Asymptomatic lipomas of the medullary conus: surgical treatment versus conservative management.

OBJECT: The goal of this study was to compare long-term results of surgery with the outcomes of conservative treatment in patients with asymptomatic lipomas of the conus medullaris. METHODS: The parents of 56 consecutive children with a diagnosis of asymptomatic lipoma of the conus medullaris underwent detailed neurosurgical consultation. The pros and cons of both prophylactic surgery and conservative treatment were carefully presented. Both options were offered, and the parents were free to choose the preferred management. A total of 32 children underwent surgical treatment, and 24 were conservatively treated. Afterward, all patients entered the same protocol of serial neurological and urological follow-up at the Centro Spina Bifida. The mean follow-up periods were 9.7 years in the surgical treatment group and 10.4 years in the conservative treatment group. RESULTS: Permanent surgical morbidity was 3.1% (1 patient). During follow-up, tethered cord syndrome occurred in 9.7% of the surgically treated patients (3 of 32 patients) and in 29.1% of the conservatively managed children (7 of 24 patients). This difference did not result in statistical significance, but a clear trend in favor of surgery emerged. Young age at surgery and a cord/sac ratio < 50% appeared to be determining factors in the prevention of subsequent tethered cord syndrome. CONCLUSIONS: The small size of this series does not provide enough statistical evidence that surgical treatment can really improve the natural history of asymptomatic lipomas of the conus medullaris. Nevertheless, surgery appears at least advisable since it reduces by 75% the odds of TCS (p = 0.067), which is quite close to statistical significance.

Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma.

Medulloblastoma (MB), the most common pediatric brain tumor, is a highly malignant disease with a 5-year survival rate of only 60%. Tumor cells invade surrounding tissue and disseminate through cerebral spinal fluid, making treatment difficult. Human reovirus type 3 exploits an activated Ras pathway in tumor cells to support productive infection as an oncolytic virus. Here, we examined the ability of human reovirus to kill MB cells lines and surgical specimens in vitro and inhibit tumor growth/metastases in vivo. Most human MB cell lines tested (five of seven = 71.4%), two MB cell lines derived from spontaneously arising tumors in Patched-1(+/-) mice (two of two = 100%) and three MB primary cultures derived from surgical specimens, were susceptible to reovirus infection. Reovirus was internalized and transcribed in both susceptible and resistant cell lines. However, viral protein synthesis was restricted to cell lines with higher levels of activated Ras, suggesting that Ras plays a critical role in reovirus oncolysis in MB. Using an in vivo Daoy orthotopic animal model, we found that a single i.t. injection of reovirus dramatically prolonged survival compared with controls (160 versus 70 days, respectively; P = 0.0003). Repeating this experiment with GFP-labeled Daoy cells and multiple i.t. administrations of reovirus, we again found prolonged survival and a dramatic reduction in spinal and leptomeningeal metastases (66.7% in control injections versus 0.0% in the live virus group). These data suggest that this oncolytic virus may be a potentially effective novel therapy against human MB. Its ability to reduce metastases to the spinal cord could allow a reduction in the dose/field of total neuroaxis cerebral-spinal radiotherapy currently used to treat/prevent cerebral spinal fluid dissemination.

Role of surgery for maintaining urological function and prevention of retethering in the treatment of lipomeningomyelocele: experience recorded in 75 lipomeningomyelocele patients.

OBJECT: The authors tried to reveal some unique features of lipomeningomyelocele (LMMC), including clinical presentation, factors precipitating onset of symptoms, pathologic entities of LMMC associated with tethered cord syndrome, and surgical outcome in LMMC patients. METHODS AND RESULTS: Seventy-five patients with LMMC were enrolled in this study. Neuro-imaging and intraoperative findings allowed classification of LMMC into three types: type I, type II, and type III. The patients were divided into two groups by age: A (51 patients), from birth to 3 years, and B (24 patients), from 3 to 24 years. For prevention of retethering of the cord, a mega-dural sac rebuilding procedure was performed in 15 patients. During a mean postoperative follow-up period of 4 years, the surgical outcome was satisfactory in terms of improved pain and motor weakness, but disappointing with reference to the resolution of bowel and bladder dysfunction. Among these 75 patients with LMMC, preoperative deficits were improved after surgery in 29 (39%), remained stable in 28 (37%), changed slightly in 13(17%), and worsened in 5 (7%). Patients in group A achieved better outcomes than those in group B. Depending on the type of lesion, patients with types I and II LMMC have better outcomes than those with type III LMMC: Finally, retethering of the cord with neurological deterioration occurred in 4 (5.3%) of the 75 patients, but no retethering was found in the 15 patients who were recently treated with a mega-dural sac rebuilding procedure. CONCLUSION: Our data continue to support the opinion that early diagnosis and optimal surgery are still essential for the treatment of patients with LMMC, since there is a high likelihood of residual neurological functions that can be preserved. Based on our surgical experience of untethering and decompression of lipomas, a mega-dural sac repair is useful to prevent retethering of the cord.

Study of the post-natal effects of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. II. Influence of low-molecular-weight polypeptide factors from the thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex and brain white substance.

The influence of the polypeptide factors extracted from thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex or brain white substance on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day of gestation. The polypeptide factors were given to the offspring as a series of s.c. injections, at a dose of 0.5 mg/rat/day, starting at one or 2.5 months of age and continuing throughout the whole of post-natal life. ENU induced tumors of the brain, spinal cord, peripheral nerves and kidneys in 94-98% of the offspring exposed to the carcinogen, with an average number of 2.3-2.6 tumors per rat, and an average survival time of 294 days. Post-natal thymus factor or pineal gland factor administration was followed by an increase in mean lifespan of approximately 2 months and a significant decrease (P < 0.05) in the total tumor number per tumor-bearing rat, as well as the incidence and multiplicity of spinal cord tumors. Pineal gland factor also decreased the incidence of peripheral nerve and kidney tumors and their number per tumor-bearing rat. Brain cortex factor and brain white substance factor treatment was followed by a decrease in total tumor multiplicity of 1.2- to 3.3-fold, and a decrease in incidence of brain tumors of 10 to 33% per rat in comparison to the controls. Brain cortex factor also decreased the total tumor incidence. At the same time, brain white substance factor administration increased the incidence of peripheral nerve tumors and decreased the mean lifespan. Both bone marrow factor and anterior hypothalamus factor did not have any modifying effects on any of the ENU-induced tumors and mean lifespan. Thus, our results show the possibility of attenuation of transplacental ENU-induced carcinogenesis with post-natal administration of some polypeptide substances.

Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid.

The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.

Excessive spinal cord toxicity from intensive central nervous system-directed therapies.

BACKGROUND: Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty-three cases of myelopathy that occurred in patients who received intensive CNS-directed therapy were evaluated to identify the determinants of this severe CNS toxicity. METHODS: Nine cases treated by the authors and 14 collected from the literature are discussed. Twelve had Burkitt's leukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 years). The dose intensity of CNS-directed therapies, including intrathecal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), systemic high dose (HD) MTX, systemic HD ara-C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses and cumulative total drug or irradiation doses over elapsed treatment durations. RESULTS: Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patient received only intrathecal ara-C before toxicity occurred; other received intrathecal ara-C and varying combinations of intrathecal MTX, HD ara-C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy-proven cord necrosis; 3 were ventilator-dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely. CONCLUSION: Both highly intensive, short CNS treatment sequences and lower intensity, long term cumulative treatments may result in this rare but severe myelopathy. The cause is multifactorial, with systemic chemotherapy, intrathecal chemotherapy, and radiation therapy contributing to toxicity. Multiple intrathecal ara-C and/or MTX doses given at frequent (daily) intervals should be avoided. Concurrent intrathecal ara-C and systemic HD ara-C also appear to be especially toxic. Intrathecal hydrocortisone given with intrathecal ara-C does not protect against myelopathy. Multiple, frequently spaced courses of CNS-directed therapies must be avoided, especially in patients who have received prior CNS radiation.

Are dermoid and epidermoid tumors preventable complications of myelomeningocele repair?

Dermoids and epidermoids found at reoperation for tethered cord following myelomeningocele repair have been attributed to inadequate excision of cutaneous elements and 'implantation' in the repair site. This study reviews the pathological findings in excised placodes from fresh myelomeningoceles and specimens from tethered cord release and concludes that hamartomatous lesions are a common feature of the myelodysplastic sequence.

More is better! Update of Dana-Farber Cancer Institute/Children's Hospital childhood acute lymphoblastic leukemia trials.

Between 1973 and 1985, 553 children with childhood acute lymphoblastic leukemia were treated on Dana-Farber Cancer Institute/Children's Hospital, Boston, protocols. The programs featured intensive remission induction therapy, CNS treatment with cranial irradiation and intrathecal drugs, doxorubicin intensification with or without asparaginase, and 2-21/2 years of conventional continuation therapy. There has been progressive improvement in event-free survival for each successive program. Leukemia control concerns pertain to: 1. late relapses (at greater than 5 years) in "standard-risk" patients; 2. an increased incidence of CNS relapses, especially in "standard-risk" patients, as preventative treatment is reduced in intensity; and 3. bone marrow relapses in "high-risk"patients. Comparisons of patients receiving the more intensive arm of each protocol with those receiving the less intensive arm support the hypothesis that more intensive chemotherapy results in improved event-free survival.

Central nervous system relapse prevention in 1165 standard-risk children with acute lymphoblastic leukemia in five BFM trials.

In treatment of childhood ALL, prevention of CNS relapse by cranial irradiation is followed by considerable long-term sequelae. In the three ALL-BFM (Berlin-Frankfurt-Münster) trials 70, 76, and 79, employing radiotherapy (8.5 Gy craniospinal, 18 or 24 Gy cranial irradiation) in all arms, the incidence of CNS relapses (isolated and combined) in standard-risk patients (SR, 60% of all children) was consistently less than 6%. A risk factor (RF) calculated from absolute blast number, liver, and spleen size at diagnosis was used to stratify patients in the subsequent trials ALL-BFM 81 and 83. In ALL-BFM 81, SR patients (RF less than 1.2) were randomized to receive 18 Gy cranial irradiation or intermediate-dose i.v. methotrexate (ID-MTX) (4 x 0.5 g/m2). In ALL-BFM 83, the SR group was further subdivided into group SR low (SR-L, RF less than 0.8) and group SR high (SR-H, RF 0.8 - less than 1.2). SR-L patients received no irradiation, and were tested by randomization for the effectiveness of an intensive reinduction regimen (protocol III). SR-H patients were randomized for 12 or 18 Gy. The results were as follows: In patients of both trials with RF less than 0.8, radiotherapy could be replaced by ID-MTX plus protocol III. Without protocol III, relapses increased from 15.7% to 31.7%. Concomitantly, the fraction of relapses with CNS involvement increased from 26.7% to 36.4%. However, SR patients with RF between 0.8 and 1.2 could not be protected by reinduction alone (isolated/overall CNS relapse rate with irradiation, 4%/5%; without irradiation, 11%/22%). Dosages of 12 and 18 Gy were found to be equally protective.

Minimal neuropsychological sequelae following prophylactic treatment of the central nervous system in adult leukaemia and lymphoma.

The potential long-term toxicity of central nervous system prophylaxis (CNS-P) in adult acute lymphoblastic leukaemia (ALL, n = 17) and non-Hodgkin's lymphoma (NHL, n = 7) was investigated in a multidisciplinary study. At least 4 years had elapsed from CNS-P (mean 11.5 years) for all patients. Neurological history and physical examination were unremarkable; minor signs were commoner in older patients (P less than 0.02). Psychometry yielded normal results, but individual verbal IQ generally exceeded performance IQ, with a trend to more marked differences in younger adults (P = 0.06). EEG was scored and differed significantly from that of controls, with a tendency to more marked (but still minor) abnormalities in younger patients (P = 0.06). Brainstem auditory evoked potentials demonstrated significant but generally minor abnormality in 24% of patients. CT brain scan revealed widening of cerebral hemisphere sulci to greater than 3 mm in 38% of patients; cerebral atrophy was commoner in the older group (P less than 0.02) and those with neurological signs (P less than 0.02). MRI brain scans were normal in all patients tested. Thus, following standard CNS-P for ALL at this hospital, there is a 5% primary CNS relapse rate, and only minimal, mainly subclinical, long-term neuropsychological toxicity.

Central nervous system relapses after bone marrow transplantation for acute lymphoblastic leukemia in remission.

This study defines the risk of central nervous system (CNS) relapse in patients undergoing bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL) in remission, with no posttransplant prophylactic CNS therapy. Ninety-two consecutive patients in complete remission received BMT for ALL (n = 82) or high-grade non-Hodgkin's lymphoma with poor prognostic factors at diagnosis (n = 10). Sixty-six patients received allogeneic BMT (Allo-BMT) and 26 patients, without an identical sibling, underwent autologous BMT (Auto-BMT). Fifteen patients had CNS involvement at diagnosis and underwent BMT in first remission. Eight patients experienced CNS relapse after BMT, corresponding to a probability of 11% at 3 years. Apart from a history of prior CNS involvement, no patient characteristic evaluated statistically influenced CNS relapse after BMT. The probability of CNS relapse was 5.5% for the 70 patients without history of CNS involvement and 27.5% for the 22 patients with prior CNS involvement. However, subgroup analysis showed that the increased risk of CNS relapse is mainly observed in Auto-BMT patients with history of prior CNS involvement, particularly in patients undergoing BMT in first remission (three of five Auto-BMT versus one of ten Allo-BMT). Taking into account the multiple factors which influence the occurrence and the treatment of CNS leukemia, the results on this retrospective study suggests that (1) for patients without CNS involvement at diagnosis and for whom BMT is performed in first remission, cranial irradiation before BMT and posttransplant prophylactic CNS therapy can be omitted because of the low probability of CNS relapse after BMT (3.4%), when total-body irradiation (TBI) is included in the conditioning regimen; and (2) the difference observed between Allo-BMT and Auto-BMT patients with previous CNS involvement and undergoing BMT in first remission could indicate that graft-versus-host leukemia acts even in the CNS in Allo-BMT patients.

[An intensification therapy of adults acute leukemia].

Between January 1980 and March 1983, a study was conducted on the effects of intensification therapy in 20 adult acute leukemia patients who had achieved complete remission with induction therapy. Intensification therapy consisted of cyclic administration of six combination therapies given at gradually longer intervals, using daunorubicin, cytosine arabinoside, 6-mercaptopurine and prednisolone (DCMP), cyclocytidine (DCyMP), vincristine (DCVP), behenoyl-ara-c (BHAC-DMP), aclacinomycin (BHAC-AMP) and (ACM-MP). Six combinations were given sequentially at one-month intervals, at 2-, 3-, 4-, 5- and eventually 6-month intervals, until 5-year survival. The median remission duration was 38 months for AML, and 17 months for ALL. The median survival was 66 months for AML, and 37 months for ALL. The five year survival rate was 50%. Nine of the 20 patients are still alive. Methotrexate and prednisolone were administered intrathecally for prophylaxis of CNS leukemia on Day 4 for each intensification therapy. There was no CNS leukemia. This intensification protocol was shown to be effective in improving the prognosis of adults acute leukemia.

Radiotherapy of primary intracranial germinomas: the case against routine craniospinal irradiation.

A retrospective study was performed on all patients with biopsy-proven intracranial germinomas and unbiopsied suprasellar or pineal region tumors treated during the past 30 years in the Department of Radiation Oncology, University of California, San Francisco. A total of 33 patients were treated: 13 with biopsy-proven germinomas, and 20 others who were unbiopsied. All patients were treated with megavoltage equipment; total dose varied between 40-55 Gy. Only two patients were treated with prophylactic spinal irradiation. No patient received initial or adjuvant chemotherapy. Follow-up times for biopsy-proven patients ranged from 0.5 to 16.7 years with a median 5.3 years. No biopsy-proven patient had a recurrence of the tumor or died; thus, actuarial relapse-free and determinate survivals at 5 years were 100%. Although only one patient in this group received prophylactic spinal irradiation, no patient failed in the spinal axis. The 20 unbiopsied patients had follow-up times ranging from 0.1 to 27.5 years with a median of 5.5 years. Six unbiopsied patients died: two from recurrent disease at the primary site, one from distant peritoneal metastases, two from complications of treatment, and one from intercurrent disease. For this group, actuarial relapse-free survival at 5 years was 72%; the corresponding determinate survival was 73%. Nineteen unbiopsied patients were treated without craniospinal irradiation. Only one developed spinal metastases. The results from this and other series indicate that the risk of spinal metastases from intracranial germinoma is too low to warrant routine prophylactic spinal irradiation. However, patients with gross tumor spill causing contamination of the CSF, malignant CSF cytology, or documented subependymal or subarachnoid metastases presumably are at higher risk for leptomeningeal failure. Craniospinal irradiation is recommended for these patients.