A Tumor Growth Inhibition Model for Low-Grade Glioma Treated with Chemotherapy or Radiotherapy

PURPOSE: To develop a tumor growth inhibition model for adult diffuse low-grade gliomas (LGG) able to describe tumor size evolution in patients treated with chemotherapy or radiotherapy. EXPERIMENTAL DESIGN: Using longitudinal mean tumor diameter (MTD) data from 21 patients treated with first-line procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) chemotherapy, we formulated a model consisting of a system of differential equations, incorporating tumor-specific and treatment-related parameters that reflect the response of proliferative and quiescent tumor tissue to treatment. The model was then applied to the analysis of longitudinal tumor size data in 24 patients treated with first-line temozolomide (TMZ) chemotherapy and in 25 patients treated with first-line radiotherapy. RESULTS: The model successfully described the MTD dynamics of LGG before, during, and after PCV chemotherapy. Using the same model structure, we were also able to successfully describe the MTD dynamics in LGG patients treated with TMZ chemotherapy or radiotherapy. Tumor-specific parameters were found to be consistent across the three treatment modalities. The model is robust to sensitivity analysis, and preliminary results suggest that it can predict treatment response on the basis of pretreatment tumor size data. CONCLUSIONS: Using MTD data, we propose a tumor growth inhibition model able to describe LGG tumor size evolution in patients treated with chemotherapy or radiotherapy. In the future, this model might be used to predict treatment efficacy in LGG patients and could constitute a rational tool to conceive more effective chemotherapy schedules. Clin Cancer Res; 18(18); 5071-80. ?2012 AACR.     

Management of malignant gliomas diagnosed during pregnancy

INTRODUCTION: Glioma is seldom diagnosed during pregnancy. In this situation management presents difficult problems for both neuro-oncologists and obstetricians. We report four cases and discuss the management of this unusual situation. CASE REPORT: The first patient was admitted to hospital at 29 weeks' gestation because of a generalized seizure and a right hemiparesis. MRI showed a left fronto-insular lesion. A stereotactic biopsy was obtained and revealed an anaplastic oligodendroglioma. With corticosteroids the patient remained stable until cesarean delivery at 36 weeks. In post-partum additional treatment with chemotherapy was started. The second patient was hospitalized at 26 weeks' gestation because of cranial hypertension, right hemiparesis and aphasia. MRI showed an important left fronto-parietal lesion. Partial resection was performed at 28 weeks. Histology revealed a glioblastoma multiforme. With corticosteroids the patient remained stable until cesarean delivery at 33 weeks. In post-partum additional treatment with radiotherapy and chemotherapy was started. The third patient was admitted to the hospital at 12 weeks' gestation because of cranial hypertension. MRI showed a left frontal lesion. A subtotal resection was done at 13 weeks. Histology revealed a glioblastoma multiforme. Two weeks after surgery the patient's neurological condition worsened and in agreement with the patient a therapeutic abortion was decided. Afterwards additional treatment with radiotherapy and chemotherapy was started. The last patient received combined treatment with radiotherapy and chemotherapy for local recurrence of a mesencephalic high-grade glioma. A posteriori it was discovered that the patient was at 4 months' gestation during this treatment. Cesarean delivery was done at 36 weeks. The child was normal at birth and is still in good health 5 years later. CONCLUSION: The management of gliomas diagnosed during pregnancy should not be different from the standard management of gliomas in young non-pregnant adults. Pregnant women because of their young age can have a long survival. Their pregnancy should not prevent them from receiving the best treatment for their glioma. Treatment will depend upon clinico-radiological presentation, histology, gestational age and the patient's desires. Generally speaking, surgical resection of high-grade gliomas should not be delayed during pregnancy. Progress in anesthesia and neurosurgery have greatly reduced the risks for the foetus. After delivery, if the delay between surgery and delivery is too long it is possible to begin cerebral radiotherapy during pregnancy. After the first trimester of gestation this treatment can be given without any important risks for the child.     

Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.     

Molecular genetic markers as predictors of response to chemotherapy in gliomas

PURPOSE OF REVIEW: This review summarizes recent studies on applications of molecular markers such as chromosome 1p/19q codeletion and MGMT status in the treatment of glioma. RECENT FINDINGS: Prospective trials confirmed that 1p/19q codeletion represents a strong and independent favourable prognostic factor in anaplastic oligodendroglial tumours. Other retrospective studies have suggested that 1p/19q loss is also predictive of chemosensitivity to alkylating agents (nitrosoureas and temozolomide) in low-grade gliomas. Recent reports have provided evidence that 1p and 19q deletions are mediated by unbalanced translocation. The targeted genes remain to be identified, however. Promoter methylation of MGMT gene silencing has been shown to predict benefit from chemotherapy in glioblastoma. MGMT promoter methylation and low expression of MGMT-encoded protein are frequently observed in low-grade gliomas and anaplastic oligodendroglial tumours. In such tumours, however, preliminary studies have yielded contradictory results on the predictive value of MGMT status regarding objective response to chemotherapy and correlation with 1p/19q deletion. SUMMARY: There is mounting evidence that 1p/19q deletion and MGMT inactivation are relevant prognostic markers and predictors of chemosensitivity in gliomas. Although such markers remain to be formally validated by ongoing and planned prospective trials, it is likely that they will soon become essential for optimizing treatment decisions.     

Absence of an interaction between iron and mycophenolate mofetil absorption

AIM: To determine whether concomitant iron affects the absorption of mycophenolate mofetil. METHODS: An open-label, single centre, randomized, crossover trial was conducted in 16 healthy males. Fasting subjects received mycophenolate mofetil alone (treatment A) or co-administered with iron (treatment B). RESULTS: The mycophenolic acid AUC(0,24 h) for treatments A and B were 42.5 +/- 10.5 and 44.7 +/- 12.4 microg ml(-1) h, respectively. anova modelling showed the relative bioavailability of mycophenolate mofetil to be similar for the two treatments (90% confidence interval 0.92, 1.19). CONCLUSIONS: There was no interaction between mycophenolate mofetil and iron supplements administered concomitantly to healthy fasting subjects.     

Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process.

Loss of telomeric repeats during cell proliferation could play a role in senescence. It has been generally assumed that activation of telomerase prevents further telomere shortening and is essential for cell immortalization. In this study, we performed a detailed cytogenetic and molecular characterization of four SV40 transformed human fibroblastic cell lines by regularly monitoring the size distribution of terminal restriction fragments, telomerase activity and the associated chromosomal instability throughout immortalization. The mean TRF lengths progressively decreased in pre-crisis cells during the lifespan of the cultures. At crisis, telomeres reached a critical size, different among the cell lines, contributing to the peak of dicentric chromosomes, which resulted mostly from telomeric associations. We observed a direct correlation between short telomere length at crisis and chromosomal instability. In two immortal cell lines, although telomerase was detected, mean telomere length still continued to decrease whereas the number of dicentric chromosomes associated was stabilized. Thus telomerase could protect specifically telomeres which have reached a critical size against end-to-end dicentrics, while long telomeres continue to decrease, although at a slower rate as before crisis. This suggests a balance between elongation by telomerase and telomere shortening, towards a stabilized 'optimal' length.     

Creatine and neurotrophin-4/5 promote survival of nitric oxide synthase-expressing interneurons in striatal cultures

Nitric oxide (NO) mediates a variety of physiological functions in the central nervous system and acts as an important developmental regulator. Striatal interneurons expressing neuronal nitric oxide synthase (nNOS) have been described to be relatively spared from the progressive cell loss in Huntington's disease (HD). We have recently shown that creatine, which supports the phosphagen energy system, induces the differentiation of GABAergic cells in cultured striatal tissue. Moreover, neurotrophin-4/5 (NT-4/5) has been found to promote the survival and differentiation of cultured striatal neurons. In the present study, we assessed the effects of creatine and NT-4/5 on nNOS-immunoreactive (-ir) neurons of E14 rat ganglionic eminences grown for 1 week in culture. Chronic administration of creatine [5 mM], NT-4/5 [10 ng/ml], or a combination of both factors significantly increased numbers of nNOS-ir neurons. NT-4/5 exposure also robustly increased levels of nNOS protein. Interestingly, only NT-4/5 and combined treatment significantly increased general viability but no effects were seen for creatine supplementation alone. In addition, NT-4/5 and combined treatment resulted in a significant larger soma size and number of primary neurites of nNOS-ir neurons while creatine administration alone exerted no effects. Double-immunolabeling studies revealed that all nNOS-ir cells co-localized with GABA. In summary, our findings suggest that creatine and NT-4/5 affect differentiation and/or survival of striatal nNOS-ir GABAergic interneurons. These findings provide novel insights into the biology of developing striatal neurons and highlight the potential of both creatine and NT-4/5 as therapeutics for HD.     

Region-specific expression of cell cycle inhibitors in the adult brain

In the adult brain, neural proliferation is almost absent and neurons are generally not renewed. By contrast, in the olfactory organ, olfactory neurons are produced continuously throughout life. To investigate whether specific cell cycle inhibitors are involved in the control of neural quiescence in adulthood, we compared their expression either in different regions of the adult brain weakly or non neurogenic or, for comparison, in the olfactory mucosa. We show that numerous cell cycle inhibitors are expressed in the adult brain either in an ubiquitous fashion (as p19Ink4d) or in specific brain regions (p15Ink4b in the forebrain, p27Kip1 and p21Cip1 in the cerebellum). By contrast p18Ink4c was expressed detectably only in the highly neurogenic olfactory epithelium. The present data suggest that various CDK inhibitors may be involved in a region-specific fashion in the maintenance of nerve cell quiescence in adults.     

Postradiation lumbosacral radiculopathy with spinal root cavernomas mimicking carcinomatous meningitis

Lumbosacral radiculopathy is a rare complication of radiotherapy and may be challenging to differentiate from diagnosis of a tumor recurrence. We reviewed the records of three patients with a past history of cancer and radiotherapy who were referred for suspicion of carcinomatous meningitis on lumbar MRI, but whose final diagnosis was radiation-induced lumbosacral radiculopathy. The three patients developed a progressive lumbosacral radiculopathy at 20, 13, and 47 years after lumbar radiotherapy delivered for renal cancer, Hodgkin's disease, and a seminoma, respectively. MRI showed a diffuse, nodular enhancement of the cauda equina nerve roots on T1 sequences, suggestive of leptomeningeal metastasis. A slowly progressive clinical course over several years and negative cerebrospinal fluid cytologic analysis ruled out the diagnosis of carcinomatous meningitis. Because of the radiologic findings, a biopsy was performed in two patients. In the first, a biopsy limited to the arachnoid excluded a malignant infiltration. In the second, a biopsy of the enhancing lesions demonstrated spinal root cavernomas. These observations, together with three recent case reports in the literature, delineate a syndrome of "radiationinduced lumbosacral radiculopathy with multiple spinal root cavernomas" that mimics carcinomatous meningitis on MRI. Its diagnosis is important in order to avoid inappropriate treatment and useless or dangerous spinal root biopsies.