Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations.

BACKGROUND: Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy. METHODS: In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival. RESULTS: A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy. CONCLUSIONS: Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy. (Funded by Novartis; ClinicalTrials.gov number, NCT02684058.).

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194.

Children's Oncology Group's 2023 blueprint for research: Central nervous system tumors.

Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving Food and Drug Administration (FDA) approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children's Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups.

High Incidence and Unique Features of Cerebral Venous Sinus Thrombosis in Hospitalized Patients With COVID-19 Infection.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) secondary to vaccine-induced thrombotic thrombocytopenia is an extremely rare side effect of adenovirus-based COVID-19 vaccines. CVST incidence associated with COVID-19 itself has not been widely reported. We report the incidence of CVST in patients hospitalized with COVID-19 during the first year of the pandemic. METHODS: We analyzed de-identified electronic medical records of a retrospective cohort of patients admitted with COVID-19 to >200 hospitals between March 2020 and March 2021. We used International Classification of Diseases, Tenth Revision codes and natural language processing extracts to identify patients with a new CVST diagnosis during COVID-19 hospitalization. The primary outcome was CVST incidence in hospitalized, COVID-19-positive patients. Secondary outcomes included CVST incidence and mortality. Incidence rates were calculated using the DerSimonian-Laird estimator method. RESULTS: Ninety-one thousand seven hundred twenty-seven patients were evaluated; 22 had new CVST diagnoses by electronic medical record review. CVST incidence in the hospitalized COVID-19 cohort was 231 per 1 000 000 person-years (95% CI, 152.1-350.8). Females<50 had the highest incidence overall (males <50: 378.4 [142-1008.2]; females<50: 796.5 [428.6-1480.4]). In patients ≥50 years old, males had a higher estimated CVST incidence (males≥50: 130.5 [54.3-313.6]; females≥50: 88.8 [28.6-275.2]). Older patients (45.5% of patients ≥50 versus 0% of <50 years of age, P=0.012) and males (44.4% of males versus 7.7% of females, P=0.023) were more likely to die in hospital. CONCLUSIONS: CVST incidence in COVID-19-positive hospitalized patients is high. Advanced age and male gender were associated with likelihood of death in hospital; further studies are required to confirm these findings.

Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas.

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

The Effect of a Shared Decision-Making Process on Acceptance of Colorectal Cancer Screening.

VISUAL ABSTRACT.

Refractory vaccine-induced immune thrombotic thrombocytopenia (VITT) managed with delayed therapeutic plasma exchange (TPE).

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a newly described hematologic disorder, which presents as acute thrombocytopenia and thrombosis after administration of the ChAdOx1 nCov-19 (AstraZeneca) and Ad26.COV2.S (Johnson & Johnson) adenovirus-based vaccines against COVID-19. Due to positive assays for antibodies against platelet factor 4 (PF4), VITT is managed similarly to autoimmune heparin-induced thrombocytopenia (HIT) with intravenous immunoglobulin (IVIG) and non-heparin anticoagulation. We describe a case of VITT in a 50-year-old man with antecedent alcoholic cirrhosis who presented with platelets of 7 × 103 /µL and portal vein thrombosis 21 days following administration of the Ad26.COV2.S COVID-19 vaccine. The patient developed progressive thrombosis and persistent severe thrombocytopenia despite IVIG, rituximab and high-dose steroids and had persistent anti-PF4 antibodies over 30 days after his initial presentation. As such, delayed therapeutic plasma exchange (TPE) was pursued on day 32 of admission as salvage therapy, with a sustained improvement in his platelet count. Our case serves as proof-of-concept of the efficacy of TPE in VITT.

An intrathecal limited postoperative chemotherapy regimen for the treatment of young children with nodular/desmoplastic medulloblastoma and medulloblastoma with extensive nodularity.

PURPOSE: Therapy for medulloblastoma in patients < 4 years old omits radiotherapy due to anticipated neurocognitive deficits. The German Pediatric Brain Tumor Study Group described a chemotherapy regimen (HIT-SKK' 92 and HIT-SKK 2000) without radiation which yielded a 5-year progression-free survival (PFS) rate of 85% in children with nodular/desmoplastic medulloblastoma (NDMB) and medulloblastoma with extensive nodularity (MBEN). We modified the HIT-SKK regimen to reduce the total number of intrathecal methotrexate (IT MTX) doses from 12 to 2 doses/cycle and obviate Ommaya reservoir implantation through the use of lumbar administration. We report the outcomes of five patients treated with our approach. METHODS: IT MTX was eliminated altogether on weeks when high-dose intravenous methotrexate was administered. On weeks when no systemic methotrexate was administered, a single dose of lumbar-administered IT MTX was substituted in place of multiple intra-Ommaya doses. Cumulative dosing of MTX was 16-24 mg/cycle (age-based) compared to 24 mg/cycle in the HIT-SKK regimen. Following chemotherapy, patients were monitored with interval imaging, observation for acute and late effects, and survival. RESULTS: Four children remained in remission 3, 5, 9, and 10 years post-treatment respectively, without observed learning difficulties. One child had recurrent tumor and metastasis 6 months post-treatment. She failed the attempted salvage regimen and continued to deteriorate, dying of disease at 3 years old. CONCLUSIONS: Review of existing literature supported our modifications well. While this report is limited by the small number of children treated, we believe there is encouraging evidence that our approach warrants further evaluation in a larger population of young children with NDMB and MBEN.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

Efficacy and Safety of Mechanical IVC Filtration for Preventing Pulmonary Embolism in High-Risk Orthopedic Patients Undergoing Total Hip or Knee Arthroplasty.

BACKGROUND: To determine the efficacy and safety of inferior vena cava (IVC) filters in preventing pulmonary embolism (PE) in high-risk patients undergoing hip or knee arthroplasty. METHODS: 2857 hip or knee arthroplasty procedures between January 2013 and December 2018 were retrospectively reviewed. Patients with a preoperative history of venous thromboembolism (VTE), either PE or deep venous thrombosis (DVT), were categorized as high-risk patients. The incidence of overall VTE, PE, and DVT were compared between patients with filters and those without. The subgroup analysis was also performed by patient risk, and filter status and the incidence of VTE, PE, and DVT were compared. Variables such as filter placement, history of hypercoagulability etcetra were evaluated as risk factors for the development of postoperative VTE. RESULTS: In the high-risk group, the use of IVC filters was significantly associated with a lower incidence of pulmonary embolism (0.8% vs 5.5%, P = .028). When compared with the low-risk group, the high-risk group had significantly higher incidence of PE (3.8% vs 2.0%, P = .038), DVT (11.6% vs 5.3%, P < .001), and overall VTE (15.0% vs 6.8%, P < .001). The history of VTE was associated with postoperative VTE (P < .001), PE (P = .042), and DVT (P < .001). There was no significant correlation between filter placement and postoperative VTE, DVT, or PE in the low-risk group. Filter retrieval was successful in 100% (96/96) of attempted patients with no complications. CONCLUSION: The use of IVC filters is significantly associated with a lower incidence in pulmonary embolism in high-risk arthroplasty patients. High-risk patients demonstrated an incidence of postoperative VTE over two times greater than other patients. Prophylactic placement of IVC filters in hip/knee arthroplasty is safe.

Response assessment in diffuse intrinsic pontine glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.

Phase 1 study of lenalidomide plus dose-adjusted EPOCH-R in patients with aggressive B-cell lymphomas with deregulated MYC and BCL2.

BACKGROUND: Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL. METHODS: The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. RESULTS: A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months. CONCLUSIONS: The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. RESULTS: In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. CONCLUSIONS: The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.

A prospective study of cerebral, frontal lobe, and temporal lobe volumes and neuropsychological performance in children with primary brain tumors treated with cranial radiation.

BACKGROUND: Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning. METHODS: Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses. RESULTS: Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups. CONCLUSIONS: This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2017;161-168. © 2016 American Cancer Society.

A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. METHODS: Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. RESULTS: Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. CONCLUSIONS: The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population.

Therapeutic activity of high-dose intratumoral IFN-ß requires direct effect on the tumor vasculature.

Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-ß to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-ß, and conditional deletion of IFN-α/ßR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.

Phase I and Phase II Objective Response Rates are Correlated in Pediatric Cancer Trials: An Argument for Better Clinical Trial Efficiency.

Although many phase I trials report tumor response, formal analysis of efficacy is deferred to phase II. We reviewed paired phase I and II pediatric oncology trials to ascertain the relationship between phase I and II objective response rate (OR%). Single-agent phase I trials were paired with corresponding phase II trials (comparable study drug, dosing schedule, and population). Phase I trials without efficacy data or a matching phase II trial were excluded. OR% was tabulated for all trials, and phase II authors' subjective conclusions regarding efficacy were documented; 35 pairs of trials were analyzed. The correlation between phase I and II OR% was 0.93. Between phase II studies with a "positive" conclusion versus a "negative" one, there was a statistically significant difference in mean phase I OR% (32.0% vs. 4.5%, P<0.001). Thirteen phase II studies were undertaken despite phase I OR% of 0%; only 1 had a "positive" conclusion, and none exceeded OR% of 15%. OR% are highly correlated between phase I and II pediatric oncology trials. Although not a formal measure of drug efficacy, phase I OR% may provide an estimate of phase II response, inform phase II study design, and should be given greater consideration.

Management of pediatric intracranial low-grade gliomas: long-term follow-up after radiation therapy.

INTRODUCTION: The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. METHODS: Thirty-four patients <21 years old with intracranial LGG who were treated with RT at the Johns Hopkins Hospital were included in this retrospective analysis. Patients were evaluated for overall survival (OS), progression-free survival (PFS), recurrence patterns, and treatment toxicities using descriptive statistics, Kaplan-Meier curves, and Cox proportional hazard regressions. RESULTS: The mean age at diagnosis was 7.9 years (range 1.2-18.3 years) and mean age at RT was 9.8 years (range 3.0-28.9 years). The median follow-up time was 9.8 years after radiation (range 0.8-33.3 years). The estimated 10-year OS and PFS after RT were 92 and 74 %, respectively. Twelve patients had disease progression after RT, and all recurrences were local. Two patients died due to disease progression 2.3 and 9.1 years after RT. One patient had malignant transformation of LGG to high-grade glioma. No significant predictors of PFS were identified on uni- or multivariate analysis. Late effects of LGG and treatment seen were endocrine deficiencies in 16 patients, visual problems in 10 patients, hearing loss in 4 patients, special education requirements for 5 patients, and a vascular injury/demyelination secondary to RT in 1 patient. CONCLUSION: Our study suggests that the use of radiation in patients with intracranial LGG results in excellent OS and PFS with acceptable toxicity at long-term follow-up.