Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 ...unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: β-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 μM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 μM). To investigate possible structure−activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds47 aggregators and 64 nonaggregatorsthat have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20−400 μM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
To describe treatment planning techniques and early clinical outcomes in patients treated with spot scanning proton therapy for chordoma or chondrosarcoma of the skull base.
From June 2010 through ...August 2011, 15 patients were treated with spot scanning proton therapy for chordoma (n=10) or chondrosarcoma (n=5) at a single institution. Toxicity was prospectively evaluated and scored weekly and at all follow-up visits according to Common Terminology Criteria for Adverse Events, version 3.0. Treatment planning techniques and dosimetric data were recorded and compared with those of passive scattering plans created with clinically applicable dose constraints.
Ten patients were treated with single-field-optimized scanning beam plans and 5 with multifield-optimized intensity modulated proton therapy. All but 2 patients received a simultaneous integrated boost as well. The mean prescribed radiation doses were 69.8 Gy (relative biological effectiveness RBE; range, 68-70 Gy RBE) for chordoma and 68.4 Gy (RBE) (range, 66-70) for chondrosarcoma. In comparison with passive scattering plans, spot scanning plans demonstrated improved high-dose conformality and sparing of temporal lobes and brainstem. Clinically, the most common acute toxicities included fatigue (grade 2 for 2 patients, grade 1 for 8 patients) and nausea (grade 2 for 2 patients, grade 1 for 6 patients). No toxicities of grades 3 to 5 were recorded. At a median follow-up time of 27 months (range, 13-42 months), 1 patient had experienced local recurrence and a second developed distant metastatic disease. Two patients had magnetic resonance imaging-documented temporal lobe changes, and a third patient developed facial numbness. No other subacute or late effects were recorded.
In comparison to passive scattering, treatment plans for spot scanning proton therapy displayed improved high-dose conformality. Clinically, the treatment was well tolerated, and with short-term follow-up, disease control rates and toxicity profiles were favorable.
Purpose
WHO grade 4 gliomas are rare in the pediatric and adolescent and young adult (AYA) population. We evaluated prognostic factors and outcomes in the pediatric versus AYA population.
Methods
...This retrospective pooled study included patients less than 30 years old (yo) with grade 4 gliomas treated with modern surgery and radiotherapy. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis.
Results
Ninety-seven patients met criteria with median age 23.9 yo at diagnosis. Seventy-seven patients were ≥ 15 yo (79%) and 20 patients were < 15 yo (21%). Most had biopsy-proven glioblastoma (91%); the remainder had H3 K27M-altered diffuse midline glioma (DMG; 9%). All patients received surgery and radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection (GTR) was associated with better PFS in multivariate analysis HR 2.00 (1.01–3.62), p = 0.023. Age ≥ 15 yo was associated with improved OS HR 0.36 (0.16–0.81), p = 0.014 while female gender HR 2.12 (1.08–4.16), p = 0.03 and DMG histology HR 2.79 (1.11–7.02), p = 0.029 were associated with worse OS. Only 7% of patients experienced grade 2 toxicity. 62% of patients experienced tumor progression (28% local, 34% distant). Analysis of salvage treatment found that second surgery and systemic therapy significantly improved survival.
Conclusion
Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. DMG was associated with worse OS than glioblastoma. Reoperation and systemic therapy significantly increased survival after disease progression. Prospective studies in this population are warranted.
Abstract
Background
To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma ...(GBM).
Methods
Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs).
Results
A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02).
Conclusions
In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.
BACKGROUND
Both intensity‐modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality ...on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity‐modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II).
METHODS
From 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard‐risk disease (63.5%). The median follow‐up was 12.8 years for group I and 8.7 years for group II.
RESULTS
The 5‐year and 10‐year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard‐risk patients and 63.1% and 57.3%, respectively, for high‐risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5‐year and 10‐year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia.
CONCLUSIONS
This analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT.
LAY SUMMARY
One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity‐modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52).
The majority of children had standard‐risk disease (63.5%).
The 5‐year and 10‐year overall survival rates were 88.8% and 85.1% for standard‐risk patients, respectively, and 63.1% and 57.3% for high‐risk patients, respectively, with no difference in overall survival by RT group (P = .81).
The 5‐year and 10‐year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).
In total, 115 children with medulloblastoma who received surgery, chemotherapy, and radiotherapy (RT) with either 3‐dimensional RT followed by an intensity‐modulated boost (n = 63) or passively scattered proton therapy (n = 52) are assessed. At 10 years after RT, there are no differences in overall survival or secondary malignant neoplasms according to RT modality.
•Proton beam therapy (PBT) provides excellent local control for pediatric patients with head and neck rhabdomyosarcoma (RMS).•Tumor size greater than 5 cm predicted increased risk of local failure, ...supporting ongoing dose escalation trial efforts.•Tumors with intracranial extension (ICE) had high rates of local and leptomeningeal relapse.•Delayed delivery of local therapy may drive higher rates of relapse seen among patients with ICE tumors.•The late toxicity profile of patients treated with PBT compares favorably to that of prior series using IMRT.
Pediatric patients with rhabdomyosarcoma (RMS) of the head and neck (H&N) are treated with multimodal therapy, often with radiotherapy (RT) as definitive local therapy. We report on the patterns of failure following proton beam therapy (PBT) for H&N RMS.
Forty-six H&N RMS patients were enrolled on a prospective registry protocol between 2006 and 2015. All were treated with a combination of chemotherapy (ChT) and PBT. Most patients (25 patients, 54%) had parameningeal tumors, of which 11 (24%) had intracranial extension (ICE). Thirteen patients (28%) had primary tumors greater than 5 cm. Median total cyclophosphamide (CPM) equivalent dose was 13.2 g/m2 (range 0–16.8 g/m2). Median RT dose was 50.4 Gy(RBE) (range 36 GyRBE–50.8 GyRBE).
With median follow-up of 3.9 years, five-year overall survival was 76%, and five-year progression-free survival was 57%. Seventeen patients (37%) experienced relapse, including 7 with local failure (LF). Five-year local control (LC) was 84%. Tumor size greater than 5 cm predicted increased risk of LF (hazard ratio HR 6.49, p = 0.03), as did the presence of ICE at diagnosis (HR 5.21, p = 0.03). Six relapses occurred in patients with ICE; all included a component of central nervous system relapse, with leptomeningeal disease and/or LF with an intracranial component. Delayed RT delivery after week 4 of ChT predicted increased risk of relapse for ICE patients (HR 10.49, p = 0.006).
PBT confers excellent LC, and a favorable late toxicity profile as compared with prior photon RT data. Our observations support ongoing trial efforts to dose-escalate RT for patients with larger tumors. However, these data raise concerns regarding excess failures among patients with ICE.
Meningiomas account for approximately one third of all primary intracranial tumors. Arising from the cells of the arachnoid mater, these neoplasms are found along meningeal surfaces within the ...calvarium and spinal canal. Many are discovered incidentally, and most are idiopathic, although risk factors associated with meningioma development include age, sex, prior radiation exposure, and familial genetic diseases. The World Health Organization grading system is based on histologic criteria, and are as follows: grade 1 meningiomas, a benign subtype; grade 2 meningiomas, which are of intermediately aggressive behavior and usually manifest histologic atypia; and grade 3, which demonstrate aggressive malignant behavior. Management is heavily dependent on tumor location, grade, and symptomatology. While many imaging-defined low grade appearing meningiomas are suitable for observation with serial imaging, others require aggressive management with surgery and adjuvant radiotherapy. For patients needing intervention, surgery is the optimal definitive approach with adjuvant radiation therapy guided by extent of resection, tumor grade, and location in addition to patient specific factors such as life expectancy. For grade 1 lesions, radiation can also be used as a monotherapy in the form of stereotactic radiosurgery or standard fractionated radiation therapy depending on tumor size, anatomic location, and proximity to dose-limiting organs at risk. Optimal management is paramount because of the generally long life-expectancy of patients with meningioma and the morbidity that can arise from tumor growth and recurrence as well as therapy itself.
Background
Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. ...However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy‐naïve.
Procedure
We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2–21 years) treated between 1997 and 2013 with craniospinal RT. Log‐rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk.
Results
Eighty‐three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty‐four of 79 (30%) patients developed disease recurrence at an average 27.0 months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log‐rank p = .016; Cox p = .03) and Week 5 (log‐rank p = .024; Cox p = .032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p = .04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0–3) or absolute lymphocyte count (ALC) below the median at any time during RT.
Conclusions
Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.
Molecular docking uses the three-dimensional structure of a receptor to screen a small molecule database for potential ligands. The dependence of docking screens on the conformation of the binding ...site remains an open question. To evaluate the information loss that occurs as the active site conformation becomes less defined, a small molecule database was docked against the holo (ligand bound), apo, and homology modeled structures of 10 different enzyme binding sites. The holo and apo representations were crystallographic structures taken from the Protein Data Bank (PDB), and the homology-modeled structures were taken from the publicly available resource ModBase. The database docked was the MDL Drug Data Report (MDDR), a functionally annotated database of 95 000 small molecules that contained at least 35 ligands for each of the 10 systems. In all sites, at least 99% of the molecules in the MDDR were treated as nonbinding decoys. For each system, the holo, apo, and modeled structures were used to screen the MDDR, and the ability of each structure to enrich the known ligands for that system over random selection was evaluated. The best overall enrichment was produced by the holo structure in seven systems, the apo structure in two systems, and the modeled structure in one system. These results suggest that the performance of the docking calculation is affected by the particular representation of the receptor used in the screen, and that the holo structure is the one most likely to yield the best discrimination between known ligands and decoy molecules, but important exceptions to this rule also emerge from this study. Although each of the holo, apo, and modeled conformations led to enrichment of known ligands in all systems, the enrichment did not always rise to a level judged to be sufficient to justify the effort of a docking screen. Using a 20-fold enrichment of known ligands over random selection as a rough guideline for what might be enough to justify a docking screen, the holo conformation of the enzyme met this criterion in eight of 10 sites, whereas the apo conformation met this criterion in only two sites and the modeled conformation in three.
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