Michel Poisson

A PROSPECTIVE STUDY OF COGNITIVE FUNCTIONS FOLLOWING CONVENTIONAL RADIOTHERAPY FOR SUPRATENTORIAL GLIOMAS IN YOUNG ADULTS: 4-YEAR RESULTS

PURPOSE To evaluate the effects of limited field conventional cerebral radiotherapy (RT) on cognitive functions of adults. METHODS AND MATERIALS A prospective neuropsychological study was performed on 17 patients who underwent conventional limited field RT for a low-grade glioma or for a good-prognosis anaplastic glioma. Results were compared with 14 control patients with low-grade gliomas who did not receive radiotherapy. RESULTS A transient significant decrease of performances for the Reaction Time test was observed at 6 months in the irradiated group with return to baseline values 12 months post-RT. Subsequently, no other significant changes were observed over a 48-month follow-up period in the irradiated and nonirradiated groups. Nonetheless, when the scores of each patient were considered over time instead of the mean values of the group, one irradiated patient (5.8%) experienced progressive deterioration while two irradiated patients (11.7%) experienced long-lasting improvement. Individual changes did not occur in the control group. CONCLUSION This study suggests that a transient early delayed drop of neuropsychological performances at 6 months is frequent following limited field conventional RT, but the risk of long-term cognitive dysfunction after irradiation is low, at least in the first 4 years after RT and when it is administered alone in young adults.

A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas.

OBJECTIVE Epidermal growth factor receptor (EGFR) is an operationally specific antigen in malignant gliomas; it is overexpressed in > 60% of these tumors, whereas its expression is very low in normal brain. This study aimed to evaluate whether an adequate amount of an anti-EGFR monoclonal antibody (MAb) could reach a tumor after a single intravenous administration. METHODS This study was open, nonrandomized, and uncontrolled. Single doses (20, 40, 100, 200, or 400 mg) of the murine MAb EMD55900 (MAb 425) were administered intravenously before surgery to 30 patients with malignant brain tumors. Serum samples were taken at defined time intervals during infusion, to determine EMD55900 concentrations, and 10, 21, and/or 42 days after infusion, to evaluate the development of human anti-mouse antibodies. Tumor samples were investigated for EGFR and EMD55900 contents. RESULTS Tolerance to EMD55900 was good. Increased liver transaminase levels were noted for three patients with Grade 1 toxicity. Twenty patients developed significant human anti-mouse antibody titers, without correlation with the administered dose. The median half-life of EMD55900 in serum ranged from 6 hours for 20 mg to 24 hours for 400 mg. In the membrane fractions of the tumors, EGFR saturation by EMD55900 varied with the injected dose of MAb. No binding was detected after a 20-mg dose. After doses of 40, 100, 200, and 400 mg, the mean saturation levels were 33, 73, 89, and 71%, respectively. CONCLUSION This study indicates that a single intravenous administration of EMD55900 is well tolerated and produces substantial in vivo tumor binding with doses > 100 mg.

Treatment of recurrent malignant supratentorial gliomas with carboplatin (CBDCA).

SummaryTwenty patients with malignant supratentorial gliomas progressing after radiation therapy and chemotherapy with nitrosoureas received intravenous carboplatin, 450 mg/m2. Courses of therapy were repeated every four weeks. Therapeutic evaluation was performed monthly using neurologic examination and CT scan of the brain. Of 19 patients evaluable for response, 2 (10%) responded to therapy and 6 (30%) had stable disease. The estimated median time to tumor progression for responding and stable patients was 6 months. Median duration of survival was 6 months for all patients. Of 20 patients evaluable for toxicity, none had renal or auditory toxicity. Side effects consisted of hematologic toxicity in 4 patients (20%): one patient had grade 4 toxicity requiring discontinuation of carboplatin and 3 patients had grade 2–3 toxicity.

Evaluation of single-photon emission tomography imaging of supratentorial brain gliomas with technetium-99m sestamibi

Single-photon emission tomography (SPET) with technetium-99m sestamibi (MIBI) was carried out in 61 adult patients with supratentorial expanding brain lesions. Thirty-one patients had pathologically proven malignant glioma. Ten patients had pathologically proven low-grade glioma, while another 12 patients had a clinical diagnosis of low-grade glioma. The other eight patients had a variety of lesions including radiation necrosis (3), abscess (2), ischaemic stroke (2) and primary brain lymphoma (1). SPET was performed 15 min after administration of 740–930 MBq MIBI and transverse, sagittal and coronal views were reconstructed. Using computed tomography or magnetic resonance imaging guidance, a MIBI uptake index was computed as the ratio of counts in the lesion to counts in the contralateral homologous region. In high-grade gliomas, the MIBI index ranged from 1.9 to 6.6 (mean 3.6 ± 1.4) whereas it ranged from 0.8 to 1.7 (1.1 ± 0.2) in the pathologically proven low-grade group (P < 0.01). No significant difference was found between the two low-grade groups (1.1 ± 0.2 vs 1.1 ± 0.2). No overlap was found between high-grade and low-grade glioma index values. Patients with suspected radiation necrosis, cerebral abscess or ischaemic stroke did not demonstrate high MIBI uptake (0.9–2.2), whereas one patient with brain lymphoma did (3.9). This study suggests that MIBI SPET imaging is of value in distinguishing low-from high-grade supratentorial gliomas in adults.

Radiation-induced cognitive dysfunction: An experimental model in the old rat

PURPOSE To develop a model of radiation-induced behavioral dysfunction. METHODS AND MATERIALS A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. RESULTS Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p < or = 0.001) and two-way avoidance (18% vs. 40%, p < or = 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p < or = 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. CONCLUSION Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes.

Intrathecal synthesis of the anti‐Hu antibody in patients with paraneoplastic encephalomyelitis or sensory neuronopathy Clinical‐immunologic correlation

We studied the intrathecal synthesis of the anti-Hu antibody (also called type 1 antineuronal nuclear autoantibody) in 14 patients with isolated paraneoplastic subacute sensory neuronopathy (SSN) and 16 with paraneoplastic encephalomyelitis (PEM). Patients with PEM had higher anti-Hu titers in the CSF (p = 0.003) but not in the serum than those with SSN. Only one patient (7%) with SSN had a positive intrathecal anti-Hu antibody synthesis whereas this was present in 14 (88%) of the 16 patients with PEM (p < 0.0001). The correlation between the intrathecal production of anti-Hu antibodies and PEM supports the role of autoimmune mechanisms in the pathogenesis of PEM. The absent intrathecal synthesis of anti-Hu antibodies in patients with SSN suggests easier accessibility of the systemic immune reaction to the sensory neurons probably due to the partial absence of blood-nerve barrier in the dorsal root ganglia.

Stevens‐Johnson syndrome in a patient receiving cranial irradiation and carbamazepine

4 / 4 0 ) , with anti-DNA 1/60 (normal, <1/20). Anti-Sm and a n t i h antibodies were also present. CH-50 was 130 U/ml (normal, 150 to 250 U/ml). Urinalysis showed 20 red blood cells and 7 WBC per highpower field, and granular casts. Results of the following tests were normal or negative: platelet count, coagulation studies, blood biochemical analysis, alpha-2 and beta globulins, IgA, IgM, C3, C4, direct and indirect Coombs’ testa, serum iron and total iron binding capacity, haptoglobin, rheumatoid factor, cryoglobulins, VDRL and FTAABS, HB,AG, and lupus anticoagulant. A biopsy taken from a skin lesion was consistent with LE. Direct immunofluorescence (DIF) revealed a granular band of immune deposits of IgA ( + ) , IgM ( + ) , C3 (+ 1, and Clq (+ +) at the dermal-epidermal junction. A biopsy taken from clinically normal skin was normal. DIF of a kidney biopsy showed diffuse IgG, IgM, IgA, and C3 deposits in the mesangium. Roentgenograms of the chest and abdomen, ECG, and echocardiogram were normal. Ten days after admission, she developed fever (39°C). fatigue, increase of the arthralgias and arthritis, oral ulcers, maculopapular and necrotic lesions on the limbs, abdominal pain, restlessness, and hoarseness without respiratory stridor. There was no throat pain. The following laboratory abnormalities were present: hemoglobin 7 g/dl, WBC 2,8OO/mm3, sedimentation rate 70 mm/hr, total proteins 4.9 g/dl, albumin 2.12 g/dl, C3 12.5 mg/dl (normal, 55 to 120 mg/dl), C4 4.5 mg/d (normal, 20 to 50 mg/dl), CH-50 25 U/ml, and a prolonged partial thromboplastin time. She was treated with prednisone (120 mg/d). Indirect laryngoscopy revealed palsy of the right vocal cord. Laryngeal tomograms demonstrated the right vocal cord was fixed during inspiration and phonation (figure). CT of the brain and chest, standard barium examination of esophagus, thyroid gammagraphy, and abdominal echography were normal. EEG showed a diffuse slowing without focal abnormalities. Gradually, the mental dysfunction, arthralgias, arthritis, and skin lesions improved. Prednisone was gradually decreased and azathioprine was added (150 mg/ d). Nine months later, she had qecrotizing pneumonia with pleural ef€usion. After 12 months, the right vocal cord palsy has not improved. Discussion. Our patient met 9 of the American Rheumatism Association criteria for the classification of SLE4: malar rash, arthritis, oral ulcers, serosal involvement, nephropathy, ANA, cerebral dysfunction, and hematologic and immunologic disturbances. The laryngeal neuromuscular manifestations in SLE include necrosis of the cricoarytenoid muscles, and unusually, vocal cord palsy due to ischemia from occlusion of the vasa nervorum of the recurrent laryngeal nerve.3 There are 4 reasons that the right vocal cord palsy in OUT patient was likely due to selective involvement of the ipsilateral recurrent nerve. First, indirect laryngoscopy showed a palsy of the right vocal cord, in paramedian position, without other visible lesions. Moreover, the cricothyroid muscle action was normal. Second, there was evidence of systemic vasculitis. Third, although both indirect laryngoscopy and laryngeal tomogram permit, in most cases, to exclude a cricoarytenoid arthritis, it is the rapid response to glucocorticoid therapy which permits us to distinguish it from recurrent nerve palsy.2 Finally, other causes of recurrent nerve palsy were excluded.6 Any region of the brain can be involved in SLE, as can the meninges, spinal cord, and cranial and peripheral nerves. The peripheral nervous system is affected in 15% of patienta.6 The patterns of reported neuropathies are variable.s The pathophysiologic mechanisms of neuropathies in SLE are poorly understood,B although probably the most common c a w is an ar ter i t i~ .~ To our knowledge, this is the 2nd case of vocal cord palsy due to involvement of recurrent laryngeal nerve in SLE, presumably from occlusion of the vasa nervorum.

Treatment of recurrent malignant supratentorial gliomas with the association of carboplatin and etoposide: a phase II study

Thirty one patients previously treated with surgery, radiation therapy and chemotherapy with a nitrosoureafor malignant supratentorial gliomas received a combination of carboplatin (CBDCA) and etoposide(VP16) at tumor progression. Carboplatin and etoposide(CE) were given, each at a dose of 100 mg/m2/day from day 1 to 3. The response was evaluated at each course and a minimum of three courses was required to definite stable patient.Tolerance was evaluated in 31 patients. None had renalor auditory toxicity. Side effects consisted of grade III hematologic toxicity in 6 patients (19%), and grade III hepatic toxicity in one patient. No gradeIV WHO toxicity was observed.All 31 patients could be evaluated for therapeutic response.A partial response was noted in 4 patients during 13, 34 +, 35 + and 51 + weeks. Ten patients had stabledisease after a minimum of 3 courses (19 to 37 weeks). The rate of partial response (PR)and stabilisation (S) was 45% (14/31). The median time to tumor progression (MTTP) for respondingand stable patients was 28 weeks. The median survival time(ST) for the entire group was 45 weeks and over 51 weeks for PR and S patients.

Treatment of malignant gliomas with surgery, intraarterial chemotherapy with ACNU and radiation therapy

SummaryFourty patients with malignant supratentorial gliomas received iterative intraarterial (IA) infusions of ACNU, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea at a dose of 150 mg repeated every 6 weeks. Group A consisted of eighteen patients previously treated with surgery, radiation therapy (RT) and sometimes chemotherapy, who received IA ACNU at tumor recurrence. Group B consisted of twenty two patients who received IA ACNU in the postoperative pre-RT period. In group A, 8/18 patients (44%) had an objective response, including 6/12 anaplastic astrocytomas (AA) and 2/6 glioblastoma multiforme (GBM), while 10/18 patients (56%) did not respond. Median survival time was 6 months for GBM and 12 months for AA.In group B, 6/22 patients (27%) had an objective response (4/18 GBM and 2/4 AA) and 16/22 patients (73%) did not respond. Nine patients had such an extensive tumor after one or two courses of IA ACNU that RT was cancelled. Median survival time was 8 months for GBM and 8 months for AA.Three patients (8%) had ophthalmologic toxicity on the infused side. There was no case of leukoencephalopathy.

Intra arterial chemotherapy with ACNU and radiotherapy in inoperable malignant gliomas

SummaryFor the non-operable malignant glioma patients, prognosis remains poor, with a survival of 8 months for the glioblastomas (G), and 15 months for anaplastic astrocytomas (AA). 27 histologic proven malignant gliomas (17 AA and 10 G) were treated between April 1991 and June 1992. Median age was 48 years. The therapeutic protocol consisted of three courses of intra arterial chemotherapy (IAC) with ACNU, at intervals of six weeks, and a localised 60 Gy radiotherapy between the first and the second IAC course. 72 courses of IAC were delivered (2,4 per patient). Response rate was 51,8%. Median survival (MS) was 13 months, with a survival rate of 28% at 24 months. For the AA, MS was 21 months, with a survival rate of 37% at 24 months. For the G, median survival was 10 months. Responders were 65 % for AA, 30% for G. Non responders all died before 24 months had relapsed with a MS of 9 months. 54% of responding patients had a 2 years survival. Toxicity were acceptable with 7% of haematological toxicity and a partial loss of visual acuity in 11% of the cases. No chronic neurological sequellae were noted. We compare theses results with two previous trials, concerning inoperable patients, treated by an association of radiotherapy and systemic chemotherapy. Survival seems to be equivalent with HeCNU and with this treatment, but toxicity decreases with ACNU. Early radiotherapy does not increase complications. This treatment can be used for patients with inoperable malignant gliomas.