The hypothesis of this retrospective study was that the duration of twice-daily (BID) thoracic radiotherapy (TRT) and time from the start of any treatment to the end of chest irradiation (SER) would predict outcomes in limited-disease small-cell lung cancer.All 81 patients received 45 Gy in 30 fractions BID with a ≥ 6-hour interval and concurrent chemotherapy of platinum and etoposide.The median radiotherapy duration was 25 days (range, 21-38 days). The 5-year overall survival rates were 26.2% (95% confidence interval [CI], 14.3%-38.0%), and the median survival time was 30 months (95% CI, 15.5-44.5 months). Using multivariate regression analysis, the significant predictors of survival were the sum of the diameters of the primary tumor and metastatic lymph nodes, male gender, age ≥ 60 years, and the duration of BID-TRT (hazard ratio [HR], 1.15; 95% CI, 1.06-1.25; HR, 2.38; 95% CI, 1.13-5.02; HR, 2.38; 95% CI, 1.10-5.17; and HR, 1.08; 95% CI, 1.01-1.15, respectively). A total of 70 of 81 patients (86%) received radiotherapy during the first chemotherapy cycle. The median SER was 29 days (range, 21-109 days). The 5-year local control rate was 48.7% (95% CI, 33.9%-63.6%). The significant predictors of local control were the sum of the diameters of the primary tumor and metastatic lymph nodes, age ≥ 60 years, and SER (HR, 1.18; 95% CI, 1.06-1.31; HR, 4.18; 95% CI, 1.23-14.24; and HR, 1.02; 95% CI, 1-1.04, respectively).The duration of BID-TRT and SER were identified as one of the significant predictors of survival and local control in limited-disease small-cell lung cancer treated with concurrent chemoradiotherapy at 45 Gy in 30 fractions, respectively.
The production of molecular hydrogen (H2) from water by hydrogenase of thermophilic cyanobacterium Synechococcus sp. strain H-1 has been studied by following the time courses of the hydrogen concentration in the gas-phase, cell mass concentration and cellular content of D-glucose in dark batch reactions at temperatures ranging from 313 to 333 K. An anaerobic, dark, NO3− starvation, neutral or alkaline pH and shaking condition was found to be a prerequisite for H2 production. Strain H-1 could multiply and produce hydrogen at all temperatures studied. A linear relation between hydrogen production and glucose consumption was observed and the yield coefficient of hydrogen in terms of D-glucose consumption was 71, 115 and 146 at initial concentrations of cell mass of 0.75, 2.5 and 9.5 g · L−1, respectively. The activation energies for the maximum specific rates of cell mass growth, D-glucose consumption and hydrogen production were found to be 62, 12.6 and 122 kJ · mol−1, respectively. The maximum specific hydrogen production rate was found to be 0.09 μmol · mg-chl a−1 · h−1 at 328 K, which is comparable to that reported in non-nitrogen-fixing unicellular cyanobacteria. It is concluded that utilization of thermophilic Synechococcus sp. strain H-1 for hydrogen production is beneficial since the contamination risk of mesophilic bacteria is low.
A previous study showed a survival benefit with maintenance therapy with pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether continuation maintenance therapy with pemetrexed is beneficial in Japanese patients. Here, we present our phase II study that assessed the efficacy and safety of cisplatin plus pemetrexed as induction chemotherapy, followed by maintenance therapy with pemetrexed in advanced NSCLC patients in Japan.Chemotherapy-naïve patients received 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin on day one every three weeks for four cycles. In patients who responded to therapy or achieved stable disease, pemetrexed was continued until disease progression. The primary endpoint of this study was the progression-free survival rate at six months (PFS-6).Of the 35 patients initially enrolled in the study, 18 (51%) received maintenance chemotherapy with pemetrexed. The median PFS was 6.7 months, and the PFS-6 was 60% (95% confidence interval [CI], 42-76%). Median overall survival (OS) was 15.5 months (95% CI, 8.3-22.7 months). The median PFS and OS in patients who received maintenance chemotherapy with pemetrexed were 9.5 months and 25.3 months, respectively. The most frequently noted severe toxicity during induction chemotherapy was neutropenia, which occurred in seven patients. Two patients discontinued maintenance therapy owing to prolonged grade 2 edema in one patient and grade 3 neutropenia in another.Continuation maintenance chemotherapy with pemetrexed is associated with a survival benefit in patients who have completed induction chemotherapy for non-squamous NSCLC.
e19095 Background: Gefitinib (GEF), shows dramatic clinical activity against advanced non small cell lung cancer (NSCLC) in patients harboring epidermal growth factor receptor (EGFR) mutations. As there are currently no evidence based studies to support the use of GEF in combination with platinum doublet therapy for patients with NSCLC, we designed a phase II trial to examine the clinical benefits and safety of first-line GEF, carboplatin (Cb), and S-1 triplet chemotherapy in patients with advanced NSCLC harboring EGFR mutations. Methods: This trial was designed as a multicenter, single arm, phase II study of Cb, S-1, and GEF for advanced NSCLC harboring EGFR mutations. Patients received 4 courses of Cb (area under the curve = 5) on day 1, 80 mg/m2 of S-1 on days 1-14, and 250 mg of GEF every day in 4 week cycles, followed by 80 mg/m2 of S-1 on days 1–14 and 250 mg of GEF every day in 4 week cycles until disease progression or unacceptable toxicity was observed. The primary endpoint was the 1-year progression free survival (PFS) rate, and secondary endpoints were response rate (RR), PFS, overall survival (OS), and safety. Results: 35 patients were enrolled between May 2011 and July 2013. The median observation time was 15.1 months. The RR was 85.7%, and the disease control rate was 97.1%. The 1-year PFS rate was 69.4%, and the median PFS was 17.6 months (95% confidence interval, 15.2–20.1 months). The median OS was not achieveded. Major adverse events grade ≥3 included leucopenia (in 8.7% of patients), neutropenia (17.1%), anemia (5.7%), and thrombocytopenia (14.3%), and major non-hematological adverse events ≥grade 3 included febrile neutropenia (2.9%), increased levels of aminotransferase (20.0%), and diarrhea (14.3%). Toxicities characteristic of GEF exposure included diarrhea (in 77.1% of patients), dermatitis acneiform (80.0%), and stomatitis (54.3%). No patient was diagnosed with interstitial lung disease. Conclusions: First-line triplet chemotherapy of S-1, Cb, and GEF was effective and well tolerated in chemotherapy-naïve patients with advanced NSCLC harboring EGFR mutations.
Somatic activating mutations such as a deletion in exon 19 or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR)are important mediators of cancer cell oncogenesis, proliferation, and survival. In the last decade, two EGFR target agents have significantly contributed to the understanding of non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)that play a key role in activating EGFR-mutated NSCLC. Although these reversible, small, molecular target agents provide a significant response and survival benefit, all responders eventually acquire resistance. Although various mechanisms of resistance have been identified, nearly 3 0% of patients who acquire resistance to EGFR-TKIs have an unknown mechanism of resistance. Approximately half the patients with EGFR-mutated NSCLC who develop acquired resistance to these molecular target agents have a secondary mutation T790M in the threonine gatekeeper residue that coexists with a primary EGFR activating mutation. The strategy for overcoming acquired resistance to first-generation EGFR-TKIs is a major clinical concept. Afatinib is a second-generation EGFR-targeting agent and an irreversible pan-HER inhibitor. It may improve survival further and help in potentially overcoming resistance to first-generation EGFR-TKIs in EGFR-mutated NSCLC. In patients harboring activating EGFR mutations, certain treatments could be suggested for subsequent therapy after failure of first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for activating EGFR-mutated, advanced NSCLC after failure of first-generation EGFR-TKIs.
This study has examined the effect of growth phase on hydrogen production from cells of a glucose tolerant mutant of Synechocystis sp. strain PCC6803. The extracellular products including hydrogen, lactate and acetate from cyanobacteria cells in dark anaerobic nitrate-free solution, yielded different excretory profiles depending on which growth phases were prepared from photosynthesis. The amount of hydrogen generated cells prepared from stationary phase was highest in HEPES buffer and nitrate-free solution, dark anaerobic condition.
The effect of D-glucose on the anaerobic production of hydrogen (H2) in the dark by bidirectional hydrogenase of Synechocystis sp. strain PCC 6803 has been studied. D-glucose addition enhanced H2 production rate. It is deduced that NAD(P)H, which is a substrate of H2 production reaction, was supplied by catabolism of D-glucose. The molar consumption ratio of H2 and total sugar consumption was low in the presence of D-glucose due to production of L-lactic acid and other metabolites. The cells photosynthetically grown in air produced lower H2 in the dark as compared with those grown in air with 6% CO2, but the lower H2 production was compensated with the addition of D-glucose at 6.4 times of control value without D-glucose. The trend of effect of pH in a growth medium and a reaction mixture on H2 production was not affected by the presence of D-glucose. This result implies that mechanisms of H2 productions with and without D-glucose are similar.
e19021 Background: Vascular endothelial growth factor (VEGF) plays an important role in NSCLC with MPE, but the evidence regarding the efficacy of Bv with PC for treatment of NSCLC with MPE is lacking. Therefore, we prospectively evaluated the efficacy and safety of Bv and PC in non-SQ NSCLC pts. Methods: Chemotherapy-naive non-SQ NSCLC pts with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. The treated pts received PC without Bv in the first cycle to prevent Bv-induced delayed wound healing after chest drainage. Subsequently, they received 2–6 cycles of PC with Bv. Patients who completed more than 3 cycles of PC and Bv without disease progression or severe toxicities continued to receive Bv alone as a maintenance therapy. The primary endpoint was overall response, although an increase in MPE was allowed in the first cycle. The plasma and MPE VEGF levels were measured at baseline and the plasma VEGF levels after 3 cycles of chemotherapy. Results: Between September 1, 2010 and June 30, 2012, 23 pts were enrolled. The overall response rate was 60.8%, and the disease control rate was 87.0%. No pts showed complete response, 14 showed partial responses, 6 showed stable disease, 2 showed disease progression, and 1 died in the first cycle. Sixteen pts received maintenance therapy, following a median of 3 cycles. The median progression-free survival period for all pts was 200 days (95% CI, 156–263 days), whereas the median overall survival was 328 days (95% CI, 206–415 days). All pts experienced high levels of hematological toxicities, with most pts experiencing neutropathic toxicities above grade 3. However, none of the pts experienced severe bleeding events. The median baseline MPE VEGF level was 1798.6 (range, 223.4–35,633.4) pg/mL. The plasma VEGF levels showed a significant decrease after 3 chemotherapy cycles (baseline, 513.6 ± 326.4 pg/mL; post-chemotherapy: 25.1 ± 14.1 pg/mL; p < 0.01), regardless of the degree of efficacy. Conclusions: The combination of PC with Bv was confirmed to be effective and reasonably well-tolerated in chemotherapy-naïve non-SQ NSCLC pts with MPE. Clinical trial information: UMIN000005284.
