NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor ...receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS).
For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated.
The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P=0.483). The OS of patients who received platinum throughout their treatment (n=186) was not statistically different from that of patients who never received platinum (n=40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n=76) was around 3 years.
No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.
Full geometry optimizations of several inorganic model clusters, CaMn(4)O(4)XYZ(H(2)O)(2) (X, Y, Z = H(2)O, OH(-) or O(2-)), by the use of the B3LYP hybrid density functional theory (DFT) have been ...performed to illuminate plausible molecular structures of the catalytic site for water oxidation in the S(0), S(1), S(2) and S(3) states of the Kok cycle for the oxygen-evolving complex (OEC) of photosystem II (PSII). Optimized geometries obtained by the energy gradient method have revealed the degree of symmetry breaking of the unstable three-center Mn(a)-X-Mn(d) bond in CaMn(4)O(4)XYZ(H(2)O)(2). The right-elongated (R) Mn(a)-X···Mn(d) and left-elongated (L) Mn(a)···X-Mn(d) structures appear to occupy local minima on a double-well potential for several key intermediates in these states. The effects of insertion of one extra water molecule to the vacant coordination site, Mn(d) (Mn(a)), for R (L) structures have also been examined in detail. The greater stability of the L-type structure over the R-type has been concluded for key intermediates in the S(2) and S(3) states. Implications of the present DFT structures are discussed in relation to previous DFT and related results, together with recent X-ray diffraction results for model compounds of cubane-like OEC cluster of PSII.
Since the first reports of oscillations in prominences in the 1930s, there have been major theoretical and observational developments to understand the nature of these oscillatory phenomena, leading ...to the whole new field of the so-called “prominence seismology”. There are two types of oscillatory phenomena observed in prominences; “small-amplitude oscillations” (2–3 km s
−1
), which are quite common, and “large-amplitude oscillations” (>20 km s
−1
) for which observations are scarce. Large-amplitude oscillations have been found as “winking filament” in H
α
as well as motion in the plane-of-sky in H
α
, EUV, micro-wave and He 10830 observations. Historically, it has been suggested that the large-amplitude oscillations in prominences were triggered by disturbances such as fast-mode MHD waves (Moreton wave) produced by remote flares. Recent observations show, in addition, that near-by flares or jets can also create such large-amplitude oscillations in prominences. Large-amplitude oscillations, which are observed both in transverse as well as longitudinal direction, have a range of periods varying from tens of minutes to a few hours. Using the observed period of oscillation and simple theoretical models, the obtained magnetic field in prominences has shown quite a good agreement with directly measured one and, therefore, justifies prominence seismology as a powerful diagnostic tool. On rare occasions, when the large-amplitude oscillations have been observed before or during the eruption, the oscillations may be applied to diagnose the stability and the eruption mechanism. Here we review the recent developments and understanding in the observational properties of large-amplitude oscillations and their trigger mechanisms and stability in the context of prominence seismology.
Aims.We report observation of a large-amplitude filament oscillation followed by an eruption. This is used to probe the pre-eruption condition and the trigger mechanism of solar eruptions.Methods.We ...used the EUV images from the Extreme-Ultraviolet Imaging Telescope on board SOHO satellite and the Hα images from the Flare Monitoring Telescope at Hida Observatory. The observed event is a polar crown filament that erupted on 15 Oct. 2002.Results.The filament clearly exhibited oscillatory motion in the slow-rising, pre-eruption phase. The amplitude of the oscillation was larger than 20 km s-1, and the motion was predominantly horizontal. The period was about 2 h and seemed to increase during the oscillation, indicating weakening of restoring force.Conclusions.Even in the slow-rise phase before the eruption, the filament retained equilibrium and behaved as an oscillator, and the equilibrium is stable to nonlinear perturbation. The transition from such nonlinear stability to either instabilities or a loss of equilibrium that leads to the eruption occurred in the Alfvén time scale (~1 h). This suggests that the onset of the eruption was triggered by a fast magnetic reconnection that destabilized the pre-eruption magnetic configuration, rather than by the slow shearing motion at the photosphere.
Retrospective analysis has shown that activating mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial ...to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48-93%). After a median follow-up of 12.7 months (range, 3.1-16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7-11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.
Full geometry optimizations followed by the vibrational analysis were performed for eight spin configurations of the CaMn4O4X(H2O)3Y (X = O, OH; Y = H2O, OH) cluster in the S1 and S3 states of the ...oxygen evolution complex (OEC) of photosystem II (PSII). The energy gaps among these configurations obtained by vertical, adiabatic and adiabatic plus zero-point-energy (ZPE) correction procedures have been used for computation of the effective exchange integrals (J) in the spin Hamiltonian model. The J values are calculated by the (1) analytical method and the (2) generalized approximate spin projection (AP) method that eliminates the spin contamination errors of UB3LYP solutions. Using J values derived from these methods, exact diagonalization of the spin Hamiltonian matrix was carried out, yielding excitation energies and spin densities of the ground and lower-excited states of the cluster. The obtained results for the right (R)- and left (L)-opened structures in the S1 and S3 states are found to be consistent with available optical and magnetic experimental results. Implications of the computational results are discussed in relation to (a) the necessity of the exact diagonalization for computations of reliable energy levels, (b) magneto-structural correlations in the CaMn4O5 cluster of the OEC of PSII, (c) structural symmetry breaking in the S1 and S3 states, and (d) the right- and left-handed scenarios for the O-O bond formation for water oxidation.
Using two-dimensional (2D) magnetohydrodynamic simulations we study the effects of resistive processes in the dynamics of magnetic flux emergence and its relation to Ellerman bombs and other dynamic ...phenomena in the Sun. The widely accepted scenario of flux emergence is the formation and expansion of -shaped loops due to the Parker instability. Since the Parker instability has the largest growth rate at finite wavelength l sub(p) 6 10H-20H, where H is the scale height (-200 km in the solar photosphere), a number of magnetic loops may rise from the initial flux sheet if it is sufficiently long. This process is shown in our numerical simulations. The multiple emerging loops expand in the atmosphere and interact with each other, leading to magnetic reconnection. At first reconnection occurs in the lower atmosphere, which allows the sinking part of the flux sheet to emerge above the photosphere. This reconnection also causes local heating that may account for Ellerman bombs. In the later stage, reconnection between the expanding loops occurs at higher levels of the atmosphere and creates high-temperature reconnection jets, and eventually a large (>>l sub(p) coronal loop is formed. Cool and dense plasma structures, which are similar to Ha surges, are also formed. This is not because of magnetic reconnection but due to the compression of the plasma in between the expanding loops.
EGFR-TKI therapy produces a dramatic clinical response in patients with NSCLC harboring EGFR mutation. However, clinical outcomes should be improved further in this cohort. Thus, we conducted a ...randomized phase II study to investigate the efficacy and safety of combinational EGFR-TKI and chemotherapy, demonstrating that the combination might be a promising strategy for advanced EGFR-mutant NSCLC.
The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation.
Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed area under the curve (AUC) = 6 and 500 mg/m2; 3-weekly. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety.
All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen hazard ratio (HR) 0.71 (0.42–1.20), P = 0.20. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively HR 0.51 (0.26–0.99); P = 0.042. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients).
This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study.
University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).
Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of ...patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL).
Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0–1 and adequate organ function were randomized to receive either oral S-1 80 mg/m2/day on days 1–21 plus cisplatin 60 mg/m2 on day 8 every 4–5 weeks, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3–4 weeks, both up to six cycles.
A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837–1.227. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin.
Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC.
UMIN000000608.
QM(UB3LYP)/MM(AMBER) calculations were performed for the locations of the transition structure (TS) of the oxygen-oxygen (O-O) bond formation in the S
4
state of the oxygen-evolving complex (OEC) of ...photosystem II (PSII). The natural orbital (NO) analysis of the broken-symmetry (BS) solutions was also performed to elucidate the nature of the chemical bonds at TS on the basis of several chemical indices defined by the occupation numbers of NO. The computational results revealed a concerted bond switching (CBS) mechanism for the oxygen-oxygen bond formation coupled with the one-electron transfer (OET) for water oxidation in OEC of PSII. The orbital interaction between the σ-HOMO of the Mn(IV)
4
-O
(5)
bond and the π*-LUMO of the Mn(V)
1
=O
(6)
bond plays an important role for the concerted O-O bond formation for water oxidation in the CaMn
4
O
6
cluster of OEC of PSII. One electron transfer (OET) from the π-HOMO of the Mn(V)
1
=O
(6)
bond to the σ*-LUMO of the Mn(IV)
4
-O
(5)
bond occurs for the formation of electron transfer diradical, where the generated anion radical Mn(IV)
4
-O
(5)
-
* part is relaxed to the *Mn(III)
4
... O
(5)
-
structure and the cation radical O
(6)
=Mn(V)
1
+
* part is relaxed to the
+
O
(6)
-Mn(IV)
1
* structure because of the charge-spin separation for the electron-and hole-doped Mn-oxo bonds. Therefore, the local spins are responsible for the one-electron reductions of Mn(IV)
4
->Mn(III)
4
and Mn(V)
1
->Mn(IV)
1
. On the other hand, the O
(5)
-
and O
(6)
+
sites generated undergo the O-O bond formation in the CaMn
4
O
6
cluster. The Ca(II) ion in the cubane- skeleton of the CaMn
4
O
6
cluster assists the above orbital interactions by the lowering of the orbital energy levels of π*-LUMO of Mn(V)
1
=O
(6)
and σ*-LUMO of Mn(IV)
4
-O
(5)
, indicating an important role of its Lewis acidity. Present CBS mechanism for the O-O bond formation coupled with one electron reductions of the high-valent Mn ions is different from the conventional radical coupling (RC) and acid-base (AB) mechanisms for water oxidation in artificial and native photosynthesis systems. The proton-coupled electron transfer (PC-OET) mechanism for the O-O bond formation is also touched in relation to the CBS-OET mechanism.
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