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S-1, an oral fluoropyrimidine derivative, is widely used for the treatment of several solid tumors. However, there are no predictive markers for its effectiveness.We retrospectively screened 108 patients with advanced non-small cell lung cancer (NSCLC) treated via S-1 monotherapy and investigated its relationship with cytokeratin 19 fragment (CYFRA 21-1) and CEA pretreatment levels.Sixty-one patients with high CYFRA 21-1 levels had a statistically significant shorter progression-free survival (PFS) and overall survival (OS) than 46 patients with normal levels (median PFS = 42 days vs. 70 days, respectively; p = 0.0014; median OS = 197 days vs. 316 days, respectively, p = 0.0239).Serum CYFRA 21-1 levels have predictive and prognostic roles in the management of patients with advanced NSCLC on S-1 monotherapy.

The optimal chemotherapy for concurrent chemoradiotherapy (cCRT) of lung cancer is still unclear.We investigated the therapeutic effect of different chemotherapy regimens for cCRT of lung cancer in 65 patients at our hospital.Of the 65 patients, 53 were male and 12 female. The median age was 64 years and 58 participants had a smoking history. The histological type was adenocarcinoma in 34 cases, squamous cell carcinoma in 22 cases, and others in 9 cases. Induction therapy consisted of cisplatin plus vinorelbine (CDDP+VNR) in 50 cases, and weekly carboplatin plus paclitaxel (CBDCA+PTX) in 15 cases. In all patients, the overall response rate, disease control rate, median progression survival, and median overall survival were 78.5%, 95.4%, 337 days, and 1,037 days, respectively. The median progression-free survival was 337 days in total; it was significantly longer for CDDP+VNR than CBDCA+PTX. The median overall survival was 1,037 days in total; it tended to be slightly longer for CDDP+VNR than CBDCA+PTX.Different chemotherapy regimens for cCRT possibly have different therapeutic effects.

Introduction: Inhaled corticosteroids (ICS) are fundamental agents to subside airway inflammation and improve forced expiratory volume in 1 s (FEV1) among asthmatics. Alveolar concentrations of nitric oxide (CANO), as well as the classical fraction of exhaled nitric oxide (FeNO50), are associated with the pathophysiology of asthma. However, the association between pretreatment CANO levels and response to anti-asthma treatments, including ICS, remains unknown. Methods: We retrospectively analyzed 107 patients newly diagnosed with asthma. ICS in combination with long-acting β2-agonists (ICS/LABA) was initiated. FEV1 and FeNO levels were evaluated at diagnosis and were followed up at 6 and 12 months after the treatment intervention. CANO levels were estimated using various expiratory flows of FeNO measurements. Factors associated with annual changes in FEV1 (ΔFEV1) were analyzed. Patients with a ΔFEV1 Results: FEV1, FeNO50, and CANO levels significantly improved by anti-asthma treatments. The average ΔFEV1 was 85 (176) mL. Eighty-two patients continuously took ICS/LABA treatment. Higher pretreatment CANO levels and continuous use of LABA were independent predictive factors for the improvement of FEV1 on multivariate analysis. The decline in FeNO50 and CANO levels by the anti-asthma treatments was significantly greater in 81 responders than in 26 poor-responders. CANO, but not FeNO50, levels at 12 months were significantly higher in poor-responders than in responders (p = 0.009). Conclusion: Levels of CANO, but not FeNO50, predict changes in pulmonary function in ICS-naïve asthmatics. Meanwhile, persistently high levels of CANO may be related to poor responsiveness to treatments assessed by ΔFEV1.

Mechanical properties of structural alloys, including Ni-based superalloy 718 (Alloy718), are degraded when hydrogen (H) is supplied: hydrogen embrittlement (HE). The presence of H notably deteriorates fatigue crack growth (FCG) property, which renders the growth rate much higher and shortens the lifetime of the components operating in the hydrogenating environment. Hence, the mechanisms behind such acceleration phenomenon in FCG should be understood comprehensively toward developing promising alloys resistant to hydrogen occlusion. In particular, Alloy718 has a meager resistance to HE, even regularly displaying superior mechanical and physical performances. Notwithstanding, the present study unveiled that the FCG acceleration by dissolved H in Alloy718 can be negligible. An abnormal deceleration of FCG can instead be pronounced by optimizing the metallurgical state, a hopeful prospect in Ni-based alloys applied to the hydrogenating environment.

Purpose This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC). Methods and Materials The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m2) on day 1 and S-1 (∼40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented. Results Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia. Conclusions CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC.

A 69-year-old woman without pre-existing disease visited our hospital due to general malaise, diarrhea, and arthralgia 3 days after a uterine cancer test. We diagnosed her with sepsis of unknown focus and started treatment immediately, but she died 20 hours after the first visit due to multi-organ failure and septic shock. Later, group A streptococcus was detected from the blood culture, and streptococcal toxic shock syndrome (STSS) was diagnosed. The strain had the emm28 genotype and a mutation in csrR with increased NADase activity. These virulence factors were considered to be related to STSS development in this patient.

A 68-year-old man visited our hospital due to anorexia, weight loss and a fever. We diagnosed the patient with disseminated Mycobacterium avium complex (MAC) and confirmed the presence of interferon (IFN)-γ neutralizing autoantibodies (IFN-γAb). His lesions improved following antibiotic therapy, but chylous ascites (CA) developed seven months after treatment. CA was able to be controlled by subcutaneous octreotide and diet therapy. IFN-γAb is recognized as having a critical role in the pathogenesis of disseminated MAC disease, but its clinical features are not fully understood. CA may be a complication that develops during the treatment of disseminated MAC infection.

After pre-charging at the gaseous phase with a concentration of ~7,000 at. ppm, solute hydrogen was discovered to have an abnormal effect on both the strength and ductility enhancement of a commercially-available, Fe-24Cr-19Ni-based, stable austenitic stainless steel that had been subjected to tensile testing at various strain-rates. Specifically, the impact of hydrogen on material strength was accompanied by amplified yield and flow stresses, as well as tensile strength, while the improvement in ductility featured extended uniform elongation and strain-to-fracture, both of which became more pronounced as hydrogen concentration intensified. The product between tensile strength and uniform elongation served as indicators of the strength-ductility balance, at which hydrogen maximally optimized the indicator at the particular intermediate strain-rate. The yield/flow stress augmentations were interpreted in terms of solid-solution strengthening, whereas the enhanced ductility was primarily ascribed to the facilitation of mechanical twinning, whereby dynamic hydrogen-dislocation interaction exerted a critical influence as was indirectly revealed by supplemental stress-relaxation experiments.

Background Organic cation transporter 6 (OCT6) encoded by solute carrier family 22 member 16 (SLC22A16) is involved in regulating cellular sensitivity and resistance to platinum derivatives. SLC22A16 has functional genetic variants but the association between these variants and the effectiveness of antitumor drugs remains unexplored. Patients and methods This study retrospectively analyzed data from 160 patients with advanced non-small cell lung cancer treated with platinum-based combination chemotherapy for first-line chemotherapy between October 2010 and May 2018. We investigated the association between the genetic variant of SLC22A16 and clinical outcomes. Results Patients with the rs714368 GG genotype had a shorter progression-free survival than those with AA or AG. Gene polymorphism was not associated with adverse effects. The predictive effect of rs714368 was confirmed in multivariate analysis using a Cox proportional hazards model. Conclusion A genetic variant of SLC22A16 is a potential predictive biomarker for response to platinum-based chemotherapy for non-small cell lung cancer.

We herein report a 74-year-old man who developed Lambert-Eaton myasthenic syndrome (LEMS) during atezolizumab treatment for extensive-stage small-cell lung cancer. He was started on maintenance immunotherapy with atezolizumab every three weeks after four cycles of atezolizumab plus carboplatin plus etoposide combination therapy. After 13 cycles of maintenance atezolizumab therapy, he complained of muscular weakness and fatigue. Findings from a nerve conduction study and positive findings for anti-P/Q-type voltage-gated calcium channel antibody resulted in a diagnosis of LEMS. This was a rare case of LEMS as a neurological immune-related adverse event induced by atezolizumab therapy.

A 63-year-old man had received chemoradiotherapy 7 years ago for stage IIIA pulmonary adenocarcinoma of the left lower lobe and stereotactic irradiation 3 years ago for stage IA pulmonary squamous cell carcinoma of the left upper lobe. An esophageal stent was placed because of esophageal narrowing caused by tumor invasion. Five months later, he was diagnosed with an aortoesophageal fistula. Because invasive surgery posed challenges, thoracic endovascular aortic repair (TEVAR) was performed. We report this rare case of aortoesophageal fistula treated using TEVAR. However, the therapeutic effect was temporary. Further studies investigating the indications for TEVAR are warranted.

Purpose ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC). Methods Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected. Results There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group. Conclusions These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.

Mycobacterium abscessus subspecies abscessus is major subspecies in the M. abscessus complex and is usually refractory to standard antibiotherapy. Genetic tracing of erm (41) T28 is a mechanism for monitoring macrolide resistance. We treated a patient with a pulmonary infection caused by M. abscessus subsp. abscessus with the erm (41) T28 polymorphism, which was susceptible to clarithromycin, and his clinical treatment course was good. The identification of the M. abscessus complex genotype is important, but clinical confirmation of clarithromycin susceptibility is also needed to plan individual treatment strategies.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2019-08-26, 資料番号: PA2010049000

Background Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel. Methods Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups. Results In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia. Conclusions Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2019-01-26, 資料番号: PA1910027000

Tension-compression fatigue tests were performed on two types of Ni-based superalloy 718 with different microstructures, to which small artificial defects of various shapes and sizes were introduced. Similar tests were also conducted on hydrogen-charged specimens with defects, with a solute hydrogen content ranging from 26.3 to 91.0 mass ppm. In the non-charged specimens in particular, the fatigue strength susceptibility to defects varied significantly according to the type of microstructural morphology, i.e., a smaller grain size made the alloy more vulnerable to defects. The fatigue limit as a small-crack threshold was successfully predicted using the √area parameter model. Depending on the size of defects, the fatigue limit was calculated in relation to three phases: (i) harmless-defect regime, (ii) small-crack regime and (iii) large-crack regime. Such a classification enabled comprehensive fatigue limit evaluation in a wide array of defects, taking into consideration (a) the defect size over a range of small crack and large crack and (b) the characteristics of the matrix represented by grain size and hardness. In addition, the effect of defects and hydrogen on fatigue strength will be comprehensively discussed, based on a series of experimental results.

A brittle-like faceted morphology of a precipitation-strengthened Fe-Ni-Cr-based superalloy after charging via exposure to high-pressure hydrogen gas (100 MPa) at elevated temperature (543 K) was interpreted based on multiple electron microscopy observations: scanning electron microscopy (SEM), electron backscatter diffraction (EBSD) and electron channeling contrast (ECC) imaging. The observation results revealed that the brittle-like facets were derived from intergranular cracking accompanied by hydrogen-assisted microvoid nucleation at the grain boundaries (GBs). Deformation twinning also played a crucial role in triggering the final grain boundary separation due to local stress concentration at its intersection with the GBs after severe strain hardening; such a process has not yet been considered to explain the hydrogen-induced ductility loss of this type of alloy.

Fatigue crack growth (FCG) tests were performed with two types of metastable austenitic stainless steels having different austenite phase stabilities under hydrogen-precharged conditions (internal hydrogen) and in gaseous hydrogen environments (external hydrogen). The materials showed a peculiarly slower FCG rate with internal hydrogen than with external hydrogen even though the hydrogen concentration was much higher under the internal hydrogen conditions. The results are interpreted in terms of hydrogen-modified plastic deformation character comprising inhibited cross-slipping or enhanced deformation twinning in combination with the sequence of hydrogen penetration and strain-induced α′ martensite formation in the local region surrounding the fatigue crack tip.

Purpose/objective(s) Although the PACIFIC trial did not suggest that the administration of durvalumab increased the risk of radiation pneumonitis (RP) compared to placebo, the timing of durvalumab administration following concurrent chemo-radiotherapy was various and the method used to evaluate RP including interstitial pneumonia was unclear. Thus, further studies are needed to better understand the development of immune-related adverse event (irAE), in particular RP. In the present study, we performed a preliminary analysis to investigate RP after concurrent chemo-proton therapy (CCPT) followed by durvalumab. Materials/methods Between October 2018 and March 2020, 17 patients were administered durvalumab (mg/kg, q2w) within 14 days after CCPT (70 GyRBE/35 fractions and cisplatin (60 mg/m2) on day 1 and S-1 (w40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 2 cycles). As a control, 47 patients who underwent CCPT in our previous phase II trial conducted between August 2013 and December 2017 were analyzed. These 47 patients were administered adjuvant chemotherapy (same regimen for up to 2 cycles) after CCPT. In patients suspected to have developed RP as a result of irAE, their treatment plans were compared with CT images obtained at the time of RP onset to examine the association between the dose distribution and RP. Results In our previous study, acute grade 2 RP within 3 months after the end of irradiation was observed in 4 patients (8.5%), and no patients developed grade 3 or higher RP. However, all occurred after completion of adjuvant chemotherapy, that is, within 2-3 months after the end of irradiation. On the other hand, 6 patients developed symptomatic grade 2 RP within 1 month of treatment among 17 patients who were administered durvalumab. Unlike CT findings of RP in the control patients, RP in 6 patients who received durvalumab was identified in the areas that received low-to-medium doses of proton irradiation and/or outside of the irradiation field, whereas the areas that received a high dose of proton irradiation exhibited little to no inflammatory response. In 3 patients who were subsequently administered steroids, CT revealed a rapid decrease in the lung volume and inflammatory response that progressed every week, in addition to traction ectasia and rapid progression of fibrosis. For the remaining 3 patients, the symptoms were mild without fever and improved only by stopping durvalmab without using steroids, and the course of CT images were similar. Conclusion Administration of durvalumab soon after CCPT resulted in the unexpected or unusual course of development of RP, which was likely an irAE. Further studies are needed to better understand the cause of immune-related RP.

Objectives: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cells. Aberrant expression of nestin is linked to poor prognosis in different cancers, including non-small cell lung cancer. However, the association between nestin expression and clinicopathological feature or prognosis has remained unclear for SCLC. This study examined whether nestin expression was associated with malignant features and clinical outcomes in SCLC. Materials and Methods: Using previously established Nestin knock-down cells and a newly established Nestin-overexpressing cell line, we examined the relationship between nestin expression and cell proliferation in vitro and in vivo and chemosensitivity. We also analyzed nestin expression in three drug-resistant lung cancer cell lines. Furthermore, we examined samples from 84 SCLC patients (16 patients with surgical resection, and 68 patients with biopsy), and immunohistochemically analyzed nestin expression. Results: Nestin expression correlated positively with cell proliferation, but negatively with chemosensitivity. Nestin expression in drug-resistant cell lines was upregulated compared to their parental cells. Among the 84 SCLC patients, 24 patients (28.6%) showed nestin-positive tumor. Nestin-positive ratio tended to be higher in operated patients than in biopsied patients. Nestin-positive and -negative patients showed no significant differences in response rate (RR) or progression-free survival (PFS) following first-line chemotherapy. However, positive expression of nestin was associated with shorter PFS following second-line chemotherapy (median PFS: nestin-positive, 81 days vs. nestin-negative, 117 days; P = 0.029). Conclusions: Nestin expression may be associated with malignant phenotype and worse outcome in SCLC patients.