Central Nervous System Chemotherapy Research Articles

Hearing Loss After Radiation and Chemotherapy for Central Nervous System and Head and Neck Tumors in Children

Hearing loss (HL) is a serious secondary effect of treatment for head and neck (H&N) and central nervous system (CNS) tumors in children. Radiation and platinum chemotherapy independently increase the risk of HL; however, combined modality treatment is routinely used and the effect of chemoradiation on HL risk is not well-studied. Using chemotherapy and cochlear radiation (RT) doses, we created a model that predicts for HL, including a nomogram that can be used in the clinical setting to calculate the risk of clinically-significant HL.In this single institution retrospective study, 171 patients with H&N or CNS tumors were treated with radiation, with or without chemotherapy and had longitudinal (≥2) audiological evaluation. SIOP-Boston (SIOP) and Chang grades were assigned to 2,420 hearing assessments of 342 ears; analyses using SIOP grades are presented here. For the nomogram, SIOP grade ≥3 was considered clinically-significant HL (requiring hearing aids). An Andersen-Gill model for recurrent events was used to obtain inverse intensity weights to account for factors explaining the number of assessments. Multivariable weighted ordinal logistic regression was fitted to evaluate the effect of clinicopathologic features on HL. Clustered robust standard errors were calculated to account for intra-patient correlation.Patients underwent a median of 6 (range 2-23) assessments over a median of 3.1 years from diagnosis to last audiogram (range 0.1-15.2 years). Cisplatin was given to 63% of patients and 34% received carboplatin. The mean cochlear doses on the right and left were 36.8 Gy (standard deviation [SD] 16.5) and 37.0 Gy (SD 16.2), respectively. Multivariable regression revealed that mean cochlear dose (odds ratio [OR] 1.04 per Gy, 95% confidence interval [CI] 1.02-1.05, P < 0.001), time since RT (OR 1.2 per year, 95% CI 1.2-1.3, P < 0.001), cisplatin use (OR 5.33, 95% CI 2.9-9.9, P < 0.001), and carboplatin use (OR 2.3, 95% CI 1.27-4.17, P = 0.006) were associated with increasing SIOP grade of HL; age at RT, hydrocephalus, surgery, amifostine, and laterality were not correlated with HL. There was no synergistic effect of RT and cisplatin (interaction term, P = 0.4) or RT and carboplatin (interaction term, P = 0.9). Cumulative incidence of high-frequency HL (> 4 kHz) was > 50% at 5 years post-RT in those who received mean dose > 20 Gy to the cochlea, while incidence of HL across all frequencies continued to increase beyond 5 years post-RT.RT and chemotherapy have an additive, not synergistic, effect on HL risk. Mean cochlear radiation dose, time since radiation, and platinum chemotherapy use were associated with HL. This modelling can guide survivorship care by multidisciplinary pediatric oncology teams with respect to audiology follow-up in an effort to that ensure suitable educational accommodations and assistive devices are in place.

41: Hearing Loss After Radiation and Chemotherapy for Central Nervous System and Head and Neck Tumours in Children

41: Hearing Loss After Radiation and Chemotherapy for Central Nervous System and Head and Neck Tumours in Children

Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1–3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study

BackgroundThis is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methodsALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). ResultsAltogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9–12.2] with alectinib and 1.4 months (95% CI: 1.3–1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08–0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17–0.59); median PFS was 7.1 months (95% CI: 6.3–10.8) with alectinib and 1.6 months (95% CI: 1.3–4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks). ConclusionAlectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registrationClinicalTrials.gov NCT02604342; Roche study MO29750

P-91 - Nerve axonal extension enhancement using plasma activated medium generated through nonthermal atmospheric pressure plasma bubbling

In this study, we developed an axonal-extension enhancement bioreactor by using plasma activated medium (PAM) generated through a non-thermal atmospheric pressure plasma (NTAPP) bubbling system. Until now, many regeneration methods to treat damaged the central nervous system (CNS) have been proposed and examined, such as transplant of nerve cells. However, there still remain problems and it is strongly required to establish an efficacious regeneration method of the CNS. We focus on PAM, which has applied to wound treatment and the restraint of the brain edema. Usage of PAM produced by NTAPP has recently led to a research explosion in plasma treatment. We fabricated a cell culture system to enhance the axonal-extension for CNS regeneration. First, we made the plasma bubbling system to produce reactive species by NTAPP in the medium. We measured amount of the reactive species in PAM, H2O2, NO2 and NO3. Second, we confirmed the effect of PAM on PC12 by measuring the axonal extension length in 72 h culture after the PAM stimulation. Optimum condition to promote PC12 axonal-extension was found using the response surface method, which was the NTAPP bubbling time 18 s and the PAM stimulation time 3.9 h. We found that PAM exhibits selective cell activation property for chemotherapy of CNS.

High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA.

Acute promyelocytic leukemia (APL) is classically characterized by chromosomal translocation (15;17), resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-trans retinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17) which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission.

A multicentre study of primary breast diffuse large B‐cell lymphoma in the rituximab era

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.

Central Nervous System Involvement in Primary Nasal Lymphoma.

Abstract 2940Poster Board II-916 Introduction.Nasal NK/T cell lymphoma (NNK/TCL) is a tumor with a low prevalence but is more frequent in Asia and South America. There is no standard treatment for these patients, although radiotherapy is usually recommended. Few reports describe the frequency of central nervous system (CNS) involvement in this type of lymphoma and, in consequence, little is known about the benefit of carrying out screening procedures such as cerebrospinal fluid (CSF) cytology or image studies, nor it is known if prophylactic radiotherapy to the CNS or intrathecal chemotherapy improves the outcome of these patients. Patients and methods.We reviewed the clinical files of 63 patients of the National Cancer Institute in Mexico City with a diagnosis of angiocentric, centrofacial or NNK/TCL between january 1996 and december 2008. We excluded those patients who had a doubtful histopathological diagnosis, who were not completely studied or who did not received treatment in our institution. We collected the following variables: age, gender, histopathological diagnosis, localization of the tumor, clinical stage, symptoms at presentation, IPI score, CNS involvement, CSF cytology, image studies, LDH level, type of treatment and global response to treatment. Results.We found a total of 48 patients with a diagnosis of primary nasal lymphoma who met the inclusion and exclusion criteria. The mean age was 45.6 (range 16-81) years. The male to female ratio was 2:1. The most frequent localization and histopathological type was the nasal T cell lymphoma (58.3% and 43.8%, respectively). Thirty one percent of the tumors were classified as diffuse large cell and small cell lymphomas due to the lack of immunopathology at the time of diagnosis. Most of the patients were at stage I or II (81.3%) of the disease and had a low or low intermediate IPI score (85.4%). Of the 48 patients 89.6% recieved combined treatment with chemotherapy (CHOP) and radiotherapy, the other 10.4% recieved treatment with radiotherapy alone. Thirty nine point six percent and 23% of the patients had complete and partial response to the treatment, respectively. The remaining patients had either stable or progressive disease. Only 10.9% of the patients complained of neurologic symptoms and 85.4% had a spinal tap done. Nine patients had central nervous system infiltration (18.8%), 55.5% presented with neurological symptoms. Seven of the nine patients with CNS infiltration were diagnosed with a positive CSF cytology (77.8%). Two patients had a negative CSF cytology but had a positive MRI (22.2%). None of these patients had a positive CT scan for CNS involvement. Eight of the nine patients were treated with combined chemo and radiotherapy and 1 patient was treated with radiotherapy alone. Three patients achieved complete response (33.3%). Although there is a great difference in complete response between the patients with and without CNS involvement (6.25% vs 54.17% respectively, p= 0.07), this difference was not statistically significant. This can be due to the small number of patients with CNS involvement. There was no significant difference in the IPI score, LDH levels, stage of the disease or age between the groups. Conclusions.CNS involvement is present in a considerable proportion of patients with primary nasal lymphoma. Based on these data we think CSF cytology should be done in all patients. The results also suggest that the CT scan is not sensitive enough to detect CNS involvement. The treatment of these patients is an open question because there is virtually no data in the literature regarding therapy for this complication. Disclosures:No relevant conflicts of interest to declare.

Knockdown of CCR7 or Its Ligands Causes a Loss of Central Nervous System Involvement in Notch1 Induced T-ALL

Intensive chemotherapy helps achieve remission in the vast majority of acute lymphoblastic leukemia (ALL) patients. A subset of these cases, T-cell ALL (T-ALL), fare significantly worse, presenting with more severe disease, lower remission rates and a greater likelihood of relapse, particularly within the central nervous system (CNS). All modern treatment protocols involve intensive prophylactic CNS chemotherapy and cranial irradiation. The dramatic increase in overall survival is thought to be worth the significant long term side effects associated with CNS treatment such as secondary tumors, neurocognitive deficits and neuroendocrine disorders. Despite its significance, very little is known about the basic mechanisms of leukemic lymphocyte infiltration into the CNS. Over 50% of T-ALL patients have activating mutations in the Notch1 protein. According to our gene expression profiling results, Notch1 activation leads to the induction of CCR7, a chemokine receptor known to play a role in normal lymphocyte homing in extramedullary tissues and CNS. To study CNS infiltration, we generated two murine models expressing activated Notch1 (N1-IC), a bone marrow transplant (WT/WTN1) and a conditional knockin. Both developed an aggressive T-ALL with immature T-cells infiltrating into secondary lymphoid tissues, but more importantly, they had CNS involvement. Numerous malignant appearing CD3 positive cells were found in the leptomeningeal space of the brain in both mouse models. When we transplanted CCR7 knock out bone marrow cells expressing N1-IC, the recipient mice (WT/CCR7KON1) developed an aggressive T-ALL as before. However, a close examination of the brain failed to show any leukemic infiltration in the host mice. In agreement, wild-type N1-IC positive cells transplanted into plt mice (plt/ WTN1) lacking the CCR7 ligands, CCL19 and CCL21, induced T-cell leukemia, but again, these cells failed to infiltrate into the CNS. In addition, WT/CCR7KON1 and plt/WTN1 mice survived longer than WT/WTN1 mice (61 and 71 vs 47 days, p<0.0001). Using real time PCR and FACS, we quantified the levels of CCR7 in 7 human T-ALL cell lines and found that all but one expressed CCR7 at varying levels. The highest expressing, CEM, and non-expressing, DND41, cell lines were transplanted into alymphoid Rag2−/−gc−/− hosts and rapid leukemic infiltration of both lines was monitored by bioluminescent imaging. We found dramatic infiltration of CEM cells, but not DND41 cells into the CNS of the recipients. Moreover, the overexpression of CCR7 in the non-expressing DND41 cells caused them to acquire the ability to infiltrate into the CNS of the hosts. These results strongly implicate CCR7 as a major mediator of CNS involvement in T-cell leukemia and would suggest that targeting the Notch1 or CCR7 pathways could provide an effective CNS therapy with reduced long term morbidity.

Secondary lymphomas of the central nervous system: risk, prophylaxis and treatment

The recurrence of non-Hodgkin lymphoma (NHL) in the central nervous system (CNS) is rapidly fatal in most cases. Highly aggressive lymphomas, such as lymphoblastic and Burkitt lymphomas, carry a high risk of CNS relapse. CNS relapse in intermediately aggressive subtypes, such as diffuse large B-cell lymphoma, is uncommon, but not rare. The risk of CNS relapse in indolent lymphomas is low. Prognostic markers of CNS relapse include elevated serum lactate dehydrogenase levels, the presence of B symptoms, and extranodal involvement at more than one site. Most centers give prophylactic CNS chemotherapy to patients considered at high risk of CNS recurrence. However, definitions of risk factors vary, and there is a lack of consensus regarding prophylaxis indications. More research is needed to define which patients might benefit from CNS prophylaxis at initial treatment and to find the optimal regimen for prophylaxis. A variety of treatments have been used to treat CNS relapse, but current regimens have had little success in extending survival after CNS relapse. Although long-term survival has been reported in a minority of patients with isolated CNS recurrence after treatment with methotrexate, more effective regimens are needed if survival times after relapse are to be prolonged.

A history of St Jude Children's Research Hospital.

A history of St Jude Children's Research Hospital.

A 3-year follow-up of the intellectual and academic functioning of children receiving central nervous system prophylactic chemotherapy for leukemia.

This prospective study compared the intellectual and academic functioning of two groups of children treated for cancer over the 3 years after their diagnosis. One group consisted of children who received central nervous system (CNS) prophylactic chemotherapy, and the other group consisted of children with cancer who did not receive CNS chemotherapy. The results suggest that the children who received CNS chemotherapy experienced more adverse effects from their treatment in the area of academic functioning than the children who did not receive CNS chemotherapy. Although there were no differences in the academic functioning of the two groups of children immediately after their diagnosis, 3 years postdiagnosis, the CNS-treated children scored more poorly on academic tests of reading, spelling, and arithmetic than the non-CNS-treated children. The results suggest that CNS chemotherapy prophylaxis may impede academic achievement.

Clinicopathological study on multiple spongy necrosis of the pontine base

Eleven cases with multiple spongy necrosis of the pontine base are reported and their clinicopathologic characteristics discussed. Seven of the cases occurred in men and four in women; age ranged from 42 to 90 years old. Eight patients had various types of cancer as background disease. Three patients received central nervous system (CNS) radiotherapy and six received chemotherapy. No consistent clinical factor (e.g., malignancy, radiotherapy, chemotherapy, severe immunosuppressive state, specific laboratory data and infection) could be found among the cases. Neuropathological findings were characterized as multiple patchy spongy areas of the pontine base with loss of myelin and axons. There were few reactive gliosis or inflammatory changes. Many axonal swellings and a small number of macrophages were scattered in the lesions. Neurons and glial cells adjacent to these lesions were not affected, and calcification was not found. Almost all of the lesions existed in the transverse fibers of the basis pontis. In the literature, malignancy or toxicity due to CNS radiotherapy or chemotherapy was suspected to be the causative factor of these lesions. In our 11 cases, however, the lesions were also found in patients who had not received radiotherapy or chemotherapy. In contrast, the neuropathological findings of the lesions in our patients were similar in each case. Electronmicroscopically, the myelin sheath was seen to be swollen in the early stage of the lesion. Excluding malignancy, radiotherapy and chemotherapy, there may be an additional unknown causative factor. Metabolic disturbances or toxic agents for myelin were suspected as causative factors.

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and off-therapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and offtherapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.

Hemiparesis and ischemic changes of the white matter after intrathecal therapy for children with acute lymphocytic leukemia

Three children with acute lymphocytic leukemia (ALL) developed delayed-onset transient hemiparesis and facial palsy after intrathecal (IT) administration of methotrexate (MTX) alone or as part of triple intrathecal chemotherapy for central nervous system (CNS) prophylaxis. The hemiparesis developed 10 to 14 days after IT therapy. Two of three children also experienced transient, profound expressive dysarthria. These episodes occurred during maintenance treatment after multiple IT administrations and without previous CNS toxicity. Two of three children received intermediate-dose MTX, 1 g/m2, not less than 5 weeks before events. These patients had not received cranial irradiation and had no evidence of CNS leukemia before or after these episodes. Ischemic changes on computerized tomographic scan or magnetic resonance imaging studies were documented in all three cases. Such changes are unusual manifestations of neurotoxicity in children after intrathecal therapy.

Delayed central nervous system (cns) radiation in childhood cns acute lymphoblastic leukemia results of a pilot trial

With the introduction of effective prophylactic central nervous system (CNS) therapy in childhood acute lymphoblastic leukemia (ALL), the incidence of CNS relapse has been significantly reduced. Nonetheless, there is a continuing need for effective CNS therapy for the 5% to 10% of children who escape prophylaxis and in whom active CNS disease develops. In July 1985, a pilot study was initiated whereby the consolidative CNS treatment, given in the form of craniospinal axis radiation, was delayed and administered after delivery of a prolonged course of intensive systemic and CNS chemotherapy. Ten leukemic patients with CNS relapse were treated according to this pilot study. One patient did not respond to pre-CNS consolidative therapy and died at 2 months with progressive disease. The remaining nine patients have completed the craniospinal axis radiation. Five patients are off all therapy and remain in remission at a median time of 38 months (range, 31 to 46 months). Two patients are near completion of therapy and are disease-free at 22 and 24 months. Testicular relapse occurred in two patients at 14 and 29 months. CNS chemotherapy, as used in this trial, appears to have allowed for a delay in the administration of the consolidative craniospinal radiation without negatively affecting the CNS remission rate or duration. In turn, this delay has allowed for the uncompromised delivery of intensive multiagent systemic chemotherapy, as well as the separation of those patients destined to early systemic relapse from those who will achieve a sustained complete remission. In both cases, a reduction in the need for multiple courses of potentially toxic CNS therapy as a result of CNS reseeding after radiation is anticipated.

Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases.

Between 1981 and 1987, L3 ALL was diagnosed in 18 adult patients, with a median age of 26 (range 16-66) and M/F ratio of 3.5. At diagnosis, 11 patients had splenomegaly, 11 had enlarged lymph nodes, and 15 patients had central nervous system (CNS) disease, of whom 10 had mental neuropathy. Anaemia was found in 13 patients, thrombocytopenia in 17 and the median white cell count was 25.5 x 10(9)/I (range 8.6-89). Surface immunoglobulins were found on the blasts of every patient. Seventeen patients had a t(8;14) (q24;q32) translocation. One had an apparently normal karyotype, but only six mitoses could be examined. During the period of the study different treatment protocols, which comprised increasingly intensive systemic and CNS chemotherapy, were used. Six patients died less than 3 weeks after admission, two of them of acute tumour lysis syndrome and two of CNS haemorrhage. In two other patients, rapid progression of CNS leukaemia was seen in spite of the treatment. Ten patients (56%) achieved complete remission (CR). Two were allografted and two were autografted early in CR. Four patients relapsed, three of the four relapses involving the CNS. A median actuarial disease-free survival was not attained, and a plateau was achieved at 57% after 7 months, with no later relapse. Median actuarial survival of the 18 patients was only 6 months, but a plateau was obtained at 31% after 11 months. Prognosis seemed related to the intensity of chemotherapy: recent patients, treated more aggressively, achieved CR more often than earlier patients, treated with less intensive protocols, although the number of patients was too small to draw any firm conclusion. The initial white cell count was also a prognostic factor, as none of the patients with more than 30 x 10(9)/I leucocytes achieved CR. Our results suggest that the outcome of adult L3 ALL can be improved, as in children, by increased intensity of treatment, particularly with regard to CNS leukaemia therapy. Early deaths are still frequent, however, but their incidence can probably be reduced by better prevention and early management of the acute tumour lysis syndrome.

Central nervous system metastases from non-hodgkin's lymphoma: Treatment and prophylaxis

Central nervous system (CNS) lymphoma was identified in 96 patients treated for non-Hodgkin's lymphoma at Memorial Sloan-Kettering Cancer Center between 1975 and 1981. During the same period, 68 other patients with non-Hodgkin's lymphoma but no CNS disease received prophylactic CNS chemotherapy. In the 156 total patients, the lymphomas were diffuse in 96 percent, and 67 percent were stage IV at diagnosis. CNS involvement was present at initial diagnosis in 27 percent, at relapse in 26 percent, and during the course of progressive systemic disease in 47 percent. CNS involvement was asymptomatic in 10 percent. Cytologic study of the cerebrospinal fluid was the most sensitive and specific laboratory test, but often (22 percent) more than one lumbar puncture was required to identify malignant cells. CNS lymphoma was treated in 85 patients, 46 by intracerebroventricular cannulae; 81 percent improved. Although median survival after the diagnosis of CNS disease was four months, there were seven longterm disease-free survivors and the CNS disease contributed to death in only 14 percent. In 52 percent of treated patients, there was no CNS lymphoma at autopsy. CNS prophylaxis was with methotrexate or cytosine arabinoside, usually by lumbar puncture; an intraventricular cannula was used in seven patients. Although this group of high-risk patients with non-Hodgkin's lymphoma had a high systemic response rate and the median projected survival was greater than five years, CNS lymphoma developed in eight patients (12 percent). In five, CNS lymphoma occurred as an apparently isolated relapse site. The role of CNS chemoprophylaxis in high-risk patients with non-Hodgkin's lymphoma is still uncertain.

BRAIN DAMAGE IN RELATION TO IRRADIATION AND CHEMOTHERAPY OF CENTRAL NERVOUS SYSTEM

BRAIN DAMAGE IN RELATION TO IRRADIATION AND CHEMOTHERAPY OF CENTRAL NERVOUS SYSTEM