Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019-2020: General view of the pathogens' antibacterial susceptibility.

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were ß-lactamase-producing ampicillin resistant and ß-lactamase-negative ampicillin resistant, respectively. Extended-spectrum ß-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-ß-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

Survival Analysis for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status Treated with Alectinib: Updated Results of Lung Oncology Group in Kyushu 1401.

LESSONS LEARNED: Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND: We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS: Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS: The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION: Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of japanese society of chemotherapy, the japanese association for infectious diseases, and the japanese society for clinical microbiology in 2016: General view of the pathogens' antibacterial susceptibility.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2016. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between February 2016 and August 2016 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1062 strains (143 Staphylococcus aureus, 210 Streptococcus pneumoniae, 17 Streptococcus pyogenes, 248 Haemophilus influenzae, 151 Moraxella catarrhalis, 134 Klebsiella pneumoniae, and 159 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 48.3%, and those of penicillin-susceptible S. pneumoniae was 99.5%. Among H. influenzae, 14.1% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 41.1% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 4.5% and 0.6%, respectively.

GABAB receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways.

BACKGROUND: High-grade chondrosarcoma, which has a high incidence of local recurrence and pulmonary metastasis despite surgical resection, is associated with poor prognosis. Therefore, new and effective adjuvant therapies are urgently required for this disease. Gamma-aminobutyric acid (GABA), which acts as a neurotrophic factor during nervous system development, is related to the proliferation and migration of certain cancer cells. The GABAergic system, which is composed of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), and GABA receptors, has an important function in nerve growth and development of neural crest. Therefore, the GABAergic system may play important functional roles in the proliferation of chondrosarcoma cells, which are derived from neural crest cells. We examined the anti-tumor effects of the GABAergic system on a chondrosarcoma cell line. METHODS: We evaluated the underlying mechanisms of the anti-tumor effects of the GABAergic system, such as the involvement of different signaling pathways, apoptosis, and cell cycle arrest, in the high-grade chondrosarcoma cell line OUMS-27. In addition, we performed whole-cell patch-clamp recordings for Ca2+ currents and evaluated the changes in intracellular Ca2+ concentration via Ca2+ channels, which are related to the GABAB receptor in high-grade chondrosarcoma cells. RESULTS: The GABAB receptor antagonist CGP had anti-tumor effects on high-grade chondrosarcoma cells in a dose-dependent manner. The activities of caspase 3 and caspase 9 were significantly elevated in CGP-treated cells compared to in untreated cells. The activity of caspase 8 did not differ significantly between untreated cells and CGP-treated cells. However, caspase 8 tended to be up-regulated in CGP-treated cells. The GABAB receptor antagonist exhibited anti-tumor effects at the G1/S cell cycle checkpoint and induced apoptosis via dual inhibition of the PI3/Akt/mTOR and MAPK signaling pathways. Furthermore, the changes in intracellular Ca2+ via GABAB receptor-related Ca2+ channels inhibited the proliferation of high-grade chondrosarcoma cells by inducing and modulating apoptotic pathways. CONCLUSIONS: The GABAB receptor antagonist may improve the prognosis of high-grade chondrosarcoma by exerting anti-tumor effects via different signaling pathways, apoptosis, cell cycle arrest, and Ca2+ channels in high-grade chondrosarcoma cells.

A practical regioselective synthesis of alkylthio- or arylthioindoles without the use of smelly compounds such as thiols.

A convenient method for the synthesis of 3-methylthioindoles has been established which does not use smelly compounds such as thiol derivatives. The method, which introduces an alkyl- or arylthio-group into the C(3)-position of the indole skeleton, was extended to the direct introduction of a methylthio or bromo group at the C(2)-position using 3-methylthioindoles. No dimerization occurred, and the reaction mechanism was confirmed. The products have the partial structure of potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) bromomethylthioindoles (MC 5-8) isolated from marine algae. Furthermore, this reaction could be applied to the synthesis of 3,3-diindolyl thioether which is a core structure of Echinosulfone A.

[Our experience with percutaneous trans-esophageal gastrotubing (PTEG)].

Percutaneous endoscopic gastrostomy (PEG) has been generally used as a long-term enteral nutrition route for patients in whom oral intake is impossible. Percutaneous trans-esophageal gastrotubing (PTEG) is useful for the patients in whom PEG insertion has not been indicated. A gastroenterologist usually performs PTEG in Japan, but in our hospital otolaryngologists have performed this procedure. From 2006 to 2012, we experienced 9 patients who underwent PTEG insertion without a life-threatening adverse event. An otolaryngologist who is accustomed to the cervical procedures can safely perform PTEG insertion.

Treatment with immune checkpoint inhibitors after EGFR-TKIs in EGFR-mutated lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the gold standard for EGFR-mutated non-small cell lung cancer (NSCLC) treatment. Immune checkpoint inhibitors (ICIs) have been developed for the treatment of several malignancies, including lung cancer. However, it is known that ICIs have poorer efficacy in EGFR-mutated NSCLC. METHODS: We collected data for patients with EGFR-mutated NSCLC receiving monotherapy with ICIs after EGFR-TKIs between December 2015 and March 2020 in three institutions, and retrospectively analyzed the association between patient characteristics and efficacy of ICIs. RESULTS: A total of 25 patients were included in this study. We defined responders as patients undergoing 90 days or longer of ICI treatment. Comparing characteristics between responders and non-responders, more tumors with L858R EGFR mutation were observed in responders than in non-responders (L858R: 66.7% and 25.0%, respectively, p < 0.05). There was no difference in incidence of T790M resistance mutation before ICI treatment. The PD-L1 positive rate was slightly higher in responders but not statistically significant (22.2% and 12.5%, respectively). Median duration of EGFR-TKI pretreatment was shorter in ICI responders compared with nonresponders (13.3 and 19.9 months, respectively). The survival of patients with L858R tumors was significantly longer than that of patients with exon 19 deletion (HR: 0.35, 95% CI: 0.13-0.93, p = 0.026). CONCLUSIONS: ICI treatment tends to have better efficacy in patients with L858R-mutated tumors. This study suggests that patients with L858R-mutated NSCLC are candidates for ICI treatment after EGFR-TKI treatment.

Prospective Multicenter Study of Chemotherapy-Induced Clostridium (Clostridioides) difficile Infection in Patients With Lung Cancer: North Japan Lung Cancer Study Group Trial 1204.

BACKGROUND: Diarrhea post-antibiotic use is primarily attributed to mucosal lesions induced by Clostridium (Clostridioides) difficile (C. difficile) infection (CDI). Cancer patients undergoing chemotherapy might have a higher risk of CDI even when prior antibiotics are not used. Thus far, the relationship between lung cancer chemotherapy and the incidence of diarrhea remains unclear. This prospective multicenter study aimed to determine the incidence of CDI in lung cancer patients undergoing chemotherapy. METHODS: The presence of C. difficile and its toxins was investigated in lung cancer patients experiencing diarrhea during chemotherapy including paclitaxel (PTX), nanoparticle albumin-bound paclitaxel (nab-PTX), docetaxel (DOC), tegafur-gimeracil-oteracil (S-1), or irinotecan (CPT-11). If grade 2 or higher diarrhea occurred, then a stool culture was performed to detect anaerobic organisms and C. difficile toxins A and B. Additional data were collected through patient interviews and medical chart review. RESULTS: A total of 263 consecutive patients were enrolled in the study; grade 2 or higher diarrhea was observed in 22 patients (8.4%); CDI was confirmed in five of them (1.9%). The incidence of CDI was 22.7% of all diarrhea cases, and 50% of patients treated with PTX were CDI positive; the incidence of CDI was significantly higher in patients treated with PTX (P=0.039). Among the diarrhea cases, CDI patients had significantly worse ECOG performance status (PS) (P=0.043) and a significantly higher neutrophil count (P=0.028) than non-CDI patients. No CDI patients received antibiotics before cancer chemotherapy. CONCLUSIONS: Although diarrhea does not always affect a large portion of lung cancer chemotherapy recipients, clinicians should consider the possibility of CDI occurrence in lung cancer patients receiving chemotherapy, particularly PTX, without prior antibiotic exposure.

Randomized phase II trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-squamous non-small cell lung cancer: NJLCG1001.

BACKGROUND: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC. METHODS: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m2 on days 1-14 and 29-42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948). RESULTS: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%). CONCLUSIONS: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.

[Sleeveresection of the left main bronchus for bronchogenic carcinoid for preserving lung parenchyma].

UNLABELLED: We performed bronchoplasty for a bronchogenic tumor of low-grade malignancy without lung parenchyma resection. A 69-year-old man visited our hospital in March 2008 because of cough. Chest computed tomography (CT) revealed atelectasis of the entire left upper lobe and a 2-cm mass with strong contrast enhancement in the lumen of the left main bronchus. Bronchoscopy identified a polypoid mass in the left main bronchus, about 3 cm distal to carina, obstructing the lumen. Biopsy led to a diagnosis of typical carcinoid tumor. Surgery : Thoracotomy showed complete atelectasis of the left upper lobe. After lymph node dissection, resection of the left main bronchus including the site of tumor origin was performed. From the extent of expansion, the left upper lobe was decided to be possible to be spared, and end-to-end anastomosis of the bronchus was performed. Postoperative respiratory rehabilitation resulted in improved aeration of the left upper lobe and markedly improved respiratory function. CONCLUSION: The judgment of whether the long-standing atelectatic left upper lobe could be spared or not was a key in choosing this procedure.

Phase II study of S-1 in patients with previously-treated invasive thymoma and thymic carcinoma: North Japan lung cancer study group trial 1203.

OBJECTIVES: Invasive thymoma (IT) and thymic carcinoma (TC) are rare epithelial neoplasms arising in the anterior mediastinum. Platinum-based chemotherapies are widely used for first-line treatment of unresectable IT and TC, but no standard treatment has been established for previously-treated IT and TC thus far. Because promising efficacy of S-1 (tegafur, gimeracil and oteracil combination) has been reported in some retrospective studies, we conducted the first prospective phase II trial to evaluate its efficacy in previously-treated patients with advanced IT and TC. MATERIALS AND METHODS: Patients progressing after at least one regimen of systemic chemotherapy received S-1 orally at a dose based on body surface area for 2 weeks followed by one week of rest until tumor progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profile. We defined an ORR of 25% as indicating potential usefulness while ORR of 10% was the lower limit of interest. RESULTS: Forty patients were enrolled (IT, n = 20; TC, n = 20). ORR was 17.5% (95% CI 7.3-32.8; IT, 10%; TC, 25%), disease control rate was 85% (IT, 95%; TC, 75%). Median PFS was 7.0 months (IT, 11.3 months; TC, 5.4 months), and median OS was 40.3 months (IT, 58.5 months; TC, 22.7 months) with a median follow-up of 51.9 months. Major toxicities (grade 3-4) were anorexia (10%), neutropenia (7.5%) and pneumonitis (5%). No treatment-related death was observed. CONCLUSION: Although the primary endpoint was not met, S-1 monotherapy did have effects similar to recently reported immunotherapies for TC but at much lower cost. S-1 could represent a treatment option for previously-treated advanced TC. This trial was registered as UMIN 000008174.

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients. Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer. Design, Setting, and Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study. Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks. Main Outcomes and Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms. Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome. Conclusions and Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option. Trial Registration: UMIN-CTR Identifier: UMIN000015949.

Simulating distribution of trihalomethane in tap water in the area receiving a combination of advanced treated water and conventionally treated different source water: 1998, 1999 and 2002 data on Osaka Prefecture and its surrounding cities, Japan.

Empirical equations for explaining trihalomethane (THM) distribution were established based on data on tap water in Osaka City before and after starting the advanced treatment and were represented by the following equations for bromodichloromethane (S(1)), dibromochloromethane (S(2)) and bromoform distribution factors (S(3)) as a function of chloroform distribution factor (S(0)), respectively: S(1) = -0.97S(0)(2) + 0.75S(0) + 0.19 (regression coefficient: r = 0.71), S(2) = 0.13S (0) (2) -0.76S(0) + 0.51 (r = 0.98) and S(3) = 0.83S(0)(2) -0.99S(0) + 0.30 (r = 0.97). Further, the derived equations were verified by THMs data of Osaka Prefecture and its surrounding cities (except for Osaka City), receiving a combination of advanced treated water and conventionally treated different source water.

Episodic trihalomethane species and levels in tap water at a start of operation of advanced treatment in Osaka Prefectural water supplies.

Dramatic changes in trihalomethanes of tap water caused by decreasing the chlorine dose from to break-point to zero at a pre-chlorination could be found during several years from starting the advanced treatment in Osaka Prefectural water utilities (from 1998 to 2002). In 1998 (break-point chlorination), chloroform was predominant (an average of 14.3 microg/L) and bromodichloromethane (5.96 microg/L), dibromochloromethane (4.19 microg/L) and bromoform (1.06 microg/L) were in the decreasing order. In contrast, in 1999 (chloramination), dibromochloromethane and bromodichloromethane were abundant trihalomethanes (6.61 and 5.72 microg/L) and followed by chloroform (4.14 microg/L) and bromoform (1.41 microg/L). Trihalomethane distribution in 2002 (non-chlorination) was almost the same as that in 1999.

Estimation of dietary intake of biotin and its measurement uncertainty using total diet samples in Osaka, Japan.

Single-laboratory method performance parameters were evaluated for analysis of biotin in total diet samples by hydrolyzed extraction and microbiological assay with Lactobacillus plantarum. The method was shown to be accurate, repeatable, rugged, and applicable for the determination of biotin in a broad range of matrixes and concentrations of total diet samples. The measurement uncertainty was evaluated with all food sample groups by combining the relative uncertainty of precision, recovery from each food group, and interday variation factors calculated from the ruggedness test results. The estimated daily intake of biotin in Osaka city and its expanded measurement uncertainty were 70.1 +/- 11.2 microg/day. The value was 1.6 times higher than the current adequate intake of biotin in Japan.

Characteristics and outcomes of patients with EGFR-mutation positive non-small-cell lung cancer receiving gefitinib beyond radiological progression.

BACKGROUND: This study aimed to analyze the characteristics and outcomes of patients suffering from non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor mutations (EGFRm+) receiving gefitinib who remained clinically stable following confirmation of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) (R-PD) and identify those who benefited from tyrosine kinase inhibitor therapy beyond PD. RESEARCH DESIGN AND METHODS: The clinical courses of patients with EGFRm+ advanced NSCLC who received first-line gefitinib were investigated. Clinical PD (C-PD) was defined as one or more of the following: (1) symptomatic PD, (2) worsening performance status resulting from PD, (3) threat to a major organ(s), or (4) unequivocal multiorgan PD. RESULTS: Of 529 patients, 258 experienced R-PD without C-PD. Among 258 patients, 91 received gefitinib beyond R-PD. Females were more likely to receive gefitinib beyond R-PD and exhibit a longer time from R-PD to C-PD than males (median days, 175 vs. 79.5). Survival beyond R-PD tended to be longer for elderly patients who received gefitinib beyond PD than for those who did not (median days, 458 vs. 336), but this was not the case for non-elderly patients (median days, 481 vs. 487). CONCLUSIONS: Some patients may benefit from continuation of gefitinib beyond PD.

Continuing EGFR-TKI beyond radiological progression in patients with advanced or recurrent, EGFR mutation-positive non-small-cell lung cancer: an observational study.

BACKGROUND: Some patients with advanced or recurrent, epidermal growth factor receptor (EGFR) mutation-positive (EGFR M+) non-small-cell lung cancer (NSCLC) continue to receive EGFR tyrosine kinase inhibitors (TKIs) beyond radiological progression. METHODS: We analysed a cohort of 577 patients with EGFR M+ NSCLC, who had received a first-line EGFR-TKI. We classified patients according to clinical course and treatment patterns at Response Evaluation Criteria in Solid Tumors (RECIST) progressive disease (PD). We evaluated the period from RECIST PD to TKI discontinuation or clinical PD and also evaluated survival after RECIST PD and compared it between groups. RESULTS: RECIST PD was documented in 451 cases, of which 283 (62.7%) were clinically stable. 186 (65.7%) discontinued and 97 (34.3%) continued the EGFR-TKI. In those who continued EGFR-TKI, median time between RECIST PD and clinical PD or TKI discontinuation was 5.1 months. Median survival after RECIST PD in patients who discontinued and continued EGFR-TKI after clinically stable RECIST PD was 14.6 and 15.3 months (p=0.5489), respectively. In multivariate analysis, continuing EGFR-TKI therapy, female gender, better performance status and exon 19 deletion subtype were likely positive predictive factors for survival after clinically stable RECIST PD. CONCLUSION: Our study suggests that some patients could benefit from receiving an EGFR-TKI beyond radiological progression.

Alectinib for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status (Lung Oncology Group in Kyushu 1401).

INTRODUCTION: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS. METHODS: Eligible patients with advanced ALK rearrangement-positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement. RESULTS: Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary. CONCLUSIONS: Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS.

[Clinical value of primary decompression operation for unilateral ureterocele with complete duplex system].

PURPOSE: To assess a value of decompression operation for a unilateral ureterocele with a complete duplex system as an initial procedure. METHODS: We reviewed records of 33 pediatric patients with a unilateral ureterocele in a complete duplex system who underwent decompression operation between 1987 and 2000. We checked the patient operative age, followup period, position of the ureterocele, type of decompression operation, and additional operation. Furthermore we also checked postoperative vesicoureteral reflux (VUR) in patients who underwent transurethral incision (TUI). RESULTS: Mean operative age and followup period were 6 months old and 82 months. Of the patients, 22 underwent TUI and 11 underwent upper moiety operation (UMO). In the TUI group, 14 (63.6%) had postoperative VUR and 13 (59.0%) underwent additional operations. These rates were higher in the patients with ectopic ureteroceles than with intravesical ureteroceles. Most additional operations were undergone for the patients with postoperative VUR in TUI group by lower complete reconstructions without UMO. All patients with non-functioning upper moiety underwent heminephrectomy at the additional operations. In the other hand, in the UMO group, 3 (27.3%) had additional operation because of persistent VUR which was found preoperatively in lower moiety or contralateral renal unit. CONCLUSION: TUI was useful approach as an initial procedure for intravesical ureteroceles because of low additional operation rate. For ectopic ureteroceles with functioning upper moiety, TUI was high additional operation rate, but it was more useful initial operation of two-staged operation than UMO because of avoiding UMO, like heminephrectomy, at additional operation. UMO was low additional operation rate for ectopic ureteroceles without preoperative VUR of renal unit excluding upper moiety. Especially heminephrectomy was a useful approach as an initial procedure if upper moiety was non-functioning.