以颅内压增高为主症的肺癌脑转移16例分析

目的：探讨以颅内压增高为主症的肺癌脑转移的临床特点及诊断。方法：对16例以颅内压增高为主症的肺癌脑转移患者的临床表现、CT、MRI、脑脊液检查进行回顾性分析。结果：颅内压增高为主症的肺癌脑转移患者亚急性起病，进行性加重，主要表现为颅内压增高及脑膜刺激征，根据增强CT、MRI，并结合脑脊液检查及原发肿瘤灶可明确诊断。结论：肺癌脑转移以颅内压增高为主要临床表现，是早期诊断肺癌脑转移的重要线索，增强CT、MRI检查及脑脊液检查是重要的诊断依据。     

Therapeutic Regimens and Prognostic Factors of BrainMetastatic Cancers

Objective: This work aims to investigate the therapeutic regimen of brain metastatic cancers and therelationship between clinical features and prognosis. Methods: Clinical data of 184 patients with brain metastaticcancers were collected and analysed for the relationship between survival time and age, gender, primary diseases,quantity of brain metastatic foci, their position, extra cranial lesions, and therapeutic regimens. Results: Theaverage age of onset was 59.1 years old. The median survival time (MST) was 15.0 months, and the patients withbreast cancer as the primary disease had the longest survival time. Females had a longer survival time than males.Patients with meningeal metastasis had extremely short survival time. Those with less than 3 brain metastaticfoci survived longer than patients with more than 3. The MST of patients receiving radiotherapy only and thepatients receiving chemotherapy only were all 10.0 months while the MST of patients receiving combinationtherapy was 16.0 months. Multiple COX regression analysis demonstrated that gender, primary diseases, andquantity of brain metastatic foci were independent prognostic factors for brain metastatic cancers. Conclusions:Chemotherapy is as important as radiotherapy in the treatment of brain metastatic cancer. Combination therapyis the best treatment mode. Male gender, brain metastatic cancers originating in the gastrointestinal tract, morethan 3 metastatic foci, and involvement of meninges indicate a worse prognosis.     

肺癌脑转移细胞的筛选及实验动物模型的建立

目的：通过反复裸鼠体内肺癌细胞接种,筛选出特异性脑转移肺癌细胞株,并建立可稳定产生脑转移的肺癌实验动物模型.方法：应用人肺癌细胞株PC-14尾静脉注射接种裸鼠,5周后处死裸鼠,取出脑转移肿瘤组织,行原代培养后再次接种裸鼠,反复几个循环,观察脑转移形成情况.结果：经过4个循环后,筛选出的PC-14/B肺癌细胞尾静脉接种可在裸鼠产生特异脑转移,可应用于建立稳定转移的肺癌脑转移实验动物模型.结论：应用肺癌细胞株行反复裸鼠体内接种,是建立肺癌脑转移实验动物模型的可行方法.     

Cellular whorls in brain tumors other than meningiomas.

Cellular whorls with or without secondary calcification are generally regarded as reliable diagnostic criteria in the differential diagnosis of meningiomas. They may however occasionally occur in other primary and metastatic brain tumors. Five cases (metastatic laryngeal carcinoma, metastatic mammary carcinoma, metastatic melanoma, medulloblastoma, and giant cell glioblastoma) are presented to illustrate this phenomenon occurring in non-meningothelial brain tumors.     

Inhibition of metastatic brain tumor growth by intramuscular administration of the endostatin gene

The cancer patients suffering from brain metastases are basically incurable. The conventional tumoricidal strategies frequently cause severe side effects instead of life prolongation of such patients. On the other hand, antiangiogenic therapy seems to be a promising strategy to avoid such unfavorable effects. In the present study, we experimentally investigated tumor dormancy effect of the excessively produced endostatin, a potent angiostatic factor, by intramuscular administration of the endostatin gene against primary cancer and metastatic brain tumor. For this purpose, we established a model system in which FM3A P-15 cells, a high metastatic mouse breast cancer cell line, were inoculated simultaneously into the brain as an artificially metastatic brain tumor (herein referred as "metastatic brain tumor") and the mammary pad as a primary cancer (referred as "primary breast cancer"), and utilized a non-viral system to deliver an expression plasmid encoding a secretable form of mouse endostatin into muscle tissues. The plasmid vector formulated with the synthetic polymer, polyvinylpyrrolidone, was administrated at 3 and 10 days after the inoculation of FM3A P-15 cells. A significant increase in the serum level of endostatin was achieved at 7 days after second administration of the plasmid vector (p=0.0066). Consequently, the growth of metastatic brain tumor was significantly retarded (p=0.0455), while no significant change in the weight of primary breast cancer was observed (p=0.1531). Intratumoral microvessel density in metastatic brain tumor but not in primary cancer as revealed by Factor VIII immunohistochemistry was significantly decreased in the endostatin gene-administrated group (p=0.0027). In conclusion, the present study demonstrates the potential efficacy of intramuscular delivery of antiangiogenic gene for treatment of metastatic brain tumor.     

单发脑转移瘤的外科治疗

本文报告了５１例单发脑转移瘤，全部为手术和病理检查所证实。５１例中，男性３２例，女性１９例，平均年龄为４６．８岁。这些患者的主要表现为颅内压增高。本研究结果表明年龄较小、身体条件好的单发脑转移瘤患者，如果他们的原发灶经过适当处理，或转移性脑瘤是可切除的，都应尽早地行手术治疗，并同时行减压术。术后患者应行全脑放疗和化疗，以便延长其生命，改善生活质量。     

Clinical trial of MCNU for malignant brain tumors

A total of 71 cases with primary brain tumors (44 cases) and metastatic brain tumors (30 cases) were entered into our clinical studies with MCNU and radiation therapy or MCNU alone. With regard to tumor reduction on CT scan, the response rates obtained for MCNU and radiation were 21.7% for malignant gliomas and 50.0% for metastatic brain tumors. With regard to improvement of neurological signs, the response rates obtained for MCNU and radiation were 62.9% for malignant gliomas and 71.4% for metastatic brain tumors. The response rates for MCNU were 5.8% for malignant gliomas and 46.1% for metastatic brain tumors. In the improvement of performance status, the response rates for MCNU and radiation were 51.8% for malignant gliomas and 64.2% for metastatic brain tumors. The response rates for MCNU were 46.1% for malignant gliomas and 30.7% for metastatic brain tumors. A minimal degree of hematological toxicity occurred but this gradually disappeared. These results suggested that MCNU has relatively effective antitumor activity against metastatic brain tumors and an enhanced effect with radiation against malignant gliomas.     

Fetal antigen 2 in primary and secondary brain tumors.

Immunohistochemical deposition and distribution of fetal antigen 2 (FA2) was examined in normal brain tissue and in primary and metastatic tumors of the brain. In normal brain tissue FA2 was exclusively found linearly around the vessels, along pia and in arachnoidea. A similar localization was seen in primary brain tumors except in gliosarcoma where FA2 was distributed diffusely in the sarcoma region and was absent in the glioma region. In metastatic carcinoma with tumor stroma a diffuse staining reaction was seen in the stroma and with a basement membrane (BM) like staining at the tumor cell/stroma interface. Intracytoplasmic FA2 staining of the tumor cells was seen in areas without tumor stroma. In metastatic melanoma a BM like FA2 staining was seen around and between individual tumor cells. The staining patterns seen in the metastatic tumors were in accordance with that of the corresponding primary tumors.     

Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors.

PURPOSE: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. EXPERIMENTAL DESIGN: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. RESULTS: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. CONCLUSIONS: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.     

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.     

非小细胞肺癌原发灶与脑转移灶EGFR基因突变状况的一致性研究

目的 探讨非小细胞肺癌（NSCLC）原发灶与脑转移灶的表皮生长因子受体（EGFR）基因突变状况,分析两者之间是否存在一致性。方法 收集2003年1月至2011年12月31例NSCLC脑转移患者的肺原发灶和脑转移灶石蜡包埋组织标本,应用DNA直接测序法进行EGFR突变分析,如发现两者突变不一致则进一步采用增殖阻碍突变系统 （ARMS）验证。结果 31例NSCLC肺原发灶中,8例存在19外显子E746-A750缺失突变、4例为21外显子L858R点突变;在31例脑转移灶样本中,8例为19外显子E746-A750缺失突变,3例存在21外显子L858R点突变,EGFR突变类型在脑转移灶和肺原发灶的分布差异无统计学意义 （P=0.793）。共有16.1％ （5／31）的肺原发灶和脑转移灶EGFR突变状况不一致,其中男性4例,女性1例;3例腺癌 （2例脑转移灶19外显子缺失突变而肺原发灶阴性突变,1例肺原发灶21外显子点突变而脑转移灶阴性突变）,1例鳞癌和1例非典型类癌 （均为脑转移灶阴性突变而肺原发灶19外显子缺失突变）。结论 NSCLC原发病灶及脑转移灶EGFR基因突变存在不一致性。     

The use of systemic therapies for the treatment of brain metastases in metastatic melanoma: Opportunities and unanswered questions

The development of brain metastases is common in patients with metastatic melanoma and heralds a particularly poor prognosis. The development of the immunological agent ipilimumab and targeted treatments such as the selective BRAF inhibitor vemurafenib have revolutionised the treatment of metastatic disease. Evidence from clinical trials suggest these drugs may be effective in the treatment of brain metastases from melanoma. However efficacy may be limited by a lack of penetration of the blood brain barrier (BBB) and by multi substrate efflux pumps expressed on the BBB. The role and sequencing of radiotherapy, both whole brain and stereotactic radiotherapy, is yet to be determined but combinations of radiotherapy and systemic therapies may further increase the effects of these drugs on brain metastases. Considering the impact of brain metastases on morbidity and mortality in metastatic melanoma, future research into systemic drug therapy for the treatment of brain metastases and improvements in BBB penetrance should be a priority.     

Adenocarcinoma of prostate presenting as brain metastasis

The diagnosis of brain metastasis from prostate carcinoma is rarely made antemortem, and has previously been reported only in patients with known extensive metastatic disease of long duration. A case of adenocarcinoma of the prostate presenting as a brain metastasis is described. Current concepts of metastatic spread of prostate carcinoma are reviewed.     

High incidence of asymptomatic brain lesions in metastatic renal cell carcinoma

Summary The metastatic pattern of renal cell carcinoma has been well established. Studies have revealed a relatively high incidence of spread to lung, liver, bone and brain. A retrospective review of the records of ninety patients with metastatic renal cell carcinoma showed seven to have evidence of brain metastases. Six of the seven were asymptomatic at time of diagnosis. This study shows a significant incidence of asymptomatic brain metastases in patients with metastatic renal cell carcinoma. Subsequent to our chart review, an additional two patients have presented to our institution with asymptomatic brain lesions from metastatic renal cell carcinoma.     

Malignant melanoma metastasis to brain: role of degradative enzymes and responses to paracrine growth factors

Mouse and human melanoma cells metastatic to the brain express degradative enzyme activities that are used for invasion of brain basement membrane and parenchyma. Compared to poorly metastatic or lung- or ovary-metastatic murine melanoma lines, the brain-metastatic sublines secreted higher levels of a variety of degradative enzymes. Brain-metastatic murine and human melanoma cells also degraded subendothelial basement membrane and reconstituted basement membrane at rates higher than other metastatic melanoma cells. In some cases these degradative activities in mouse and human melanoma cells can be induced by paracrine factors known to be present in the brain parenchyma, such as nerve growth factor (NGF). NGF stimulates the expression of degradative enzymes, such as the endo--glucuronidase heparanase, that are important in basement membrane penetration but this factor does not stimulate melanoma cell growth. The growth of brain-metastasizing melanoma cells appears to be stimulated by other paracrine growth factors, such as paracrine transferrin. Melanoma cells metastatic to brain express higher numbers of transferrin receptors and respond and proliferate at lower concentrations of transferrin than do melanoma cells metastatic to other sites or poorly metastatic melanoma cells. The results suggest that degradation and invasion of brain basement membrane and responses to paracrine neurotrophins and paracrine transferrins are important properties in brain metastasis of murine and human malignant melanoma cells.     

Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression

Background

The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases.

Results

In this study, we examined the function and regulation of calcium-activated potassium (K_Ca) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a K_Ca channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a K_Ca channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found K_Ca channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of K_Ca channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of K_Ca channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of K_Ca channels, which may contribute to the overexpression of K_Ca channels in tumor microvessels and selectivity of BTB opening.

Conclusion

These findings suggest that K_Ca channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.     

Transitional Cell Carcinoma presenting as a solitary brain lesion: A case report and review of the world literature

Transitional cell carcinoma of the urinary tract will account for roughly 50,000 new cases of cancer in the US this year. Metastatic involvement to the brain is uncommon with this malignancy. When it does occur, it is usually in the setting of widespread metastatic disease. A rare case of transitional cell carcinoma of the bladder presenting as a solitary brain lesion is reported. In addition, we reviewed the world literature regarding transitional cell carcinoma metastatic to the central nervous system. Our review suggests that metastatic transitional cell carcinoma of the central nervous system has become increasingly common as more effective chemotherapeutic regimens have been developed to control the primary disease. The recent literature also suggests that, much like other metastatic disease to the brain, outcome and survival in patients without widespread disease is improved by aggressive surgical and oncological management.     

Brain metastasis of breast tumors and blood brain barrier

Brain metastases are prevalent in solid tumours and lymphomas. They are associated with poor survival. The brain is regarded as a sanctuary site for metastatic tumour cells where they exist partially protected from drugs by the blood brain barrier. Amongst the different molecular sub-types of breast cancer, HER2 positive tumours and triple negative tumours exhibit the highest incidence of brain metastasis. Specific strategies are needed to fight brain metastatic disease. Preclinical models for brain metastasis have been developed, yielding mechanistic molecular knowledge and new therapeutic approaches.     

The biology of metastasis to a sanctuary site.

Metastasis to the brain is prevalent in solid tumors and lymphomas, and is associated with shortened survival. The brain is regarded as a sanctuary site for metastatic tumor cells where they exist partially protected from drugs by the blood-tumor barrier. Model systems for brain metastasis have been developed and are now yielding mechanistic insights into the roles of angiogenesis, energy metabolism, the Her-2 and Stat3 signaling pathways, and dormancy. Specific, new approaches to combat brain metastatic disease are needed.     

Brain metastases of colorectal cancer--a case report

Metastatic brain tumors from colorectal cancers are relatively rate. In previous reports, the incidence, ranged from 1.9 to 3.5 percent of all metastatic brain tumors. We reported 2 cases of metastatic brain tumors from colorectal cancers. Metastasis to the lung and liver were not found in 2 cases at the time of the diagnosis of the single brain metastasis. The CEA levels in the serum were highly elevated in these 2 cases. On a contrast-enhanced CT scan, tumors were equally demonstrated as high density and cystic, with a ring-like mass with surrounding brain edema. Brain metastases of colorectal cancer were discussed with a review of the literature.