Analysis of intrapatient heterogeneity of circulating tumor cells at the single-cell level in the cerebrospinal fluid of a patient with metastatic gastric cancer.

BACKGROUND: The aims of this study were to detect circulating tumor cells (CTCs) at the single-cell level in cerebrospinal fluid (CSF) and to identify intrapatient heterogeneity of CTCs in a patient with gastric cancer (GC) with leptomeningeal metastasis (LM) using Di-Electro-Phoretic Array technology. MATERIALS AND METHODS: The CSF samples were drawn from a patient who was diagnosed with GC with LM. The CSF samples were centrifuged and stained with antibody cocktail to recognize 4',6-diamidino-2-phenylindole, cytokeratin, and epithelial cell adhesion molecule (EpCAM). Gene sequencing was also conducted to evaluate the status of the gene alteration profile of CSFCTCs as compared with those of the CSF non-CTCs and the primary tumor tissue. RESULTS: Among total 38 cells from the samples, 25 cells represented CK+ (EpCAM+), which boiled down to 0.53 CTCs in 1 mL of CSF. Each CTC was heterogeneous in terms of morphology and degree of marker expression. Some CTCs have a spindle-like shape, whereas others have a round shape. Based on molecular profiling between the 25 CK+ (EpCAM+) CTCs and 13 CK-/EpCAM- cells (i.e., the non-CTCs), CSFCTCs harbored mutations such as MDM2, TP53, KRAS, STK11, and ALK, whereas mutation of these genes was not observed in the CSF non-CTCs. Four genes of nine mutational genes totally observed in the CSFCTCs were also noted in the primary tumor tissue. CONCLUSIONS: We enriched CTCs through a single-cell sorting process in CSF samples of a GC patient with LM. We also demonstrated the intrapatient heterogeneity of the CTCs at the single-cell level.

[Response of Erlotinib in Lung Adenocarcinoma Harboring EGFR Sensitive Mutation in Cerebrospinal Fluid: Case Report].

BACKGROUND AND OBJECTIVE: One of the most often distance metastasis site of non-small cell lung cancer (NSCLC) is brain and the standard treatment of brain metastasis was radiotheraphy including whole brain irradiation (WBI) and stereotactic radiotherapy (SRT). It has been reported that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) had the active response in brain metastasis of lung cancer. In the present study, we reported one case of EGFR 19el in cerebrospinal fluid tested by ARMS got partial response given erlotinib. METHODS: Cerebrospinal fluid was collected through lumbar puncture, then cast-off cells and EGFR mutation was analysed. Erlotinib was given with dose of 150 mg, qd. Objective response was evaluated by Response Evaluation Criteriation in Solid Tumours (RECIST) v1.1 and adeverse events were evaluated according to Common Terminology Criteria for Adverse Events v4.0 (CTC AE v4.0). RESULTS: Heterocyst cells were found in cerebrospinal fluid and EGFR mutation was tested as 19del. The patient achieved partial response (PR) of brain metastasis and the effective response in lung was stable disease (SD) after 4 weeks of erlotinib. The progression-free survival (PFS) and overall survival (OS) of brain metastasis was 10.5 months and 11 months respectively. The main adverse event was rash (Grade I). CONCLUSIONS: It was feasible to test EGFR mutation in cerebrospinal fluid and the combination of erlotinib with chemotheraphy would be an appropriate choice to those lung cancer patients who had brain metastasis harboring EGFR sensitive mutation.

Rare case of pancreatic cancer with leptomeningeal carcinomatosis.

Leptomeningeal carcinomatosis occurs very rarely in patients with pancreatic cancer. Leptomeningeal carcinomatosis is characterized by multifocal seeding of the leptomeninges by malignant cells that originate from a solid tumor. To the best of our knowledge, brain metastasis from pancreatic cancer is extremely rare. Leptomeningeal carcinomatosis is estimated to occur in 3% to 8% of cases of solid tumors. The clinical manifestation usually involves neurological symptoms, including dizziness, headache, vomiting, nausea, and hemiparesis, symptoms similar to those of meningitis or brain tumors. Diagnostic methods for leptomeningeal carcinomatosis include brain magnetic resonance imaging and cerebrospinal fluid examination. Here, we describe a case of leptomeningeal carcinomatosis in which the primary tumor was later determined to be pancreatic cancer. Brain magnetic resonance imaging findings showed mild enhancement of the leptomeninges, and cerebrospinal fluid cytology was negative at first. However, after repeated spinal taps, atypical cells were observed on cerebrospinal fluid analysis and levels of tumor markers such as carbohydrate antigen 19-9 in cerebrospinal fluid were elevated. Abdominal computed tomography, performed to determine the presence of extracerebral tumors, revealed pancreatic cancer. Pancreatic cancer was confirmed histopathologically on examination of an endoscopic ultrasound-guided fine needle aspiration specimen.

An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis in lung adenocarcinoma cancer patients.

Leptomeningeal carcinomatosis (LC) is a metastatic cancer invading the central nervous system (CNS). We previously reported a metabolomic diagnostic approach as tested on an animal model and compared with current modalities. Here, we provide a proof of concept by applying it to human LC originating from lung cancer, the most common cause of CNS metastasis. Cerebrospinal fluid from LC (n = 26) and normal groups (n = 41) were obtained, and the diagnosis was established with clinical signs, cytology, MRI and biochemical tests. The cytology on the CSF, the current gold standard, exhibited 69% sensitivity (~100% specificity) from the first round of CSF tapping. In comparison, the nuclear magnetic resonance spectra on the CSF showed a clear difference in the metabolic profile between the LC and normal groups. Multivariate analysis and cross-validation yielded the diagnostic sensitivity of 92%, the specificity of 96% and the area under the curve (AUC) of 0.991. Further spectral and statistical analysis identified myo-inositol (p < 5 × 10(-14)), creatine (p < 7 × 10(-8)), lactate (p < 9 × 10(-4)), alanine (p < 7.9 × 10(-3)) and citrate (p < 3 × 10(-4)) as the most contributory metabolites, whose combination exhibited an receiver-operating characteristic diagnostic AUC of 0.996. In addition, the metabolic profile could be correlated with the grading of radiological leptomeningeal enhancement (R(2) = 0.3881 and p = 6.66 × 10(-4)), suggesting its potential utility in grading LC. Overall, we propose that the metabolomic approach might augment current diagnostic modalities for LC, the accurate diagnosis of which remains a challenge.

MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity.

An accurate, nonsurgical diagnostic test for brain tumors is currently unavailable, and the methods of monitoring disease progression are not fully reliable. MicroRNA profiling of biological fluids has recently emerged as a diagnostic tool for several pathologic conditions. Here we tested whether microRNA profiling of cerebrospinal fluid (CSF) enables detection of glioblastoma, discrimination between glioblastoma and metastatic brain tumors, and reflects disease activity. We determined CSF levels of several cancer-associated microRNAs for 118 patients diagnosed with different types of brain cancers and nonneoplastic neuropathologies by quantitative reverse transcription PCR analysis. The levels of miR-10b and miR-21 are found significantly increased in the CSF of patients with glioblastoma and brain metastasis of breast and lung cancer, compared with tumors in remission and a variety of nonneoplastic conditions. Members of the miR-200 family are highly elevated in the CSF of patients with brain metastases but not with any other pathologic conditions, allowing discrimination between glioblastoma and metastatic brain tumors. Quantification of as few as 7 microRNAs in CSF enables differential recognition of glioblastoma and metastatic brain cancer using computational machine learning tools (Support Vector Machine) with high accuracy (91%-99%) on a test set of samples. Furthermore, we show that disease activity and treatment response can be monitored by longitudinal microRNA profiles in the CSF of glioblastoma and non-small cell lung carcinoma patients. This study demonstrates that microRNA-based detection of brain malignancies can be reliably performed and that microRNAs in CSF can serve as biomarkers of treatment response in brain cancers.

[Value of tumor markers in the cerebrospinal fluid in the diagnosis of meningeal carcinomatosis].

OBJECTIVE: To assess the diagnostic value of tumor markers in the cerebrospinal fluid (CSF) for meningeal carcinomatosis (MC). METHODS: Twenty-one MC patients (including 13 adenocarcinoma and 8 non-adenocarcinoma patients), 72 patients with tuberculous meningitis (TBM) and 23 with primary intracerebral tumors (PIT) were enrolled in this study. Blood and CSF tumor markers including CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, AFP and NSE were measured by Roche E170 electrochemiluminescence analyzer and sandwich assay. RESULTS: CSF tumor markers CEA, CA125, CA199 and CYFRA21-1 and the serum tumor markers CEA, CA125, CA153, CA199 and AFP were significantly higher in MC group than in the other two groups. CSF CEA and CA15-3 were significantly higher in adenocarcinoma MC than in non-adenocarcinoma MC patients, but no significant differences were found in the serum tumor markers between the two groups (P>0.05). CSF tumor markers including CEA, CA125, CA15-3, CA72-4 and CYFRA21-1 were positively correlated to the serum tumor markers (P<0.05). CA199 was positively correlated to the disease course (P<0.05), and age was not correlated to any of the indexes (P>0.05). CONCLUSION: Detection of the tumor markers in the CSF, especially CEA, CA125, CA19-9 and CYFRA21-1, may help in the early diagnosis of MC. CEA and CA15-3 can serve as indicators for differential diagnosis of adenocarcinoma and non-adenocarcinoma.

Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer.

BACKGROUND: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420. METHOD: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8. RESULTS: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean +/- SD CSF concentrations of erlotinib and OSI-420 were 54 +/- 30 ng/ml and 10.8 +/- 8.2 ng/ml, respectively. The mean +/- SD CSF penetration rates of erlotinib and OSI-420 were 5.1% +/- 1.9% and 5.8% +/- 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC50) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene. CONCLUSION: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

Meningeal dissemination from an ovarian carcinoma with effective response to intrathecal chemotherapy.

Meningeal dissemination is rare in the clinical course of ovarian carcinoma, and its prognosis is poor. Although it is treated by the intrathecal administration of methotrexate (MTX) and/or total brain irradiation, these treatments are usually ineffective. We report a 58-year-old woman with stage IIIc ovarian cancer who had received nine courses of adjuvant chemotherapy after surgery. But her carbohydrate antigen (CA) 125 serum level had increased further (38.9 U/ml) after five courses of biweekly paclitaxel (Taxol; Bristol-Myers Squibb, Tokyo, Japan; BT) maintenance therapy. Fainting occurred, with a few seconds of unconsciousness, as did severe headaches. However, results of head computed tomography (CT), head magnetic resonance imaging, and electroencephalogram were normal. Lumbar puncture (LP) was performed. The opening pressure was 30 cmH2O or greater. Meningeal dissemination of the ovarian cancer was diagnosed, as adenocarcinoma cells were found by cerebrospinal fluid (CSF) cytology. We started chemotherapy with intrathecal injections of MTX and hydrocortisone acetate. Establishing a diagnosis of carcinomatous meningitis may be difficult. Clinical signs and biological data are not conclusive. In this patient, CSF cytology was very effective in establishing the diagnosis, and the intrathecal administration of MTX and hydrocortisone was very effective.

Carcinomatous meningitis from urachal carcinoma: the first reported case.

Carcinomatous meningitis (CM) occurs in less than 10% of cancer patients. Although patients frequently present with a focal complaint, multifocal signs are often found following careful neurological examination. The gold standard for diagnosis remains the demonstration of neoplastic cells in the cerebrospinal fluid. Despite the discouraging prognosis, palliative treatment may improve quality of life and lengthen lifespan. We report a patient with known primary carcinoma of the urachus who presented with headaches, nausea, vomiting and ataxia 1 week following resection of a nodular arachnoidal metastasis (indenting the cerebellum). Lumbar cerebrospinal fluid subsequently confirmed carcinomatous meningitis. This is the first reported case of carcinomatous meningitis resulting from metastatic urachal carcinoma.

[Retrospective study of a series of 26 carcinomatous meningitis secondary to lung cancer]. / Etude rétrospective d'une série de 26 cas de méningite carcinomateuse secondaire à un cancer bronchique.

Carcinomatous meningitis occur in approximately 5 to 18% of bronchial carcinoma. We report here the analysis of a retrospective study of 26 cases of carcinomatous meningitis secondary to a bronchial carcinoma. The most frequently involved histological types are adenocarcinoma and small cell lung cancer. The diagnosis is difficult because of the clinical polymorphism and the inconstant presence of neoplasic cells in the cerebrospinal fluid. The prognosis is very poor with a median survival time of 4 weeks. Development of new molecules as well as an earlier diagnosis could contribute to improve the outcome.

[Carcinomatous meningitis presenting with isolated headache]. / Céphalées isolées révélatrices d'une méningite carcinomateuse.

INTRODUCTION: Carcinomatous meningitis reveals a solid cancer in 10 percent of cases. OBSERVATION: Our patient developed isolated headache which progressively worsened. Cranial Computerized Tomography (CT) was normal. Brain MRI showed multiples areas of contrast enhancements meningeal tissue associated with small nodulars deposits. Repeated cerebrospinal fluid (CSF) examinations revealed elevated tumor markers suspect cells. The diagnosis of pulmonary adenocarcinoma was established during systematic follow-up. CONCLUSION: The diagnosis of carcinomatous meningitis can be difficult to establish because of the non-specific clinical presentation and the absence of suggestive context; negative CSF-cytology is frequent. MRI and elevated tumor markers in the CSF compared with the serum level contribute significantly to diagnosis.

Gallbladder carcinoma cells in cerebrospinal fluid as the first manifestation of a tumor. A case report.

BACKGROUND: Meningeal carcinomatosis (MC) rarely occurs as the first evidence of a tumor. In such cases cytology of the cerebrospinal fluid is crucial to the diagnosis. The most frequent primary MCs are lung and breast cancers. MC from a gallbladder carcinoma is uncommon. CASE: A 58-year-old woman presented with paroxysmal headaches, seizures and coma. Analysis of the cerebrospinal fluid revealed carcinoma cells and a low protein concentration. Only postmortem examination discovered gallbladder adenocarcinoma to be the source of the tumor cells. CONCLUSION: A case with the onset of MC secondary to rare mucinous adenocarcinoma of the gallbladder is presented. Cytology of the cerebrospinal fluid was the only examination that uncovered malignancy. Nine similar cases were found in the literature. Low cerebrospinal fluid protein seems to be of diagnostic value.

Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration in a man with esophageal adenocarcinoma.

We report a case of paraneoplastic cerebellar degeneration (PCD) associated with adenocarcinoma of the esophagus and anti-Yo antibodies in a male patient. The patient presented with progressive ataxia, dysarthria, and significant weight loss. Extensive work-up suggested paraneoplastic neurologic syndrome. A wide search for a cancer was undertaken and a small mass was identified in the distal esophagus on upper endoscopy. Biopsies of this lesion revealed well-differentiated invasive adenocarcinoma of the esophagus. The endoscopic ultrasound staged the tumor as T3N1M0. Despite trials of multiple therapeutic modalities, the patient's cerebellar dysfunction progressed. This is only the second report of PCD caused by esophageal adenocarcinoma and the fourth report of anti-Yo antibodies occurring in a male patient.

[Leptomeningeal carcinomatosis as the first clinical manifestation of lung adenocarcinoma: case report]. / Carcinomatose leptomeníngea como primeira manifestação de adenocarcinoma pulmonar: relato de caso.

Leptomeningeal carcinomatosis is a neurological complication of several systemic tumors and is characterized by multifocal invasion of the meninges by neoplastic cells. It is estimated that 5% of all patients with cancer will present leptomeningeal carcinomatosis at some time during the course of the illness. Clinical manifestations are heterogeneous and present with signs and symptoms related to involvement of multiple areas of the nervous system, particularly cranial nerves and spinal roots. The diagnosis is based on suggestive clinical findings, cerebrospinal fluid (CSF) testing and imaging studies. The most informative findings come from CSF where the presence of neoplastic cells is definitive for the diagnosis. The purpose of this report is to describe, along with a review of the literature, a clinical case of a 42 years old man in whom the first clinical signs of a lung cancer manifested with symptoms suggestive of meningeal involvement.

[Meningeal carcinomatosis in gastric cancer]. / Méningite carcinomateuse et cancer de l'estomac.

Meningeal carcinomatosis is an uncommon complication in patients with advanced gastric cancer. We report four cases of meningeal carcinomatosis occurring 18 months (mean) after the diagnosis. The presenting manifestations were headache, visual troubles and seizure. Cytological cerebrospinal fluid (CSF) examination was the most useful diagnostic tool for leptomeningeal carcinomatosis, considering the normality of brain CT scan and MRI in our patients. Intrathecal methotrexate administration achieved a rapid improvement in neurological symptoms in all cases, but for a short 2-3 months duration. We conclude that survival improvement in advanced gastric cancer, due to chemotherapy, may allow emergence of unusual complications such as carcinomatous meningitis. This diagnosis should be evoked in the presence of unexplained neurologic symptoms and confirmed by CSF examination in order to propose a treatment and to delay serious neurologic disability and prolong survival.

Leptomeningeal metastases from ethmoid sinus adenocarcinoma: clinico-radiological correlation.

A patient with sinonasal adenocarcinoma is presented with leptomeningeal metastases affecting multiple cranial nerves and spinal nerve roots. Head and neck cancer is known to be an extremely rare source for leptomeningeal metastatic spread. The cranial nerves, the spinal cord and roots and the cerebral hemispheres can be affected in case of leptomeningeal metastatic spread. Examination of the CSF is the hallmark of the diagnosis if leptomeningeal metastatic spread is suspected, but this case illustrates that the combination of specific clinical features on one hand and specific lesions on the Gd-enhanced T1-weighted MRI study on the other hand is reliable enough to make a presumed diagnosis if the CSF analysis remains negative. We suggest that in our patient direct leptomeningeal spread occurred through the cribriform plate to the CSF, followed by further spread in a gravity dependent way.

Prostate-specific antigen in the cerebrospinal fluid leads to diagnosis of solitary cauda equina metastasis: a unique case report and review of the literature.

A 79-year-old male patient presented with a subacute cauda syndrome caused by an intradural metastasis of the lumbosacral caudate fibres from an adenocarcinoma of the prostate, which had been treated 5 years earlier with external beam radiation therapy. Diagnosis could not be established by repeated magnetic resonance images (MRIs) during a 2-year period of increasingly severe radicular pain. Eventually, a small tumour mass could be visualized on the fourth MRI. Repeated normal serum prostate-specific antigen (PSA) did not hint at a prostate cancer metastasis (range 2.4-5.1 ng ml(-1)); however, PSA in the cerebrospinal fluid was found to be elevated (29.1 ng ml(-1)). Empirical radiation therapy of the caudate region did not improve radicular pain. Therefore, an exploratory surgical procedure was conducted, which confirmed the suspicion of an intradural prostate cancer metastasis. In conclusion, PSA in the cerebrospinal fluid provides a useful diagnostic tool for detecting intradural prostate cancer metastasis.