Difference between revisions of "Hafnium OxideBased Nanoplatform for Blended Chemoradiotherapy"

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Radiation metrics, procedural time, and clinical outcomes were compared between groups. When the traditional protocol group was compared with the multimodality protocol group, a significant reduction was described for total fluoroscopy time (31.6 min vs. 26.2 min), dose of contrast per kilogram (1.8 mL/Kg vs. 0.9 mL/Kg), DAP/kg (26.6 µGy·m2/kg vs. 19.9 µGy·m2/kg), and Air Kerma (194 mGy vs. 99.9 mGy). A reduction for procedure time was noted (140 min vs. 116.5 min), but this was not statistically significant. There was no difference in clinical outcomes or the presence of complications between groups. The combination of novel technology in PPVI caused a significant reduction in radiation metrics without increasing the complication rate in our population.Hazardous drinking by persons living with HIV (PLHIV) is a well-established determinant of sub-optimal HIV care and treatment outcomes. Despite this, to date, few interventions have sought to reduce hazardous drinking among PLHIV in sub-Saharan Africa (SSA). We describe an iterative cultural adaptation of an evidence-based multi-session alcohol reduction intervention for PLHIV in southwestern Uganda. The adaptation process included identifying core, theoretically informed, intervention elements, and conducting focus group discussions and cognitive interviews with community members, HIV clinic staff and patients to modify key intervention characteristics for cultural relevance and saliency. Adaptation of evidence-based alcohol reduction interventions can be strengthened by the inclusion of the target population and key stakeholders in shaping the content, while retaining fidelity to core intervention elements.We propose a new space of phylogenetic trees which we call wald space. The motivation is to develop a space suitable for statistical analysis of phylogenies, but with a geometry based on more biologically principled assumptions than existing spaces in wald space, trees are close if they induce similar distributions on genetic sequence data. As a point set, wald space contains the previously developed Billera-Holmes-Vogtmann (BHV) tree space; it also contains disconnected forests, like the edge-product (EP) space but without certain singularities of the EP space. We investigate two related geometries on wald space. [https://www.selleckchem.com/products/sr-717.html Selleck SR-717] The first is the geometry of the Fisher information metric of character distributions induced by the two-state symmetric Markov substitution process on each tree. Infinitesimally, the metric is proportional to the Kullback-Leibler divergence, or equivalently, as we show, to any f-divergence. The second geometry is obtained analogously but using a related continuous-valued Gaussian process on each tree, and it can be viewed as the trace metric of the affine-invariant metric for covariance matrices. We derive a gradient descent algorithm to project from the ambient space of covariance matrices to wald space. link2 For both geometries we derive computational methods to compute geodesics in polynomial time and show numerically that the two information geometries (discrete and continuous) are very similar. In particular, geodesics are approximated extrinsically. link3 Comparison with the BHV geometry shows that our canonical and biologically motivated space is substantially different.<br />To evaluate targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement as potential new LI-RADS features for differentiating hepatocellular carcinoma (HCC) from other non-HCC primary liver carcinomas (PLCs).<br />This IRB-approved, retrospective study was performed at two liver transplant centers. The final population included 375 patients with pathologically proven lesions imaged between 2007 and 2017 with contrast-enhanced CT or MRI. The cohort consisted of 165 intrahepatic cholangiocarcinomas and 74 combined hepatocellular-cholangiocarcinomas, with the addition of 136 HCCs for control. Two abdominal radiologists (R1; R2) independently reviewed the imaging studies (112 CT; 263 MRI) and recorded the presence of targetoid appearance on T2-weighted images and features of tumor vascular involvement including encasement, narrowing, tethering, occlusion, and obliteration. The sensitivity and specificity of each feature were calculated for the diagnosis of non-HCC PLCs. Cohen's kappa (k) tensitivity of signs of tumor vascular involvement decreases for both readers (1.7-20.3%), while the specificity increases reaching values higher than 94.2%. • The inter-reader agreement is substantial for targetoid appearance on T2-weighted images (k = 0.74) and moderate to substantial for signs of tumor vascular involvement (k = 0.48-0.77).<br />• Targetoid appearance on T2-weighted imaging and signs of tumor vascular involvement have high specificity (92-100%) for the diagnosis of non-HCC PLCs, regardless of the presence of liver risk factors. • In the subset of patients with risk factors for HCC, the sensitivity of signs of tumor vascular involvement decreases for both readers (1.7-20.3%), while the specificity increases reaching values higher than 94.2%. • The inter-reader agreement is substantial for targetoid appearance on T2-weighted images (k = 0.74) and moderate to substantial for signs of tumor vascular involvement (k = 0.48-0.77).<br />A subtrochanteric proximal femur fracture occurs in the 5cm of bone immediately distal to the lesser trochanter. UK national guidelines advise that adults with subtrochanteric fractures should be treated with an intramedullary nail (IMN). This study aims to compare peri-operative outcome measures of patients with subtrochanteric fractures treated with either an IMN or a dynamic hip screw (DHS) construct.<br />We retrospectively reviewed subtrochanteric fractures presenting at our institution over 4.5years (October 2014-May 2019), classifying them into two treatment groups; IMN and DHS. These groups were compared on outcome measures including surgical time, blood loss, radiation dose area product (DAP), length of stay, re-operation rate and mortality.<br />During the time period studied, 86 patients presented with a subtrochanteric fracture of the femur; with 74 patients (86%) receiving an IMN and 12 (14%) receiving a DHS. The comparative outcome measures reaching statistical significance were blood loss and radianteric fractures with an IMN; the outcome measures assessed in our study did not show use of an IMN to be superior to a DHS. The DHS group showed a lower estimated blood loss and a reduced DAP. This, along with the reduced financial cost associated with a DHS, may support the use of DHS over IMN for certain subtrochanteric fractures of the femur. There may not be a single favourable implant for the treatment of subtrochanteric fractures as a whole; instead different subtypes of fracture may be amenable to a number of fixation devices. Choice of implant should be determined locally and based on existing and future clinical and health economic research.<br />Instability of the posterior pelvic ring may be stabilized by lumbopelvic fixation. The optimal osseous corridor for iliac screw placement from the posterior superior iliac spine to the anterior inferior iliac spine requires multiple ap- and lateral-views with additional obturator-outlet and -inlet views. The purpose of this study was to determine if navigated iliac screw placement for lumbopelvic fixation influences surgical time, fluoroscopy time, radiation exposure, and complication rates.<br />Bilateral lumbopelvic fixation was performed in 63 patients. Implants were inserted as previously described by Schildhauer. A passive optoelectronic navigation system with surface matching on L4 was utilized for navigated iliac screw placement. To compare groups, demographics were assessed. Operative time, fluoroscopic time, and radiation were delineated.<br />Conventional fluoroscopic imaging for lumbopelvic fixation was performed in 32 patients and 31 patients underwent the procedure with navigated iliac screw placemereduction of radiation exposure for patients and OR personnel.Atypical femoral fractures are often attributed to the use of anti-resorptive medications such as bisphosphonates (BP). Whilst they have proven effects on fragility fracture prevention, clinical and laboratory evidence is evolving linking BP-related suppression of bone remodelling to the development of atypical stress-related sub-trochanteric fractures (Shane et al. in JBMR 291-23, 2014; Odvina et al. in JCEM 901294-301, 2005; Durchschlag et al. in JBMR 21(10)1581-1590, 2006; Donnelly et al. in JBMR 27672-678, 2012; Mashiba et al. in Bone 28(5)524-531, 2001; Dell et al. in JBMR 27(12)2544-2550, 2012; Black et al. in Lancet 3481535-1541, 1996; Black et al. in NEJM 3561809-1822, 2007; Black et al. in JAMA 2962927-2938, 2006; Schwartz et al. in JBMR 25976-82, 2010). Injuries may present asymptomatically or with prodromal thigh pain and most can be successfully managed with cephalomedullary nailing and discontinuation of BP therapy. Such injuries exhibit a prolonged time to fracture union with high rates of non-union and metal-work failure when compared to typical subtrochanteric osteoporotic femoral fractures. Despite emerging literature on AFFs, their management continues to pose a challenge to the orthopaedic and extended multi-disciplinary team. The purpose of this review includes evaluation of the current evidence supporting the management of AFFs, clinical and radiological features associated with their presentation and a review of reported surgical strategies to treat and prevent these devastating injures.<br />The aim of this investigation was to better understand the differences in local bone quality at the distal femur and their correlation with biomechanical construct failure, with the intention to identify regions of importance to optimize implant anchorage.<br />Seven fresh-frozen female femurs underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) to determine bone mineral density (BMD) within three different regions of interest (distal, intermedium, and proximal) at the distal femur. In addition, local bone quality was assessed by measuring the peak torque necessary to break out the trabecular bone along each separate hole of a locking compression plate (LCP) during its instrumentation. Finally, biomechanical testing was performed using cyclic axial loading until failure in an AO/OTA 33 A3 fracture model.<br />Local BMD was highest in the distal region. This was confirmed by the measurement of local bone quality using DensiProbe<br />. The most distal holes represented locations with the highest breakaway torque resistance, with the holes on the posterior side of the plate indicating higher values than those on its anterior side. We demonstrated strong correlation between the cycles to failure and local bone strength (measured with DensiProbe<br />) in the most distal posterior screw hole, having the highest peak torque.<br />The local bone quality at the distal femur indicates that in plated distal femur fractures the distal posterior screw holes seem to be the key ones and should be occupied. Measurement of the local bone strength with DensiProbe<br />is one possibility to determine the risk of construct failure, therefore, thresholds need to be defined.<br />The local bone quality at the distal femur indicates that in plated distal femur fractures the distal posterior screw holes seem to be the key ones and should be occupied. Measurement of the local bone strength with DensiProbe™ is one possibility to determine the risk of construct failure, therefore, thresholds need to be defined.
Patients exhibiting the CD133<br />/CD109<br />signature upon recurrence representing E-to-C transition displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that<br />was tightly correlated with the core TIC marker<br />and was linked to shorter patient survival. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, glioblastoma edge-derived tumor growth in vivo and subsequent mouse survival, suggesting its essential role in the E-to-C-mediated glioblastoma progression.<br />E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.<br />E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.<br />NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models.<br />We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage.<br />Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.<br />Hypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients.<br />We measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [<br />F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation.<br />Eleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The her hypoxia or normalize tumor vasculature in glioblastoma.<br />Giant cell glioblastoma (gcGBM) is a rare histologic subtype of glioblastoma characterized by numerous bizarre multinucleate giant cells and increased reticulin deposition. Compared with conventional isocitrate dehydrogenase (IDH)-wildtype glioblastomas, gcGBMs typically occur in younger patients and are generally associated with an improved prognosis. Although prior studies of gcGBMs have shown enrichment of genetic events, such as<br />alterations, no defining aberrations have been identified. The aim of this study was to evaluate the genomic profile of gcGBMs to facilitate more accurate diagnosis and prognostication for this entity.<br />Through a multi-institutional collaborative effort, we characterized 10 gcGBMs by chromosome studies, single nucleotide polymorphism microarray analysis, and targeted next-generation sequencing. These tumors were subsequently compared to the genomic and epigenomic profile of glioblastomas described in The Cancer Genome Atlas (TCGA) dataset.<br />Our analysis identified a specifierences in survival, and suggests new therapeutic vulnerabilities.<br />Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM.<br />mRNA expression data of patient-derived GBM (<br />= 1279) and normal brain tissue (<br />= 46) samples were collected from Gene Expression Omnibus and The Cancer Genome Atlas. Functional genomic mRNA profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, a class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on (1) known interactions with antineoplastic drugs, (2) current drug development status in humans, and (3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo.<br />We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interaction with antineoplastic agents. Seventeen of the 27 genes, including<br />and<br />, have been clinically evaluated in GBM with limited efficacy. For the remaining 10 genes,<br />,<br />(<br />,<br />), and<br />play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth.<br />The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.<br />The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.<br />Melanoma brain metastases (MBMs) have historically poor overall survival (OS). Recently introduced systemic anticancer therapies (SACTs), namely targeted therapies such as BRAF inhibitors and immunotherapy, to control advanced disease have shown improved survival. Today, increasingly aggressive strategies are sought for MBM. We review outcomes in MBM after surgery or stereotactic radiosurgery (SRS) and the survival impact in advanced systemic disease when combined with novel anticancer therapies.<br />A retrospective cohort study of patients referred to a regional neuro-oncology multidisciplinary team (MDT) meeting with MBM. Demographic data, extent of systemic disease, and data on surgical and oncological management were collected, plus the use of SACT. The primary outcomes were median OS, 12- and 24-month survival, and progression-free survival.<br />Between 2010 and 2018, 142 patients with MBM were referred. Following the introduction of SACT, the rate of referrals to MDT more than doubled from 11.6 to 25.7 patients per year. Focal brain metastasis was treated surgically in 23 (16.2%) patients and by SRS in 29 (20.4%). Fifty-six (39.4%) patients underwent palliative whole-brain radiotherapy and 34 (23.9%) did not receive treatment. Median OS was 11 months for the surgical cohort, 9 months for the SRS cohort, and increased when treatment with or without SACT was considered to 23 and 12 months, respectively.<br />In the setting of SACTs, survival in MBM is significantly improved after surgery or SRS even in patients with advanced and uncontrolled systemic disease at the time of presentation, supporting an aggressive approach to MBM management.<br />In the setting of SACTs, survival in MBM is significantly improved after surgery or SRS even in patients with advanced and uncontrolled systemic disease at the time of presentation, supporting an aggressive approach to MBM management.<br />We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [<br />F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.<br />We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [<br />F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [<br />F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.<br />In a preclinical mouse model, we illustrated that [<br />F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [<br />F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.<br />Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [<br />F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.<br />Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.There is an increasing need for improved endpoints to assess clinical trial effects in Parkinson's disease. We propose the Parkinson's Disease Comprehensive Response as a novel weighted composite endpoint integrating changes measured in three established Parkinson's outcomes, including OFF state Movement Disorder Society Unified Parkinson's Disease Rating Scale Motor Examination scores; Motor Experiences of Daily Living scores; and total good-quality ON time per day. The data source for the initial development of the composite described herein was a recent Phase II trial of glial cell line-derived neurotrophic factor. A wide range of clinically derived relative weights was assessed to normalize for differentially scoring base rates with each endpoint component. [https://www.selleckchem.com/products/tbk1-IKKe-in-1-compound1.html this website] The Parkinson's disease comprehensive response, in contrast to examining practically defined OFF state Unified Parkinson's Disease Rating Scale Motor Examination scores alone, showed stability over 40 weeks in placebo patients, and all 432 analyses in re presented to further the debate of how current regulatory approved rating scales may be combined to address some of the recognized limitations of using individual scales in isolation.India's rapid economic growth has been accompanied by slower improvements in population health. Given the need to reconcile the ambitious goal of achieving Universal Coverage with limited resources, a robust priority-setting mechanism is required to ensure that the right trade-offs are made and the impact on health is maximised. Health Technology Assessment (HTA) is endorsed by the World Health Assembly as the gold standard approach to synthesizing evidence systematically for evidence-informed priority setting (EIPS). India is formally committed to institutionalising HTA as an integral component of the EIPS process. The effective conduct and uptake of HTA depends on a well-functioning ecosystem of stakeholders adept at commissioning and generating policy-relevant HTA research, developing and utilising rigorous technical, transparent, and inclusive methods and processes, and a strong multisectoral and transnational appetite for the use of evidence to inform policy. These all require myriad complex and complementary capacities to be built at each level of the health system .

Latest revision as of 10:54, 25 October 2024

Patients exhibiting the CD133
/CD109
signature upon recurrence representing E-to-C transition displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that
was tightly correlated with the core TIC marker
and was linked to shorter patient survival. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, glioblastoma edge-derived tumor growth in vivo and subsequent mouse survival, suggesting its essential role in the E-to-C-mediated glioblastoma progression.
E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.
E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.
NEO212 is a novel small-molecule anticancer agent that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH) to the alkylating agent temozolomide (TMZ). It is undergoing preclinical development as a therapeutic for brain-localized malignancies. The aim of this study was to characterize metabolism and pharmacokinetic (PK) properties of NEO212 in preclinical models.
We used mass spectrometry (MS) and modified high-performance liquid chromatography to identify and quantitate NEO212 and its metabolites in cultured glioblastoma cells, in mouse plasma, brain, and excreta after oral gavage.
Our methods allowed identification and quantitation of NEO212, POH, TMZ, as well as primary metabolites 5-aminoimidazole-4-carboxamide (AIC) and perillic acid (PA). Intracellular concentrations of TMZ were greater after treatment of U251TR cells with NEO212 than after treatment with TMZ. The half-life of NEO212 in mouse plasma was 94 min. In mice harboring syngeneic GL261 brain tumors, the in particular AIC and PA, will provide useful equivalents for PK studies during further drug development and clinical trials with NEO212.
Hypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients.
We measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [
F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation.
Eleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The her hypoxia or normalize tumor vasculature in glioblastoma.
Giant cell glioblastoma (gcGBM) is a rare histologic subtype of glioblastoma characterized by numerous bizarre multinucleate giant cells and increased reticulin deposition. Compared with conventional isocitrate dehydrogenase (IDH)-wildtype glioblastomas, gcGBMs typically occur in younger patients and are generally associated with an improved prognosis. Although prior studies of gcGBMs have shown enrichment of genetic events, such as
alterations, no defining aberrations have been identified. The aim of this study was to evaluate the genomic profile of gcGBMs to facilitate more accurate diagnosis and prognostication for this entity.
Through a multi-institutional collaborative effort, we characterized 10 gcGBMs by chromosome studies, single nucleotide polymorphism microarray analysis, and targeted next-generation sequencing. These tumors were subsequently compared to the genomic and epigenomic profile of glioblastomas described in The Cancer Genome Atlas (TCGA) dataset.
Our analysis identified a specifierences in survival, and suggests new therapeutic vulnerabilities.
Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM.
mRNA expression data of patient-derived GBM (
= 1279) and normal brain tissue (
= 46) samples were collected from Gene Expression Omnibus and The Cancer Genome Atlas. Functional genomic mRNA profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, a class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on (1) known interactions with antineoplastic drugs, (2) current drug development status in humans, and (3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo.
We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interaction with antineoplastic agents. Seventeen of the 27 genes, including
and
, have been clinically evaluated in GBM with limited efficacy. For the remaining 10 genes,
,
(
,
), and
play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth.
The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.
The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.
Melanoma brain metastases (MBMs) have historically poor overall survival (OS). Recently introduced systemic anticancer therapies (SACTs), namely targeted therapies such as BRAF inhibitors and immunotherapy, to control advanced disease have shown improved survival. Today, increasingly aggressive strategies are sought for MBM. We review outcomes in MBM after surgery or stereotactic radiosurgery (SRS) and the survival impact in advanced systemic disease when combined with novel anticancer therapies.
A retrospective cohort study of patients referred to a regional neuro-oncology multidisciplinary team (MDT) meeting with MBM. Demographic data, extent of systemic disease, and data on surgical and oncological management were collected, plus the use of SACT. The primary outcomes were median OS, 12- and 24-month survival, and progression-free survival.
Between 2010 and 2018, 142 patients with MBM were referred. Following the introduction of SACT, the rate of referrals to MDT more than doubled from 11.6 to 25.7 patients per year. Focal brain metastasis was treated surgically in 23 (16.2%) patients and by SRS in 29 (20.4%). Fifty-six (39.4%) patients underwent palliative whole-brain radiotherapy and 34 (23.9%) did not receive treatment. Median OS was 11 months for the surgical cohort, 9 months for the SRS cohort, and increased when treatment with or without SACT was considered to 23 and 12 months, respectively.
In the setting of SACTs, survival in MBM is significantly improved after surgery or SRS even in patients with advanced and uncontrolled systemic disease at the time of presentation, supporting an aggressive approach to MBM management.
In the setting of SACTs, survival in MBM is significantly improved after surgery or SRS even in patients with advanced and uncontrolled systemic disease at the time of presentation, supporting an aggressive approach to MBM management.
We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [
F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.
We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [
F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [
F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.
In a preclinical mouse model, we illustrated that [
F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [
F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.
Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [
F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.
Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.There is an increasing need for improved endpoints to assess clinical trial effects in Parkinson's disease. We propose the Parkinson's Disease Comprehensive Response as a novel weighted composite endpoint integrating changes measured in three established Parkinson's outcomes, including OFF state Movement Disorder Society Unified Parkinson's Disease Rating Scale Motor Examination scores; Motor Experiences of Daily Living scores; and total good-quality ON time per day. The data source for the initial development of the composite described herein was a recent Phase II trial of glial cell line-derived neurotrophic factor. A wide range of clinically derived relative weights was assessed to normalize for differentially scoring base rates with each endpoint component. this website The Parkinson's disease comprehensive response, in contrast to examining practically defined OFF state Unified Parkinson's Disease Rating Scale Motor Examination scores alone, showed stability over 40 weeks in placebo patients, and all 432 analyses in re presented to further the debate of how current regulatory approved rating scales may be combined to address some of the recognized limitations of using individual scales in isolation.India's rapid economic growth has been accompanied by slower improvements in population health. Given the need to reconcile the ambitious goal of achieving Universal Coverage with limited resources, a robust priority-setting mechanism is required to ensure that the right trade-offs are made and the impact on health is maximised. Health Technology Assessment (HTA) is endorsed by the World Health Assembly as the gold standard approach to synthesizing evidence systematically for evidence-informed priority setting (EIPS). India is formally committed to institutionalising HTA as an integral component of the EIPS process. The effective conduct and uptake of HTA depends on a well-functioning ecosystem of stakeholders adept at commissioning and generating policy-relevant HTA research, developing and utilising rigorous technical, transparent, and inclusive methods and processes, and a strong multisectoral and transnational appetite for the use of evidence to inform policy. These all require myriad complex and complementary capacities to be built at each level of the health system .

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