Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide

BackgroundOptimal adjuvant management of adult low-grade gliomas is controversial. Recently described tumor classification based on molecular subtype has the potential to individualize adjuvant therapy but has not yet been evaluated as part of a prospective trial.MethodsPatients aged 18 or older with newly diagnosed World Health Organization grade II low-grade gliomas and gross residual disease after surgical resection were enrolled in the study. Patients received monthly cycles of temozolomide for up to 1 year or until disease progression. For patients with available tissue, molecular subtype was assessed based upon 1p/19q codeletion and isocitrate dehydrogenase-1 R132H mutation status. The primary outcome was radiographic response rate; secondary outcomes included progression-free survival (PFS) and overall survival (OS).ResultsOne hundred twenty patients were enrolled with median follow-up of 7.5 years. Overall response rate was 6%, with median PFS and OS of 4.2 and 9.7 years, respectively. Molecular subtype was associated with rate of disease progression during treatment (P<.001), PFS (P=.007), and OS (P<.001). Patients with 1p/19q codeletion demonstrated a 0% risk of progression during treatment. In an exploratory analysis, pretreatment lesion volume was associated with both PFS (P<.001) and OS (P<.001).ConclusionsWhile our study failed to meet the primary endpoint for objective radiographic response, patients with high-risk low-grade glioma receiving adjuvant temozolomide demonstrated a high rate of radiographic stability and favorable survival outcomes while meaningfully delaying radiotherapy. Patients with 1p/19q codeletion are potential candidates for omission of adjuvant radiotherapy, but further work is needed to directly compare chemotherapy with combined modality therapy

Probing the phosphatidylinositol 3‐kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low‐grade gliomas

BackgroundActivation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population.MethodsFifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [Kps ] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment.ResultsFor patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P < .001 for an improvement from the historical rate of 17%). Evidence of PI3K/mTOR activation by immunohistochemistry for phosphorylated ribosomal S6Ser240/244 (p-S6Ser240/244 ) was associated with worse progression-free survival (PFS; hazard ratio [HR], 3.03; P = .004) and overall survival (HR, 12.7; P = .01). Tumor perfusion decreased after 6 months (median decrease in fBV, 15%; P = .03; median decrease in Kps , 12%; P = .09), with greater decreases associated with improved PFS (HR for each 10% fBV decrease, 0.71; P = .01; HR for each 10% Kps decrease, 0.82; P = .04).ConclusionsPatients with recurrent LGGs demonstrated a high degree of disease stability during treatment with everolimus. PI3K/mTOR activation, as measured by immunohistochemistry for p-S6, was associated with a worse prognosis. Tumor vascular changes were observed that were consistent with the antiangiogenic effects of mTOR inhibitors. These results support further study of everolimus for LGGs. Cancer 2017;123:4631-4639. © 2017 American Cancer Society

Live vaccines after pediatric solid organ transplant: proceedings of a consensus meeting, 2018

Growing evidence suggests receipt of live-attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2-day consortium of experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post-SOT. For consideration of VV and MMR post-transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post-SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell-depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in-depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of "low-level" immune suppression as defined in the document

Clinical spectrum and outcome of treatment for autoimmune cytopenias in rag deficiency

Univ Debrecen, Fac Med, Dept Immunol, Debrecen, HungaryHarvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA USAHarvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USAMassachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USAUniv Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran, IranMayo Clin, Lab Med & Pathol, Rochester, MN USAWeill Cornell Med Coll Qatar, Pediat, Doha, QatarSidra Med & Res Ctr, Allergy & Immunol, Doha, QatarHamad Med Corp, Doha, QatarKuwait Univ, Fac Med, Dept Pediat, Safat 13060, KuwaitAmer Univ Beirut, Ctr Infect Dis Res, Dept Pediat & Adolescent Med, Beirut, LebanonBambino Gesu Pediat Hosp, Dept Oncohematol, Stem Cell Transplant Unit, Rome, ItalyCincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USACincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USAGreat Ormond St Hosp Sick Children, Dept Paediat Immunol, London, EnglandGreat Ormond St Hosp Sick Children, Dept Paediat Immunol, London, North IrelandUC Irvine, CHOC Childrens Hosp, Pediat Hematol, Orange, CA USAChildrens Hosp Bambino Gesu, Dept Pediat, Rome, ItalyUniv Roma Tor Vergata, Sch Med, Rome, ItalyUniv Utah, Dept Pediat, Div Allergy Immunol & Rheumatol, Salt Lake City, UT USAHarvard Univ, Sch Med, Dept Pediat, Immunol Div,Boston Childrens Hosp, Boston, MA 02115 USAUniv Fed Sao Paulo, Dept Allergy Clin Immunol & Rheumatol, Sao Paulo, BrazilNIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USABoston Childrens Hosp, Dept Immunol, Boston, MA USAHarvard Univ, Sch Med, Boston, MA USAUniv Colorado, Sch Med, Childrens Hosp Colorado, Div Allergy & Immunol, Boulder, CO 80309 USAImmunol Outpatient Clin, Vienna, AustriaUniv Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USANatl Jewish Hlth, Dept Pediat, Div Pediat Allergy & Clin Immunol, Denver, CO USANIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USAMayo Clin, Div Pediat Allergy Immunol, Rochester, MN USAAghia Sophia Childrens Hosp, Specialized Ctr, Dept Immunol Histocompatibil, Athens, GreeceAghia Sophia Childrens Hosp, Referral Ctr Primary Immunodeficiencies Pediat Im, Athens, GreeceOsped Pediat Bambino Gesu, Dept Pediat Hematol & Oncol, Rome, ItalyIRCCS Bambino Gesu Childrens Hosp, Dept Pediat Hematol & Oncol, Rome, ItalyBaylor Coll Med, Dept Pediat, Houston, TX 77030 USATexas Childrens Hosp, Sect Allergy & Immunol, Houston, TX 77030 USAErciyes Univ, Sch Med, Dept Pediat Hematol & Oncol, Kayseri, TurkeyErciyes Univ, Sch Med, Dept Pediat Immunol, Kayseri, TurkeyUniv Calif San Fransisco, Pediat Immunol & Bone Marrow Transplantat, San Francisco, CA USAChildrens Hosp Los Angeles, USC Keck Sch Med, Los Angeles, CA 90027 USAUniv Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, GermanyDuke Univ, Sch Med, Div Allergy & Immunol, Durham, NC USAHarvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USAUniv Fed Sao Paulo, Dept Allergy Clin Immunol & Rheumatol, Sao Paulo, BrazilWeb of Scienc

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease

Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Multicenter prospective cohort study. Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years’ initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Current follow-up can only detect large differences in ESKD and death outcomes. Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes