Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) of childhood has a dismal prognosis. Clinical trials of new agents are vital and it is essential that the correct endpoints and disease assessments are chosen. A retrospective review of magnetic resonance imaging (MRI) scanning in a pure population of DIPG was undertaken. Baseline diagnostic MRI findings included; local tumour extension in upper medulla (74%) or midbrain (62%), metastatic disease (3%), basilar artery encasement (82%), necrosis (33%), intratumoural haemorrhage (26%), hydrocephalus (23%) and dorsal exophytic component (18%). Post-treatment MRI scans demonstrated increases in; leptomeningeal metastatic disease (16%), cystic change/necrosis (48%), enhancement (72%) and intratumoural haemorrhage (32%). Response rates were calculated according to both RECIST (4%) and WHO (24%) criteria. No MRI parameter in either the diagnostic or response scans had prognostic significance. We recommend that currently primary endpoints for DIPG clinical trials should be overall or possibly progression free survival and that new advanced functional imaging techniques should be explored as possible surrogate markers for novel therapy activity rather than conventional MRI response criteria.     

Young age may predict a better outcome for children with diffuse pontine glioma

BACKGROUND: Because diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown. METHODS: The authors reviewed clinical and radiologic characteristics of all children aged <3 years with DPG who were evaluated at their institution. Inclusion followed standard magnetic resonance imaging criteria for the diagnosis of DPG. RESULTS: The median age at diagnosis in 10 patients was 2.2 years (range, 0.8-2.7 years). The median interval between the onset of symptoms and diagnosis was 2.5 months. All patients presented with cranial nerve palsy with (n = 7) or without (n = 3) other neurologic deficits attributable to brainstem involvement. All patients had pons-based tumors involving >50% of this brainstem segment. Histologic confirmation was attempted in 2 patients who had atypical radiologic features at diagnosis. Four patients initially were observed only. All patients received therapy, which consisted of radiation therapy (RT) (n = 2), RT and chemotherapy (n = 6), or chemotherapy only (n = 2). Four patients died of tumor progression after a median of 0.7 years (range, 0.5-3.7 years). Six patients have survived for a median of 2.3 years (range, 0.9-8 years). The 3-year progression-free and overall survival rates were 45% +/- 19% and 69% +/- 19%, respectively. CONCLUSIONS: Children aged <3 years with DPG potentially may fare better than older patients with the same diagnosis despite the use of similar therapy. The current results suggested that DPG in younger children may be distinct biologically from similar tumors in older age groups.     

End-of-life care of children with diffuse intrinsic pontine glioma

Although atypical meningioma recurs frequently in spite of total resection and/or radiotherapy, no consensus on optimal adjuvant management was found. However, several retrospective studies analysed the additional effect of adjuvant radiotherapy in atypical meningioma with inconsistent results. Therefrom, the purpose of this study was to evaluate prognostic factors influencing the recurrence/progression and progression-free survival (PFS) rates of atypical meningioma, particularly focused on the role of postoperative adjuvant radiotherapy. Between February 2001 and March 2015, 161 atypical meningioma resections were performed in our Department of Neurosurgery, of which, 128 cases underwent surgical treatment alone and 33 cases underwent surgery and radiotherapy. Kaplan–Meier analysis was used to provide median point estimates and PFS rates. The Cox-regression model was used in the univariate and multivariate analysis to identify significant factors associated with treatment. The extent of resection (Simpson grade I and II) significantly influenced the risk of recurrence (hazard ratio?=?1.8, CI (95%) 1.3–2.6, p-value?=?0.0004). There was no significant benefit for progression-free survival after adjuvant radiotherapy (hazard ratio?=?1.48, CI (95%) 0.76–2.86, p-value?=?0.22). Additionally, meningioma located at the anterior and posterior fossa showed a significantly longer PFS compared to other locations (p-value?=?0.03). Adjuvant postoperative radiotherapy had no significant impact on recurrence/progression rate or PFS. The extent of resection according to Simpson grade remains the most important prognostic factor associated with lower recurrence/progression rates and longer PFS in patients with atypical meningioma. The location of the tumours at the anterior or posterior fossa was an independent factor associated with improved PFS.     

Prospective collection of tissue samples at autopsy in children with diffuse intrinsic pontine glioma

BACKGROUND:

Brain tissue obtained at autopsy has been used in research for non‐oncologic disorders. However, to the best of the authors' knowledge, this tool has never been systematically used in large investigational studies for cancer. A prospective, multicenter study was conducted to assess the feasibility of tissue collection at autopsy and its suitability for molecular analyses in children with diffuse intrinsic pontine glioma.

METHODS:

Tumor tissue was collected at the time of diagnosis, if clinically indicated, or at autopsy. Normal brain tissue was also collected at autopsy. The integrity of DNA and RNA was evaluated in all samples. Logistic data regarding autopsies were recorded. The feasibility of tissue collection at autopsy was assessed for patients treated at a single institution over a 43‐month period.

RESULTS:

Tumor samples were collected at the time of diagnosis (n = 3) or at autopsy (n = 38) at 29 centers across the United States; samples were obtained at diagnosis and autopsy in 2 cases. The median interval from death to autopsy was 7.7 hours. DNA and RNA with minimal or partial degradation, which were suitable for genome‐wide analysis, were obtained from 100% and 63% of tumor samples, respectively. At the coordinating institution, approximately 40% of parents consented to autopsy and 40% declined. During the study period, 12 autopsies were performed on patients who did not receive therapy at the coordinating center.

CONCLUSIONS:

Multicenter, biological studies based on tissue obtained at autopsy appear to be feasible in children with brain cancer. The current experience established a new paradigm for brain tissue collection, which may increase the potential for research studies in patients with cancer. Cancer 2010. © 2010 American Cancer Society.     

The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma

Perfusion estimates and microvascular leakage (MVL) were recently correlated with glioma angiogenesis and aggressiveness, but their role in predicting outcome of patients (pts) with unfavorable low-grade gliomas (ULGG) is unclear. Their prognostic value was then investigated, versus conventional factors such as age, neurological status, tumor size, and contrast enhancement (CE). Clinical and anatomical magnetic resonance imaging (MRI) criteria of a cohort of ULGG pts were prospectively evaluated. A dynamic T2*-weighted MR sequence was included to detect high-perfusion areas, using the maximal value of the relative cerebral blood volume (rCBV) estimate, and MVL. Conventional and microvascular characteristics were correlated with progression-free survival (PFS). Among the 46 pts included, the following features were present in 61%, 26%, 67%, and 26%, respectively: age ≥40 years, neurological deficits, tumor size ≥6 cm, and CE. High perfusion value was noted in 30% of cases and MVL in 52%. With median follow-up of 22 months (range 4–46 months), median PFS was 32 months [95% confidence interval (CI) 17–45 months]. On univariate analysis, CE, rCBV, and MVL were significantly correlated with PFS. On multivariate analysis, only CE and MVL were unfavorable factors, with hazard ratio of 3.0 and 7.3 and P value of 0.04 and 0.02, respectively. Different prognostic subgroups were identified, with 2-year PFS of 86%, 57%, and 19% for pts with no MVL, MVL without CE, and MVL with CE, respectively. MVL and CE seem to predict short-term outcome in ULGG pts.     

Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma

Summary Purpose We performed a retrospective study of patients with diffuse pontine glioma (DPG) who suffered neuraxis metastasis (NM) and characterized the incidence, clinical features, radiologic findings, and patterns of disease dissemination. Methods Magnetic resonance imaging (MRI) of brain and spine was used to assess NM. Some patients also underwent magnetic resonance spectroscopy (MRS) (6 patients) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans (13 patients) to further evaluate areas of metastatic disease. Three patients had histologic confirmation of disease at the site of NM. Results Between 1986 and 2003, 18 of 96 patients (17.3%) with DPG developed NM. The median age at diagnosis was 8 years (range, 4–17). All patients had adjuvant chemotherapy and/or focal radiotherapy at diagnosis. The NM occurred at a median of 15 months from diagnosis of DPG (range, 3–96). Three patterns of NM were seen on MRI of brain and spine in these patients; 8 (39%) had parenchymal (PM), 4 (22%) leptomeningeal (PM), 2 (11%) subependymal, and in 5 a combination of two or more patterns. The MRS and FDG-PET scan of suspected areas of metastatic disease was consistent with tumor in 6 of 6 and 12 of 13 patients who underwent these procedures respectively. Three patients also had histologic confirmation of malignant glioma at the site of NM. Despite salvage therapy, all 18 patients have died of disease at a median of 5 months (range, 0.5–20) from diagnosis of neuraxis spread. Conclusion Our study emphasizes the need for screening patients with DPG for NM at the time of recurrence. ^★Presented in part at the International Society of Pediatric Neuro-Oncology Meeting held in Boston, MA June 13–16, 2004.     

Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Background

Although diffuse intrinsic pontine glioma (DIPG) carries the worst prognosis of all pediatric brain tumors, studies on prognostic factors in DIPG are sparse. To control for confounding variables in DIPG studies, which generally include relatively small patient numbers, a survival prediction tool is needed.

Methods

A multicenter retrospective cohort study was performed in the Netherlands, the UK, and Germany with central review of clinical data and MRI scans of children with DIPG. Cox proportional hazards with backward regression was used to select prognostic variables (P < .05) to predict the accumulated 12-month risk of death. These predictors were transformed into a practical risk score. The model''s performance was validated by bootstrapping techniques.

Results

A total of 316 patients were included. The median overall survival was 10 months. Multivariate Cox analysis yielded 5 prognostic variables of which the coefficients were included in the risk score. Age ≤3 years, longer symptom duration at diagnosis, and use of oral and intravenous chemotherapy were favorable predictors, while ring enhancement on MRI at diagnosis was an unfavorable predictor. With increasing risk score categories, overall survival decreased significantly. The model can distinguish between patients with very short, average, and increased overall survival (medians of 7.0, 9.7, and 13.7 mo, respectively). The area under the receiver operating characteristic curve was 0.68.

Conclusions

We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.     

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

Journal of Neuro-Oncology - Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early...     

Proton magnetic resonance spectroscopy predicts survival in children with diffuse intrinsic pontine glioma

Patients with diffuse intrinsic pontine glioma (DIPG) face a grim prognosis with limited treatment options. Many patients will enroll on investigational trials though the role of chemotherapy or immunotherapy is unclear. Radiographic changes on conventional MRI are used to evaluate tumor response and progression, but are not predictive of outcome in these patients. More sensitive measures of tumor biology are needed to improve patient management. We evaluated changes in magnetic resonance spectroscopy (MRS) biomarkers in patients with DIPG. Thirty-eight patients were enrolled prospectively on an IRB-approved protocol, which included standard MRI, single voxel spectroscopy (SVS) and multi-slice multi-voxel spectroscopy (MRSI). Scans were performed at multiple time points during each patient’s clinical course, with a total of 142 scans. The prognostic values of Choline:N-acetylaspartate (Cho:NAA), Cho:Creatine (Cho:Cr) and the presence of lactate and lipids (+Lac/Lip) were evaluated. Cho:NAA and variance in Cho:NAA values among different voxels within a tumor were each predictive of shorter survival. This prospective study shows that MRS can be used to identify high-risk patients and monitor changes in tumor metabolism, which may reflect changes in tumor behavior.     

Conventional MRI does not reliably distinguish radiation necrosis from tumor recurrence after stereotactic radiosurgery

Distinguishing radiation necrosis (RN) from tumor recurrence after stereotactic radiosurgery (SRS) for brain metastases is challenging. This study assesses the sensitivity (SN) and specificity (SP) of an MRI-based parameter, the "lesion quotient" (LQ), in characterizing tumor progression from RN. Records of patients treated with SRS for brain metastases between 01/01/1999 and 12/31/2009 and with histopathologic analysis of a subsequent contrast enhancing enlarging lesion at the treated site at a single institution were examined. The LQ, the ratio of maximal nodular cross sectional area on T2-weighted imaging to the corresponding maximal cross sectional area of T1-contrast enhancement, was calculated by a neuroradiologist blinded to the histopathological outcome. Cutoffs of <0.3, 0.3-0.6, and >0.6 have been previously suggested to have correlated with RN, mixed findings and tumor recurrence, respectively. These cutoff values were evaluated for SN, SP, positive predictive value (PPV) and negative predictive value (NPV). Logistic regression analysis evaluated for associated clinical factors. For the 51 patients evaluated, the SN, SP, PPV and NPV for identifying RN (LQ < 0.3) were 8, 91, 25 and 73 %, respectively. For the combination of recurrent tumor and RN (LQ 0.3-0.6) the SN, SP, PPV and NPV were 0, 64, 0 and 83 %. The SN, SP, PPV and NPV of the LQ for recurrent tumor (LQ > 0.6) were 59, 41, 62 and 39 %, respectively. Standard MRI techniques do not reliably discriminate between tumor progression and RN after treatment with SRS for brain metastases. Additional imaging modalities are warranted to aid in distinguishing between these diagnoses.     

Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma

The purpose of this study is to evaluate the efficacy and toxicity of radiation therapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG). Newly diagnosed patients younger than 18 years with histologically proven DIPG were treated with focal radiotherapy to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m(2)/day). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m(2)/day, days 1-5) was given every 28 days up to six cycles. Responses/progressions were assessed by clinical and 2-monthly MRI follow-up studies. Between September 2005 and September 2009, 21 patients with newly diagnosed histologically confirmed DIPG were eligible for this study. Median age at diagnosis was 6.4 years (range 4-16 years). At last update in August 2010, 17 children have died, 1 child was alive with progressive disease and 3 with stable disease. Metastatic relapse was documented in the cerebral site in two patients and in spinal cord in two cases. The median time to progression was 7.5 months (range 28 days-14.5 months) and the median survival was 11.7 months (range 26 days-17.5 months). The 1-year PFS and the 1-year OS were 33 and 50%, respectively. Five patients presented radiological findings compatible with pseudoprogression during the treatment. Haematological toxicity (Grade III/IV thrombocytopenia and leucopenia) was the most commonly found and led to dose reductions of TMZ in 58% of the patients. TMZ with radiation therapy has not yielded any significant improvement in outcome of children with DIPG and is associated with higher toxicity compared with radiotherapy alone. Novel treatment modalities are needed to improve the outcome of these patients.     

A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands

Introduction: Children with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with a median overall survival of 9 months. Our aims are to determine the incidence of DIPG in the Netherlands and to identify points for improvement in clinical research, a prerequisite for increasing the chance to find a cure. Methods: We performed a population-based retrospective cohort study by evaluating all children diagnosed with DIPG in the Netherlands between 1990 and 2010. Results: The incidence of DIPG in the Netherlands corresponds with international literature. Between 1990 and 2010, a large heterogeneity of treatment schedules was applied and only a minority of patients was included in clinical trials. Discussion: Given the rarity of DIPG, we emphasize the need for (inter-)national trials to facilitate the identification of potentially effective therapeutics in the future. This can be supported by the recent development of a European DIPG registry enabling international study collaborations.     

Pretreatment apoptotic scores do not predict response to radiation therapy in oropharyngeal squamous cell carcinoma

The prognostic value of tumor apoptosis was studied in patients with oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Forty-eight patients with oropharyngeal squamous cell carcinoma who received radical radiotherapy between 1990 and 1995 were enrolled in the study. The radiation treatment for all patients involved the administration of 65 Gy in 26 fractions over a 6.5-week period. The apoptotic index (AI; the apoptotic cell count per 1000 tumor cells ) was distributed from 0 to 10 with a median at 2 and a mode of 1. There was a significant linear correlation between the AI and mitotic index (MI) (r=0.393, 95% confidence interval: 0.129-0.605). The cause-specific 5-year survival for patients with AI greater than the median was 46% and for the counterpart was 41%. There was no difference in cause-specific survival between AI/MI greater than the median (50%) and AI/MI smaller than the median (36%). The number of patients was too small to draw definite conclusions, but the AI and the AI/MI before treatment were not shown to have a prognostic value for oropharyngeal squamous cell carcinoma in our study. The primary sites and treatment methods may influence the prognostic value of AI even for the same histological types.