Tumoral micro-blood vessels and vascular microenvironment in human astrocytic tumors. A transmission electron microscopy study

The development of peritumoral edema is thought to be due to extravasation of plasma water and macromolecules through a defective blood–brain barrier (BBB), but the exact mechanism by which occurs is poorly understood. The aim of this study was analyze at submicroscopic level the morphological changes in both micro-blood vessels and vascular microenvironment of astrocytic tumors in an attempt of understanding the pathological aspects that may help in the future researches for the design of future therapeutic strategies. Biopsies of 25 patients with pathological diagnosis of astrocytic tumors were examined with the transmission electron microscope. Both open and close tight junctions were observed in the micro-blood vessels, inclusive in a same tumor. Cytoskeletal disorganization associated with disintegrated perijunctional actin filaments were seen. The paracellular space showed enlargement and commonly occupied by fluid proteinaceous, endothelial cells display oncotic and ischemic changes, basal lamina reveals enlargement, edema, vacuolization and collagen fibers disposed in irregular array. Pericytes exhibited edema and phagocytoced material, astrocytic perivascular-feet showed signs of oncosis and necrosis, cooption vessels totally surrounding by neoplastic cells also were seen. The ultrastructural abnormalities observed in both junctional complexes and vascular microenvironment suggest a multi-factorial pathobiology process, probably hypoxia intratumoral, calcium overload in endothelial cells, and degradative effects of metalloproteinases over the basal membrane appear as determinant factors that leading to structural modifications of junctional complexes, therefore, treatment with both HIF-1α and metalloproteinases inhibitors possibly can contribute with the pharmacological handling of the peritumoral edema associated with astrocytic tumors.     

A transmission and scanning electron microscopic study of tumoral and peritumoral microblood vessels in human gliomas

Summary The tumor microblood vessels (MBVs) of 25 cases of gliomas of varying grades were studied and compared with those in peritumoral region using both transmission and scanning electron microscopy (TEM and SEM). The TEM study revealed numerous villous projections with pinocytotic vesicles (PCVs) and large vacuoles (LVs) concentrated mainly at the luminal aspect in tumor MBVs which increased with increasing severity of edema. The peritumoral MBVs, in addition to showing some increase in villous projections on the luminal surface, also showed increased number of PCVs and LVs concentrated at the abluminal aspect with some of them even communicating with the extravascular space. The SEM study largely corroborated the TEM findings. The sites of formation of PCVs and LVs appeared as small pits or large craters on the luminal surface of the endothelial cells of tumor MBVs. We feel that the morphological evidence of increased permeability in tumor MBVs represents their role in the development of edema and that the occurrence of reverse pinocytosis in peritumoral MBVs is a distinct possibility which may be associated with resorption of edema fluid.     

Cerebral edema associated with meningiomas: the role of peritumoral brain tissue

We undertook a morphological study of small pieces of peritumoral brain tissue removed from seven patients with meningiomas submitted to surgery. All patients had cerebral edema, as shown by preoperative C.T. and N.M.R.. Control specimens were obtained from five patients undergoing ventriculo-peritoneal shunt. The tissue fragments were fixed in glutaraldehyde-osmium and embedded in Epon. In semi-thin sections observed under light microscopy peritumoral endothelial cells exhibited voluminous cytoplasm and nucleus. Morphometrical evaluation confirmed that these endothelial cell nuclei were significantly larger than controls. Under the electron microscope those cells showed nuclei rich in euchromatin and cytoplasm rich in pinocytotic vesicles. The morphological changes observed suggest a process of dedifferentiation of brain peritumoral capillary cells and are compatible with an increase in permeability. Both events, which may be due to diffusion of a tumoral vascular permeability factor, favour the hypothesis that peritumoral brain tissue contributes to edema fluid that accumulates around meningiomas.     

Binding of lectins to human mammary tumors: Ultrastructural study

Summary The site of several lectin receptors in human mammary tumors and stroma was studied with the electron microscope. The advantage of the ultrastructural over light microscopic study was that lectin receptors could be localized with precision on the different cell types of the tumor and stroma. Eighteen human mammary carcinomas were incubated with three peroxidase-labeled lectins: peanut agglutinin (PNA),Helix pomatia, andUlex europaeus I (UEA). These lectins reacted in a selective way; some tumors were negative and others showed reaction in some areas of the tumor and/or the stroma. No correlation was found, however, between the presence of these lectin receptors on the tumor cells and either hormone receptors or histological type of the tumors. These results show that the value of the presence of lectin receptors in human mammary tumors as markers for evaluation of mammary lesions is more complex than thought up to now. The most relevant observations on the stroma cells and inflammatory infiltrates were: (A) Some lymphocytes were positive with PNA, probably representing sessile T cells. In two carcinomas, abundant plasma cells were present in the infiltrates, always with PNA receptors. (B) In all mammary tumors where blood vessels were present in the sections, these were always stained with UEA. This supports the use of UEA as a marker for human endothelial cells even in pathologically altered tissues.     

Polyamines in human brain tumors

Summary Polyamine levels have been studied in brain tumor patients. We focused our study on the relationship between tumor, cerebrospinal fluid (CSF) and red blood cell (RBC) polyamine levels. Our results are the following: (1) Polyamine levels in CSF are consistently increased, whatever the histological type may be. (2) The highest tumoral concentrations are found in medulloblastomas. (3) In glioblastomas, the RBC spermidine levels are higher than in the other types of tumors and there is a highly significant correlation between the spermidine/spermine ratio in tumor and RBC. Therefore, RBC polyamine determinations might be of clinical interest in the monitoring of patients with glioblastomas.Supported in part by Research Grant of Ligue Nationale Française Contre le Cancer, Fondation pour la Recherche Médicale Française, Fondation Jean Langlois.     

Reversion of phenotype of endothelial cells in brain tissue around glioblastomas

Summary With the aim of studying the putative involvement of peritumoral microvessels in the formation of brain edema, small pieces of peritumoral brain tissue were removed from six patients with glioblastoma multiforme submitted to surgery. All patients had cerebral edema, as shown by preoperative C.T. and N.M.R. Control specimens were obtained from four patients undergoing ventriculo-peritoneal shunt. The tissue fragments were fixed in glutaraldehyde-osmium and embedded in Epon. In semi-thin sections observed under light microscopy peritumoral endothelial cells exhibited voluminous cytoplasm and nucleus.Under the electron microscope, capillary cells from glioblastoma patients differed from controls mainly by showing nuclei rich in euchromatin, cytoplasm rich in pinocytotic vesicles and with occasional fenestrations. All these morphological characteristics are compatible with a process of reversion of phenotype of capillaries around glioblastomas to that of periphery as well as an increase in permeability. Both events may be due to diffusion of a tumoral vascular permeability/endothelial growth factor. This peripheral vessel phenotype of peritumoral microvessels supports their participation in the formation of brain edema and may provide a new clue for therapeutic intervention: for example it fits quite well to the known increase in permeability by leukotrienes and decrease in permeability by corticosteroids in tumoral edema.     

血管内皮生长因子在脑膜瘤及瘤周脑组织中的表达

 目的　研究血管内皮生长因子（VEGF）在脑膜瘤瘤周水肿形成中的作用。方法　对经手术证实的幕上脑膜瘤37例患者共40个脑膜瘤进行研究,通过免疫组织化学法及Western blot检测肿瘤组织和瘤周脑组织中VEGF的蛋白表达,通过反转录PCR法检测VEGF的mRNA表达情况,以与β-actin的比值为其相对表达量;通过水肿指数（EI）评估术前瘤周水肿的严重程度,并分析其与VEGF表达的相关性。结果　在VEGF阳性病例中,VEGF蛋白水平在肿瘤组织、瘤周水肿脑组织和正常脑组织之间呈梯度降低（相对表达量分别为0.38±0.08、0.20±0.03、0.04±0.02）。在肿瘤组织中,VEGF的蛋白水平、RNA水平和EI呈正相关（r＝0.892、0.875,均P＜0.05）;在瘤周脑组织中,仅VEGF的蛋白水平和EI呈正相关（r＝0.912,P＜0.05）,而RNA则几乎未表达（0.06±0.02）。结论　VEGF在脑膜瘤瘤周水肿的形成过程中可能起着重要作用;VEGF可能是由肿瘤组织产生的,并扩散到瘤周脑组织中形成水肿。     

Glycosaminoglycan changes in human gliomas. A biochemical study

Summary Glycosaminoglycans (GAGs) were isolated, separated by electrophoresis and quantified in 36 neurosurgical specimens of human gliomas and in 8 samples of normal white and gray matter. Gliomas of various degrees of malignancy exhibited different GAG patterns. Total GAG concentration was three times higher in low grade gliomas than in normal white matter. The mean percentage of single GAG classes was usually similar in both tissues, although in certain tumor samples a higher percentage of hyaluronate was found. GAG patterns in anaplastic astrocytomas, however, more closely resembled normal white and gray matter, both quantitatively and qualitatively. Glioblastomas, on the other hand, showed high GAG concentrations, in particular of heparan sulfate and dermatan sulfate. This finding could be secondary to the abundant vessels and mesodermal material associated with this oncotype. The hyaluronate/sulfated GAGs ratio was lower in oligodendrogliomas than in low grade astrocytomas. This biochemical feature may be correlated with the alcianophilia found in the honey-comb degeneration of oligodendrogliomas. The significance of these findings as they relate to tumor histology and biology have been discussed.     

人脑星形细胞瘤转化生长因子α表达与肿瘤瘤周脑水肿的相关研究

目的 探讨人脑星形细胞瘤转化生长因子α（TGF—α）表达及其与肿瘤瘤周脑水肿之间的内在关系。方法 用免疫组织化学方法检测50例人脑星形细胞瘤标本中TGF—α蛋白表达；通过测量患者头颅CT影像上瘤周低密度区评估肿瘤瘤周脑水肿程度。结果 实验组50例人脑星形细胞瘤中，TGF—α蛋白表达总阳性率64％（32例）。不同程度瘤周脑水肿组，TGF—α蛋白表达强弱不同且与患者瘤周脑水肿程度之间存在等级相关性（rs=0．999，P〈0．01）。结论 TGF—α在人脑星形细胞瘤中高表达，且可能加重患者瘤周脑水肿的程度。     

Histologic assessment of peritumoral edema in soft tissue sarcoma

PURPOSE: To evaluate whether satellite tumor cells can be identified histologically in the tissues surrounding a soft tissue sarcoma and whether their presence correlates with increased T(2)-weighted signal intensity on MRI. METHODS AND MATERIALS: Fifteen patients with a high-grade extremity or truncal soft tissue sarcoma underwent preoperative MRI. The extent of high T(2)-weighted signal changes in the tissues surrounding tumor, thought to represent peritumoral edema/reactive changes, was determined. Twelve patients received i.v. gadolinium, and contrast enhancement was determined. All patients underwent surgical resection in the absence of preoperative chemotherapy or radiotherapy. The presence of tumor cells in the surrounding tissues was determined histologically in representative paraffin-embedded sections and correlated with the MRI findings. RESULTS: The extent of peritumoral T(2)-weighted MRI signal changes ranged from 0 to 7.1 cm (mean, 2.5 cm); contrast enhancement ranged from 0 to 5.3 cm (mean, 1.1 cm). Sarcoma cells were identified histologically in the tissues beyond the tumor in 10 of 15 cases. In 6 cases, tumor cells were located within 1 cm of the tumor margin, and in 4 cases, malignant cells were found at a distance >1 cm and up to a maximum of 4 cm. The location of tumor cells beyond the margin did not correlate with tumor size nor did it correlate with the location or extent of peritumoral changes. CONCLUSION: The ability to identify tumor cells beyond the margin of a soft tissue sarcoma has important implications in planning appropriate targets for treatment. This could influence the use of new radiotherapy technologies such as intensity-modulated radiotherapy that aim to minimize treatment volumes through conformal planning.     

胶质瘤瘤周水肿、病理级别、Ki-67表达三者相关性研究

目的：探讨胶质瘤患者瘤周水肿（ PTBE）程度、肿瘤病理级别、Ki-67阳性表达率三者之间的相关性。方法收集新疆自治区人民医院神经外科2010—2013年经手术切除,病理证实的胶质瘤患者病历资料及标本74例,根据术前磁共振成像（ MRI ）资料判断肿瘤 PTBE程度,免疫组织化学检测Ki-67表达情况,HE染色区别肿瘤病理级别。结果本组研究中90.54%（67/74）伴发PTBE,其中Ⅰ、Ⅱ、Ⅲ、Ⅳ级别组PTBE发生率各为100%（3/3）、78.95%（15/19）、83.33%（15/18）及100%（34/34）;75.68%（56/74）Ki-67表达呈阳性;Ⅰ、Ⅱ、Ⅲ、Ⅳ级别组阳性率分别为0、36.84%（7/19）、94.44%（17/18）、94.12%（32/34）;无水肿、Ⅰ度水肿与Ⅱ水肿组中Ki-67表达阳性率分别为57.14%（4/7）、60.00%（6/10）、80.70%（46/57）。经Kruskal-Wallis H检验,PTBE在不同级别胶质瘤的总体差异有统计学意义（H＝11.304,P＝0.010）;Ki-67在不同级别胶质瘤中总体差异有统计学意义（H＝38.530,P﹤0.05）;Ki-67在不同PTBE组中表达的总体差异有统计学意义（ H＝6.478,P＝0.039）。Spearman等级相关分析显示胶质瘤PTBE程度随肿瘤病理级别增加而增加（ r＝0.385,P＝0.001）;Ki-67表达阳性率随肿瘤病理级别增加而增加（ r ＝0.692,P ﹤0.05）;Ki-67表达阳性率随胶质瘤 PTBE 增加而增加（ r ＝0.256,P＝0.028）。结论术前根据PTBE的大小可预测肿瘤的恶性程度与增殖活性,Ki-67既可作为肿瘤增殖活性的指标,也可当做病理分级的重要依据。     

Expression of synaptic vesicle protein 2A in epilepsy-associated brain tumors and in the peritumoral cortex

Synaptic vesicle protein 2A (SV2A) has been identified as the binding site for the antiepileptic drug levetiracetam and is thought to decrease neuronal excitability. Since knockout of SV2A in mice leads to seizures, we hypothesized that a reduction in SV2A expression promotes seizure generation in epilepsy-associated brain tumors. We compared the SV2A expression and distribution in surgically removed tumor tissue (n = 63) and peritumoral cortex (n = 31) of patients with glial and glioneuronal tumors to normal control cortex obtained at autopsy in nonbrain tumor patients (n = 6). Additionally, we compared the SV2A expression and distribution in tumor patients with epilepsy (n = 39) with SV2A expression in tumor patients without epilepsy (n = 24). Immunohistochemistry in control cortex demonstrated strong and diffuse SV2A immunoreactivity (IR) throughout all cortical layers. Similar strong SV2A IR (with the same diffuse distribution pattern) was observed in the peritumoral cortical specimens in both patients with and without epilepsy. Modest SV2A IR was observed within the tumor area. The SV2A-positive cells detected within the tumor area were mainly entrapped neurons. Oligodendrogliomas and glioneuronal tumors displayed variable SV2A neuropil staining. In ganglioglioma (GG), strong SV2A IR was present along the dysplastic neuronal cell borders and processes. In both GG and dysembryoplastic neuroepithelial tumors, SV2A IR was occasionally observed within the neuronal perikarya. We found no differences in SV2A expression in the peritumoral cortex between the patients with and without epilepsy, which suggests that the role of SV2A in epileptogenesis in patients with glial tumors is questionable. The distinct pattern of SV2A IR in glioneuronal tumors suggests a redistribution of SV2A.     

Editor's choice: Medical management of brain tumors and the sequelae of treatment

Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction.     

Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors

Somatostatin analogs are well established in the treatment of malignant endocrine pancreatic tumors (EPTs). Our goal is to individualize their treatment using receptor-subtype-specific analogs and, therefore, exploring the receptor expression is highly important. We have examined the expression of somatostatin receptor (sst) subtypes 1–5 on tumor cells and in intratumoral vessels in 28 tumor tissues from malignant EPTs with immunohistochemistry using sst-subtype-specific polyclonal antibodies. We found that sst₂ and sst₄ stained positive in 90% and sst₁ in 70% of the tumor tissues, whereas sst₃ and sst₅ stained positive in only 50% of the tumor tissues. Sst expression in intratumoral vessels was high for sst₂ and sst₄ (80%), moderate for sst₁ (40%), and low for sst₃ and sst₅ (10%). The ssts were evenly distributed among the different tumor subtypes. However, tumors belonging to the same subgroup of EPTs showed a variable expression of receptor subtypes. No differences in receptor-subtype expression could be seen between poorly and well-differentiated tumors, nor between primary tumors and metastases. Prior medical treatment did not influence sst expression pattern. In conclusion, sst₂ and sst₄ were expressed in most tumor tissues and intratumoral vessels from EPTs. However, sst₃ and sst₅ were lacking in half of the tumor tissues and in most of the intratumoral vessels. These differences indicate the importance of determining each tumor’s subset of receptors before treatment with receptor-subtype-specific analogs is initiated. The importance of sst expression in intratumoral vessels is not yet known.     

脑膜瘤组织中NKCC-1和VEGF的表达与瘤周水肿的相关性研究

目的:探讨脑膜瘤组织中钠钾氯协同转运蛋白1(NKCC-1)和血管内皮生长因子(VEGF)的表达与脑膜瘤瘤周水肿(PTBE)之间的关系.方法:以2017年1月至2019年1月我院接收的108例脑膜瘤患者作为此次研究对象,运用相关检测方法了解其NKCC-1和VEGF水平,借助统计学软件分析其与脑膜瘤PTBE之间的关系.结果...     

A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema

Background: Human corticotropin-releasing factor (hCRF) is an endogenous peptide responsible for the secretion and synthesis of corticosteroids. In animal models of peritumoral brain edema, hCRF has significant anti-edematous action. This effect, which appears to be independent of the release of adrenal steroids, appears mediated by a direct effect on endothelial cells. We conducted a feasibility and phase I study with hCRF given by continuous infusion to patients with brain metastasis.Patients and methods: Peritumoral brain edema documented by MRI and the use of either no steroids or stable steroid doses for more than a week were required. MRIs were repeated at completion of infusion and estimations by dual echo-image sequence (Proton density and T2-weighted images) of the amount of peritumoral edema were performed. The study was performed in two stages. In the feasibility part, patients were randomized to receive either 0.66 or 1 µg/kg/h of hCRF or placebo over 24 hours. The second part was a dose finding study of hCRF over 72 hours at escalating doses.Results: Seventeen patients were enrolled; only one was receiving steroids (stable doses) at study entrance; dose-limiting toxicity (hypotension) was observed at 4 µg/kg/h × 72 hours in two out of four patients, while zero of five patients treated at 2 µg/kg/h developed dose-limiting toxicities. Flushing and hot flashes were also observed. Improvement of neurological symptoms and/or exam were seen in 10 patients. Only small changes were detected by MRI. Improvement in symptoms did not correlate with changes in cortisol levels, and changes in cortisol levels were not correlated with changes in peritumoral edema.Conclusions: hCRF is well tolerated in doses up to 2 µg/kg/h by continuous infusion × 72 hours. Hypotension limits administration of higher doses. The observation of clinical benefit in the absence of corticosteroids suggests hCRF may be an alternative to steroids for the treatment of patients with peritumoral brain edema. Further exploration of this agent in efficacy studies is warranted.     

Effects of glucocorticoid and chemotherapy on the peritumoral edema and astrocytic reaction in experimental brain tumor

To study the effects of glucocorticoids and chemotherapeutic agents on the pathophysiology of the tumor-induced brain edema, the site of Evans blue-albumin extravasation, the distribution of extravasated serum albumin, and the extent of local astrocytic reaction were examined in a rat model of implanted brain tumor. Experimental brain tumors were produced by implanting small pellets of Walker 256 carcinosarcoma into the cerebral cortex of Wistar rats. In the steroid group, rats were administered with intraperitoneal methylprednisolone succinate (15 mg/kg) daily on and after the 6th day postimplantation, and sacrificed on the 14th day. In the chemotherapy group, rats were given an intravenous injection of cyclophosphamide (30 mg/kg) on the 14th day, and sacrificed on the 21st day. Rats in the untreated group were sacrificed on the 14th day without any therapy. Each animal was sacrificed by the transcardiac perfusion with paraformaldehyde 30 min after intravenous injection of Evans blue. Firstly, coronal blocks of the brain were examined for Evans blue staining macroscopically. Paraffin embedded sections were studied for the Evans blue fluorescence and for the immunohistochemical reaction to serum albumin and GFAP. The examination of Evans blue demonstrated that the origin of extravasation of serum albumin was the tumor and the adjacent brain with dense tumor cell infiltration in any group of rats. The extravasated serum albumin distributed widely and the astrocytic reaction was prominent in the brain of the untreated group. A positive correlation was observed between the intensity of albumin immunoreaction and the degree of astrocytic proliferation. Chemotherapy effectively decreased the size of tumor and reduced the extravasation of serum albumin. The astrocytic reaction was however, not reduced. In the steroid group, the size of tumor was not significantly affected but the albumin extravasation as well as astrocytic reaction was markedly reduced. It was concluded that glucocorticoid is an effective drug against tumor-induced brain edema, which not only reduces the extravasation of serum components but also prevents histologic alterations of the brain.     

Cellular characterization of the peritumoral edema zone in malignant brain tumors

Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so-called perifocal edema or brain swelling imposes in T2-weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin-4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2-weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment. ( Cancer Sci  2009; 100: 1856–1862)     

Genetic alterations and chemotherapeutic response in human diffuse gliomas

Although for many years adjuvant chemotherapy has been used in the management of human diffuse gliomas, the survival of a large proportion of patients with these tumors has remained unchanged. To date, little is known about the factors that render some of these patients resistant to cytotoxic drugs. Since response to chemotherapy has been heterogeneous irrespective of glioma type, it has been proposed that some genetic alterations associated with glioma formation and progression may be responsible for the variations in the sensitivity of these tumors to adjuvant chemotherapy. In this paper, we review the literature and discuss the usefulness of some of the common genetic alterations in predicting chemotherapeutic response in gliomas.     

促肾上腺皮质激素治疗伽玛刀术后顽固性肿瘤周围脑水肿的研究

目的 研究促肾上腺皮质激素(ACTH)治疗伽玛刀术后顽固性肿瘤周围血管源性脑水肿(PVBE)的疗效及其作用机制.方法 对79例伽玛刀术后常规脱水治疗无效的顽固性PVBE患者予以ACTH治疗,并对其中再次手术获取的27例肿瘤标本进行组织学和超微结构研究.结果 ACTH治疗前79例患者的血清ACTH测定值与健康对照组差异无显著性(P>0.05),水肿指数(EI)为4.7～9.6,首次治疗1个月后PVBE-EI降至1.1～2.9(P<0.05).27例伽玛刀治疗后顽固性PVBE的主要病理改变为病灶坏死和间质增生,肿瘤血管壁可呈纤维样坏死变性;VEGF和PCNA染色阳性表达明显降低;电镜检查肿瘤血管内皮细胞皱缩扁平,内皮细胞间连接缝隙增大甚至中断.结论 ACTH可明显降低伽玛刀术后顽固性PVBE的EI,其疗效与病灶周围脑水肿区域血脑屏障的受损及修复程度有关并呈一定的药物依赖性变化.