Angiogenesis,Metastasis, and Endogenous Inhibition

Angiogenesis and the development of metastases are intrinsically connected. Experimental data suggest that establishment and growth of metastases are influenced by soluble factors secreted from the originating solid tumor. Among these factors are so-called endogenous inhibitors of angiogenesis which keep metastasis in a non-proliferating quiescent state. For a number of tumors it has been shown that this dormant state is mediated through inhibition of angiogenesis. This dormant state is characterized by normal proliferation, increased apoptosis, and insufficient neovascularization. Removal of inhibiting anti-angiogenic factors led to growth of dormant metastases. A number of endogenous inhibitors have been identified and have shown success in experimental therapeutic trials. This might be of special interest for the treatment of cerebral metastases which are the most common type of malignant brain tumors. Similar to the spread of metastases, it is known that single glioma cells can be found in distant parts of the brain. While local recurrence is a common phenomenon in glioma, formation of clinical apparent distant metastasis occurs rarely. Several lines of evidence suggest that growth inhibition of remote glioma cells may be mediated by an endogenous inhibitory mechanism.     

The History, Evolution, and Clinical use of Dendritic Cell-Based Immunization Strategies in the Therapy of Brain Tumors

Despite advancements in therapeutic regimens, the prognosis remains poor for patients with malignant gliomas. Specificity has been an elusive goal for current modalities, but immunotherapy has emerged as a potential means of designing more tumor-specific treatments. Dendritic cells (DC) are the specialized antigen presenting cells of the immune system and have served now as a platform for therapeutic immunizations against such cancers as lymphoma, multiple myeloma, melanoma, prostate cancer, renal cell carcinoma, non-small cell lung carcinoma, colon cancer, and even malignant gliomas. DC-based immunizations offer a number of advantages over traditional immunotherapeutic approaches to brain tumors, approaches that have proved promising despite concerns over central nervous system immune privilege and glioma-mediated immunosuppression. The future success of clinical trials will depend on the optimization and standardizing of procedures for DC generation, loading, and administration.     

持续灌注榄香烯(elemene)治疗恶性脑肿瘤

目的探讨持续灌注榄香烯治疗恶性脑肿瘤的疗效.方法总结分析我院1996年1月～1998年11月间,采用持续灌注榄香烯化疗23例恶性脑肿瘤患者的疗效.恶性胶质瘤13例,脑转移瘤10例.榄香烯400～800mg/d,6～12g/疗程,2～3个疗程,每疗程间隔1～1.5个月.经皮颈内动脉穿刺插管,或经皮锁骨下静脉或肘正中静脉穿刺插管,用泵持续灌注.根据治疗前后肿瘤体积变化,平均生存期,体能状态评分评价疗效.结果1)治疗前后肿瘤体积(cm3)平均缩小62.2%,P＜0.01.2)全组CR3例,PR14例,CR+PR17例,有效率73.9%(95%可信区间±13.4%).对照组29例,CR2例,PR10例,CR+PR12例,有效率40.9%(95%可信区间±17.9%)(P＜0.02).3)治疗前后KPS平均记分差为6.5,P＜0.01.4)治疗组平均生存期25.8个月,对照组平均生存期17.4月(P＜0.01).结论持续灌注榄香烯化疗对恶性脑肿瘤疗效明显,能延长患者高质量的生存期,值得进一步探讨.     

Cytokine Immuno-Gene Therapy for Treatment of Brain Tumors

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor. Conventional treatments such as surgery, radiation therapy and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. In this report approaches involving cytokine gene therapy in treatment of malignant brain tumors are reviewed and contrasted to a strategy developed in this laboratory involving the use of allogeneic cells genetically modified to secrete cytokines. In our studies, mice with an i.c. glioma, melanoma or breast carcinoma treated solely by intratumoral injections with allogeneic cells genetically modified to secrete interleukin-2 (IL-2) were found to survive significantly longer than mice in various control groups. The anti-tumor response was mediated predominantly by T-cell subsets (CD8+ and NK/LAK cells). The injections resulted in the killing of only the neoplastic cells; non-neoplastic cells were unaffected. Experiments involving treatment of animals with i.c. tumor using subcutaneous injections of cytokine-secreting allogeneic cells in the presence of tumor antigens demonstrated no effect in prolonging survival in spite of the development of a vigorous systemic anti-tumor immune response. Of special interest, mice injected intracerebrally with the cytokine-secreting allogeneic cells alone exhibited no neurologic defect and there were no adverse effects on survival. The injection of cytokine-secreting allogeneic cells into the microenvironment of an i.c. tumor is hypothesized to induce an anti-tumor immune response capable of prolonging survival. This pre-clinical animal data directly translates into clinical treatments for patients with a malignant i.c. tumor.     

含替尼泊甙联合化疗同时放疗治疗脑恶性胶质瘤

目的 :评价含替尼泊甙的联合化疗治疗恶性脑神经胶质瘤的治疗效果和毒副作用 ,探讨有效的辅助化疗方案 ,以期提高恶性脑神经胶质瘤的疗效 ,延长患者的生存期。方法 :不能手术、术后残留或复发的恶性脑神经胶质瘤 2 5例 ,其中大脑半球胶质瘤 15例 ,包括星形细胞瘤Ⅲ级 11例 ,Ⅳ级 4例 ;脑干胶质瘤 8例 ;小脑胶质瘤 2例。采用含替尼泊甙的联合化疗方案 :1)TV方案 :紫杉醇 135mg m2 ,静脉滴入d1;替尼泊甙 2 0 0mg m2 ,分 3天静脉滴入 ,(d1～d3) ,3周后可重复。 2 )MV方案 :司莫司汀 10 0mg m2 ,d1晚顿服 ,替尼泊甙 (用法同前 ) ,6周后重复。第 1周期化疗后常规局部外放疗 ,DT5 0～ 60Gy。结果 :2 5例患者有效 17例 ,总有效率 68 0 % ,其中大脑半球胶质瘤有效率 60 0 % (9 15 ) ,脑干胶质瘤有效率 87.5 % (7 8) ,小脑胶质瘤有效率 5 0 0 % (1 2 )。经χ2 检验 ,两种化疗方案有效率差异无显著性。主要毒性为骨髓抑制 ,特别是中性粒细胞减少 ,其中Ⅲ、Ⅳ度毒性反应 5例 ,占 2 0 0 % ,经对症处理均恢复正常。远期疗效正在观察中。结论 :替尼泊甙加紫杉醇或司莫司汀联合化疗同时放疗治疗恶性脑胶质瘤安全、有效 ,为脑瘤辅助化疗提供了新方案     

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。     

Local Anti-angiogenic Brain Tumor Therapies

The critical role of angiogenesis in the growth of solid tumors, including neoplasms of the central nervous system, has provided the impetus for research leading to the discovery of inhibitors of tumor neovascularization. The therapeutic potential of systemically administered antiangiogenic drugs for brain tumors, however, is limited by a variety of anatomic and physiologic barriers to drug delivery. Implantable controlled-release polymers for local drug administration directly into the tumor parenchyma have therefore been developed to achieve therapeutic concen-trations of these drugs within the brain while minimizing systemic toxicity. With use of these polymers, successfull antiangiogenic therapy for treatment of experimental intracranial malignancies has been achieved. This has been demonstrated with a variety of otherwise unrelated drugs – including the angiostatic steroids, tetracycline derivatives, and amiloride – which modulate collagenase activity, and thus, basement membrane and interstitial matrix metabolism. Controlledrelease polymers provide a clinically practicable method of achieving sustained antian-giogenic therapy which can be readily used in combination with other treatment modalities such as cytoreductive surgery, radiation, and cytotoxic chemotherapy.     

Efficacy of Proton Magnetic Resonance Spectroscopy Inclinical Decision Making for Patients with Suspected Malignant Brain Tumors

We wished to determine the utility of single voxel proton (¹H) magnetic resonance spectroscopy (MRS) when used as an alternative or adjunct to brain biopsy in patients harboring lesions suggestive of brain tumors identified by MRI scan. Fifteen patients (age 7–58 years) with MRI scans and clinical histories suggestive of primary brain tumors underwent single voxel ¹H-MRS. MRS (16 regions of interest in 15 patients) was used to aid in differentiation between tumor and other pathologies such as stroke or demyelinating plaque (n=6), radiation necrosis (n=5), or edema (n=5). Spectra were quantified to determine absolute molar values of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), lactate (LAC), and myo-inositol (mI), metabolite ratios relative to Cr were calculated, and spectra were interpreted based on metabolite ratios. Subsequent clinical management was based on MRS interpretation, and patients were then followed to determine if MRS interpretation accurately predicted clinical outcome or surgical findings. Mean follow-up was 12.5 months (range 3–28 months). MRS suggested the presence of recurrent tumor in 7 cases, all of which were subsequently confirmed by tumor resection (n=4) or disease progression (n=3). MRS suggested the presence of new tumor in 1 case, subsequently confirmed by surgical resection. MRS suggested the presence of necrosis in 3 patients; all 3 remained radiographically stable during the follow-up period, and one was confirmed by stereotactic biopsy. MRS suggested non-neoplastic lesions in 4 cases, 3 of whom were followed until radiographic resolution of lesions and one of which was confirmed as a pyogenic abscess via stereotactic aspiration. Overall, MRS accurately predicted the pathological nature and clinical outcome of lesions in 15/16 (96%) situations, influenced clinical decision making in 12 cases, and altered surgery planning in 7 patients. In appropriate circumstances MRS can reduce the need for biopsy and provide an important guide for clinical decision-making in difficult cases.     

Intralesional Mitoxantrone Biopolymer-Mediated Chemotherapy Prolongs Survival in Rats with Experimental Brain Tumors

The present study was designed to test the efficacy of intratumoral biopolymer-mediated mitoxantrone chemotherapy in the rat brain 9L glioma model. Mitoxantrone polymers were tested in vitro in 9L and C6 cell cultures for 10 days. Subsequently, adult Fisher 344 rats were implanted with 5 x 10(4) 9L glioma cells in the frontal region of the brain. In a first experiment, 2 days after cells inoculation, one group of rats were implanted with a biopolymer loaded with 4 mg of mitoxantrone at the tumor site. A second group of rats received drug-free biopolymers and served as controls. In a second experiment, rats were implanted with a biopolymer loaded with 2 mg of mitoxantrone. Another group of rats received 2 mg of mitoxantrone intraperitoneally. Controls received drug-free biopolymers. Rats were sacrificed as soon as they developed progressive neurological deficits. In the first experiment mean survival of mitoxantrone-treated rats was 10+/-2 vs. 15+/-2 days for the control group (P = 0.0003). Early morbidity was seen in 60%, and impaired wound healing was seen in 40% of the 4 mg mitoxantrone treated animals. In the second experiment mean survival of mitoxantrone-treated rats was significantly longer than that of the control group (P < 0.0001) with 33+/-7 vs. 13.8+/-2 days for the control group. Only transient early morbidity (20%) was observed at this dose. All rats in the intraperitoneally mitoxantrone-treated group died within the first 4 days after injection. We conclude that controlled-release EVAc carriers deliver biologically active mitoxantrone in a sustained fashion. In vivo biopolymer-mediated mitoxantrone in loco chemotherapy can significantly prolong survival in rats with intracerebral 9L gliomas. Morbidity is mainly dose related, and can be reduced at acceptable levels without compromising the therapeutic effect.     

Penetration of Idarubicin into Malignant Brain Tumor Tissue

Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in glioma. In patients with glioma anthracyclines are not effective possibly because the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin is more lipophilic than the other anthracyclines and is more cytotoxic in glioma cell lines. The uptake of idarubicin and its major metabolite idarubicinol in brain tumor tissue were measured in a patient with a brain metastasis from breast cancer and in 4 patients with malignant glioma after an oral dose of idarubicin (45 mg/m² in 1 patient; 25 mg/m² in 4 patients), given 15–24 h before brain tumor resection. The concentrations of idarubicin and of idarubicinol in tumor tissue exceeded the concurrent plasma concentrations as well as the peak plasma concentrations in all cases. The median tumor: concurrent plasma ratio of idarubicinol was 5.7 (range 1.7–18). The concentration of idarubicinol in the marginal zone between brain and tumor tissue was lower than in central tumor tissue, but was still higher than the plasma concentration in 2 of the 3 examined cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4) occurred after a single dose of 45 ml/m². No toxicity was seen at a dose of 25 mg/m². These results, the in vitro activity of idarubicin in glioma, the convenience of oral administration, and its toxicity profile make clinical studies with idarubicin in malignant glioma, and perhaps also in brain metastases from breast cancer worthwhile.     

Immunotherapeutic Treatment Strategies for Primary Brain Tumors

Opinion statement  Primary brain tumors account for a minor fraction of cancer diagnoses made worldwide and remain one of the most difficult to treat. Despite ongoing efforts to improve the quality of life and overall survival of these patients, current multimodality therapy has achieved only modest gains; the median survival is approximately 14 months among patients with the deadliest form of primary brain tumor, glioblastoma multiforme. Although the brain has been long considered an immunologically privileged organ, there is increased awareness of and appreciation for the complex interplay between the nervous system and the immune system in the setting of many disease states, including neoplastic. Although the concept of harnessing the specificity, activity, and memory of the immune system toward the treatment of brain tumors has been in existence for several decades and the neuro-oncology literature holds many publications that once promised of a breakthrough, only recently has a strategy emerged that addresses many of the limitations identified through past failures. It is with cautious optimism that the authors review the past and discuss the present status of immunotherapy and its role in the management of patients with primary brain tumors.     

Single Brain Metastases of Carcinoid Tumors

Carcinoid tumors are one among the most uncommon source of metastatic lesion to the brain. Four cases of single brain metastases from carcinoid tumors operated upon and verified by both histology and immunohistochemical staining are reported. The site of the primary carcinoid tumor was the lung in two cases, ileum in one and the left colon in another. The location of the brain metastasis was supratentorial in two cases and cerebellar in two. A high vascular tumor with large blood channels was found at surgery. Immunohistochemical studies showed in all four cases positive staining for synaptophysin, neuron-specific enolase, chromogranine and cytocheratine and negative staining for S-100 and HMB-45. The postoperative survival time ranged from 5 to 18 months. The epidemiological, surgical and pathological features of brain metastases from carcinoid tumors are also discussed from the analysis of 44 well-documented cases reported in the literature.     

Imaging Changes after Stereotactic Radiosurgery of Primary and Secondary Malignant Brain Tumors

After radiosurgery of malignant tumors, it can be difficult to discriminate between transient treatment effects, radiation necrosis, and tumor progression on post-treatment imaging. Misinterpretation of an enlarging lesion may lead to inappropriate treatment and contribute to disagreements about treatment efficacy. In an effort to clarify this problem, we reviewed our experience with interpreting post-radiosurgical imaging in patients with malignant primary and secondary brain tumors. We reviewed results of radiosurgery of 30 malignant gliomas and 35 metastatic brain tumors with minimum follow up of 1 year or until death. Of 30 gliomas, 73% were larger a mean of 13 weeks after radiosurgery. Of 35 metatstatic tumors, 22% were larger a mean of 10 weeks after radiosurgery. Eleven had ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET) of enlarging lesions. Eight showed increased activity with respect to brain; three decreased activity. Of the eight, six predicted incorrectly based upon the patients' subsequent courses (all alive, mean follow up of 27 months), and two correctly, with the patients dying from the imaged lesions 8 and 13 months later. Of the three with FDG uptake less than brain, one patient was alive with 32 weeks of follow up, and two patients died from the imaged lesion 13 and 21 months later. Radiographic enlargement after radiosurgery is common, especially for gliomas. Physicians caring for these patients should be aware of this phenomenon and be cautious in interpreting post-treatment images. MRI appearance may be useful for metastases. FDG-PET seems unreliable. Further evaluation of Tl-201 and HMPAO SPECT or MRS is warranted.     

High Dose Chemotherapy with Autologous Stem Cell Rescue in Adults with Malignant Primary Brain Tumors

High dose chemotherapy (HDCT) with autologous (bone marrow or peripheral blood) stem cell rescue (ASCR) has had success in the treatment of some malignant pediatric brain tumors. We report a series of adults enrolled in one of three HDCT and ASCR protocols for malignant primary brain tumors.Overall toxic mortality was 18%; chemotherapy regimen, tumor type, and prior treatment did not predict transplant-related mortality. Patients over the age of 30 had a higher rate of toxic mortality. Patients with recurrent medulloblastoma had a significant improvement in long-term survival (median: 34 months) as compared with historical reports; two patients with glioblastoma survive beyond four years without progression, but overall, a significant improvement in long-term survival could not be demonstrated for malignant gliomas.     

中西医结合治疗脑肿瘤的临床研究进展

脑肿瘤（brain tumor）又称颅内肿瘤（intracranial tumors）,是恶性程度高、治疗难度大、预后差、严重危害人类健康的恶性肿瘤之一,虽然手术、化疗、放疗对颅内肿瘤治疗效果明显,但同时毒副作用大、预后差也是影响脑肿瘤患者恢复和继续治疗的重要因素。中医药联合手术、化疗、放疗治疗脑肿瘤较单纯手术、化疗、放疗治疗脑肿瘤有着毒副反应轻,治疗效果好的优点。全文就近年来中西医结合治疗脑肿瘤的临床研究进展作一综述。     

Survivin in Brain Tumors: An Attractive Target for Immunotherapy

Survivin, a member of the inhibitor of apoptosis proteins gene family, was recently shown to be expressed by tumors originating from different cell lineages. There are also cumulative evidences that spontaneous immune response against survivin derived epitopes may occur. Here, using RT-PCR, Western-blot analysis and immunohistochemistry, we show that survivin is widely expressed by gliomas, meningiomas and schwannomas, both in vitro and in vivo. These data indicate that survivin may serve as an attractive target for immunotherapies designed for brain tumors.     

中西医结合治疗恶性脑瘤对照观察

 目的　中西医药辩证施治对38例恶性脑瘤的临床疗效与传统的放化疗的疗效对照观察。方法　治疗组38例用VM26+MeCCNU化疗与中医药辨证配合;对照组18例按常规仅作放疗或化疗。结果　治疗组总有效率(CR+PR)76.3%(29/38),胶质瘤与转移瘤有效率分别为91.6%(22/24)和50%(7/14)。对照组有效率33.3%(6/18)。主要毒副反应为食欲下降,恶心呕吐,骨髓抑制,多为Ⅱ～Ⅲ级。大部分病人通过中药调理,能达到“增效”和“减毒”之目的。结论　运用中医辨证论治配合化疗,治疗恶性脑瘤的综合有效率为76.3%,与传统单一放化疗的疗效33.3%有显著的差异(P＜0.05)。     

恶性脑肿瘤的化学治疗进展

1 恶性脑肿瘤的流行病趋势 恶性脑肿瘤的发病率国内尚没有准确的流行病学资料,全国第三次死因回顾抽样调查显示,抽样地区恶性脑肿瘤位居恶性肿瘤的第七位,占恶性肿瘤死亡率的2.3%[1].