Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL. PATIENTS AND METHODS: Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%). RESULTS: Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P = 0.03). CONCLUSIONS: The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. CLINICAL TRIALS NUMBER: NCT01956695.

A concurrent ultra-fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma.

We report on a phase II clinical trial to determine the effect of a concurrent ultra-fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m(2) for 7 days a week. After a 4-week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5-day regimen. Tolerance and toxicity were the primary endpoints; survival and progression-free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra-fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long-term survivors were noted. Concurrent ultra-fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.

Phase II study of a radiotherapy/etoposide combination for patients with newly malignant gliomas.

PURPOSE: Etoposide, a semisynthetic derivative of podophyllotoxine, is a topoisomerase II inhibitor. This drug is currently used in several types of human cancer. The aim of this study was to evaluate the efficacity and tolerance of a near-concurrent association of radiotherapy and etoposide for newly malignant gliomas. METHODS: From May 1995 to December 1996, 30 malignant glioma patients were included in this phase II study; 16 patients underwent surgical tumor resection, and a stereotactic biopsy was performed in 14 patients. Standard cranial irradiation and six courses of etoposide (100 mg/m2, x days 1-3) were administered. The first course of etoposide was administered on days 1-3 of radiotherapy and was resumed in the week following the end of radiotherapy. Treatment was consolidated by further courses of etoposide every 4 weeks. RESULTS: Only 26 patients could be evaluated for the purpose of our study. The median age was 60.1 years, and the median Karnofsky performance score (KPS) was 80.2. The rate of objective response for evaluable patients was 34.6%, and four complete responses (CR) and five partial responses (PR) were noted. The median survival (MST) was 12 months, and the average overall survival was 12.5 months. Hematological toxicity was mild, and grade 3 or 4 neutropenia (white blood cell count < 1500/ml) was noted in three patients, without any sepsis or bleeding. CONCLUSIONS: The results obtained in this study are comparable to the best reported results on the combination of radiotherapy and nitrosoureas. The near-concurrent combination of radiotherapy and etoposide seems to be effective and well tolerated in the treatment of newly malignant gliomas.

Etoposide sensitivity of radioresistant human glioma cell lines.

PURPOSE: Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Etoposide, a topoisomerase-II-inhibitor agent, is one of the most active and useful antineoplastic agents. However, etoposide is not usually used on these tumors. We undertook an in vitro study to prove that etoposide is a useful drug for malignant gliomas. METHODS: Five human glioma cell lines were the basis for this study. Following exposure to various concentrations of etoposide, the glioma cell lines were found to be sensitive; the median concentration inhibiting the number of cells by 50% (IC50) was 8.76 microg/ml (range 8-15.8 microg/ml). Since topoisomerase II is the critical target for etoposide, it was of interest to determine the topoisomerase II activity (decatenation of kinetoplast DNA isolated from Cryphtidia fasciculata) and the etoposide-induced inhibition of topoisomerase II activity. RESULTS: The topoisomerase II activity was homogeneous in glioma cell lines (average of 50% decatenation with 7,000 cells), and topoisomerase II was the target of the etoposide. CONCLUSIONS: Our results suggest that topoiomerase II-reactive agents may prove to be clinically useful drugs for patients with malignant gliomas.

Involvement of the glutathione S-conjugate compounds and the MRP protein in Tc-99m-tetrofosmin and Tc-99m-sestamibi uptake in glioma cell lines.

The objective of this study was to compare the accumulation of Tc-99m-tetrofosmin and Tc-99m-sestamibi in four grade IV glioma cell lines and to correlate their accumulation with the multidrug resistance of the cells. Tc-99m-tetrofosmin in all glioma cell lines showed slightly higher uptake and more efficient release beyond 150 min than Tc-99m-sestamibi and the retention of both tracers in the cells was to a certain extend inversely proportional to their degree of multidrug resistance. The results obtained showed that the efflux of both tracers was carried out only in part through the MRP/GS-X pump system. Tc-99m-tetrofosmin showed good potential as a marker of recurrent malignant glioma and in vivo studies are currently underway to confirm these observations.

Gonadotropic pituitary carcinoma: case report.

A 37-year-old man developed multiple intracranial, intraspinal, and general metastases from an invasive nonfunctioning pituitary adenoma after surgery and radiation therapy. This is the first gonadotropic pituitary carcinoma reported in literature.

Diffuse vertebral body metastasis from a glioblastoma multiforme: a technetium-99m Sestamibi single-photon emission computerized tomography study.

The authors report on a case of right temporal glioblastoma multiforme (GBM) that metastasized to multiple bone regions (dorsolumbar vertebrae and iliac bone) 8 months after initial diagnosis, despite combined radio- and chemotherapy. Results of a whole-bone single-photon emission computerized tomography (SPECT) study using the imaging agent Sestamibi (MIBI) revealed extracranial metastases from the GBM. A magnetic resonance imaging study of the dorsolumbar spinal region completed the radiological investigation. Cells immunoreactive to glial fibrillary acidic protein were observed in a specimen obtained from the right iliac bone. Postmortem examination confirmed metastasis to extracranial bone and revealed two other metastatic localizations in the lung and heart. This is the first reported case of extracranial bone metastasis from a GBM demonstrated on a whole-bone MIBI SPECT scan. In patients with malignant glioma and lower-back pain (especially prolonged pain), bone metastasis, although uncommon, does occasionally occur and its possibility should be investigated; a MIBI SPECT study may prove useful in this regard.

Correlation of 99mTc-MIBI brain spect (functional index ratios) and survival after treatment failure in malignant glioma patients.

AIM: This preliminary study was conducted to determine the association between 99mTc-SESTAMIBI (MIBI) brain SPECT and survival in malignant glioma patients after treatment failure. MATERIALS AND METHODS: Twenty-five malignant glioma patients with clinical deterioration were studied. Tomoscintigraphy was performed 15 minutes after intravenous injection of 1110 Mbq MIBI. The images were obtained from a dual head gamma camera using fan beam collimators. Transverse, coronal and sagittal views were reconstructed. Maximum uptake of MIBI in the lesion was expressed as a ratio to that in the controlateral hemisphere. RESULTS: A MIBI uptake was found in all 25 patients. This uptake was correlated to tumour recurrence proved by histological fragments and/or the rapid fatal evolution of these patients. From scintigraphic parameters, two groups of patients were noted. Group 1 (20 patients) had a significantly better survival time (8.25 months) than did Group 2 (5 patients) (2.9 months). Tumour volume predicted survival (group 1 vs group 2, p < 0.0006). A significant correlation between the tumour/background ratio and survival time for each group was observed. CONCLUSION: A correlation between functional index ratios and the time of survival of patients was noted. The functional index ratios of brain SPECT are in accordance with the potential aggressiveness of the recurrent malignant glioma.

Development of an intracerebral glioma model in whole body irradiated hairless rats.

AIMS: To study the in vivo radiosensitivity of malignant gliomas, an animal glioma model was developed using the implantation of glioma cell lines into the brain of the Hairless rat (a mutant from the Sprague-Dawley strain, characterised by its complete absence of hair). METHODS: 10(6) malignant cells were suspended in 10 microliters phosphate buffered saline (PBS) and injected at a 4 microns depth into the left frontal lobe of an anaesthetised animal through a small craniotomy hole without opening the dura mater. The glioma cell line C6 (obtained from a chemically-induced rat glioblastoma) was introduced into 11 animals, and the human glioblastoma line G5 into 12 animals. RESULTS: The tumour take was checked using histological criteria. It was poor: 0% for the G5 line and only 27.3% for the C6 line. To improve the tumour growth rate, rats were subjected to a single dose (3.5 Gray) total body irradiation, 24 hours prior to injection, causing a marked immunosuppression. 84.6% of the rats grafted with the C6 line then produced tumours. Similar results (75% tumour take) were obtained using a stereotactic inoculation of the tumour cells. CONCLUSIONS: Thanks to the contribution of whole body irradiation, an animal intracerebral glioma model was establish, which can be used for clinical and biological studies.

99mTc-MIBI uptake in a primitive leptomeningeal melanoma.

Primitive leptomeningeal melanoma is a rare and aggressive condition. The authors report on a case of primitive leptomeningeal melanoma imaged with 99mTc-Sestamibi (MIBI). There was an intense accumulation of the radiotracer in the frontal and parietal leptomeningeal regions and even after injections of gadolinium the MRI continued to reveal a cystic image of the brain. In view of the diagnosis, MRI demonstrated only limited usefulness. On the other hand, this case highlights the important role of MIBI for the imaging of malignant tumors.

[Sensitivity to etoposide of human malignant glioma cell lines. Mechanisms of action]. / Etude de la sensibilité à l'étoposide de lignées humaines de gliomes malins. Mécanismes d'action.

AIM OF THE STUDY: Etoposide, a Topoisomerase II inhibitor agent, is currently being explored as a therapeutic agent for brain tumors. The aim of this experimental study was to compare the in vitro etoposide sensitivity of human glioma cells vs human squamous cell carcinoma (SCC) cells. MATERIAL AND METHODS: Twelve human cell lines (six malignant glioma cell lines and six head and neck SCC cell lines) were used for this comparative study. A standard colony formation assay was used to assess cell survival. Since Topoisomerase II is the critical target for etoposide, it was of interest to determine Topoisomerase II activity and etoposide induced inhibition of Topoisomerase II activity for the glioma cells vs the SCC cells. RESULTS: Except for etoposide-induced inhibition of Topoisomerase II activity, no difference was found for etoposide sensitivity and Topoisomerase II activity between the both type of cells. CONCLUSION: These results suggested that the Topoisomerase II reactive agents may prove to be clinically a useful drug for patients presenting with malignant gliomas.

[Is cerebral tomoscintigraphy with 99mTc-MIBI useful in the diagnosis of local recurrence in patients with malignant gliomas?]. / La tomoscintigraphie cérébrale au 99mTc-MIBI est-elle utile au diagnostic de récidive locale chez les patients atteints de gliomes malins.

PURPOSE: 99mTc-MIBI, an alternative radiopharmaceutical for myocardial perfusion study has been proposed for use as a tumor imaging agent, including breast cancer, lung cancer, lymphomas, melanomas, and brain tumors. After routine radiation therapy, deteriorating clinical status or treatment failure may be due to either radiation changes or recurrent tumor. CT and MRI offer imperfect discrimination of tumor viability and radionecrosis. MATERIALS AND METHODS: Thirty-five malignant glioma patients with clinical deterioration were studied retrospectively. Tomoscintigraphy was performed 15 minutes after intravenous injection of 1110 Mbq 99mTc-MIBI. The images were obtained from a dual headed gamma camera using fan beam collimator. Transverse, coronal and sagittal views were reconstructed. RESULTS: A dramatic MIBI uptake was found in 31 patients. This uptake was correlated to tumor recurrence proven by histological fragments and/or the rapid, fatal evolution of these patients. Death occurred after the brain SPECT had been performed for those cases showing MIBI uptake, an average 5.48 months later. No MIBI uptake was found for these four remaining patients: their evolution can be currently considered to be a disease-free time. CONCLUSIONS: According to our results, the sensibility and specificity of 99mTcMIBI brain SPECT seems to be high. Moreover, this investigation is more accurate for discriminating tumor recurrence from radionecrosis than a CT scan or MRI.

[Complications of lumboperitoneal shunts. A retrospective study of a series of 195 patients (214 procedures)]. / Complications des dérivations lombo-péritonéales. Etude rétrospective d'une série de 195 patients (214 interventions).

BACKGROUND AND PURPOSE: We report our experience with the lumboperitoneal shunt (LPS) in 195 patients. The aim of this retrospective study was to assess and compare the rate of complications and to discuss 4 indications. MATERIAL AND METHOD: Between January 1983 and July 1994, 195 patients including 14 pediatric cases were treated with a LPS. Sex ratio was 1.24. The mean age at insertion was 59.5 years (from 6 months to 88 years) and the follow-up in this series was from 6 months to 12.5 years. The indications for a LPS were: chronic idiopathic hydrocephalus (115 cases), post-hemorrhagic hydrocephalus (37 cases), cerebrospinal fluid fistula (11 cases), post-traumatic hydrocephalus (9 cases), post-surgical hydrocephalus (8 cases), hydrocephalus of the child (6 cases), post-meningitis hydrocephalus (4 cases), benign intracranial hypertension (4 cases), post-radiotherapy hydrocephalus (1). Forty patients (20.5%) presented with at least one complication. A total of 47 complications were observed: chronic subdural effusion (8 cases), meningitis (10 cases), mechanical failures (28 cases), acquired Chiari abnormality (1 case). Mechanical complications varied with the type of shunt. CONCLUSION: Complications of LPS in adults are less frequent than is usually reported after ventricular atrial or peritoneal shunting. In adults, LPS can be used as the first valuable treatment in case of chronic communicating hydrocephalus. LPS is also valuable in the treatment of benign intracranial hypertension or recurrent CSF fistulae. Conversely, in the pediatric cases general and specific complications are frequent, so an indication for LPS must be strictly discussed.

Response to intrathecal infusions of Depocyt® in secondary diffuse leptomeningeal gliomatosis. A case report.

UNLABELLED: Secondary diffuse leptomeningeal gliomatosis, in which a glioma of the brain or spinal cord infiltrates the leptomeninges, is an uncommon clinical metastatic complication of malignant glioma, for which there is no consensus regarding treatment. In an ante mortem series in which the diagnosis of leptomeningeal gliomatosis was based on neuroradiological results, an incidence of 2% was reported. The appearance of leptomeningeal gliomatosis is a pre-terminal event. CASE REPORT: A 44 year-old woman rapidly developed intracranial pressure and impairment of cognitive function. A huge right temporal tumor was diagnosed and an incomplete resection performed. Histology showed it was a glioblastoma and a concurrent radiation therapy with temozolomide was administered. Her clinical status was subnormal. A first course of adjuvant chemotherapy, temozolomide, was administered, and her neurological status suddenly worsened in days: deterioration of cognitive function status, inability to walk, and aphasia were reported. The cerebrospinal fluid showed an elevated protein content of 2 g/l, and glucose concentration was low. Cytology of cerebrospinal fluid showed no malignant cells. Systemic nitrosourea chemotherapy (fotemustine) was administered. Intrathecal sustained-release cytarabine, Depocyt®, was initiated (an induction cycle followed by a consolidation). After a second intrathecal infusion, her clinical status significantly improved, and she was discharged to a medical unit. The duration of response was approximately 6 months. CONCLUSION: Intrathecal infusions of Depocyt®, recommended for the treatment of lymphoma neoplastic meningitis, seems to be effective in treatment of secondary diffuse leptomeningeal gliomatosis.

Concomitant bone marrow metastasis of a glioblastoma multiforme revealed at the diagnosis.

The rare occurrence of extra-neural metastases in patients having a tumour of the central nervous system (CNS) could mean that the symptoms of a metastatic lesion are confused with a second pathology. We recently treated a patient with a glioblastoma multiforme who was developing a pancytopaenia at the initial diagnosis. The frequent red cell and platelet transfusions were transitorily active. An extensive radiological investigation and a unilateral iliac bone marrow aspirate and biopsy were performed. Cells immunoreactive to glial fibrillary acidic protein were detected in a specimen obtained from the iliac bone. Post-mortem examination confirmed metastasis to extra-cranial bone and revealed other metastases in lung, mediastinal lymph node and spleen. Therefore, in patients with malignant glioma tumours, bone marrow metastasis, though not common, should be investigated when bone pain or cytopaenia occur.

Response to a phase II study of concomitant-to-sequential use of etoposide and radiation therapy in newly diagnosed malignant gliomas.

We evaluated the antitumor efficacy of and patient tolerance to a phase II study of concomitant-to-sequential use of etoposide and radiotherapy for newly diagnosed malignant gliomas. Fifty-two supratentorial malignant glioma patients were enrolled in this phase II study between May 1995 and May 1998. Standard cranial irradiation and six courses of etoposide (100 mg/m2 - xdays 1-3) were administered. The first course of etoposide was given on days 1 to 3 of radiotherapy and was resumed in the week following the end of radiotherapy. Treatment was consolidated by further courses of etoposide every 4 weeks. Fifty-one patients were assessable for toxicity, response, and survival. A complete surgical resection was only noted for 17 patients. Six patients had a confirmed complete response, and eight patients displayed a partial response. Six patients progressed within the first 3 months of starting treatment. The rate of objective response for assessable patients with residual tumor was 41.1%. Hematologic toxicity was mild; grade 3 or 4 neutropenia was noted in five patients, without sepsis. The overall median survival time (MST) was 12.5 months, and the mean survival of this population was 14.9 months. These results suggest a certain efficacy of this regimen testing a concomitant-to-sequential use of etoposide and radiotherapy for newly diagnosed malignant gliomas, and that continued evaluation of this combination is warranted, especially because this treatment is also well tolerated.

Ecological mapping: A framework for delimiting forest management units.

Ecological mapping attempts to objectively and spatially delimit and represent the natural organization and structure of the landscape. It offers nested levels of resolution, based upon a regionalization process, and provides an ecological basis for planning activities that may impact upon the environment.The essential principles of ecological mapping, as applied by the Quebec Ministry of Environment and Wildlife, are summarized. A methodological mapping approach is proposed for the determination of significant land portions for forest management using an ecological map at a scale of 1:50 000. At this scale, two nested levels of perception are expressed: 1) the topographic complex, and 2) the topographic entity. The topographic entity can be further subdivided into working units based upon operational criteria oriented to forest management. Within each nested level from topographic complex to working unit, there is a corresponding increase in the amount of detailed information available. Ecological mapping undertaken at 1:50 000 scale can provide a reliable and robust tool for planning forest management activities. In most cases, major ecological variations can be expressed and mapped at this scale; however, a greater degree of generalization must be accepted in the planning process when working at this scale rather than at larger scales.

The role of technetium-99m sestamibi single photon emission tomography in the follow-up of malignant melanoma and the detection of lymph node metastases.

In the follow-up of patients with malignant melanoma treated by surgical resection of the cutaneous tumour, it is important to achieve early detection of possible lymph node metastasis. In many cases, clinical examination alone will not be sufficient. In our study, single-photon emission tomography (SPET) with technetium-99m sestamibi (MIBI) was used in the assessment of 30 patients with previously resected malignant melanoma when the clinical examination raised the suspicion of lymph node metastasis. Using MIBI, 16 out of 17 lymph node metastases were detected and confirmed by histology. No false-positive results were obtained during this prospective study. It is concluded that MIBI scintigraphy may be useful in the early detection of lymph node metastases of malignant melanomas. If our preliminary results are confirmed, early detection of lymph node metastasis of previously resected malignant melanoma by 99mTc-MIBI scintigraphy may have a significant impact on the management of these patients.

Technetium-99m sestamibi brain single-photon emission tomography for detection of recurrent gliomas after radiation therapy.

Technetium-99m sestamibi (MIBI), an alternative radiopharmaceutical for myocardial perfusion imaging, has also been proposed for use as an imaging agent for various tumours, including breast cancer, lung cancer, lymphomas, melanomas and brain tumours. After routine radiation therapy, deteriorating clinical status or treatment failure may be due to either radiation-induced changes or recurrent tumour. Computed tomography and magnetic resonance imaging offer imperfect discrimination of tumour viability and radionecrosis. Against this background we undertook a retrospective study of 35 malignant glioma patients in whom clinical deterioration had occurred, in order to clarify the value of 99mTc-MIBI SPET in identifying tumour recurrence. SPET was performed 15 min after intravenous injection of 1110 MBq with a dual-headed gamma camera using a fan-beam collimator. Transverse, coronal and sagittal views were reconstructed. Intense MIBI uptake was found in 31 patients. This uptake was correlated with tumour recurrence as proved by histology and/or rapid, fatal evolution of these cases. The statistical analysis performed on this population of patients with MIBI uptake revealed a group of patients with a long mean survival and a group with a short mean survival. Two subgroups were found within each of these groups, according to the functional index ratio (tumour uptake/pituitary gland uptake ratio). No MIBI uptake was found in four patients who are still alive and can be considered to be disease-free. In those cases showing MIBI uptake, death occurred an average of 6.69 months following brain SPET. According to our results, the specificity and sensitivity of 99mTc-MIBI brain SPET seem to be high. Moreover, this technique is more accurate than computed tomography or magnetic resonance imaging for discriminating between tumour recurrence and radionecrosis.

Aggressive treatment with complete remission in primary diffuse leptomeningeal gliomatosis--a case report.

Primary leptomeningeal gliomatosis is rare, and the diffuse form (PLDG) is even more unusual. The following report is an example. A 17 year-old man developed a syndrome characterized by extensive basal and chronic spinal meningitis. Routine biological tests showed elevated levels of CSF proteins, and moderate mononuclear pleocytosis, with no direct evidence of neoplasia, leading to a diagnosis of chronic meningitis. A second meningeal biopsy, guided by MRI and performed in the left frontal region, led to the specific diagnosis of primary diffuse leptomeningeal gliomatosis. Treatment including ventricular and lumbar shunting, a course of cortico-spinal radiation, and three courses of an eight-drug systemic chemotherapy with intrathecal methotrexate lead to complete remission over 15 months. We believe that this is the first report of such a remission in the literature.