Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. PATIENTS AND METHODS: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

Precise Measurement of Differential Cross Sections of the Σ

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470

Correction: Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis.

Owing to the insufficient specificity of the anti-myeloproliferative leukemia protein (MPL) antibody in the original version of this Article, Figure 6 and parts of Figures 2a, 4e, and 5a do not represent the correct information. The corrected version of Figure 6 is in this correction and those of Figures 2a, 4e, and 5a are shown in the supplemental information.

Spatial variations of 226Ra, 228Ra, 134Cs, and 137Cs concentrations in western and southern waters off the Korean Peninsula in July 2014.

We examined the spatial distributions of 226Ra, 228Ra, 134Cs, and 137Cs concentrations (activities) in seawater off the western and southern Korean Peninsula in July 2014. Radium-228 (and 226Ra) concentrations in water samples varied widely from 5 to 14 mBq/L (2-4 mBq/L), showing a negative correlation with salinity, particularly at the surface off the western Korean Peninsula. This indicates that the seawaters in this area are fundamentally comprised of 228Ra-poor and high-saline Kuroshio Current water and 228Ra-rich and low-saline water (e.g., continental shelf water), with various mixing ratios. Although Fukushima Dai-ichi Nuclear Power Plant (FDNPP)-derived 134Cs was below the detection limit (<0.08 mBq/L) in waters off the western Korean Peninsula, low level 134Cs (0.1-0.2 mBq/L) was detected in waters off the southern Korean Peninsula accompanied by higher 137Cs concentrations (1.6-1.9 mBq/L) relative to that off the western Korean Peninsula. Combined with the lower radium concentrations, the detection of 134Cs is explained by mixing of FDNPP-derived radiocesium-contaminated Kuroshio Current water.

Temporal and spatial variations of 134Cs and 137Cs levels in the Sea of Japan and Pacific coastal region: Implications for dispersion of FDNPP-derived radiocesium.

To investigate the dispersion of Fukushima Dai-ichi Nuclear Power Plant (FDNPP)-derived radiocesium in the Sea of Japan and western Pacific coastal region and determine the sources of radiocesium in these areas, we examined the temporal and spatial variations of 134Cs and 137Cs concentrations (activities) during 2011-2016 in seawaters around the western Japanese Archipelago, particularly in the Sea of Japan. In May 2013, the surface concentration of 134Cs was ∼0.5 mBq/L (decay-corrected to March 11, 2011), and that of 137Cs exceeded the pre-accident level in this study area, where the effects of radiocesium depositions just after the FDNPP accident disappeared in surface waters in October 2011. Subsequently, radiocesium concentrations gradually increased during 2013-2016 (∼0.5-1 mBq/L for 134Cs), exhibiting approximately homogeneous distributions in each year. The temporal and spatial variations of 134Cs and 137Cs concentrations indicated that FDNPP-derived radiocesium around the western Japanese Archipelago, including the Sea of Japan, has been supported by the Kuroshio Current and its branch, Tsushima Warm Current, during 2013-2016. However, in the Sea of Japan, the penetration of 134Cs was limited to depths of less than ∼200 m during three years following the re-delivery of FDNPP-derived radiocesium.

Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis.

Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation. We showed that TPO or a TPO receptor agonist directly induces fibrocyte differentiation using murine fibrocyte cell lines and a murine MF model. Conversely, elimination of macrophages expressing MPL by clodronate liposomes reversed the MF phenotype of the murine model, suggesting that fibrocyte differentiation induced by MPL activation contributes to the progression of MF. Furthermore, we revealed that SLAMF7high MPLhigh monocytes in human peripheral blood mononuclear cells were possible fibrocyte precursors and that these cells increased in number in MF patients not treated with ruxolitinib. Our findings confirmed a link between fibrocytes and the TPO/MPL signaling pathway, which could result in a greater understanding of the pathogenesis of MF and lead to the development of novel therapeutic interventions.

Simple 40K removal by acidified water leaching for estimating low levels of radiocesium in fishery products following Fukushima Dai-ichi Nuclear Power Plant accident.

We developed a simple method for 40K removal by acidified water leaching combined with ammonium phosphomolybdate coprecipitation, for estimating low levels of radiocesium in Japanese flounder. 40K removal from ashed samples was approximately 98%, with the radiocesium yield of ~98%. The treatment reduced the γ-spectral baseline to ~1/5 at ground and ~3/100 at underground levels (1.04 and 0.11 cph/keV, respectively). Faint signal of 134Cs, which is embedded in the Compton continuum of 40K in an untreated sample, was detected.

Migration of the FDNPP-derived 134Cs and 137Cs along with 226Ra and 228Ra concentrations across the northwestern North Pacific Ocean.

We examined lateral distributions of 134Cs, 137Cs, 226Ra, and 228Ra in the surface seawaters around the Kuril Islands and the Kamchatka Peninsula in the northwestern North Pacific Ocean during June 2014. The sampling area included three water current areas, the Oyashio Current, the current from the Okhotsk Sea, and the coastal current along the east Kamchatka Peninsula. 226Ra and 228Ra distributions differed along the three currents. Low levels of 134Cs were detected in the surface waters of the Oyashio Current (0.09-0.35 mBq/L), but it was <∼0.1 mBq/L at the surface along the other two currents. This indicates that the distribution of Fukushima Dai-ichi Nuclear Power Plant (FDNPP)-derived radiocesium in surface waters off the Kamchatka and along the Kuril Islands is predominantly governed by the Oyashio current system.

Observation of Spin-Dependent Charge Symmetry Breaking in ΛN Interaction: Gamma-Ray Spectroscopy of _{Λ}

The energy spacing between the spin-doublet bound state of _{Λ}^{4}He(1^{+},0^{+}) was determined to be 1406±2±2 keV, by measuring γ rays for the 1^{+}→0^{+} transition with a high efficiency germanium detector array in coincidence with the ^{4}He(K^{-},π^{-})_{Λ}^{4}He reaction at J-PARC. In comparison to the corresponding energy spacing in the mirror hypernucleus _{Λ}^{4}H, the present result clearly indicates the existence of charge symmetry breaking (CSB) in ΛN interaction. By combining the energy spacings with the known ground-state binding energies, it is also found that the CSB effect is large in the 0^{+} ground state but is vanishingly small in the 1^{+} excited state, demonstrating that the ΛN CSB interaction has spin dependence.

Observation of Λ(4)H Hyperhydrogen by Decay-Pion Spectroscopy in Electron Scattering.

At the Mainz Microtron MAMI, the first high-resolution pion spectroscopy from decays of strange systems was performed by electron scattering off a (9)Be target in order to study the Λ binding energy of light hypernuclei. Positively charged kaons were detected by a short-orbit spectrometer with a broad momentum acceptance at 0° forward angles with respect to the beam, efficiently tagging the production of strangeness in the target nucleus. Coincidentally, negatively charged decay pions were detected by two independent high-resolution spectrometers. About 10(3) pionic weak decays of hyperfragments and hyperons were observed. The pion momentum distribution shows a monochromatic peak at pπ≈133 MeV/c, corresponding to the unique signature for the two-body decay of hyperhydrogen Λ(4)H→(4)He+π(-), stopped inside the target. Its Λ binding energy was determined to be BΛ=2.12±0.01 (stat)±0.09 (syst)MeV with respect to the (3)H+Λ mass.

Accumulation of accident-derived radiocesium in lake and coastal sediments at 300-700 km distance from Fukushima area.

The accumulation of accident-derived radiocesium was investigated in nine water bodies located 300-700 km from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP). (134)Cs from the accident was detected in surface sediment of five water bodies. The (134)Cs concentration, corrected to the time of the accident in 2011, was generally lower than that of (137)Cs, and its spatial pattern does not fully correspond to that of (137)Cs. These results suggest that radiocesium derived from both FDNPP and past global fallout can be separately observed and that the contributions of both sources are non-uniform within these sites. The (134)Cs inventory in surface sediments is smaller than its deposition, suggesting that almost all deposited (134)Cs remains within the catchment and/or a part has been discharged from the saline and brackish water bodies.

Identification of lactic acid bacteria in the rumen and feces of dairy cows fed total mixed ration silage to assess the survival of silage bacteria in the gut.

The survival of silage lactic acid bacteria (LAB) in the gut of dairy cows was evaluated by examining the LAB communities of silage and gut contents. Samples were collected at 2 different research institutes (Mie and Okayama) that offered total mixed ration (TMR) silage throughout the year. Silage and feces were sampled in August, October, and November at the Mie institute, whereas silage, rumen fluid, and feces were sampled in June and August at the Okayama institute. Denaturing gradient gel electrophoresis using Lactobacillus-specific primers was performed to detect LAB species in the samples. The selected bands were purified for species identification and the band patterns were used for principal component analysis. Lactic acid was the predominant fermentation product in all the TMR silages analyzed, and the lactic acid level tended to be constant regardless of the sampling time and region. A total of 14 LAB species were detected in the TMR silage samples, of which 5 (Lactobacillus acetotolerans, Lactobacillus pontis, Lactobacillus casei, Lactobacillus suebicus, and Lactobacillus plantarum) were detected in the dairy cow feces. Most of the denaturing gradient gel electrophoresis bands for the feces samples were also detected in the rumen fluid, suggesting that any elimination of silage LAB occurred in the rumen and not in the postruminal gut segments. The principal component analysis indicated that the LAB communities in the silage, rumen fluid, and feces were separately grouped; hence, the survival of silage LAB in the cow rumen and lower gut was deemed difficult. It was concluded that, although the gut LAB community is robust and not easily affected by the silage conditions, several LAB species can inhabit both silage and feces, which suggests the potential of using silage as a vehicle for conveying probiotics.

Delivery mechanism of (134)Cs and (137)Cs in seawater off the Sanriku Coast, Japan, following the Fukushima Dai-ichi NPP accident.

To assess the delivery mechanism of radiocesium emitted from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), we examined vertical profiles of (134)Cs, (137)Cs, and (228)Ra concentrations and the (228)Ra/(226)Ra ratio in the water columns off the Sanriku Coast in the northwestern Pacific Ocean, in July 2012, along with their surface lateral variations in July 2009. Radiocesium concentrations exhibited maximum peaks (3-5 mBq/L for (134)Cs) at depths of 100-200 m, accompanied by high (228)Ra concentrations (0.6-0.8 mBq/L) in comparison with shallower depths (∼0.4 mBq/L). Taking the circulation patterns of currents in the area into account, it was inferred that radioactive depositions were supplied to the (228)Ra-rich Tsugaru Warm Current Water (TWCW) in the offshore area of the Sanriku Coast following the FDNPP accident, and that after the spring of 2011, this water (∼26.5σθ) was covered by lower density surface water, which helped intrude its way to depths of 100-200 m.

Isotopic Pu, Am and Cm signatures in environmental samples contaminated by the Fukushima Dai-ichi Nuclear Power Plant accident.

Dust samples from the sides of roads (black substances) have been collected together with litter and soil samples at more than 100 sites contaminated heavily in the 20-km exclusion zones around Fukushima Dai-ichi Nuclear Power Plant (FDNPP) (Minamisoma City, and Namie, Futaba and Okuma Towns), in Iitate Village located from 25 to 45 km northwest of the plant and in southern areas from the plant. Isotopes of Pu, Am and Cm have been measured in the samples to evaluate their total releases into the environment from the FDNPP and to get the isotopic compositions among these nuclides. For black substances and litter samples, in addition to Pu isotopes, (241)Am, (242)Cm and (243,244)Cm were determined for most of samples examined, while for soil samples, only Pu isotopes were determined. The results provided a coherent data set on (239,240)Pu inventories and isotopic composition among these transuranic nuclides. When these activity ratios were compared with those for fuel core inventories in the FDNPP accident estimated by a group at JAEA, except (239,240)Pu/(137)Cs activity ratios, fairly good agreements were found, indicating that transuranic nuclides, probably in the forms of fine particles, were released into the environment without their large fractionations. The obtained data may lead to more accurate information about the on-site situation (e.g., burn-up, conditions of fuel during the release phase, etc.), which would be difficult to get otherwise, and more detailed information on the dispersion and deposition processes of transuranic nuclides and the behavior of these nuclides in the environment.

Developmental α2-adrenergic regulation of noradrenergic synaptic facilitation at cerebellar GABAergic synapses.

In the central nervous system, the normal development of neuronal circuits requires adequate temporal activation of receptors for individual neurotransmitters. Previous studies have demonstrated that α2-adrenoceptor (α2-AR) activation eliminates spontaneous action potentials of interneurons in the cerebellar molecular layer (MLIs) and subsequently reduces the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Purkinje cells (PCs) after the second postnatal week. The magnitude of the α2-adrenergic reduction in sIPSC frequency is enhanced during the third postnatal week because of an increase in firing-derived sIPSCs. However, little is known about the effects of α2-AR activation by noradrenaline (NA) on cerebellar GABAergic synaptic transmission that is accompanied by the activation of other AR subtypes, α1- and ß-ARs. Here, we developmentally examined the roles of α2-AR activation in the noradrenergic facilitation of sIPSCs in cerebellar PCs. Until the second postnatal week, when substantial inhibitory effects of α2-ARs are absent, NA potentiated sIPSCs and maintained the increased sIPSC frequency, suggesting that NA causes long-lasting facilitation of GABAergic synaptic transmission through α1- and ß-AR activation. After the second postnatal week, NA transiently increased the sIPSC frequency, whereas blocking α2-ARs sustained the noradrenergic sIPSC facilitation and increase in the firing rate of MLIs, suggesting that α2-AR activation suppresses the noradrenergic facilitation of GABAergic synaptic transmission. The simultaneous activation of α1- and ß-ARs by their specific agonists mimicked the persistent facilitation of sIPSC frequency, which required extracellular signal-regulated kinase 1/2 activation. These findings indicate that NA acts as a neurotrophic factor that strengthens GABAergic synaptic transmission in the developing cerebellar cortex and that α2-ARs temporally restrain the noradrenergic facilitation of sIPSCs after GABAergic synaptogenesis.

Trans fatty acids exacerbate dextran sodium sulphate-induced colitis by promoting the up-regulation of macrophage-derived proinflammatory cytokines involved in T helper 17 cell polarization.

Numerous reports have shown that a diet containing large amounts of trans fatty acids (TFAs) is a major risk factor for metabolic disorders. Although recent studies have shown that TFAs promote intestinal inflammation, the underlying mechanisms are unknown. In this study, we examined the effects of dietary fat containing TFAs on dextran sodium sulphate (DSS)-induced colitis. C57 BL/6 mice were fed a diet containing 1·3% TFAs (mainly C16:1, C18:1, C18:2, C20:1, C20:2 and C22:1), and then colitis was induced with 1·5% DSS. Colonic damage was assessed, and the mRNA levels of proinflammatory cytokines and major regulators of T cell differentiation were measured. The TFA diet reduced survival and exacerbated histological damage in mice administered DSS compared with those fed a TFA-free diet. The TFA diet significantly elevated interleukin (IL)-6, IL-12p40, IL-23p19 and retinoic acid-related orphan receptor (ROR)γt mRNA levels in the colons of DSS-treated animals. Moreover, IL-17A mRNA levels were elevated significantly by the TFA diet, with or without DSS treatment. We also examined the expression of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and peritoneal macrophages. These cells were exposed to TFAs (linoelaidic acid or elaidic acid) with or without LPS and the mRNA levels of various cytokines were measured. IL-23p19 mRNA levels were increased significantly by TFAs in the absence of LPS. Cytokine expression was also higher in LPS-stimulated cells exposed to TFAs than in unexposed LPS-stimulated cells. Collectively, our results suggest that TFAs exacerbate colonic inflammation by promoting Th17 polarization and by up-regulating the expression of proinflammatory cytokines in the inflamed colonic mucosa.

Surgery for endometrial cancers with suspected cervical involvement: is radical hysterectomy needed (a GOTIC study)?

BACKGROUND: Radical hysterectomy is recommended for endometrial adenocarcinoma patients with suspected gross cervical involvement. However, the efficacy of operative procedure has not been confirmed. METHODS: The patients with endometrial adenocarcinoma who had suspected gross cervical involvement and underwent hysterectomy between 1995 and 2009 at seven institutions were retrospectively analysed (Gynecologic Oncology Trial and Investigation Consortium of North Kanto: GOTIC-005). Primary endpoint was overall survival, and secondary endpoints were progression-free survival and adverse effects. RESULTS: A total of 300 patients who underwent primary surgery were identified: 74 cases with radical hysterectomy (RH), 112 patients with modified radical hysterectomy (mRH), and 114 cases with simple hysterectomy (SH). Median age was 47 years, and median duration of follow-up was 47 months. There were no significant differences of age, performance status, body mass index, stage distribution, and adjuvant therapy among three groups. Multi-regression analysis revealed that age, grade, peritoneal cytology status, and lymph node involvement were identified as prognostic factors for OS; however, type of hysterectomy was not selected as independent prognostic factor for local recurrence-free survival, PFS, and OS. Additionally, patients treated with RH had longer operative time, higher rates of blood transfusion and severe urinary tract dysfunction. CONCLUSION: Type of hysterectomy was not identified as a prognostic factor in endometrial cancer patients with suspected gross cervical involvement. Perioperative and late adverse events were more frequent in patients treated with RH. The present study could not find any survival benefit from RH for endometrial cancer patients with suspected gross cervical involvement. Surgical treatment in these patients should be further evaluated in prospective clinical studies.

228Ra/226Ra ratio and 7Be concentration in the Sea of Japan as indicators for water transport: comparison with migration pattern of Fukushima Dai-ichi NPP-derived 134Cs and 137Cs.

To assess the migration patterns of radiocesium emitted from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), we analyzed (228)Ra/(226)Ra ratios and (7)Be concentrations and compared them with (134)Cs and (137)Cs concentrations in seawater samples collected within the Sea of Japan before and after the FDNPP accident (i.e., during the period 2007-2012) using low-background γ-spectrometry. The (228)Ra/(226)Ra ratios in surface waters exhibited lateral and seasonal variations, reflecting the flow patterns of surface water. This indicates the transport patterns of the FDNPP-derived radiocesium by surface water. Cosmogenic (7)Be (half-life: 53.3 d) exhibited markedly high concentrations (5-10 mBq/L) at depths shallower than 50 m, with concentrations decreasing steeply (0.2-2 mBq/L) at depths of 50-250 m. The distribution of (7)Be concentrations suggests that the downward delivery of the FDNPP-derived radiocesium to below 50 m depth was negligible for a few months prior to its removal from the Sea of Japan.