Takeshi Kaneko

Stereotactic Ablative Body Radiation Therapy for Octogenarians With Non-Small Cell Lung Cancer

PURPOSEnTo retrospectively investigate treatment outcomes of stereotactic ablative body radiation therapy (SABR) for octogenarians with non-small cell lung cancer (NSCLC).nnnMETHODS AND MATERIALSnBetween 2005 and 2012, 109 patients aged ≥80 years with T1-2N0M0 NSCLC were treated with SABR: 47 patients had histology-unproven lung cancer; 62 patients had pathologically proven NSCLC. The prescribed doses were either 50 Gy/5 fractions for peripheral tumors or 40 Gy/5 fractions for centrally located tumors. The treatment outcomes, toxicities, and the correlating factors for overall survival (OS) were evaluated.nnnRESULTSnThe median follow-up duration after SABR was 24.2 (range, 3.0-64.6) months. Only limited toxicities were observed, except for 1 grade 5 radiation pneumonitis. The 3-year local, regional, and distant metastasis-free survival rates were 82.3%, 90.1%, and 76.8%, respectively. The OS and lung cancer-specific survival rates were 53.7% and 70.8%, respectively. Multivariate analysis revealed that medically inoperable, low body mass index, high T stage, and high C-reactive protein were the predictors for short OS. The OS for the operable octogenarians was significantly better than that for inoperable (P<.01).nnnCONCLUSIONSnStereotactic ablative body radiation therapy for octogenarians was feasible, with excellent OS. Multivariate analysis revealed that operability was one of the predictors for OS. For medically operable octogenarians with early-stage NSCLC, SABR should be prospectively compared with resection.

Screening of tuberculosis by interferon-γ assay before biologic therapy for rheumatoid arthritis

Infection with Mycobacterium tuberculosis (M. tuberculosis) is a critical complication in anti-TNF therapies. In 141 BCG vaccinated healthy individuals and 71 rheumatoid arthritis (RA) patients as screening before anti-TNF therapies, M. tuberculosis specific immune responses were evaluated by tuberculin skin test (TST) and enzyme-linked immunospot assay (ELISPOT), which detected antigen specific IFN-gamma secreting cells in peripheral blood mononuclear cells simulated with either purified protein derivative (PPD), early secretory antigen target 6 (ESAT-6) or culture filtrate protein 10 (CFP-10). Induration over 5 mm in TST was found in 87.9% of controls and 21.4% of RA patients. Erythema size in TST was significantly suppressed in RA patients, especially those receiving prednisolone (PSL), whereas the PPD specific IFN-gamma secretion was less attenuated. Significant responses to either ESAT-6 or CFP-10 in ELISPOT were detected in 14.1% of RA patients including those having positive TST, while the ELISPOT assay was negative in all healthy individuals and 73.3% of RA patients having positive TST. Of ELISPOT positive RA patients, mean dosage of PSL was 4.58 mg and 1.25 mg in TST negative and positive patients, respectively. Thus, ELISPOT is useful for screening of tuberculosis in RA patients, even in those receiving corticosteroids.

Sensitivity and specificity of the Streptococcus pneumoniae urinary antigen test for unconcentrated urine from adult patients with pneumonia: A meta‐analysis

Studies on the sensitivity and specificity of the Binax Now Streptococcus pneumonia urinary antigen test (index test) show considerable variance of results. Those written in English provided sufficient original data to evaluate the sensitivity and specificity of the index test using unconcentrated urine to identify S.u2009pneumoniae infection in adults with pneumonia. Reference tests were conducted with at least one culture and/or smear. We estimated sensitivity and two specificities. One was the specificity evaluated using only patients with pneumonia of identified other aetiologies (‘specificity (other)’). The other was the specificity evaluated based on both patients with pneumonia of unknown aetiology and those with pneumonia of other aetiologies (‘specificity (unknown and other)’) using a fixed model for meta‐analysis. We found 10 articles involving 2315 patients. The analysis of 10 studies involving 399 patients yielded a pooled sensitivity of 0.75 (95% confidence interval: 0.71–0.79) without heterogeneity or publication bias. The analysis of six studies involving 258 patients yielded a pooled specificity (other) of 0.95 (95% confidence interval: 0.92–0.98) without no heterogeneity or publication bias. We attempted to conduct a meta‐analysis with the 10 studies involving 1916 patients to estimate specificity (unknown and other), but it remained unclear due to moderate heterogeneity and possible publication bias. In our meta‐analysis, sensitivity of the index test was moderate and specificity (other) was high; however, the specificity (unknown and other) remained unclear.

Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells.

Heme oxygenase-1 (HO-1) is induced by a variety of stress stimuli and by many antitumor agents. We investigated involvement of HO-1 in chemoresistance of cisplatin in human lung epithelial adenocarcinoma cell line, A549, which constitutively expressed HO-1. We found that treatment with cisplatin further augmented HO-1 expression, which was associated with activation of the epidermal growth factor receptor (EGFR) mediated signaling pathway and subsequent nuclear translocation of NF-kappaB. In concordance with the findings, treatment with EGFR-selective tyrosine kinase inhibitor (AG1478) or an Akt inhibitor, which interfere with the post-EGFR signaling pathway, suppressed cisplatin induced HO-1 expression. While either AG1478 or HO-1 siRNA alone did not alter cell viability of A549 cells, both agents significantly augmented cytotoxicity of cisplatin. The similar data also found in large cell carcinoma cell line, H460. Collectively, the results indicate that resistance to cisplatin in A549 cells is associated with HO-1 through EGFR mediated signaling pathway including activation of the PI3k/Akt and NF-kappaB systems. Our data also suggest that the chemosensitivity of A549 cells to cisplatin is restored by EGFR-selective tyrosine kinase inhibitor and an Akt inhibitor.

Role of MexZ and PA5471 in transcriptional regulation of mexXY in Pseudomonas aeruginosa

MexXY, a drug efflux pump in Pseudomonas aeruginosa, confers resistance to aminoglycoside antibiotics. We recently reported that MexZ binds to the promoter region of the mexXY operon. Electrophoretic mobility shift assay (EMSA) using recombinant MexZ and oligonucleotide probes prepared from the intergenic region between mexZ and mexX revealed that MexZ binds to a 20 bp palindromic sequence. Culture of P. aeruginosa in the presence of tetracycline induced higher levels of MexX and MexZ, as measured by immunoblotting and EMSA, than in the absence of antibiotics. When MexZ was expressed by a mexZ expression plasmid, the plasmid-borne MexZ repressed drug-induced MexX production, further confirming that MexZ acts as a repressor of the mexXY operon. PA5471 protein has been reported to be essential for drug-induced MexXY production. Similarly to that report, we observed that plasmid-borne PA5471 induced both MexX and MexZ production in PAO1 cells. Interestingly, interaction between MexZ and PA5471 was observed in a yeast two-hybrid assay. Furthermore, EMSA and in vitro transcription assays revealed that interaction between PA5471 and MexZ reduced MexZ DNA-binding ability, leading to mexXY transcription. These findings contribute to the understanding of the molecular mechanisms underlying the transcriptional regulation of mexZ and mexXY by drug-induced PA5471 expression.

SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women

Purpose The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer. Experimental Design We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.–617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients’ overall survival. Results Patients harboring wild-type (WT) homozygous (c.–617C/C), SNP heterozygous (c.–617C/A), and SNP homozygous (c.–617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.–617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.–617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank pu200a=u200a0.021). Conclusion SNP homozygous (c.–617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.

Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies

BackgroundRecent observational studies have suggested that use of statins reduces mortality in patients suffering from chronic obstructive pulmonary disease. However, no meta-analysis has reported the pooled hazard ratio of statins to all-cause mortality.MethodsWe searched for eligible articles using five databases. We included randomized controlled trials and cohort studies written in English using original data reporting the hazard ratio of statins to all-cause, cardiovascular-related, cancer-related, or respiratory-related mortality. A fixed model with the confidence interval method was used. Publication bias was evaluated by funnel plot and Begg’s test, and was corrected using Duval’s trim and fill method. Sensitivity analyses were also conducted.ResultsWe included 10 out of 128 articles. The pooled hazard ratio of statins to all-cause mortality involving 16269 patients was 0.81 (95% CI: 0.75-0.86, Pu2009<u20090.001) with moderate heterogeneity (I2u2009=u200952%, Pu2009=u20090.032). The sensitivity analysis and funnel plot suggested the existence of publication bias. After three possibly unpublished cohorts were imputed, the pooled hazard ratio of 0.83 (95% CI: 0.78-0.88, Pu2009<u20090.001) still suggested a favorable prognosis in statin-treated patients. The pooled hazard ratio of statins to cardiovascular-related, cancer-related, and respiratory-related mortality were 0.52 (95% CI: 0.27-1.01, Pu2009=u20090.052), 0.57 (95% CI: 0.32-1.01, Pu2009=u20090.056), and 0.55 (95% CI: 0.43-0.78, Pu2009<u20090.001), respectively, although these results were not conclusive as we could not find a sufficient number of original studies dealing with those forms of mortality.ConclusionsThe use of statins for patients suffering from chronic obstructive pulmonary disease may reduce all-cause mortality. This conclusion should be re-evaluated by a registered large-scale randomized controlled trial.

A case of Poncet’s disease (tuberculous rheumatism)

We describe a 37-year-old woman with recurrent polyarthritis, and recurrent erythema nodosum on the flexible side of her left forearm. On an X-ray of the chest, infiltration of the right upper lobe was observed. Transcription-reverse transcription concerted reaction in sputum samples revealed Mycobacterium tuberculosis (M. tuberculosis). Resolution of the polyarthritis with anti-tuberculosis (TB) drugs occurred in 3xa0days. We diagnosed her with Poncet’s disease (PD). PD is considered to be a reactive arthritis, which is a different entity from tuberculous arthritis. Although PD is a rare disease, we should be aware of it as one of the differential diagnoses, even in patients without typical symptoms of TB.

Circulating Carbon Monoxide Level Is Elevated After Sleep in Patients With Obstructive Sleep Apnea

BACKGROUNDnPatients with obstructive sleep apnea (OSA) have an increased risk of cardiovascular morbidity. This study aimed to determine circulating carbon monoxide (CO) levels, which have been suggested to be a marker of cardiovascular risk in patients with OSA.nnnMETHODSnVenous blood samples were obtained from 35 patients with OSA and 17 age-matched, healthy control subjects before and after polysomnography. Concentrations of venous CO and serum heme oxygenase (HO)-1 were determined by gas chromatography and enzyme-linked immunosorbent assay, respectively.nnnRESULTSnCirculating CO levels in OSA patients were significantly increased in the morning, but not in the evening. The change in CO level, which was defined as a gap between the presleep and postsleep CO levels, correlated with apnea-hypopnea index and hypoxia duration as a percentage of total sleep time. No difference was found in serum HO-1 levels between OSA patients and control subjects. Treatment with continuous positive airway pressure (CPAP) resulted in normalization of the postsleep CO level.nnnCONCLUSIONSnThe postsleep circulating CO level is helpful for assessing the clinical severity of OSA. Moreover, treatment of OSA with CPAP can potentially reduce the risk of the disease associated cardiovascular events.

Feasibility study of stereotactic body radiotherapy for peripheral lung tumors with a maximum dose of 100 Gy in five fractions and a heterogeneous dose distribution in the planning target volume

We evaluated toxicity and outcomes for patients with peripheral lung tumors treated with stereotactic body radiation therapy (SBRT) in a dose-escalation and dose-convergence study. A total of 15 patients were enrolled. SBRT was performed with 60 Gy in 5 fractions (fr.) prescribed to the 60% isodose line of maximum dose, which was 100 Gy in 5 fr., covering the planning target volume (PTV) surface (60 Gy/5 fr. − (60%-isodose)) using dynamic conformal multiple arc therapy (DCMAT). The primary endpoint was radiation pneumonitis (RP) ≥ Grade 2 within 6 months. Toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Using dose–volumetric analysis, the trial regimen of 60 Gy/5 fr. − (60%-isodose) was compared with our institutional conventional regimen of 50 Gy/5 fr. − (80%-isodose). The enrolled consecutive patients had either a solitary peripheral tumor or two ipsilateral tumors. The median follow-up duration was 22.0 (12.0–27.0) months. After 6 months post-SBRT, the respective number of RP Grade 0, 1 and 2 cases was 5, 9 and 1. In the Grade 2 RP patient, the image showed an organizing pneumonia pattern at 6.0 months post-SBRT. No other toxicity was found. At last follow-up, there was no evidence of recurrence of the treated tumors. The target volumes of 60 Gy/ 5 fr. − (60%-isodose) were irradiated with a significantly higher dose than those of 50 Gy/5 fr. − (80%-isodose), while the former dosimetric parameters of normal lung were almost equivalent to the latter. SBRT with 60 Gy/5 fr. − (60%-isodose) using DCMAT allowed the delivery of very high and convergent doses to peripheral lung tumors with feasibility in the acute and subacute phases. Further follow-up is required to assess for late toxicity.