identified as an independent predictor of overall survival (OS) (adjusted hazard ratio 1.53, 95% CI, 1.09-2.09, P = 0.015). Performance status was poor in 82% of survivors of pneumonitis; in 62% of survivors, the PS worsened after the pneumonitis improved. Additionally, 54% of survivors received no further systemic anti-cancer therapy after pneumonitis. The median survival time of survivors after pneumonitis was 3.5 months (95% CI, 2.3-7.2 months). CONCLUSIONS: Our study indicated that 6% of patients with advanced NSCLC developed pneumonitis during systemic anti-cancer therapy. The early mortality rate of pneumonitis is high, and the survival and PS after pneumonitis is extremely poor. Additionally, pneumonitis has an adverse impact on the survival of patients with advanced NSCLC. These data should be considered for the management of pneumonitis, and we recommend that future work focuses on pneumonitis particularly to improve the survival of patients with advanced NSCLC.

Transformation to large cell neuroendocrine carcinoma as acquired resistance mechanism of EGFR tyrosine kinase inhibitor.

OBJECTIVES: Several different acquired resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy have been described. Although rare, the transformation from adenocarcinoma to small cell carcinoma (SCLC) is one of these important mechanisms. We report a rare case that indicates transformation into large-cell neuroendocrine carcinoma (LCNEC) as an acquired resistance mechanism to EGFR-TKI therapy. MATERIALS AND METHODS: The patient was a 68-year-old male with a diagnosis of cT2N2M0 pulmonary adenocarcinoma with L858R mutation on exon 21. He received lobectomy and underwent several courses of chemotherapies, including EGFR-TKIs, each time he relapsed. He finally relapsed with a mass that protruded into his left main bronchus. Resection of the metastatic site identified LCNEC that retained the original EGFR mutation. Immunohistochemistry revealed the loss of expression of EGFR and retinoblastoma (Rb) in the LCNEC. CONCLUSIONS: This case highlights acquisition of EGFR-TKI resistance by transformation to LCNEC, not SCLC. Loss of EGFR and Rb expression in the LCNEC suggests the same mechanism as transformation to SCLC. Further study is needed to elucidate this mechanism, especially regarding the similarities and differences to SCLC.

Second-line Chemotherapy for Patients with Small Cell Lung Cancer and Interstitial Lung Disease.

BACKGROUND: The safety and efficacy of second-line chemotherapy for treating patients with small cell lung cancer (SCLC) and interstitial lung disease (ILD) have not been elucidated to date. PATIENTS AND METHODS: Between January 2005 and September 2013, we analyzed 23 patients with SCLC and ILD who received second-line chemotherapy. Pre-existing ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography results. RESULTS: The overall objective response rates and disease control rates were 22% and 52%, respectively. The median respective durations of progression-free survival and overall survival were 2.1 months (95% confidence interval (CI)=2.0-3.0 months) and 7.1 months (95% CI=3.6-11.3 months), respectively. Three patients with unusual interstitial pneumonia pattern (13%) developed chemotherapy-related pneumonitis. CONCLUSION: Second-line treatment may be an effective and safe option for SCLC patients with ILD after sufficient evaluation of risks and benefits.

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.

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.

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.