Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.

BACKGROUND: 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. PATIENTS AND METHODS: 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/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. RESULTS: 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). CONCLUSION: 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. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).

The basolateral nucleus of the amygdala mediates caloric sugar preference over a non-caloric sweetener in mice.

Neurobiological and genetic mechanisms underlying increased intake of and preference for nutritive sugars over non-nutritive sweeteners are not fully understood. We examined the roles of subnuclei of the amygdala in the shift in preference for a nutritive sugar. Food-deprived mice alternately received caloric sucrose (1.0 M) on odd-numbered training days and a non-caloric artificial sweetener (2.5 mM saccharin) on even-numbered training days. During training, mice with sham lesions of the basolateral (BLA) or central (CeA) nucleus of the amygdala increased their intake of 1.0 M sucrose, but not saccharin. Trained mice with sham lesions showed a significant shift in preference toward less concentrated sucrose (0.075 M) over the saccharin in a two-bottle choice test, although the mice showed an equivalent preference for these sweeteners before training. No increased intake of or preference for sucrose before and after the alternating training was observed in non-food-deprived mice. Excitotoxic lesions centered in the BLA impaired the increase in 1.0M sucrose intake and shift in preference toward 0.075 M sucrose over saccharin. Microlesions with iontophoretic excitotoxin injections into the CeA did not block the training-dependent changes. These results suggest that food-deprived animals selectively shift their preference for a caloric sugar over a non-caloric sweetener through the alternate consumption of caloric and non-caloric sweet substances. The present data also suggest that the BLA, but not CeA, plays a role in the selective shift in sweetener preference.

TGF-ß1-siRNA delivery with nanoparticles inhibits peritoneal fibrosis.

Gene therapies may be promising for the treatment of peritoneal fibrosis (PF) in subjects undergoing peritoneal dialysis (PD). However, a method of delivery of treatment genes to the peritoneum is lacking. We attempted to develop an in vivo small interfering RNA (siRNA) delivery system with liposome-based nanoparticles (NPs) to the peritoneum to inhibit PF. Transforming growth factor (TGF)-ß1-siRNAs encapsulated in NPs (TGF-ß1-siRNAs-NPs) dissolved in PD fluid were injected into the peritoneum of mice with PF three times a week for 2 weeks. TGF-ß1-siRNAs-NPs knocked down TGF-ß1 expression significantly in the peritoneum and inhibited peritoneal thickening with fibrous changes. TGF-ß1-siRNAs-NPs also inhibited the increase of expression of α-smooth muscle actin-positive myofibroblasts. These results suggest that the TGF-ß1-siRNA delivery system with NPs described here could be an effective therapeutic option for PF in subjects undergoing PD.

Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).

BACKGROUND: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 µg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Structures and immunolocalization of Na+, K+ -ATPase, Na+ /H+ exchanger 3 and vacuolar-type H+ -ATPase in the gills of blennies (Teleostei: Blenniidae) inhabiting rocky intertidal areas.

The structure and immunolocalization of the ion transporters Na(+) ,K(+) -ATPase (NKA), Na(+) /H(+) exchanger (NHE3) and vacuolar-type H(+) -ATPase (VHA) were examined in the gills of teleosts of the family Blenniidae, which inhabit rocky shores with vertical zonation in subtropical seas. These features were compared among the following species with different ecologies: the amphibious rockskipper blenny Andamia tetradactylus, the intertidal white-finned blenny Praealticus tanegasimae and the purely marine yaeyama blenny Ecsenius yaeyamaensis. Light and electron microscopic observations indicated that thick gill filaments were arranged close to each other and alternately on two hemibranches of a gill arch in the opercular space of A. tetradactylus. Many mucous cells (MC) and mitochondrion-rich cells (MRC) were present in the interlamellar regions of the gill filament. An immunohistochemical study demonstrated that numerous NKA, NHE3 and some VHA were located predominantly on presumed MRCs of gill filaments and at the base of the lamellae. Analyses using serial (mirror image) sections of the gills indicated that only a few NKA immunoreactive cells (IRC) were colocalized with VHA on some MRCs in the filaments. In the gills of P. tanegasimae, NKA- and NHE3-IRCs were observed in the interlamellar region of the filaments and at the base of the lamellae. VHA-IRCs were located sparsely on the lamellae and filaments. In the gills of E. yaeyamaensis, the lamellae and filaments were thin and straight, respectively. MCs were located at the tip as well as found scattered in the interlamellar region of gill filaments. NKA-, NHE3- and VHA-IRCs were moderately frequently observed in the filaments and rarely on the lamellae. This study shows that the structure and distribution of ion transporters in the gills differ among the three blennid species, presumably reflecting their different ecologies.

Significant background rates of HBV and HCV infections in patients and risks of blood transfusion from donors with low anti-HBc titres or high anti-HBc titres with high anti-HBs titres in Japan: a prospective, individual NAT study of transfusion-transmitted HBV, HCV and HIV infections.

BACKGROUND: The Japanese Red Cross (JRC) conducted a prospective study to evaluate the frequency of transfusion-transmitted HBV, HCV and HIV infections to assess the risk of transfusion of blood components routinely supplied to hospitals. STUDY DESIGN AND METHODS: Post-transfusion specimens from patients at eight medical institutes were examined for evidence of infection with HBV (2139 cases), HCV (2091) and HIV (2040) using individual nucleic acid amplification testing (NAT). If these specimens were reactive, pre-transfusion specimens were also examined for the virus concerned by individual NAT. In the event that the pre-transfusion specimen was non-reactive, then all repository specimens from implicated donors were tested for the viruses by individual donation NAT. In addition, a further study was carried out to evaluate the risk of transfusion of components from donors with low anti-HBc titres or high anti-HBc with high anti-HBs titres. RESULTS: Transfusion-transmitted HCV and HIV infections were not observed. One case of post-transfusion HBV infection was identified (rate, 0·0004675; 95% CI for the risk of transmission, 1 in 451-41,841). The background rates of HBV, HCV and HIV infections in patients prior to transfusion were 3·4% (72/2139), 7·2% (150/2091) and 0% (0/2040), respectively. Sixty-four anti-HBc- and/or anti-HBs-reactive blood components were transfused to 52 patients non-reactive for anti-HBc or anti-HBs before and after transfusion (rate, 0; 95% CI for the risk of transmission, <1 in 22). CONCLUSION: This study demonstrated that the current criteria employed by JRC have a low risk, but the background rates of HBV and HCV infections in Japanese patients are significant.

Unconventional ferroelectric transition in the multiferroic compound TbMnO3 revealed by the absence of an anomaly in c-polarized phonon dispersion.

TbMnO(3) exhibits a spontaneous electric polarization along c concomitantly with a spiral spin ordering modulated along b below T_{C} = 28 K. We have performed inelastic x-ray scattering measurements on a single crystal of TbMnO(3) to clarify whether phonon anomalies related to the ferroelectricity exist. We measured transverse modes, especially the Mn-O-Mn bending mode polarized along c and propagating along b, which we expect is most relevant to the ferroelectricity. However, no anomaly was found in the phonon dispersion below 50 meV across T_{C}. The present result suggests that the mechanism of ferroelectricity in TbMnO(3) is different from that of a conventional displacive-type ferroelectric. The weak coupling between electric polarization and lattice in TbMnO(3) strongly suggests that the ferroelectricity is mainly derived from the spiral spin ordering.

Paraneoplastic neurological syndrome and polyglandular autoimmune syndrome type 2 in a case of small cell lung cancer.

We report a female patient with small cell lung cancer (SCLC) and clinical findings consistent with polyglandular autoimmune syndrome type 2 (PGA2) and paraneoplastic neurological syndrome (PNS). To the best of our knowledge, this is the first reported case of SCLC associated with PGA2 and PNS. All of the autoantibodies detected before anticancer treatment decreased below the upper normal limits after serial treatment, and the patient's clinical symptoms also improved. Cross reactivity of autoantibodies may have contributed to the complicated clinical picture of this patient.

Appropriate timing of CD40 ligation for RNA-Pulsed DCs to induce antitumor immunity.

Dendritic cell (DC) based anti-cancer immunotherapy is believed to be a promising treatment. However, appropriate conditioning including the method of antigen loading and stimulation for DC maturation is still unclear. Total RNA pulsing is one of the most attractive methods to load antigen, since RNA is easily replicated by the PCR technique and is absolutely free of tumor cell contamination. On the other hand, CD40 ligation is capable of producing one of the most potent signals for immature DCs to start functional maturation, which is required to induce adaptive immunity, resulting in altered migration ability to secondary lymphoid organs and augmented antigen presenting activity. Here, we demonstrate that DCs pulsed with total RNA extracted from tumor cells required CD40 stimulation with an appropriate sequence to present tumor-associated antigens. RNA derived antigens were presented for both CD4+ and CD8+ T cells in an antigen-specific manner. Dendritic cells that were pulsed with RNA followed by the stimulation through CD40 successfully primed antitumor effector T cells in draining LNs and subsequently induced antitumor protective immunity.

Generation of anti-tumour effector T cells from naïve T cells by stimulation with dendritic/tumour fusion cells.

Tumour-draining lymph node T cells are an excellent source of effector T cells that can be used in adoptive tumour immunotherapy because they have already been sensitized to tumour-associated antigens in vivo. However, such tumour-specific immune cells are not readily obtained from the host due to poor immunogenicity of tumours and reduced host immune responses. One obstacle in implementation of adoptive immunotherapy has been insufficient sensitization and expansion of tumour-specific effector cells. In this study, we aim to improve adoptive immunotherapy by generating anti-tumour effector T cells from naïve T lymphocytes. We attempted to achieve this by harnessing the advantages of dendritic cell (DC)-based anti-cancer vaccine strategies. Electrofusion was routinely employed to produce fusion cells with 30-40% efficiency by using the poorly immunogenic murine B16/F10 cell line, D5 cells, and DC generated from bone marrow cells. CD62L-positive T cells from spleens of naïve mice and the fusion cells were cocultured with a low concentration of IL-2. After 9 days of culture, the antigen-specific T cells were identified with an upregulation of CD25 and CD69 expression and a downregulation of CD62L expression. These cells secreted IFN-gamma upon stimulation with irradiated tumour cells. Moreover, when transferred into mice with 3-day established pulmonary metastases, these cells with coadministration of IL-2 exhibited anti-tumour efficacy. In contrast, naïve T cells cocultured with a mixture of unfused DC and irradiated tumour cells did not exhibit anti-tumour efficacy. Our strategy provides the basis for a new approach in adoptive T cell immunotherapy for cancer.

A woman who required long-term mechanical ventilation to treat limbic encephalitis during pregnancy.

We describe our experience with a woman who had severe non-herpetic acute limbic encephalitis at 20 weeks' gestation. Despite receiving mechanical ventilation for about 3 months because of impaired consciousness and frequent convulsions, she had a normal delivery and an uneventful recovery with no sequelae. The patient did not respond to treatment with antiviral agents. Anticonvulsant agents were given while monitoring plasma drug concentrations. Early treatment and the prevention of complications apparently contributed to good outcomes in the mother and child.

Imaging of cauda equina edema in lumbar canal stenosis by using gadolinium-enhanced MR imaging: experimental constriction injury.

BACKGROUND AND PURPOSE: It has been reported that disturbance of blood flow arising from circumferential compression of the cauda equina by surrounding tissue plays a major role in the appearance of neurogenic intermittent claudication (NIC) associated with lumbar spinal canal stenosis (LSCS). We created a model of LSCS to clarify the mechanism of enhancement within the cauda equina on gadolinium-enhanced MR images from patients with LSCS. METHODS: In 20 dogs, a lumbar laminectomy was performed by applying circumferential constriction to the cauda equina by using a silicon tube, to produce 30% stenosis of the circumferential diameter of the dural tube. After 1 and 3 weeks, gadolinium and Evans blue albumin were injected intravenously at the same time. The sections were used to investigate the status of the blood-nerve barrier function under a fluorescence microscope and we compared gadolinium-enhanced MR images with Evans blue albumin distribution in the nerve. The other sections were used for light and transmission electron microscopic study. RESULTS: In this model, histologic examination showed congestion and dilation in many of the intraradicular veins, as well as inflammatory cell infiltration. The intraradicular edema caused by venous congestion and Wallerian degeneration can also occur at sites that are not subject to mechanical compression. Enhanced MR imaging showed enhancement of the cauda equina at the stenosed region, demonstrating the presence of edema. CONCLUSION: Gadolinium-enhanced MR imaging may be a useful tool for the diagnosis of microcirculatory disorders of the cauda equina associated with LSCS.

Observation of modulated quadrupolar structures in PrPb3.

Neutron diffraction measurements have been performed on the cubic compound PrPb(3) in a [001] magnetic field to examine the quadrupolar ordering. Antiferromagnetic components with q = (1/2 +/- delta 1/2 0), (1/2 1/2 +/- delta 0) (delta approximately 1/8) are observed below the transition temperature T(Q) (0.4 K at H = 0) whose amplitudes vary linear with H and vanish at zero field, providing the first evidence for a modulated quadrupolar phase. For H < 1 T, a nonsquare modulated state persists even below 100 mK suggesting quadrupole moments associated with a Tau(3) doublet ground state to be partially quenched by hybridization with conduction electrons.

Commensurate-incommensurate crossover of charge stripe in La2-xSrxNiO4 (x approximately 1/3).

The temperature (T) dependence of the charge-stripe order in La2-xSrxNiO4 has been investigated in the vicinity of x approximately 1/3 by synchrotron radiation x-ray diffraction measurements. With decreasing T, a prominent commensurate-incommensurate (C-IC) crossover is observed in the x<1/3 region, while for the x>1/3 region the IC order is dominant over the whole T range. Such a C-IC crossover is interpreted as the entropy-driven self-doping of the charge stripes, and its x dependence indicates the clear electron-hole asymmetry with the x=1/3 compound as the Mott insulator.

Membrane formation mechanism of cross-linked polyurea microcapsules by phase separation method.

This research was conducted to clarify the membrane formation mechanism of cross-linked polyurea microcapsules by phase separation method, especially the role of polymeric surfactant, such as poly(ethylene-alt-maleic anhydride) (poly(E-MA)) at the interface of O/W emulsion. It was found that poly(E-MA) was necessary for the formation of cross-linked polyurea membrane. The addition of sodium dodecyl sulphate (SDS) prohibited the membrane formation reaction at the interface, even in the case of poly(E-MA) concentration enough for polymeric microcapsule formation. From the results in this study, poly(E-MA) was found to be adsorbed on the O/W emulsion and provide the reaction site for the membrane formation of polymeric microcapsules.

Phase I/II study of daily carboplatin, 5-fluorouracil and concurrent radiation therapy for locally advanced non-small-cell lung cancer.

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities and the response rate of carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, unresectable stage IIIA or IIIB non-small-cell lung cancer (NSCLC) were enrolled. Carboplatin (20-40 mg m(-2) 2-h infusion, daily) and 5-fluorouracil (200 mg m(-2) 24-h continuous infusion, daily) were administered concurrently with radiotherapy on days 1-33. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions on days 1-40. In the phase I portion, the daily dose of carboplatin was escalated from 20 to 40 mg m(-2). Once the maximum tolerated dose (MTD) and recommended dose (RD) of carboplatin was determined, the study entered the phase II portion. In the phase I portion, the daily MTD and RD of carboplatin were 40 and 35 mg m(-2), respectively. The dose-limiting toxicity was neutropenia. In the following phase II study, 30 patients were entered and the objective response rate was 76.7% (95% CI, 62-92%) and the local control rate was 85.7%. The median survival time was 19.8 months, with a survival rate of 70% at 1 year, 36.7% at 2 years. The major toxicities of treatment were neutropenia (>or=grade 3, 87.9%) and thrombocytopenia (>or=grade 3, 23.3%). This combined therapy for locally advanced non-small-cell lung cancer is promising and shows acceptable toxicity.