Purpose: Although cytologic examination of CSF is the primary method for the evaluation of response to therapy for leptomeningeal metastases (LMMs), the procedure's sensitivity decreases throughout the course of protracted therapy. We studied whether this response could be monitored more accurately through the detection of numerical chromosomal aberrations by interphase cytogenetics, using fluorescence in situ hybridization (FISH), Patients and Methods: Seven patients treated for LMMs and with a known numerical aberration for chromosome; 1 in their pretreatment CSF were included in this study, Up to 16 consecutive CSF samples were analyzed by means of the fluorescence in situ hybridization (FISH) technique for cells with aberrant chromosome 1 content, The results of routine cytology and FISH analyses were compared and were correlated with each patient's neurologic status. Results: Routine cytology detected malignancies in only 24 of the 76 samples, all of which were classified as chromosomally abnormal by FISH (except for two samples that could not be evaluated). Moreover, FISH demonstrated aneusomic cells in 32 additional samples, which could therefore be classified as malignant, The FISH results correlated better with patient neurologic status in that more malignant cells were detected in the CSF of neurologically deteriorating patients. Conclusion: Using FISH in addition to performing routine cytologic examination of CSF leer to a more accurate evaluation of response to treatment in patients treated for LMMs. J Clin Oncol 18:2053-2058.