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Idiopathic obliterative bronchiolitis (OB) is a rare disease that usually requires a surgical lung biopsy. A 25-year-old woman with progressive exertional dyspnea for several months showed a severe mixed restrictive and obstructive pattern on spirometry. Chest computed tomography showed a mosaic pattern, and pulmonary ventilation-perfusion scintigraphy showed a matched defect. The bronchoscopic specimens obtained from both the alveolar and bronchiolar regions of the predicted lesion area contributed to the diagnosis of OB. She had no underlying causes of secondary OB, and she was diagnosed with idiopathic OB. Since lung transplantation was indicated, she was referred to a lung transplantation-certified hospital.

Background Cryobiopsy enables specialists to perform high-quality, large, entirely circumferential biopsies; therefore, it may improve the diagnostic yield of peripheral pulmonary lesions (PPLs), as has been previously observed with regard to endobronchial tumors and interstitial lung diseases. Research Question How do the diagnostic accuracy and safety change by cryobiopsy when performed alongside conventional biopsy for PPLs? Study Design and Methods Consecutive patients who underwent cryobiopsy in addition to conventional biopsies for PPL diagnosis at our institution between June 2017 and May 2018 were reviewed retrospectively. The target location was estimated and sampling was performed using conventional devices (i.e., forceps, brush, and/or aspiration needle), and cryobiopsy was performed at the same location. Diagnostic outcomes and cryobiopsy safety when performed in addition to conventional sampling methods were analyzed in this observational study. Results In total, 257 patients were analyzed, and the overall diagnostic yield was 89.9%. Among them, 22 lesions were diagnosable by cryobiopsy exclusively, which improved the rate of diagnosis by 8.6%. Advantages of the use of cryobiopsy were the most apparent when lesions were adjacent to areas assessed via radial endobronchial ultrasound (69.4% vs. 84.3%). Multivariable analysis identified bronchus sign (positive/negative, P=0.001), lobe (other lobes/right upper lobe + left upper segment, P=0.028), and visibility on X-ray (visible/invisible, P=0.047) as factors that significantly affected diagnostic yield. On the other hand, three instances of severe hemorrhage (1.2%), and two of pneumothorax (0.8%) occurred. Although most complications were minor, two patients required hospitalization due to cerebral infarction and lung abscess. Interpretation Cryobiopsy improves the diagnostic yield of PPLs when combined with other conventional sampling methods; however, caution is required due to the possibility of complications.

Invasive aspergillosis is a significant cause of mortality in patients with hematological malignancy. Early diagnosis of invasive pulmonary aspergillosis (IPA) by bronchoscopy is recommended but is often difficult to perform because of small lesion size and bleeding risk due to thrombocytopenia. A 71-year-old woman had received initial induction therapy for acute myeloid leukemia. On day 22 of chemotherapy, she had a high fever, and the chest computed tomography scan revealed a 20-mm-sized nodule with a halo sign. Bronchoscopy assisted by virtual bronchoscopic navigation (VBN) and endobronchial ultrasonography with a guide sheath (EBUS-GS) was performed, and Aspergillus terreus was identified from the culture of obtained specimens. A. terreus is often resistant to amphotericin B; thus, voriconazole is usually recommended for treatment. However, the obtained A. terreus isolate showed minimal inhibitory concentrations of 2 µg/mL for voriconazole and 0.5 µg/mL for amphotericin B. Therefore, the patient was successfully treated with liposomal amphotericin B. For patients suspected of having IPA, early diagnosis and drug susceptibility testing are very important. This case suggests that bronchoscopy using VBN and EBUS-GS is helpful for accurate diagnosis and successful treatment even if the lesion is small and the patient has a bleeding risk.

Electrochemical processes are an effective method for detecting dangerous food ingredients. The synergistic between the reduction-oxidation (redox) processes inspired several papers and spurred research towards studying the new materials that can further adapt to optimize the rapid detection of chemical compounds. In this study, we report the eco-synthesis using graphene/TiO

Background Precision medicine in non-small cell lung cancer requires attainment of a sufficient amount of high-quality tumor tissue. Transbronchial cryobiopsy has emerged as a new diagnostic method for non-neoplastic lung disease with a better potential to assess morphology compared with conventional methods. However, the influence of cryobiopsy on specimen quality, particularly detection of protein expression, is unknown. We performed a comparative immunohistochemical study in specimens obtained by cryobiopsy versus conventional sampling to evaluate the feasibility of cryobiopsy for lung cancer diagnosis. Methods Pairs of artificial biopsy specimens, collected using a cryoprobe or conventional scalpel, were obtained from 43 surgically resected primary lung tumors. Formalin-fixed, paraffin-embedded blocks were prepared in an ISO15189-certified laboratory. Immunohistochemical staining of thyroid transcription factor-1, p40, Ki67 and programmed death-ligand 1 (22C3) was performed. The H-scores for thyroid transcription factor-1 and p40, labeling index for Ki67 and tumor proportion score for programmed death-ligand 1 were assessed. Pearson’s correlation coefficients between two sampling types were calculated. Results The thyroid transcription factor-1 and p40 H-scores showed perfect correlations between the cryobiopsy and conventional scalpel-obtained specimens (R2 = 0.977 and 0.996, respectively). Ki67 labeling index and PD-L1 tumor proportion score also showed strong correlations between the two sample types (R2 = 0.896 and 0.851, respectively). Five cases (11.6%) exhibited differences in tumor proportion score category between sample types, potentially because of intratumoral heterogeneity. Conclusions Immunohistochemical expression of certain tumor markers showed a high concordance between cryobiopsy and conventional scalpel sampling. Cryobiopsy is feasible for pathological diagnostics including PD-L1 evaluation.

Background A balloon occlusion technique is suggested for use in cryobiopsy for interstitial lung diseases because of the bleeding risk. However, it may interfere with selection of the involved bronchus for peripheral pulmonary lesions (PPLs). A two-scope technique, in which two scopes are prepared and hemostasis is started using the second scope immediately after cryobiopsy, has also been reported. This study aimed to evaluate the safety and diagnostic utility of transbronchial cryobiopsy using the two-scope technique for PPLs. Methods Data of patients who underwent conventional biopsy followed by cryobiopsy using the two-scope technique for PPLs from November 2019 to March 2021 were collected. The incidence of complications and risk factors for clinically significant bleeding (moderate to life-threatening) were investigated. Diagnostic yields were also compared among conventional biopsy, cryobiopsy, and the combination of them. Results A total of 139 patients were analyzed. Moderate bleeding occurred in 25 (18.0%) patients without severe/life-threatening bleeding. Although five cases required transbronchial instillation of thrombin, all bleeding was completely controlled using the two-scope technique. Other complications included two pneumothoraces and one asthmatic attack. On multivariable analysis, only ground-glass features (P P = 0.28). The total diagnostic yield was 89.9%, significantly higher than conventional biopsy alone (P Conclusions The two-scope technique provides useful hemostasis for safe cryobiopsy for PPLs, with a careful decision needed for ground-glass lesions.

Objectives We conducted a clinical phase II study to evaluate the modified weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimen in pretreated patients with advanced non-small cell lung cancer (NSCLC). Materials and methods This multicenter single-arm phase II study enrolled patients with advanced NSCLC who had previously received >1 chemotherapy regimen. Patients received nab-paclitaxel at 80 mg/m2 on days 1, 8, and 15 (21-d cycle). The primary endpoint was the investigator-assessed overall response rate (ORR). Secondary endpoints included overall survival, progression-free survival (PFS), disease control rate, and safety. The planned enrollment was 30 patients according to a Simon 2-stage minimax design. Results Thirty patients were enrolled between November 2015 and August 2017. Seventeen patients (56.7%) had received >2 regimens. The ORR was 23.3% (95% confidence interval [CI], 8.2%-38.4%), meeting the primary objective of the study. Median PFS was 5.7 months (95% CI, 3.4-9.0 mo), and median overall survival was 12.6 months (95% CI, 8.7-20.8 mo). The median number of treatment cycles was 4 (range, 1 to 20) over the entire study period, and median dose intensity was 63.6 mg/m2/wk (range, 45.7 to 100.0 mg/m2/wk). No new safety signals were reported; the most common grade ≥3 adverse events were neutropenia (56.7%), leukopenia (23.3%), and infection (10.0%). No cases of febrile neutropenia were observed. Conclusions Nab-paclitaxel monotherapy with a dose and schedule suitable for outpatients showed high ORR, long median PFS, and acceptable toxicity for patients with previously treated NSCLC. This dosage method may be useful for selected patients.

BACKGROUND Malignant pleural mesothelioma (MPM) is rarely an asbestos-related cancer with a poor prognosis that is difficult to distinguish from some benign conditions by using conventional biopsy techniques. The purpose of this study was to evaluate the utility of a novel biopsy technique using a cryoprobe during flex-rigid pleuroscopy for diagnosing MPM. METHODS Consecutive patients who underwent pleural cryobiopsy during flex-rigid pleuroscopy from June through November 2017 to diagnose the cause of pleural effusion were collected. From these, cases ultimately diagnosed as MPM were selected. Pleural biopsies were performed by using conventional instruments followed by a cryoprobe. The obtained samples were histologically examined and compared with regard to the quality (sample size, tissue depth, and crush rate), immunohistochemical (IHC) staining, and p16 by fluorescence in situ hybridization (FISH). RESULTS In total, five patients ultimately diagnosed as MPM were enrolled. The sample collected was significantly larger for cryobiopsy than conventional biopsy (18.9 mm2 vs. 6.7 mm2, P < 0.001). Full-thickness biopsies were achieved in four cases by using cryobiopsy compared with one case by conventional biopsy. Moreover, the crush rate was significantly less for cryobiopsy than conventional biopsy (9% vs. 35%, P < 0.001). The results of IHC staining and p16 by FISH were similar between biopsy techniques. Cryobiopsy successfully led to accurate diagnosis of MPM in all cases, whereas conventional biopsy was diagnostic in one case. No severe complications developed after either biopsy technique. CONCLUSION Cryobiopsy during flex-rigid pleuroscopy is a feasible and convenient biopsy technique that supports precise diagnosis of MPM.

BACKGROUND: Ultrasound (US)-guided percutaneous needle biopsy is a useful diagnostic technique with short examination time and real-time monitoring at the bedside. However, there are only a few studies that report on thoracic lesions, whereas the computed tomography (CT)-guided biopsy is well established. There is also limited data comparing US- and CT-guided biopsy. We aimed to clarify the efficacy and safety of US-guided biopsy for thoracic lesions adjacent to the chest wall. METHODS: We retrospectively enrolled consecutive patients who underwent US- or CT-guided percutaneous biopsies for thoracic lesions adjacent to the chest wall between April 2012 and December 2017. Clinical characteristics, lesion size, lesion-pleura contact arc length (LPCAL), diagnostic rate, and complications were compared between the 2 groups. RESULTS: This study enrolled 61 US-guided and 70 CT-guided biopsies. No significant difference was found in age or sex. The lesion size and LPCAL in the US-guided group were significantly larger than those in the CT-guided group (P40 mm was significantly higher in the US-guided group than in the CT-guided group (P=0.009). Complication rates were significantly lower in the US-guided group (3.3%) than in the CT-guided group (24.3%) (P

Background Bronchoscopy is important to diagnose lung cancer. However, some patients who undergo bronchoscopic procedures develop respiratory tract infections. Little is known about the proportion of pathogen-positive results in bacterial cultures from diagnostic bronchoscopy samples in patients with suspected lung cancer. This study aimed to determine the rate of positive bacterial cultures after diagnostic bronchoscopy in patients with suspected lung cancer and the relationship among culture results, clinical characteristics, and respiratory tract infections. Methods We retrospectively reviewed the medical records of all immunocompetent patients who underwent bronchoscopy and had culture and histological samples for the diagnosis of peripheral pulmonary lesions from September 2012 to August 2014 at the National Cancer Center in Tokyo. We analyzed data and classified radiological lesions into the following categories: calcifications, cavitations, low-density areas, margin irregularities, and satellite nodules. Results The study population consisted of 328 patients (median age, 69 years). We found that 65.9% of patients had malignant lesions and 4.2% of patients had positive cultures for pathogenic bacteria. The number of calcifications (p = 0.002, 95% CI: 2.17–41.10) was significantly higher in patients with positive bacterial isolates, according to the multivariate analysis, and bacterial culture positivity was not associated with the development of respiratory complications after bronchoscopy. Of the three patients with respiratory complications, all presented with cavitations. Conclusion Because of the low prevalence of positive bacterial cultures in patients with suspected lung cancer, bacterial culture may be limited to specific patients, such as those with calcifications. Lesions with cavitation warrant close monitoring.

Background Patients treated for non-squamous (non-Sq) non-small cell lung cancer (NSCLC) often require repeat biopsies to determine the optimal subsequent treatment. However, the differences between rebiopsy and initial biopsy in terms of their diagnostic yields and their ability to test the molecular profiles using bronchoscopy with radial endobronchial ultrasound guidance in patients with advanced NSCLC remain unclear. Hence, we aimed to compare the diagnostic yields and ability for molecular analyses of rebiopsies with those of initial biopsies. Methods We investigated 301 patients with advanced non-Sq NSCLC who underwent radial endobronchial ultrasound-guided transbronchial biopsy (TBB) for peripheral pulmonary lesions (PPLs) between August 2014 and July 2017. Patients were divided into the rebiopsy and initial biopsy groups: the latter referred to the biopsy that determined the definitive diagnosis. The diagnostic yields and ability for molecular analyses were compared between the two groups, and the factors affecting the TBB diagnostic yield were identified using univariate and multivariate analyses. Results The diagnostic yields of the rebiopsy and initial biopsy groups were comparable (86.8 and 90.8%, respectively; p = 0.287). Furthermore, 93.0 and 94.0% of the patients in the rebiopsy and initial biopsy groups, respectively, had adequate specimens for gene profiling and mutational analysis (p = 0.765). The factors that increased the diagnostic yield were a positive bronchus sign (p p = 0.026). Conclusions The PPL diagnostic yield of the rebiopsy group was as high as that of the initial biopsy group. Hence, TBB for PPLs is feasible for patients requiring rebiopsy as well as for those with initial diagnoses. Adequate, high-quality biopsy specimens can be obtained by transbronchial rebiopsy for molecular testing.

Cryobiopsy enables specialists to perform high-quality, large, entirely circumferential biopsies; therefore, it may improve the diagnostic yield of peripheral pulmonary lesions (PPLs), as has been previously observed regarding endobronchial tumors and interstitial lung diseases.How do the diagnostic accuracy and safety change by cryobiopsy when performed alongside conventional biopsy for PPLs?Consecutive patients who underwent cryobiopsy in addition to conventional biopsies for PPL diagnosis at our institution between June 2017 and May 2018 were reviewed retrospectively. The target location was estimated and sampling was performed using conventional devices (ie, forceps, brush, aspiration needle), and cryobiopsy was performed at the same location. Diagnostic outcomes and cryobiopsy safety when performed in addition to conventional sampling methods were analyzed in this observational study.In total, 257 patients were analyzed, and the overall diagnostic yield was 89.9%. Among them, 22 lesions were diagnosable by cryobiopsy exclusively, which improved the rate of diagnosis by 8.6%. Advantages of the use of cryobiopsy were the most apparent when lesions were adjacent to areas assessed via radial endobronchial ultrasound (69.4% vs 84.3%). Multivariable analysis identified bronchus sign (positive/negative, P = .001), lobe (other lobes/right upper lobe and left upper segment, P = .028), and visibility on radiograph (visible/invisible, P = .047) as factors that significantly affected diagnostic yield. On the other hand, three instances of severe hemorrhage (1.2%) and two of pneumothorax (0.8%) occurred. Although most complications were minor, two patients required hospitalization because of cerebral infarction and lung abscess.Cryobiopsy improves the diagnostic yield of PPLs when combined with other conventional sampling methods; however, caution is required because of the possibility of complications.

Background: Alectinib is an oral drug developed for the treatment of patients with fusion gene encoding echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged non-small cell lung cancer (NSCLC). Here, we present the case of a patient treated with alectinib who developed a hypersensitivity reaction with successful rechallenge treatment. Case Presentation: A 39-year-old woman who was a passive smoker was referred to Osaka City University Hospital for the evaluation of a skin event caused by treatment for NSCLC with the fusion gene EML4-ALK. The skin reaction was observed on the anterior chest, upper arms, and ear auricles on day 11 of treatment with oral alectinib. The skin event presented as widely distributed erythematous macules that were confluent, indicating a severe and life-threatening form. The skin lesions started to resolve after the initiation of treatment with 40 mg prednisolone. After regrowth of the tumor, she received a rechallenge program for alectinib for 2 weeks; thereafter, alectinib treatment was successfully reinitiated. Conclusion: To the best of our knowledge, we present the first case in which alectinib, which binds to the adenosine triphosphate site of EML4-ALK, induced erythema multiforme. Moreover, successful readministration of alectinib through our rechallenge program has not been reported so far.

For precision medicine, it is required to obtain enough amount high-quality tumor tissue. Transbronchial cryobiopsy (TBC) has emerged as a new method in non-neoplastic lung disease that has better morphological assessment potential. However, it has not been examined yet how the cryobiopsy influences the quality of the specimen, especially of protein. We performed the comparative IHC study between cryobiopsy and standard sampling to evaluate the feasibility of TBC in lung cancer diagnosis. Design: We sampled a pair of artificial biopsy specimens using cryoprobe and standard sampling knife from 43 surgically resected lung cancer. Formalin-fixed, paraffin-embedded blocks were made at the ISO15189-certified laboratory. IHC was performed using primary antibodies against thyroid transcription factor-1 (TTF-1), p40, Ki67, and programmed death-ligand 1 (PD-L1, 22C3). H-score for TTF-1 and p40 with cut-off value of 50, proportion score for Ki67 and PD-L1 were assessed by two or more observers, and confirmed by a pathologist. Pearson’s correlation coefficient was calculated. Results: There was a perfect correlation between cryoprobe and sampling knife specimens in TTF-1 and p40 (R2=0.977, 0.996, respectively). Ki67 and PD-L1 also showed a strong correlation (R2=0.896, 0.851, respectively). Concerning PD-L1 judgment, 4 cases (9%) resulted in a different category which can be explained by intratumoral heterogeneity. Conclusion: This study revealed high concordance of IHC results between cryobiopsy and standard sampling. TBC is feasible for pathological diagnostics including IHC evaluation.

Diagnostic yield of bronchoscopy for peripheral pulmonary lesions has improved since the application of R-EBUS. R-EBUS enables us to confirm not only solid nodules but also ground-glass nodules (GGNs). However, diagnostic bronchoscopy for GGNs still has been challenging because of their subtle pathologic changes. Recently, cryobiopsy has made a great impact for the diagnosis of interstitial lung disease. We tried to apply cryobiopsy for GGNs, and researched the utility. Fifteen outpatients who underwent diagnostic bronchoscopy for GGNs at our hospital from June to September 2017 were enrolled. All procedures were performed using R-EBUS, virtual bronchoscopy, and X-ray fluoroscopy guidance under local anesthesia. After usual sampling (forceps, brush, or aspiration needle), cryobiopsy was added. The diagnostic value and the safety of cryobiopsy were reviewed. The median (range) size of total and solid part were 23.7 (14.4-35.3) and 12.5 (0-24.4) mm. Six nodules located in upper lobe, 11 nodules located at peripheral 1/3, and 6 nodules showed negative bronchus sign. We performed 67 times forceps biopsy and 17 times cryobiopsy. The median (range) area of specimens were significantly larger in cryobiopsy (12.6 [1.26-27.0] vs. 1.77 [0.116-5.88] mm2, p Cryobiopsy enabled us to obtain specimens with better quantity and quality. We could diagnose GGNs more precisely using cryobiopsy under controllable complications.

Endobronchial ultrasound-guided needle aspiration (EBUS-TBNA) is a well-established procedure with high diagnostic yield and safety. However, the standard 22 gauge needles sometimes cause major bleeding particularly in hypervascular tumors like metastatic lung tumors from renal cell carcinoma (RCC). The 25 gauge needles are already introduced to endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), and are considered as one of the standard devices due to their comparable diagnostic outcome, lower complication risk, and the better manipulability. Recently, the new 25 gauge needles have been applied to EBUS-TBNA. In present case, we were able to obtain a definitive diagnosis of the metastatic RCC by EBUS-TBNA using the 25 gauge needle. The new thin needle might be a better option for hypervascular tumors of the lung.

Background Amrubicin hydrochloride (AMR) is a key agent for lung cancer. NADPH quinone oxidoreductase 1 (NQO1) metabolizes the quinone structures contained in both amrubicin (AMR) and amrubicinol (AMR-OH). We hypothesized that NQO1 C609T polymorphism may affect AMR-related pharmacokinetics and clinical outcomes. Methods Patients received AMR doses of 30 or 40 mg/m2/day on days 1–3. Plasma sampling was performed 24 hours after the first and third AMR injections. Concentrations of AMR and AMR-OH were determined by HPLC and the NQO1 C609T polymorphism was assayed by RT-PCR. Results A total of 35 patients were enrolled. At a dose of 40 mg/m2, the T/T genotype exhibited a tendency toward a relationship with decrease concentrations of AMR-OH on days 2 and 4. The genotype also showed a significant decrease of hematological toxicities ( P < 0.05). Conclusions NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities.

Objective The utility of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions is unclear. The aim of this study was to evaluate the role of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions. Methods Consecutive patients who underwent endobronchial ultrasound with a guide sheath for the diagnosis of peripheral pulmonary lesions at our hospital between September 2012 and July 2014 were included in this retrospective study. Cytology slides were air-dried, and modified Giemsa (Diff-Quik) staining was used for rapid on-site evaluation. Additional smears were prepared for Papanicolaou staining and tissue samples were placed in formalin for histologic evaluation. The results of rapid on-site evaluation were compared with the final diagnoses of endobronchial ultrasound with a guide sheath. Results A total of 718 cases were included in the study population. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions was 88.6%, 65.9%, 81.2%, 77.7% and 80.1%, respectively. There were no procedure-related deaths. Conclusions Rapid on-site evaluation during endobronchial ultrasound with a guide sheath had high sensitivity for peripheral pulmonary lesions. When carrying out rapid on-site evaluation of transbronchial biopsy samples from peripheral pulmonary lesions, careful interpretation and clinical correlation are necessary.

While epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) lead to longer progression-free survival (PFS) when compared with conventional chemotherapy in non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR-TKI remains unclear in EGFR-wild-type (WT) NSCLC.This article reviews selected data from randomized trials regarding the use of TKIs in EGFR-WT NSCLC. Nine randomized phase III trials have compared EGFR-TKI with chemotherapy in NSCLC patients in a second or later line setting. Two of these trials, TAILOR and DELTA, which were designed to investigate treatment benefits according to EGFR genotype, demonstrated that docetaxel chemotherapy displayed significantly better in progression-free survival (PFS) when compared with the EGFR-TKI erlotinib. Biomarkers to predict clinical benefits of the drug against EGFR WT tumor, and the efficacy of combination regimens using erlotinib or single-use afatinib against tumors are also covered in this article.Considering the modest benefits of erlotinib for EGFR-WT tumors, future studies are warranted, including the exploration of useful biomarkers and new treatment strategies for EGFT-TKI use, as well as the development of more sensitive EGFR mutation tests.

Purpose Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. Patients and methods Systemic therapy-naive patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500mg/m 2 , and gefitinib was sequentially administered on days 2–16. This treatment regimen was repeated every 3 weeks until disease progression. Results Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1–35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7–98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9–100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0–21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5–35.5 months). There were no treatment-related deaths. Conclusions The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.

The reaction kinetics for anaerobic biodegradation of volatile acid components, including acetic, propionic and butyric acids commonly contained in the wastewater from beer brewery factories, was investigated in a granular sludge bed. For the degradation of each single substrate component in the granular sludge bed reactor, the reaction scheme was specified and the Monod kinetic parameters were evaluated. In addition, the degradation sequences and their kinetics were also identified for multiple substrate systems with combinations of the three volatile acid components including acetic, propionic and butyric acids. The batch degradation sequences for the single and multiple substrates in the batch sludge bed reactor were explained well by the numerical solutions of multiple differential mass balance equations for the components involved on the basis of the Monod kinetics associated with or without competitive and non-competitive inhibition mechanisms for the specified combinations of the substrate components.

Background Renal toxicity is a clinical problem that affects 28 − 42% of patients undergoing treatment with cisplatin. Renal toxicity can be minimized by high volume hydration with mannitol diuresis. Recent reports have shown that cisplatin induces depletion of Mg and that Mg supplementation can reduce renal toxicity. We hypothesized that Mg infusion combined with low volume hydration may not be sufficient to overcome cisplatin-induced renal toxicity. Methods In total, 85 patients with lung cancer receiving their first cycle of cisplatin-based chemotherapy at the Osaka City University Hospital were classified into three groups: those administered high volume hydration without Mg infusion (high-volume Mg-), high volume hydration with Mg infusion (high-volume Mg+), and with low volume hydration with Mg infusion (low-volume Mg+). Serum creatinine (sCr) and creatinine clearance (CrCl) were examined before and after treatment with cisplatin. Multivariable analysis was carried out to identify the most important contributing factors. Results There were no significant differences in pre-treatment sCr levels or CrCl between groups. In the high-volume Mg- group, post-treatment sCr significantly increased compared with pre-treatment levels, while post-CrCl significantly decreased compared with pre-treatment CrCl (p

Chronological changes in the morphology of the ankle, a joint that consists primarily of chondral components in children, were investigated by arthrography and plain radiography. Arthrography was performed in 57 ankles of 40 patients with normal ankles (aged from 2 months to 3 years, 4 months; mean, 1 year, 7 months), and plain radiography was performed on 183 joints of 126 patients with normal ankles (aged from 3 years, 6 months to 14 years, 5 months (mean, 7 years, 8 months). The angle of the distal tibial joint surface was then measured on each radiograph. Despite being evident at birth, valgus inclination in the ankle rapidly changed during the first and second years of life. Thereafter, change continued gradually and spontaneously, and the ankles were in the neutral position by 3 years of age. However, the morphology of the ankles did not change much after that time. Normal ankles show valgus inclination at birth, but this configuration is changed naturally over time, and the ankles are in the neutral or slightly varus position by the age of bone maturity.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), routinely used to treat advanced non-small-cell lung cancer (NSCLC) patients with activated EGFR mutations, are associated with excellent response and improved performance status. Recently, pro-inflammatory cytokines, such as regulated upon activation normal T cell expressed and secreted (RANTES), interleukin (IL)-10 and IL-8 have been proposed as mediators of cancer development. EGFR-TKIs have been found to affect this network of pro-inflammatory cytokines. Methods EGFR-TKIs (erlotinib, 150 mg/day; and gefitinib, 250 mg/day) were administered once per day. Treatment was continued until disease progressed or the patient developed intolerable symptoms of toxicity, or withdrew his/her consent for study participation. The treatment was a part of standard care. We investigated the correlation between plasma pro-inflammatory cytokines (including plasma RANTES, IL-10, and IL-8) levels and clinical outcomes following EGFR-TKI treatment in lung cancer patients. Pro-inflammatory cytokine levels were evaluated at diagnosis and on treatment day 30 after the first administration of EGFR-TKIs. Results Overall, 33 patients were enrolled. Plasma pro-inflammatory cytokine levels were determined for all patients at diagnosis. Plasma samples from 26 patients were obtained on treatment day 30. High level of RANTES at diagnosis was associated with severe general fatigue (P = .026). Low level of RANTES at diagnosis was significantly associated with long-term survival (P = .0032). Percent decrease change of IL-10 was associated with severity of rash (P = .037). The plasma IL-8 level on treatment day 30 (median, 5.48 pg/mL; range, 0.49–26.13 pg/mL) was significantly lower than the level at diagnosis (median 10.45 pg/mL; 3.04–54.86 pg/mL; P = .021). Conclusions These results suggest that EGFR-TKIs may suppress systemic inflammation and promote tumor shrinkage. The network of pro-inflammatory cytokines was affected by EGFR-TKI treatment for NSCLC. In addition, the clinical outcomes of EGFR-TKI treatment were influenced by the status of the plasma pro-inflammatory cytokines at diagnosis.

Fullowing on from experimdntal results, we have used the technique of vascular bundle transplantation in cases of Perthes' disease.The results of three cases are described in this paper.The follow-up period ranged from 7 to 10 years' and the results of the operation were examined roentgenographically and clinically.On final examination, the J. O. A score was 100 points in all cases, and roentgenogenographical evaluation using the Mose method classified all cases as good.

Background Malnutrition in non-small cell lung cancer (NSCLC) is associated with advanced stage of disease and is needed for careful choice of treatment. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used for the treatment of advanced NSCLC with EGFR active mutations, which are promising the excellent responses. Recently, pro-inflammatory cytokines have been proposed as mediators of cancer cachexia. Adipose tissue produces and release substances called adipokines which include tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, and resistin. Adiponectin suppresses the secretion of inflammatory cytokines such as IL-8, TNF-α, and induces the secretion of anti-inflammatory cytokines such as IL-10. It has been hypothesized that EFGR-TKI therapy may affect this adipokine network. Methods The prospective study which evaluated correlations between the pre and post-treatment point of days 30 plasma adipokines and cytokines after EGFR-TKIs administration and clinical outcomes in advanced NSCLC was conducted at Osaka City University Hospital. Plasma adipokines and cytokines were analyzed by Luminex 200 PONENT system (Milliplex MAP kits; Millipore). Results A total of 33 patients were enrolled. We obtained plasma samples for analyses 33 patients on pre-treatment point, and 23 patients on days 30 point. Plasma adiponectin level on the pre-treatment point (40.34 ± 32.00ng/ml) was significantly lower than those on days 30 point (45.07 ± 26.38ng/ml, p = 0.01). On the pre-treatment point of plasma IL-8 (16.70 ± 16.01pg/ml), IL-10 (13.06 ± 29.69pg/ml), insulin (656.9 ± 514.6pg/ml) levels were significantly higher than those on days 30 point (7.154 ± 5.674 pg/ml p = 0.02; 11.53 ± 30.92pg/ml, p = 0.04; and 551.4 ± 520.2pg/ml, p = 0.02, respectively). The levels of leptin and resistin had no significant changes between pre and on days 30 points. Conclusions The EGFR-TKIs treatment for NSCLC increased the plasma adiponectin levels and decreased the plasma insulin, IL-8 and IL-10 levels. Increase of adiponectin levels by EGFR-TKIs may resolve the inflammation and increase insulin sensitivity with reduced output of insulin. Disclosure All authors have declared no conflicts of interest.

Aim: Gefitinib (G) is the key drug for patients (pts) with Non-Small Cell Lung Cancer (NSCLC) harboring mutations of EGFR as a first line treatment. However, they have disease progression in most cases. Pemetrexed (PEM) and G are reported to have a schedule-depended cytotoxic synergism. We evaluated the efficacy and safety of G and PEM as a first line chemotherapy in pts with NSCLC harboring mutations of EGFR. Methods: Eligibilities were histological or cytologically proven non-squamous NSCLC with EGFR active mutation, chemotherapy naive, measurable lesion, ECOG PS 0-1, adequate organ function, life expectancy longer than 12 weeks and written informed consent. G (250mg/body) was administered on day 2-16 and PEM (500mg/m2) was administered on day1. The combination was repeated every 3 weeks until progressive disease (PD). Primary endpoint was overall response rate (ORR) and secondary endpoints were toxicities, disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The planed sample size was 26 pts. Results: From March 2010 to January 2013, 26 pts were enrolled and eligible: males/females 13/13; median age 66 (range 58-84); PS 0/1 3/23; stage III/IV 1/25; Adeno/Others 26/0. All pts were eligible for efficacy and toxicity; a total 398 cycles (median 16 cycles, range 1-35) were given. Major grade 3/4 toxicities were neutropenia, infection, and liver dysfunction. There was no treatment-related death. ORR was 84.6%, and DCR was 96.2%. Median PFS was18.0 months, and median OS was 32.0 months. Conclusions: This combination showed high ORR, long median PFS, and acceptable toxicity. Randomized trial of PEM + G compare with G alone is warranted. Disclosure: All authors have declared no conflicts of interest.

7564 Background: To determine a recommended dose (RD) of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation (AHF) for stage III non-small cell lung cancer (NSCLC). Methods: Eligible patients had unresectable stage III NSCLC, age of less than 75 years, PS: 0 or 1, V20 of 35% or less. PET was used for staging. Cisplatin (80mg/m2) was administered on day 1 and vinorelbine (20mg/m2) was administered on days 1 and 8 for two cycle. Twice-daily radiation therapy (1.5 Gy per fraction) without elective nodal irradiation started on day 1. Total doses were 60Gy in 40 fractions and 66Gy in 44 fractions at levels 1 and 2 respectively. After concurrent chemoradiotherapy, consolidation chemotherapy regimen was cisplatin (80mg/m2) on day 1 and vinorelbine (20mg/m2) on days 1 and 8 every 4 week for three cycles. The dose-limiting toxicity (DLT) was defined as grade ≥ 3 esophagitis, grade 3 neutropenic fever, grade ≥ 3 other non-hematologic toxicities and interruption of irradiation for more than 2 weeks. DLT was monitored for 90 days. Results: A total of 12 patients were enrolled (6 patients in Level 1, 6 patients in Levels 2). DLTs were noted in 2 patients at Level 1, which were grade 3 esophagitis and grade 3 febrile neutropenia. Radiation dose was escalated up to 66 Gy in 44 fractions (Level 2), and there was no DLT. In principle, Sixty-six Gy in 44 fractions (Level 2) should be the RD. Major toxicities were leucopenia, neutropenia, and anemia. The response rate, the median progression free survival time, and the median overall survival time was 83.3%, 10.4 months, and 36.3 months for all patients, respectively. Conclusions: The RD was 66 Gy in 44 fractions (Level 2). The toxicity of this chemoradiothrapy regimen was manageable and efficacy is promising. The efficacy and safety of this regimen should be confirmed in a phase II study. Clinical trial information: UMIN000003769.

Background Amrubicin hydrochloride (AMR) is a novel synthetic aminoanthracycline derivative. AMR is metabolized to amrubicinol (AMR-OH), and the cytotoxic activity of AMR-OH is 18–220 times more potent than that of AMR. NADPH quinone oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone structures which are contained in both AMR and AMR-OH. Recent report showed that C609T polymorphisms of NQO1 had a significant inverse correlation with in vitro AMR-OH cytotoxicity. Previously, we reported that the plasma concentration of AMR-OH on day 4 is correlated with hematological toxicities (anti-cancer drugs 2009). We hypothesized that the C609T polymorphisms of NQO1 may relate to the AMR-OH plasma concentrations and clinical outcomes. To test this hypothesis, a pharmacogenomics study was carried out on patients with lung cancer received AMR at a dose of 30 or 40 mg/m2/day on days 1–3. Plasma sampling was carried out at the time points of 24 h after the third AMR injection (AMR on day 4 and AMR-OH on day 4). Methods The concentrations of AMR and AMR-OH were determined by the HPLC method. DNA was isolated from blood and C609T was assayed using RT–PCR. Results Thirty-five patients were enrolled. The C/C, C/T and T/T were observed in 12 (34.3%), 16 (45.7%) and 7 (20%) patients, respectively. A dose of 30 mg/m2 was administered to 19 patients, and 40 mg/m2 was administered to 16 patients. The mean plasma concentrations of AMR-OH on day 4 at a dose of 30 and 40 mg/m2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (P = 0.005). No significant correlations were observed between NQO1 genotypes and clinical outcomes in patients with AMR at a dose of 30 mg/m2. In patients with AMR at a dose of 40 mg/m2, the plasma concentrations of AMR-OH on day 4 exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C 20.5 ± 5.89, C/T 15.9 ± 5.43 and T/T 11.2 ± 4.47 ng/ml (P = 0.066). The significant relations were observed between NQO1 genotypes and decrease percentage changes in WBC, hemoglobin and platelet counts (P = 0.01, 0.03 and 0.0005, respectively). Conclusions The NQO1 genotype appears to be the candidate biomarker of hematological toxicities of AMR treatment at a dose of 40 mg/m2.

Background Amrubicin hydrochloride (AMR) is a novel synthetic aminoanthracycline derivative, that is metabolically activated to amrubicinol (AMR-OH) by carbonyl reductase. The cytotoxic activity of AMR-OH is promising for small cell lung cancer and considered as a key agent. NADPH Quinone Oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone structures contained in both AMR and AMR-OH. NQO1 expression genotyped homozygous for minor alleles (T/T) was low compared with homozygous for major alleles (C/C) or heterozygous (C/T). We hypothesized that NQO1 C609T polymorphisms may relate to the AMR pharmacokinetics and clinical outcomes. Methods The patients with lung cancer received AMR at a dose of 30 or 40mg/m2/day on day 1-3 at Osaka City University Hospital were enrolled. Plasma sampling was performed at the time points of 24h after the third AMR injection. The concentrations of AMR and AMR-OH were determined by HPLC method. NQO1 C609T polymorphism was assayed using real-time polymerase chain reaction methods. Results A total of 35 patients were enrolled. The C/C, C/T, and T/T were observed in 12 (34.3%), 16 (45.7%), and 7 (20%) patients, respectively. A dose of 30 mg/m2 was administered to 19 patients, and 40mg/m2 was administered to 16 patients. The mean plasma concentrations of AMR-OH on day4 at a dose of 30mg/m2 and 40mg/m2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (p = 0.005). In patients with AMR at a dose of 40mg/m2, the plasma concentrations of AMR-OH on day4 exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C 20.5 ± 5.89, C/T 15.9 ± 5.43, and T/T 11.2 ± 4.47ng/ml (p = 0.066). The C/C was related to decrease changes in WBC, hemoglobin, and platelet counts (p = 0.01, p = 0.03, and p = 0.0005, respectively). No significant correlations were observed between NQO1 genotypes and clinical outcomes at a dose of 30mg/m2. Conclusions NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities. NQO1 genotype appears to be the candidate biomarker of hematological toxicities of AMR treatment at a dose of 40mg/m2. Disclosure All authors have declared no conflicts of interest.