scholarly journals Reirradiation practices for children with diffuse intrinsic pontine glioma

2020 ◽  
Author(s):  
Chantel Cacciotti ◽  
Kevin X Liu ◽  
Daphne A Haas-Kogan ◽  
Katherine E Warren
Keyword(s):  
Progressive Disease ◽  
Response Rate ◽  
Clinical Status ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Current Standard ◽  
Concurrent Use ◽  
Median Total Dose ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
Systemic Agents

Abstract Background Diffuse intrinsic pontine gliomas (DIPGs) are a leading cause of brain tumor deaths in children. Current standard of care includes focal radiation therapy (RT). Despite clinical improvement in most patients, the effect is temporary and median survival is less than 1 year. The use and benefit of reirradiation have been reported in progressive DIPG, yet standardized approaches are lacking. We conducted a survey to assess reirradiation practices for DIPG in North America. Methods A 14-question REDCap survey was disseminated to 396 North American physicians who care for children with CNS tumors. Results The response rate was 35%. Participants included radiation-oncologists (63%; 85/135) and pediatric oncologists/neuro-oncologists (37%; 50/135). Most physicians (62%) treated 1 to 5 DIPG patients per year, with 10% treating more than 10 patients per year. Reirradiation was considered a treatment option by 88% of respondents. Progressive disease and worsening clinical status were the most common reasons to consider reirradiation. The majority (84%) surveyed considered reirradiation a minimum of 6 months following initial RT. Doses varied, with median total dose of 2400 cGy (range, 1200-6000 cGy) and fraction size of 200 cGy (range, 100-900 cGy). Concurrent use of systemic agents with reirradiation was considered in 46%, including targeted agents (37%), biologics (36%), or immunotherapy (25%). One-time reirradiation was the most common practice (71%). Conclusion Although the vast majority of physicians consider reirradiation as a treatment for DIPG, total doses and fractionation varied. Further clinical trials are needed to determine the optimal radiation dose and fractionation for reirradiation in children with progressive DIPG.

scholarly journals DIPG-01. REIRRADIATION PRACTICES FOR DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii287-iii287
Author(s):  
Chantel Cacciotti ◽  
Kevin Liu ◽  
Daphne Haas-Kogan ◽  
Katherine Warren
Keyword(s):  
Treatment Option ◽  
Clinical Status ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Current Standard ◽  
Radiation Oncologists ◽  
Concurrent Use ◽  
Median Total Dose ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
One Year

Abstract INTRODUCTION Diffuse intrinsic pontine gliomas (DIPG) are a leading cause of brain tumor deaths in children. Current standard of care includes focal radiation therapy (RT). Despite clinical improvement in the majority of patients, the effect is temporary and median survival is less than one year. The use of reirradiation and possible benefit has been reported in progressive DIPG, yet standardized approaches are lacking. We conducted an internet-based survey to assess physicians’ practices in pediatric DIPG. METHODS A 14-question REDCap survey regarding re-irradiation practices was emailed to 396 physicians identified through an International Pediatric Neuro-Oncology and Radiation-Oncology database. RESULTS Response rate was 35% overall (radiation-oncologists, 28%; pediatric oncologists, 57%). Two participants were excluded (did not treat DIPG). Participants included radiation-oncologists (62%), pediatric oncologists (7%), and pediatric neuro-oncologists (29%). Most physicians (62%) treated 1–5 DIPG patients per year, with 10% treating >10/year. Reirradiation was considered a treatment option in 88%. Progressive disease or worsening clinical status were the most common reasons to consider reirradiation. The majority (84%) considered reirradiation a minimum of 6 months following initial RT. Doses varied, with median total dose 24Gy (range 12–60); 2Gy/fraction (range 1–9). Concurrent use of systemic agents with reirradiation was considered in 46%, mainly with targeted agents (37%), biologics (34%), or immunotherapy (25%). One-time reirradiation was the most common practice (71%). Interestingly, 9% of respondents would not consider reirradiation. CONCLUSION Although, the vast majority of physicians agree with re-irradiation as a treatment option for DIPG the total doses varied, and further clinical trials are needed.

A Direct Comparison of High Dose Cytarabine to Combination of Gemtuzumab and High Dose Cytarabine for Acute Myeloid Leukemia Patients in First Relapse Confirmed the Benefit of Gemtuzumab Based Regimens.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2051-2051
Author(s):  
Thomas Prébet ◽  
Aude Charbonnier ◽  
Anne Etienne ◽  
Evelyne D'Incan ◽  
Sabine Fürst ◽  
...  
Keyword(s):  
Overall Survival ◽  
Response Rate ◽  
Standard Of Care ◽  
Allogeneic Transplantation ◽  
Control Group ◽  
High Dose ◽  
Current Standard ◽  
Advanced Phase ◽  
High Dose Cytarabine ◽  
First Relapse

Abstract Abstract 2051 Poster Board II-28 Acute meyloid leukemia (AML) in first relapse is associated with a poor outcome when treated with standard dose cytarabine regimens and intermediate to high dose cytarabine (IHDAraC) is the current standard of care. During the last years, Gemtuzumab Ozogamycin (GO) has demonstrated a relevant clinical activity in relapsed and refractory AML. This antibody directed against CD33 is conjugated to calicheamycin that triggers apoptosis when hydrolyzed in the leukemic blasts. Combination regimen of GO are currently extensively studied in both frontline and advanced phase disease. Nevertheless, analysis of the litterature showed that only few data are available regarding a direct comparison of IHDAraC and IHDAraC+GO regimen. To this respect, we conduced a retrospective analysis of response (CR and CRi) and survival for patients with first relapse AML treated in our centre with either IHDAraC or IHDAraC+GO regimen. A total of 84 patients were included in the analysis: 28 were induced in the IHDAraC+GO group (mean GO dose: 6mg/m2, range:[3-9], including 82% of combination with anthracyclines or etoposide) and 56 in the IHDAraC group (including 57% of combination with other agents, mostly etoposide and anthracyclines). Patients characteristics were comparable between the IHDAraC+GO group and the control group in terms of median age (51y vs 49y), Performance Status at relapse (1 vs 1), median time to relapse (221 days vs 280 days), cytogenetic risk group clustering and previous allogeneic transplantation in first CR (21% vs 16%). Median Follow-up was 24 months. Univariate analysis showed that IHDAraC+GO induction, as compared with IHDAraC, was associated with a better response rate (68% vs 48%, p=0.08), a lower relapse rate (31% vs 66%, p=0.02), a better Overall Survival (median 35 months vs 19 months, p=0.02) and a better Event Free Survival (median Not Reached vs 10 months, p=0.02). Of note, the better response rate in the IHDAraC+GO group allowed to bring more patients to allogeneic transplantation in second CR (33% vs 16% respectively, p=0.08).Multivariate analysis using logistic regression method for response evaluation and Cox model for survival showed that treatment in the IHDAraC+GO group was an independent prognosis factor with a favorable impact on both response (HR:2.8, 95%CI:[1.1-7.7], p=0.048) and Overall Survival (HR:1.9, 95%CI:[1.1-3.4], p=0.047). It is already known that combination of IHDAraC and GO could give good results for advanced phase AML patients but, to our knowledge, this report is the first that directly compared the results of IHDAraC+GO with the current standard of care regimen on an homogeneous sample of patients in first relapse. This report also underline the importance of a prospective comparison in order to define the best combination therapy. Disclosures: No relevant conflicts of interest to declare.

A Phase II Add-on Study of Vorinostat (VOR) in Higher Risk Myelodysplastic Syndrome with Failure of Hypomethylating Agents (HMA): The GFM Azavor Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2900-2900
Author(s):  
Thomas Prebet ◽  
Jacques Delaunay ◽  
Eric Wattel ◽  
Thorsten Braun ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Standard Of Care ◽  
Median Number ◽  
Current Standard ◽  
Stage Design ◽  
Early Evaluation ◽  
Positive Results

Abstract Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival. Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients. Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months. Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

Ultrasonography

2019 ◽  
pp. 808-815
Author(s):  
Santiago Naranjo-Sierra ◽  
Lauren K. Ng Tucker
Keyword(s):  
Intensive Care Unit ◽  
Emergency Medicine ◽  
Visual Information ◽  
Point Of Care ◽  
Clinical Status ◽  
Standard Of Care ◽  
Sound Waves ◽  
Current Standard ◽  
Point Of Care Ultrasonography ◽  
Management Changes

Ultrasonography is the use of sound waves to create images and is used mainly for diagnostic purposes and for real-time guidance during procedures. Point-of-care ultrasonography is widely used in fields such as anesthesia, critical care, and emergency medicine, in which it is becoming an important part of the current standard of care because of its ability to provide accurate visual information about a patient, either to rapidly evaluate clinical status or to provide guidance for procedures, without requiring transfers to other areas. For patients in an intensive care unit, focused ultrasonography has been reported to result in management changes in more than 50%.

scholarly journals DIPG-57. TRANSCRIPTOMIC AND PROTEOMIC ANALYSES OF DIPG RESPONSE TO ONC201

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii298-iii298
Author(s):  
Sreepradha Sridharan ◽  
Arif Harmanci ◽  
Ajay Sharma ◽  
Yanlai Lai ◽  
Bridget Kennis ◽  
...  
Keyword(s):  
Intraperitoneal Administration ◽  
Pediatric Brain Tumor ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Tumor Burden ◽  
Current Standard ◽  
Extrinsic Factors ◽  
Altered Expression ◽  
Ic50 Values

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. Current standard of care has shown no improvements in survival. Here, we report our study of ONC201, a first-in-class small molecule developed by Oncoceutics, Inc., against a panel of DIPG cells in vitro and in mouse orthotopic models. ONC201 inhibits signaling through dopamine receptor D2 (DRD2), a G protein-coupled receptor (GPCR). MTT assays revealed a delayed but more robust response to ONC201, as measured by IC50 values, in DIPGs with histone H3.3-K27M expression compared to cells expressing wildtype (WT) or K27M mutant histone H3.1. Interestingly, transcriptomic profiling identified an association of this response delay with an elevation of genes controlling the cellular unfolded protein response, lysosomal and vacuole organization, and a decline in nucleic acid biosynthetic genes. These cells were also more committed to neuronal and oligodendrocytic lineage specification. By contrast, WT-H3 DIPGs that survived ONC201 treatment were stem-like and exhibited altered expression of genes controlling cell proliferation and apoptosis induction, respectively. Single cell proteomics validated the increase in anti-apoptotic proteins in these cells. Intraperitoneal administration of ONC201 for 7-weeks in mice bearing pontine xenografts of histone H3.1-K27M mutant DIPGs, caused a complete blockade of tumor growth relative to untreated controls. However, identical treatment of animals with forebrain tumors resulted only in a partial reduction in tumor burden, suggesting that the tumor microenvironment may be involved in the differential effect. These data indicate that tumor intrinsic and extrinsic factors may contribute to the response of DIPG tumors to ONC201.

Phase Ib study of brentuximab vedotin (BV) with low-dose total skin electron beam (LD-TSEB) for treatment of mycosis fungoides (MF) and Sezary syndrome (SS).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20037-e20037
Author(s):  
Shiyu Song ◽  
Beata Holkova ◽  
Nitai Mukhopadhyay ◽  
Daeryl Williamson ◽  
Molly Dickinson
Keyword(s):  
Short Duration ◽  
Assessment Tool ◽  
Response Rate ◽  
Skin Toxicity ◽  
Standard Of Care ◽  
Skin Lesions ◽  
Brentuximab Vedotin ◽  
Current Standard ◽  
Open Label ◽  
Duration Of Response

e20037 Background: MF is generally not curable, causing severe symptoms and eventually leading to patient (pt) death. LD-TSEB is currently used for diffuse skin lesions but with short duration of response. BV is effective and approved for MF but also limited by short duration of response. In this study we proposed to evaluate the feasibility of combining these 2 treatments by assessing the safety and response rate/duration in these pts. Methods: Pts with stage IB - IVA CD30+ MF or SS who were candidates for TSEB were recruited for a 2-cohort open-label phase 1b trial. Cohort A included pts with earlier stage disease; cohort B included pts with more advanced disease. BV was given at 1.8 mg/kg 3 wks before initiation of TSEB and then every 3 wks. Pts in Cohort A received 3 doses of BV; pts in Cohort B continued BV until disease progression or unacceptable toxicity, up to 2 years. Standard 12 Gy TSEB was administered in 6 fractions (2/wk) beginning 3 wks after the first dose of BV. The Modified Severity Weighted Assessment Tool (mSWAT) was used to determine skin involvement at baseline and during and after treatment. Skindex-16 was used to assess pt-reported symptoms and toxicities. Pts were seen weekly during TSEB, monthly after TSEB, and every 3 months after the last dose of BV for response evaluation and time to progression (TTP). Results: Five pts were enrolled and treated in this study. Two were enrolled to Cohort A, and 3 were enrolled to Cohort B. One pt in Cohort B expired before completing study treatment due to comorbidity unrelated to MF. The other pt data is listed in the table. None of the pts developed grade 4 or 5 toxicities; pt 1 developed recurrent neuropathy and stopped BV after 5 cycles. Conclusions: As BV became approved for the indication, accrual slowed, and the trial was stopped with very few pts. These pt cohorts are heavily treated before trial entry, making conclusions regarding response hard to generalize. However, the combination of BV and TSEB is well tolerated with no significant increase in skin toxicity. Response rate seems comparable to current standard of care, though with no improvement in duration of response over BV alone. Clinical trial information: NCT02822586 . [Table: see text]

Acute Rejection Following Kidney Transplantation: State-of-the-Art and Future Perspectives

2020 ◽  
Vol 26 (28) ◽  
pp. 3468-3496
Author(s):  
Emilio Rodrigo ◽  
Marcio F. Chedid ◽  
David San Segundo ◽  
Juan C.R. San Millán ◽  
Marcos López-Hoyos
Keyword(s):  
Kidney Transplantation ◽  
Acute Rejection ◽  
Rescue Therapy ◽  
Standard Of Care ◽  
Rejection Rate ◽  
New Drugs ◽  
High Dose ◽  
Current Standard ◽  
Antibody Mediated Rejection ◽  
Cellular Rejection

: Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. : According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

scholarly journals Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 864
Author(s):  
Christopher L. Cioffi
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Therapeutic Potential ◽  
Opioid Analgesic ◽  
Critical Role ◽  
Analgesic Efficacy ◽  
Standard Of Care ◽  
Current Standard ◽  
Glycine Transporters ◽  
Pathological Pain

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na+/Cl−-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain.

scholarly journals Updated Insights on EGFR Signaling Pathways in Glioma

2021 ◽  
Vol 22 (2) ◽  
pp. 587
Author(s):  
Alexandru Oprita ◽  
Stefania-Carina Baloi ◽  
Georgiana-Adeline Staicu ◽  
Oana Alexandru ◽  
Daniela Elise Tache ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Egfr Signaling ◽  
Current Standard ◽  
Egfr Amplification ◽  
Epidermal Growth ◽  
New Diagnosis ◽  
Clear Clinical Benefit

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

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