The clinical findings and response to treatment of leptomeningeal metastases from solid tumors are analyzed in 90 patients treated at Memorial Sloan-Kettering Cancer Center during the period from January 1975 to February 1980. Patients included those who had either typical clinical findings of leptomeningeal tumor or conclusive laboratory evidence supporting the diagnosis. Carcinoma of the breast (46 patients), lung (23 patients) and melanoma (11 patients) were the common primary tumors. Symptoms of leptomeningeal metastasis occurred as the presenting sign in five patients and as late as ten years after the primary tumor was diagnosed in four other patients. Most patients had active systemic disease outside the nervous system. Signs and symptoms could be classified as involving either the brain, cranial nerves, or spinal nerves. Most patients had either symptoms or signs in more than one area at the time the diagnosis was established. The initial spinal fluid examination was abnormal in all but three patients, but only 49 had cytologic evidence of leptomeningeal metastases. Repeated spinal fluid assay yielded a positive cytology in 82 patients. Measurement of biochemical markers, including beta-glucuronidase, carcinoembryonic antigen and lactic dehydrogenase, assisted in the diagnosis. Approximately half of the patients treated by intraventricular methotrexate experienced improvement or stabilization of neurological symptoms for more than a month; median survival was 5.8 months after diagnosis, with a range of 1--29 months. In 18 patients disease was limited to the nervous system, and median survival was eight months, with four patients surviving one year and two patients for two years. Side effects of therapy were, for the most part, minor. We conclude that vigorous treatment of leptomeningeal metastases with intrathecal chemotherapeutic agents improves symptomatology in some patients, and at times prolongs survival.

Diagnosis and treatment of leptomeningeal metastases from solid tumors: Experience with 90 patients

The increasing problem of multidrug-resistant Gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of Bacillus polymyxa in 1947; only two of them, polymyxin B and E (colistin), have been used in clinical practice. Their effectiveness in the treatment of infections due to susceptible Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been generally questioned. However, their use was abandoned, except in patients with cystic fibrosis, because of concerns related to toxicity. We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005). It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature. New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature.

/pdf/toxicity-of-polymyxins-a-systematic-review-of-the-evidence-4n53bm3ncg.pdf

Toxicity of polymyxins: a systematic review of the evidence from old and recent studies

In a randomized, double-blind, placebo-controlled study to evaluate the efficacy of trimethoprim–sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia, we studied 160 patie...

Successful Chemoprophylaxis for Pneumocystis carinii Pneumonitis

Leptomeningeal invasion by systemic cancer was diagnosed clinically or pathologically in 50 patients over four years. All had neurological symptoms referable to tumor seeding the meninges. Clinical diagnosis was suggested by the simultaneous occurrence of symptoms or signs in more than one area of the neuraxis. Neurological signs were much more prominent than symptoms. Clinical diagnosis was confirmed by the presence of malignant cells in the cerebrospinal fluid (CSF), multiple examinations of CSF sometimes being necessary. The disease was usually inexorably progressive, but in some instances responded to radiation and intrathecal chemotherapy. At autopsy there were leptomeningeal thickening, occasionally tumor nodules along the cauda equina and, in some patients, hydrocephalus. Sometimes, despite prominent clinical signs, there were no gross pathologic abnormalities. Microscopic changes were multifocal rather than diffuse, making extensive sampling of leptomeninges necessary to establish the pathologic diagnosis.

Infiltration of the leptomeninges by systemic cancer. A clinical and pathologic study.

This article argues the case for the creation of a new group classification of intraocular retinoblastoma. The current Reese-Ellsworth group classification has not been updated since it was published 35 years ago. The proposed classification is based on the natural history of intraocular retinoblastoma and on the risk of loss of the eye following primary therapy.

Intraocular retinoblastoma: the case for a new group classification.

A histopathologic study was performed to evaluate the distribution and extension of intracranial leukemic infiltrates and their relationship to other morphological disturbances of the central nervous system (CNS) in childhood acute lymphocytic leukemia Of 126 brains examined, 70 had arachnoid leukemia at the time of autopsy The earliest evidence of leukemia was seen in the walls of superficial arachnoid veins With more advanced arachnoid leukemia, the disease was seen to extend into the deep arachnoid surrounding blood vessels as they course through the brain The arachnoid leukemia followed a predictable expanding pattern to eventual invasion of brain parenchyma with destruction of the pia-glial membrane Leukemic infiltrate at the capillary-neural tissue interface was present only following destruction of pia-glial membrane secondary to deep arachnoid leukemia Arachnoid fibrosis and certain brain parenchymatous lesions were found in association with arachnoid leukemia The brain lesions included gliosis, necrosis, cerebral hemorrhage, and nonhemorrhagic degenerative encephalopathy This study demonstrates that CNS leukemia is primarily an arachnoid disease Disturbances of brain parenchyma apparently result from leukemic extension through pia-glial membrane or interference with local perfusion due to constriction of blood vessels by perivascular arachnoid leukemia

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197303%2931%3A3%3C520%3A%3AAID-CNCR2820310306%3E3.0.CO%3B2-2

The central nervous system in childhood leukemia: I. The arachnoid

Fatalities During Remission of Childhood Leukemia

The present study was undertaken to define criteria for classification of chronic myelocytic leukemia in children and adolescents From April, 1963 through July, 1971, 18 patients were available for study Evaluation of the clinical, laboratory, and histopathologic features demonstrates three distinct subgroups: adult, juvenile, and familial chronic myelocytic leukemia Parameters of most value in this distinction are the level of the white blood cell count, presence of thrombocytopenia or thrombocytosis, the bone marrow myeloid to erythroid ratio, and the presence or absence of well-defined malpighian corpuscles in the spleen One patient with acute lymphocytic leukemia in remission manifested some unique features and may represent a fourth form of chronic myelocytic leukemia, resulting from previous chemotherapy or irradiation The use of chemotherapy has not significantly prolonged survival in our patients Two patients with familial chronic myelocytic leukemia are surviving in remission 9 years following splenectomy

https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%28197409%2934%3A3%3C670%3A%3AAID-CNCR2820340325%3E3.0.CO%3B2-7

Classification of chronic myelocytic leukemia in children.

Forty-two consecutive patients with retinoblastoma were evaluated by a new staging system and combined modality therapy instituted according to stage. Nineteen patients had bilateral tumors and 23 had unilateral tumors. The staging system was effective in identifying subpopulations of patients and successfully predicted those at greater risk of recurrence or death. Thirty-nine of 42 patients survive (Median survival time, 42 months). Two of 4 children with tumor extension beyond the eye died while 37 of 38 children with tumor presumed confined to the eye survive. Toxicity of the chemotherapy was mild. Radiation therapy of intraocular tumor was associated with cataract formation but most children had satisfactory vision after extraction and the use of corrective lenses. Ophthalmologic findings did not always correlate with histologic extent of tumor and both should be used in planning and evaluating treatment. Recommendations are made on the role of chemotherapy and the need to reduce the morbidity of treatment.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819800301%2945%3A5%3C851%3A%3AAID-CNCR2820450505%3E3.0.CO%3B2-P

Stage-related combined modality treatment of retinoblastoma. Results of a prospective study.

Pneumocystis carinii pneumonia was diagnosed in 19 children with cancer. The diagnosis was made in 14 children by pulmonary needle aspiration and demonstration of the organism by methenamine silver nitrate stain. Two children had tension pneumothorax and one had postaspiration hemoptysis following needle aspiration, but there was no mortality from the procedure. Seventeen children were treated with pentamidine isethionate; nine recovered. Toxicity to pentamidine consisted of elevated blood urea nitrogen levels and hypoglycemia .

Warren W. Johnson

Papers

The central nervous system in childhood leukemia: I. The arachnoid

Fatalities During Remission of Childhood Leukemia

Classification of chronic myelocytic leukemia in children.

Stage-related combined modality treatment of retinoblastoma. Results of a prospective study.

Pneumocystic carinii pneumonia in children with cancer. Diagnosis and treatment.