| Chapter one Spatial distribution of brain metastases in small cell lung cancer and identification of risk areasBackground:Prophylactic cranial irradiation(PCI)has been widely used to prevent brain metastases in patients with small cell lung cancer(SCLC).Although there are strong evidences supporting PCI for SCLC,there is an increased risk of neurotoxicity,which may lead to cognitive decline.Whole brain radiation therapy(WBRT)that protects the hippocampus(HS)has been shown to reduce the adverse effects of neurocognitive decline.Whether PCI of SCLC brain metastases also requires hippocampal protection,what is the risk of hippocampal metastasis after exemption from irradiation,and whether other parts besides hippocampal protection also need to be protected?Firstly,it is necessary to understand the spatial distribution of SCLC brain metastases,understand the risk of metastasis in each brain region,and identify risk areas.However,no study on spatial distribution of SCLC brain metastases has been found by searching domestic and foreign literature.Objectives:This study aimed to explore the spatial distribution of brain metastases(BMs)in SCLC and determine the level of metastasis risk in brain regions.Methods:T1-enhanced magnetic resonance imaging(MRI)from SCLC patients were retrospectively reviewed from three medical institutions in China.All images were registered to the standard brain template provided by the Montreal Neurological Institute(MNI)152 database,followed by transformation of the location of all BMs to the space of standard brain.The MNI structural atlas and Anatomical Automatic Labeling(AAL)atlas and modified AAL atlas(38 brain regions)were used to identify anatomic brain regions,respectively,and the observed and expected rates of BMs were compared using the two-tail proportionality hypothesis test.After the images were standardized,the location and size of the lesions were analyzed and the high-risk and low-risk brain region were identified.Results:A total of 215 eligible patients with 1033 lesions were screened by MRI,including 157(73%)males and 58(27%)females.The incidence of crucial structures were as follows:hippocampus 0.68%,parahippocampal 0.97%,brainstem 2.05%,cauate 0.68%,putamen 0.68%,pallidum 0.2%,thalamus 1.36%.No BMs were found in the amygdala,pituitary gland,or pineal gland.The cumulative frequency of the important structures was 6.62%.Based on the results of MNI structural atlas,the cerebellum,deep white matter and brainstem was identified as a higher-risk region than expected for BMs(P=9.80×10-15,9.04×10-6),whereas temporal lobe were low-risk regions(P=1.65×10-4).More detailed AAL atlas revealed that the lowrisk regions for BMs was inferior frontal gyrus(P=6.971×10-4),while the high-risk regions for BMs was cerebellar hemispheres(P=1.177×10-9).Conclusion:Many crucial structures including the hippocampus,parahippocampus,pituitary gland and thalamus had low frequency of brain metastases in a population of SCLC patients.This study provided the help to investigate the clinical feasibility of HA-WBRT and non-uniform dose of PCI in a population of SCLC patients.Chapter two Differences in spatial distribution of brain metastases between small cell lung cancer and non-small cell lung cancerBackground:At present,the literatures on the difference of spatial distribution of BMs are very limited,and the results of some studies are often contradictory.Almost all of these studies have focused on analyzing differences between breast and lung cancer.It is well known that small cell lung cancer(SCLC)and non-small cell lung cancer(NSCLC)patients have different patterns of gene mutation and tumor biological behavior,so we hypothesized that their spatial distribution may differ.In addition,the current radiotherapy strategies for brain metastases of small cell lung cancer and nonsmall cell lung cancer are also different,so it is necessary to explore the differences in spatial distribution of brain metastases between them.The study of its spatial distribution is not only helpful to predict the location of BMs,but also to optimize the protection of important structures in whole brain radiotherapy.Objectives:The aims of our study were to investigate the difference of spatial distribution of brain metastases(BMs)between small-cell lung cancer(SCLC)and non-small-cell lung cancer(NSCLC),and to identify the metastatic risk in brain regions.Methods:T1-enhanced MR images of 2997 BMs from 728 eligible SCLC and NSCLC patients from three independent medical institutions in China were retrospectively analyzed.After the contour of BMs was confirmed by 3 radiologists,the location of metastases was delineated layer by layer on MITK software,and all images were spatially normalized to the standard spatial template.The brain regions in the normalized image were identified based on the combined AAL map(41 brain regions),and all the brain regions were mapped to the brain regions in the normalized image.Chi-square test and Wilcoxon rank-sum test were used to compare the clinical characteristics of patients with SCLC and NSCLC.The observed rate of BMs was compared with the expected rate based on area volume using a two-tailed proportionality hypothesis test to determine the metastatic risk area.The frequency difference of BMs between SCLC and NSCLC was statistically significant at the level of 1.219×10-3 by multiple comparison with Bonferroni correction.Results:In both SCLC and NSCLC,BMs were biased to the deep white matter(22.51%and 17.96%,respectively),cerebellar hemisphere(9.84%and 7.46%,respectively),and middle frontal gyrus(6.72%and 7.97%,respectively).The cerebellar hemisphere(P=1.18x10-9)was a high-risk brain region in SCLC.The precentral gyrus(P=1.75×1015),middle frontal gyrus(P=1.15×10-5),paracentral lobule(P=4.49×10-4),and cerebellar hemisphere(P=1.87×10-4)were at high risk of BM in NSCLC.The inferior frontal gyrus(P=6.97×10-4)was a low-risk brain region in SCLC and the temporal pole(P=6.77×10-4)was at low risk of BM in NSCLC.In both SCLC and NSCLC,no BM was found in the amygdala,pituitary gland,or pineal gland.Conclusion:There were slight differences in the frequency of metastasis in various brain regions between SCLC and NSCLC,and no significant differences were found after more rigorous multiple test correction analysis.The cerebellar hemisphere in patients with SCLC or NSCLC showed a high risk of developing BMs.In comparison,several critical brain regions,including the brainstem,bilateral thalamus,hippocampus,parahippocampal gyrus,amygdala,and temporal pole had relatively low frequency of BMs from both SCLC and NSCLC,where the low-dose distribution of radiation may be given under the condition of adequate preoperative evaluations.Chapter three Construction,quantification and influencing factors of spatial distribution map of common cancer brain metastasesBackground:A search of domestic and foreign literature showed that few studies provided maps of brain metastases of common intracranial cancers and quantitative analysis data of metastasis rates in each brain region.In addition,due to the limitations of metastatic tumor location analysis technology,many previous studies mostly recorded the anatomical location of tumors only by observing image data,which lacked accuracy and made it difficult to accurately locate specific brain functional areas.With the advent of image registration and 3D structure deformation algorithms,it is possible to transform and register a single brain image onto an average standard brain image,and even detect small differences in spatial distribution.We can fine-tune brain regions to the extent that we want to through different anatomical autolabeling atlas.Quantitative analysis of the data allows clinicians to review and assess the risk of metastasis in different brain regions.At present,there is no unified conclusion on the factors affecting the spatial distribution of BMs,and almost all previous studies focused on a single factor,lacking integrity.The mechanical capture theory of tumor embolism holds that the sudden change of vascular diameter and slow blood flow lead to the occurrence of tumor embolism,which is the main reason affecting the distribution of BMs.Paget’s "seed and soil"theory suggests that certain tumor cells(seeds)have a special affinity for the environment of certain organs(soil),and that metastasis can only occur if the seeds and soil are compatible.Many literatures also support the influence of primary pathological differences on the spatial distribution of BMs.But are there other factors also affect?There is no systematic analysis due to the influence of image analysis technology and sample size.Objectives:The spatial distribution map of brain metastases of common cancer species was constructed to quantitatively analyze the frequency of metastasis in different brain functional areas.To explore the factors influencing spatial distribution of brain metastases.Methods:On the basis of previous studies,the sample size was further expanded,and the inclusion conditions were no longer limited to lung cancer,but increased the number of patients with brain metastasis from breast cancer,esophageal cancer,colon cancer,kidney cancer,and other rare tumors.According to the previous method,brain metastases were delineated manually,image registration,centroid calculation and visual frequency heat map were constructed.Based on MNI152 brain atlas(10 regions),ALL brain atlas(118 regions)and modified merged ALL atlas(38 regions),the observed metastasis frequency of each brain functional region was segmented automatically by computer.The pituitary gland,pineal gland,brain stem,cerebellar vermis and cerebellar hemisphere were delineated manually in MNI standard brain template by MITK software.For each brain region,the number and frequency of brain metastases in different tumor types were calculated.Factors that may affect the spatial distribution of BMs were divided into internal factors and external factors.Internal factors include cerebrovascular and blood flow factors.The "watershed region" model map was used to construct the cerebrovascular marginal region template,and the map after registration was automatically segmented to obtain the spatial distribution characteristics of BMs in each watershed region.External factors include pathological factors,therapeutic interventions,gene mutation status,and primary site.Group comparison was carried out according to different factors.Internal software is used to automatically calculate the distance(depth)from the brain surface to the center of each lesion.The differences of depth of brain metastasis under different factors were analyzed.Results:A total of 914 patients with brain metastases were included,including 4014 metastases.Among them,728 patients with lung cancer had 2997 metastases,and 59 patients with breast cancer had 461 metastases.There were 21 cases of esophageal cancer,13 cases of colon cancer,11 cases of kidney cancer and 82 cases of other cancers.The visualized heat map shows uneven brightness in different functional areas of the brain.Partial frontal lobe,bilateral cerebellum and brainstem regions were prominent,and the incidence of brain metastasis was high.The brightness of bilateral temporal lobe and part of occipital lobe was low,and the incidence of brain metastasis was low.The spatial distribution characteristics of metastases from different pathological sources can also be seen on the heat map.The frequency of BMs in each brain region was as follows:Frontal lobe 1209(17.34%),parietal lobe 739(13.95%),cerebellum 711(9.26%),temporal lobe 454(10.04%),occipital lobe 415(7.26%),deep white matter and brain stem 292(7.27%),thalamus 53(1.30%),putamen 39(0.86%),Insula 48(0.83%),caudate 54(0.70%).Analysis of the combined ALL atlas(38 regions)showed that the top ten brain regions with metastasis rate and the number of metastatic foci(metastasis rate)were as follows:Deep white matter and brain stem 865(21.55%),Cerebellar 333(8.28%),middle frontal gyrus 291(7.24%),superior frontal gyrus 254(6.34%),precentral gyrus 207(5.16%),cerebellar foot 206(5.13%),occipital gyrus 161(4.00%),posterior central gyrus 159(3.96%),precuneus 125(3.11%),middle temporal gyrus 123(3.06%).The metastasis rates of some functional areas of the brain deserving special attention including hippocampus,parahippocampal gyrus,globus pallidus,callosal fissure and peripheral cortex and temporal pole were 0.52%,0.54%,0.07%,2.04%and 0.96%,respectively.The analysis of internal vascular and blood flow factors showed that the rate of metastasis was significantly higher than expected in the anterior(P=1.404×10-35),posterior(P=9.302×10-12)and cerebellum watershed(P=9.364×10-34).However,the rate of metastasis in the deep gray matter junction was lower than expected(P=0.004).The source of pathological tissue had a significant effect on the spatial distribution of patients.Lung cancer was at high risk in cerebellar hemisphere(P=2.59×10-15)and low risk in temporal lobe(P=5.18×10-11),while breast cancer was at high risk in cerebellar hemisphere(P=14.92×10-7),but low risk in temporal lobe was not significant.The most frequently metastasized brain regions of colorectal cancer are located in the posterior fossa:deep white matter,brainstem and cerebellar hemisphere.The most common metastatic sites of renal carcinoma were deep white matter and brain stem,middle frontal gyrus and inferior temporal gyrus.The most common metastatic sites of esophageal cancer were deep brain white matter and brain stem,cerebellum and middle frontal gyrus.Patients with EGFR mutation were at high-risk of cerebellum(P=0.007)and low temporal lobe(P=0.029).However,no risk regions were found in patients without EGFR mutations,P>0.05 in all MNI subdivision(10 brain regions).Based on the combined ALL subdivision,the middle frontal gyrus(P=0.006×10-1),precentral gyrus(P=0.007)were at high risk in patients with EGFR mutation and the The temporal pole were at low-risk area(P=0.005),while this phenomenon was not found in patients without EGFR mutation.From the perspective of metastasis depth,it was found that the depth of metastasis in patients with EGFR mutation was greater than that in patients without mutation,but with no statistical significance.Whether chemotherapy had been received before metastasis had no significant effect on the risk of brain region in MNI atlas(10 sub-regions),which both showed high risk of cerebellum and low risk of temporal lobe.Based on the analysis of the combined ALL atlas,it was found that the distribution of patients after chemotherapy shows an increase in relative unevenness.Three low-risk areas were increased compared with patients without chemotherapy:superior marginal gyrus 0.003×10-1,superior temporal gyrus 0.003,and temporal pole 0.009.The location of the left and right sides of the primary foci in lung cancer patients had no effect on the distribution of metastatic tumor(P>0.05 in all brain regions).Conclusion:We constructed the spatial distribution map of brain metastases of common cancer types through multi-center large sample study,and quantitatively analyzed the frequency of metastasis in different brain functional areas.The spatial distribution of BMs was found to be uneven.The distribution of BMs was influenced by the factors of internal blood vessel and blood flow distribution,source of external pathological tissue,EGFR mutation status and treatment before BMs,but the left and right location of primary foci had no influence on the spatial distribution of BMs.Compared with the expected frequency,a series of risk areas were screened out,which may provide necessary help for the strategy of radiotherapy for brain metastases. |
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