Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases.

PURPOSE: We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. METHODS AND MATERIALS: We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other). RESULTS: With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). CONCLUSIONS: In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.

Radiation effects on human leptomeningeal cell response to cerebrospinal fluid and PDGF-BB.

PURPOSE: The pathogenesis of meningiomas remains largely unknown, but there is evidence that exposure radiation increases the risk of meningiomas. We therefore evaluated whether radiation stimulates human leptomeningeal cell proliferation and activates growth regulatory pathways. MATERIALS AND METHODS: Cultures from six human primary leptomeningeal cells were established and irradiated with 0.5, 1 or 2 Gy. Cells were subsequently maintained for approximately 3-6 months and then treated with the mitogen, platlet-derived growth factor-BB (PDGF-BB), or human cerebrospinal fluid (CSF) obtained from patients with no neurological disease. Cell proliferation was evaluated by CyQUANT, and changes in the regulatory activation levels of signal transducer and activator of transcription (STAT3), mitogen-activated protein kinase kinase 1/2 (MEK1/2), mitogen activated protein kinase (MAPK 44/42), Akt, and mammalian target of rapamycin (mTOR) were assessed by Western blot. RESULTS: At both 3 and 6 months post-irradiation, CSF stimulated cell proliferation in all six leptomeningeal cultures. At 3 months, radiation was associated with an increase in STAT3, MEK 1/2, p44/42 MAPK and variable Akt activation, and at 6 months, STAT3, p44/42 MAPK, variable Akt and mTOR activation was observed in response to PDGF-BB and CSF. CONCLUSIONS: Irradiation of fetal leptomeningeal cells was associated with loss of heterozygosity of 1p36 and persistent sensitization leading to upregulation in growth pathways in response to PDGF and CSF. These findings suggest a mechanistic basis for radiation's role in meningioma initiation.

A comparison of optic nerve dosimetry in craniospinal radiotherapy planned and treated with conventional and intensity modulated techniques.

BACKGROUND AND PURPOSE: Some CNS tumours present leptomeningeal dissemination. Craniospinal radiotherapy is complex and recurrences may occur at sites of target volume underdosage. IMRT, being highly conformal to the target, could theoretically underdose the optic nerves if they are not specifically targeted leading to optic nerve recurrences. We analyzed optic nerve dosimetry when they are not specifically targeted. MATERIALS AND METHODS: We designed 3D-conformal and tomotherapy plans for our last five patients treated to the craniospinal axis, not including the optic nerves in the target volume. We analyzed the dose delivered to the optic nerves, to the anterior and posterior half of the optic nerves, and to a theoretical optic nerve-PTV. RESULTS: The dose delivered to the optic nerves was similar for both plans in all patients (V95% close to 100%) except one in whom tomotherapy considerably underdosed the anterior optic nerves. The dose to the optic nerve-PTV was lower with tomotherapy in all patients. CONCLUSION: Despite not intentionally targeting the optic nerves, the dose to the optic nerves with IMRT was similar to 3D-conformal plans in most cases but left no margin for setup error. In individual cases the anterior half of the optic nerves could be significantly underdosed.

Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment.

Leptomeningeal involvement in patients with CLL is relatively rare and the prognosis is usually considered to be poor. The authors reviewed all CLL patients treated in a tertiary referral center to assess the incidence and outcome of leptomeningeal involvement (LI) in CLL. They found an incidence of 1-2% of LI. Most of the patients with LI had a longterm survival, despite failure to clear the cerebrospinal fluid from tumor cells.

Developmental vascular anomalies of the spinal cord as a background for post radiation necrotizing myelopathy.

Radiation myelopathy is a well-known complication of irradiation therapy of neoplasms in the vicinity of the spinal cord. In the case presented myelopathy developed after therapeutic Co 60 irradiation of lingual carcinoma on the background of spinal vasculo-dysraphic malformation. The pathogenetic mechanism of necrotic myelopathy in this case is discussed.

The behaviour of meningeal cells following glial cell transplantation into chemically-induced areas of demyelination in the CNS.

Following transplantation of cultures of CNS glia containing leptomeningeal cells into ethidium bromide-induced demyelinating lesions, meningeal cells adopt either compacted or diffuse arrangements. The compacted arrangements involved no interactions with other cellular components of the remyelinating environment, and were particularly prominent following transplantation of cultures containing a high proportion of fibronectin-positive meningeal cells. The diffuse arrangements involved interactions with astrocytes, Schwann cells and endothelial cells, and contributed to a fragmented appearance of the lesion. Such observations indicate that meningeal cell contamination should be avoided when attempts are being made to repopulate glial-deficient lesions in the CNS by transplanting central glial cells, since their effect is to partition the glial environment.

[MR imaging of the meninges: normal and pathological findings]. / MR-Darstellung der Meningen: Normale und pathologische Befunde.

The MR appearance of normal and pathological meninges was studied in 23 patients. Amongst twelve normals, T1-weighted images demonstrated the meninges as slightly hyperintense density structures (compared with CSF) which increased in signal intensity somewhat after the administration of gadolinium-DTPA. On T2-weighted images, the subarachnoid space and meninges were isointense. In eleven patients with inflammatory disease or tumourous infiltration of the meninges, abnormal findings were evident in the unenhanced images as well as after administration of gadolinium-DTPA. Compared with CT, MR proved greatly superior in the diagnosis of meningeal abnormalities.

Intrathecal therapy with 198Au-colloid for meningosis prophylaxis.

Telecobalt irradiation in combination with intrathecal (IT) methotrexate has been replaced by IT 198Au-colloid and methotrexate for meningosis prophylaxis in leukemia. Seventy-seven children received 56-200 MBq 198Au-colloid. The distribution was measured with a scintillation camera having a data processing facility. The radiopharmaceutical is adsorbed at the surface of the spaces with cerebrospinal fluid (CSF) 10-20 h after application. The normal retention of the administered radioactivity in the intracranial subarachnoid space (ISS) and in the spinal subarachnoid space (SSS) were 52 +/- 10% and 26 +/- 9%, respectively. An impairment of the normal distribution was observed after IT methotrexate and also postinjection CSF leakage. The calculated radiation absorbed doses in the cerebral and spinal meninges at a depth of 0.01 cm, i.e. the thickness of the pia, were 45 +/- 17 mGy and 189 +/- 91 mGy, respectively, for 1 MBq administered 198Au-colloid. The dosimetry shows that an effective radiation absorbed dose of 18 Gy can be delivered to the cerebral meninges by the application of 400 MBq 198Au-colloid.

Postirradiation syndrome and eeg findings in children with acute lymphoblastic leukaemia.

Out of 12 children with acute lymphoblastic leukaemia treated with craniospinal irradiation during primary haematologic remission, 8 developed a postirradiation syndrome characterized by fever and tiredness. The symptoms lasted 1-2 weeks and subsided spontaneously. Longitudinal EEG studies revealed no acute disturbances during the irradiation therapy but in all cases studied, moderate to severe diffuse general slowing developed during the postirradiation syndrome. Complete normalization of the EEG occurred in all children at follow-up. It is concluded that the described EEG abnormalities constitute an integral part of the postirradiation syndrome.

The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: XII. Results of examination of the calvarium, brain, and meninges.

Tissue reactions were found around the monitor (dosimeter) assemblies that had been implanted beneath the scalp of the five pocket mice that flew on Apollo XVII. Mitosis in the dentate gyrus of the hippocampal formation was considerably reduced in comparison with that in control animals. Otherwise the brain tissue as well as the menings in the flight animals appeared unaltered. Since the animals were exposed primarily to high Z-high energy (HZE) cosmic ray particles at the lower end of the high LET spectrum, the lack of changes in the brain cannot be taken as evidence that the brain will suffer no damage from the heavier HZE particles on prolonged manned missions.

Meningeal localisation of acute leukaemias.

A preventive chemoradiotherapeutic treatment of the central nervous system has to be started as soon as a complete remission is obtained in acute lymphoid leukemia. Any meningeal localisation is barely sensitive to treatment and reduces the long term chances of survival. The best treatment, according to our study, consists in the intrathecal administration of methotrexate and cytosine arabinoside followed by an irradiation of the central nervous system at a dose of 1,500 rads. The present trials have attempted to reduce the number of intrathecal injections, to increase the irradiation dose to 2,400 rads, and to restrict it to the skull.