A deep learning-based method for the prediction of temporal lobe injury in patients with nasopharyngeal carcinoma.

PURPOSE: To establish a deep learning-based model to predict radiotherapy-induced temporal lobe injury (TLI). MATERIALS AND METHODS: Spatial features of dose distribution within the temporal lobe were extracted using both the three-dimensional convolution (C3D) network and the dosiomics method. The Minimal Redundancy-Maximal-Relevance (mRMR) method was employed to rank the extracted features and select the most relevant ones. Four machine learning (ML) classifiers, including logistic regression (LR), k-nearest neighbors (kNN), support vector machines (SVM) and random forest (RF), were used to establish prediction models. Nested sampling and hyperparameter tuning methods were applied to train and validate the prediction models. For comparison, a prediction model base on the conventional D0.5cc of the temporal lobe obtained from dose volume (DV) histogram was established. The area under the receiver operating characteristic (ROC) curve (AUC) was utilized to compare the predictive performance of the different models. RESULTS: A total of 127 nasopharyngeal carcinoma (NPC) patients were included in the study. In the model based on C3D deep learning features, the highest AUC value of 0.843 was achieved with 5 features. For the dosiomics features model, the highest AUC value of 0.715 was attained with 1 feature. Both of these models demonstrated superior performance compared to the prediction model based on DV parameters, which yielded an AUC of 0.695. CONCLUSION: The prediction model utilizing C3D deep learning features outperformed models based on dosiomics features or traditional parameters in predicting the onset of TLI. This approach holds promise for predicting radiation-induced toxicities and guide individualized radiotherapy.

Dosimetric parameters predict radiation-induced temporal lobe necrosis in nasopharyngeal carcinoma patients: A systematic review and meta-analysis.

This systematic review examines the role of dosimetric parameters in predicting temporal lobe necrosis (TLN) risk in nasopharyngeal carcinoma (NPC) patients treated with three-dimensional conformal RT (3D-CRT), intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). TLN is a serious late complication that can adversely affect the quality of life of NPC patients. Understanding the relationship between dosimetric parameters and TLN can guide treatment planning and minimize radiation-related complications. A comprehensive search identified relevant studies published up to July 2023. Studies reporting on dosimetric parameters and TLN in NPC patients undergoing 3D-CRT, IMRT, and VMAT were included. TLN incidence, follow-up duration, and correlation with dosimetric parameters of the temporal lobe were analyzed. The review included 30 studies with median follow-up durations ranging from 28 to 110 months. The crude incidence of TLN varied from 2.3 % to 47.3 % and the average crude incidence of TLN is approximately 14 %. Dmax and D1cc emerged as potential predictors of TLN in 3D-CRT and IMRT-treated NPC patients. Threshold values of >72 Gy for Dmax and >62 Gy for D1cc were associated with increased TLN risk. However, other factors should also be considered, including host characteristics, tumor-specific features and therapeutic factors. In conclusion, this systematic review highlights the significance of dosimetric parameters, particularly Dmax and D1cc, in predicting TLN risk in NPC patients undergoing 3D-CRT, IMRT, and VMAT. The findings provide valuable insights that can help in developing optimal treatment planning strategies and contribute to the development of clinical guidelines in this field.

Late vascular complications after cranial radiotherapy: A report of two illustrative cases.

Cranial radiotherapy (CRT) is used to treat a large variety of benign and malignant disorders. We present two cases of late neurological complications after CRT and briefly discuss its diagnosis and their shared pathophysiological aspects. The first case is a patient with cognitive impairment associated to mineralizing microangiopathy ten years after CRT for nasopharyngeal carcinoma and the second one is a woman with Stroke-like Migraine Attacks after Radiation Therapy (SMART) syndrome two years after CRT for anaplastic meningioma. Nowadays, higher survival rates might cause an increase in appearance of late neurological complications after CTR. These reported cases show that late complications can mimic a wide variety of neurological conditions and the importance of magnetic resonance image (MRI) to get a diagnosis.

MRI-based brain structural changes following radiotherapy of Nasopharyngeal Carcinoma: A systematic review.

PURPOSE: Nasopharyngeal carcinoma (NPC) radiotherapy (RT) irradiates parts of the brain which may cause cerebral tissue changes. This study aimed to systematically review the brain microstructure changes using MRI-based measures, diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI) and voxel-based morphometry (VBM) and the impact of dose and latency following RT. METHODS: PubMed and Scopus databases were searched based on PRISMA guideline to determine studies focusing on changes following NPC RT. RESULTS: Eleven studies fulfilled the inclusion criteria. Microstructural changes occur most consistently in the temporal region. The changes were correlated with latency in seven studies; fractional anisotropy (FA) and gray matter (GM) volume remained low even after a longer period following RT and areas beyond irradiation site with reduced FA and GM measures. For dosage, only one study showed correlation, thus requiring further investigations. CONCLUSION: DTI, DKI and VBM may be used as a surveillance tool in detecting brain microstructural changes of NPC patients which correlates to latency and brain areas following RT.

Effects of transcranial magnetic stimulation over the left posterior superior temporal gyrus on picture-word interference.

Word-production theories argue that during language production, a concept activates multiple lexical candidates in left temporal cortex, and the intended word is selected from this set. Evidence for theories on spoken-word production comes, for example, from the picture-word interference task, where participants name pictures superimposed by congruent (e.g., picture: rabbit, distractor "rabbit"), categorically related (e.g., distractor "sheep"), or unrelated (e.g., distractor "fork") words. Typically, whereas congruent distractors facilitate naming, related distractors slow down picture naming relative to unrelated distractors, resulting in semantic interference. However, the neural correlates of semantic interference are debated. Previous neuroimaging studies have shown that the left mid-to-posterior STG (pSTG) is involved in the interference associated with semantically related distractors. To probe the functional relevance of this area, we targeted the left pSTG with focal repetitive transcranial magnetic stimulation (rTMS) while subjects performed a picture-word interference task. Unexpectedly, pSTG stimulation did not affect the semantic interference effect but selectively increased the congruency effect (i.e., faster naming with congruent distractors). The facilitatory TMS effect selectively occurred in the more difficult list with an overall lower name agreement. Our study adds new evidence to the causal role of the left pSTG in the interaction between picture and distractor representations or processing streams, only partly supporting previous neuroimaging studies. Moreover, the observed unexpected condition-specific facilitatory rTMS effect argues for an interaction of the task- or stimulus-induced brain state with the modulatory TMS effect. These issues should be systematically addressed in future rTMS studies on language production.

Microstructural Injury to Left-Sided Perisylvian White Matter Predicts Language Decline After Brain Radiation Therapy.

PURPOSE: Our purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors. METHODS AND MATERIALS: Patients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores. RESULTS: DKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores. CONCLUSIONS: Patients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation.

Machine-learning based MRI radiomics models for early detection of radiation-induced brain injury in nasopharyngeal carcinoma.

BACKGROUND: Early radiation-induced temporal lobe injury (RTLI) diagnosis in nasopharyngeal carcinoma (NPC) is clinically challenging, and prediction models of RTLI are lacking. Hence, we aimed to develop radiomic models for early detection of RTLI. METHODS: We retrospectively included a total of 242 NPC patients who underwent regular follow-up magnetic resonance imaging (MRI) examinations, including contrast-enhanced T1-weighted and T2-weighted imaging. For each MRI sequence, four non-texture and 10,320 texture features were extracted from medial temporal lobe, gray matter, and white matter, respectively. The relief and 0.632 + bootstrap algorithms were applied for initial and subsequent feature selection, respectively. Random forest method was used to construct the prediction model. Three models, 1, 2 and 3, were developed for predicting the results of the last three follow-up MRI scans at different times before RTLI onset, respectively. The area under the curve (AUC) was used to evaluate the performance of models. RESULTS: Of the 242 patients, 171 (70.7%) were men, and the mean age of all the patients was 48.5 ± 10.4 years. The median follow-up and latency from radiotherapy until RTLI were 46 and 41 months, respectively. In the testing cohort, models 1, 2, and 3, with 20 texture features derived from the medial temporal lobe, yielded mean AUCs of 0.830 (95% CI: 0.823-0.837), 0.773 (95% CI: 0.763-0.782), and 0.716 (95% CI: 0.699-0.733), respectively. CONCLUSION: The three developed radiomic models can dynamically predict RTLI in advance, enabling early detection and allowing clinicians to take preventive measures to stop or slow down the deterioration of RTLI.

Radiation induced temporal lobe necrosis in nasopharyngeal cancer patients after radical external beam radiotherapy.

Radiation-induced temporal lobe necrosis (TLN) is one of the late post-radiotherapy complications in nasopharyngeal cancer (NPC) patients. Since NPC is common to have skull base infiltration, irradiation of the temporal lobes is inevitable despite the use of the more advanced intensity-modulated radiotherapy (IMRT). Moreover, the diagnosis and treatment of TLN remain challenging. In this review, we discuss the diagnosis of TLN with conventional and advanced imaging modalities, onset and predictive parameters of TLN development, the impact of IMRT on TLN in terms of incidence and dosimetric analyzes, and the recent advancements in the treatment of TLN.

Temporal lobe sparing radiotherapy with photons or protons for cognitive function preservation in paediatric craniopharyngioma.

BACKGROUND AND PURPOSE: Reducing radiation exposure to the temporal lobes could be beneficial to preserve cognitive function in paediatric brain tumour patients. The distribution of doses to brain substructures associated with cognition (BSCs) both within and outside of the temporal lobe have not been reported. The aim of this study was therefore to investigate temporal lobe sparing photon vs. proton therapy for paediatric suprasellar tumours. MATERIAL AND METHODS: Data from ten anonymized craniopharyngioma patients were used in this study. Temporal lobe sparing volumetric modulated arc therapy (VMAT) and pencil beam scanning (PBS) proton therapy plans were optimized to maintain consistent target metrics as in the delivered double scattering proton therapy (DSPT) plans. Thirty BSCs were delineated, including temporal lobe substructures (i.e. amygdala, hippocampus, entorhinal cortex). The dose/volume fractions to each BSC were analysed, and intelligence quotient (IQ) as well as memory scores were estimated to compare the different modalities. RESULTS: The exposed volumes of the temporal lobes and their substructures were consistently reduced with PBS compared to DSPT and VMAT, e.g. the left hippocampus V10Gy from 100% (VMAT) or 41% (DSPT) to 5% with PBS (p = 0.002). Some of the ventricular substructures were better spared with VMAT compared to both proton modalities. The reduced doses to the temporal lobes achieved with PBS translated into improved predicted memory outcomes, but not for the estimated IQ. CONCLUSION: The irradiated volumes of temporal lobe BSCs were consistently the lowest with PBS, whereas the model-based estimates of cognitive outcomes were less consistent.

Electric field causes volumetric changes in the human brain.

Recent longitudinal neuroimaging studies in patients with electroconvulsive therapy (ECT) suggest local effects of electric stimulation (lateralized) occur in tandem with global seizure activity (generalized). We used electric field (EF) modeling in 151 ECT treated patients with depression to determine the regional relationships between EF, unbiased longitudinal volume change, and antidepressant response across 85 brain regions. The majority of regional volumes increased significantly, and volumetric changes correlated with regional electric field (t = 3.77, df = 83, r = 0.38, p=0.0003). After controlling for nuisance variables (age, treatment number, and study site), we identified two regions (left amygdala and left hippocampus) with a strong relationship between EF and volume change (FDR corrected p<0.01). However, neither structural volume changes nor electric field was associated with antidepressant response. In summary, we showed that high electrical fields are strongly associated with robust volume changes in a dose-dependent fashion.

Quantitative Imaging Biomarkers of Damage to Critical Memory Regions Are Associated With Post-Radiation Therapy Memory Performance in Brain Tumor Patients.

PURPOSE: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT). METHODS AND MATERIALS: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory. RESULTS: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance. CONCLUSIONS: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.

The Effect of rTMS over the Different Targets on Language Recovery in Stroke Patients with Global Aphasia: A Randomized Sham-Controlled Study.

OBJECTIVE: To evaluate and compare the effects of repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis of the posterior inferior frontal gyrus (pIFG) and the right posterior superior temporal gyrus (pSMG) in global aphasia following subacute stroke. METHODS: Fifty-four patients with subacute poststroke global aphasia were randomized to 15-day protocols of 20-minute inhibitory 1 Hz rTMS over either the right triangular part of the pIFG (the rTMS-b group) or the right pSTG (the rTMS-w group) or to sham stimulation, followed by 30 minutes of speech and language therapy. Language outcomes were assessed by aphasia quotient (AQ) scores obtained from the Chinese version of the Western Aphasia Battery (WAB) at baseline and immediately after 3 weeks (15 days) of experimental treatment. RESULTS: Forty-five patients completed the entire study. The primary outcome measures include the changes in WAB-AQ score, spontaneous speech, auditory comprehension, and repetition. These measures indicated significant main effect between the baseline of the rTMS-w, rTMS-b, and sham groups and immediately after stimulation (P<0.05). Compared with the sham group, the increases were significant for auditory comprehension, repetition, and AQ in the rTMS-w group (P<0.05), whereas the changes in repetition, spontaneous speech, and AQ tended to be higher in the rTMS-b group (P<0.05). CONCLUSIONS: Inhibitory rTMS targeting the right pIFG and pSTG can be an effective treatment for subacute stroke patients with global aphasia. The effect of rTMS may depend on the stimulation site. Low-frequency rTMS inhibited the right pSTG and significantly improved language recovery in terms of auditory comprehension and repetition, whereas LF-rTMS inhibited the right pIFG, leading to apparent changes in spontaneous speech and repetition.

An Adult Patient With Rare Primary Intracranial Alveolar Rhabdomyosarcoma.

We report a rare case of primary intracranial alveolar rhabdomyosarcoma (ARMS) in the right temporal lobe of a 51-year-old male. ARMS is one of 3 histological subtypes of rhabdomyosarcoma that most commonly presents in older children and younger adults. To our knowledge, there have been no prior published reports of primary intracranial ARMS in adults. Known cases of intracranial ARMS in adults are due to central nervous system (CNS) metastases from the head and neck and extremities. Diagnostic workup did not reveal any primary source outside the CNS. Given that risk factors for ARMS have not been studied in adults, it is difficult to ascertain what aspects of this patient's clinical history may have contributed to his diagnosis. Interestingly, he had prior history of traumatic brain injury requiring evacuation of a right fronto-temporal intraparenchymal hematoma.

Redefining Ventricular Target Volume in Germinoma: Is Inclusion of Temporal Horns Necessary?

PURPOSE: We reviewed the outcomes of a retrospective germinoma cohort and analyzed radiation therapy plans to determine dosimetric differences for critical structures. METHODS AND MATERIALS: Data from pediatric patients treated with photon radiation for intracranial germinoma were analyzed for clinical outcomes and dosimetry to critical structures, with particular interest in the temporal ventricular horns (TVHs). A consensus contour was generated for TVH-sparing ventricular clinical target volumes (CTVs) via deformable image registration. RESULTS: Twelve and 10 patients had their TVHs included or excluded in their ventricular CTVs, respectively. All patients were living at the time of analysis. One patient relapsed in the fourth ventricle, which had been omitted from the radiation therapy field. Mean dose was significantly lower to the hippocampi (Δ = -578 cGy, P = .0016) and temporal lobes (Δ = -599 cGy, P = .0007) in the TVH-excluded cohort compared with those with TVHs included in the treatment field. CONCLUSIONS: Exclusion of the TVHs from the CTV results in significant dose sparing to the hippocampi and temporal lobes. Clinical outcomes remain excellent with no deaths and no TVH failures. Exclusion of TVHs from the ventricular CTV in germinoma requires prospective study.

Development and validation of a model for temporal lobe necrosis for nasopharyngeal carcinoma patients with intensity modulated radiation therapy.

PURPOSE: To develop and validate a quantitative complication model of temporal lobe necrosis (TLN). To analyze the effect of clinical and dosimetric factors on TLN. PATIENTS AND METHODS: In this study the prediction model was developed in a training cohort that consisted of 256 nasopharyngeal carcinoma (NPC) patients from January 2009 to December 2009. Dosimetric and clinical factors were extracted for model building. Dosimetric factors including the maximum dose, minimum dose, mean dose, dose covering specific volume and dose of percentage volume. Clinical factors include age, gender, T/N-stage, overall stage, diabetes and hypertension. LASSO (least absolute shrinkage and selection operator) regression model was used for feature selection, and prediction model building. A testing cohort containing 493 consecutive patients from January 2010 to December 2010 was used for model validation. The performance of the prediction model was assessed with respect to its calibration, discrimination. RESULTS: The prediction model, which consisted of two dosimetric features (D0.5cc and D10), is significantly associated with LN status (P < .001 for both training and testing cohorts). None of clinical factors show direct prediction value. The model shows good discrimination, with a C-index of 0.685 (95% CI: 0.6048-0.765) on testing set, and a consistent trend in calibration on testing set. CONCLUSION: This study presents a prediction model can be conveniently used to facilitate the individualized prediction of TLN in patients with NPC. Clinical factors have no direct impact on TLN.

Dosimetric predictors of temporal lobe injury after intensity-modulated radiotherapy for T4 nasopharyngeal carcinoma: a competing risk study.

BACKGROUND: In patients with T4 nasopharyngeal carcinoma (NPC), death may occur prior to the occurrence of temporal lobe injury (TLI). Because such competing risk death precludes the occurrence of TLI and thus the competing risk analysis should be applied to TLI research. The aim was to investigate the incidence and predictive factors of TLI after intensity-modulated radiotherapy (IMRT) among T4 NPC patients. METHODS: From March 2008 to December 2014, T4 NPC patients treated with full-course radical IMRT at our center were reviewed retrospectively. A nested case-control study was designed for this cohort of patients. The cases were patients with TLI diagnosed by MRI during the follow-up period, and the controls were patients without TLI after IMRT matched 1:1 to each case by gender, age at diagnosis, intercranial involvement, and follow-up time. The end point was time to TLI or death without prior TLI. We analyzed the cumulative incidence function (CIF) and performed a competing risk regression model to identify the predictors of TLI. RESULTS: With a median follow-up of 40.1 months, 63 patients (63/506, 12.5%) developed TLI as diagnosed by MRI, and 136 deaths occurred during the period. The cumulative incidence of TLI at 5 years was 13.2%, while 26.7% died without prior TLI. The univariate analysis showed that all selected dosimetric parameters were associated with the occurrence of TLI. On multivariate analysis, D1cc and V20 remained statistically significant. Based on the area-under-the-curve (AUC) values, D1cc was considered the most predictive. The patients with D1cc > 71.14 Gy had a 7.920-fold increased risk of TLI compared with those with D1cc ≤71.14 Gy (P < 0.05). Similarly, V20 > 42.22 cc was found to result in a statistically significant higher risk of TLI (subdistribution hazard ratio [sHR] =3.123, P < 0.05). CONCLUSIONS: TL D1cc and V20 were predictive of TLI after IMRT for T4 NPC. They should be considered as first and second priorities of dose constraints of the TL. D1cc ≤71.14 Gy and V20 ≤ 42.22 cc could be useful dose-volume constraints for reducing the occurrence of TLI during IMRT treatment planning without obviously compromising the tumor coverage.

A low percentage of metastases in deep brain and temporal lobe structures.

BACKGROUND: Whole-brain radiotherapy (WBRT) in patients with brain metastases (BM) is associated with neurocognitive decline. Given its crucial role in learning and memory, efforts to mitigate this toxicity have mostly focused on sparing radiation to the hippocampus. We hypothesized that BM are not evenly distributed across the brain and that several additional areas may be avoided in WBRT based on a low risk of developing BM. METHODS: We contoured 2757 lesions in a large, single-institution database of patients with newly diagnosed BM. BM centroids were mapped onto a standard brain atlas of 55 anatomic subunits and the observed percentage of BM was compared with what would be expected based on that region's volume. A region of interest (ROI) analysis was performed in a validation cohort of patients from 2 independent institutions using equivalence and one-sample hypothesis tests. RESULTS: The brainstem and bilateral thalami, hippocampi, parahippocampal gyri, amygdala, and temporal poles had a cumulative risk of harboring a BM centroid of 4.83% in the initial cohort. This ROI was tested in 157 patients from the validation cohort and was found to have a 4.1% risk of developing BM, which was statistically equivalent between the 2 groups (P < 1 × 10-6, upper bound). CONCLUSION: Several critical brain structures are at a low risk of developing BM. A risk-adapted approach to WBRT is worthy of further investigation and may mitigate the toxicities of conventional radiation.

Tumor-Infiltrating T Cell Receptor-Beta Repertoires are Linked to the Risk of Late Chemoradiation-Induced Temporal Lobe Necrosis in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Temporal lobe necrosis (TLN), a late complication of nasopharyngeal carcinoma (NPC) after concurrent chemoradiotherapy (CCRT), causes permanent neurologic deficits. We aimed to investigate the risk factors for the development of CCRT-induced TLN in locally advanced NPC patients. METHODS AND MATERIALS: The incidence of CCRT-induced TLN was assessed in consecutive patients with NPC initially staged with T3-4N0-3M0 receiving curative intensity modulated radiation therapy (IMRT) and cisplatin-based chemotherapy with long-term follow-up. The TLN risk was evaluated with radiation dose-volume histograms (a dosimetric risk indicator of organ injury) and the dynamics of blood circulating neutrophil-to-lymphocyte ratios (a clinical indicator of systemic inflammation) by linear and logistic regression models. High-throughput unbiased T cell receptor-beta (TCRbeta) sequencing was performed to correlate the different TCRbeta repertoires of NPC-infiltrating lymphocytes (a biological factor of the immune microenvironment) with TLN incidence. RESULTS: In the era of modern IMRT-based CCRT, radiation doses of up to 74 Gy achieved local control rates of more than 90% in both T3 and T4 diseases but still induced a remarkably higher incidence of TLN in the T4 patients (30.14%) compared with the rare incidence of TLN observed in the T3 patients (2.78%) (P < .0001). We found that in the T4 NPC patients, univariate and multivariate analyses showed the radiation tolerance dose-volume effect was not an absolutely independent factor influencing TLN occurrence. However, increased TLN risk was observed in association with higher pre-CCRT baseline and post-CCRT neutrophil-to-lymphocyte ratios. There was also a link between intratumoral TCRbeta repertoire subtypes and TLN incidence. Combining the inherent TCRbeta genomic susceptibility with the clinical variable neutrophil-to-lymphocyte ratio better predicted the risk of TLN for T4 NPC patients after CCRT. CONCLUSIONS: The associations of tumor-infiltrating lymphocyte repertoires and blood circulating neutrophil-to-lymphocyte ratios with TLN occurrence in T4 NPC patients suggest that the immune and inflammatory milieus play roles in the late brain damage caused by CCRT. Modulated or provoked by CCRT locally and systemically, the reciprocal interactions of neutrophils and lymphocytes in the intracranial NPC-associated immune microenvironment could be a key driver of chronic TLN pathogenesis.

Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury.

BACKGROUND: Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury (TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed. METHODS: We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided. RESULTS: We identified a promoter variant rs17111237 (A > G, minor allele frequency [MAF] = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, Pcombined=3.18 × 10-7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29-1.66, Pcombined= 6.17 × 10-9). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway. CONCLUSIONS: This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.