Cerebrospinal Fluid Tumor Markers Research Articles

Lymphocytic Infundibuloneurohypophysitis Diagnosis Owing to Positive Anti-rabphilin-3A Antibody Test Result in an 8-year-old Boy with Early-onset Central Diabetes İnsipidus.

Childhood-onset lymphocytic infundibuloneurohypophysitis (LINH) has rarely been reported. Pathological evaluation via pituitary biopsy is necessary for a definitive diagnosis of LINH. However, pituitary biopsy is a highly invasive procedure. Recently, anti-rabphilin-3A antibody (RPH3A-Ab) has been reported as a promising diagnostic marker for LINH in adults; however, there are few such reports in the pediatric population. We report the case of an 8-year-old boy with central diabetes insipidus (CDI) who was clinically diagnosed with LINH based on RPH3A-Ab positivity. He was diagnosed with CDI using a water deprivation test combined with desmopressin administration. Serum and cerebrospinal fluid tumor markers were negative, and T1-weighted magnetic resonance imaging (MRI) revealed the absence of high signal intensity in the posterior pituitary gland and an enlarged pituitary stalk. Anterior pituitary function tests revealed no abnormalities. No pituitary biopsy was performed because of its invasive nature, and desmopressin treatment was initiated. Three months after CDI onset, the patient tested positive for RPH3A-Ab. MRI performed 9 months after CDI onset revealed amelioration of the pituitary stalk enlargement, and the clinical course corroborated our diagnosis of LINH. RPH3A-Ab may be useful as an early diagnostic tool for LINH in the pediatric population.

Germ cell tumors of the central nervous system: A brief review and site-specific considerations.

Germ cell tumors of the central nervous system (GCT-CNS) arise predominantly in midline locations of the CNS and affect young patients in their first to third decades of life. Involvement of the CNS is thought to be a sequelae of residual primordial germ cells with incomplete embryologic migration. Clinically, GCT-CNS present with symptoms of ventricular obstruction or compression of affected brain structures. Histologically, these tumors are analogous to their gonadal and extra-gonadal counterparts. Diagnosis relies heavily on morphology and immunohistochemical findings, and can be complicated by limited tumor sampling. There is currently only a limited role for molecular studies. Treatment of these lesions is made difficult by their involvement of deep and vital brain structures and accurate pathologic diagnosis is essential for appropriate therapy. Diagnosis should involve review of the clinical history, imaging studies, and assessment of serum and cerebrospinal fluid tumor markers. Current therapeutic strategies involving radiation therapy with or without chemotherapy are quite effective, in spite of the locational difficulties that often prevent gross total resection.

Clinical Outcomes and Diagnostic Consistency of Serum and CSF Tumor Markers in Pediatric Intracranial Germ Cell Tumors in Thailand: A Multicenter Study.

The diagnostic and treatment outcomes of intracranial germ cell tumors (ICGCTs) among low and middle income countries are limited. A total of 63 ICGCTs patients with a median age of 11.6 years were studied. A 30 (47.6%) and 33 (52.4%) patients were classified as pure germinomas and nongerminomatous germ cell tumors (NGGCTs), respectively. The concordances between serum and cerebrospinal fluid (CSF) alpha-fetoprotein (84.3%) and beta-human chorionic gonadotropin (68.4%) were addressed. The 5-year overall survival (OS) and event-free survival (EFS) rates of pure germinomas versus NGGCTs were 83.9 versus 69.1% and 74.6 versus 57.7%, respectively. Patients undergoing radiation had higher 5-year OS and EFS than those without radiation treatment with P < .001. Chemotherapy combined with radiation is a cornerstone treatment to achieve outcomes. Adverse prognostic factors included age <8 years, surgery, and nonradiation treatment. Either serum or CSF tumor markers were adequately required as a diagnostic test among patients with ICGCTs.

Central Nervous System Tumors in Children.

Central Nervous System Tumors in Children.

1265P Combined detection of tumor markers and ctDNA in cerebrospinal fluid: A good strategy in diagnosis of leptomeningeal metastases

The main purpose is to select a more effective method for the diagnosis of leptomeningeal metastases (LM) by comparing various detection methods. The secondary purpose is to identify specific mutation patterns of genes in cerebrospinal fluid (CSF) with LM and to explore the value of CSF tumor markers and circulating tumor DNA (ctDNA) testing in guiding clinical treatment.

Diagnostic Value of Locally Produced Tumor Markers and Blood Brain Barrier Integrity in Lung Cancer Patients with Leptomeningeal Metastasis

背景与目的脑脊液(cerebrospinal fluid, CSF)中肿瘤标志物(tumor markers, TM)对软脑膜转移(leptomeningeal metastasis, LM)具有诊断意义，但因TM在CSF中浓度很大程度上取决于血清水平以及血脑屏障(blood brain barrier, BBB)的状态，因此，CSF中TM诊断LM的价值常常被忽视。明确鞘内TM合成、BBB的完整性可为LM临床诊断提供帮助。因此，本研究从BBB完整性和鞘内TM合成角度出发，进一步探讨CSF中TM对肺癌LM诊断的临床价值。方法收集2016年12月-2020年3月于南京鼓楼医院治疗的肺癌伴LM的患者25例，另选本院同期治疗的57例非恶性神经系统疾病(nonmalignant neurological diseases, NMNDs)患者为对照组，分析比较BBB完整性和鞘内TM合成的差异，评估LM组CSF中TM检出阳性率与鞘内TM合成的相关性，并动态监测1例LM患者脑室内化疗过程中CSF细胞学、BBB完整性以及鞘内TM合成的变化。结果LM患者中94%存在BBB破坏。所有LM患者CSF中至少存在一项TM的鞘内合成，其中1例患者，首次CSF细胞学阴性，但是存在鞘内TM合成，重复腰穿CSF细胞学阳性确诊为LM。LM组CSF中TM检出阳性率与TM鞘内合成不一致。对照组中仅3.5%(2/57)NMNDs患者有BBB破坏，且未在鞘内合成TM，差异有统计学意义(P < 0.05)。另外，动态监测CSF细胞学、BBB完整性和CSF鞘内合成的TM与疗效评价一致，且鞘内TM合成的变化早于细胞学。结论BBB的评估及鞘内TM合成的分析可为LM患者提供一个早期辅助诊断的工具，动态监测TM可能有助于疗效评估，值得临床推广应用。

GERM-02. MANAGEMENT STRATEGY FOR CHEMO-REFRACTORY, PROGRESSIVE PEDIATRIC IMMATURE TERATOMA

BackgroundLocalized NGGCT, a heterogeneous entity, treated with chemo-radiotherapy harbors an overall survival of around 93% based. Here, we present a case of a child whose immature teratoma progressed on chemotherapy, while tumor markers remain within normal range. Salvage therapy for progressive immature teratoma is variable, and can include surgery, chemotherapy and/or craniospinal radiation. Case: 10 year old boy with precocious puberty presented to the local Emergency room with tonic-clonic seizures. Imaging showed a localized pineal mass, with mixed cystic and solid components. Biopsy results were diagnostic for mixed germ cell tumor with components of immature teratoma. Prior to the start of chemotherapy, serum and cerebrospinal fluid (CSF) tumor markers showed slight elevation of both alpha feto- protein (AFP) and beta-human chorionic gonadotropin hormone (β-HCG). The patient underwent two cycles of chemotherapy per ACNS1123, stratum 1, with normalization of tumor markers. Unfortunately, near the end of Cycle 2 of chemotherapy, patient presented with clinical signs of herniation, and was noted to have significant progression of pineal mass on imaging. Tumor was gross totally resected, with pathology conclusive for only immature teratoma. Pre- and post-operative tumor markers remained normal. Proton-beam craniospinal radiation was then administered. Patient is now almost 6 months off therapy, with unremarkable serum and CSF tumor markers, as well as serial imaging that remains negative for disease, with neurological development appropriate for age. ConclusionThis case highlights the unusual nature of progression of an immature teratoma with no elevation of tumor markers while on chemotherapy. While salvage chemotherapy, in the form of a metronomic regimen or high-dose consolidative regimen, can be considered, these do present quite a bit of short-term and long-term toxicity to the growing child. Craniospinal irradiation followed by close monitoring is a reasonable alternative, with less short-term toxicity, for an entity that is radio-sensitive.

Auxiliary Diagnostic Value of Tumor Markers in the Cerebrospinal Fluid and Blood for Leptomeningeal Metastasis from Non-small Cell Lung Cancer

背景与目的软脑膜转移（leptomeningeal metastasis, LM）是指恶性肿瘤细胞浸润软脑膜，并在脑脊液（cerebrospinal fluid, CSF）中播散，预后极差，是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者致死的重要原因之一，因此早期的诊断和及时的治疗具有重要意义，CSF细胞学是LM诊断的金标准，但常常伴随着检测敏感性低、无法评估疗效等问题。本文旨在探讨血清及CSF中肿瘤标志物（tumor markers, TM）在NSCLC伴LM患者诊治的临床价值。方法选取NSCLC伴LM患者19例，另选同期27例神经系统良性肿瘤（nonmalignant neurological diseases, NMNDs）患者作为对照组。观察比较两组患者血清和CSF中癌胚抗原（carbohydrate antigen, CEA）、糖类抗原125（carbohydrate antigen-125, CA125）、细胞角蛋白19片断抗原（cytokeratin 19 fragments, CYFRA21-1）和神经元烯醇化酶（neurone specific enolase, NSE）检测水平和检出阳性率，比较不同组TM的敏感性和特异性，并分析血清与CSF中TM检出情况相关性，最后动态监测2例LM患者血清和CSF中TM水平，分别评估颅外和颅内治疗疗效。结果LM组CSF和血清中TM水平和检出阳性率均高于对照组（P < 0.05），同时LM组CSF中CEA、CYFRA21-1、NSE水平高于血清，差异有统计学意义（P < 0.05）。CSF中TM检出阳性率与血清差异不具有统计学意义（P > 0.05）。CSF中CYFRA21-1敏感性最高（88.2%），CEA特异性最好（92.3%），联合指标中CEA或NSE任一项超过临界值则敏感性和阴性预测值为100%，特异性为74.1%。CYFRA21-1和NSE同时超过临界值时特异性和阳性预测值为100%，敏感性为78.9%。亚组分析显示，CSF细胞学阳性人群TM检出阳性率超过有磁共振成像（magnetic resonance imaging, MRI）异常的人群，但不具有统计学差异（P > 0.05）。LM组血清与CSF中TM检出阳性率不一致。另外，脑室中CSF与腰穿中CSF具有相同的生化性质，动态监测血清和CSF中TM浓度，可分别评估颅外和颅内病灶的疗效。结论血清和CSF中TM为NSCLC伴LM患者增加了一个早期辅助诊断指标，动态监测可评估治疗疗效，值得临床推广应用。

New Frontiers in Diagnosis and Therapy of Circulating Tumor Markers in Cerebrospinal Fluid In Vitro and In Vivo.

One of the greatest challenges in neuro-oncology is diagnosis and therapy (theranostics) of leptomeningeal metastasis (LM), brain metastasis (BM) and brain tumors (BT), which are associated with poor prognosis in patients. Retrospective analyses suggest that cerebrospinal fluid (CSF) is one of the promising diagnostic targets because CSF passes through central nervous system, harvests tumor-related markers from brain tissue and, then, delivers them into peripheral parts of the human body where CSF can be sampled using minimally invasive and routine clinical procedure. However, limited sensitivity of the established clinical diagnostic cytology in vitro and MRI in vivo together with minimal therapeutic options do not provide patient care at early, potentially treatable, stages of LM, BM and BT. Novel technologies are in demand. This review outlines the advantages, limitations and clinical utility of emerging liquid biopsy in vitro and photoacoustic flow cytometry (PAFC) in vivo for assessment of CSF markers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA), proteins, exosomes and emboli. The integration of in vitro and in vivo methods, PAFC-guided theranostics of single CTCs and targeted drug delivery are discussed as future perspectives.

Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

Diagnostic value of circulating tumor cells in cerebrospinal fluid.

ObjectiveTo assess circulating tumor cells in cerebrospinal fluid as a diagnostic approach to identify meningeal metastasis in patients with non-small cell lung cancer by using tumor marker immunostaining–fluorescence in situ hybridization (TM-iFISH).MethodsIn 5 non-small cell lung cancer patients who were confirmed to have developed meningeal metastasis by cerebrospinal fluid cytology, 20 ml of cerebrospinal fluid was obtained through lumbar puncture, from which 7.5 ml was utilized for TM-iFISH to identify and quantitate circulating tumor cells, 10ml for cerebrospinal fluid cytology, and 2.5ml for detection of cerebrospinal fluid tumor markers.ResultsTM-iFISH examination identified 18 to 1,823 circulating tumor cells per 7.5ml cerebrospinal fluid. In contrast, cytology assessment revealed tumor cells in only 2 cases. The expression levels of cerebrospinal fluid tumor markers were all increased in all 5 patients when compared with their respective serum levels. Contrast-enhanced MRI scans demonstrated presence of meningeal metastasis in all 5 cases.ConclusionTM-iFISH may become a novel cerebrospinal fluid-based diagnostic strategy to identify circulating tumor cells and meningeal metastasis as compared to traditional diagnostic approaches, although its superior sensitivity and specificity needs to be confirmed through additional studies with a larger sample size.

The concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid can be useful indicators for diagnosis of meningeal carcinomatosis of lung cancer

We aimed to investigate the concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid (CSF) and to explore their clinical value in the meningeal carcinomatosis (MC) of lung cancer. So that, sensitive and specificity of CSF examination can be improved in the initial diagnosis of MC. A total of 35 lung cancer patients and 35 patients with benign brain tumor in the same period enrolled in this study. The concentrations of tumor markers CEA, CYFRA 21-1 and NSE in CSF and peripheral blood were examined. The concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum and CSF were obviously higher than that of benign disease group. In MC patients, the concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum were significant lower than that in CSF. The maximum of Youden's index was identified as the cutoff value of indicator of MC in three tumor markers in CSF which were CEA > 4.7 μg/L, NSE > 14.6 μg/L and CYFRA21-1 > 5.5 μg/L respectively. Based on the cutoff values, the CEA had the highest sensitivity while the CYFRA21-1 had the highest specificitiy. Three tumor markers in the CSF had higher positive rate than those in blood serum. We combined the levels of CEA, NSE and CYFRA21-1 in CSF to diagnosis of MC. Positive of CEA or CYFRA21-1 had the greatest sensitivity of 100% while the specificity of 91.4%; the positive of both CEA and CYFRA21-1 had the highest specificity of 100% while the sensitivity of 74.3%. Both positive predictive value and negative predictive value were 100% when combination positive were confirmed when the all three markers were positive. The combination of CEA and CYFRA21-1 can be recommended in early screening of meningeal carcinoma. Especially, for the patient who was difficult to be diagnosed by CSF histology and MRI, it will be a useful auxiliary marker in diagnosis of MC. The combination of CEA, NSE and CYFRA21-1 can be an effective clinically confirmation and exclusively diagnose indictor of MC.

Optimal cut-off values for tumor markers in cerebrospinal fluid with ROC curve analysis

To select optimal cut-off values of tumor markers in cerebrospinal fluid for the diagnosis of meningeal carcinomatosis, the concentrations of CEA, CA125, CA153, CA199, CA724, CYFRA21-1, AFP and NSE were determined by means of double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) in 21 MC patients, 25 cancer patients without leptomeningeal disease (group one) and 45 meningitis patients (group two) using the Roche E170 modular immunoassay analyzer. Optimal cut-off values were selected based on a receiver-operating characteristic curve. The results showed that CA125 and CEA in CSF were optimal diagnostic indices distinguishing between MC patients and cancer patients without leptomeningeal disease. Cut-off values for CA125 and CEA were 1.715 microliters and 0.274 microgram/l, respectively. In addition, CEA in CSF was the optimal diagnostic index distinguishing MC patients from meningitis patients. The cut-off value for CEA was 4.522 microgram/l.

The determination of medical reference values for tumor markers in cerebrospinal fluid

To determine medical reference values for tumor markers in cerebrospinal fluid. Concentrations of CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, AFP, NSE, SCC and HCG were determined by means of double-antibody sandwich ELISA in 110 patients excluding primary tumors and meningeal carcinomatosis using Roche E170 modular immunoassay analyzer. The determined medical reference values for tumor biomarkers in cerebrospinal fluid were as follows: CEA<0.573 microg/L, CA125<2.591 U/ml, CA15-3<2.045 U/ml, CA19-9<2.272 U/ml, CA72-4<1.252 U/ml, CYFRA21-1<1.44 ng/ml, AFP<0.968 microg/L, NSE<57.666 ng/ml, SCC<0.5 microg/L, HCG<0.769 U/L. There was no correlation between any tumor marker and age (P>0.05). Concentrations of tumor markers were not affected by gender (P>0.05). Medical reference values for CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, AFP, NSE, SCC and HCG in cerebrospinal fluid were first determined.

Optimal cut-off values for tumor markers in cerebrospinal fluid with ROC curve analysis

Optimal cut-off values for tumor markers in cerebrospinal fluid with ROC curve analysis

Intrathecal synthesis of tumor markers is a highly sensitive test in the diagnosis of leptomeningeal metastasis from solid cancers

Identification of neoplastic cells in cerebrospinal fluid (CSF) by cytological analysis is the key diagnostic feature of leptomeningeal metastasis (LM). Because of the lack of sensitivity of this test, considerable efforts have been made to identify alternative diagnostic markers. Data from the literature suggest that measurement of tumor markers (TM) in CSF may be helpful for improving the diagnosis. We analyzed the concentrations of the TM carcinoembryonic antigen (CEA), CA15.3, CA125 and CA19.9 in both CSF and serum from 18 patients with neoplastic meningitis diagnosed by CSF cytology. We also performed these same measurements in 50 patients affected by other neurological diseases (OND) in order to evaluate putative intrathecal synthesis. In addition, CSF and serum concentrations of the proangiogenic factor VEGF (vascular endothelial growth factor) were evaluated. All LM patients showed intrathecal synthesis for at least one TM. In one patient, a negative CSF cytology after treatment paralleled normalization of tumor marker synthesis. None of the OND patients displayed intrathecal TM synthesis. The VEGF Index (CSF/serum VEGF relative to CSF/serum albumin ratios) was significantly higher in LM patients compared with the control group. However, significant overlap between LM patients and values seen in those with OND was observed. Evaluation of intrathecal TM synthesis is a specific, sensitive, reliable, and reproducible diagnostic tool, and is useful to support diagnosis of carcinomatous meningitis.

Neuroendoscopic Management of a Solitary Pineal Region Tumor. Case Report of an Adenocarcinoma Metastasis

The present case describes a two-step endoscopic management of hydrocephalus and diagnosis of a single pineal region metastasis arising from a gastric adenocarcinoma. A 62-year-old man presenting with signs of subacute obstructive hydrocephalus from a pineal region mass had at first been treated with an endoscopic third ventriculostomy. As cerebrospinal fluid tumor markers (alpha-fetoprotein, beta-human chorionic gonadotropin) were negative, an endoscopic biopsy of the pineal region tumor was performed through a more anterior frontal burr hole. Pathology showed an adenocarcinoma and primary tumor work-up revealed an unsuspected gastric tumor, the pathology of which matched with the intracranial metastasis. The present report emphasizes the role of neuroendoscopy in pineal region tumors and reports a rare case of a solitary gastric adenocarcinoma metastasis in this location.

Correlation of endoscopic biopsy with tumor marker status in primary intracranial germ cell tumors

We retrospectively analyzed the results of eight patients who underwent endoscopic biopsy of a newly diagnosed primary intracranial germ cell tumor (GCT), and correlated tumor pathology with serum and cerebrospinal fluid (CSF) tumor markers and treatment outcome in order to determine the reliability of GCT sampling by this method. A biopsy diagnosis was made in each patient, and the tumor histology correlated with tumor marker measurements for all six patients diagnosed with germinoma and for one with a yolk sac tumor. One biopsy revealed only mature teratoma, an inconclusive result since the patient's serum and CSF tumor markers were elevated. No morbidity was experienced as a result of the operative procedure. Five of six patients diagnosed with germinoma responded completely to radiation therapy and are without evidence of disease, while one suffered a likely germinoma recurrence and was subsequently successfully retreated. We conclude that endoscopic biopsy of marker-negative germ cell tumors is a safe, reliable method of establishing a diagnosis of germinoma. However, endoscopic biopsy may fail to yield an accurate diagnosis in cases of malignant non-germinomatous tumor. We would thus conclude that when primary germ cell tumor is considered, endoscopic tumor biopsy is recommended in patients with a negative biochemical analysis, but not suggested for patients presenting with elevated tumor markers.

Isolated Leptomeningeal Carcinomatosis (Carcinomatous Meningitis) after Taxane-Induced Major Remission in Patients with Advanced Breast Cancer

Objectives: To identify the incidence of leptomeningeal carcinomatosis (LMC), as the first site of systemic progression, in breast cancer patients after having obtained a major response (CR or near CR) to first-line taxane-based chemotherapy and compare these findings in retrospect with a matched-pair group of historical control patients from our database treated with nontaxane regimens. Patients and Methods: Patients with histologically proven breast cancer having either metastatic disease or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155), and compared, as regards the incidence of LMC, to a matched-pair retrospective group of 155 patients treated with nontaxane regimens in our unit. Results: Seven patients with a median age of 54 years (range 40–70) developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range 2–18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while 1 patient received i.t. methotrexate and RT to the lumbar spine. Two patients responded to treatment for LMC, while 2 achieved stable disease and 3 progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range 1–17+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, p = 0.019). Seven out of 86 responders (8.13%) in the taxane group versus 1 out of 72 responders (1.4%) in the non-taxane-treated group developed LMC as the first sign of progression after a major response to first-line chemotherapy (p < 0.1). Conclusions: LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased, but not significantly so, when compared retrospectively to non-taxane-treated patients. Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multi-institutional trials is warranted and identification of potential prognostic factors might help to identify patients requiring appropriate prophylactic therapy.

Leptomeningeal carcinomatosis after major remission to taxane-based front-line therapy in patients with advanced breast cancer.

To determine the incidence of leptomeningeal carcinomatosis (LMC), as the first manifestation of systemic progression, in breast cancer patients after obtaining a major response (complete response, CR or >80% partial response, PR) to first-line taxane-based chemotherapy treated between 1996 and 2000 in our Medical Oncology Unit. Patients with histologically proven breast cancer having either metastatic disease, or high-risk locoregional disease that were entered into treatment protocols with first-line taxane (paclitaxel or docetaxel) plus anthracyclines or mitoxantrone combinations and developed LMC as the first evidence of progression after major response (CR or >80% PR) were analyzed in the present study (n = 155). Seven patients with a median age of 54 (range: 40-70) years developed LMC as their first evidence of progression after taxane-based regimens with a median interval of 6 months (range: 2-18) from start of treatment to diagnosis of LMC. Five patients received intrathecal (i.t.) methotrexate treatment and whole brain radiotherapy (RT), while one patient received i.t. methotrexate and RT to lumbar spine. Two patients responded to treatment for LMC, while two achieved stable disease and three progressed. Two patients had elevated cerebrospinal fluid tumor markers (more than serum marker levels) that proved useful in monitoring response to treatment. Median survival after LMC was 3.6 months (range: 1-31+) and correlated positively to the interval from the initiation of taxane-based therapy to LMC (r = 0.84, P = 0.019). Seven out of 86 responders (8.1%; 95% confidence interval, 2.4-13.9) developed LMC as the first sign of progression after a major response to first-line chemotherapy. LMC after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared in retrospect to non-taxane-treated patients. Prospective evaluation of the incidence of LMC after taxane versus non-taxane-based treatment from large randomized multiinstitutional trials is warranted and identification of potential prognostic factors might help identify patients requiring appropriate prophylactic therapy.