Glioblastoma (GBM) is a fatal tumor whose aggressiveness, heterogeneity, poor blood-brain barrier penetration, and resistance to therapy highlight the need for new targets and clinical treatments. A ...step toward clinical translation includes the eradication of GBM tumor-initiating cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrated that the selective lysine-specific histone demethylase 1 inhibitor DDP_38003 (LSD1i) is able to penetrate the brain parenchyma in vivo in preclinical models, is well tolerated, and exerts antitumor activity in molecularly different GBMs. LSD1 genetic targeting further strengthens the role of LSD1 in GBM TIC maintenance. GBM TIC plasticity supports their adaptation and survival under a plethora of environmental stresses, including nutrient deficiency and proteostasis perturbation. By mimicking these stresses in vitro, we found that LSD1 inhibition hampers the induction of the activating transcription factor 4 (ATF4), the master regulator of the integrated stress response (ISR). The resulting aberrant ISR sensitizes GBM TICs to stress-induced cell death, hampering tumor aggressiveness. Functionally, LSD1i interferes with LSD1 scaffolding function and prevents its interaction with CREBBP, a critical ATF4 activator. By disrupting the interaction between CREBBP and LSD1-ATF4 axis, LSD1 inhibition prevents GBM TICs from overcoming stress and sustaining GBM progression. The effectiveness of the LSD1 inhibition in preclinical models shown here places a strong rationale toward its clinical translation for GBM treatment.
With a view to improving the prognosis for patients with metastatic medulloblastoma, we tested the efficacy and toxicity of a hyperfractionated accelerated radiotherapy (HART) regimen delivered after ...intensive sequential chemotherapy.
Between 1998 and 2007, 33 consecutive patients received postoperative methotrexate (8 g/m(2)), etoposide (2.4 g/m(2)), cyclophosphamide (4 g/m(2)), and carboplatin (0.8 g/m(2)) in a 2-month schedule, then HART with a maximal dose to the neuraxis of 39 Gy (1.3 Gy/fraction, 2 fractions/d) and a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/d). Patients with persistent disseminated disease before HART were consolidated with two myeloablative courses and circulating progenitor cell rescue.
Patients were classified as having M1 (n = 9), M2 (n = 6), M3 (n = 17), and M4 (n = 1) disease. Seven patients younger than 10 years old who achieved complete response after chemotherapy received a lower dose to the neuraxis (31.2 Gy). Twenty-two of the 32 assessable patients responded to chemotherapy; disease was stable in five patients and progressed in five patients. One septic death occurred before radiotherapy. Eight patients experienced relapse after a median of 12 months. Fourteen of the 33 patients underwent consolidation therapy after HART. With a median 82-month survivor follow-up, the 5-year event-free, progression-free, and overall survival rates were 70%, 72%, and 73%, respectively. No severe clinical complications of HART have emerged so far.
HART after intensive postoperative chemotherapy, followed by myeloablative chemotherapy in selected cases, proved feasible in children with metastatic medulloblastoma. The results of our treatment compare favorably with other series treated using conventional therapies.
Reliable data on large cohorts of patients with glioblastoma are needed because such studies differ importantly from trials that have a strong bias toward the recruitment of younger patients with a ...higher performance status. We analyzed the outcome of 676 patients with histologically confirmed newly diagnosed glioblastoma who were treated consecutively at a single institution over a 7-year period (1997-2003) with follow-up to April 30, 2006. Survival probabilities were 57% at 1 year, 16% at 2 years, and 7% at 3 years. Progression-free survival was 15% at 1 year. Prolongation of survival was significantly associated with surgery in patients with a good performance status, whatever the patient's age, with an adjusted hazard ratio of 0.55 (p < 0.001) or a 45% relative decrease in the risk of death. Radiotherapy and chemotherapy improved survival, with adjusted hazard ratios of 0.61 (p = 0.001) and 0.89 (p = 0.04), respectively, regardless of age, performance status, or residual tumor volume. Recurrence occurred in 99% of patients throughout the follow-up. Reoperation was performed in one-fourth of these patients but was not effective, whether performed within 9 months (hazard ratio, 0.86; p = 0.256) or after 9 months (hazard ratio, 0.98; p = 0.860) of initial surgery, whereas second-line chemotherapy with procarbazine, lomustine, and vincristine (PCV) or with temozolomide improved survival (hazard ratio, 0.77; p = 0.008). Surgery followed by radiotherapy and chemotherapy should be considered in all patients with glioblastoma, and these treatments should not be withheld because of increasing age alone. The benefit of second surgery at recurrence is uncertain, and new trials are needed to assess its effectiveness. Chemotherapy with PCV or temozolomide seems to be a reasonable option at tumor recurrence.
Histopathologic grading based on increasing anaplasia predicts clinical behavior of pediatric medulloblastomas. The present study was aimed at grading 86 medulloblastomas of adult patients (aged 18 ...and older) by anaplasia and analyzing the predictive power. Nodularity, desmoplasia, nuclear size, nuclear pleomorphism, necrosis, and endothelial proliferations have been evaluated. Morphometric analysis of nuclear size was performed using the Eclipse Net program. Patients treated with standard postoperative radiotherapy (35 Gy to craniospinal axis and 50 Gy to posterior fossa) were considered for correlation with survival. Pathologic data and total survival were compared by Kaplan-Meier and logrank analysis. No correlation was found between total survival duration and individual pathologic features. Cooccurrence of nuclear pleomorphism, large nuclear diameter, microvascular proliferations, and necroses did not predict outcome. Severe nuclear pleomorphism was found in 4 of 86 cases; the only large-cell medulloblastoma was from an 18-year-old patient. Histopathologic factors have no clinical use for stratification of patients in risk groups. The histologic spectrum of medulloblastoma in adults is different from that in children.
Oligoastrocytomas are mixed gliomas harboring different genetic alterations and with heterogeneous clinical evolution. We have looked for correlations between genetic losses and clinical evolution in ...34 oligoastrocytomas. Loss of heterozygosity (LOH) with different microsatellite markers was studied on chromosomes 1p, 10q, 17p, and 19q. LOH on 1p was found in 44% of the tumors, on 10q in 24%, on 17p in 18%, and on 19q in 38%. LOH on 1p and 19q was combined in 29% of the patients. LOH on 1p was associated with significantly longer overall survival (p = 0.0092) and LOH on 10q with shorter overall survival (p = 0.0206). The observation that LOH on 10q predicts a short survival in oligoastrocytomas is novel and provides further evidence that genetic analysis may help to predict the clinical evolution of different gliomas, giving a more rationale basis to therapeutic options.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this study 32 newly diagnosed anaplastic oligoastrocytoma patients were enrolled (median age of 41 years, range 19-63; median Karnofsky performance status of 90, range 70-100). All patients were ...treated with Cisplatin (109 mg/m2) and BCNU (160 mg/m2). The chemotherapy started in the first week after surgery and it was administered every 6 weeks (5 scheduled cycles) for a total of 127 cycles. After the second cycle of chemotherapy all patients received radiotherapy (56.5 Gy). The median follow-up was 63.2 months (10-91). Nine patients were reoperated-on. The median time to tumor progression (TTP) and median survival time (ST) for the whole group of patients were 54.6 and 70.1 months, respectively. A proportional hazard model was used to look at potential prognostic factors for survival including lower age (< 40 years), extent of surgery (total/subtotal versus partial) and reoperation. When we analyzed the group of patients with total/subtotal surgery or age under 40 years the median ST could not be assessed due to the high number of surviving patients after a follow-up of 52 months. The median ST for the older patients or for patients partially operated-on was 54.1 and 42.2 months. In our study only total/subtotal surgery predicted for longer survival (p < 0.001). This schedule of treatment provides durable response in a selected group of anaplastic oligoastrocytoma patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigate the redshift and luminosity evolution of the galaxy colour-density relation using the data from the First Epoch VIMOS-VLT Deep Survey (VVDS). The size (6582 galaxies with good quality ...redshifts), depth ($I_{AB}\leq 24$) and redshift sampling rate (20% on the mean) of the survey enable us to reconstruct the 3D galaxy environment on relatively local scales ($R=5$$\,h^{-1}$ Mpc) up to redshift $z \sim 1.5$. Particular attention has been devoted to calibrate a density reconstruction scheme, which factors out survey selection effects and reproduces in an unbiased way the underlying “real” galaxy environment. We find that the colour-density relation shows a dramatic change as a function of cosmic time. While at lower redshift we confirm the existence of a steep colour-density relation, with the fraction of the reddest(/bluest) galaxies of the same luminosity increasing(/decreasing) as a function of density, this trend progressively disappears in the highest redshift bins investigated. Our results suggest the existence of an epoch (more remote for brighter galaxies) characterized by the absence of the colour-density relation on the $R=5$$\,h^{-1}$ Mpc scales investigated. The rest frame $u^{*}-g'$ colour–magnitude diagram shows a bimodal pattern in both low and high density environments up to redshift $z\sim 1.5$. We find that the bimodal distribution is not universal but strongly depends upon environment: at lower redshifts the colour–magnitude diagrams in low and high density regions are significantly different while the progressive weakening of the colour-density relation causes the two bimodal distributions to nearly mirror each other in the highest redshift bin investigated. Both the colour-density and the colour–magnitude-density relations, on the $R=5$$\,h^{-1}$ Mpc scales, appear to be a transient, cumulative product of genetic and environmental factors that have been operating over at least a period of 9 Gyr. These findings support an evolutionary scenario in which star formation/gas depletion processes are accelerated in more luminous objects and in high density environments: star formation activity is progressively shifting with cosmic time towards lower luminosity galaxies (downsizing), and out of high density environments.
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Aims: In this paper we discuss the mix of star-forming and passive galaxies up to z ~ 2, based on the first epoch VIMOS-VLT Deep Survey (VVDS) data. Methods: We compute rest-frame magnitudes and ...colors and analyse the color-magnitude relation and the color distributions. We also use the multi-band VVDS photometric data and spectral templates fitting to derive multi-color galaxy types. Using our spectroscopic dataset we separate galaxies based on a star-formation activity indicator derived combining the equivalent width of the OII emission line and the strength of the D_n(4000) continuum break. Results: In agreement with previous works we find that the global galaxy rest-frame color distribution follows a bimodal distribution at z
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Context.The VIMOS VLT Deep Survey (VVDS) was undertaken to map the evolution of galaxies, large scale structures, and active galaxy nuclei from the redshift spectroscopic measurements of ~105 objects ...down to an apparent magnitude $I_{AB} = 24$, in combination with a multi-wavelength acquisition for radio, infrared, optical, ultraviolet, and X-rays data. Aims.We present the evolution of the comoving star formation rate (SFR) density in the redshift range $0 < z < 5$ using the first epoch data release of the VVDS, that is 11564 spectra over 2200 arcmin2 in two fields of view, the VVDS-0226-04 and the VVDS-CDFS-0332-27, and the cosmological parameters ($\Omega_\mathrm{M}$, $\Omega_{\Lambda}$, $h)=(0.3$, 0.7, 0.7). Methods.We study the multi-wavelength non dust-corrected luminosity densities at $0 < z < 2$ from the rest-frame far ultraviolet to the optical passbands, and the rest-frame 1500 Å luminosity functions and densities at $2.7 < z < 5$. Results.They evolve from $z=1.2$ to $z=0.05$ according to $(1+z)^{x}$ with $x = 2.05, 1.94, 1.92, 1.14, 0.73, 0.42$, and 0.30 in the FUV-1500, NUV-2800, U-3600, B-4400, V-5500, R-6500, and I-7900 passbands, respectively. From $z=1.2$ to $z=0.2$ the B-band density for the irregular-like galaxies decreases markedly by a factor 3.5 while it increases by a factor 1.7 for the elliptical-like galaxies. We identify several SFR periods; from $z=5$ to 3.4 the FUV-band density increases by at most 0.5 dex, from $z=3.4$ to 1.2 it decreases by 0.08 dex, from $z=1.2$ to $z=0.05$ it declines steadily by 0.6 dex. For the most luminous $M_{AB}(1500~\AA)<-21$ galaxies the FUV-band density drops by 2 dex from $z=3.9$ to $z=1.2$, and for the intermediate $-21<M_{AB}(1500~\AA)<-20$ galaxies it drops by 2 dex from $z=0.2$ to $z=0$. Comparing with dust corrected surveys, at $0.4 \la z \la 2$ the FUV seems obscured by a constant factor of ${\sim}1.8$–2 mag, while at $z<0.5$ it seems progressively less obscured by up to ${\sim}0.9$–1 mag when the dust-deficient early-type population is increasingly dominating the B-band density. Conclusions.The VVDS results agree with a downsizing picture where the most luminous sources cease to efficiently produce new stars 12 Gyrs ago (at $z\simeq 4$), while intermediate luminosity sources keep producing stars until 2.5 Gyrs ago (at $z\simeq 0.2$). A modest contribution of dry mergers and morphologies evolving towards early-type galaxies might contribute to increase the number density of the bright early types at $z<1.5$. Our observed SFR density is not in agreement with a continuous smooth decrease since $z\sim4$.
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