Biomedical subjects

Jacques Grill

Publications and source records attributed to Jacques Grill.

31 records · Page 2Linked to original sources

PubMed2004

Critical risk factors for intellectual impairment in children with posterior fossa tumors: the role of cerebellar damage.

OBJECT: Intellectual impairment is a major concern after treatment of malignant posterior fossa tumors in children. The effects of age at diagnosis and radiotherapy have been widely documented. Little is known, however, about perioperative factors, especially neurological damage to the cerebellum, the role of which in cognition and learning has been recently indicated. The authors studied the effects in 76 children treated for a malignant posterior fossa tumor in a cross-sectional study. METHODS: Two thirds of the tumors were medulloblastoma. Neuropsychological evaluation was performed at least 6 months after the end of treatment, and findings were correlated with clinical risk factors for intellectual impairment. The mean verbal intelligence quotient (VIQ) score was 87 +/- 19 (+/- standard deviation) and the mean performance IQ (PIQ) score was 76 +/- 17.5. A single neuropsychological test measuring hand skills (the Purdue Pegboard) was the strongest predictor of low IQ scores including items testing higher cognitive functions. A low VIQ was associated with impaired hand skills (p < 0.0001) and the presence of preoperative hydrocephalus (p = 0.02), whereas a low PIQ was associated with impaired hand skills (p < 0.0001) and incision of the vermis (p = 0.02). Impaired hand skills were associated with postoperative cerebellar mutism, oculomotor deficits, cerebellar syndrome, and therapeutic requirements. CONCLUSIONS: When treatment schedules are adapted to risk of disease and age, surgery-related risk factors then become critical for predicting intellectual impairment. Children with cerebellar damage are particularly at risk for long-term neuropsychological dysfunction and require active rehabilitation measures. Reducing surgery-related morbidity should be the next goal to reduce posterior fossa surgery-specific deficits.

Adolescent↗

PubMed2003

Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy aimed at avoiding radiotherapy during first-line treatment of children with progressive optic pathway tumors (OPT), by exclusively administering multiagent chemotherapy during 16 months. PATIENTS AND METHODS: Between 1990 and 1998, 85 children with progressive OPT were enrolled onto this multicenter nationwide trial. Chemotherapy alternating procarbazine plus carboplatin, etoposide plus cisplatin, and vincristine plus cyclophosphamide was given every 3 weeks. At the time of relapse or progression, second-line chemotherapy was authorized before recourse to radiotherapy. RESULTS: Objective response rate (partial response [PR] + complete response [CR]) to chemotherapy was 42%. Five-year progression-free survival (PFS) and overall survival rates were 34% and 89%, respectively. The 5-year radiotherapy-free survival rate was 61%. In the multivariate analysis of the 85 patients that entered onto the study, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.047) and absence of neurofibromatosis type 1 (P =.035). In the multivariate analysis of the 74 patients that remained on study after the first cycle of chemotherapy, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.0053) and no objective response to chemotherapy (P =.0029). Three-year PFS was 44% in infants < or = 1 year versus 66% in children older than 1 year. Three-year PFS was 53% in the absence of an objective response to chemotherapy versus 68% after a PR or CR. CONCLUSION: A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function.

Age Factors↗

PubMed2003

In vivo antitumor activity of S16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts.

New active drugs are needed for the treatment of primary brain tumors in both children and adults. S16020 is a cytotoxic olivacine derivative that inhibits topoisomerase II. The aim of the study was to determine its antitumor activity in athymic mice bearing subcutaneous medulloblastoma (IGRM33, 34, 57) and glioblastoma (IGRG88, 93, 121) xenografts treated at an advanced stage of tumor growth in comparison with that of doxorubicin. Animals were randomly assigned to receive i.v. S16020 or doxorubicin weekly for three consecutive weeks. The optimal dose was 80 mg/kg per week. S16020 demonstrated a significant antitumor activity in two out of three medulloblastoma xenografts. IGRM57 xenografts were highly sensitive with 100% tumor regressions and a tumor growth delay (TGD) of 102 days, while one of eight IGRM34 xenografts showed a partial regression with a TGD of 16 days. Doxorubicin was significantly more active than S16020 in these two models. IGRM33, a model established from a tumor in relapse after chemotherapy and radiotherapy, was refractory to both drugs. S16020 demonstrated a significant antitumor activity in the three glioblastoma xenografts evaluated. The wild-type p53 IGRG93 xenograft was highly sensitive with 100% tumor regressions and a TGD of 54 days. IGRG121 (wt p53) and IGRG88 (mutant p53) were moderately sensitive with TGDs of 33 and 23 days, respectively. Doxorubicin showed greater activity in two of these models. All six xenografts exhibited low expression of mdr1 as quantitated by RT-PCR, and no correlation was found with the activity of either drug. Conversely, a low activity of the two drugs was significantly associated with a high expression of MRP1 in medulloblastomas. Finally, no relationship was observed between drug sensitivity to either drug and expression of their target, topoisomerase IIalpha. In conclusion, S16020 and doxorubicin showed significant antitumor activity in brain tumor xenografts treated at an advanced stage of tumor growth. Their activity was related to MRP1 expression in medulloblastomas.

Animals↗

PubMed2003

Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective study of 104 patients.

In addition to multiple peripheral neurofibromas, Neurofibromatosis 1 (NF1) predisposes to CNS tumours. Most of them are pilocytic astrocytomas, arise in children and are located in the optic pathways or in the brainstem. The majority are indolent, but factors predictive of poor prognosis have yet to be identified. Furthermore, the incidence and natural history of gliomas of a higher grade, arising in adults or involving other locations are largely unknown in NF1. In order to address these issues, we performed a retrospective study of 104 patients followed in seven French centres between 1982 and 2000. Inclusion criteria were a diagnosis of NF1, according to the National Institutes of Health criteria, and the presence of a CNS tumour, regardless of type, location or age of onset. The series included 88 children (age range 3 months to 17 years) and 16 adults (age range 19-52 years). The median follow-up was 5.6 years. One hundred and twenty-seven CNS tumours were observed in the 104 patients. Eighty-four (66%) were optic pathway tumours (OPT) and 43 (34%) extra-optic pathway tumours (extra-OPT) (brainstem: n = 21; other locations: n = 22). Twenty-one patients (20%) had multiple CNS tumours. OPT were symptomatic in 50 patients and extra-OPT in 19. Main clinical findings at presentation included visual loss (n = 29; 58%) and precocious puberty (n = 5; 10%) for OPT, increased intracranial pressure (n = 9; 48%) for extra-OPT. Fourteen out of the 27 symptomatic tumours with histology were pilocytic astrocytomas. The overall survival rate was 90% at 5 years (95% confidence interval 82-95%). Extra-optic location, tumour diagnosis in adulthood and symptomatic tumours were independent factors associated with shorter survival time (P < 0.05, Cox model). Radiotherapy for OPT was associated with vascular complications (ischaemic strokes) and growth hormone deficiency in 32 and 46% of patients, respectively. In conclusion, mortality is high in extra-OPT, particularly in adults, whereas OPT are only exceptionally life-threatening. Radiotherapy of OPT is associated with an important morbidity in NF1.

Adolescent↗

PubMed2003

Childhood ependymoma: a systematic review of treatment options and strategies.

Childhood intracranial ependymoma have a dismal prognosis, especially in young children and when a gross total resection cannot be performed. Even in the absence of a radiologically proven residuum, around two-thirds of these young children will have a recurrence. Adjuvant therapy is therefore necessary for most, if not all, patients. Despite some indication that benign ependymoma (WHO grade II) could show a better outcome, histology cannot be used at present to stratify treatment protocols.Craniospinal irradiation combined with posterior fossa boost has deleterious adverse effects on cognition. Consequently, pediatric oncology teams have, firstly, tried to use chemotherapy to delay or avoid irradiation, and secondly, progressively reduced irradiation fields to the tumor bed without altering the prognosis. Cisplatin, at a dose of 120 mg/m(2) (cumulated response rate of 34% [95% CI 19-54%]) is the only single agent that has reproducibly shown some efficacy in ependymoma. Despite some combinations showing efficacy in the adjuvant setting, childhood intracranial ependymomas can, in general, be considered as chemoresistant. The overexpression of the multidrug resistance-1 gene and the 06-methylguanine-DNA methyltransferase have been implicated as possible mechanisms for this phenomenon. As the use of chemotherapy with current agents is questionable, phase II studies with new agents and combinations are necessary. Since the main problem of this disease is local relapse, it may not be necessary to irradiate the whole posterior fossa. However, local control of the disease by irradiation has to be improved. In this respect, hyperfractionation or radiosensitizers may be valuable therapeutic options. The treatment of children with ependymoma is a challenge for all caregivers. There is no doubt that any possible improvement in the management of this rare tumor will only be the result of well designed cooperative trials.

Adolescent↗

PubMed2003

[Conditionally replicative adenoviruses: a second wind for cancer gene therapy].

Cancer gene therapy has offered many hopes but its first use in humans revealed some pitfalls and at least three main problems: lack of efficacy and specificity of current vectors to deliver therapeutic genes, poor diffusion of the therapeutic effects inside the tumor (absence of bystander effect), poor distribution of the vectors injected inside the tissue. To address some of these issues, several teams have developed tumor selective replicating adenoviruses, some of them being already in the clinic. First results are promising but complementary studies are needed to define if these agents will take place in the therapeutic armentorium against cancer.

Adenoviridae↗

PubMed2002

Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic potency.

Conditionally replicative adenoviruses (CRAds) hold promise as anticancer agents. Their potency depends on their replication efficiency in cancer cells and their capacity to destroy these cells by oncolysis. In this regard, a critical determinant is the capacity of CRAds to induce cell death at late stages of infection to release their progeny. One of the cell death pathways that are exploited by adenoviruses involves the tumor suppressor protein p53. Unfortunately, many cancer cells have a nonfunctional p53 pathway and thus do not effectively support CRAd-induced cell death. We hypothesized that restoration of the p53-dependent cell death pathway in cancer cells would promote CRAd-induced cell lysis. Exogenous expression of p53 in human cancer cells during adenovirus replication accelerated cell death by several days and augmented early virus progeny release. The p53-enhanced oncolysis occurred independent of E1A binding to pRb and independent of E3 functions. On the basis of these findings, we constructed a new CRAd, AdDelta24-p53. This virus expressed functional p53 while replicating in cancer cells. Most importantly, AdDelta24-p53 exhibited enhanced oncolytic potency on 80% of tested human cancer cell lines of various tissue origins and with different p53 status. CRAd potency was increased up to >100-fold by p53 expression. We conclude that CRAds expressing p53 are promising new agents for more effective treatment of many human cancers.

Adenoviridae↗

PubMed2002

Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy.

The use of replication-competent adenoviruses (Ads) for cancer therapy is receiving widespread attention, especially for the treatment of tumors refractory to current treatments such as glioblastoma. AdDelta24, which carries a 24-bp deletion in E1A and replicates in cells with a retinoblastoma-defective pathway, produced a strong antitumor effect in glioma. To improve infection efficiency of primary glioma cells, which express low levels of coxsackie adenovirus receptor (CAR), the tropism of AdDelta24 was expanded toward alphav integrins by insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob (Ad5-Delta24RGD). We show that Ad5-Delta24RGD had a stronger oncolytic effect than the non-RGD-expressing variant on a broad panel of primary glioma cells, in particular on those with low CAR expression. The effects of Ad5-Delta24RGD were also assessed on a panel of primary organotypic glioma spheroids. In all cases, Ad5-Delta24RGD strongly decreased the viability of these small tumor nodules in vitro. In s.c. glioblastoma xenografts expressing low levels of CAR, five intratumoral injections of 1 x 10(7) plaque-forming units Ad5-Delta24RGD resulted in complete tumor regression in 9 of 10 mice and long-term survival in all treated mice. Preclinical evaluations and clinical trials of replication-competent Ad have shown more promising results when combined with conventional therapeutics. Therefore, we assessed the effects of Ad5-Delta24RGD in combination with radiotherapy. Low-dose irradiation before Ad5-Delta24RGD infection decreased viability of glioma cells more effectively than Ad5-Delta24RGD alone with effects ranging from additive to supra-additive. In addition, combination treatment with Ad5-Delta24RGD and irradiation was studied in glioma xenografts. Five injections of 1 x 10(6) plaque-forming units Ad5-Delta24RGD induced significant tumor growth delay of >119 days compared with untreated controls and led to long-term survival in 6 of 9 mice. When viral treatment was combined with irradiation, tumor regression occurred in all mice resulting in long-term survival without evidence of tumor regrowth in 10 of 10 cases. This study thus provides evidence that Ad5-Delta24RGD has strong antitumor activity in malignant glioma, which can be additionally enhanced by irradiation such that the same therapeutic effect is achieved when a 10-fold lower viral dose is applied. These results support further development of Ad5-Delta24RGD in combination with radiation therapy for treatment of these highly malignant tumors.

Adenoviridae↗

PubMed2002

Comparative genomic hybridization detects specific cytogenetic abnormalities in pediatric ependymomas and choroid plexus papillomas.

Pathogenesis and genetic abnormalities of ependymomas are not well known and differential diagnosis with choroid plexus tumors may be difficult when these tumors are located in the ventricles. We analyzed 16 samples of primary pediatric ependymomas and seven choroid plexus tumors for significant gains or losses of genomic DNA, using comparative genomic hybridization (CGH). Four ependymoma samples were obtained after surgery for relapse, including one patient whose tumor was analyzed at diagnosis and at first and second relapses. Three out of 16 ependymomas and none of the choroid plexus tumors appeared normal by CGH. In the remaining ependymomas, the number of regions with genomic imbalance was limited. The most frequent copy number abnormality in ependymomas was 22q loss. In one patient from whom multiple samples could be analyzed during tumor progression, no abnormality was present at diagnosis; gain of chromosome 9 and loss of 6q were observed at first relapse and, at second relapse, additional genomic imbalances were loss of 3p, 10q, and chromosome 15. In choroid plexus tumors, recurrent abnormalities were gains of chromosome 7 and region 12q. The recurrent chromosomal abnormalities were clearly different between ependymomas and choroid plexus papillomas (CPP). Recurrent loss of 22q suggests that this region harbors tumor suppressor genes important in the pathogenesis of ependymomas; however, other pathogenic pathways may exist involving 6q and chromosome 10 losses or gain of 1q and chromosome 9. CPP can be distinguished from ependymoma on the basis of CGH abnormalities.

Brain Neoplasms↗

PubMed2002

Oncolytic activity of the E1B-55 kDa-deleted adenovirus ONYX-015 is independent of cellular p53 status in human malignant glioma xenografts.

Treatment of malignant gliomas remains a major challenge in adults and children because of high treatment failure. The E1B 55 kDa-gene deleted adenovirus, ONYX-015 (ONYX Pharmaceuticals), was demonstrated to replicate selectively in and lyse tumor cells. Currently ongoing clinical trials of ONYX-015 in head and neck tumors are promising. Here, we demonstrate ONYX-015-mediated cell lysis and antitumor activity in three of four s.c. human malignant glioma xenografts deriving from primary tumors. Intratumoral injections of ONYX-015, 1 x 10(8) plaque-forming units daily for 5 consecutive days, yielded significant tumor growth delay in the p53 mutant xenografts IGRG88 and the p53 wild-type IGRG93 and IGRG121 treated at an advanced tumor stage. The p53 wild-type tumors IGRG93 and IGRG121 experienced 45% and 82% complete tumor regressions. Four and 8 of 11 animals, respectively, survived tumor free 4 months after treatment. Widespread intratumoral adenoviral replication was observed in tumor cells of these two xenografts compared with only scattered replication in the p53-mutant tumors. In addition to a fast tumor growth rate, wild-type p53 status was associated with increased antitumor activity of the E1B-attenuated virus, and induction of functional p53 may therefore determine adenoviral cytolysis in tumor cells. In conclusion, ONYX-015 displayed a major antitumor activity in human xenografts derived from primary malignant glioma supporting its development in the treatment of these highly malignant tumors.

Adenoviridae↗

PubMed2002

Efficient and selective gene transfer into primary human brain tumors by using single-chain antibody-targeted adenoviral vectors with native tropism abolished.

The application of adenoviral vectors in cancer gene therapy is hampered by low receptor expression on tumor cells and high receptor expression on normal epithelial cells. Targeting adenoviral vectors toward tumor cells may improve cancer gene therapy procedures by providing augmented tumor transduction and decreased toxicity to normal tissues. Targeting requires both the complete abolition of native tropism and the addition of a new specific binding ligand onto the viral capsid. Here we accomplished this by using doubly ablated adenoviral vectors, lacking coxsackievirus-adenovirus receptor and alpha(v) integrin binding capacities, together with bispecific single-chain antibodies targeted toward human epidermal growth factor receptor (EGFR) or the epithelial cell adhesion molecule. These vectors efficiently and selectively targeted both alternative receptors on the surface of human cancer cells. Targeted doubly ablated adenoviral vectors were also very efficient and specific with primary human tumor specimens. With primary glioma cell cultures, EGFR targeting augmented the median gene transfer efficiency of doubly ablated adenoviral vectors 123-fold. Moreover, EGFR-targeted doubly ablated vectors were selective for human brain tumors versus the surrounding normal brain tissue. They transduced organotypic glioma and meningioma spheroids with efficiencies similar to those of native adenoviral vectors, while exhibiting greater-than-10-fold-reduced background levels on normal brain explants from the same patients. As a result, EGFR-targeted doubly ablated adenoviral vectors had a 5- to 38-fold-improved tumor-to-normal brain targeting index compared to native vectors. Hence, single-chain targeted doubly ablated adenoviral vectors are promising tools for cancer gene therapy. They should provide an improved therapeutic index with efficient tumor transduction and effective protection of normal tissue.

Adenoviridae↗

PubMed2002

Gene therapy for meningioma: improved gene delivery with targeted adenoviruses.

OBJECT: Due to their surgical inaccessibility or aggressive behavior, some meningiomas cannot be cured with current treatment strategies. Gene therapy is an emerging strategy for the treatment of brain tumors, which the authors investigated to determine whether adenoviruses could be used for gene transfer in meningioma cells. METHODS: The presence of the high-affinity Coxsackievirus and adenovirus receptor (CAR) for adenovirus type 5, as well as endothelial growth factor receptor (EGFR) and alpha, integrins (ITGAVs), were analyzed in primary tumors by using immunohistochemical studies and in primary meningioma cell cultures by using fluorescence-activated cell sorting. Targeting of adenoviruses to EGFR was achieved using bispecific antibodies, whereas targeting of adenoviruses to the ITGAVs was accomplished by insertion of an RGD (arginine-glycine-aspartic acid) motif in the adenovirus fiber H1 loop. Gene transfer efficiency of untargeted and targeted vectors was compared in primary cell cultures and in spheroids derived from patients' resected tumor material. The presence of CARs was observed in all tumors and in all but one of the derived primary meningioma cells. The higher expression of EGFRs and ITGAVs indicated that these receptors could be used as alternative targets to redirect the adenoviruses. Redirection of adenoviruses to the EGFRs or integrins enhanced gene transfer threefold (range two-sevenfold) for EGFRs in primary meningioma cells and ninefold (range three-23-fold) for integrins (p = 0.002, analysis of variance). The effect of adenovirus targeting was confirmed in spheroids composed of primary meningioma cells. CONCLUSIONS: Gene transfer with adenoviruses targeted to tumor-specific receptors is very effective in primary meningioma cells and spheroids. These vectors are promising agents for gene therapy of meningiomas.

Adenoviridae↗

PubMed2002

The organotypic multicellular spheroid is a relevant three-dimensional model to study adenovirus replication and penetration in human tumors in vitro.

The use of adenoviruses for gene transfer and as oncolytic agents is currently receiving widespread attention. As specific constraints to adenovirus distribution and spread cannot be studied in cell cultures, there is a need for an in vitro three-dimensional (3D) model mimicking the in vivo biology of tumors. We studied the interactions between tumor and adenoviruses using multicellular spheroids grown from primary brain tumor material. Using beta-galactosidase and luciferase reporter genes expressed by replication-defective adenoviruses, we showed that infection was restricted to the first layer of cells. Using a replication-competent adenovirus expressing the luciferase gene, we showed that transgene expression in the spheroid was considerably enhanced and that viral spreading deep into the 3D structure took place. In addition, a tetrazolium salt-based metabolic assay could be used to compare the oncolytic activity of different concentrations of replication-competent adenoviruses. We can conclude that organotypic spheroids offer a versatile in vitro system for studying distribution, spread, and oncolysis by adenoviruses in a clinically relevant model.

Adenoviridae↗